Research Report 2013 Faculty of Medicine Faculty of Medicine Research Report 2013 Research

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Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 1 CONTENTS

Table of contents

Preface...... 6 Institute of Medical Physics Abbreviations...... 9 Chair of Medical Physics...... 38

PRECLINICAL INSTITUTES Institute of the History of Medicine and Medical Ethics Chair of the History of Medicine ...... 40 Institute of Anatomy Professorship for Medical Ethics ...... 42 Chair of Anatomy I...... 10 Chair of Anatomy II ...... 12 Nikolaus-Fiebiger-Center of Molecular Medicine Chair of Experimental Medicine I

Institute of Biochemistry – Emil-Fischer-Center (Molecular Pathogenesis Research) ...... 44 Chair of Biochemistry and Molecular Medicine ...... 14 Chair of Experimental Medicine II Chair of Biochemistry and Pathobiochemistry...... 16 (Molecular Oncology) ...... 46 Professorship of Bioinformatics ...... 18 CLINICAL CHAIRS Institute of Cellular and Molecular Physiology Chair of Physiology (Vegetative Physiology)...... 20 Department of Orthopedics in the Waldkrankenhaus St. Marien gGmbH Institute of Physiology and Pathophysiology Chair of Orthopedics and Orthopedic Surgery ...... 48 Chair of Physiology ...... 22 Division of Orthopedic Rheumatology ...... 50

CLINICAL THEORETICAL INSTITUTES Institute for Biomedicine of Aging Chair of Internal Medicine (Geriatrics) ...... 52

Institute and Outpatient Clinic of Occupational, Social, and Environmental Medicine UNIVERSITY HOSPITAL Chair of Occupational and Social Medicine ...... 24 Department of Anesthesiology Chair of Anesthesiology ...... 54 Institute of Experimental and Clinical Pharmacology Division of Molecular Pneumology ...... 56 and Toxicology Division of Palliative Medicine ...... 58 Chair of Pharmacology and Toxicology...... 26 Chair of Clinical Pharmacology and Clinical Toxicology...... 26 Department of Cardiac Surgery Doerenkamp-Chair for Innovations in Animal and Chair of Cardiac Surgery ...... 60 Consumer Protection ...... 30 Division of Pediatric Cardiac Surgery ...... 62

Institute of Forensic Medicine Department of Dermatology Chair of Forensic Medicine ...... 32 Chair of Skin and Veneral Diseases ...... 64 Division of Immune Modulation ...... 66 Institute of Medical Informatics, Biometry, and Epidemiology Department of Medicine 1 – Chair of Medical Biometry and Epidemiology...... 34 Gastroenterology, Lung Diseases, and Endocrinology Chair of Medical Informatics...... 36 Chair of Internal Medicine I ...... 68

2 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Department of Medicine 2 – Department of Pediatric and Adolescent Medicine Cardiology and Angiology Chair of Pediatrics ...... 98 Chair of Internal Medicine II...... 70 Division of Pediatric Cardiology ...... 100

Department of Medicine 3 – Department of Plastic and Hand Surgery ...... 102 Rheumatology and Immunology

Chair of Internal Medicine III...... 72 Department of Psychiatry and Psychotherapy Division of Molecular Immunology ...... 74 Chair of Psychiatry and Psychotherapy...... 104 Division of Child and Adolescent Mental Health ...... 106 Department of Medicine 4 – Division of Psychosomatics and Psychotherapy ...... 108 Nephrology and Hypertension Chair of Internal Medicine IV...... 76 Department of Radiation Oncology Chair of Radiotherapy ...... 110 Department of Medicine 5 – Hematology and Oncology Department of Surgery Chair of Hematology and Oncology ...... 78 Chair of Surgery ...... 112 Division of Pediatric Surgery ...... 114 Department of Neurology Division of Thoracic Surgery ...... 116 Chair of Neurology ...... 80 Division of Transfusion Medicine and Hemostaseology...... 118 Division of Molecular Neurology ...... 82 Division of Trauma Surgery ...... 120

Department of Neurosurgery Department of Urology Chair of Neurosurgery ...... 84 Chair of Urology ...... 122

Department of Nuclear Medicine Chair of Clinical Nuclear Medicine ...... 86 Departments of Dentistry Department of Operative Dentistry and Peridontology

Department of Obstetrics and Gynecology Chair of Dental, Oral, and Maxillofacial Medicine – Chair of Obstetrics and Gynecology ...... 88 especially Operative Dentistry, Periodontology, and Pediatric Dentistry ...... 124 Department of Ophthalmology Department of Orthodontics and Orofacial Orthopedics Chair of Ophthalmology ...... 90 Chair of Dental, Oral, and Maxillofacial Medicine – especially Orofacial Orthopedics...... 126 Department of Oral and Cranio-Maxillofacial Surgery Chair of Dental, Oral, and Maxillofacial Medicine – Department of Prosthodontics especially Oral and Maxillofacial Surgery ...... 92 Chair of Dental, Oral, and Maxillofacial Medicine – especially Prosthetic Dentistry...... 128 Department of Otorhinolaryngology – Head and Neck Surgery Institute of Clinical and Molecular Virology Chair of Otorhinolaryngology ...... 94 Chair of Clinical Virology ...... 130 Division of Phoniatrics and Pediatric Audiology ...... 96 Division of Experimental Therapeutics ...... 132

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 3 CONTENTS

Institute of Clinical Microbiology, Immunology, Imaging Science Institute (ISI) ...... 161 and Hygiene Interdisciplinary Center for Aging Research (ICA) ...... 162 Chair of Microbiology and Immunology of Infection ...... 134 Interdisciplinary Center for Public Health (IZPH) ...... 163 Division of Infection Biology ...... 136 Interdisciplinary Center for Ophthalmic Preventive Medicine and Imaging (IZPI) ...... 164 Institute of Human Genetics Chair of Human Genetics ...... 138 Medical Immunology Campus Erlangen ...... 165

Medical Technology Test and Application Center Institute of Neuropathology (METEAN) of the Fraunhofer Institute for Chair of Neuropathology ...... 140 Integrated Circuits IIS ...... 166

Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ) ...... 167 Institute of Pathology Central Institute of Medical Engineering (ZiMT) ...... 168 Chair of General Pathology and Pathological Anatomy ...... 142 Division of Nephropathology ...... 144 DFG COLLABORATIVE RESEARCH CENTERS AND

Institute of Radiology PRIORITY PROGRAMS Chair of Diagnostic Radiology ...... 146 Division of Neuroradiology ...... 148 Collaborative Research Center 643: Strategies of Cellular Immune Intervention...... 169

DEGREE PROGRAMS Collaborative Research Center 796: Reprogramming of Host Cells by Microbial Effectors...... 170 Human Medicine ...... 150 Priority Program 1468: Osteoimmunology – Dentistry ...... 151 IMMUNOBONE – A Program to Unravel the Mutual Molecular Medicine ...... 152 Interactions between the Immune System and Bone...... 171 Medical Process Management ...... 153 Speech Therapy ...... 154 JOINT RESEARCH PROJECTS OF THE BMBF AND

CENTRAL FACILITIES OF FACULTY AND OTHER NETWORKS UNIVERSITY HOSPITAL BMBF Leading Edge Cluster „Center of Excellence for

Interdisciplinary Center for Clinical Research (IZKF) ...... 155 Medical Technology – Medical Valley EMN“ ...... 172

Preclinical Experimental Animal Center (PETZ) BMBF-Network „Clinics and Pathophysiology of of the Franz-Penzoldt-Center (FPZ) ...... 156 Osteophytes and Ankylosis (ANCYLOSS)“...... 173

Center for Clinical Studies (CCS Erlangen) ...... 157 BMBF-Core Program „Molecular Diagnostics“ ...... 174 Comprehensive Cancer Center Erlangen-EMN ...... 158 BMBF-Network „Eating Disorders Diagnostic and Treatment Network“ (EDNET) ...... 175 INTERDISCIPLINARY CENTERS AND German Chronic Kidney Disease (GCKD-Study): CENTRAL INSTITUTES National Cohort Study on Chronic Kidney Disease ...... 176

Emil Fischer Center (EFC) ...... 159 National Genome Research Network – Erlangen Center for Infection Research (ECI) ...... 160 Mental Retardation Network (MRNET) ...... 177

4 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Bavarian Immunotherapy Network (BayImmuNet): BioMedTec International Graduate School of Science Adoptive Immunotherapy ...... 178 (BIGSS): Lead Structures of Cell Function ...... 193

Bavarian Research Cooperation for Adult neuronal Erlangen Graduate School in Advanced Optical Stem Cells (ForNeuroCell II) ...... 179 Technologies (SAOT) ...... 194

National Reference Center for Retroviruses ...... 180 RESEARCH SUPPORT AND FOUNDATIONS RESEARCH UNITS Advancement of Women and Gender Clinical Research Unit 130: Determinants and Research Promotion ...... 195

Modulators of Postoperative Pain ...... 181 ELAN-Program for Supporting Clinical Research Clinical Research Unit 257: Molecular pathogenesis and Teaching...... 196 and optimized therapy of chronic inflammatory Jakob-Herz-Prize ...... 197 bowel disease (CEDER) ...... 182 Johannes and Frieda Marohn-Foundation ...... 198 Research Unit 661: Research Foundation of Medicine ...... 199 Multimodal Imaging in Pre-Clinical Research...... 183 Further Foundations for Research Support...... 200

Research Unit 832: ACADEMIC SOCIETY Regulators of Humoral Immunity ...... 184

Research Unit 894: Physico-Medical Society Erlangen ...... 201 Fluid Mechanical Basis of the Human Voice ...... 185

Research Unit 1228: APPENDIX Molecular Pathogenesis of Myofibrillar Myopathies...... 186 Selection of Honors and Prizes ...... 202 Project Group of the Academy of Science and Literature, Mainz ...... 187 Doctorate Theses, Board Qualifications, Additional Qualifications, Habilitations ...... 204 RESEARCH TRAINING GROUPS AND In Memoriam ...... 217 PROGRAMS Personnel Index ...... 219 Imprint ...... 220 Integrated Research Training Group within SFB 643: Strategies of Cellular Immune Intervention ...... 188

Integrated Research Training Group within SFB 796: Erlangen School of Molecular Communication ...... 189

Research Training Group 1071: Viruses of the Immune System...... 190

Research Training Group 1660: Key Signals of Adaptive Immune Response ...... 191

Emil Fischer Graduate Program of Pharmaceutical Sciences and Molecular Medicine (EFS) ...... 192

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 5 PREFACE

Medical Research in Erlangen

It is with great pleasure that the Faculty of Medicine of the Friedrich- The Dean of the Faculty of Medicine, Alexander-Universität Erlangen-Nürnberg (FAU) presents the research Prof. Dr. med. Dr. h.c. Jürgen Schüttler report for the years 2011 – 2012. Following an established tradition, this report gives an overview of the research areas and projects carried out by the various preclinical and clinical theoretical institutes and by the chairs established at the departments and divisions of the FAU and the Universitätsklinikum Erlangen (UK Erlangen). It is meant to be read by anyone interested from inside and/or outside the university area. It is intended to serve as a base for the intensification of both, internal and interdisciplinary communication, and to encourage suggestions for future cooperative projects.

The Faculty of Medicine of the FAU has established four focal areas of research, all of which were given a high rating by the German Science Council in 2006: 1. Immunology and infection research In the course of the report period 2011 - 2012, diverse activities were 2. Renal and vascular research carried out, aiming at moving forward with the process of enhancing the 3. Neurosciences, including pain and ophthalmology research 4. Tumor research. reputation of our Faculty of Medicine as an international top player in the fields of research and education. The research focus of our Faculty of These research focuses are interconnected through three interdiscipli- Medicine is reflected by the existence of the Interdisciplinary Center for nary fields: Molecular Medicine, Medical Technology, and Clinical Stud- Clinical Research (IZKF), the Franz Penzoldt Center (FPZ), as well as the ies. Translational Research, i.e. an active effort to transpose findings from Center for Clinical Studies (CCS). The latter is responsible, among others, basic research into clinical studies involving patients, is the overarching for coordinating the legal aspects of bench-to-bedside research projects. purpose of all research activity at the Faculty of Medicine. Thus, the objective of medical research is seen not solely as being that of discovering The multitude of outstanding research initiatives requires increased lab new facts and expanding medical knowledge for its own sake; it is also space. This is met by different construction projects which shall meet seen as being that of striving for effectiveness in the pursuit of better the need for more research areas. With the Translational Research Center therapeutic outcomes for our patients. (TRC) – topping-out ceremony on March 2012 –, the UK Erlangen will provide an innovative interdisciplinary infrastructure for clinical research, The current fields of research are to be pursued in the future consistently. so far unprecedented by another German university. The TRC will join all However, new questions that emerge at interdisciplinary interfaces will areas with a need to translate research into diagnostic and therapeutic be advanced, so that they can develop into potential research focuses. process in an exemplary manner. Thus, our Faculty of Medicine will be Such focal research areas are characterized by interdisciplinary networks able to counteract the many times emphasized lack of advancement in supported by third-party funding provided in the framework of collabo- clinical research and to create new research focuses on the basis of a rative research centers, research training groups, DFG research groups, planned strategy. as well as network projects funded by the BMBF and the EU. A new clinical research group funded by the DFG could be established at the A further improvement of research conditions resulted from the DFG’s Department of Medicine 1 – Gastroenterology, Lung Diseases, and Endo- introduction of a lump sum to cover indirect costs incurred by projects. crinology on “Molecular pathogenesis and optimized therapy of chronic Part of this sum is passed on by the FAU or the UK Erlangen to insti- inflammatory bowel disease”. A more detailed account of these networks tutes or departments to use at their own discretion for research-related and research groups is given in the second part of this report. purposes. With the introduction of a project lump sum by the BMBF in 2011, this research support for the institutes and departments could be Moreover, our Faculty of Medicine plays an important role in the scien- increased considerably. However, the distribution of research fundings as tific research focuses of the FAU “Molecular Life Sciences and Medicine“, well as the execution of joint research funding programs is difficult due “Medical Technology“, as well as “Optics and Optical Technologies”. to a financial separation within the Faculty of Medicine administration There is a close cooperation between the Faculty of Medicine and the rel- (UK Erlangen’s budget versus non-clinical institutes’ budget). A working evant science and engineering faculties in the various research networks. group on the structures of our Faculty of Medicine is endeavoring to develop tools to overcome this organizational separation by integrating the The third-party funding has been rising continuously for the last few structures. The measures are supported by the Bavarian State Ministry years. In 2011, the Faculty of Medicine attracted almost 40 million Euro within an agreement on objectives. of third-party funding which ranks Erlangen among the “Top Ten” of all German medical faculties regarding third-party funding. In the fields of In July 2012, the “Center of Excellence for Medical Technology”, funded microbiology, virology, and immunology, Erlangen even holds the lead- by BMBF under the roof of the Medical Valley EMN at the Leading Edge ing position nationwide. Cluster competition, was granted a prolongation of its funding until

6 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 2015 in this highly competitive environment thanks to convincing re- tors. Funds from this source are also used to finance research projects in sults and future-oriented visions gained in the first funding period. The teaching. Networked courses continue to be created in interdisciplinary aim of the Center of Excellence for Medical Technology is to develop subjects, all courses are systematically evaluated, and the professionaliza- technologies which increase life expectancy, improve quality of life, and tion of student management in the practical year (11th and 12th term) reduce costs in the public health sector. The Imaging Science Institute continues to be pursued. (ISI), founded as a joint venture between Siemens Healthcare and the Institute of Radiology of the FAU in 2005, plays an important role for On behalf of the Faculty of Medicine administration I would like to thank the development and implementation of innovative imaging methods all those members of our staff who helped produce this report. Particular within the Medical Valley EMN. The close cooperation between chairs of thanks go to U. Niederweis, Prof. Dr. K. Schiebel, and Dr. S.A. Thomas the medical, technical, and natural sciences faculties of the FAU, Siemens for their active involvement in formulating the text. The report can be Healthcare, the Fraunhofer IIS, and more than 50 companies in the field downloaded from the website of the Dean’s office of the Faculty of Med- of medical technology from the metropolitan area complement the out- icine as well as from the homepage of the UK Erlangen. standing research conditions in Erlangen. Additionally, the Central Insti- tute of Medical Engineering (ZiMT) further supports the interdisciplinary We hope our readers enjoy the information we have provided on the cooperation in the field of medical engineering. wide range of research carried out at our Faculty of Medicine. The scientists involved will be happy to answer questions on their projects in oral New developments in teaching or written form.

It was already in 2006 that the Science Council underscored the trans- Erlangen, July 2013 regional activities carried out by our Faculty of Medicine to promote further development of teaching. Therefore, our report also lists information on teaching for each facility at the Faculty of Medicine.

The completion of the newly built medical lecture halls meets not only the need of the Faculty of Medicine for more lecture halls and class- Prof. Dr. med. Dr. h.c. Jürgen Schüttler rooms, but also offers excellent venues for congresses, meetings, and Dean other public events during term breaks. The generous foyer is an attractive location for receptions and poster presentations, too.

The Faculty of Medicine of the FAU currently has five degree programs: Human Medicine, Dentistry, Molecular Medicine (Bachelor of Science and Master of Science), Speech Therapy (Bachelor of Science), and Med- ical Process Management (Master of Science). These degree programs will be presented in more details in the second part of the research report. Since 2007, the students at the Faculty of Medicine have regularly ranked among the best out of 36 medical faculties in the first phase of degree examinations and have also been in the top group in terms of grades received on state examinations relating to clinical training. Our Faculty of Medicine has consistently undertaken efforts to seize on and apply new ideas in teaching in order to maintain these rankings. A changeover to the bachelor’s and master’s degree system is not planned in Erlangen for the degree programs Human Medicine and Dentistry, given that this is not expected to produce any time advantages in the training of students and, as such, would not enable graduates to find a medical occupation any earlier. In a memorandum, our Faculty of Medi- cine stated its opposition to the general implementation of the “Bologna Process” for the medical education. However, bachelor’s and master’s degree structures have been firmly established in specialized fields, such as Medical Process Management, Molecular Medicine, and Speech Ther- apy.

In summer term 2007, a skills lab, PERLE (Practice, Experience, and Learning), was created with money taken from tuition fees. PERLE helps students to improve their skills and prepare for practical examinations. The students are supported by medical specialists and trained student tu-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 7 8 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) ABBREVATIONS

Abbrevations

• B.Sc.: Bachelor of Science

• BMBF: Federal Ministry of Education and Research

• DFG: German Research Foundation

• FAU: Friedrich-Alexander-Universität Erlangen-Nürnberg

• GK: Research Training Group

• IZKF: Interdisciplinary Center for Clinical Research

• M.Sc.: Master of Science

• NFZ: Nikolaus-Fiebiger-Center of Molecular Medicine

• SFB: Collaborative Research Center

• UK Erlangen: Universitätsklinikum Erlangen

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 9 PRECLINICAL INSTITUTES

Institute of Anatomy Chair of Anatomy I

Address tonin and myosin typing of striated esophageal morphological methods in order to define pro- Krankenhausstraße 9 muscle in mouse and human. tein domains relevant for the respective locali- 91054 Erlangen Afferent vagal terminals around myenteric gan- zation. As a first result, transport of merlin into Phone: +49 9131 8522265 glia, so-called intraganglionic laminar endings the nucleus was found to be coupled to spe- Fax: +49 9131 8522863 (IGLEs), are putative mechanosensors probably cific membranes of the endolysosomal system www.anatomie1.med.uni-erlangen.de exerting also additional purposes in the enteric whose origin is the focus of ongoing research. neuronal circuitry. They were further charac- Head of Department terized with respect to their equipment with Teaching Prof. Dr. Winfried Neuhuber muscarinic acetycholine and CGRP receptors. In addition, presynaptic proteins, e.g. synapto- Both anatomical chairs collaborate in teaching Contact tagmin1 and bassoon, were detected in IGLEs, anatomy. In particular, the Chair of Anatomy I Prof. Dr. Winfried Neuhuber further supporting the idea of their synaptic in- is concerned with courses in gross antomy and Phone: +49 9131 8522265 fluence onto enteric neurons. parts of interdisciplinary clinical-anatomical Fax: +49 9131 8522863 Morpho-chemical phenotyping of enteric neu- seminars and courses of neuroanatomy. The [email protected] rons in healthy human intestines was contin- dissection course with its small group format erlangen.de ued. In addition, morphological and immu- with correlated main lecture is of pivotal impor- nohistochemical characterization of enteric tance. Seminars, partly in PBL problem-based Research Focus neurons in Chagas-induced megacolon was learning format and using electronic me- •• Innervation of the gastrointestinal tract initiated in collaboration with Prof. Dr. A. da dia, provide opportunity for students to train •• Nervous system, inflammation, and pain Silveira (Brazil). This line of research is serving practical application of knowledge they have •• Cell biology of the NF2 tumor suppressor as a paradigm for forthcoming investigations acquired in the dissection room (seminars of protein on the enteric nervous system in other gastro- imaging methods, surface anatomy, clinical intestinal disorders. anatomy). Members of the Institute provide Structure of the Department lectures and courses also for other faculties. Nervous system, inflammation, Together with the Chair of Anatomy II, the Chair and pain Selected Publications of Anatomy I composes the Institute of Anato- Project manager: Prof. Dr. W. Neuhuber Jabari S, da Silveira AB, de Oliveira EC, Neto SG, Quint K, my. Altogether, 16 persons are employed, five In collaboration with colleagues of the Depart- Neuhuber W, Brehmer A (2011) Partial, selective survival of them on an external funding basis. Research ment of Medicine 4 - Nephrology and Hyper- of nitrergic neurons in chagasic megacolon. Histochem Cell Biol, 135: 47-57 is conducted by six scientists (chairman, senior tension, nerve fiber populations relevant for Kustermann A, Neuhuber W, Brehmer A (2011) Calretinin scientists, postdoctoral fellows), eight doctoral nephritis pathophysiology were studied. In col- and Somatostatin Immunoreactivities Label Different thesis students (both, MD and PhD), and six laboration with the Institute of Physiology and Human Submucosal Neuron Populations Anat Rec, 294: technicians. The Chair of Anatomy I provides Pathophysiology, studies on innervation of the 858-869 the facilities and logistics for gross anatomy, cranial dura and neuronal modulation in ex- Hempfling C, Neuhuber WL, Wörl J (2012) Serotonin-im- including body donation. This is essential not perimental colitis were continued. munoreactive neurons and mast cells in the mouse esophagus suggest involvement of serotonin in both motility only for teaching, but also for applied clinical control and neuroimmune interactions. Neurogastroen- research and postgraduate training. Cell biology of the NF2 tumor terol Motil, 24: e67-78 Most of the teams investigate various aspects of suppressor protein Horling L, Neuhuber WL, Raab M (2012) Pitfalls using tyr- autonomic innervation, in particular of the gas- Project manager: PD Dr. M. Kressel amide signal amplification (TSA) in the mouse gastrointes- trointestinal tract; one group studies cell biol- The neurofibromatosis type 2 (NF2) protein tinal tract: endogenous streptavidin-binding sites lead to false positive staining. J Neurosci Methods, 204: 124-32 ogy of tumor suppressor genes. A broad spec- merlin is a classical tumor suppressor protein. trum of conventional histology, histochemistry, Disturbed function or loss of function, e.g. Jabari S, da Silveira AB, de Oliveira EC, Neto SG, Quint K, Neuhuber W, Brehmer A (2012) Selective survival of and immunohistochemistry, light-, confocal, through inherited NF2 gene mutation, typi- calretinin- and vasoactive-intestinal-peptide-containing and electron microscopy, electrophysiology (in cally results in neurinomas of the VIIIth cranial nerve elements in human chagasic submucosa and muco- collaboration with the Institute of Physiology nerve. Data from Drosophila suggest the NF2 sa. Cell Tissue Res, 349: 473-81 and Pathophysiology) and in vitro preparations protein as one of the regulatory components Jabari S, da Silveira AB, de Oliveira EC, Quint K, Neuhuber W, Brehmer A (2012) Preponderance of inhibitory versus of isolated organs as well as molecular biology of the so-called hippo pathway which turned excitatory intramuscular nerve fibres in human chagasic is applied. Equipment and laboratory facilities out to be a universal cellular regulator of limb megacolon. Int J Colorectal Dis, 27: 1181-9 are available also for other groups both, within and organ size. Cell biology studies in order to and outside the Faculty of Medicine. elucidate the function of the NF2 protein were International Cooperations continued. We focused on subcellular localiza- Prof. Dr. H.-R. Berthoud, University of Louisiana, Baton Research tion of merlin, since one isoform turned out to Rouge: USA be a nucleo-cytoplasmic shuttle protein. This Prof. C. Chiang, Department of Cell and Developmental Innervation of the gastrointestinal extended the classical view of merlin from a Biology, University Medical Center, Nashville: USA tract purely plasma membrane associated protein Dr. M. Giovannini, Institut Curie, INSERM, Paris: France Project managers: Prof. Dr. W. Neuhuber, Prof. towards a nuclear regulator of proliferation. Prof. S. Pulst, Neurogenetics Lab and Division of Neurolo- Dr. J. Woerl, PD Dr. M. Raab, Prof. Dr. A. Brehmer The mechanisms determining cytoplasmic and gy, Cedars-Sinai Medical Center, Los Angeles: USA Studies on the esophagus focused on novel nuclear localization, respectively, are being Prof. F. Schrödl, Augenklinik SALK, University of Salzburg, mediators of enteric co-innervation, e.g. sero- studied with a set of molecular biological and Salzburg: Austria

10 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Prof. Dr. A. da Silveira, Department of Anatomy, University of Uberlandia, Uberlandia: Brazil Prof. Y. Shimizu, Department of Basic Veterinary Science, Gifu University, Gifu: Japan Prof. J.-P. Timmermans, Institute of Histology and Cell Biol- ogy, University of Antwerp, Antwerp: Belgium

Meetings and International Training Courses 23.-25.02.2011: 8th International Course on Diagnostics and Surgery of Salivary Gland Diseases in Consideration of New Techniques (gemeinsam mit HNO-Klinik Erlangen), Erlangen 17.-20.05.2011: 10th International Erlangen Course in Fa- cial Plastic Surgery (gemeinsam mit HNO-Klinik Erlangen), Erlangen 05.-06.10.2012: Aufbau- und Masterkurs der Gesellschaft für Fußchirurgie, Erlangen Motor endplate in the mouse esophagus labeled with 08.12.2012: Fortgeschrittenenkurs im Rahmen des 28. a-bungarotoxin (red) receiving vagal cholinergic (blue) Nürnberger Arthroskopiekurses und Gelenksymposiums and enteric serotoninergic (green) innervations. (gemeinsam mit Klinik für Unfall- und Orthopädische Chir- urgie des Klinikums Nürnberg), Erlangen

Striated muscle fibers in the mouse esophagus immuno- labeled for fast myosin (green). Motor endplates (red) receive enteric VIP positive axons (blue).

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 11 PRECLINICAL INSTITUTES

Institute of Anatomy Chair of Anatomy II

Address In 2012, Prof. Dr. F. Paulsen was offered a chair neurons showed functional changes which Universitätstraße 19 for Anatomy at the Medical University of Vien- suggest the involvement of photoreceptor cells 91054 Erlangen na which he has declined by now. within the degenerative process of the retina in Phone: +49 9131 8522864 these animals. In our studies, we found both, Fax: +49 9131 8522862 Research a reduction in the thickness of the outer plexi- www.anatomie2.med.uni-erlangen.de form layer of the retina which is the area of Pathophysiology of the Meibomian first synaptic connections for the transmission Head of Department gland dysfunction (MGD) of visual signals as well as age-dependent and Prof. Dr. med. Friedrich Paulsen Project managers: F. Garreis, Dr. U. Hampel, progressive degenerative changes in the struc- Prof. Dr. F. Paulsen tural morphology of the rod ribbon synapses Contact Meibomian gland dysfunction (MGD), a term itself. This synaptic phenotype was described Prof. Dr. med. Friedrich Paulsen used to describe a diffuse abnormality of the for the first time and contributes significantly Phone: +49 9131 8522865 meibomian glands which are specialized seba- to the further understanding of the pathogene- Fax: +49 9131 8522862 ceous glands in the eye lids, is considered to be sis of degenerative changes within the retina of [email protected] the most common cause of dry eye syndrome this animal model. (DES), a disease with an estimated prevalence Research Focus of 12 million people alone in Germany. It is Characterization and detection of •• Pathophysiology of the Meibomian gland currently thought that MGD is caused primar- surfactant proteins dysfunction (MGD) ily by terminal duct obstruction due to hyper- Project managers: M. Schicht, Prof. Dr. L. •• Neurodegenerative changes in the retina of keratinization of the ductal epithelium and an Bräuer, Prof. Dr. F. Paulsen the DBA/2J mouse increased viscosity of meibum. However, the Besides the evolving investigation and char- molecular mechanisms that underlie this pro- •• Characterization and detection of surfactant acterization of the known surfactant proteins cess are unclear. Many proteins being essential proteins in different tissues and organs, two new yet for epidermal differentiation and keratinization •• Project test anxiety unknown proteins could be detected for the constitute the ‘epidermal differentiation com- •• Investigations in glaucoma pathogenesis first time by means of genome analysis. Both plex’ (EDC). They function beside epidermal proteins, named SP-G and SP-H, may represent differentiation and keratinization also in innate Structure of the Department a new class of surfactant proteins. Using bioin- immune defense belonging to the group of an- formatics and genome analyses, RT-PCR exper- timicrobial peptides (AMP). The hypotheses are: The Institute of Anatomy consists of the Chair iments as well as immunological investigations Chronic inflammatory conditions at the ocular of Anatomy I and the Chair of Anatomy II. Since (Western-Blot, immunohistochemistry), the surface induce upregulation of AMPs which are the inauguration of Prof. Dr. F. Paulsen in 2010 two unknown proteins could be detected and correlated to genes of the EDC that function as new director, the Department has been in a characterized for the first time at RNA/DNA- in epidermal differentiation and keratinization. continuous restructuring and renovation which and protein level within a variety of human tis- Thus, induction of EDC associated AMPs trig- is expected to be completed in late 2014. In sues (e.g. tissues of the ocular system, kidney, gers hyperkeratinization of Meibomian glands the past two years, most of the office space was liver, and lung). In addition, we were able to and increases viscosity of meibum. The goal renovated, newly furnished, and equipped. The of the study is to get deeper insights into the show that different strains of Staphylococcus renewal of some of the laboratory space has al- pathophysiology of MGD by performing in vivo aureus and Pseudomonas aeruginosa express ready begun. Currently, 25 staff members are experiments in an established mouse model of and secrete proteins that react with commer- employed at the Institute. In the period from dry eye and in vitro experiments using cultivat- cially available antibodies against human sur- 2011 to 2012, seven employees were funded ed human Meibomian gland epithelial cells in factant proteins. The results may reflect the by grants. Eight PhD students, two gradu- three-dimensional culture to determine factors existence of a new group of bacterial surfactant ate students, and a Bachelorand of molecular that could serve as possible targets for thera- proteins currently lacking in the relevant se- medicine were involved in scientific work. The peutic intervention in MGD. quence and structure databases. functional anatomy of the body, including embryology, the entire microscopic anatomy, Neurodegenerative changes in the Project test anxiety and parts of neuroanatomy were represented retina of the DBA/2J mouse Project managers: Dr. O.Y. Tektas, PD Dr. M. in teaching. In addition, members of the Chair Project managers: PD Dr. M. Scholz, Prof. Dr. Scholz, Prof. Dr. F. Paulsen of Anatomy II participated in the lessons of the F. Paulsen Test anxiety (TA) is an underestimated and macroscopic anatomy given by the Chair of In close cooperation with the Department of widespread problem among students. It can Anatomy I. There were collaborations with oth- Ophthalmology (Prof. Dr. J. Kremers; Experi- result in poor course achievements, psychiat- er projects, particularly with regard to the SFB mental Ophthalmology) and the Chair of An- ric and somatic disorders as well as in addictive initiative "hoarseness" and several long-time imal Physiology at the Department of Biology disorders. The Chair of Anatomy II offers a pilot international collaborations. Since 2011, the (Prof. Dr. J.H. Brandstätter), morphological and project which addresses affected students and W2 professorship of the Chair has been held by molecular studies on the structure and changes is supported by several collaborators. The pro- Prof. Dr. L. Bräuer who works on surface-active in the retina of the DBA/2J mouse model were gram comprises a series of lectures with guest proteins (mainly surfactant proteins) and sup- performed. Previous electrophysiological inves- lecturers as well as different tutorials which are ports the research interests of the Department. tigations of the stimulation responses of retinal conducted by specialized psychologists. At the

12 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Fuchs M, Scholz M, Sendelbeck A, Atorf J, Schlegel C, Enz R, Brandstätter JH (2012) Rod photoreceptor ribbon synapses in DBA/2J mice show progressive age-related structural changes. PLoS ONE, 7: e44645 Hampel U, Klonisch T, Sel S, Schulze U, Garreis F, Paulsen FP (2012) Relaxin 2 is functional at the ocular surface and promotes corneal wound healing. Invest Ophthalmol Vis Sci, 53: 7780-90 Tektas¸ OY, Paulsen F. (2012) Medizinstudium: Gegen die Prüfungsangst. Deutsches Ärzteblatt, 109: 29-30 Rausch F, Schicht M, Paulsen F, Ngueya I, Bräuer L, Brandt W (2012) “SP-G”, a putative new surfactant protein--tissue localization and 3D structure. PLoS ONE, 7: e47789

Rod photoreceptor synaptic ribbons disintegrate in aging DBA/2J mice. Synaptic ribbon profiles were classified as rod- International Cooperations shaped (A), club-shaped (B), and spherical-shaped (C). Scale bar: 0.2 mm. E. Cuerda, University, Madrid: Spain same time, research approaches are performed anatomy with accompanying demonstration M. Wilcox, University, Sydney: Australia about this topic within the project. A huge courses and the general and specific histology Y. Diebold, University, Valladolid: Spain census revealed important findings about the (including embryology) in combination with M. Berry, University, Bristol: UK prevalence of test anxiety, its impacts to study the courses of microscopic anatomy and associ- P. Kaufman, University, Madison: USA specific performances, and its correlations to ated seminars. In the seminar on functional and D. Overby, University, London: UK drug and alcohol consumption behavior. Cur- clinical anatomy of the musculoskeletal system, J. Danias, University, New York City: USA rently, long term effects of different therapies the students were increasingly teached on wet D. Sullivan, University, Boston: USA and supervision procedures are investigated. specimens that have been created continuously since 2010. The microscopic anatomy is con- Investigations in glaucoma ceptually transformed into a model of the fu- pathogenesis ture that makes use of the virtual histology. In Project managers: Dr. O.Y. Tektas, Prof. Dr. M. this context, in collaboration with the Institute Eichhorn, Prof. Dr. E. Lütjen-Drecoll of Anatomy at the University of Regensburg Glaucoma comprises a number of different eye (Chair of Histology, Prof. Dr. R. Witzgall) and in diseases and is defined as a progressive dam- close cooperation with the Fraunhofer Institute age of the optic nerve. One of the main risk for Integrated Circuits and the Virtual University factors for the disease is an elevated intraocular of Bavaria, a first online course "General ana- pressure. The exact pathogenesis of the disease tomy with clinical implications" can be booked is not known yet. In collaboration with several at the virtual University of Bavaria which is free workgroups (Münster/Germany, London/GB, for all students at Bavarian universities. In addi- Wisconsin and New York City/USA), changes of the aqueous humor pathways and the optic tion, most of the histological specimens used nerve are investigated at the Chair of Anatomy in the courses in Erlangen and Regensburg II. Besides molecular and morphological investi- can be viewed online with high resolution. All gations of donor tissues from patients suffering courses are attended by students of medicine, from different types of glaucoma (pigment dis- dentistry, and molecular medicine. In addition, persion syndrome, uveitis induced glaucoma, students of the study course Medical Process primary open angle glaucoma), the workgroup Management were teached in anatomy. Prof. performs research using different animal mod- Dr. M. Eichhorn and Prof. Dr. F. Paulsen are in- els. In collaboration with the group of Dr. J. Da- cluded in teaching courses of MAOT and SAOT nias (New York City), changes of the trabecular graduate schools and organize lectures and meshwork of sheep eyes with drug treatment demonstration courses for interested students are investigated. In a further cooperation with of the study course medical engineering. the group of Dr. D. Overby (London), it could recently be demonstrated that changes in the Selected Publications trabecular meshwork of mice eyes with drug Garreis F, Gottschalt M, Schlorf T, Gläser R, Harder J, Wor- treatment could induce intraocular pressure litzsch D, Paulsen FP (2011) Expression and regulation of elevation. antimicrobial peptide psoriasin (S100A7) at the ocular surface and in the lacrimal apparatus. Invest Ophthalmol Vis Sci, 52: 4914-22 Teaching Bräuer L, Schicht M, Stengl C, Heinemann F, Götz W, Scholz M, Paulsen F (2012) Detection of surfactant pro- The Chair of Anatomy II has performed the teins A, B, C, and D in human gingiva and saliva. Biomed lectures on the functional aspects of human Tech (Berl), 57: 59-64

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 13 PRECLINICAL INSTITUTES

Institute of Biochemistry – Emil-Fischer-Center Chair of Biochemistry and Molecular Medicine

Address the human GlyR-genes are associated with neu- behavior as shown for the murine Glrb in the Fahrstraße 17 romotor-disorders, such as hyperekplexia (star- mouse model spastic can cause disease. Sera 91054 Erlangen tle disease, stiff baby syndrome), leading to from patients suffering from a late onset form Phone: +49 9131 8524191 enhanced startle reactions and episodic muscle of hyperekplexia contain anitbodies against the Fax: +49 9131 8522485 stiffness. The GlyR is a pentameric ion channel glycine receptor. www.biochem.uni-erlangen.de comprising 2 a- and 3 b-subunits. Every subunit encloses a large extracellular ligand bind- In vivo functions of glycine transporters Head of Department ing domain followed by four transmembrane Project manager: Dr. V. Eulenburg Prof. Dr. rer. nat. Michael Wegner (acting head) domains connected by loops. The focus of Neurotransmission with high temporal and our research is the investigation of the patho- spatial resolution requires the rapid termina- Contact mechanisms of GlyR channelopathies. Human tion of synaptic transmission. At glycinergic Prof. Dr. phil. nat. Ralf Enz hyperekplexia is inherited either dominantly synapses, this is achieved by rapid uptake of Phone: +49 9131 8524185 or recessively with incomplete penetrance. A the presynaptically released glycine into the Fax: +49 9131 8522485 newly characterized dominant mutation in the nerve terminal and the surrounding glial cells [email protected] extracellular domain alters - due to its position by high affinity transporters named GlyT1 and in the ligandbinding domain - the binding of GlyT2. By complex genetical, biochemical, Research Focus glycine, whereas most known recessive muta- and behavioral approaches, we have shown •• Receptors and receptor associated diseases tions in the ligandbinding domain lead to re- that neuronal and glial expressed Glyt1 have of the nervous system duced surface expression. This can be attribut- different functions depending of the cell type •• In vivo functions of glycine transporters ed to endoplasmatic retention and accelerated expressing the transporter. We could show that •• Molecular heterogeneities and posttransla- proteasomal degradation of the glycin recep- inactivation of GlyT1 in glial cells results in se- tional modifications of proteins tor. This altered biogenesis of glycine receptor vere hyotonic movement disorders, whereas •• Structure and function of synaptic signaling variants leads eventually to impaired surface the loss of neuronal GlyT1 results in disturbanc- complexes in the central nervous system localization of the receptor. es in higher brain functions, like learning and Murine models carrying mutations within the memory. Interestingly, the precise functions of Structure of the Department GlyR display a similar phenotype as compared the respective GlyTs appear to change during to humans (spastic, spasmodic, and oscillator). development. Directly after birth the extracel- The Institute of Biochemistry comprises the Here, our group has shown previously that the lular glycine concentration is exclusively con- Chair of Biochemistry and Molecular Medicine mutant mouse line spastic that is characterized trolled by GlyT1. At later developmental stages, and the Chair of Biochemistry and Pathobio- by a strong reduction in glycine receptor ex- however, GlyT2 contributes to the regulation chemistry. In addition, the Professorship of pression carries an insertion of a retrotranspo- of the extracellular transmitter concentration, Bioinformatics is integrated in the Institute. son called LINE element in the glycine receptor too. These changes in function are accompa- The Institute of Biochemistry constitutes the gene Glrb. Since the insertion is not within the nied by alterations in the expression levels of interdisciplinary Emil-Fischer-Center together coding region for the glycine receptor b subu- the respective transporters. In conclusion, our with the Institute of Experimental and Clinical nit, we investigated an alternative mechanism research has contributed to a better under- Pharmacology and Toxicology of the Faculty of that explains the reduction in expression. We standing of how glial and neuronal expressed Medicine and the Institute of Pharmaceutical could show that the insertion of the LINE al- transporters influence synaptic transmission. Chemistry of the Science Faculty. ters the splicing of the Glrb mRNA and that this The Chair has a total of 30 employees (half of alteration is dependent on the genomic con- Molecular heterogeneities and post- them funded by grants), including eight scien- text. translational modifications of proteins tists, seven postgraduate students, and eight In another project, sera from patients suffer- Project manager: Dr. W. Xiang technicians. ing from the non-heridiatry form of stiff-per- The identification of pathological molecular al- son-syndrome were analyzed for presence terations is crucial for the development of im- Research of anti-GlyR autoantibodies. The recognized proved diagnostic and therapeutic approaches epitopes are identified and mapped within the of neurodegenerative diseases and many other Receptors and receptor associated amino acid sequence of the receptor. In addi- neurological disorders. We develop mass spec- diseases of the nervous system tion, in vitro experiments to elucidate the patho- trometry-based methods to determine molecu- Project managers: Prof. Dr. C.-M. Becker, Dr. mechanism were performed. lar heterogeneities, focusing on pathology rele- C.J. Kluck, Prof. Dr. C. Villmann, Dr. V. Eulen- In summary, by analysis of newly described vant genetic polymorphisms and mutations as burg, Dr. N. Vogel mutations leading to amino acid changes in well as alterations of lipid profiles. We also char- Glycine is the most important inhibitory neuro- the glycine receptor a1 subunit, we could en- acterize posttranslational modifications (PTMs) transmitter in the human spinal cord and brain hance our knowledge about critical loops and of proteins using MALDI-TOF MS as well as stem. Upon binding of glycine to postsynaptic their roles in protein folding and assembly into LC-ESI-MS/MS: After separation of complex glycine receptors (GlyR), a member of the Cys- functional pentamers. Furthermore, the domi- protein mixtures, peptide mass fingerprint data Loop receptor superfamily, an intrinsic chloride nant mutation points to the sensitivity of the are compared to database entries. We gain fur- channel opens which is responsible for inhibi- ligand binding pocket for spatial changes in ther information about the site of modification tion of the postsynaptic cell. Mutations within ligand binding. Also a complex altered splicing by using LC-ESI-MS/MS.

14 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) demonstrated expression of multimeric signal E. Buratti und F. Baralle, International Center of Genetic complexes, consisting of GABAcR, PNUTS/PP1, Engineering and Biotechnology, University Triest, Triest: Italy and ZIP3/PKC, or of mGluRs, PP1, and SUMO T. F. Outeiro und H. V. Miranda, Cell and Molecular Neu- proteins. These protein complexes regulate in- roscience Unit, Instituto de Medicina Molecular, University tracellular signal cascades and subcellular tar- Lisbon, Lisbon: Portugal geting of neurotransmitter receptors. Research Equipment The Fragile X Syndrome is an autism spectrum disorder which is caused by the loss of a sin- Bruker Daltonik, Esquire 6000 ESI-IT MS gle protein, the Fragile X Mental Retardation Bruker Daltonik, Autoflex 1 MALDI-TOF MS Protein FMRP. FMRP regulates excitation driven protein synthesis depending on mGluR signal- Patch-clamp technique on hippocampal neurons ing. For this purpose, FMRP may associate with Oxidative stress is an important pathological approximately 4% of all mRNAs in the mam- modifier in the pathogenesis of many neu- malian brain and thereby governs their trans- rodegenerative disorders. Oxidative stress is port and translation. We analyze the relevance characterized by elevated levels of free radicals of two novel proteins in this matter. which can induce increased PTMs of amino acid residues. To understand the molecular Teaching and cellular effects of oxidative stress regarding PTMs, we investigate oxidative stress-induced Both chairs of the Institute jointly carry out the PTMs of a-Synuclein, the crucial protein in the curricular education (lectures, seminars, prac- pathogenesis of Parkinson’s disease. Our stud- tical courses) in biochemistry and molecular ies show that oxidative PTMs can significantly biology for students of medicine, dentistry, and alter the structural and functional characteris- molecular medicine as well as the biochemical tics of a-Synuclein. More importantly, several practicals of students of pharmacy. For students oxidative PTMs accelerate the accumulation of molecular medicine, the Chair organizes the of a-Synclein species which lead eventually to module of neuroscience. neuronal cell death. Selected Publications Structure and function of synaptic Dütting E, Schröder-Kress N, Sticht H, Enz R (2011) signaling complexes in the central SUMO E3 ligases are expressed in the retina and regulate nervous system SUMOylation of the metabotropic glutamate receptor 8b. Biochem J, 435: 365-71 Project managers: Prof. Dr. R. Enz, Dr. R. Dahl- Urbanczyk A, Jünemann A, Enz R (2011) PKC -interacting haus b protein ZIP3 is generated by intronic polyadenylation, and The electric excitability of the central nervous is expressed in the brain and retina of the rat. Biochem J, system is regulated by a coordinated interplay 433: 43-50 of neurotransmitter receptors and ion channels Becker K, Braune M, Benderska N, Buratti E, Baralle F, with enzymes and scaffold proteins that as- Villmann C, Stamm S, Eulenburg V, Becker CM (2012) A retroelement modifies pre-mRNA splicing: the murine semble into macromolecular signal complexes Glrb(spa) allele is a splicing signal polymorphism ampli- at synapses. Malfunction may cause diseases, fied by long interspersed nuclear element insertion. J Biol including epilepsy und autism. Thus, synaptic Chem, 287: 31185-94 proteins represent interesting targets for thera- Guo D, Xiang W, Seebahn A, Becker CM, Strauss O (2012) + peutic intervention. Modulation of TTX-sensitive voltage-dependent Na channels by b-bungarotoxin in rat cerebellar neurons. To investigate molecular mechanisms of syn- BMC Neurosci, 13: 36 aptic signal transduction, we analyze structure, Lall D, Armbruster A, Ruffert K, Betz H, Eulenburg V (2012) expression, and function of synaptically local- Transport activities and expression patterns of glycine ized macromolecular signal complexes that are transporters 1 and 2 in the developing murine brain stem associated with metabotropic glutamate re- and spinal cord. Biochem Biophys Res Commun, 423: 661-6 ceptors (mGluRs) and GABAc receptors (GAB- Unterer B, Becker CM, Villmann C (2012) The importance AcR). As mGluR binding partners, we identified of TM3-4 loop subdomains for functional reconstitution of the proteinphosphatase PP1, members of the glycine receptors by independent domains. J Biol Chem, SUMOylation cascade and band 4.1 proteins. 287: 39205-15 Furthermore, we observed that GABAcR inter- International Cooperations act with PNUTS and ZIP proteins. We compared S. Lummis, Department of Biochemistry, University of the expression of interacting proteins in the Cambridge, Cambridge: UK retina, mapped binding regions, and analyzed A. Vincent, Wetherall Institute, University of Oxford, Ox- their 3D-structure. Based on these studies, we ford: UK

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 15 PRECLINICAL INSTITUTES

Institute of Biochemistry – Emil-Fischer-Center Chair of Biochemistry and Pathobiochemistry

Address Research SoxE Proteins Fahrstraße 17 Project manager: Prof. Dr. M. Wegner 91054 Erlangen Transcription factors as regulators of Transgenic mouse models have shown that the Phone: +49 9131 8524621 neural development three closely related group E Sox proteins, Sox8, Fax: +49 9131 8522484 Several groups are interested in the characteri- Sox9, and Sox10, have numerous functions www.biochem.uni-erlangen.de zation of transcriptional regulators that partic- during nervous system development. Sox9 and ipate during development of the mammalian Sox10 are essential for survival and pluripoten- Head of Department nervous system in determination and differen- cy of neural crest stem cells, the source for most cells of the peripheral nervous system. Sox9 Prof. Dr. rer. nat. Michael Wegner tiation of neural stem cells to glia and neurons. and Sox10 furthermore determine which de- Work is mainly focused on transcription factors rivatives develop from neural crest stem cells. Contact of the Sox protein family and their interacting In Sox10-deficient mice, glial cells are missing Prof. Dr. rer. nat. Michael Wegner partners. Analysis of these transcription factors from the peripheral nervous system. The enter- Phone: +49 9131 8524620 will lead to a better understanding of develop- ic nervous system is completely absent. mental defects, tumor formation, and regener- Fax: +49 9131 8522484 In the central nervous system, Sox9 and Sox10 ative processes in the nervous system. [email protected] regulate several steps in gliogenesis. Sox9 is responsible for the specification of neural stem Research Focus SoxC Proteins cells into oligodendrocytes, whereas Sox10 •• Transcription factors as regulators of neural Project manager: PD Dr. E. Sock guides terminal differentiation and myelination development All SoxC proteins occur according to our own in oligodendrocytes as a direct activator of mye- •• SoxC Proteins data in many tissues and organs during embryo- lin genes. During the period between specifica- •• SoxD Proteins genesis. Whereas loss of Sox4 or Sox11 leads tion and terminal differentiation, oligodendro- •• SoxE Proteins to severe developmental defects (such as heart cyte development is jointly regulated by Sox9 •• Signal transduction processes at the forming and outflow tract malformations, B-cell matu- and Sox10. Functional support comes from the neuromuscular synapse ration defects, asplenia, skeletal malformations, related Sox8 which is co-expressed at lower lev- and hypoplasias of several organs), Sox12 dele- •• GCM proteins as switches in organ develop- els. Their mode of action includes recruitment tion remains without obvious phenotypic con- ment of the basal transcription machinery in a medi- sequences in the mouse. Despite of the strong ator-dependent manner as well as interactions •• b-thymosins, substrates of transglutaminases expression of all three SoxC proteins in the with chromatin-remodeling complexes. during blood coagulation, angiogenesis, developing nervous system, neural defects be- Functions of group E Sox proteins were not wound healing, and apoptosis come visible only upon combined deletion of only obvious in transgenic mouse models, but are equally reflected in human disease. Hete- Structure of the Department more than one SoxC protein. Nervous system defects are predominantly caused by changes rozygous haploinsufficient Sox10 mutations in proliferation and apoptosis. Overexpression lead to Waardenburg-Hirschsprung disease, The Chair of Biochemistry and Pathobiochem- studies in the mouse have, however, also point- whereas dominant-negative heterozygous mu- istry, the Chair of Biochemistry and Molecular ed to an influence of SoxC proteins on neural tations present as a combination of Waarden- Medicine, and the Professorship of Bioinfor- maturation. burg-Hirschsprung disease, peripheral neurop- matics constitute the Institute of Biochemistry. athy, and central leukodystrophy. They are furthermore part of the Emil-Fischer- SoxD Proteins Center which in addition harbors the Institute Signal transduction processes at the Project manager: Prof. Dr. C. Stolt of Experimental and Clinical Pharmacology forming neuromuscular synapse The three closely related SoxD proteins Sox5, and Toxicology (Faculty of Medicine), the Project manager: Prof. Dr. S. Hashemolhosseini Sox6, and Sox13 participate as regulatory pro- Muscle-specific MuSK and Lrp4 act as the main Chair of Medicinal Chemistry, and the Chair teins in the development of several neuronal switches for synaptogenesis at the postsynap- of Food Chemistry (both Faculty of Natural subpopulations and glial cells of the nervous tic apparatus of the neuromuscular junction. Sciences). The Chair of Biochemistry and Pa- system. Own studies indicate that SoxD pro- Own work identified, among more than ten thobiochemistry employs 36 scientists and teins function as modulators of SoxE function candidates, Erbin and CK2 as binding part- technicians of whom 22 are funded by grant in glia. Both, Sox5 and Sox6, antagonize Sox9 ners of MuSK. Protein kinase CK2 furthermore money. and Sox10 during embryonic development in bound MuSK via its b subunit, phosphorylates Several groups study transcription and post- oligodendrocytes and thereby prevent preco- MuSK and thereby regulates the stability of transcriptional processes as well as b-thymo- cious specification and terminal differentiation acetylcholine (AChR) clusters. Muscle-specific sins with regard to molecular mechanisms and within this cell lineage. A similar mode of action CK2b-deficient mice are myasthenic. To iden- physiological roles in development, disease, has also been determined for SoxD proteins in tify the cause for the destabilization of AChR and regeneration of the nervous system and neural crest derivatives such as melanocytes. aggregates in CK2b-deficient muscles, their other organ systems. The technological spec- Here, SoxD proteins recruit transcriptional phenotype is compared with the one of CK2a/ trum is broad and ranges from biochemical co-repressors to the regulatory regions of those CK2a’-deficient muscles. Behavioral tests and and molecular methods to the generation and genes that would otherwise be activated by electrophysiological studies are performed and characterization of transgenic mice. SoxE proteins in a cell-specific manner. changes of transcriptome and phosphopro-

16 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) teome are determined in muscle cells deficient intracellular distribution in living cells. Surpris- International Cooperations for CK2 subunits. For the first time, the molecu- ingly, thymosin b-4 is actively transported and Dr. D. Metzger, Department of Physiological Genetics Dr. lar function of CK2 subunits at the postsynapse enriched in the nucleus. The signal sequence D. Metzger, Department of Physiological Genetics and can be determined and the contribution of responsible for the translocation into the nucle- Nuclear Signaling, University Strasbourg IGBMC, Stras- bourg: France CK2-dependent signal transduction to human us resides in the N-terminal part of the peptide. myasthenia and myopathy can be understood. Because of the size (5000 da), thymosin b-4 Dr. H. Kleinman, NIDCR, NIH, George Washington Univer- sity, Bethesda: USA was expected to freely diffuse through the nuclear pore complex into the nucleus. However, Dr. A. Goldstein, Department of Biochemistry and Molec- GCM proteins as switches in organ ular Biology, George Washington University, Washington: development when thymosin b-4 is added to permeabilized USA cells, it is evenly distributed within cytoplasm, Project manager: Prof. Dr. S. Hashemolhosseini Dr. P. Charnay, Developmental Biology Section, IBENS, Mammals contain GCMa and GCMb as mem- but excluded from the nucleus. Present studies École normale supérieure, Paris: France bers of the GCM family of transcription factors. aim at the mechanisms for the asymmetric dis- Dr. D. Meijer, Department of Genetics, Erasmus Medical GCMa is selectively expressed in placenta, kid- tribution of thymosin b-4 in cells and its impact Center, Rotterdam: The Netherlands ney, and thymus, whereas GCMb occurs exclu- on apoptosis and cancerogenesis. Dr. V. Lefebvre, Department of Cell Biology, Cleveland sively in the parathyroid gland. All GCM pro- Clinic, Cleveland: USA teins regulate differentiation as transcriptional Teaching Dr. L. Sommer, Anatomisches Institut, University Zurich, switches. Altered GCMa expression has been Zurich: Switzerland associated with pre-eclampsia and intra-uterine The Chair of Biochemistry and Molecular Med- Dr. U. Suter, Institut für Zellbiologie, ETH Zurich, Zurich: growth retardation, GCMb malfunctions with icine and the Chair of Biochemistry and Patho- Switzerland hypoparathyroidism and tumors of thyroid and biochemistry jointly organize and carry out all Dr. A. Schedl, Institute of Biology Valrose, University Nice, parathyroid glands. Current work focuses on curricular activities (lectures, seminars, practical Nice: France the role of GCMa in kidney and thymus of the courses) in biochemistry and molecular biology Dr. A. Hörnblad, Umeå Centre for Molecular Medicine (UCMM), University Umea, Umea: Sweden adult organism, particularly under pathological for students of medicine and dentistry during conditions. the preclinical phase of their studies. Similar- Dr. R. Hill, MRC Human Genetics Unit, Edinburgh Western ly, all teaching in biochemistry and molecular General Hospital, Edinburgh: Scotland b-thymosins, substrates of transglu- biology for students of molecular medicine is taminases during blood coagulation, performed by the two chairs. The Chair of Bio- angiogenesis, wound healing, and chemistry and Pathobiochemistry furthermore apoptosis contributes significantly to teaching activities Project manager: Prof. Dr. E. Hannappel in neurobiology, cell biology, and developmen- Thymosins were originally isolated from thymus, tal biology for students of molecular medicine. but do not represent thymic hormones. Thymo- Together with the Chair of Biochemistry and Molecular Medicine, it ensures the biochemical sin b-4 is now regarded as the main intracellular G-actin sequestering peptide in most mamma- training of students from the Department of Medicinal Chemistry. lian cells. Domains of thymosin b-4 were identified which are important for the interaction with G- and F-actin. Apart from this intracellular Selected Publications function of thymosin b-4, this peptide seems to Küspert M, Hammer A, Bösl MR, Wegner M (2011) Olig2 regulates Sox10 expression in oligodendrocyte precursors be a player in wound healing and inflammation. through an evolutionary conserved distal enhancer. Nu- b-thymosins are substrates of transglutaminas- cleic Acids Res, 39: 1280-93 es. Glutaminyl residues of b-thymosins can be Küspert M, Weider M, Müller J, Hermans-Borgmeyer I, cross-linked to amino groups of other mole- Meijer D, Wegner M (2012) Desert hedgehog links tran- cules. Surprisingly, these derivatives are still able scription factor Sox10 to perineurial development. J Neu- rosci, 32: 5472-80 to sequester G-actin. Blood platelets contain a high concentration of thymosin b-4. During Shakhova O, Zingg D, Schaefer SM, Hari L, Civenni G, Blunschi J, Claudinot S, Okoniewski M, Beermann F, Mi- aggregation of blood platelets, thymosin b-4 hic-Probst D, Moch H, Wegner M, Dummer R, Barrandon is cross-linked by factor XIIIa to the fibrin clot. Y, Cinelli P, Sommer L (2012) Sox10 promotes the forma- This research thus also provides insight into how tion and maintenance of giant congenital naevi and melanoma. Nat Cell Biol, 14: 882-90 small, soluble peptides can be fixed to extracellular structures by transglutaminases to promote Wahlbuhl M, Reiprich S, Vogl MR, Bösl MR, Wegner M (2012) Transcription factor Sox10 orchestrates activity of further physiological effects. a neural crest-specific enhancer in the vicinity of its gene. b-Thymosins can be labeled by fluorescent de- Nucleic Acids Res, 40: 88-101 rivatives of cadaverine. The fluorescentb -thy- Weider M, Küspert M, Bischof M, Vogl MR, Hornig J, Loy mosins are comparable to the natural b-thymo- K, Kosian T, Müller J, Hillgärtner S, Tamm ER, Metzger D, Shown is an immunohistochemical staining of peripher- Wegner M (2012) Chromatin-remodeling factor Brg1 is sins with respect to their G-actin sequestering al nerves at different developmental timepoints (getting required for Schwann cell differentiation and myelination. older from top to bottom). Nerve boundaries are marked ability. Therefore, these fluorescent peptides Dev Cell, 23: 193-201 by white stippled lines. Nearly all cell nuclei (blue) in the are novel tools to study the interaction of Wegner M (2013) Mighty bugs: leprosy bacteria turn nerves are positive for Sox10 (green). The presence of dif- b-thymosins with other proteins as well as their schwann cells into stem cells. Cell, 152: 15-6 ferent proteins (red) was analyzed in diverse mouse lines.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 17 PRECLINICAL INSTITUTES

Institute of Biochemistry - Emil-Fischer-Center Professorship of Bioinformatics

Address ed in investigating molecular interactions by a about the conformational stability and energe- Fahrstraße 17 variety of computational tools (e.g. sequence tics of an interaction that can hardly be deduced 91054 Erlangen data analysis, molecular modeling, and molec- from static structures alone. These methods are Phone: +49 9131 8524614 ular dynamics). for example applied to study the structure of Fax: +49 9131 8522484 Molecular dynamics simulations are used to herpesviral glycoproteins that are pivotal for http://www.biochem.uni-erlangen.de/ study the dynamics of viral proteins (e.g. HIV binding to the host cell and following fusion forschung/arbeitsgruppe.php?arbeitsgruppe=6 protease), the conformational transitions of hu- with the cell membrane. Furthermore, we in- man proteins (e.g. Alzheimer ab-Amyloid), or vestigate the molecular dynamics of viral regu- Head of Division the effect of covalent modifications on molecu- lator proteins and their interaction with cellular Prof. Dr. rer. nat. Heinrich Sticht lar recognition processes. Molecular modeling targets. is used to generate the structure of isolated Contact proteins or biomolecular complexes which pro- Design of novel Alzheimer drugs Prof. Dr. rer. nat. Heinrich Sticht vides the basis for a molecular understanding via computer simulations of protein Phone: +49 9131 8524614 of the effects of mutations on protein stability aggregation Fax: +49 9131 8522484 and binding properties. In addition, sequence Protein conformational diseases are unique [email protected] based methods are developed that allow an since a change in the three-dimensional struc- improved detection of functional linear interac- ture of a protein leads to a biological loss Research Focus tion motifs. Such motifs play an important role and/or gain of function. Most often, a stable •• Bioinformatics of biomolecular interactions for the interactions of numerous pathogens change in conformation involves a structural •• Host-pathogen interactions: Computational with the target molecules of their host. conversion from primarily a-helical conforma- analysis of linear interaction motifs and glo- tion with good solubility to an insoluble b-sheet bular protein interfaces in effector proteins Host-pathogen interactions: Compu- conformation. Cells have evolved mechanisms •• Design of novel Alzheimer drugs via computational analysis of linear interaction to clear these insoluble deposits; however, ter simulations of protein aggregation motifs and globular protein interfaces once clearance pathways are overloaded, these •• Application of methods from information in effector proteins proteins are deposited in the form of insoluble theory in protein-protein docking analysis Specific interactions with host proteins are intracellular inclusions or extracellular plaques. •• Molecular mechanisms of drug resistance of pivotal for a successful infection by a patho- Protein deposits or aggregates are also hall- HIV-1 protease gen. This project focuses on the prediction mark of many neurodegenerative diseases. The and structural characterization of host-patho- most prevalent neurodegenerative disease is Structure of the Department gen protein interactions using computational Alzheimer’s disease which is characterized by tools. The recognition processes either occur extracellular protein deposition of the peptide The Professorship of Bioinformatics builds to- between short sequence motifs that bind com- fragment ab from the amyloid precursor pro- gether with the Chair of Biochemistry and Mo- plementary adapter modules or between pairs tein (APP), and intracellular tau-containing fila- lecular Medicine and the Chair of Biochemistry of globular protein domains. These types of in- ments, called neurofibrillary tangles. and Pathobiochemistry the Institute of Bio- teractions do not only differ from a structural The 3D structure of the Alzheimer’s amyloid-b chemistry. The Institute of Biochemistry consti- point of view, but also with respect to the com- (1-42) deposits revealed the overall topology tutes the interdisciplinary Emil-Fischer-Center putational tools required for their prediction of the fibrils, but gives only limited information together with the Institute of Experimental and and analysis. about the role of individual residues for fibril Clinical Pharmacology and Toxicology of the One particular problem for the prediction of formation. The latter type of information, how- Faculty of Medicine and the Institute of Phar- functional interaction motifs is the short length ever, is important for the development of novel maceutical Chemistry of the Science Faculty. of the respective sequence patterns resulting drugs that are capable of preventing aggrega- The Professorship has nine employees (seven in a large number of false-positive hits which tion or of solubilizing aggregates by targeting of them are funded by grants), including four prove to be non-functional in subsequent ex- those residues that represent the ”hot spots” of scientists and five graduate students. periments. Therefore, we aim at improving the binding affinity in the fibrillar structure. We ad- specificity of the predictions by assessing the dress this point by molecular dynamics simula- Research importance of motif-specific flanking sequence tions of fibrillar ba 42 oligomers and thermody- regions. In order to further increase the relia- namic analyses of the aggregation interfaces. In Bioinformatics of biomolecular bility of the predictions, modeling of sequence addition, we investigate the effect of different interactions motifs in complex with the respective adapter solvent environments on the conformational Protein-protein interactions play a crucial role domains is performed, thus allowing for judg- stability of such ab42 oligomers. for the transduction of information in biological ing the likelihood of an interaction based on a Another aspect of the project focuses on the signaling pathways. The identification of the three-dimensional structure. molecular modeling of Abeta in complex with underlying principles of molecular recognition For the analysis of host-pathogen interactions different ligands. These ligands which are ex- is important for the understanding of regulato- formed between globular proteins domains, a perimentally characterized by our collaboration ry mechanisms and for the prediction of novel, combination of molecular modeling, docking, partners were shown to block ab aggregation physiologically relevant protein interactions. and molecular dynamics simulations is used. by binding to small ab oligomers. Compu- The bioinformatics group is primarily interest- The latter technique provides information tational tools were employed to identify the

18 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Model of the Tio protein from Herpes- Protein-Protein-Docking: Relevant inter- Molecular dynamics simulations of fi - Structure of HIV-protease bound to the virus ateles (stick presentation) in com- actions in the complex structure of the brillar Amyloid-b-oligomers. a) double inhibitor Amprenavir (shown as sticks) plex with human TRAF3 (space-fi lled Dual-Specifi city Phosphatase VHR (red) stack of 2x12 ab-molecules (colored in presentation). with the SH2 domain of the STAT factor shades of blue and red) after 50 ns of 5a (green) predicted by docking. simulation. B) Hybrid compound JM169 bound to a nonameric ab-oligomer. binding site of these known ligands and also strate and resulting in a catalytically inactive Jardin C, Sticht H (2012) Identifi cation of the structural for the design of novel, more affi ne ligands. enzyme. A major problem, however, is the features that mediate binding specifi city in the recognition of STAT proteins by dual-specifi city phosphatases. J Biomol rapid development of resistance to antiretro- Struct Dyn, 29: 777-92 viral drugs resulting from mutations of amino Application of methods from Othersen OG, Stefani AG, Huber JB, Sticht H (2012) Appli- information theory in protein-protein acids in the protease. Mutations can occur at cation of information theory to feature selection in protein docking analysis a large variety of locations in HIV-protease and docking. J Mol Model (Online), 18: 1285-97 Molecular docking represents a versatile and can also confer different levels of resistance for Rücker P, Wieninger SA, Ullmann GM, Sticht H (2012) important computational method for deter- distinct inhibitors. The mechanism of most of pH-dependent molecular dynamics of vesicular stomatitis virus glycoprotein G. Proteins, 80: 2601-13 mining the structure of protein-protein com- these mutations cannot fully be explained on plexes. Despite considerable efforts during the the basis of the static three-dimensional struc- past years, a general solution to this problem tures available. Using molecular dynamics sim- is not yet within reach. One major challenge ulations, we were able to show that several is the defi nition of suitable criteria for a scor- mutations in HIV-protease affect the dynamics ing function that allows the identifi cation of a of the protein, thus decreasing the affi nity of good docking solution among many false ar- inhibitor binding. Moreover, these simulations rangements. reveal novel target sites within the protease In our group, we have adapted the concepts and should therefore facilitate the design of from information theory to treat the biological novel and more effective drugs. problem of protein-protein docking. We have developed a formalism based on the concept of Teaching mutual information (MI) to investigate different features with respect to their information con- The Professorship of Bioinformatics organizes tent in protein docking. We have also shown lectures, seminars, and practical courses in the that the MI-values of these features can suc- course program of molecular medicine and cessfully be converted into a scoring function. computer sciences. Current work includes the analysis of larger Selected Publications datasets and more sophisticated structural features to obtain a robust and widely applicable Hochdörffer K, März-Berberich J, Nagel-Steger L, Epple M, Meyer-Zaika W, Horn AH, Sticht H, Sinha S, Bitan approach. G, Schrader T (2011) Rational design of b-sheet ligands against Ab42-induced toxicity. J Am Chem Soc, 133: Molecular mechanisms of drug 4348-58 resistance of HIV-1 protease Muller-Schiffmann A, Andreyeva A, Horn AHC, Gottmann The Human Immunodefi ciency Virus (HIV) is a K, Korth C, Sticht H (2011) Molecular Engineering of a Se- creted, Highly Homogeneous, and Neurotoxic ab Dimer. member of the retrovirus family. The HIV-pro- ACS Chem Neurosci, 2: 242-248 tease is essential for replication and assem- Pötzsch S, Spindler N, Wiegers AK, Fisch T, Rücker P, Sticht bly of the virus and therefore has become an H, Grieb N, Baroti T, Weisel F, Stamminger T, Martin-Parras important target for the design of antiviral L, Mach M, Winkler TH (2011) B cell repertoire analysis identifi es new antigenic domains on glycoprotein B of agents. These drugs bind to the active site of human cytomegalovirus which are target of neutralizing the protease, thus blocking access of the sub- antibodies. PLoS Pathog, 7: e1002172

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 19 PRECLINICAL INSTITUTES

Institute of Cellular and Molecular Physiology Chair of Physiology (Vegetative Physiology)

Address systems (cell culture, heterologous expression ENaC which cause a hereditary form of severe Waldstraße 6 systems), transgenic and knock-out mice are salt-sensitive arterial hypertension (Liddle's syn- 91054 Erlangen used to study the function and regulation of drome). Phone: +49 9131 8522301 ion transport processes in native tissues and The molecular mechanisms involved in ENaC Fax: +49 9131 8522770 in the whole animal. This integrated approach regulation are still incompletely understood www.physiologie2.uni-erlangen.de provides fascinating opportunities to gain nov- and involve a complex network of regulatory el insights into physiological and pathophysio- proteins, kinases, and proteases. Proteolytic Head of Department logical mechanisms and may lead to a better activation of ENaC may be pathophysiolog- Prof. Dr. med. Christoph Korbmacher understanding of disease processes. ically relevant in the context of inflammatory kidney disease and may contribute to sodium Contact Research retention in nephrotic syndrome. The group Prof. Dr. med. Christoph Korbmacher uses a combination of electrophysiological and Phone: +49 9131 8522301 Renal epithelial ion channels molecular biological techniques to characterize Fax: +49 9131 8522770 Project manager: Prof. Dr. C. Korbmacher the functional interaction of ENaC with regu- [email protected] In the kidney and other epithelial tissues, ion latory proteins and to identify channel regions channels are involved in the highly selective that are relevant for ENaC regulation by kinas- Research Focus and regulated control of ion fluxes across apical es and proteases. Moreover, it investigates the •• Renal epithelial ion channels and basolateral membranes of epithelial cells. role of lipid microdomains ('lipid rafts') in the •• Cardiac ion channels These ion channels are important for intracellu- plasma membrane for ENaC function and its lar ion homeostasis and transepithelial electro- association with regulatory proteins. Structure of the Department lyte transport. The delicate regulation of these A better understanding of the molecular mech- ion channels is pivotal for the maintenance of anisms involved in ENaC regulation will hope- The Institute of Cellular and Molecular Physiol- a healthy ‘milieu interieur' as evidenced by se- fully provide novel insights into the physiology and pathophysiology of arterial hypertension. ogy (Chair of Physiology (Vegetative Physiolo- vere disease states that result from abnormal This ultimately may lead to new diagnostic and gy)) is housed in a teaching and research build- ion channel function. Indeed, the study of mo- therapeutic concepts. ing located centrally in Erlangen. In addition lecular mechanisms involved in epithelial ion to modern research laboratories, the building channel regulation is likely to be relevant to un- Cardiac ion channels offers a lecture hall with a capacity for 200 stu- derstand a range of diseases (e.g. cystic fibrosis, Project manager: Prof. Dr. T. Volk dents as well as seminar rooms for small group kidney stones, high arterial blood pressure, and The key interest of this group is to identify teaching and practical classes. The Institute salt wasting syndromes). cellular and molecular mechanisms that regu- makes a substantial contribution to the physiol- Acute and chronic diseases of the kidney are of- late the function and expression of cardiac ion ogy teaching of preclinical medical and dental ten associated with high blood pressure. More- channels and thereby lead to differences in ac- students and is also involved in the molecular over, the kidney is thought to play a critical role tion potential duration (APD) and contractility medicine course. The renal physiology research in the pathogenesis of essential hypertension, in the heart. group in the Institute is headed by the head a condition affecting about 50% of the pop- It is well established that regional differences in of the Institute, Prof. Dr. C. Korbmacher, the ulation over the age of 50. There is emerging APD in different areas of the heart are of great additional cardiac physiology research group is evidence that subtle damage to the kidney may importance for a normal course of repolariza- headed by an associate professor, Prof. Dr. T. compromise renal salt excretion causing salt tion. Within the left ventricular free wall, for ex- Volk. retention which may lead to arterial hyperten- ample, APD is much longer in endocardial than The research focus of the Institute is the study sion. In particular, sodium transport processes in epicardial myocytes with the consequence of renal and cardiac ion channels. This research in the distal nephron and collecting duct ap- that endocardial myocytes repolarize last, al- area is of pathophysiological relevance since an pear to be important for the long term control though they become depolarized first. Hence, inappropriate regulation of renal and cardiac of blood pressure. Therefore, it is important the wave of excitation travels from endocardial ion channels may cause arterial hypertension to understand the molecular mechanisms in- to epicardial regions, while the wave of repolar- or cardiac arrhythmias, respectively. volved in the regulation of these transport pro- ization travels in the opposite direction. The analysis of ion channels involves studies cesses. Under pathological conditions, such as cardiac at the level of the cell membrane, but also In this context, the group investigates the com- hypertrophy or failure, this well-organized se- includes aspects of cellular physiology, such plex mechanisms involved in the regulation of quence of events is altered which is thought to as protein trafficking, endocytosis/exocytosis, the epithelial sodium channel (ENaC). Ion flux contribute to the increased risk of cardiac ar- protein-protein interactions between trans- through ENaC is the rate limiting step for so- rhythmia and sudden cardiac death of patients port and regulatory proteins as well as inter- dium absorption in the aldosterone sensitive with cardiac hypertrophy or failure. An increas- actions with elements of the cytoskeleton. The distal nephron. The appropriate regulation of ing body of evidence supports the observation experimental investigation of these complex ENaC activity is critical for the maintenance of that cardiac hypertrophy or failure leads to an topics requires a range of sophisticated elec- body sodium balance and hence for the long increase in APD primarily in epicardial regions, trophysiological, cellular, molecular, and bio- term control of arterial blood pressure. This is whereas midmyocardial or endocardial regions logical methods. In addition to cellular model evidenced by 'gain of function' mutations of are less affected.

20 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Microdissected collecting duct of a mouse kidney. One prin- Isolated cardiomyocyte from a rat heart. Fluorescence dyes were used to stain nuclei in blue and actin fibers in red. cipal cell was stained with fluorescein via a patch pipette.

In order to understand the mechanisms un- course of molecular medicine. The Institute of (2012) Four subunits (abγd) of the epithelial sodium chan- derlying this region-specific effect of cardiac Cellular and Molecular Physiology contributes nel (ENaC) are expressed in the human eye in various locations. Invest Ophthalmol Vis Sci, 53: 596-604 hypertrophy, this group investigates the con- to the teaching of cellular physiology and is Nesterov V, Dahlmann A, Krueger B, Bertog M, Loffing J, sequences of cardiac hypertrophy in animal responsible for teaching the physiology of or- Korbmacher C (2012) Aldosterone-dependent and -in- models. Using the patch-clamp technique on gan systems (e.g. heart, circulation, kidney, salt dependent regulation of the epithelial sodium channel isolated myocytes from different regions of the and water homeostasis, respiration, acid-base (ENaC) in mouse distal nephron. Am J Physiol Renal Phys- iol, 303: F1289-99 left ventricular free wall of rats with ascending homeostasis, gastrointestinal physiology, hor- aortic stenosis, a decrease in the transient out- mones). In addition, the Institute contributes International Cooperations ward potassium current (Ito) was identified as to a course entitled Molecular Pathomecha- Prof. N. Bunnett, PhD, Monash University (MIPS), Mel- the primary cause underlying the increase in nisms for molecular medicine students and also bourne: Australia APD in epicardial regions. The specific impor- offers advanced practicals and thesis projects Prof. L.G. Dobbs, MD, University of California (UCSF), San Francisco: USA tance of Ito for an altered organization of repo- for these students. An overview of the subject larization in cardiac hypertrophy is underlined and its theoretical foundation is presented in Prof. Dr. M. Edwardson, University of Cambridge, Cam- bridge: UK by the observation that other ionic currents, traditional lectures which are supplemented by Prof. R. Parmer, University of California (UCSD), San Die- such as the L-type Ca2+ current, are largely un- interactive small group seminars. These semi- go: USA affected by hypertrophy. nars reinforce the topics of the lectures and Prof. J. Teulon, Université Pierre et Marie Curie, Paris: Apart from affecting the regional organization emphasize relevant clinical aspects. In practical France of repolarization, alterations in the magnitude classes, theoretical concepts are illustrated by Prof. B.C. Rossier & Prof. E. Hummler, University of of Ito indirectly influence the intracellular Ca2+ experiments and the students have the oppor- Lausanne, Lausanne: Switzerland homeostasis of ventricular myocytes. A reduc- tunity to acquire practical skills. They cover top- Prof. D. Cook, University of Sydney, Sydney: Australia tion of I leads to an increase in transmem- ics such as cardiac and circulatory physiology, to Prof. Dr. J. Loffing, University of Zurich, Zurich: Switzer- brane Ca2+ influx, a phenomenon which can ECG, blood, kidney, metabolism, respiration, land also be observed as a result of a reduction of and spiroergometry. The progress of the stu- Prof. J.-J. Cassiman & Prof. H. Cuppens, Katholieke Univer- Ito in cardiac hypertrophy, thereby suggesting dents is monitored by multiple choice exams. siteit Leuven, Leuven: Belgium a mechanism by which cellular contractility is increased. Selected Publications It is hoped that a more detailed characteriza- Stewart AP, Haerteis S, Diakov A, Korbmacher C, Edward- tion of cardiac ion channels will lead to a better son JM (2011) Atomic force microscopy reveals the architecture of the epithelial sodium channel (ENaC). J Biol understanding of the mechanisms underlying Chem, 286: 31944-52 cardiac repolarization and will help to develop Wagner M, Moritz A, Volk T (2011) Interaction of gonadal therapeutic strategies to influence the organi- steroids and the glucocorticoid corticosterone in the reg- zation of repolarization and hence prevent the ulation of the L-type Ca2+ current in rat left ventricular car- development of malignant arrhythmia. diomyocytes. Acta Physiol (Oxf), 202: 629-40 Foltz WU, Wagner M, Rudakova E, Volk T (2012) N-ace- tylcysteine prevents electrical remodeling and attenuates Teaching cellular hypertrophy in epicardial myocytes of rats with ascending aortic stenosis. Basic Res Cardiol, 107: 290 Both Chairs of Physiology (Institute of Physiolo- Haerteis S, Krappitz M, Diakov A, Krappitz A, Rauh R, Korb- gy and Pathophysiology and Institute of Cellu- macher C (2012) Plasmin and chymotrypsin have distinct lar and Molecular Physiology) jointly organize preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel. J Gen all curricular teaching of physiology (lectures, Physiol, 140: 375-89 seminars, and practical classes) for medical and Krueger B, Schlötzer-Schrehardt U, Haerteis S, Zenkel dental students and for students following the M, Chankiewitz VE, Amann KU, Kruse FE, Korbmacher C

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 21 PRECLINICAL INSTITUTES

Institute of Physiology and Pathophysiology Chair of Physiology

Address rons. The overall research spectrum ranges cific topics are sensitization by tissue acidosis, Universitätsstraße 17 from cellular and molecular biological topics inflammatory mediators, and gasotransmitters 91054 Erlangen and the microphysiology of neuronal networks as well as their intracellular signal transduction. Phone: +49 9131 8522295 to behavioral physiology and human studies, Transgenic mouse strains lacking different me- Fax: +49 9131 8522497 with the latter including microneurography, tabotropic and ionotropic receptors or ther- www.physiologie1.uni-erlangen.de functional imaging, and psychophysics in mally activated ion channels (e.g. TRPV1) are

healthy volunteers and chronic pain patients. studied. Voltage-controlled ion channels (NaV, Head of Department HCN) came in focus, because only few sub- Prof. Dr. med. Christian Alzheimer Research types decide on excitability, i.e. on generation, frequency, and propagation of action poten- Contact Neurophysiologic substrates of higher tials to the central nervous system. Neuroim- Prof. Dr. med. Christian Alzheimer brain functions/Biophysics and munology is a rapidly growing field that, for Phone: +49 9131 8522400 functions of voltage-dependent ion example, studies the interaction of substance P Fax: +49 9131 8522497 channels with the immune system which may essentially [email protected] Project manager: Prof. Dr. C. Alzheimer contribute to chronic inflammatory, including Our research focuses on the electric behavior autoimmune diseases. Research Focus of CNS neurons under normal and pathological •• Neurophysiologic substrates of higher brain conditions. Using high resolution neurophysio- Trigeminal nociception and headache functions/Biophysics and functions of voltage- logic techniques, we investigate function and generation dependent ion channels regulation of ion channels and synapses. Our Project manager: Prof. Dr. K. Messlinger •• Transduction, integration, plasticity in prima- aim is to understand fundamental neural pro- Our group is working on nociceptive mecha- ry nociceptive neurons cesses which are essential for cognitive and nisms in the cranial dura mater, the trigeminal •• Trigeminal nociception and headache gen- motor functions as well as for affective behav- ganglion, and the spinal trigeminal nucleus as eration ior and whose dysfunctions might give rise to the neurobiological basis for the generation of •• Properties of peripheral human C-fibers neuropsychiatric disorders. In particular, we are headaches. Extracellular recordings from single •• Functional imaging of brain activity by fMRI studying the following topics: afferent fibres in the isolated rodent dura mater 1) Role of activin, a member of the Transform- are performed to study the sensitivity and re- Structure of the Department ing Growth Factor b family, as a "master mol- sponse of meningeal afferents and the role for ecule" tuning glutamatergic and GABAergic receptors and ion channels which are proba- The Institute comprises one chair and two neurotransmission, and its impact on cogni- bly involved in the generation of headaches in professorships of physiology with their work tion, emotions, and neuroprotection; humans. In a similar preparation, we examine groups and two further groups led by an aca- 2) Interaction between BACE1, a crucial en- by which mechanisms the neuropeptide CGRP demic director and a professor emeritus. In ad- zyme in the amyloid cascade of Alzheimer’s is released from the cranial dura mater as an dition, the Institute houses collaborating work disease, and properties and expression of Na+ indicator for trigeminovascular activation. Us- groups from the Departments of Medicine I and K+ channels; ing immunohistochemical and molecular bi- and IV, Anesthesiology, and Neurology of the 3) Role of microtubule-associated tau protein in ological methods, we aim at detecting the UK Erlangen. In the context of long-standing synaptic function; intracellular signal pathways that are induced scientific collaborations, the Institute regularly 4) Neurophysiologic mechanisms of deep brain by these substances. To study the central pro- welcomes guest scientists from the USA, Japan, stimulation in Parkinson’s disease. cesses of headache generation, we examine Czech Republic, Hungary, and Romania who the response properties of neurons in the spinal often stay for extended research periods. Transduction, integration, plasticity in trigeminal nucleus, record the peripheral and A total of 80 persons works at the Institute, 20 primary nociceptive neurons central blood flow, and assess the effects of po- of them are funded by grants. The research is Project manager: Prof. Dr. P.W. Reeh tential headache therapeutics. conducted by 17 PhD/MD scientists, 35 doc- The research focuses on primary nociceptive toral students, and 19 technical assistants. neurons, their electrophysiological and neu- Properties of peripheral human The Institute has successfully integrated new rochemical responses to noxious and prurito- C-fibers work groups who study synapses and ion chan- genic stimuli and chemical mediators. Isolated Project manager: PD Dr. B. Namer nels of central nervous system neurons using preparations and cultured dorsal root ganglion Morphological and electrical properties of pe- electrophysiological and cell biological meth- cells as well as transfected cell lines are used to ripheral unmyelinated neurons (C-fibers) are ods, thereby bringing new biophysical and study action potential discharge, ionic currents, studied directly in healthy subjects and patients molecular biological expertise to the Institute. calcium transients, and release of the neuro- with painful and painless neuropathies. The fo- Many common interests and technical syn- peptides substance P and calcitonin gene-re- cus lies on nociceptors and mechanisms which ergies arise from the established groups who lated peptide. Aim is to elucidate nociceptive contribute to genesis of pain, in particular focus on pain physiology and predominantly transduction and integration of stimuli as well spontaneous neuropathic pain. The methods work on primary and secondary sensory neu- as possible pharmacological interventions. Spe- to examine C-fibers in awake humans include

22 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) non-invasive assessment of axon reflexes and from the UK Erlangen are integrated into the Prof. Dr. A. Babes, University of Bucharest, Bucharest: Romania psychophysical studies as well as microneuro- lecture series in neurophysiology to promote graphy. The main topics are: translational thinking. Prof. Dr. S. Werner, Institute of Molecular Health Sciences, ETH Zurich, Zurich: Switzerland 1) Effects of pharmacological modulation of The Institute participates with lectures, semi- Prof. Dr. V. Vlachova, Department of Cellular Neurophysi- voltage gated sodium channels on biophysical nars, and practical courses in the bachelor and ology, Academy of Sciences, Prague: Czech Republic properties of human C-fibers (microneurogra- master program "molecular medicine". Prof. Dr. H. van Brederode, University of Washington, phy und axon-reflexes), epidermal nerve fiber In addition, interdisciplinary lectures are given Seattle: USA density and altered pain sensation of humans to students of natural and technical sciences, Prof. Dr. C. Woolf, Prof. Dr. B. Bean, Harvard University, (psychophysics); to pharmacists, and to students of psychology Boston: USA 2) Microneurographic and psychophysical as- who select medicine as a subsidiary subject or sessment of C-fiber properties of patients with a main focus. For them, not only neurophysi- erythromelalgy with and without mutations in ology, but all topics of physiology are covered. voltage-gated sodium channels; 3) Microneurography of C-fibers in patients Selected Publications with painful and painless neuropathies, espe- Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun cially with small fiber neuropathy. D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D’Hooge R, Alzheimer C, Mandelkow EM (2011) Tau-induced defects in synaptic plasticity, learning, and memory Functional imaging of brain activity are reversible in transgenic mice after switching off the by fMRI toxic Tau mutant. J Neurosci, 31: 2511-25 Project manager: Prof. Dr. C. Forster Zheng F, Lammert K, Nixdorf-Bergweiler BE, Steigerwald Functional magnetic resonance imaging F, Volkmann J, Alzheimer C (2011) Axonal failure during (fMRI) is a well established method to image high frequency stimulation of rat subthalamic nucleus. J Physiol, 589: 2781-93 the activity of the human brain during the pro- Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, cessing of various stimuli and tasks. The meth- Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka od is used to identify brain regions involved F, Lasischka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, in the central processing of pain and itch. By Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani Cortical activation pattern induced by delayed onset N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert muscle soreness (DOMS). Dotted line: central sulcus, variation of the experimental paradigms, the PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, M1/S1 primary motor/sensory cortex, SMA supplemen- function of various brain regions and their con- Haberkorn U, Brownlee M, Reeh PW, Nawroth PP (2012) tary motor area, P. Lobule somatosensory association tribution in the perception of the correspond- Methylglyoxal modification of Nav1.8 facilitates nocicep- cortex. Red-yellow: higher changes in BOLD-signal dur- tive neuron firing and causes hyperalgesia in diabetic neu- ing stimulus should be determined. Common ing DOMS-related painful contraction; blue-green clus- ropathy. Nat Med, 18: 926-33 ters: higher changes in BOLD-signal during non-painful projects with the Department of Psychiatry De Col R, Messlinger K, Carr RW (2012) Repetitive activity contraction of the left quadriceps group. Strongest and and Psychotherapy analyze the central chang- slows axonal conduction velocity and concomitantly in- widespread DOMS pain-related activation was located es induced by psychogenic or emotional stress creases mechanical activation threshold in single axons of in the primary motor and sensory cortex in areas soma- the rat cranial dura. J Physiol, 590: 725-36 totopically related to the thigh (from: Zimmermann K et or by addiction. al (2012). PLoS ONE 7 (10):e47230) Kankel J, Obreja O, Kleggetveit IP, Schmidt R, Jørum E, Schmelz M, Namer B (2012) Differential effects of low Teaching dose lidocaine on C-fiber classes in humans. J Pain, 13: 1232-41 In the preclinical curricula of medicine and Vetter I, Touska F, Hess A, Hinsbey R, Sattler S, Lampert dentistry, the Institute contributes to the teach- A, Sergejeva M, Sharov A, Collins LS, Eberhardt M, Engel ing of the basics of cellular physiology and pro- M, Cabot PJ, Wood JN, Vlachová V, Reeh PW, Lewis RJ, Zimmermann K (2012) Ciguatoxins activate specific cold vides the complete education in neurophysiol- pain pathways to elicit burning pain from cooling. EMBO ogy. Besides the traditional teaching methods J, 31: 3795-808 including lectures, practical courses, and seminars, the Institute also offers internet-based International Cooperations seminars. Half of the practical courses are held Dr. I. Vetter, Institute of Molecular Bioscience, St. Lucia: in a contiguous time block which is highly ap- Australia preciated by the students. The positive evalua- Prof. Dr. J. Olesen, Glostrup Hospita, Copenhagen: Den- mark tion of the practical courses is also due to the continuous up-grade of the experimental set- Prof. Dr. P. Kemppainen, Institute of Dentistry, University of Turku, Turku: Finland ups thanks to funds provided by the students’ Prof. Dr. P. McNaughton, University of Cambridge, fees. To bridge the gap between preclinical Cambridge: UK education and clinical work, elective seminars Prof. Dr. K. Mizumura, College of Life and Health Sciences, on the neurobiological principles of neuropsy- Chubu University Kasugai, Kasugai: Japan chiatric diseases are offered on a regular basis. Prof. Dr. E. Jørum, Department of Clinical Neurophysiolo- Furthermore, presentations by clinical experts gy, University of Oslo, Oslo: Norway

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 23 CLINICAL THEORETICAL INSTITUTES

Institute and Outpatient Clinic of Occupational, Social, and Environmental Medicine Chair of Occupational and Social Medicine

Address materials” of the Commission of the Investiga- of the Environment and Public Health and the Schillerstraße 25/29 tion of Health Hazards of Chemical Compounds German Federal Environment Agency. 91054 Erlangen in the Work Area of the DFG and houses the Phone: +49 9131 8522312 scientific offices of these work groups. Dermatoxicology Fax: +49 9131 8522317 Next to this, the Institute is in charge of the At the Institute different research projects deal www.arbeitsmedizin.uni-erlangen.de German External Quality Assessment Scheme with procedures to determine dermal penetra- (G-EQUAS) which has been carried out since tion of chemicals and standardize preclinial skin Head of Department 1982 on behalf of the German Association for damages. Prof. Dr. med. Hans Drexler Occupational and Environmental Medicine All the scientific projects focussing on skin pen- (DGAUM). etration examine influence factors of dermal Contact The laboratories of the Institute serve as refer- penetration by using in vitro models (static Prof. Dr. rer. nat. Thomas Göen ence laboratories for G-EQUAS and other qual- diffusion chamber, microdialysis on freshly ex- Phone: +49 9131 8526121 ity assessment schemes worldwide. cidized human skin) and in vivo models (micro- Fax: +49 9131 8522317 dialysis of volunteers). These projects are sup- [email protected] Research ported by the DFG and the German employer's liability insurance association. Furthermore one Research Focus Work related health research work group of the Institute deals with the eval- •• Work related health research Manifest diseases, resulting from chronic ex- uation of skin penetration for the establishment •• Population related health studies posure at work, often cause substantial so- of occupational medical threshold values for •• Dermatoxicology cial-medical problems. Therefore, the Institute the Commission of Investigation of Health Haz- •• Molecular markers of exposure to hazardous carries out field studies at the work place which ards of Chemical Compounds in the Work Area substances aim at detecting physiological and pathophysi- of the DFG. The ad hoc group ”skin absorp- •• Psychomental occupational medicine ological changes long before manifest diseases tion” has developed a systematic approach for •• Quality assurance of biomonitoring methods appear. Questions always arise when new tech- labeling hazardous substances which is highly •• Quality assurance of health promoting ac- nologies or working materials are introduced. recognized on an international level. This work tions For example new welding techniques used in group also labels chemical substances with a the aluminum processing industry or the re- skin designation in Germany. Structure of the Department placement of classical solvents by alternative Additionally, procedures to early diagnose pre- solvents are named here. Furthermore allergi- clinical skin damages and irritations, like the Er- The Institute and Outpatient Clinic of Occu- cally mediated diseases at the workplace are langer Skin-Score, are developed and validated. pational, Social, and Environmental Medicine still a problem although hygienic conditions belongs to the clinical theoretical institutes of have been clearly improved. Therefore, an im- Molecular markers of exposure to haz- the FAU. portant focus for the Institute is on the assess- ardous substances The Institute has 45 employees (21 of them are ment of exposure and on the effect of toxic, This research area develops and validates pro- financed by third-party funds). Research is car- mutagenous, and sensitizing working mate- cedures for the quantitative assessment of ried out by twelve PhD scientist, five PhD stu- rials. Many qualified field studies determine molecular markers of individual exposure to dents, and eleven technical assistants. cutaneous absorption by carefully considering hazardous substances (exposure monitoring), Different work groups develop molecular mark- the data of ambient monitoring (air pollution for the disposition for hazardous substances ers of exposure to hazardous substances as well and dermal exposure) and biomonitoring with in the metabolism (susceptibility monitoring), as procedures to quantify skin penetration of regard to the workplace conditions. These and the effects of hazardous substances (bio- hazardous substances. They also standardize studies are often carried by the Gesetzliche logical effect monitoring). A special focus is on diagnostical premedical findings. Furthermore, Unfallversicherungsträger (German Social In- the biological effect monitoring which particu- the Institute examines work-related exposure surance) or the German Ministry of Labor and larly quantifies reaction products of mutagen- of employees and the exposure of the general Social Affairs. ous substances, covalently bound as adducts population within the framework of population to macromolecules, like proteins or DNA. The studies. Population related health studies valency of the single biomarkers is examined The department of the medical officers for the Environmental medicine relates to occupation- in studies which give information about the FAU is located at the Institute. Its doctors car- al medical questions by critically proving ex- specificy, sensitivity, and toxicokinetic behavior ry out the preventive medical checkups of all posure and its possible effects. The Institute in of the different parameters. the university’s employees and students. They particular has to offer fast and adequate help if An important pre-requisite for sensitive and also advice the heads of FAU and UK Erlangen the public is postulated with high exposure to specific biomonitoring is the use of very sen- in terms of occupational health protection and chemical agents, like PCB in schools, phthalates sitive and molecular-structural distinguishing offer measures for health promotion. in pharmaceuticals/toys, or aromatic amines in analyzing techniques. The Institute therefore The Institute directs the work groups „Bio- clothes. These studies are often carried by the possesses excellent technical equipment which logical limit values” and „Analysis in biological local authorities, the Bavarian State Ministry is modernized on a regular basis. Gas chroma-

24 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) tographic techniques as well as high perfor- for these programs is to assess the consistency mance liquid chromatographic systems which and feasibility of their objectives. Other tasks are particularly connected to one-dimensional are to evaluate the applied measures, their suit- and multiple-dimensional mass spectrometry ability, and efficiency and to rate their sustain- (GC-MS/MS and LC-MS/MS) and to modern ability in general. analytical techniques for the determination of metals in body fluids (GF-AAS und ICP/MS) be- Teaching long to the equipment. Since 2006, Prof. Dr. H. Drexler has been Dean Psychomental occupational medicine of Students for graduates in the clinical area. This work group deals with evidence-based The science of occupational, social, and envi- examinations of interventions after psychic ronmental medicine (lecture, field work, and traumatization caused by extreme situations at E-learning) is based on the Medical Licensure work. This concerns not only combat mission Act. There is a cross section coordination of Q3 forces and disaster relief forces, but also em- and Q10. ployees of the police, bank, retail, healthcare, and public transport sector. Important and Selected Publications necessary components of preventive concepts Eckert E, Schmid K, Schaller B, Hiddemann-Koca K, Drexler are the immediate and fast acute care of those H, Göen T (2011) Mercapturic acids as metabolites of alkylating substances in urine samples of German inhabitants. affected in order to cope with psychic traumati- Int J Hyg Environ Health, 214: 196-204 Psycho-social acute care of an employee from the public zation and to prevent manifest diseases. Göen T, Dobler L, Koschorreck J, Müller J, Wiesmüller GA, transport sector (© VBG) A recent research project of the Institute inves- Drexler H, Kolossa-Gehring M (2011) Trends of the inter- tigates how far these concepts are scientifically nal phthalate exposure of young adults in Germany--follow-up of a retrospective human biomonitoring study. Int evident by examining the psycho-social acute J Hyg Environ Health, 215: 36-45 care of employees from the public transport Weistenhöfer W, Baumeister T, Drexler H, Kütting B (2011) sector after accidents, suicides, and attacks. How to quantify skin impairment in primary and secondary prevention? HEROS: a proposal of a hand eczema score Quality assurance of biomonitoring for occupational screenings. Br J Dermatol, 164: 807-13 methods Göen T, Schaller KH, Drexler H (2012) External quality assessment of human biomonitoring in the range of envi- On behalf of the German Association for Oc- ronmental exposure levels. Int J Hyg Environ Health, 215: cupational and Environmental Medicine, the 229-32 Institute currently organizes the most compre- Korinth G, Schaller KH, Bader M, Bartsch R, Göen T, Ross- hensive external quality assessment scheme bach B, Drexler H (2012) Comparison of experimentally determined and mathematically predicted percutaneous worldwide for the evaluation of occupation- penetration rates of chemicals. Arch Toxicol, 86: 423-30 al and environmental biomarkers. The 50th Korinth G, Wellner T, Schaller KH, Drexler H (2012) Po- round robin test of G-EQUAS was finished with- tential of the octanol-water partition coefficient (logP) to in the report period. At the moment G-EQUAS predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions. Toxicol Lett, 215: 49-53 comprises 151 analysis parameters; 150 to 200 laboratories worldwide (2/3 international) take International Cooperations part in G-EQUAS every six months. A. LeBlanc, Institut National de Santé Publique du Québec, INSPQ, Centre de Toxicologie, Québec: Canada Quality assurance of health promoting Dr. T. Berman, Department of Environmental Health, Israel actions Ministry of Health, Jerusalem: Israel Within the framework of company health Dr. J. Cocker, Health and Safety Laboratory (HSL), Buxton: management, companies often offer and im- UK plement measures which support the health Prof. P. Grandjean, MD, Harvard School of Public Health, resources and wellbeing of the employees. The Boston: USA Institute develops concepts to examine the ef- P. J. Parsons, PhD, Department of Health (DOH), State of fectivity and sustainability of health promotion New York, Albany: USA in companies and uses them in practice. The Research Equipment evaluation concepts are developed and implemented for individual companies or networks Sciex API 2000, LC-MS/MS-System like ”Erlanger model of workplace health pro- Agilent, GC-MS/MS System 7000 motion” or ”Medical Valley” (program for the Agilent, ICP-MS System 7500 cx region of Nürnberg-Fürth). One evaluation task

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 25 CLINICAL THEORETICAL INSTITUTES

Institute of Experimental and Clinical Pharmacology and Toxicology Chair of Pharmacology and Toxicology

Address Clinical Pharmacology and Clincal Toxicology, and a strongly enhanced If. HCN2 and HCN4 Fahrstraße 17 a drug information service is provided for cli- were the predominantly expressed subunits in 91054 Erlangen nicians of the UK Erlangen as well as for physi- healthy and hypertrophied hearts. Unexpect- Phone: +49 9131 8522771 cians in private practice. edly, only HCN1 was significantly upregulated Fax: +49 9131 8522774 in response to hypertrophy. Nevertheless, the www.pharmakologie.uni-erlangen.de Research combined deletion of HCN2 and HCN4 dis-

rupted ventricular If completely. The lack of If Head of Department Mechanisms of cardiac pacemaking in hypertrophic double-knockouts resulted in Prof. Dr. med. Andreas Ludwig Project managers: PD Dr. J. Stieber, Dr. S. Herr- a strong attenuation of pro-arrhythmogenic mann, Prof. Dr. A. Ludwig parameters since action potential prolonga- Contact The complex mechanisms of rhythmogenesis tion was significantly decreased and length- Prof. Dr. med. Andreas Ludwig in the sinoatrial node are examined by using ening of the QT interval was reduced. We sug- Phone: +49 9131 8522220 various knock-in and knock-out mouse models. gest that the strongly increased HCN channel Fax: +49 9131 8522774 Principally two different mechanisms of cardiac activity in hypertrophied myocytes prolongs [email protected] pacemaking are currently discussed including the repolarization of the ventricular action po- ion channel-dependent processes as well as tential and thereby increases the arrhythmo- Research Focus cytoplasmic Ca-dependent mechanisms. Both genic potential. •• Mechanisms of cardiac pacemaking hypotheses are studied by using conditional •• Ventricular hypertrophy mouse mutants. A sinoatrial deletion of the HCN channels and pain •• HCN channels and pain cardiac sodium-calcium exchanger NCX1 was Project managers: Dr. S. Herrmann, Prof. Dr. A. •• Pharmacological imaging and image analysis generated. Resulting animals display a signifi- Ludwig cantly reduced heart rate and cardiac failure. The processing of painful stimuli in the dor- Structure of the Department Ca transients and other parameters are current- sal root ganglion involves among several ion ly analyzed in sinoatrial cells of these mutants. channels probably also HCN channels. We The Chair of Pharmacology and Toxicology, In addition the role of I for generation of the found that HCN2 constitutes the predominant the Chair of Clinical Pharmacology and Clinical f spontaneous cardiac rhythm was analyzed HCN isoform in nociceptive neurons and char- Toxicology, and the Doerenkamp-Chair for In- further. We could show that beneath HCN4, acterized nociceptive-selective HCN2-knock- novations in Animal and Consumer Protection HCN1 is strongly expressed in the sinoatrial out animals. Conditional deletion of HCN2 together form the Institute of Experimental and node (low levels of HCN2 were also found). was accomplished by using the Cre/loxP-sys- Clinical Pharmacology and Toxicology. Therefore an inducible HCN triple-mutant tem (figure 1). Basal pain responsiveness of the The position of executive director of the Insti- (HCN1/2/4-KO) was generated. These mu- mutants was normal, whereas hypersensitivity tute rotates between the Chair of Pharmacol- tants display a complete lack of I in sinoatri- in inflammatory and neuropathic pain models ogy and Toxicology (Prof. Dr. A. Ludwig) and f al node cells. Remarkably, the lack of I is in- was severely reduced. This finding could be the Chair of Clinical Pharmacology and Clinical f reproduced in wildtype animals by applica- Toxicology (Prof. Dr. M.F. Fromm) on a two- compatible with life since animals die several year basis. weeks after induction and develop a deep tion of an unspecific HCN blocker, however, The Chair has a staff of 27 employees. Research bradycardia. In addition, a strong chrono- the substance had no effect in mutants. Sin- work is carried out by six PhD graduates, five tropic incompetence is observed. Action po- gle-fiber recordings from isolated inflamed postgraduate students, and five research tech- tentials recorded from isolated sinoatrial node skin-nerve preparations were performed in nicians. cells display similar changes. These results collaboration with Prof. Dr. P.W. Reeh, Insti- tute of Physiology and Pathophysiology of Main research areas are the function of various demonstrate the pivotal role of If for cardiac ion channels and exchangers (HCN channels, pacemaking. the FAU. These experiments demonstrated a calcium channels, Na/Ca-exchanger) in the significantly reduced discharge activity in mu- heart focusing on the generation of the car- Ventricular hypertrophy tants as compared to wildtype. In addition, diac rhythm and mechanisms of hypertrophy Project managers: Dr. S. Herrmann, Prof. Dr. A. the HCN-mediated mechanical sensibilization and failure. In addition, the role of HCN chan- Ludwig involves not only peripheral, but also spinal nels in the nervous system, in particular for the Cardiac hypertrophy is accompanied by re- terminals of DRG neurons. Functional MRI generation of pain, is studied. Another research programming of gene expression where the analyses (work group PD Dr. A. Hess) showed field is small animal imaging, focusing mainly, altered expression of ion channels increas- that mutant animals indeed generated less but not exclusively, on pain processing mech- es the risk of life-threatening arrhythmias. nociceptive input to various supraspinal pain anisms. The role of the depolarizing current If was processing areas. Our results demonstrated These areas are explored by combining meth- analyzed which has been recently suggest- that HCN2 channels are critically involved in ods from molecular biology, mouse genetics, ed to contribute to arrhythmogenesis in the peripheral as well as central pain sensitization. whole-animal studies, electrophysiology, and hypertrophied ventricle. Mice with induced Hence, this ion channel constitutes a novel tar- functional MRI. Research is supported by the ventricular hypertrophy showed an increased get in the therapy of neuropathic and inflam-

DFG and BMBF. Together with the Chair of number of If positive ventricular myocytes matory pain conditions.

26 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Pharmacological imaging and image icine, and pharmacy students. The pharma- analysis cology course for medical students consists Project manager: PD Dr. A. Hess of lectures and a problem-based small group In the last two years the group focused its re- tutorials. Students of molecular medicine are search on the unique superiority of functional trained by lectures, a seminar focusing on the Magnetic Resonance Imaging (fMRI) for trans- molecular mechanisms of drug actions, and lational research from mice to patients. Utiliz- various laboratory internships. ing different transgenic mice models, we were In addition, the Chair provides the complete able to reveal in cooperation with Prof. Dr. P.W. training in pharmacology for pharmacy stu- Reeh (Institute of Physiology and Pathophysiol- dents (as required to acquire the license to ogy) that ciguatoxin induces cold allodynia in practice pharmacy). This includes lectures wild-type mice which is absent in TRPA-1 defi- covering pharmacology and pathophysiology, cient mice. Ciguatoxins are activator toxins of terminology as well as seminars and laboratory sodium channels and cause the most common internships. Figure 1: NospHCN2-knockout mice lack HCN2 selective- form of ichthyosarcotxism in man. In coopera- ly in nociceptive DRG neurons (upper panels). Asterisks tion with the group of Prof. Dr. A. Ludwig, we Selected Publications mark HCN2-positive nociceptive neurons in the wildtype could demonstrate by fMRI in a neuropathic Herrmann S, Layh B, Ludwig A (2011) Novel insights into (lower panels). Boxed areas are enlarged to the right. pain model that HCN2 deficient mice show the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol, 51: 997-1006 significantly reduced mechanical hyperalgesia. Christel CJ, Cardona N, Mesirca P, Herrmann S, Hofmann The translational aspect of fMRI was strongly F, Striessnig J, Ludwig A, Mangoni ME, Lee A (2012) Dis- demonstrated in cooperation with Prof. Dr. G. tinct localization and modulation of Cav1.2 and Cav1.3 Schett (Department of Medicine 3). Investigat- L-type Ca2+ channels in mouse sinoatrial node. J Physiol, 590: 6327-42 ing the hTNF overexpressing mice as a model of Froese A, Breher SS, Waldeyer C, Schindler RF, Nikolaev rheumatoid arthritis, we could show that inflix- VO, Rinné S, Wischmeyer E, Schlueter J, Becher J, Simrick imab, an TNF antibody, provokes a very rapid S, Vauti F, Kuhtz J, Meister P, Kreissl S, Torlopp A, Liebig pain relieve within 24h after the first applica- SK, Laakmann S, Müller TD, Neumann J, Stieber J, Ludwig A, Maier SK, Decher N, Arnold HH, Kirchhof P, Fabritz L, tion. This fast and unexpected effect could be Brand T (2012) Popeye domain containing proteins are repeated in fMRI investigations of RA-patients essential for stress-mediated modulation of cardiac pace- after infliximab treatment. Solely fMRI, but no making in mice. J Clin Invest, 122: 1119-30 established clinical measure was able to objec- Hofmann F, Fabritz L, Stieber J, Schmitt J, Kirchhof P, Lud- wig A, Herrmann S (2012) Ventricular HCN channels de- tify the fast and significant reduction of pain crease the repolarization reserve in the hypertrophic heart. rating in patients. Recently, applying advanced Cardiovasc Res, 95: 317-26 graph-theoretical analyses, we were able to Vetter I, Touska F, Hess A, Hinsbey R, Sattler S, Lampert show that certolizumab, another TNF antibody, A, Sergejeva M, Sharov A, Collins LS, Eberhardt M, Engel also was able to significantly reduce activity M, Cabot PJ, Wood JN, Vlachová V, Reeh PW, Lewis RJ, Zimmermann K (2012) Ciguatoxins activate specific cold within the pain-matrix of patients. In this study, pain pathways to elicit burning pain from cooling. EMBO we were also able to differentiate anti-TNF re- J, 31: 3795-808 sponders and non-responders. This differentiation might open new ways to tailor pharmaco- International Cooperations logical treatments to individualized therapeutic Dr. M. Mangoni, Institut de Génomique Fonctionnelle, applications. In our project within the Emerging Université de Montpellier I et II, Montpellier: France Field Inititative of the FAU Neurotrition (cooper- Prof. A. Tinker, The London School of Medicine & Den- tistry, London: UK ation with Prof. Dr. M. Pischetsrieder), we discovered the ”craving” potential of potato-chips Prof. M. Boyett, PhD, School of Medicine, University of Manchester, Manchester: UK for rats. MEMRI MRI in rats fed with potato chips Prof. Dr. T. Brand, Faculty of Medicine - Cardiovascular revealed significant enhanced activity in brain Sciences, Imperial College London, London: UK areas devoted to addiction, but also locomotor Dr. H. Wakimoto, Department of Genetics, Harvard Medi- activity and a deactivation of sleep relevant are- cal School, Boston: USA as in the brain stem. Finally, we supported small Prof. C.T. Kuo, MD, Department of Cell Biology, Pediatrics animal imaging for a large variety of projects and Neurobiology, Duke University Medical Center, Dur- within the Faculty of Medicine. ham: USA

Teaching Research Equipment Figure 2: Depicted are cerebral activation patterns after Bruker, 4,7 Tesla small animal-MRT mild painful thermal stimulation for mouse (a), rat (b), and after a slight mechanical compression of the hand Pharmacology and toxicology is taught to Zeiss, confocal Laserscanning-Microscop LSM 5 for human (c). Please note the dramatic change in pro- medical students, students of molecular med- portions. The white bars in all three images indicate 1 cm.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 27 CLINICAL THEORETICAL INSTITUTES

Institute of Experimental and Clinical Pharmacology and Toxicology Chair of Clinical Pharmacology and Clinical Toxicology

Address tion service is available for the physicians of the structures, such as specific amino acids for the Fahrstraße 17 UK Erlangen and for external physicians. transport function of these transporters, was 91054 Erlangen The following topics, funded e.g. by the DFG, still limited. With the performed studies which Phone: +49 9131 8522772 the German Cancer Aid, the German Federal are funded by the DFG, we could show that Fax: +49 9131 8522773 Ministry of Health (BMG), and the BMBF, are the positive charge of certain lysine residues of www.pharmakologie.uni-erlangen.de in the focus of our studies: Uptake and efflux OATP1B3 is important for its transport func- transporters for drugs, genetic determinants tion. Using molecular modeling, we found that Head of Department of drug effects (pharmacogenomics), drug the difference in substrate spectrum within the Prof. Dr. med. Martin F. Fromm uptake in tumors, cardiovascular pharmacol- OATP-family is influenced by the pore size of ogy and risk factors, alterations of the L-argi- the different OATP members. Furthermore, we Contact nine-NO-metabolism, and safety in drug ther- showed that flavonoids which are constituents Prof. Dr. med. Martin F. Fromm apy. of food and herbal drugs are able to inhibit the Phone: +49 9131 8522772 cellular uptake of drugs mediated by hepatical- Fax: +49 9131 8522773 Research ly expressed drug uptake transporters. This is a [email protected] further mechanism for food-drug-interactions. Molecular characterization of drug Research Focus transporters Personalized drug therapy •• Molecular characterization of drug transport- Project managers: Prof. Dr. J. König, Dr. F. Project managers: PD Dr. O. Zolk, Prof. Dr. M.F. ers Müller, Prof. Dr. M.F. Fromm Fromm •• Characterization and interactions of the drug Transport proteins located in distinct mem- Marked differences in treatment effects be- brane domains are important for the uptake, uptake transporter OATP1B3 tween individual patients are frequently ob- distribution, and excretion of drugs and drug served, leading to treatment failure or en- •• Personalized drug therapy metabolites. Therefore, the molecular charac- hanced toxicity. Unlike standard therapy •• Molecular and clinical characterization of terization of drug transporters is in the focus of (‘one-size-fits-all’), personalized therapy aims therapeutic targets in the L-arginine-NO-ni- our research. at identifying clinically relevant subpopulations trate pathway Analyzing transporter-mediated drug-drug of patients for a targeted treatment. Genetic, •• Analysis of drugs and endogenous substan- interactions, we could demonstrate that oral molecular, or cellular markers are the basis for ces antidiabetic drugs or non-steroidal anti-inflam- the selection of patients suitable for a specif- •• Safety in drug therapy matory drugs not only inhibit transporter-me- ic therapy. The central topic of our research is diated statin uptake, but at low concentrations Structure of the Department the identification of (genetic) markers which also stimulate statin transport which is a new allow prediction of ‚responder’ and ‚non-re- and only partially investigated mechanism of sponder’ to a pharmacotherapy. A collabora- The Chair of Clinical Pharmacology and Clin- transporter-mediated drug-drug interactions. tive project with the Heart Center Bad Krozin- ical Toxicology constitutes together with the For the investigation of transcellular transport gen revealed an association of genetic markers Chair of Pharmacology and Toxicology and the processes and for the analysis of transporter- (polymorphisms in the drug metabolizing en- Doerenkamp-Chair for Innovations in Animal metabolism interplay, several multiple-trans- zyme CYP2C19) with the antiplatelet effect of and Consumer Protection the Institute of Ex- fected cell lines were established recombinantly clopidogrel, a frequently prescribed drug for perimental and Clinical Pharmacology and Tox- overexpressing transport proteins or transport- patients with coronary artery disease. The cur- icology. The position of the executive director ers together with metabolizing enzymes. Using rently most important field of applications for of the Institute rotates between the Chair of such a double-transfected cellular model, we personalized drug therapy, however, is cancer Pharmacology and Toxicology (Prof. Dr. A. Lud- could clarify the molecular mechanism of the treatment. The basic question of another col- wig) and the Chair of Clinical Pharmacology renal secretion of the antimalarial drug chloro- laborative research project (together with the and Clinical Toxicology (Prof. Dr. M.F. Fromm) quine. Department of Otorhinolaryngology, Head and on a two-year basis. In cooperation with Dr. A. Birkenfeld (Char- Neck Surgery, UK Erlangen) was whether the 31 persons are working at the Chair with 14 of ité, Berlin) we characterized the human sodi- expression of transport proteins in tumor tis- them being funded by extramural sources. Re- um-coupled citrate transporter NaCT which is sue correlates with the efficiency of anticancer search is conducted by eight scientists, three of now under further investigations regarding its drugs and thus survival of patients with head- them being specialists in clinical pharmacology, possible role for drug therapy. neck squamous cancer. ten MD or PhD students, and eight technicians. The groups at the Chair of Clinical Pharmacol- Characterization and interactions of Molecular and clinical characterization ogy and Clinical Toxicology investigate mech- the drug uptake transporter OATP1B3 of therapeutic targets in the L-argi- anisms underlying interindividual differences Project manager: PD Dr. H. Gläser nine-NO-nitrate pathway in drug effects using molecular and cellular bi- The clinical relevance of hepatically expressed Project manager: Prof. Dr. R. Maas ology as well as clinical studies. The Chair has OATP uptake transporters for drug action and A major focus of the group is the experimental excellent opportunities for drug analytics and elimination is already well understood. How- and clinical characterization of new cardiovas- a clinical trial unit. In addition, a drug informa- ever, the understanding of certain molecular cular risk factors as potential targets for thera-

28 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) peutic intervention. Presently we study the reg- addition, problems of safety of drug therapy in ulation of the L-arginine-NO-nitrate pathway elderly patients are in the focus of collaborative by endogenously formed compounds, such as projects (see figure). ADMA and SDMA and the metabolic fate and transport of these compounds. For in vitro and Teaching in vivo investigations, new isotope and mass spectrometry-based methods are developed. The Chair coordinates the interdisciplinary Collaborating with the Department of Medi- lecture series and seminar Clinical Pharmacol- cine 4 in an intramural IZKF-project, we cur- ogy/Pharmacotherapy for medical students rently investigate alternative pathways for the applying problem-based learning. In addi- Analysis of the medication at discharge in 45,809 patients from geriatric units in Bavaria. The figure also metabolism of methylarginines. In a DFG-fund- tion, we teach students of dental medicine, shows the proportion of patients receiving at least one ed collaboration project with the local Institute molecular medicine, pharmacy, and medical drug classified as potentially inappropriate for elderly ac- and Outpatient Clinic of Occupational, Social, process management in clinical pharmacolo- cording to the PRISCUS list (cooperation with Prof. Dr. and Environmental Medicine and the Framing- gy by lectures, seminars, and practical exer- K.-G. Gaßmann, Geriatrie-Zentrum Erlangen, and GiB- DAT). ham Heart Study in the USA, we currently ex- cises. Students of pharmacy and medicine are amine the human nitrate metabolism. welcome to work with us during their final year. Analysis of drugs and endogenous substances Selected Publications Project manager: Dr. M. Mieth Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Ju- The drug analysis unit uses samples from rczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montal- both, cell culture experiments and clinical vo A, Fischer-Rosinsky A, Spranger J, Pfeiffer AF, Jordan J, trials. Analytical methods are developed, op- Fromm MF, König J, Lieske S, Carmean CM, Frederick DW, Weismann D, Knauf F, Irusta PM, De Cabo R, Hel- timized, and validated in our laboratory. The fand SL, Samuel VT, Shulman GI (2011) Deletion of spectrum of the analytes ranges from various the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and drugs, such as pravastatin, rosuvastatin, eze- insulin resistance in mice. Cell Metab, 14: 184-95 timibe, metformin, clopidogrel, trimethoprim, König J, Glaeser H, Keiser M, Mandery K, Klotz U, Fromm and some b-lactam antibiotics, to endogenous MF (2011) Role of organic anion-transporting polypep- substances, such as derivatives of arginine and tides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos, 39: 1097-102 b-aminobutyric acid. Challenges are very low concentrations, small sample volumes, and the Mandery K, Sticht H, Bujok K, Schmidt I, Fahrmayr C, Balk B, Fromm MF, Glaeser H (2011) Functional and structural determination of an analyte in different matri- relevance of conserved positively charged lysine residues ces (e.g. lysate, plasma, urine). in organic anion transporting polypeptide 1B3. Mol Phar- macol, 80: 400-6

Safety in drug therapy Strobel J, Mieth M, Endreß B, Auge D, König J, Fromm MF, Maas R (2012) Interaction of the cardiovascular risk Project managers: Prof. Dr. R. Maas, Prof. Dr. marker asymmetric dimethylarginine (ADMA) with the hu- M.F. Fromm man cationic amino acid transporter 1 (CAT1). J Mol Cell Cardiol, 53: 392-400 An important research focus is safety in drug therapy. Here we are partners in a project Fromm MF, Maas R, Tümena T, Gaßmann KG (2013) Potentially inappropriate medications in a large cohort funded by the BMG to implement and evalu- of patients in geriatric units: association with clinical and ate measures to improve therapeutic safety in functional characteristics. Eur J Clin Pharmacol, 69: 975-84 an emergency ward. Prerequisite for this was Zolk O, Schnepf R, Muschler M, Fromm MF, Wendler O, the creation of an infrastructure that permits Traxdorf M, Iro H, Zenk J (2013) Transporter gene expression in human head and neck squamous cell carcinoma identification and recording of adverse drug and associated epigenetic regulatory mechanisms. Am J events. This infrastructure is now available for Pathol, 182: 234-43 other projects as well. We investigated new approaches to improve drug therapy safety that International Cooperations are based on the evaluation of the local risk Prof. M. Niemi, Department of Clinical Pharmacology, profile and the application of the "Paretro prin- University of Helsinki, Helsinki: Finland ciple". In addition, we developed an improved Prof. R. Vasan, Framingham Heart Study, Framingham: USA classification system for adverse drug events. As a partner in the BMBF funded cluster ”Medical Prof. C. Zoccali, CNR-IBIM and Nephrology-Transplant Unit, Ospedali Riuniti, Reggio Calabria: Italy Valley Europäische Metropolregion Nürnberg” therapeutic systems project, we currently work Research Equipment on new software and chemoinformatic data- Applied Biosystems, API 4000 MS/MS System Package bases to improve drug safety in psychiatry. In Zeiss, confocal laserscanning-Microskope LSM 5 Pascal

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 29 CLINICAL THEORETICAL INSTITUTES

Institute of Experimental and Clinical Pharmacology and Toxicology Doerenkamp-Chair for Innovations in Animal and Consumer Protection

Address vasive imaging techniques in experimental Recently, COX-inhibitors were shown to cause Krankenhausstraße 9 pain research. This approach turned out to be cardiac infarctions and accelerated artheroscle- 91054 Erlangen extremely successful. Together with Prof. Dr. rosis in certain patients. Using NT-proBNP, a Phone: +49 9131 8522292 H.U. Zeilhofer (Zurich), we could identify the new biomarker (N-terminal pro-Brain natriu- Fax: +49 9131 8526898 role of glycinergic receptors in the spinal cord retic peptide), we could show that determining www.pharmakologie.uni-erlangen.de/ for pain control. Together with Dr. J.M. Pen- the NT-proBNP level is helpful in singling out doerenkamp ninger (Vienna) and Dr. C.J. Woolf (Boston), patients at risk. we could employ this technology to identify Finally, it is helpful to connect individual data of Head of Division pain controlling genes which had been iden- patients in the clinic of internal medicine with Prof. Dr. med. Dr. h.c. Kay Brune tified in a drosophila assay system. One gene information about the drugs applied in order to turned out to be of major importance not only detect unwanted drug effects in time. Contact for pain perception, but also for synesthetic Searching for undiscovered risks of COX-inhib- Angelika Münch-Holzmeier experiences encountered by about 4% of the itors, we observed that amateur and profes- Phone: +49 9131 8522293 human population. Moreover, employing ge- sional athletes abuse these drugs in dangerous Fax: +49 9131 8526898 netically modified mice (e.g. overexpressing proportions. Several publications in German Angelika.Muench-Holzmeier@pharmakologie. TNFa), we could show that anti-TNFa-treat- print media led to a first boost of awareness. uni-erlangen.de ment in mice (overexpressing TNFa) and men These investigations will be continued. Results (rheumatoid arthritis patients) instantaneous- of this investigation are published and given in Research Focus ly relieves pain in experimental animals and the figure. •• Non-invasive functional imaging (Animal men. Protection) The successful implementation of functional Teaching •• Analgesics (Consumer Protection) MR-imaging has proven to be a successful tool for non-invasive, non-demanding animal ex- The engagement of Prof. Dr. Dr. h.c. K. Brune Structure of the Department perimentation in pain research. The activity of as speaker at international conferences and his the group will continue under the leadership membership in several administrative bodies The endowed Doerenkamp-Chair is one of of Prof. Dr. M. Uder, who has taken over the and advisory structures has led to many addi- three full professorships implemented at the administrational control of the unit devoted to tional invitations to comment on current prob- Institute of Experimental and Clinical Pharma- employ imaging techniques in experimental lems of drug therapy in man. In addition, Prof. cology and Toxicology. research involving animals. There is hope that Dr. Dr. h.c. K. Brune is engaged in the produc- The funding of the Doerenkamp-Chair will be this division will continue to flourish. tion of many national and international guide- ending on June 30, 2013. Funds, donated by lines, textbooks, etc. A sample of publications the person the chair is named after, are used to Analgesics related to these activities can be found on the finance the chair holder, one administrative/ac- (Consumer Protection) homepage of the Institute. Prof. Dr. Dr. h.c. K. ademic management person, and up to three Cyclooxygenase (COX) inhibitors (analgesics, Brune is a member of the Executive Commit- academic co-workers. In addition, there is a anti-rheumatics) are the most widely used close collaboration of this Chair with research- drugs. They are effective, but also prone to tee of IUPHAR (International Union of Basic and ers of the other two chairs. Together with these cause unwanted drug effects. Together with Clinical Pharmacology). senior scientists, grants finance currently two Prof. Dr. B. Hinz, we analyzed PK/PD of the Selected Publications post-doctoral and two doctoral collaborators. most common drugs, including acetami- The research goals of the endowed Doeren- nophen, aspirin, diclofenac, etoricoxib, ibu- Neely GG, Hess A, Costigan M, Keene AC, Goulas S, Lang- eslag M, Griffin RS, Belfer I, Dai F, Smith SB, Diatchenko kamp-Chair are pursued in close collaboration profen, lumiracoxib, etc., by applying an ex L, Gupta V, Xia CP, Amann S, Kreitz S, Heindl-Erdmann with Prof. Dr. B. Hinz (formerly senior scientist vivo technique in volunteers. We could show C, Wolz S, Ly CV, Arora S, Sarangi R, Dan D, Novatchk- at the Institute, presently chairman of the De- that acetaminophen is a selective (preferential) ova M, Rosenzweig M, Gibson DG, Truong D, Schramek D, Zoranovic T, Cronin SJ, Angjeli B, Brune K, Dietzl G, partment of Toxicology and Pharmacology at inhibitor of COX-2, associated with unrelated Maixner W, Meixner A, Thomas W, Pospisilik JA, Alenius M, the University of Rostock) and PD Dr. A. Hess serious hepatotoxicity. The data accrued are Kress M, Subramaniam S, Garrity PA, Bellen HJ, Woolf CJ, (member of the Chair of Pharmacology and presently used as argument to eliminate aceta- Penninger JM (2010) A genome-wide Drosophila screen for heat nociception identifiesa 2d3 as an evolutionarily Toxicology at the Institute). In collaboration minophen from the OTC-market. conserved pain gene. Cell, 143: 628-38 with these senior co-workers, the following re- We found that most new and old inhibitors are Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Ser- sults were achieved. chronically overdosed in most patients. With geeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns the aid of our ex vivo PK/PD analyzing concept O, Doerfler A, Brune K, Schett G (2011) Blockade of TNF-a rapidly inhibits pain responses in the central nervous sys- Research for tissue, toxicity sparing doses were devel- tem. Proc Natl Acad Sci U S A, 108: 3731-6 oped. Ruff CT, Morrow DA, Jarolim P, Ren F, Contant CF, Kaur Non-invasive functional imaging The analysis of older drugs, including (aside A, Curtis SP, Laine L, Cannon CP, Brune K (2011) Evalua- (Animal Protection) of acetaminophen) metamizol (dipyrone), tion of NT-proBNP and high sensitivity C-reactive protein for predicting cardiovascular risk in patients with arthritis One of the central aims of the endowed showed that dipyrone is overdosed under clin- taking longterm nonsteroidal antiinflammatory drugs. J Doerenkamp-Chair was to establish non-in- ical conditions. Rheumatol, 38: 1071-8

30 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Hinz B, Brune K (2012) Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Ann Rheum Dis, 71: 20-5 Renner B, Walter G, Strauss J, Fromm MF, Zacher J, Brune K (2012) Preoperative administration of etoricoxib in patients undergoing hip replacement causes inhibition of inflammatory mediators and pain relief. Eur J Pain, 16: 838-48 Küster M, Renner B, Oppel P, Niederweis U, Brune K (2013) Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study. BMJ Open, 3:e002090

Research Equipment Bruker, BioSpec 70/30 (small animal-MRT 7.0. Tesla)

Analgesics do not improve the performance during a marathon, but increase the risk of organ damage.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 31 CLINICAL THEORETICAL INSTITUTES

Institute of Forensic Medicine Chair of Forensic Medicine

Address trol of therapies applied by different hospitals Comparison of laser and mercury-arc Universitätsstraße 22 as well as medical practices. lamp for the detection of body fluids 91054 Erlangen on different substrates Phone: +49 9131 8522272 Research Project manager: Prof. Dr. S. Seidl Fax: +49 9131 8522274 The performance of two detection techniques www.recht.med.uni-erlangen.de Development and validation of for body fluids, the Spectra-Physics Reveal port- PCR-multiplex systems for forensic able forensic laser system and the mercury-arc Head of Department DNA analysis lamp Lumatec Superlite 400, was evaluated Prof. Dr. med. Peter Betz Project manager: PD Dr. T. Lederer with various biological stains on different sub- Since the beginning of the development of mo- strates. Serial dilutions of neat, 1/10, 1/100 Contact lecular methods for forensic stain analysis and and 1/1,000 using fluid semen, saliva, urine, PD Dr. rer. nat. Thomas Lederer paternity testing in 1985, in particular the PCR and blood were applied on glazed tiles, glass, Phone: +49 9131 8522294 (polymerase chain reaction)-based typing of PVC, wood, metal, stone, formica, carpet, and Fax: +49 9131 8522272 STR (short tandem repeat)-polymorphisms has cotton. Apart from the fact that blood traces [email protected] been spread around the world. Not only due were not detectable with the laser, both light to a large number of successful investigations sources showed comparable results regarding Research Focus which can be put down to the establishment their detection capability. Clear advantages of •• Development and validation of PCR-multi- of national and international databases, DNA the Lumatec Superlite 400, however, are its plex systems for forensic DNA analysis analysis can be regarded as an indispensable lower size, weight, and purchase costs as well •• Comparison of laser and mercury-arc lamp tool in forensic casework analysis. In 1998, as the possibility to operate this light source by for the detection of body fluids on different the Federal Criminal Police Office of Germany battery. substrates (BKA) established a central genetic database •• Highly sensitive simultaneous detection of of offenders and suspects to facilitate compar- Highly sensitive simultaneous detec- psychoactive drugs and their metabolites us- isons with biological samples of future criminal tion of psychoactive drugs and their ing UPLC/MS-MS offenses. metabolites using UPLC/MS-MS In our recent work, a variety of PCR-multiplex Project manager: Dr. K. Müller Structure of the Department systems was established which allows the si- The availability of the coupling of liquid chro- multaneous amplification of up to twelve auto- matography with mass spectroscopy enables The Institute of Forensic Medicine with its divi- somal STR markers. It could be shown that all more and more the finding and quantification sions forensic medicine, forensic genetics, and multiplexes are robust and reliable typing tools of uncommon analytes and the parallel detec- forensic toxicology belongs to the clinical the- for a diversity of forensic specimen and are well tion of a parent compound with phase-I- and oretical institutes of the FAU. Beside responsi- suited in the case of paternity testing. phase-II-metabolites. Such results allow in- bilities in the field of research and education, It has already been mentioned that national creasingly better estimation about acute influ- official expertises are made for other medical and international databases for genetic pro- ence, time, and frequency of consumption and facilities and by order of justice, for prosecu- files and a cross-national usage of these data if applicable to individual variants in genetic tion, and police authorities in the North Ba- are an important tool of investigations by the polymorphisms of the metabolic enzymes. varian region. Moreover - even though less police. An European-wide standardization and Especially the analysis of samples of elder peo- frequently - services are offered to private extension of the respective databases as well as ple or the suspicion of the administration of a persons, lawyers, probation officers, and in- the establishment of new typing systems is in rape drug should lead to the possible detection surance companies. Predominantly, expertises the focus of current discussions and develop- of a singular exposition. Target compounds are related to forensic investigations on injury ments. Therefore, within our work, the existing are not the classical illicit drugs, but the active patterns including crime reconstruction in the multiplex systems were expanded by five more agents of pharmaceutical products. Matrix case of domestic violence, child abuse, and STR-loci (”European recommended loci”). Fur- could be especially blood, urine, and hair. criminal assault. In the case of deceased, the thermore, population data of the new markers The purchase of an UPLC/MS-MS instrument expertises include statements on the cause have been surveyed. offers the possibility of an extremely sensi- of death as well as on specific questions (ac- Beside autosomal polymorphisms, gonosomal tive and specific analysis of a great number of cident? suicide? homicide?). Genetic analyses localized systems play an upcoming role in the compounds in different biological matrices. are carried out for clarification of personal forensic diagnostics. In particular, y-chromo- Up to now, we established sample prepara- identity, for the individual assignment of bi- somal DYS-systems have to be mentioned in tion procedures and detection routines for 48 ological specimen, and in paternity cases. this context. These systems are well qualified psychotropics and their active metabolites (i.e. Toxicological analyses are done to ascertain for stain and paternity testing. However, the sedatives, antidepressants, narcotics, antipsy- poisoning and to evaluate personal capacities basis of a further distribution of these systems chotics). Predominantly these procedures have at a definite time (fitness to drive? criminal -re will be the establishment of worldwide data- already passed an external audit. Furthermore, sponsibility?). The determination of the alco- bases containing haplotype frequencies and the simultaneous detection of opiates and their hol concentration is performed in body fluids the development of PCR-multiplex systems. Be- glucuronides and the quantification of ethyl- of dead and living persons. Many findings are cause of that reason, different analysis-systems glucuronide as a specific metabolite of ethanol used in diagnostic procedures and for the con- for these markers were established. were validated.

32 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Teaching Selected Publications Research Equipment Grobosch T, Schwarze B, Stoecklein D, Binscheck T Applied Biosystems, DNA-Sequenzer (2012) Fatal poisoning with Taxus baccata: quantifica- The Institute of Forensic Medicine performs the Waters, UPLC/MS-MS tion of paclitaxel (taxol A), 10-deacetyltaxol, baccatin III, education given by the Statutes of the Medical 10-deacetylbaccatin III, cephalomannine (taxol B), and Act (ÄAppO) for students residing in the clini- 3,5-dimethoxyphenol in body fluids by liquid chroma- cal part of the study course human medicine. tography-tandem mass spectrometry. J Anal Toxicol, 36: This includes lectures, seminars, and specific 36-43 activities. In addition, courses are held for stu- Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, dents of the faculty of justice and the faculty of Koesters R, Bachmann S, Betz P, Schley G, Schödel J, natural sciences as well as for medical students Willam C, Winkler T, Amann K, Eckardt KU, Maxwell P, from the University of Regensburg. Although Wiesener MS (2012) Renal Tubular HIF-2a Expression Requires VHL Inactivation and Causes Fibrosis and Cysts. research associations with other facilities of the PLoS ONE, 7: e31034 university do not exist in the classical sense due Wiest I, Alexiou C, Kuhn C, Schulze S, Kunze S, Mayr D, to the specific character of the subject "foren- Betz P, Jeschke U, Dian D (2012) Expression of different sic medicine", many smaller cooperations with carbohydrate tumour markers and galectins 1 and 3 in clinical and theoretical disciplines are main- normal squamous and malignant epithelia of the upper aaerodigestive tract. Anticancer Res, 32: 2023-9 tained. Furthermore students are welcome during the whole year to sit in on autopsies, Grobosch T, Schwarze B, Felgenhauer N, Riesselmann B, Roscher S, Binscheck T (2013) Eight cases of fatal and court trials, and practical courses in the field of non-fatal poisoning with Taxus baccata. Forensic Sci Int, forensic analytic. 227: 118-26

Luminescence signals of different blood-dilutions on carpet using the reagents “Bluestar” (left) and “Luminol” (right)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 33 CLINICAL THEORETICAL INSTITUTES

Institute of Medical Informatics, Biometry, and Epidemiology Chair of Medical Biometry and Epidemiology

Address with the help of classical boosting techniques. titude, and behavior regarding skin cancer risk Waldstraße 6 For example, a new boosting algorithm for factors and sun protection. 91054 Erlangen modeling ordinal outcomes was developed. Phone: +49 9131 8522750 The suggested algorithm can e.g. be used to Cooperative epidemiological and Fax: +49 9131 8522721 predict cancer stages (measured on an ordinal clinical studies www.imbe.med.uni-erlangen.de scale) using small sets of marker genes that This area of activity comprises diverse research are automatically selected by the boosting topics addressed in cooperation with different Head of Department algorithm. Classical boosting methods were departments and institutes. Usually, biometri- Prof. Dr. rer. nat. Olaf Gefeller further extended to generalized additive mod- cal aspects of study design and statistical anal- els for location, scale, and shape (GAMLSS). ysis have been performed by our institute in Contact GAMLSS are a popular statistical approach for these cooperative projects. The most important Prof. Dr. rer. nat. Olaf Gefeller simultaneously modeling multiple parameters projects in the reporting period include: Phone: +49 9131 8522750 of a response distribution in regression mod- • A cross-sectional study in the field of occupa- Fax: +49 9131 8522721 els. Current fitting procedures for GAMLSS are tional medicine addressing the association be- [email protected] infeasible for high-dimensional data setups tween exposure to CS2 in the viscose industry and require heuristic (or potentially biased) and a number of neurological and cardiovascu- Research Focus feature selection methods. The new algorithm lar endpoints; •• Computational Biostatistics allows for simultaneous estimation of predic- • A study coordinated by the Institute of Bio- •• Dermatoepidemiology tor effects and feature selection in GAMLSS. medicine of Aging regarding risk factors of frail- •• Cooperative epidemiological and clinical In the course of the project, boosting meth- ty and sarcopenia; studies ods were further analyzed with regard to their • A multi-centric European studying on "Accel- general performance as optimization method erated Partial Breast Irradiation", a controlled Structure of the Department for AUC-based performance criteria in classifi- clinical trial on the multimodal therapy of rec- cation and survival analysis. tal cancer (CAO/ARO/AIO-04), and a controlled The Institute comprises the Chair of Medical clinical trial on radiochemotherapy in patients Informatics (Prof. Dr. H.U. Prokosch) and the Dermatoepidemiology with locally advanced head/neck tumors stage Chair of Medical Biometry and Epidemiolo- Project managers: Prof. Dr. A. Pfahlberg, Prof. III and IVA-B (PACCIS), all chaired by the Depart- gy. Staff of the chair of Medical Biometry and Dr. W. Uter ment of Radiation Oncology of the UK Erlangen; Epidemiology includes 14 scientists (seven In clinical contact allergy research, a close co- • The multi-centric "German Chronic Kidney post-docs, seven doctoral students) and two operation with the German contact dermatitis Disease Study (GCKD)", funded by the BMBF further employees. Of all staff positions, six are group (DKG) e.V. and the multi-centric project and the "Kuratorium für Heimdialyse"; financed by external funds. information network of department of derma- • The implementation of the "German Weight Different working groups address biostatistical tology (IVDK), maintained by an institute at the Maintenance" registry and biostatistical sup- methods and epidemiological research. More- University of Göttingen, has been established. port of a multi-center study on the therapy of over, the Chair cooperates with various clinical Pooled data collected in the participating al- eating disorders (INTERBED), chaired by the researchers. A computing cluster with 36 nodes lergy departments are analyzed in terms of Department of Psychiatry and Psychotherapy is available as infrastructure for computer-in- contact allergy surveillance, i.e. early detection of the UK Erlangen; tensive biostatistical simulation studies. of trends in contact allergy (increase, possibly • The multicenter POLYPROBE Study examines in particular subgroups) and for quality con- the expression of 61 marker genes in patients Research trol purposes. Additionally, research projects with carcinoma of the colon, using PCR. The prompt special analyses, for instance sensiti- association with UICC stages, survival, and re- Computational Biostatistics zation to common biocides and fragrances. sponse to (radio-) chemotherapy will be ana- Project managers: PD Dr. M. Schmid, Prof. Dr. Moreover, the network "ESSCA" has been col- lyzed. O. Gefeller lecting and analyzing such data on a European The statistical analysis of high-dimensional level since 2002, with the data center at the Teaching data containing large numbers of features has Chair. become increasingly important in biomedical The epidemiology of malignant melanoma and In the context of curricular teaching, the Chair practice. Consequently, statistical methods for acquired melanocytic nevi is a further research contributes to the "Querschnittsbereich I" analyzing data with complex dependency pat- interest: Acquired melanocytic nevi, surrogate (medical informatics, biometry, and epidemi- terns and for separating informative features or potential precursor of malignant melano- ology) for medical students (lecture and sem- from non-informative ones are needed. Boost- ma, are addressed by the current MONA-study inars in small groups, one contact hour each). ing is a promising statistical method to address which includes standardized assessment of stu- Moreover, this introduction to biometry and these issues. The project focuses on improving dent cohorts. In 2011, a repeat-survey ("Erlking epidemiology (lecture and seminars in small and developing boosting methodology for 2011") with parents of children at kindergarten groups, one contact hour each) is part of the data structures that cannot yet be analyzed age was performed, addressing knowledge, at- bachelor phase of the course on "molecular

34 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) medicine" together with a seminar on the prac- Prof. G.E. Eide, Haukeland Hospital, University of Bergen, tice of data analysis (two contact hours) which Bergen: Norway teaches basic programming knowledge in the Prof. A.-M. Giménez-Arnau, Hospital del Mar, IMAS, Au- tonomous University of Barcelona, Barcelona: Spain statistical programme "R". Regarding the new master course "Medical Process Management", the Chair is responsible for a part of module 2.2 "health care management II", namely "public health and evidence-based medicine" (seminar, three contact hours). For students of medicine and dental medicine, a seminar on "design and data analysis in clinical and experimental studies" is being offered twice each term. This seminar can be used by the students to discuss any statistical issues they encounter when working Distribution of 4 UICC stages in patients with colorectal at their medical thesis. As compulsory elective carcinoma in different grades of expression of the gene COL10A1, ordered by size (POLYPROBE-Study) seminar in the master part of the course "Life Science Engineering" of the technical faculty, the Chair offers a module in epidemiology. Moreover, biometry and epidemiology are part of an introductory seminar for students of information science specializing in medical informatics.

Selected Publications Schmid M, Hielscher T, Augustin T, Gefeller O (2011) A robust alternative to the schemper-henderson estimator of prediction error. Biometrics, 67: 524-35 Li J, Uter W, Pfahlberg A, Gefeller O (2012) A comparison of patterns of sun protection during beach holidays and everyday outdoor activities in a population sample of young German children. Br J Dermatol, 166: 803-10 Mayr A, Gefeller O, Prokosch HU, Pirkl A, Fröhlich A, de Zwaan M (2012) Web-based data collection yielded an additional response bias--but had no direct effect on outcome scales. J Clin Epidemiol, 65: 970-7 Schmid M, Potapov S (2012) A comparison of estimators to evaluate the discriminatory power of time-to-event models. Stat Med, 31: 2588-609 Uter W, Aberer W, Armario-Hita JC, Fernandez-Vozme- diano JM, Ayala F, Balato A, Bauer A, Ballmer-Weber B, Beliauskiene A, Fortina AB, Bircher A, Brasch J, Chow- dhury MM, Coenraads PJ, Schuttelaar ML, Cooper S, Czarnecka-Operacz M, Zmudzinska M, Elsner P, English JS, Frosch PJ, Fuchs T, García-Gavín J, Fernández-Redondo V, Gawkrodger DJ, Giménez-Arnau A, Green CM, Horne HL, Johansen JD, Jolanki R, Pesonen M, King CM, Krêcisz B, Chomiczewska D, Kiec-Swierczynska M, Larese F, Mahler V, Ormerod AD, Peserico A, Rantanen T, Rustemeyer T, Sánchez-Pérez J, Sansom JE, Silvestre JF, Simon D, Spiewak R, Statham BN, Stone N, Wilkinson M, Schnuch A (2012) Current patch test results with the European baseline series and extensions to it from the ‘European Surveillance System on Contact Allergy’ network, 2007-2008. Contact Dermatitis, 67: 9-19 Uter W, Gefeller O, Geier J, Schnuch A (2012) Methyl- chloroisothiazolinone/methylisothiazolinone contact sensitization: diverging trends in subgroups of IVDK patients in a period of 19 years. Contact Dermatitis, 67: 125-9

International Cooperations Prof. J. Duus Johansen, National Allergy Research Center, Gentofte Hospital, University of Copenhagen, Copenha- gen: Denmark

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 35 CLINICAL THEORETICAL INSTITUTES

Institute of Medical Informatics, Biometry, and Epidemiology Chair of Medical Informatics

Address sponsible for the university hospital´s routine tronic interventions on the increase of medica- Krankenhausstraße 12 operative business and its strategic information tion safety. 91054 Erlangen processing development. In the BMBF project "personalized pharma- Phone: +49 9131 8526720 cotherapy in psychiatry", a chemo-informat- Fax: +49 9131 8526754 Research ics-based approach is used, considering the www.imi.med.uni-erlangen.de/ chemical structure and physicochemical prop- Architecture of health information erties of the drugs. Based on this, a data-and Head of Division systems model-driven software module for individual- Prof. Dr. biol. hom. Hans-Ulrich Prokosch For many years, the major issue concerning the ized, optimized pharmacotherapy for psychi- design, implementation, and management of atric outpatient and inpatient care is designed Contact Hospital Information Systems (HIS) has been and developed as a prototype. Prof. Dr. biol. hom. Hans-Ulrich Prokosch the optimization of communication processes Another project implemented knowl- Phone: +49 9131 8526721 and the integration of heterogeneous depart- edge-based support functions within the pa- Fax: +49 9131 8526754 mental systems into a comprehensive HIS. To- tient data management system (PDMS) of an [email protected] day, the integration efforts go beyond the bor- intensive care unit to allow for example for ders of one institution with the goal to establish monitoring of dangerously low blood glucose Research Focus health telematics networks. Within the hospital, levels with direct feedback as text messages •• Architecture of health information systems requirements have also changed. The focus has on the DECT-phone, for the calculation and •• Medical ontologies and medical knowledge moved from simple order entry/results review trending of scores, and for quality assurance processing and medical documentation towards intelli- measures supporting the DRG-based billing in •• Evaluation of health information systems gent support for clinical pathways and work- complex ICU patients. •• Analysis, assessment, and visualization of flows with integrated electronic decision sup- medical data port functions. Evaluation of health information •• IT-infrastructure applications for medical re- Within the OPAL Health project, a wireless sen- systems search sor network for logistics has been designed and When introducing new information technolo- •• Translational cancer research developed. Furthermore, the applicability of gies, it is essential to evaluate their effect on this technology for mobile device management user satisfaction, work processes, and process Structure of the Department and transfusion safety was evaluated. costs to avoid adverse effects of these technol- Shared decision making and patient guidance ogies on medical care. Successful use of IT in The Chair of Medical Informatics and the Chair services are the main topics in the EU-project medicine may be hindered by negative user of Medical Biometry and Epidemiology togeth- eHealthMonitor. Innovative information and attitudes, user-unfriendly interfaces, and insuf- er constitute the Institute of Medical Informat- knowledge management technologies syner- ficient usability in general. ics, Biometry, and Epidemiology within the Fac- gize to bring the most adequate information to We have initiated before/after evaluation stud- ulty of Medicine of the FAU. Furthermore, the physicians, patients, and their relatives. ies in the context of the introduction of a new Chair of Medical Informatics has a secondary In addition to such grant funded projects, the patient data management system in ICU of UK affiliation within the Technical Faculty, namedly Chair of Medical Informatics also pursues and Erlangen. Further studies have used Thinking the Research Group Medicine. supports several pilot projects embedded in Aloud and Cognitive Walkthrough methods The Chair of Medical Informatics has 20 staff the SOARIAN® hospital information system en- and a small mobile usability laboratory to eval- members, with 15 of them being funded by vironment and within various health telematics uate the usability of different order entry sys- research grants. projects. tems with the formative goal to develop bet- The research projects comprise the design and ter user interfaces for such systems. Finally, we implementation of electronic medical records, Medical ontologies and medical have participated in a study financed by the the integration of clinical decision support knowledge processing Barmer Health Insurance to evaluate the usage functions into hospital information systems, The use of knowledge processing systems in of a personal electronic health record. the modeling and optimization of clinical medicine is aimed at optimizing the quality of The project Prospective Health Technology As- workflows including visualization of clinical medical care by prospective measures (decision sessment (ProHTA), part of the cluster of excel- pathways, data warehouse and data mining support and decision monitoring). lence initiative, uses simulation tools to forecast applications, concepts and architectures for in- In this context, our research projects concen- the potential impact of future technologies and tersectoral health networks as well as personal trate on knowledge modeling and the imple- their potential return on invest even before de- electronic health records for citizens, the eval- mentation of standardized knowledge modules velopment is even started. uation of electronic information systems, the for example to support drug therapy and drug use of mobile technologies in medicine, and prescription or within intensive care units (ICU). Analysis, assessment, and visualization the design of IT-infrastructures for clinical and The BMBF project "systematic optimization of of medical data translational research. the medication process in hospitals to promote An increasing amount of data is documented The head of the Chair of Medical Informatics, medication safety" uses decision-support func- electronically in clinical IT systems during rou- Professor Dr. H.-U. Prokosch, is (as Chief In- tions for early alerting of potentially hazardous tine patient care. To avoid information over- formation Officer of the UK Erlangen) also re- situations and measures the effect of the elec- load or overlooking of essential facts, appro-

36 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) priate and flexible visualization methods are Within the EFPIA-funded Innovative Medicine Schultheiss UT, Seuchter SA, Sitter T, Sommerer C, Walz required. A further important new challenge Initiative, we are partner in the EHR4CR-pro- G, Wanner C, Wolf G, Zeier M, Titze S (2012) The German Chronic Kidney Disease (GCKD) study: design and meth- for medical informatics might be the possible ject developing adaptable, reusable, and scal- ods. Nephrol Dial Transplant, 27: 1454-60 increase of the efficiency of clinical and trans- able solutions for reusing data from electronic Mayr A, Gefeller O, Prokosch HU, Pirkl A, Fröhlich A, de lational research by reusing such data for re- health record systems for clinical research. The Zwaan M (2012) Web-based data collection yielded an search projects. Current technologies support solutions are validated for different scenarios additional response bias--but had no direct effect on out- data extraction and data consolidation, but (e.g. patient identification and recruitment, come scales. J Clin Epidemiol, 65: 970-7 rarely semantic integration between diverse clinical trial execution, adverse event report- Prokosch HU, Mate S, Christoph J, Beck A, Köpcke F, Stephan S, Beckmann MW, Rau T, Hartmann A, Wullich databases, navigation in huge databases, or ing), across different therapeutic areas, and B, Breil B, Eckardt KU, Titze S, Habermann JK, Ingenerf J, appropriate visualization of their content. across several European countries. Hackmann M, Ries M, Bürkle T, Ganslandt T (2012) De- In cooperation with Harvard University Medi- signing and implementing a biobanking IT framework for cal Center, the i2b2 (informatics for integrating Translational cancer research multiple research scenarios. Stud Health Technol Inform, 180: 559-63 biology and the bedside) platform has been A special research focus for the reuse of clini- integrated with the UK Erlangen Clinical Data Ries M, Golcher H, Prokosch HU, Beckmann MW, Bürkle T cal data in the research context is the efficient (2012) An EMR based cancer diary - Utilisation and initial Warehouse and enhanced by semantic inte- IT support in the context of cancer care and usability evaluation of a new cancer data visualization tool. gration between databases und timeline-based translational cancer research. Here, we have Stud Health Technol Inform, 180: 656-60 visualization methods. It serves as a research in- designed and established a comprehensive sin- Strobel J, Jörns H, Weisbach V, Ganslandt T, Zimmermann tegration platform for several projects at UK Er- gle source framework of IT components sup- R, Eckstein R (2012) Audit on the usage of plasma derived/ langen, but also within national collaborations. recombinant coagulation factor concentrates at a German porting tissue banking, multicenter cancer tri- university hospital. Vox Sang, 103: 122-9 The project "cloud4health" aims at automat- als, cancer registration, and routine cancer care ically unlocking the information contained in documentation. International Cooperations free text, discharge summaries, and surgical While interfacing the new cancer registry da- reports for further analysis. A combined ap- Prof. Dr. K.-P. Adlassnig, Section for Medical Expert and tabase of UK Erlangen’s Comprehensive Can- Knowledge-Based Systems, Medical University of Vienna, proach of textual analysis and data warehouse cer Center with our EHR-system, we designed Vienna: Austria technologies is used and can be deployed as a a reference model for cancer documentation Prof. Dr. E. Ammenwerth, Institute for Medical Informat- cloud-based service. comprising a set of elementary documenta- ics, UMIT-University for Health Sciences, Hall: Austria tion packages, related processes within patient Prof. Dr. P. Dégoulet, Hôpital Européen George Pompidou, IT-infrastructure applications for care, quality assurance and research, respective Paris: France medical research information systems as well as interfaces to be Prof. I. Kohane, MD, PhD, i2b2 National Center for Bio- Today, medical research is often pursued within established. medical Computing, Boston: USA networked multi center structures which re- One of our publications from this project was quire efficient and safe IT-infrastructures. The awarded the Rolf Hansen prize for the best arti- Chair of Medical Informatics has designed and cle on electronic medical records at the medical established such web-based electronic data informatics Europe conference 2012 in Pisa. capture systems for many medical multicenter research projects, such as the Epidermolysis Teaching Bullosa Research Network, the Polyprobe Study, the German Weight Control Registry, and the The Endowed Chair of Medical Informatics is nation-wide Registry for Chronic Kidney Diseas- teaching medical students in the cross-section- es, GCKD. Current activities further comprise al subject medical informatics, biometry, and IT infrastructures to support biobanking and epidemiology. It further offers medical infor- single source reuse of patient data for clinical matics courses for computer science students research. The Chair of Medical Informatics is of the technical faculty and has a considerable member and active in many projects and work- teaching part in the Master course Medical Pro- ing groups of the TMF (German technology cess Management of the Faculty of Medicine and methods platform for networked medical as well as the Bachelor and Master program research) and has promoted the foundation of Medical Devices Technology of the Technical the new GMDS working group ”Use of elec- Faculty. tronic patient records for clinical research”. In this context, the Chair of Medical Informatics Within the project „EHR-based patient recruit- has mentored 22 master and diploma theses ment for clinical trials”, we have analyzed re- as well as nine bachelor theses and one term cruitment processes and currently available HIS paper in the years 2011/2012. components to support these processes within five German university hospitals. This led to Selected Publications the design of a generic architecture for EHR-integrated IT components supporting patient re- Eckardt KU, Bärthlein B, Baid-Agrawal S, Beck A, Busch M, Eitner F, Ekici AB, Floege J, Gefeller O, Haller H, Hilge R, cruitment and to the successful evaluation of Hilgers KF, Kielstein JT, Krane V, Köttgen A, Kronenberg F, this concept. Oefner P, Prokosch HU, Reis A, Schmid M, Schaeffner E,

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 37 CLINICAL THEORETICAL INSTITUTES

Institute of Medical Physics Chair of Medical Physics

Address mography (CT) where the institute has gained the IMP - a team formed of doctoral, diploma, Henkestraße 91 a world-wide leading position, the research fo- and master students - performs state-of-the-art 91054 Erlangen cuses on magnetic resonance imaging (MRI), research to further improve the technology and Phone: +49 9131 8522310 PET/MR imaging, and medical imaging pro- to assess and to validate further clinical applica- Fax: +49 9131 8522824 cessing. Selected research projects are de- tions of PET/MR hybrid imaging. Also clinical www.imp.uni-erlangen.de scribed briefly in the following. studies are scientifically supported. The spectrum of research projects encompasses devel- Head of Department Research opment of new methods for MR-based attenu- Prof. Dr. Dr. med. h.c. mult. Willi A. Kalender, ation and motion correction, development and PhD Multimodal Imaging in Pre-clinical technical integration of PET-transparent radi- Research ofrequency coils for integrated PET/MR hybrid Contact From 10/2006 to 09/2012, the DFG support- imaging, facilitation of the clinical workflow for Prof. Dr. Dr. med. h.c. mult. Willi A. Kalender, ed the Research Unit 661: ”Multimodal Im- maximization of diagnostic information while PhD aging in Pre-clinical Research” (Speaker: Prof. reducing PET/MR data acquisition time, as well Phone: +49 9131 8522310 Dr. Dr. h.c. W.A. Kalender). At the Institute of as strategies for improving the quantification of Fax: +49 9131 8522824 Medical Physics, the projected CT develop- PET data, to name just a few. In cooperation [email protected] ments, in particular for micro-CT, focussed on with the laboratory for pattern recognition, optimization of image quality at minimal dose, new methods for MR-based attenuation cor- Research Focus the implementation of dual-energy methods, rection are developed and evaluated. •• Multimodal Imaging in Pre-clinical Research and the development of tools for dynamic •• PET/MR Hybrid Imaging micro-CT. More detailed information on this 3D Imaging and Image Processing for •• 3D Imaging and Image Processing for Mus- project can be found in the section describing Musculoskeletal Applications culoskeletal Applications special research areas or major research pro- Project manager: Prof. Dr. K. Engelke jects funded by the DFG within this research The focus of the image processing activities is Structure of the Department report. the development of the 3D segmentation and analysis toolkit MIAF (medical image analysis In addition to the chair and full professorship PET/MR Hybrid Imaging framework) which is now widely used in the of Medical Physics, the Institute of Medical Project manager: Prof. Dr. H.H. Quick field of osteoporosis with the aim of improving Physics (IMP) comprises the professorship of In April 2010, the world’s first installation of a fracture prediction and monitoring treatment Magnetic Resonance Imaging (held by Prof. diagnostic system for simultaneous PET/MR effects of anti osteoporosis medication. In the Dr. H.H. Quick since 10/2009). The Institute whole-body hybrid imaging has been installed at framework of the BMBF funded project ‘Bio- employs a total of 60 persons, whereof 42 are the IMP. The hybrid system (Biograph mMR, Sie- mechanically founded individualized osteopo- financed by third-party funds. The researchers, mens AG, Erlangen) consists of a 3.0 Tesla high- rosis Assessment and treatment’ (BMBF, Bio- 30 of them doctoral students, are working on field magnetic resonance (MR) system in which Asset 01EC1005D), a 3D segmentation and a wide range of topics in the area of medical a MR compatible positron emission tomography analysis module was developed for the com- physics. The projects focus on different issues (PET) detector has been fully integrated. This plete thoracolumbar spine that includes an of the following research areas: allows for simultaneous acquisition of MR data analysis of the disk volume and the 3D shape • Computed tomography with excellent soft tissue contrast and high spa- of the vertebrae. Further areas of applications • Dosimetry and Radiation Protection tial resolution as well as of PET data providing targeted recently and partly supported by the • Magnetic Resonance Tomography high sensitivity in detecting tumor cells that have BMBF funded project ‘A Network on Clin- • Medical Imaging been labeled with a specific radiotracer. ics and Pathophysiology of Osteophytes and • Medical Image Processing This new technology is being investigated at Ankylosis’ (BMBF, Ankyloss 01EC1002D) are • Preclinical Imaging the IMP in close research collaboration with rheumatoid arthritis and osteoarthritis. The • Osteoporosis Research. the industrial partner Siemens AG and with the onset of rheumatoid arthritis is characterized An important basis for the research at the In- Department of Nuclear Medicine, the Institute by the development of bone erosions. As an stitute is fundraising: Public grants by the Eu- of Radiology, and the Department of Neurora- example, figure 2 shows an advanced erosion ropean Union, BMBF, DFG, Bavarian Research diology from the UK Erlangen. within the metacarpophalangeal joints in a pa- Foundation and cooperations with industrial The systematic technical testing (figure 1) of tient with rheumatoid arthritis along with the partners reach an amount of about one and a the system performed at the IMP was followed outer bone surface. half million Euros per year. by first clinical evaluation and validation of 100 MIAF also provides sophisticated CT-CT and The focus of the 35 ongoing research projects oncologic patients. Since July 2011, the hybrid CT-MRI registration functionalities which were and cooperations is the development and the system has been CE certified and has reached recently used to characterize bone marrow application of imaging procedures in medical medical product status. Currently (03/2013), lesions of the knee in patients with osteoar- diagnosis and image-guided therapy. Besides about 40 of such hybrid systems are installed thritis. The quantification of BMD and bone the achievements in the field of computed to- worldwide. The MR imaging research group at structure in addition to the measurement of

38 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) cartilage properties may improve the diagno- courses, the Institute regularly offers lectures Research Equipment sis of osteoarthritis, another important muscu- and seminars on special subjects of medical Siemens, Biograph mMR loskeletal disease affecting in particular large physics, medical imaging and medical image Siemens, C-Bogen-CT-Scanner Axiom Artis zeego parts of the elderly population. The next step processing, and osteoporoses research. CT imaging, Erlangen, In-vivo Micro-CT-Scanner is the incorporation of muscle properties, such An essential part of the education program at Siemens, Somatom Dual-Source CT Scanner Flash as the amount of intramuscular fat that deteri- the Institute is the supervision of diploma and orates muscle function which eventually con- master theses in different fields and of doctoral tributes to the decrease of bone strength. This studies to graduate as Dr. rer. biol. hum. work will be conducted within the research collaboration ‘Research Consortium Muscle Selected Publications Wasting (Sarcopenia) and Osteoporosis - Con- Braun H, Ziegler S, Paulus DH, Quick HH (2012) Hybrid PET/MRI imaging with continuous table motion. Med sequences of impaired tissue regeneration in Phys, 39: 2735-45 the elderly (FORMOsA)’ that recently has re- Engelke K (2012) Assessment of bone quality and strength ceived funding from the Bavarian Research with new technologies. Curr Opin Endocrinol Diabetes Foundation. Industrial partners of the IMP Obes, 19: 474-82 within Formosa are Miha Body Tech GmbH Engelke K, Stampa B, Timm W, Dardzinski B, de Papp AE, Genant HK, Fuerst T (2012) Short-term in vivo precision (Augsburg), Siemens Healthcare (Erlangen), of BMD and parameters of trabecular architecture at the and Physiomed Elektromedizin AG (Schnait- distal forearm and tibia. Osteoporos Int, 23: 2151-8 tach/Laipersdorf). The aim of FORMOsA is the Paulus DH, Braun H, Aklan B, Quick HH (2012) Simultane- development of diagnostic criteria for sarcope- ous PET/MR imaging: MR-based attenuation correction of local radiofrequency surface coils. Med Phys, 39: 4306-15 nia and their standardization in order to better Zerfass P, Lowitz T, Museyko O, Bousson V, Laouisset L, assess the effect of potential interventions in Kalender WA, Laredo JD, Engelke K (2012) An integrated combination with an experimental preclinical segmentation and analysis approach for QCT of the knee and clinical program to explore intervention to determine subchondral bone mineral density and tex- ture. IEEE Trans Biomed Eng, 59: 2449-58 strategies. Quick HH, von Gall C, Zeilinger M, Wiesmüller M, Braun H, Ziegler S, Kuwert T, Uder M, Dörfler A, Kalender WA, Teaching Lell M (2013) Integrated Whole-Body PET/MR Hybrid Im- aging: Clinical Experience. Invest Radiol, 48: 280-9 The Institute participates in the education of International Cooperations medical students in the area of medical im- Figure 2: Examples of segmented erosions. In the last aging by offering lectures and seminars. The Prof J.-D. Laredo, Assistance Hôpitaux Publique de Paris, Paris: France case, the periosteal surface had to be reconstructed man- course on the basics of medical physics includes ually due to the large cortical break. Apart from that, the Prof. J.M. Boone, Department of Radiology, UC Davis practical exercises and gives students of natural segmentation in these examples worked fully automati- Medical Center, Sacramento: USA cally. Also, in the last image, concentric VOIs (Volume sciences the opportunity to learn more about Prof. CA Mistretta, Department of Medical Physics, Univer- of Interest) for BMD (Bone Mineral Density) calculations this field of physics. Besides these elementary sity of Wisconsin, Madison: USA are shown.

Figure 1: (A) Integrated PET/MR Hybrid System (Biograph mMR, Siemens AG) at IMP. (B) MR data of a patient with bronchial carcinoma and additional metastasis. (C) PET data of the same patient that were acquired simultaneously with MR data. (D) Exact fusion of MR and PET data in a PET/MR hybrid imaging data set. MR data provides highly detailed image resolution and excellent soft tissue contrast while PET data shows accumulation of radiotracer in the tumor with high sensitivity.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 39 CLINICAL THEORETICAL INSTITUTES

Institute of the History of Medicine and Medical Ethics Chair of the History of Medicine

Address of medical ethics (e.g. medicine in NS-Germa- Case studies include the medical encyclopedia Glückstraße 10 ny, history of the Faculty of Medicine Erlangen, of Paulos Nikaios (approximately 7th/9th AD), 91054 Erlangen medical ethics in Germany after 1945). the early modern receptions of ancient illnesses Phone: +49 9131 8522308 contributed by physicians to the contempo- Fax: +49 9131 8522852 Research raneous witchcraft debate (lycanthropy, incu- www.igem.med.uni-erlangen.de bus), and early trauma concepts in 19th cen- Galen - Compendium and Catalogue of tury medicine. Head of Department Galenic Writings Prof. Dr. med. Karl-Heinz Leven Project manager: Prof. Dr. K.-H. Leven Leprosy and Vagrancy in Southern The Greek physician Galenus of Pergamum German Free Imperial Cities Contact (129 - approx. 210 AD) figures as the most Project managers: PD Dr. F. Dross, Dr. A. Kin- Prof. Dr. med. Karl-Heinz Leven influencal medical author of the Roman impe- zelbach Phone: +49 9131 8522094 rial period. A very prolific writer, the extent of Extensive research has been done on medieval Fax: +49 9131 8522852 his œuvre surpasses what remains of any other leprosaria; nevertheless, their contextualization [email protected] ancient author; his work decidedly influenced with (municipal) health care is still deficient. not only his successors in late antiquity, but This project focuses on a social group which Research Focus was of fundamental importance for all premod- is especially hard to pinpoint - vagrant lepers •• Galen - Compendium and Catalogue of ern medicine. “Galenism” profoundly shaped whose traces in archive material tied to a cer- Galenic Writings medieval science across cultural and religious tain place are particularly elusive. Extensive ar- •• Receptions of Ancient Psychopathology boundaries (Byzantium, Islamic medicine, the chival research concentrates on Free Imperial •• Leprosy and Vagrancy in Southern German Latin West), it was constitutional to Renaissance Cities (Reichsstädte) in Swabia and Franconia Free Imperial Cities medicine in the 16th century, and remained in- with the intention of establishing basic facts ur- •• Early 18th Century Medical Practice: Physi- fluential well into modern times. This research gently needed for further resarch. Furthermore, cian Johann Christoph Götz (1688 - 1733) project aims at a comprehensive depiction of this research is able to shed light on the very from Nürnberg Galenism both, in its time of emergence and its beginnings of health care policies in medieval •• Ernst Wilhelm Baader (1892 - 1962), Occu- impact on medicine in the historical contexts urban communities. pational Medicine and Nazism named. •• Medical Crime and the Social Practice of Ter- On the one hand the project is devoted to a Early 18th Century Medical Practice: ror - SS-Physicians in Concentration Camps, compendium of Galenic Medicine. On the Physician Johann Christoph Götz 1934 - 1945 other hand an annotated catalogue of all re- (1688 - 1733) from Nürnberg •• History of the Bavarian Society for Gynecolo- maining Galenic writings (approximately 400) Project manager: Prof. Dr. M.M. Ruisinger gy and Obstetrics in the 20th Century (in co- is devised to provide a much needed reference This project is part of the DFG funded research operation with the Department of Obstetrics work for scholars in the field. cluster on 17th to 19th century medical prac- and Gynecology) tices (“Ärztliche Praxis im 17.-19. Jahrhun- •• The Establishment of Medical Applications of Receptions of Ancient dert”, spokesperson Prof. Dr. Dr. M. Stolberg, X-Ray-Technology: Radiation Poisoning, Ra- Psychopathology Würzburg). It is dedicated to quantitative and diation Protection, and Radiotherapy in Early Project manager: Dr. N. Metzger qualitative analysis of the early 18th centu- 20th Century The look back to ancient medicine and its ry medical records by the hand of J.C. Götz most illustrious protagonists has been seminal which have fortunately been preserved in the Structure of the Department to physicians, their learning and identity for Trew Collection of the local university library centuries. They have drawn onto ancient texts Erlangen. His patients, their ailments and so- The Chair of the History of Medicine and the for orientation, legitimation, and distancing, cial status, furthermore his arrangements and Professorship for Medical Ethics (see separate thus using the ancient for their own purposes. contemporaneous medical knowledge can be report) constitute the Institute of the History of Madness is intertwined like no other medical brought to surface. Selected case stories espe- Medicine and Medical Ethics. It includes the Fo- concept with its cultural background, therefore cially rich in detail are closely scrutinized. rum “Medizin und Menschenrechte” (“Forum reception of ancient psychopathology is deeply on Medicine and Human Rights”), founded affected by new medical outlooks, epistemo- Ernst Wilhelm Baader (1892 - 1962), in 2006, and the Coordinating Office of the logical developments, and cultural surround- Occupational Medicine and Nazism Clinical Ethics Committee. Furthermore, the ings and can be used to line out the changing Project managers: Prof. Dr. K.-H. Leven, P. Rauh Institute harbors the Erlangen Medical Collec- faces of medicine in history. Funded by Stifterverband für die Deutsche tion. In total, the staff of the Institute consists This project focuses on reception in Byzantine Wissenschaft and Deutsche Gesellschaft für Ar- of 14 members, twelve are academic person- late antiquity, early modern times, and the 19th beitsmedizin und Umweltmedizin e.V. nel including seven part-time positions. Chair century. In all three epochs, fundamental social Directed to optimize physical performance and and Professorship cooperate in joint research and epistemological changes left their mark on work output, occupational medicine played a projects on history and contemporary history how physicians read their ancient counterparts. leading role in NS health, labor, and social pol-

40 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) icy. This project evaluates the contribution of The Establishment of Medical Applica- The lecture series “Über den Tellerrand” caters E.W. Baader, one of the dominating figures in tions of X-Ray-Technology: Radiation current research topics to a wider audience. the field during the times of Weimar Republic, Poisoning, Radiation Protection, and Invited external medical historians give insight NS, and early Bundesrepublik, in relation to its Radiotherapy in Early 20th Century into their work in the monthly “Medizinhisto- respective cultural and ideological background. Project manager: PD Dr. F. Dross rische Vortragsreihe”. Research focuses on Baader's scientific contri- The curator of the Medical Collection Erlan- bution, his leeway of choices especially in the gen is member of the advisory board for the Selected Publications NS era, his relationships with exiled Jewish col- establishment of the Siemens MedMuseum Dross F, Kinzelbach A (2011). „nit mehr alls sein burger, leagues, his reestablishment during the early (to be opened in 2014) at the Siemens Med sonder alls ein Frembder.“ Fremdheit und Aussatz in früh- neuzeitlichen Reichsstädten. Medizinhist J, 46: 1-23 days of the Bundesrepublik, and, channeling all Archiv (director: D.M. Vittinghoff) and curates the part on radiation protection and radio- Rauh P (2011) Victory for the „most enduring“ hearts: The the questions mentioned, the complex issue of treatment of physically exhausted soldiers in the German therapy. Vergangenheitsbewältigung. Drawing on so far Army (1914-1918). Neuere Med Wiss Quellen Stud, 26: 160- 82 unused archive material, the formation of Ger- Teaching man occupational medicine during Baader's K.-H. Leven: Apolls Sonne über dem Abendland. Medizin zwischen Orient und Okzident. In: Sitzungsberichte der lifetime is to be reassessed. Medical Terminology (first term students in hu- Physikalisch-Medizinischen Sozietät zu Erlangen. Neue The concluding volume will be published in Folge, Bd. 11, Heft 4. Erlangen, Jena 2011, S. 1-22. man medicine/dentistry); Querschnittsbereich K.-H. Leven, P. Rauh: E. W. Baader (1892-1962) und die early 2013. Q 2 “History, Theory, and Ethics of Medicine” Arbeitsmedizin im Nationalsozialismus. Arbeitsmedizin, (seventh term medicine) and “History of Sci- Sozialmedizin, Umweltmedizin 47 (2012), S. 72-75. Medical Crime and the Social Practice ence and Ethics” (degree program in molecular R. Wittern-Sterzel: Frauenärztinnen in der ersten Hälfte des of Terror - SS-Physicians in Concentra- medicine), Querschnittsbereich Q 7 "Medicine 20. Jahrhunderts. In: C. Anthuber, M. W. Beckmann, J. Di- tion Camps, 1934 - 1945 and Aging" in the section concerned with old etl, F. Dross, W. Frobenius (Hrsg.) Herausforderungen. 100 Project managers: Prof. Dr. K.-H. Leven, P. Rauh Jahre Bayerische Gesellschaft für Geburtshilfe und Frauen- age in past and present. heilkunde, Stuttgart: Thieme 2012, S. 47-59. This project surveys the biographical develop- Medical Terminology introduces students to N. Metzger: Wolfsmenschen und nächtliche Heimsuch- ment of SS-physicians active in German con- the specific technical language employed in ungen. Zur kulturhistorischen Verortung vormoderner centration camps between 1934 and 1945, anatomy and clinical medicine. At the same Konzepte von Lykanthropie und Ephialtes, Remscheid: Gardez Verlag 2011. focusing on their group-specific characteristics. time it aims at placing medicine in its social and Consisting of two parts, the study aims at out- historical context. Meetings and International Training lining socialization, mentality, and actions, in- History, Theory, and Ethics of Medicine includes Courses cluding their role in concentration camps on lectures dedicated to the basic principles of 26.-28.09.2011: Medizin und Technologie: XIII. Medizin- the one hand and their subsequent careers in the medical humanities while the specific skills historische Gemeinschaftstagung, Posen, Polen both German states after 1945 on the other are imparted in seminars. Teaching methods hand. In this second part of the project, a well include text interpretation, discussion of case defined group is employed to methodically histories, role play, multimedia presentations, analyze - for the first time - how both German and excursions. states dealt with these people and their crimi- Elective seminars offer further insight into historical and ethical subjects to students with nal past. special interest in the medical humanities (Wahlpflichtfach), such as "Death and Dying in History of the Bavarian Society for Cultural Perspective", Chair of History of Medi- Gynecology and Obstetrics in the cine in collaboration with the Chair of Anatomy 20th Century (in cooperation with I, furthermore “Introduction to methods and the Department of Obstetrics and objectives of medical historiography”. Semi- Gynecology) nars on selected topics close to current research Project managers: PD Dr. F. Dross, PD Dr. W. interests are offered each term, in certain cases Frobenius in conjunction with the Master Program “Mit- The Bavarian Society for Gynecology and telalter- und Renaissance-Studien” and/or col- Obstetrics (“Bayerische Gesellschaft für Ge- leagues in the Philosophical Faculty. burtshilfe und Frauenheilkunde” [BGGF]) was In addition, courses in ethics and interpersonal established in 1912. On the occasion of its cen- skills are provided as part of the Introduction tenary, this project is dedicated to the history of to Clinical Medicine. Courses range from “Skills the society focusing on its professional policy in in Ethical Communication” over “Breaking Bad 20th century Western Germany. The role of the News” and “Speaking about Death and Dying” society and its members in Nazi Germany will to “Intercultural Communication”, some of Lecture series for a wider audience on current research be highlighted as well as its dealing with this those featuring simulated patients to practice of the Institute of the History of Medicine and Medical matter afterwards. difficult communicative situations. Ethics

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 41 CLINICAL THEORETICAL INSTITUTES

Institute of the History of Medicine and Medical Ethics Professorship for Medical Ethics

Address ning of life (prenatal diagnosis, pregnancy chal- of the 1960s, even more frequent revelations Glückstraße 10 lenges, neonatology etc.) during a crisis (oncol- about unethical research on disadvantaged and 91054 Erlangen ogy, genetic advice, psychiatry, transplantation) vulnerable populations and the widely publi- Phone: +49 9131 8526430 and at the end of life (advance directives, eutha- cised Thalidomide tragedy had prompted calls Fax: +49 9131 8522852 nasia, terminal care). Some important means of for greater state regulation. In June 1964, after www.igem.med.uni-erlangen.de clinical ethics are the analysis of arguments of years of debate, the WMA adopted the Decla- applied medical ethics and bioethics, advice via ration during its General Assembly in Helsinki, Head of Division ethics committees, and empirical research. Finland. Efforts to safeguard human subjects in Prof. Dr. med. Andreas Frewer, M.A. The field ”Medicine and Human Rights” deals non-therapeutic experiments have intensified with several aspects of the relationships be- ever since the first Helsinki Declaration and are Contact tween human rights, medicine, and the biolog- now codified in many national and internation- PD Dr. phil. Lutz Bergemann ical sciences (”Dual obligations” of physicians, al laws and regulations. The implementation Phone: +49 9131 8526430 health care for migrants and „Sans Papiers”, of Institutional Review Boards (Research Ethics Fax: +49 9131 8522852 female genital mutilation, torture and medicine Committees) was a key element in that devel- [email protected] etc.). This topic is unique at a Faculty of Med- opment. The current process of revising the icine in Germany. It is grounded institutionally Declaration of Helsinki is meant to coincide Research Focus in the ”Forum Medicine and Human Rights”. with the 50th anniversary of this important doc- •• Clinical Ethics and Ethics Counseling The field ”Philosophy of Medicine and En- ument which is why it receives global attention •• Project Title: Medical Ethics and Human hancement” covers theoretical questions con- (Funding: Fondation Brocher, Wellcome Trust, Rights: Reassessing 50 Years of the Declara- cerning the concept ”disease” and medical Thyssen Stiftung). tion of Helsinki (1964 - 2014) ethical issues with respect to the increase of •• Medicine and Human Rights the life span and the enhancement of cognitive Medicine and Human Rights •• Philosophy of Medicine and Enhancement and emotional capacities. Project managers: Prof. Dr. A. Frewer, Dr. S.L. Sorgner, H. Furtmayr, M. Mylius, Dr. S. Kolb, Structure of the Department Research Dr. J. Graf, Dr. K. Krása, W. Bornschlegl This field of research bears on problems of de- The Professorship for Medical Ethics togeth- Clinical Ethics and Ethics Counseling termining the place of human dignity and hu- er with the Chair of the History of Medicine Project managers: Prof. Dr. A. Frewer, PD Dr. L. man rights in the area of medical and bioeth- constitute the Institute of the History of Med- Bergemann, Dr. F. Bruns, L. Fröhlich-Güzelsoy, ical controversy. The possibilities and limits of icine and Medical Ethics. It includes the Forum Dr. K. Krása a rights-based medical ethics and bioethics are Medicine and Human Rights ("Forum Medizin A main field of expertise of the Professorship for considered from a theoretical perspective and und Menschenrechte"), founded in 2006, and Medical Ethics is research concerning clinical several dimensions of the concepts of human the Coordinating Office of the Clinical Ethics ethics counseling whereby a close cooperation dignity and human rights are investigated in this Committee. Furthermore, the Institute harbors with the Clinical Ethics Committee is given. context. In a practical vein, this area of research the Erlangen Medical Collection. In total, 16 Theoretical groundwork and documentation of involves questions of medical investigation and employees work at the Institute, of which 14 ethics counseling and the evaluation of ethical the documentation of human rights violations, are academic personnel with eight in part-time counseling belong to this field of inquiry. Files application of the Istanbul Protocol of the Unit- positions. Chair and Professorship cooperate in of patient’s advocates are being dealt with in ed Nations to document torture, but also the joint research projects on history and contem- the project ”Clinical Ethics from the Patient’s participation of physicians in human rights porary history of medical ethics (e.g. medicine Perspective”. violations. Not least of all, it inquires into the in NS-Germany, history of the Faculty of Medi- A further field of research are end of life con- therapy and ”prophylaxis” of human rights vio- cine Erlangen, medical ethics in Germany after flicts, e.g. projects on ethical counseling, lations, such as wartime sexual violence, torture, 1945). cultures of dying and advance directives. As recruitment of children as soldiers, and female 25 doctoral theses are being supervised at the part of this field of research an annual ”Ethics genital mutilation. In connection with this area Professorship for Medical Ethics and ten aca- Day” and an intensive course ”Clinical Ethics” of research, a public lecture series is being or- demic book series are being edited. (BMBF) were organized, the ”Yearbook Ethics ganized and the academic book series ”Medi- The main areas of research are clinical ethics in Clinics” and the book series ”Clinical Ethics” cine and Human Rights” is being edited. and ethics counseling, medicine and human are being edited. rights, and the philosophy of medicine and en- Philosophy of Medicine and hancement. Project Title: Medical Ethics and Human Enhancement The field of clinical ethics deals with foundation- Rights: Reassessing 50 Years of the Project managers: Prof. Dr. A. Frewer, Dr. S.L. al ethical questions concerning the adequate Declaration of Helsinki (1964 - 2014) Sorgner supply of patients, motivation of the acts of The Declaration of Helsinki is one of the most The field of enquiry ”Philosophy of Medicine physicians during the daily routine, and conflict important landmarks in human subject research and Enhancement” deals with questions con- situations in hospital and other medical facilities. which is aimed at protecting human partici- cerning the notion ”disease” and human ag- Central questions deal with issues at the begin- pants in experimental science. By the beginning ing, moral evaluations of various aspects of hu-

42 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) man enhancement, preimplantation diagnosis, In cooperation with the Philosophical Faculty, and deep brain stimulation. In this context, courses on medical ethics and bioethics are be- two academic book series are being edited: ing offered. ”Ars moriendi nova” and ”Beyond Humanism: Furthermore, a lecture course on ”Medicine, Trans- and Posthumanism”. Ethics, and Human Rights” and an interdiscipli- Genetic enhancement discusses the moral rele- nary series of presentations on questions con- vance of promoting genes; neuroenhancement cerning the history and ethics of medicine en- deals with ethical questions on the improve- titled ”Jenseits des Tellerrands” (”Beyond one’s ment of capacities of the brain in particular by own Nose”) are being offered. means of psychoactive and neuroactive substances, but also via deep brain stimulation or Selected Publications brain-computer interfaces. Frewer, A./Bruns, F./May, A. (Hrsg.) (2012) Ethikberatung in der Medizin. Heidelberg u.a. Teaching Schäfer, D./Müller-Busch, C./Frewer, A. (Hrsg.) (2012) Pers- pektiven zum Sterben. Ars moriendi nova, Band 2. Stuttgart. Frewer, A./Bruns, F./Rascher, W. (Hrsg.) (2012) Medizin, The Institute of the History of Medicine and Moral und Gefühl. Emotionen im ethischen Diskurs. JEK Medical Ethics is responsible for teaching the 5. Würzburg. following courses according to medical curric- Frewer, A./Bruns, F./Rascher, W. (Hrsg.) (2011) Gesund- ulum: Medical Terminology (1st term students heit, Empathie und Ökonomie. Kostbare Werte in der Medizin. JEK 4. Würzburg. in human medicine/dentistry); Querschnittsbe- reich (cross-sectional area) Q 2 "History, Theo- Bruns, F./Frewer, A. (2011) Ethics Consultation and Em- pathy. Finding the Balance in Clinical Settings. In: HEC BMBF Project ‘Clinical Ethics’: Professorship for Medical ry, and Ethics of Medicine" (7th term medicine) Forum (2011) DOI 10.1007/s10730-011-9164-7. Ethics edits new basic book. and "History of Science and Ethics" (degree Frewer, A. (2011) Strangers in the Hospital? In: Historia program in molecular medicine). Furthermore, Hospitalium 27 (2011), S. 105-114. it contributes to cross-sectional area Q 7 "Med- icine and Aging" in the section concerned with International Cooperations old age in past and present. Dr. A. Reis, World Health Organisation, Geneva: Switzerland Medical Terminology introduces students to Prof. U. Schmidt, PhD, Rutherford College, University of the specific technical language employed in Kent, Canterbury: UK anatomy and clinical medicine; this includes basic understanding of Latin grammar and Meetings and International Training vocabulary necessary for anatomical terms, fur- Courses thermore Greek for clinical usage. At the same 25.05.2011: Aktuelle Stunde zur Medizinethik. Vorge- burtliche Diagnostik, Behinderung und Gesellschaft. Fo- time it aims at placing medicine in its social and rum in Zusammenarbeit mit dem Klinischen Ethikkomitee, historical context. Erlangen History, Theory, and Ethics of Medicine includes 29.06.2011: Workshop des Klinischen Ethikkomitees und lectures dedicated to the basic principles of the der Professur für Ethik in der Medizin: Ethikberatung in der Medizin. Grundlagen - Modelle - Praxis, Erlangen medical humanities while the specific skills are 21.-23.10.2011: Transforming Human Nature in Science, imparted in seminars. In these seminars, small Technology, and the Arts. Internationale Konferenz unter groups of students are made familiar with cur- Beteiligung der Professur für Ethik in der Medizin, Dublin, rent questions, methods, and approaches in Ireland the field. They aim at sharpening the student's 05.11.2011: 10. Ethiktag des Klinischen Ethikkomitees und der Professur für Ethik in der Medizin: Emotion und eye for social, ethical, and institutional prob- Ethik in der Medizin, Erlangen lems. Teaching methods include text interpre- 23.05.2012: Workshop des Klinischen Ethikkomitees und tation, discussion of case histories, role play, der Professur für Ethik in der Medizin: Fehler in der Mediz- Emotions in Medicine and Ethics - an important field of multimedia presentations, and excursions. in - wie gehen wir damit um? Erlangen expertise: Yearbook of the Professorship for Medical Eth- In addition, courses in ethics and interperson- 27.10.2012: 11. Ethiktag des Klinischen Ethikkomitees: ics documents scientific discourse. al skills are procured as part of the ”Introduc- Risiko - Patient - Medizin. Fehler als Herausforderungen in der Gesundheitsversorgung, Erlangen tion to Clinical Medicine”. Courses range from "Skills in Ethical Communication" over "Break- ing Bad News" and "Speaking about Death and Dying", "Intercultural Communication" to "Medical Acting on Borders", some of those featuring simulated patients to practice difficult communitative situations.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 43 CLINICAL THEORETICAL INSTITUTES

Nikolaus-Fiebiger-Center of Molecular Medicine Chair of Experimental Medicine I (Molecular Pathogenesis Research)

Address Ang II-induced cardiac damage to a point of dation machinery. These results suggest that the Glückstraße 6 therapeutic utility. Since our data suggested PRR is essential for podocyte function and survival 91054 Erlangen an interaction of the renin-angiotensin system, by maintaining autophagy and protein turnover Phone: +49 9131 8529100 immune system, and target organ damage (see machinery. We are now investigating the effect Fax: +49 9131 8526341 EM-figure), we are investigating the role of an- of PRR deletion in other cell types, namely T cells, www.em1.molmed.uni-erlangen.de giotensin II in autoimmunity. pancreatic b-cells and renin-producing cells. In collaboration with Prof. Dr. R. Linker (Depart- Head of Department ment of Neurology), we investigated whether The role of fibulin-4 in the mechano- Prof. Dr. rer. nat. Jürgen Behrens blockade of the RAS improves non-cardiovascu- stability of the muskuloskeletal (acting head) lar autoimmunity. Our results suggest that by connective tissue blocking the aspartyl protease renin, ACE, and Project manager: Dr. T. Sasaki Contact the AT1 receptor, autoimmune encephalitis in Fibulin-4 is a 50 kDa extracellular matrix pro- Prof. Dr. rer. nat. Klaus von der Mark rodents can be effectively inhibited. tein which is essential - together with elastin Phone: +49 9131 8529104 We are now extending our immunological and fibrillin - for assembly and function of elas- Fax: +49 9131 8526341 studies to the investigation of inflammatory tic fibers of the cardiovascular, musculoskeletal, [email protected] activation in the interstitium by hyperosmolar- and lung elastic tissues. Patients with a reces- ity through sodium. This line of investigation sive missense mutation in fibulin-4 display not Research Focus was initiated with Prof. Dr. J. Titze (NFZ), with only defects in elastogenesis, but also multiple •• The immune system, salt, and hyperten- whom we have an intensive collaboration. With bone fractures at birth; two patients showed sion-induced target organ damage dietary sodium excess, sodium accumulates in arachnodactyly. Deficiency in fibulin-4 in mice •• Cardiovascular and non-cardiovascular func- the skin and activates the osmotic stress gene is perinatally lethal due to cardiovascular and tions of the (pro)renin receptor tonicity-responsive enhancer binding protein lung abnormalities and leads to joint contrac- •• The role of fibulin-4 in the mechanostability (TonEBP/NFAT5) in macrophages. TonEBP ac- tures during fetal development. The goal of of the muskuloskeletal connective tissue tivity in macrophages results in secretion of this DFG-funded project is to clarify the role of •• Molecular mechanisms of endochondral os- VEGF-C promoting the clearance of hypertonic fibulin-4 in skeletal development. To this aim, sification and skeletal development fluid from the interstitium. This circuit is critical- the skeletal phenotype of fibulin-4 deficient ly dependent on macrophages and their abili- mouse embryos is analyzed using morphologi- Structure of the Department ty to ward off hypertension in case of excess cal, immunohistochemical, and in situ hybridi- sodium supply. We have initiated a program zation techniques. Potential impairment of cell The Chair of Experimental Medicine I is located to determine how hypertonicity induced by differentiation, alterations of matrix assembly, at the NFZ and is, together with the Chair of deranged sodium chloride storage affects the and dysregulation of TGF-b/BMP signaling are Experimental Medicine II, responsible for the or- differentiation of T cells and macrophages. assessed in vitro, using primary cells isolated ganization and administration of the Center. In from wild type and fibulin-4 deficient mice. 2011 - 2012, about seven scientists and technical Cardiovascular and non-cardiovascular Particular attention is paid to identify further staff were involved in research and teaching at the functions of the (pro)renin receptor fibulin-4 binding proteins in order to elucidate Chair of Experimental Medicine I, three of them The (pro)renin receptor (PRR) is a relatively the mechanisms by which the absence of fib- supported by grants. Prof. Dr. D.N. Müller hold newly discovered member of the renin-angio- ulin-4 leads to abnormalities in mice and hu- the Chair from April 2011 until October 2012. tensin system (RAS). Initially, PRR was believed man. Furthermore, pathological consequences Since then, Prof. Dr. J. Behrens has been acting as to directly contribute to cardiovascular disease of missense mutations found in human patients temporary chairman. Prof. Dr. K. von der Mark (re- by activating the RAS and several signaling will be analyzed using mutagenized, recombi- tired) continued to lead a research group financed cascades. However, recent publications have nantly produced fibilin-4 mutants in vitro. The by grants and participated in teaching molecular shown that PRR plays an essential and non- proposed studies will provide novel insights medicine. In a translational approach, the Müller RAS related role in the activation of Wnt signal into the role of fibulin-4 in skeletal system as lab focuses on the vessels, hearts, kidneys with the transduction and cellular development. In light well as in the development and homeostasis of recent work extending these concepts to analyze of this, our understanding of the role of the PRR cardiovascular tissue. how epigenetic factors, such as high salt, influence in physiology and pathology has changed dra- immune cells, and target organ damage. matically and we are now focused on determin- Molecular mechanisms of endochondral ing these non-RAS functions of PRR. ossification and skeletal development Research We have initiated several PRR tissue-specific Project manager: Prof. Dr. K. von der Mark conditional knockout models. Generation of Cartilage cells (chondrocytes) have two rather The immune system, salt, and hyper- podocyte-specific PRR knockout mice (cKO) re- adverse properties and functions in the fetal and tension-induced target organ damage sulted in the death of the animals ~2-3 weeks the adult skeleton: A transient role during skeletal Project manager: Prof. Dr. D.N. Müller after birth. Within 14 days, these cKO animals development and a permanent in adult cartilages The research of this working group is aimed developed nephrotic syndrome and albuminu- of the joint, trachea, and in elastic cartilages of at better understanding the role of innate and ria, due to podocyte foot process fusion (com- nose and ear. During development of the verte- adaptive immunity in hypertension-induced pare figure) and cytoskeletal changes. bral skeleton, chondrocytes shape the cartilage organ damage. T cells, macrophages, and Our in vivo and in vitro findings indicated a func- model of the subsequent bony skeleton. They dendritic cells all harbor the AT1 receptor. We tional block in autophagosome-lysosome fusion grow and differentiate rapidly and will be re- also observed that regulatory T cells modulate and overload of the proteasome protein degra- placed by bone cells in a complex process called

44 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) ”endochondral ossification”. For reproducible Selected Publications Markó L, Kvakan H, Park JK, Qadri F, Spallek B, Binger skeletal growth, a precise spatially and temporal- KJ, Bowman EP, Kleinewietfeld M, Fokuhl V, Dechend R, Gelse K, Klinger P, Koch M, Surmann-Schmitt C, von der Müller DN (2012) Interferon-g signaling inhibition ame- ly coordinated control of endochondral ossifica- Mark K, Swoboda B, Hennig FF, Gusinde J (2011) Throm- liorates angiotensin II-induced cardiac damage. Hyperten- tion is an absolute requirement. Similar processes bospondin-1 prevents excessive ossification in cartilage sion, 60: 1430-6 also occur during fracture callus healing and de- repair tissue induced by osteogenic protein-1. Tissue Eng Part A, 17: 2101-12 Park J, Bauer S, Pittrof A, Killian MS, Schmuki P, von der velopment of osteophytes in osteoarthritic joints. Mark K (2012) Synergistic control of mesenchymal stem Therefore, elucidation of factors and mechanisms Klinger P, Surmann-Schmitt C, Brem M, Swoboda B, Dis- cell differentiation by nanoscale surface geometry and tler J, Carl HD, von der Mark K, Hennig FF, Gelse K (2011) involved in endochondral ossification is essential immobilized growth factors on TiO2 nanotubes. Small, Chondromodulin 1 stabilizes the chondrocyte phenotype 8: 98-107 not only for our understanding of the regulation and inhibits endochondral ossification of porcine cartilage of normal skeletal growth and skeletal dysplasias, repair tissue. Arthritis Rheum, 63: 2721-31 International Cooperations but also for the development of new tools in the Riediger F, Quack I, Qadri F, Hartleben B, Park JK, Potthoff diagnosis and therapy of joint degeneration, SA, Sohn D, Sihn G, Rousselle A, Fokuhl V, Maschke U, Prof. Dr. C. Hartmann, Institute of Molecular Pathology, fracture healing, and cartilage and bone repair. Purfürst B, Schneider W, Rump LC, Luft FC, Dechend IMP, Institute of Molecular Pathology, IMP, Vienna: Austria The analysis of these factors by means of in vitro R, Bader M, Huber TB, Nguyen G, Muller DN (2011) Dr. G. Nguyen, College de France, Paris: France Prorenin receptor is essential for podocyte autophagy and techniques, cell and organ culture systems, and survival. J Am Soc Nephrol, 22: 2193-202 Prof. T. Hattori, Graduate School of Dentistry and Medi- transgenic mouse models is currently the major cine, Okayama University, Okayama: Japan Eitzinger N, Surmann-Schmitt C, Bösl M, Schett G, Engel- focus of a DFG-funded research project. ke K, Hess A, von der Mark K, Stock M (2012) Ucma is not Prof. B. de Crombrugghe, MD, Anderson Cancer Center, The development of a collagen 10-specific tar- necessary for normal development of the mouse skeleton. Texas University, Houston: USA geting vector for recombination into BACs (bac- Bone, 50: 670-80 Dr. M. Kleinewietfeld, Yale Medical School, New Haven: USA terial artificial chromosomes) allowed the specific expression of transgenes, such as lacZ reporter genes, cre-recombinase as well as the transcription factor Sox9 in the hypertrophic zone of the murine growth plate. Overexpression of Sox9 significantly blocked resorption of hypertrophic cartilage, capillary invasion, and bone marrow formation in the developing long bones, resulting in impaired skeletal growth and reduced bone length. This demonstrated for the first time a novel role of Sox9 as angiogenic inhibitor of cartilage vascularization. The generation of Col10-specific Cre-deleter mice opened the possibilities for specific deletion of floxed genes in the hypertrophic zone of the growth plate. Mat- ing the Col10-Cre mice with conditional b-catenin mice (Prof. Dr. R. Kemler, Freiburg) with floxed catenin alleles resulted in transgenic mice lacking trabecular bone in the subchondral zone of the diaphysis (compare figure). This deficiency was due to enhanced RANKL activity stimulating osteoclast differentiation in b-catenin deficient EM shows normal epithelial cells and foot processes in control animals (left). cKO mice (right) developed foot process cartilage (compare figure). Several cooperations fusion (c=capillary, p=podocyte). were started with laboratories in Vienna (Prof. Dr. C. Hartmann), Boston (Prof. Dr. B. Lanske), Houston (Prof. B. de Crombrugghe, MD) and Freiburg (Prof. Dr. B. Zabel) for specific gene inactivation studies of the hypertrophic zone using the Col10-Cre deleter mouse.

Teaching

The Chairs of Experimental Medicine I and II organize lectures, seminars, and experimental classes in cell, molecular, and developmental biology at basic and advanced levels for students of molecular medicine, human medicine, and biology. Special lectures, including tumor biology and oncology, molecular mechanism of cell differentiation, and development, cell-cell and cell-extracellular matrix interactions are given.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 45 CLINICAL THEORETICAL INSTITUTES

Nikolaus-Fiebiger-Center of Molecular Medicine Chair of Experimental Medicine II (Molecular Oncology)

Address the serine/threonine phosphorylation sites of ent during the G1/S phase and highest during Glückstraße 6 b-catenin lead to stabilization of b-catenin and G2/M. Following exit from mitosis, conduc- 91054 Erlangen trigger constitutive signaling to the nucleus. tin expression levels decline in parallel with Phone: +49 9131 8529110 Such b-catenin mutations are also found in a those of mitotic regulators, such as cyclin B1. Fax: +49 9131 8529111 multitude of other tumor types suggesting that In line, Wnt/b-catenin target genes are low at www.molmed.uni-erlangen.de aberrant activation of Wnt signaling is a key G2/M and high at G1/S, and b-catenin phos- mechanism of oncogenic transformation. Dur- phorylation oscillates during the cell cycle in Head of Department ing the report period, we have characterized a conductin-dependent manner. Conductin is Prof. Dr. rer. nat. Jürgen Behrens novel APC binding partners identified by our degraded by the anaphase-promoting com- groups, the Amer proteins, as regulators of Wnt plex/cyclosome cofactor CDC20. Knockdown Contact signaling and the cytoskeleton. We also found of CDC20 blocks Wnt signaling through con- Prof. Dr. rer. nat. Jürgen Behrens that the negative Wnt regulator Conductin/ ductin. CDC20-resistant conductin inhibits Phone: +49 9131 8529109 Axin2 is regulated during the cell cycle leading Wnt signaling and attenuates colony forma- Fax: +49 9131 8529111 to differential activity of the Wnt pathway at tion of colorectal cancer cells. We propose that [email protected] different cell cycle phases. Finally, we showed CDC20-mediated degradation of conductin that truncated APC tumor suppressor protein regulates Wnt/b-catenin signaling for maximal Research Focus serves an essential function in colorecla cancer activity during G1/S. •• Molecular oncology of Wnt signaling by regulating Wnt pathway activity. •• Amer proteins Tumor suppressor APC •• Role of conductin during the cell cycle Amer proteins Project managers: Dr. V. Chandra, Dr. J. Schnei- •• Tumor suppressor APC Project managers: Dr. K. Tanneberger, Dr. A. kert •• Functional genomics of renal cell carcinoma Pfister, K. Brauburger The tumor suppressor APC is truncated in most The Amer protein family consists of three colon cancers, but is not completely lost. It Structure of the Department members, Amer1, Amer2, and Amer3. These is not clear why colon cancer cells retain the proteins are characterized by their ability to in- truncated APC fragment. We found that the The Chair of Experimental Medicine II is situ- teract with APC, and Amer1 and Amer2 were transcriptional repressor C-terminal binding ated at the NFZ. There are 16 staff members, shown to be able to recruit APC to the plasma protein (CtBP) promotes the oligomerization nine of them scientists financed by third-party membrane. Hence the name Amer for ”APC of truncated APC through binding to the 15 funds. During the reported period there were membrane recruitment” was chosen. Amer3 amino acid repeats of truncated APC. CtBP can six PostDocs, six PhD students, three techni- lacks membrane association and interacts with bind to either first, third, or fourth 15 amino cians, and one secretary. Our main goal is to APC at the microtubule cytoskeleton and in acid repeats, but not to the second. CtBP-me- investigate the molecular mechanisms of tu- the cytoplasm. Amer1 is identical to the tumor diated oligomerization requires both, dimeriza- mor development and progression by cell and suppressor WTX and can inhibit Wnt/ -catenin tion domains of truncated APC as well as CtBP molecular biological methods to find new ways b dimerization. This suggests that the sensitivity for diagnosis, prognosis, and therapy. signaling which requires membrane binding of Amer1. Moreover, we found that Amer1 acts as of truncated APC to oligomerization by CtBP Research a positive regulator of Wnt signaling by binding constitutes an essential facet of tumor develop- to the LRP 6 receptor and thereby promoting its ment. Molecular oncology of Wnt signaling phosphorylation (figure). We have furthermore RNA interference was used to down-regulate The Wnt signaling pathway regulates various characterized the related Amer2 protein. Amer2 truncated APC in several colorectal cancer cell processes during embryonic development and interacts with APC, like Amer1, thus reducing lines expressing truncated APCs of different can lead to cancer. Wnts are secreted glycopro- Wnt signal transduction. In addition, Amer2 lengths, thereby performing an analysis cover- teins which induce the accumulation of b-cat- binds to the microtubule-associated EB1 pro- ing most of the mutation cluster region. The enin in cytoplasm and nucleus by binding to tein and can lead to microtubule stabilization. consequences on proliferation in vitro, tumor frizzled and LRP receptors. b-Catenin interacts Thus, Amer proteins act as regulators of Wnt formation in vivo, and the level and transcrip- with TCF transcription factors and activates signaling, but are also involved in other path- tional activity of b-catenin were investigated. target genes. The destruction of b-catenin is ways and molecular mechanisms suggesting a Down-regulation of truncated APC results in an induced by phosphorylation in a multi-protein complex picture of Amer function for which the inhibition of tumor cell population expansion complex which consists of the scaffold com- in vivo consequences are not yet clear. in vitro in six cell lines out of six and inhibition ponent conductin, the serine/threonine kinase of tumor outgrowth in vivo as analyzed in one GSK3b and the tumor suppressor APC (Adeno- Role of conductin during the cell cycle of these cell lines, HT29. Down-regulation of matous Polyposis Coli). The Wnt signal inhib- Project managers: Dr. M. Hadjihannas, M. truncated APC is accompanied by an up-regu- its phosphorylation of b-catenin and thereby Brückner lation of the transcriptional activity of b-catenin leads to its stabilization. In colorectal tumors, We found that conductin levels are regulated and in most cases b-catenin levels, indicating mutations of APC or conductin or mutations of during the cell cycle with lowest levels pres- that truncated APC can still modulate Wnt sign-

46 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) aling through controlling the level of b-catenin. Teaching Pfister AS, Hadjihannas MV, Roehrig W, Schambony A, Thus, truncated APC is an essential compo- Behrens J (2012) Amer2 protein interacts with EB1 protein and adenomatous polyposis coli (APC) and controls nent of colorectal cancer cells, required for cell Training in cell biology for students of Molec- microtubule stability and cell migration. J Biol Chem, 287: proliferation, possibly by adjusting b-catenin ular Medicine in cooperation with the Chair of 35333-40 signaling to the "just right" level. Experimental Medicine I. Pfister AS, Tanneberger K, Schambony A, Behrens J (2012) Amer2 protein is a novel negative regulator of Wnt/b-catenin signaling involved in neuroectodermal patterning. J Functional genomics of renal cell Selected Publications Biol Chem, 287: 1734-41 carcinoma Schneikert J, Brauburger K, Behrens J (2011) APC muta- Project managers: Dr. I. Wacker, Dr. M. Sachs tions in colorectal tumours from FAP patients are select- International Cooperations ed for CtBP-mediated oligomerization of truncated APC. We have established gene expression patterns Hum Mol Genet, 20: 3554-64 Dr. V. Bryja, Institute of Experimental Biology, University of of renal cell carcinomas in order to identify Brno, Brno: Czech Republic Tanneberger K, Pfister AS, Brauburger K, Schneikert genes relevant for the tumor biology and clin- J, Hadjihannas MV, Kriz V, Schulte G, Bryja V, Behrens J Prof. Dr. O. Ritvos, Biomedicum Helsinki, University of Hel- ical course of this disease. We found that Ac- (2011) Amer1/WTX couples Wnt-induced formation of sinki, Helsinki: Finland PtdIns(4,5)P(2) to LRP6 phosphorylation. EMBO J, 30: tivin B, a member of the TGFb family, is highly 1433-43 Research Equipment overexpressed in kidney tumors as compared Tanneberger K, Pfister AS, Kriz V, Bryja V, Schambony A, Dako Cytomation, MoFlo - cell sorter to normal kidneys and that its expression is Behrens J (2011) Structural and Functional Characteriza- regulated by the VHL/HIF system. In the report tion of the Wnt Inhibitor APC Membrane Recruitment 1 Applied Biosystems, Genetic Analyzer ABI 3130 (Amer1). J Biol Chem, 286: 19204-14 period, we found that Activin B regulates Rho/ Hadjihannas MV, Bernkopf DB, Brückner M, Behrens J Rac signaling, thus altering cell morphology (2012) Cell cycle control of Wnt/b-catenin signalling by and the invasiveness of renal cancer cells. conductin/axin2 through CDC20. EMBO Rep, 13: 347-54

Regulation of LRP6 Phosphorylation by Amer1. Amer1 is recruited to the plasma membrane after Wnt-stimulated synthesis of Phosphatidylinositol(4,5)bisphosphate (PIP2) by PI4KII and PIP5KI and associates with LRP6. As a consequence, associated protein kinases GSK3 und CK1g are recruited to the vicinity of LRP6 and phosphorylate its cytoplasmic domain. Phosphorylated LRP6 inhibits b-Catenin degradation, thereby initiating the Wnt/b-catenin signaling cascade.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 47 CLINICAL CHAIRS

Department of Orthopedics in the Waldkrankenhaus St. Marien gGmbH Chair of Orthopedics and Orthopedic Surgery

Address The clinical focuses of our Department are: To- Radiostereometric analysis for quality Rathsbergerstraße 57 tal hip-, knee-, and shoulderarthroplasty, spine control in total hip arthroplasty 91054 Erlangen surgery, pediatric orthopedics, foot surgery, tu- Project managers: Prof. Dr. R. Forst, Dr. S. Ses- Phone: +49 9131 8223303 morsurgery, arthroscopic operations. selmann Fax: +49 9131 8523565 Recent studies lead to the conclusion that a www.orthopaedie.med.uni-erlangen.de Research measurement of migration within the first two years forms a basis for predicting the long-term Head of Department Computer assisted surgery of the hip outcome of the acetabular and femoral compo- Prof. Dr. med. Raimund Forst joint nent when considered separately. The quality Project managers: Prof. Dr. R. Forst, PD Dr. L. control is achieved with thorough documenta- Contact Müller tion and precise analysis of fixation. Dr. med. Albert Fujak The aim of this study is to develop a naviga- Measurements on conventional radiographs Phone: +49 9131 8223303 tion system for total hip arthroplasty and to can have an accuracy of 1-5mm and 1°- 6° de- Fax: +49 9131 8523565 use it for the surgery process as well as to test pending on the technique employed, the ana- [email protected] the accuracy of the system with integrated tomic region investigated, and the number of modules. The system works with three-dimen- examiners. RSA has proven to be an accurate Research Focus sional CT-data. The received data are used for and safe method to objectify skeletal kinemat- •• Computer assisted surgery of the hip joint the virtual positioning of the implant preoper- ics. RSA is based on radiographic examinations •• Computertomography-assisted periprosthet- atively. Intraoperatively, the navigation system of calibration cages and object markers im- ic osteodensitometry after total hip arthro- compares the virtual data with the surgical planted in the skeleton. Accurate measurement plasty (THA) view to achieve an exact position of the im- of radiographs and computer-assisted calcula- •• Radiostereometric analysis for quality control plant. The preoperative CT is then compared tion can provide a three-dimensional motion in total hip arthroplasty with a new postoperative CT to evaluate the analysis. RSA can be performed with an accu- •• Neuromuscular disorders racy of 10-250 m and 0.03°-0.6°. Altogether, accuracy of the implantation. Postoperatively, m 200 patients have been supervised with RSA osteointegration of the implant is analyzed Structure of the Department after total hip replacement in Erlangen since using CT-osteodensitometry. Thus for all steps 1998. The following examinations are carried (planning, surgery, and evaluation) of com- 14 medical doctors work in the Department of out with these clients in different studies: Mea- puter assisted surgery, highly precise mea- Orthopedics in the Waldkrankenhaus St. Ma- suring of migration of polyethylene cups after surements are conducted which allow an rien gGmbH. The research is accomplished by bone grafting and reinforcement of acetabular exact comparison of the received data. 50 pa- two postdoctorate medical doctors, 20 gradu- ring with hook for severe acetabular dysplasia, tients will be analyzed. ate students, and one study nurse. measuring of initial stability of acetabular com- In the endoprosthesis working group, apart ponents with alumina and polyethylene liner in Computertomography-assisted peri- from the standardized clinical and radiologi- a comparison essay, measuring of migration of prosthetic osteodensitometry after cal long-term investigations for quality control cemented femoral components into depend- total hip arthroplasty (THA) after navigated and non-navigated total hip ence of various cementing techniques in a Project managers: Prof. Dr. R. Forst, PD Dr. L. and knee surgery, periprosthetic bone density comparison essay, and measuring of migration Müller measurements are accomplished by means of of uncemented femoral components after early The reaction of the bone which occurs after computer tomography (CT)-assisted osteoden- load transfer. sitometrie and radiostereometric analysis (RSA) THA is important for the stability of the im- for the evaluation of the migration pattern of plant and thus the long term prognosis. This Neuromuscular disorders the prostheses. The influence of navigation, the study was designed to analyze the changes Project managers: PD Dr. J. Forst, Dr. A. Fujak, prosthesis design, and the prosthesis coating of femoral and periacetabular bone after Prof. Dr. R. Forst on the longevity of the implant is investigated THA introducing a novel method of CT-as- The research group for neuromuscular disor- by these procedures. sisted bone density measurement in vivo. A ders is engaged in an evaluation of orthope- The research group for neuromuscular disor- special software tool is used (CAPPA postOP, dic symptoms, conservative and operative ders is engaged in a study and evaluation of CAS Innovations AG, Erlangen) which allows treatment in children and adult patients with conservative and operative treatment in chil- for a separate view of femoral and acetabu- neuromuscular disorders. The aim of research is dren and adult patients with neuromuscular lar bone. CT-investigations are performed ten the optimization of orthopedic treatment, im- disorders (anterior horn cell diseases, spinal days, one, three, and five years post-opera- provement of the medical care and quality of muscular atrophies, post polio syndrome, mus- tively. Cortical and cancellous bone density as life of these patients. The studies are particular- cular dystrophies). well as bone area and bone-implant contact ly focused on anterior horn cell diseases, spinal The common aim of research in care for pa- are measured. Bone density measurements muscular atrophies, post polio syndrome, and tients with cerebral palsy is the evaluation of are undertaken in respect to fixation meth- muscular dystrophies. results of botulinum toxin therapy and optimiz- ods (cemented/uncemented), coating (e.g. Although knowledge of the gene defect and ing of orthopedic treatment strategies to im- hydroxyapatite), and design (collum femoris the coded protein - the dystrophin - is given, prove the quality of life of these patients. preserving/standard). there is no causal therapy of Duchenne mus-

48 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) cular dystrophy (DMD) - the most common neuromuscular disease. The natural history of this disease includes beside the obligatory restrictive respiratory insufficiency the cardiomyopathy contractures of the extremities and progressive scoliosis in almost all patients. The results of operative treatment of contractures of lower extremities particularly in early course of the disease are investigated in prospective study in collective of more 500 patients with genetically confirmed diagnosis of DMD. Positive effect of this treatment could be proven, and a stage-oriented therapy concept could be developed. In close cooperation with the Department of Anesthesiology, the special features in anesthesia and pain therapy in patients with the neuro- CT-osteodensitometry: Distribution of forces after femoral neck-conserving versus standard hip endoprothesis. muscular disorders are investigated. In common projects with the Division of Pedi- atric Cardiology and the Institute of Radiology, the participation of the heart musculature in DMD is examined.

Teaching

Beside the traditional teaching forms (main lecture and practical courses), hospitations and fellowships can be undertaken anytime.

Selected Publications Fujak A, Kopschina C, Forst R, Mueller LA, Forst JX (2011) Use of orthoses and orthopaedic technical devices in proximal spinal muscular atrophy. Results of survey in 194 SMA patients. Disabil Rehabil Assist Technol, 6: 305-11 Kress AM, Schmidt R, Vogel T, Nowak TE, Forst R, Mueller LA (2011) Quantitative computed tomography-assisted osteodensitometry of the pelvis after press-fit cup fixation: a prospective ten-year follow-up. J Bone Joint Surg Am, 93: 1152-7 RSA after hip joint replacement surgery is based on the radiologic research of marked carcass sections and enables a Müller LA, Wenger N, Schramm M, Hohmann D, Forst R, 3D-analysis of micro-movement with an accuracy of 1-250 mm and 0.03°- 0.6°. Carl HD (2011) 17-year follow-up of the rough-blasted threaded Weill cup in uncemented total hip arthroplasty. Arch Orthop Trauma Surg, 131: 557-61 Fujak A, Raab W, Schuh A, Kreß A, Forst R, Forst J (2012) Operative treatment of scoliosis in proximal spinal muscular atrophy: results of 41 patients. Arch Orthop Trauma Surg, 132: 1697-706 Fujak A, Müller K, Legal W, Legal H, Forst R, Forst J (2012) [Long-term results of Imhäuser osteotomy for chronic slipped femoral head epiphysiolysis]. Orthopade, 41: 452-8 Kress AM, Schmidt R, Nowak TE, Nowak M, Haeberle L, Forst R, Mueller LA (2012) Stress-related femoral cortical and cancellous bone density loss after collum femoris preserving uncemented total hip arthroplasty: a prospective 7-year follow-up with quantitative computed tomography. Arch Orthop Trauma Surg, 132: 1111-9

International Cooperations Institute Duchenne de Boulogne, Poitiers: France RSAcore, Department of Orthopaedics, LUMC, Leiden: The Netherlands

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 49 CLINICAL CHAIRS

Department of Orthopedics in the Waldkrankenhaus St. Marien gGmbH Division of Orthopedic Rheumatology

Address tient care and one technician. Three scientists notype of articular chondrocytes. In a project Rathsberger Straße 57 are funded by the DFG. funded by the DFG, it could be demonstrated 91054 Erlangen that Chondromodulin-I (Chm-I) and Throm- Phone: +49 9131 8223305 Research bospondin-1 (TSP-1) exert a stabilizing effect Fax: +49 9131 8223340 on the chondrocyte phenotype and inhibit the www.orthop-rheum.med.uni-erlangen.de Arthroscopic synovectomy terminal differentiation. Both factors exerted a Project managers: PD Dr. H.-D. Carl, Prof. Dr. strong anti-angiogenic effect in vitro and could Head of Division B. Swoboda prevent inadvertent excessive endochondral Prof. Dr. med. Bernd Swoboda Clinical studies investigated the effect of arthro- ossification in cartilage defects in an animal scopic synovectomies in patients with rheuma- cartilage repair model. Gene expression studies Contact toid arthritis. Arthroscopic synovectomies of indicated that the observed effects depend on Prof. Dr. med. Bernd Swoboda the knee joint were combined with a radiosyn- an inhibitory effect on the cell cycle, since the Phone: +49 9131 8223305 oviorthesis. The long-term effect of this proce- cell cycle inhibitor p21cip/waf was identified Fax: +49 9131 8223340 dure was evaluated using joint replacement as as one of the main upregulated target genes. an end point. [email protected] Furthermore, the inhibition of the expression erlangen.de of GADD45b seemed to prevent terminal chon- Dynamic pedobarography drocyte differentiation. Project managers: PD Dr. H.-D. Carl, Dr. J. Paus- Research Focus Further gene expression analyses (cDNA ar- er •• Arthroscopic synovectomy rays) demonstrated that a number of inhibitory Dynamic pedobarography is a computer-based •• Dynamic pedobarography factors, such as the BMP-inhibitor Grem-1 or method to assess forces from the ground-sole •• Endoprostheses for degenerative and inflam- the Wnt-inhibitors FRZB1 or WISP3, are signifi- interface with sensor-loaded insoles. The pa- matory joint diseases cantly higher expressed in permanent articular rameter ”peak plantar pressure” has been in •• Cellular and molecular basis of cartilage de- cartilage as compared to the transient type of the focus of several studies, as it has been degeneration and regeneration - Mechanisms cartilage (e.g. osteophyte cartilage). These ob- scribed as a risk factor for plantar ulcers and for the stabilization of the chondrocyte phe- servations imply that the generation of hyaline metatarsal fractures. The Division of Orthope- notype dic Rheumatology currently conducts the fol- repair cartilage does not solely rely on chondrogenic growth factors, but also on inhibi- Structure of the Department lowing studies: - Foot loading with partial weight bearing fol- tory-acting factors which may particularly be lowing total hip and knee replacement; of immanent importance to prevent terminal The Division of Orthopedic Rheumatology is an - Foot loadings in elite male soccer players; chondrocyte differentiation and inadvertent os- independent institution of the FAU which is as- - Evaluation of several orthotic devices that in- sification of repair cartilage tissue. Thus, in fu- sociated with the Department of Orthopedics tend to reduce foot loading; ture therapeutic settings, it would be useful to in the Waldkrankenhaus St. Marien gGmbH. - Foot loading in relation to knee joint mobility. load bioactive matrices with a cocktail of spe- Clinical activities focus on the treatment of cific stimulatory and inhibitory factors for the patients with degenerative and inflammatory Endoprostheses for degenerative and generation of hyaline repair cartilage and for joint diseases. The head of the Division is also inflammatory joint diseases the inhibition of excessive ossification. speaker of the Erlangen Arthritis Center which Project managers: Dr. A. Jendrissek, Prof. Dr. B. is an interdisciplinary association of physicians Swoboda Teaching treating these patients. Clinical studies are conducted on the clinical out- Clinical research activities concentrate on the come of large joint arthroplasty, especially in pa- Staff of the Division of Orthopedic Rheumatol- evaluation of surgical treatments. Of interest tients with degenerative and inflammatory joint ogy is active in the curriculum for general or- are preventive procedures, like synovectomies. diseases. For this purpose, different preoperative thopedics. Specialized lectures are offered on Comparing joint replacements in patients with findings, surgical requirements, postoperative problems of arthritis surgery and the basics of degenerative and inflammatory joint disea- outcome, and patient satisfaction are examined. osteoarthritis induction and progression. ses will help to identify different preoperative First and foremost, the long-term treatment re- Students are welcome to visit us when treat- findings, different intraoperative challenges as sults are observed in the different patient groups. ing ambulant patients or in the operation room well as long term patients´ satisfaction. The main focus of this work is knee replacement. when doing surgery on rheumatoid patients. Another focus of basic research are the mechanisms of induction and progression of osteoar- Cellular and molecular basis of carti- Selected Publications thritis. Projects are funded by the DFG. A better lage degeneration and regeneration - Goetz M, Klug S, Gelse K, Swoboda B, Carl HD (2011) understanding of osteoarthritis will help to de- Mechanisms for the stabilization of Combined arthroscopic and radiation synovectomy of the velop new therapeutic approaches, like tissue the chondrocyte phenotype knee joint in rheumatoid arthritis: 14-year follow-up. Ar- throscopy, 27: 52-9 engineering. Project manager: PD Dr. K. Gelse Gusinde J, Pauser J, Swoboda B, Gelse K, Carl HD (2011) The scientific projects are performed by three This project focuses on the mechanisms that Foot loading characteristics of different graduations of medical doctors which are also involved in pa- induce chondrogenesis and stabilize the phe- partial weight bearing. Int J Rehabil Res, 34: 261-4

50 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Klinger P, Surmann-Schmitt C, Brem M, Swoboda B, Dis- tler J, Carl HD, von der Mark K, Hennig FF, Gelse K (2011) Chondromodulin 1 stabilizes the chondrocyte phenotype and inhibits endochondral ossification of porcine cartilage repair tissue. Arthritis Rheum, 63: 2721-31 Pauser J, Jendrissek A, Swoboda B, Gelse K, Carl HD (2011) Inaccuracy of a physical strain trainer for the monitoring of partial weight bearing. Arch Phys Med Rehabil, 92: 1847-51 Carl HD, Swoboda B (2012) Presurgical and postsurgical orthotic management of the rheumatoid foot. Z Rheuma- tol, 71: 680-4 Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, Hen- nig FF, Klinger P (2012) Molecular differentiation between osteophytic and articular cartilage - clues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage, 20: 162-71

International Cooperations Prof. Dr. T. Kirsch, PhD, Department of Orthopedic Sur- gery, Director of the Musculoskeletal Research Center NYU Hospital for Joint Diseases, New York City: USA

Meetings and International Training Courses 21.05.2011: “Schulter-Nacken-Schmerz - Häufige Symp- tome in der täglichen Praxis”, Internistische Schwerpunkt- praxis, Erlangen 23.06.2012: “Was Sie schon immer über “Rheuma” wissen wollten”, Schindlerhof, Nürnberg

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 51 CLINICAL CHAIRS

Institute for Biomedicine of Aging Chair of Internal Medicine (Geriatrics)

Address in the Elderly, one research project focused on obesity has been supposed to be one major Kobergerstraße 60 the nutritional and health situation of home- risk factor and has led to the concept of sar- 90408 Nürnberg cared older adults in Germany. This cross-sec- copenic obesity. The dietary animal model of Phone: +49 911 5302 96150 tional multicenter study was funded by the aging high fat rat enables us to study mole- Fax: +49 911 5302 96151 German Federal Ministry of Food, Agriculture, cular mechanisms by which obesity might be www.iba.med.uni-erlangen.de and Consumer Protection and performed on linked with sarcopenia. Employing Magnetic behalf of the German Nutrition Society (DGE). Resonance Imaging und Magnetic Resonance Head of Department In Germany, the majority (70%) of about 2.5 spectroscopy techniques, we further monitor Prof. Dr. med. Cornel C. Sieber million persons in need of care is living in pri- the morphology of the muscle and muscular vate households and is being cared for by rela- features with functional impact (such as fat Contact tives and professional service providers. Never- and iron content) as well as the whole body fat Prof. Dr. med. Cornel C. Sieber theless, only little is known about the nutritional distribution. During the whole lifetime of the Phone: +49 911 5302 96150 situation of this specific population group. Aim rats, blood samples were collected and at 24 Fax: +49 911 5302 96151 of this study was a detailed evaluation of the month of age, the animals were sacrificed and [email protected] nutritional situation of German home care re- the organs were stored frozen. In the last years ceivers considering nutritional status, food, and several devices were renewed and bought from Research Focus nutrient intake as well as structural, social, and third party funding and university grants (real •• Clinical nutrition in the elderly health factors. Recommendations to improve time quantitative PCR with TaqManTM; Chem- •• Impact of long term high fat diets on the de- the situation and to reduce the burden on the iDoc MP Imaging System from BioRad). Fur- velopment of sarcopenia caregivers should be derived. In a total of 353 thermore a method was established for anal- •• Sarcopenia home cared adults aged 65 years or older, nu- ysis of fatty acid profiles in blood and muscle •• Intensive care medicine tritional problems were frequently observed. samples using the gas chromatography-mass •• Emergency medicine They were, however, less pronounced than in spectrometry instrument in our laboratory. Aim institutionalized elderly. The awareness of nu- of this study is the establishment of new me- Structure of the Department trition as one important contributor for health tabolic biomarkers for sarcopenia induced by a and functionality should be increased in the high fat diet. Based on this preparatory work, The Institute for Biomedicine of Aging (IBA) is home care setting by expanding information the samples will be analyzed for pathologic ab- part of the Chair of Internal Medicine - Geriat- and counseling, by integration of the topic normalities induced by the dietary intervention rics at the FAU under the direction of Prof. Dr. ”nutrition” in training and specialized courses using multiple biochemical and histological C.C. Sieber. Research is clinically-epidemiolog- for nurses and doctors, and by routine screen- approaches. We are especially interested in the ically and experimentally oriented and focused ing for malnutrition in the older population. pathways of AMP-activated protein kinase and on nutrition and metabolism in the elderly, In another project, nutritional situation of com- the Peroxisome proliferator-activated receptor age-related decline of muscle mass and func- munity-dwelling older patients was evalua- g coactivator 1-a which are essential regulation (sarcopenia) and frailty. The clinical nutri- ted in cooperation with general practitioners. tors of the metabolism and functionality of the tion research is performed within the Theo and Based on a standardized screening, kind and muscle cells. This project is part of the Bavarian Friedl Schöller Foundation Professorship for prevalence of nutritional problems and result- Research Association Sarcopenia and Osteopo- Clinical Nutrition in the Elderly, hold by Prof. ing need for advice and intervention were ex- rosis - consequences of reduced regeneration Dr. D. Volkert. Experimental research is headed amined in outpatients aged 75 years or older at old age (FORMOsA). by Prof. Dr. C. Bollheimer with a translational in the family doctors practices. In patients with approach. Main focus there is aging with obe- malnutrition or at risk of malnutrition, adequate Sarcopenia sity and the accompanying loss of muscle mass nutrition was mainly compromised or jeopard- Project manager: Dr. M. Drey and function, so-called sarcopenic obesity. The ized by health problems, pain, xerostomia, and The Institute for Biomedicine of Aging was Institute is characterized by a high degree of chewing problems. Due to lacking cooperation involved in an international, multicentric, ran- interdisciplinary research with staff having a of family doctors, the results cannot be regard- domized, controlled trial for sarcopenia, spon- nutritonal, nursing, sports science, biology, and ed as representative and should be substantia- sored by third-party funds. Aim of the study was biochemistry background. It forms part of the ted by future studies. to investigate the improvement of physical per- Interdisciplinary Center of Aging Research (ICA; formance in community dwelling older adults compare own report) of the FAU. Impact of long term high fat diets on by a nutritional supplement. Recruitment end- the development of sarcopenia ed in August 2012. Results are expected on an Research Project managers: Prof. Dr. C. Bollheimer, Dr. R. international level at the end of 2013. Kob, Dr. B. Fischer Besides the mentioned nutritional interven- Clinical nutrition in the elderly Sarcopenia denotes the exceeding decline of tion in sarcopenic patients, the Institute has Project manager: Prof. Dr. D. Volkert muscle mass, strength, and performance with focused on neurodegenerative aspects in the Within the scope of the Theo and Friedl Schöller age which could be induced by a lot of dif- onset of sarcopenia. For that reason, an elec- Foundation Professorship for Clinical Nutrition ferent pathological conditions. For example, tromyographical technique, called the Motor

52 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Unit Number Index (MUNIX), coming from duction of prospective trials to improve quality Neurology for monitoring the loss of motoneu- in treatment is the main focus of the scientific rons in patients suffering from Amyotrophic work in this area. Lateralsclerosis (ALS), was used in sarcopenic patients. In sarcopenia, the age associated loss Teaching of motoneurons should lead to a degeneration of its muscle fibers, ending in muscle loss. In ”Instant Aging” is a simulation model of ag- the cohort of sarcopenic patients from the ing. It was integrated in the practical geriatric aforementioned study, it could be shown that training of the Internal Medicine (Q 7). ”Instant the mean MUNIX of the hypothenar muscle Aging” provides tools for medical students to was between the mean MUNIX of ALS patients bodily experience different age- and illness-re- and the mean MUNIX of healthy controls. 25% lated limitations of activity. The compulsory of the sarcopenic patients had pathological elective subject "Clinical Nutrition" focuses on MUNIX values suggesting that this subgroup nutritional issues of hospital patients. suffers from sarcopenia caused by loss of motoneurons. In an EU-Cooperation Project FP7 Selected Publications (support code: 01QE1107B), the hypothesis Bollheimer LC, Buettner R, Pongratz G, Brunner-Ploss R, was tested whether older adults with patho- Hechtl C, Banas M, Singler K, Hamer OW, Stroszczynski C, Sieber CC, Fellner C (2012) Sarcopenia in the aging high- logical MUNIX values suffer from muscle loss fat fed rat: a pilot study for modeling sarcopenic obesity in compared to healthy controls. Additionally, the rodents. Biogerontology, 13: 609-20 concentration of C-terminal-Agrin Fragment Drey M, Zech A, Freiberger E, Bertsch T, Uter W, Sieber (CAF) was measured to investigate the relation- CC, Pfeifer K, Bauer JM (2012) Effects of Strength Training versus Power Training on Physical Performance in Prefrail ship to the degeneration of the neuromuscular Community-Dwelling Older Adults. Gerontology, 58: 197- junction as a cause of muscle loss. The study 204 will be finished in 2013. Heppner HJ, Singler K, Kwetkat A, Popp S, Esslinger AS, Bahrmann P, Kaiser M, Bertsch T, Sieber CC, Christ M (2012) Do clinical guidelines improve management of Intensive care medicine sepsis in critically ill elderly patients? A before-and-after Project managers: PD Dr. H.J. Heppner, Dr. K. study of the implementation of a sepsis protocol. Wien Singler, Dr. P. Bahrmann Klin Wochenschr, 124: 692-8 The research group is engaged in life-threat- Wirth R, Voss C, Smoliner C, Sieber CC, Bauer JM, Volkert D (2012) Complications and mortality after percutaneous ening diseases in old adults and their intensive endoscopic gastrostomy in geriatrics: a prospective multi- care treatment. The main research is diagno- center observational trial. J Am Med Dir Assoc, 13: 228-33 sis and therapy of severe infections, primarily Bollwein J, Diekmann R, Kaiser MJ, Bauer JM, Uter W, Sie- in lower respiratory tract in this patient group. ber CC, Volkert D (2013) Dietary quality is related to frailty in community-dwelling older adults. J Gerontol A Biol Sci The researchers light the physiological specific Med Sci, 68: 483-9 characteristics within infections as well as the Bollwein J, Volkert D, Diekmann R, Kaiser MJ, Uter W, Vidal difficulties in finding diagnosis and initiating K, Sieber CC, Bauer JM (2013) Nutritional Status Accord- treatment. Infections and sepsis in the elderly ing to the Mini Nutritional Assessment (MNA®) and Frailty in Community Dwelling Older Persons: A Close Relation- are the main focus of their scientific work. PD ship. J Nutr Health Aging, 17: 351-6 Dr. H.J. Heppner is speaker of the Geriatric section of the German Sepsis Society. International Cooperations European Academy for Medicine of Ageing (EAMA), Sion: Emergency medicine Switzerland Project managers: PD Dr. H.J. Heppner, Dr. K. Singler, Dr. P. Bahrmann Furthermore improvement of diagnosis and treatment of geriatic patients in the emergency department is another topic the research group is dealing with in tight collaboration with the emergency department of the Nuremberg Hospital. The target is to ensure appropriate treatment and supply according to the demographic shift. Implementation of structured clinical pathways, teaching of the medical staff, strengthening of geriatric know-how, and con-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 53 UNIVERSITY HOSPITAL

Department of Anesthesiology Chair of Anesthesiology

Address ed at the Department of Anesthesiology. An medicine. Therefore these curricula could be Krankenhausstraße 12 autonomous unit with an Extraordinariate for brought into the line of modern concepts of 91054 Erlangen Molecular Pneumology (Prof. Dr. S. Finotto) is educational sciences, indicated by a strong ori- Phone: +49 9131 8533676 affiliated to the Chair of Anesthesiology. An entation on competencies and modularisation. Fax: +49 9131 8539191 endowed chair for palliative medicine (Prof. In order to broaden the range of teaching, www.anaesthesie.uk-erlangen.de Dr. C. Ostgathe) has been established since the KfA set up and improved several innova- 2010. The Department of Anesthesiology em- tive teaching projects, like the elective subject Head of Department ploys 112 medical doctors and nine scientific ”perioperative medicine” and an internship in Prof. Dr. med. Dr. h.c. Jürgen Schüttler members with responsibilities in research and the emergency rescue service. We have been teaching. very successful at launching courses for emer- Contact gency care in the fields of pediatric anesthesia Prof. Dr. med. Dr. rer. nat. Helmut Schwilden Research and over several weeks an interprofessional Phone: +49 9131 8539150 one-day-course for all staff of the KfA on crisis Fax: +49 9131 8539161 Clinical and experimental management. In the latter course, a scientific [email protected] pharmacology of anesthesia focus was set on blockings in the communica- This research focus considered a quantitative tion over a hierarchy. Research Focus mathematical modeling of the pharmacokinet- Another focus in the research on medical edu- •• Clinical and experimental pharmacology of ics and pharmacodynamics of anesthetic sub- cation is the study within a virtual environment. anesthesia stances and neuromuscular blocking agents. With the help of two initial fundings by ELAN, •• Research projects furthering the curriculum Aims of this undertaking were: Model identi- the KfA together with the chair for education- and the medical education fication, computer simulation of the dynamics al psychology continued a research project •• Medical technology of diagnostic and thera- in time of anesthetic interventions to improve studying the learning process in a situational peutic procedures scientific study design and for educational pur- simulated environment with the focus on the •• Pain research: Determinants and modulators poses, and model based dosing strategies for determining factors of each type. of perioperative and palliative pain therapeutic optimization. In cooperation with the Department of Oral Pharmacokinetic and pharmacodynamic mod- and Cranio-Maxillofacial Surgery, we start- Structure of the Department eling were performed for hydromorphon and ed a research project in order to improve the sufentanil. In conjunction with the Department emergency competencies of dentists on basis The Department of Anesthesiology maintains of Anesthesiology, University Turku, Finland, of a blended-learning-concept, initiated by an 50 anesthesia units, 37 of which are run con- the pharmacokinetics of the a2-agonist dex- elaborate needs assessment. tinuously, to provide anesthesia service to 15 medetomidine during long term sedation in in- surgical departments or independent divisions tensive care patients were investigated. Special Medical technology of diagnostic and and several diagnostic and interventional de- focus was given on the influence of individual therapeutic procedures partments of the UK Erlangen. The Department variability and covariates. Within the scope of the National Leading Edge of Anesthesiology also includes an outpatient’s The investigation of the clinical pharmacology Cluster Medical Valley EMN for Medical Tech- anesthesia division with a unit for lung function of neuromuscular blocking agents focused on nology, our research is focused on the devel- diagnostics and a pain clinic. The Department the anesthetic management with respect to the opment of new technologies for continuous of Anesthesiology is responsible for the man- interaction of i.v. anesthetics with muscle relax- and variable application of fluid drugs through agement of the interdisciplinary surgical inten- ants, especially for orthopedic surgery caused miniaturized infusion pumps for a personalized, sive care unit with 36 beds and, together with by the disease progression of muscle atrophy patient-individual, and effect-controlled drug the Department of Neurology, holds the Center type Duchenne. treatment. New methods for a more precise for Interdisciplinary Pain Therapy. Additionally, measurement of opioid concentration in blood the Department of Anesthesiology is respon- Research projects furthering the plasma have been developed, and the accuracy sible for the management of the ambulance curriculum and the medical education of existent dosing algorithms has been investi- service for the city of Erlangen, the county of The Department of Anesthesiology (KfA) imple- gated. On the basis of the gathered experienc- Erlangen-Höchstadt, and the Herzogenaurach mented several projects with the aim to gain es, the next step will be the implementation of location. The Department also engages in the further scientific insight as well as to improve new dosing strategies including the patient re- field of air rescue with the air ambulance of the the quality of the curriculum, the medical edu- sponse to the target effect and the monitoring region (Christopher 27) as well as ambulance cation, and training. of analgesic adverse effects by respiratory and aircrafts for repatriation of patients. The KfA made an important contribution for cardio-vascular parameters. The Chair of Anesthesiology of the FAU (Prof. the compilation of the new sample-curriculum In the Medical Technology Test and Demon- Dr. Dr. h.c. J. Schüttler) as well as the extra for the specialization in anesthesiology on be- stration Center (METEAN), we investigated Ordinariates for Experimental Anesthesiology half of the German Medical Association and new methods for continuous and non-invasive (Prof. Dr. Dr. H. Schwilden) and Anesthesiolo- also gave important impetus for the speciali- acquisition of biosignals of the respiratory and gy/Pain Research (Prof. Dr. C. Nau) are locat- zations in intensive care, emergency, and pain cardiovascular system for therapy-relevant pa-

54 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) rameters for hemodynamic monitoring in co- organized as an interdisciplinary lecture series operation with the Fraunhofer Institute for In- in the first lecture week of each term. The area tegrated Circuits and the Max-Schaldach Chair Q14 Pain Medicine was first introduced in 2012 for Medical Technology. An important goal of and has besides anesthesiology contributions this research concentrated on the development from neurology and psychiatry. The curricular of techniques for continuous, non-invasive, class "Klinische Anästhesiologie" teaches the long-term acquisition of the central arterial scientific foundation of anesthesia for surgical blood pressure under daily standard condi- interventions. Additionally, the Department of- tions. A further research goal concentrated on fers six elective classes and some non-curricular the mathematical modeling of the arterial pulse classes in the fields of anesthesiology, intensive wave. care medicine, emergency medicine, pain therapy, and palliative medicine as lectures, intern- Pain research: Determinants and ships, seminars, and exercises. modulators of perioperative and The Department of Anesthesiology hosts the palliative pain oral examination for the European Diploma in An interdisciplinary clinical research unit (KFO Anesthesiology and Intensive Care (EDA). 130, compare own report) focused on postoperative pain that persists beyond the expected Selected Publications healing period. It was funded by the DFG un- Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C til the end of 2012. The interdisciplinary and (2011) Activation of TRPA1 by membrane permeable local anesthetics. Mol Pain, 7: 62 translational team focused on mechanisms in Tschaikowsky K, Hedwig-Geissing M, Braun GG, the peripheral and central nervous system that Radespiel-Troeger M (2011) Predictive value of procalci- contribute to postoperative pain sensitization, tonin, interleukin-6, and C-reactive protein for survival in on the influence of anesthetic and analgesic postoperative patients with severe sepsis. J Crit Care, 26: 54-64 substances as well as on the questions in which Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, cortical and subcortical regions postoperative Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka pain sensitization is represented, which genetic F, Lasischka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, factors determine increased postoperative pain Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert and the risk for the development of persistent PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, pain, and which psychological traits predict Haberkorn U, Brownlee M, Reeh PW, Nawroth PP (2012) Methylglyoxal modification of Nav1.8 facilitates nocicep- postoperative pain. The team employed basic, tive neuron firing and causes hyperalgesia in diabetic neu- disease-, and patient-related methods of pain ropathy. Nat Med, 18: 926-33 research. Iirola T, Ihmsen H, Laitio R, Kentala E, Aantaa R, Kurvinen Other preclinical projects investigated the role JP, Scheinin M, Schwilden H, Schüttler J, Olkkola KT (2012) Population pharmacokinetics of dexmedetomidine during of TRP-channels in hereditary pain diseases, the long-term sedation in intensive care patients. Br J Anaesth, role of the nociceptive-specific ion channels 108: 460-8 Nav1.7 and Nav1.8 in diabetic neuropathy, Muenster T, Mueller C, Forst J, Huber H, Schmitt HJ (2012) and the interaction of Nav1.7 with local anes- Anaesthetic management in patients with Duchenne muscular dystrophy undergoing orthopaedic surgery: a review thetics. of 232 cases. Eur J Anaesthesiol, 29: 489-94 Pain research in palliative medicine focuses on Fechner J, Ihmsen H, Schüttler J, Jeleazcov C (2013) The the improvement of pain therapy of in- and impact of intra-operative sufentanil dosing on post-oper- outpatients with cancer. ative pain, hyperalgesia and morphine consumption after cardiac surgery. Eur J Pain, 17: 562-70 Teaching International Cooperations Prof. Y. Tian, Department of Anesthesiology Tongji Medi- The Department of Anesthesiology organizes cal College, Huazong University for Science and Technol- the three cross-sectional areas Q8, Q12, Q14. ogy, Wuhan: China Professional lecturers and instructors of the Prof. B. Yu, Department of Anesthesiology Rui Jin Hospital, Department of Anesthesiology organize the Shanghai Jiao Tong University, Shanghai: China cross-sectional area Q8 Emergency Medicine Prof. K.T. Olkkola, Department of Anaesthesiology, Inten- and are firmly committed to apply new con- sive Care, Emergency Care, and Pain Medicine, University of Turku, Turku: Finland cepts of teaching, such as the use of teaching Prof. S.G. Waxman, Center for Neuroscience and Regener- simulators installed in the simulation and train- ation Research, Yale School of Medicine, New Haven: USA ing center of the Department of Anesthesiol- Prof. S. Shafer, Department of Anesthesiology, Stanford ogy. Cross-sectional area Q12 Rehabilitation is University Medical School, San Francisco: USA

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 55 UNIVERSITY HOSPITAL

Department of Anesthesiology Division of Molecular Pneumology

Address dren after rhinovirus infection (PreDicta). For transcription factor inducing IFN-g, resulted in Hartmannstraße 14 this study, we collaborate with several groups in enhanced lung tumor load and metastasis far 91052 Erlangen Europe and with the Department of Pediatrics beyond that seen in the wild type littermates in Phone: +49 9131 8535883 and Adolescent Medicine in Erlangen (Prof. Dr. the same model. We are thus currently investi- Fax: +49 9131 8535977 T. Zimmermann’s division of allergy and pul- gating disregulation of anti-tumor immune re- www.molekulare-pneumologie.uk-erlangen. monary diseases). A variety of molecular and sponse present in T-bet deficient mice to better de/ cellular methods is applied for the investigation understand this disease. Moreover, we recently of isolated and purified lung immuno-compe- found increased IL-17A in the absence of T-bet Head of Division tent cells. We are indebted to the numerous and are investigating the role of IL-17A in lung Prof. Dr. rer. nat. Susetta Finotto, PhD collaborations with different scientific depart- adenocarcinoma both, in experimental setting ments worldwide which are providing us with as well as in translational studies in humans. Contact updated material to advance our understand- Along with IL-17A, we are investigating the role Prof. Dr. rer. nat. Susetta Finotto, PhD ing and improvement of the therapy against of IL-6 and TGF-b, two Th17 inducing cytokines Phone: +49 9131 8535883 these two world spreading lung diseases. in lung adenocarcinoma. Allergic asthma is a Fax: +49 9131 8535977 disease characterized by imbalance of the [email protected] Research CD4+ T helper cell subsets Th2/Th1 cytokines and transcription factors with a pathological Research Focus Immunopathogenesis of lung tumor expansion of the Th2 cells associated with a •• Immunopathogenesis of lung tumor and and allergic asthma defect in T regulatory cells. We first identified allergic asthma During the last five years our laboratory identi- GATA-3 as the main transcription factor of Th2 fied a number of genes which play a protective cells involved in the pathogenesis of allergic Structure of the Department or pathogenetic role in the immuno-regulation asthma and blocked it locally by intranasal of lung cancer development. Some examples delivery of an antisense molecule achieving in- The Division of Molecular Pneumology consists for those genes are described below: EBV-inhibition of inflammation, airway hyperrespon- of eleven employees, currently supported by duced gene 3 (EBI-3) encodes for a soluble type I siveness in treated mice comparable to steroid the Division, a grant from the SFB 643 (Role receptor homologous to the p40 subunit of treatment. We then discovered that targeted of NFAT family members in lung tumor), the IL-12 that is expressed by APCs following acti- deletion of T-bet in experimental asthma re- DFG (Immuno-regulatory role of IL-28/Interfer- vation. In a recent study we demonstrated that sulted in an asthmatic phenotype. Local block- on l in allergic asthma), the GK (Role of BATF targeting EBI-3 leads to a T-bet-mediated CD8+ ade of IL-13 in T-bet deficient mice resulted in in allergic asthma), and the European grant anti-tumor T cell response in a murine model amelioration of the asthmatic phenotype in the (Post-infectious reprogramming and its asso- of lung melanoma. T-bet (T-box-expressed in absence of T-bet. Moreover, blockade of the a ciation with persistence and chronicity of res- T cells) is a transcription factor expressed by chain of the IL-6R resulted in local expansion piratory allergic diseases, PreDicta). Research is T cells which controls Interferon g production. of positive CD4+CD25+FoxP3+ Tregs with in- conducted by ten scientists (besides Chairman T regulatory cells are also known as T suppres- creased immunosuppressive functions. Thus, one postdoctoral fellow, five PhD students, sor cells because they inhibit the immuno-re- we found that local inhibition of IL-6 signaling and four technicians). The team investigates sponse and as such are increased in tumor. It emerges as a novel molecular approach for the the immunological responses present in exper- is therefore the aim of our research to set up treatment of allergic asthma. We are currently imental lung tumor and allergic asthma. This therapeutical tools to inhibit the T regulato- investigating the role of IL-6 in T-bet deficiency comprises analysis of the lung tumor infiltrating ry cells which are present in the lung bearing induced asthma. In addition, Tyrosine kinase lymphocytes and lung lymphocytes present in tumor. It has been recognized that the most 2 (Tyk2) is an ubiquitously expressed member allergic asthma. In collaboration with the Divi- important transcription factor of the T regu- of the mammalian Janus kinase (JAK) family of sion of Thoracic Surgery, directed by Prof. Dr. latory cells is Forkhead box P 3 (FoxP-3). We non-receptor protein tyrosine kinases which H. Sirbu, the Institute of Pathology (Prof. Dr. A. have recently described reduction of Nuclear consists of three additional kinases (JAK1-3). Hartmann and Prof. Dr. R. Rieker), and Prof. Dr. Factor of Activated T cells -2 (NFATc2) mRNA We recently discovered that Tyk-2 signaling is L. Bräuer/Dr. M. Schicht of the Chair of Anato- expression in the lungs of patients with bron- involved in IL-17A production and are analyz- my II at the FAU, our Division analyzes changes chial adenocarcinoma. Engagement of GITR ing the molecular mechanism involved in this in immunological parameters at the protein with an agonistic antibody, known to suppress disregulation. and mRNA level in tissue after lung resection, T regulatory cells and expand effector T cells, obtained from patients with lung tumor. The in NFATc2 (-/-) mice induced IFN-g in the air- Teaching aim of this study is to identify important genes ways which reversed the suppression by T(reg) involved in the pathogenesis of lung cancer to cells, and co-stimulated effector and memory The Division is teaching basic immunology at set up new experimental molecular therapeuti- T cells, resulting in abrogation of carcinoma the Division of Molecular Immunology and at cal strategies to cure lung cancer. In addition, progression delineating new possible strategies the Institute of Clinical Microbiology, Immunol- we recently received support from a European to turn on an immunoresponses in lung cancer. ogy, and Hygiene of the FAU. Seminars using Grant, investigating the immunological re- We recently described that targeted deletion electronic media are given on a weekly basis to sponse in asthmatic and non-asthmatic chil- of T-bet (T-box expressed in T cells), the main train new students in the Division.

56 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Selected Publications Koltsida O, Hausding M, Stavropoulos A, Koch S, Tzelepis G, Ubel C, Kotenko SV, Sideras P, Lehr HA, Tepe M, Klucher KM, Doyle SE, Neurath MF, Finotto S, Andreakos E (2011) IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease. EMBO Mol Med, 3: 348-61 Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev, 22: 83-9 Reppert S, Boross I, Koslowski M, Türeci Ö, Koch S, Lehr HA, Finotto S (2011) A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer. Nat Commun, 2: 600 Andreev K, Graser A, Maier A, Mousset S, Finotto S (2012) Therapeutical measures to control airway tolerance in asthma and lung cancer. Front Immunol, 3: 216 Karwot R, Übel C, Bopp T, Schmitt E, Finotto S (2012) In- creased immunosuppressive function of CD4(+)CD25(+) T cell differentiation in allergic asthma Foxp3(+)GITR+ T regulatory cells from NFATc2((-/-)) mice After allergen challenge, dendritic cells mature and re- controls allergen-induced experimental asthma. Immu- lease proinflammatory mediators, such as IL-6 which nobiology, 217: 905-11 directs Th0 differentiation into Th2 cells which in turn Neurath MF, Finotto S (2012) The emerging role of T cell releases IL-4, IL-5, and IL-13, and are increased in aller- cytokines in non-small cell lung cancer. Cytokine Growth gic asthma. IL-6 inhibits T regulatory cells and Th1 cells, Factor Rev, 23: 315-22 both known to have a protective role in asthma.

International Cooperations Prof. N.G. Papadopoulos, Allergy and Clinical Immunol- ogy Unit, 2nd Pediatric Clinic, National and Kapodistrian University of Athens (NKUA), Athens: Greece Prof. M.L. Kowalski, Department of Immunology, Rheu- matology and Allergy, Faculty of Medicine, Medical Uni- versity, Central University Hospital, Medical University of Lodz, Lodz: Poland Dr. C. Bachert, Upper Airway Research Laboratory (UGENT), University of Ghent, Ghent: Belgium T. Jartti, MD, Department of Pediatrics, Turku University Hospital, Hospital District of Southwest Finland, Turku: Finland Dr. C. I. Ho, MD, Department of Rheumatology, Harvard University, Brigham and Women’s Hospital, Boston, Mas- sachusetts: USA L.H. Glimcher, MD., Weill Cornell Medical College, New York: USA

Lung Tumour infiltrating Lymphocytes (TIL) In lung adenocarcinoma, we found that lung tumor infiltrating lymphocytes release much IL-17A, a cytokine which inhibits according to our findings interferong (IFN-g), an anti-tumor cytokine. IL-17R= IL-17A receptor

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 57 UNIVERSITY HOSPITAL

Department of Anesthesiology Division of Palliative Medicine

Address Research This documentation system is recommended Krankenhausstraße 12 by the DGP for quality management of pallia- 91054 Erlangen Outcome Criteria and Quality Indica- tive care services. It assesses a data set with per- Phone: +49 9131 8534064 tors in Palliative and Hospice Care in sonal data of patients, their social situation, the Fax: +49 9131 8534066 Germany stage of their disease, the individual symptom www.palliativmedizin.uk-erlangen.de Currently, the discussion about appropriate burden, current medication, and all measures quality indicators in palliative medicine is con- and activities carried out to support the patient Head of Division troversial and still open. Whilst quality indica- as well as satisfaction with treatment. Core data Prof. Dr. med. Christoph Ostgathe tors for symptom control are widely established from HOPE is transferred to the National Hos- (e.g. symptom check lists), there is a lack of pice and Palliative Care Register and used for a Contact generally accepted indicators for psychosocial nationwide benchmarking of institutions. Prof. Dr. med. Christoph Ostgathe and spiritual support. Therefore, the task force We succeeded in publishing further investiga- Phone: +49 9131 8534064 `research´ of the German Association of Palli- tions on this research topic in 2012: The vali- Fax: +49 9131 8534066 ative medicine (DGP) initiated a research pro- dation of the symptom- and problem checklist [email protected] gram for the identification of outcome criteria of HOPE investigated - according to the self-as- as quality indicators in palliative medicine. sessment instrument Minimal Documentation Research Focus The research program is divided in several System (MIDOS²) - the extended multidimen- •• Outcome Criteria and Quality Indicators in phases: sional symptom and problem checklist (HOPE- Palliative and Hospice Care in Germany The first phase is relating to the record of ma- SP-CL) from the core documentation HOPE. •• Quality Management in Palliative Care in terial dimensions and ongoing used measuring Another publication on the use of antibiotics in Germany devices. A discourse analysis for the definition palliative medicine reflects barriers and strate- •• Desire for Hastened Death in Patients Receiv- of palliative medicine and a focus group discus- gies for decision-making, indication, treatment ing Palliative Care sion on outcome indicators were performed and withdrawal and withholding of antibiotics. Fears concerning life-shortenings effects or •• Health Care Research published. Furthermore, a systematic analysis of literature towards ongoing measuring de- prolongation of the dying phase are discussed. Structure of the Department vices was conducted. The corresponding orig- Special research attempts were focused on the inal publication deals with the question how non-cancer patients in specialized palliative The Division of Palliative Medicine provides quality in palliative care can be determined. care in Germany. care to patients suffering from advanced or The second project phase is meant to describe More research attempts concentrated on the analysis of subjective definitions of symptoms terminal disease and aims at improving qual- meta-concepts and to develop a framework for the evaluation of central outcome indicators. and problems from team members in palliative ity of life for patients and their relatives. The In the third project phase, potential quality in- care. holistic view of care requires flexible and indicators will be identified and evaluated. dividual concepts of different professionals. In a subproject of OPCARE9 "European collabo- Desire for Hastened Death in Patients Since July 2011, the palliative care consulta- ration to optimise research and clinical care for Receiving Palliative Care tion team (physicians, nurses, psychosocial cancer patients in the last days of life", quality Project managers: Dr. S. Stiel, Prof. Dr. C. Ost- worker) has adviced other hospital units of indicators were tested upon feasibility for use in gathe the UK Erlangen on inquiry. Advice can be the dying phase (2012). Overall, 34 indicators A multicenter study funded by the DFG investi- given for palliation of symptoms, palliative relating to the dying phase could be identified gated three highly relevant topics using mixed care, psychosocial support, counseling in and seven of them were evaluated useable for methodology. Two work packages will be in- modification of therapy objective, medical in- clinical practice. The development of valid and troduced here. formation, and clarification of further patient reasonable indicators is of special interest for a) The desire for hastened death (DhD) in ter- care. the dying phase. minally ill patients is an important end-of-life is- Research is besides clinical practice and sue. Although this wish is expressed only by few teaching one of the main cornerstones of this Quality Management in Palliative Care patients receiving palliative care, it may cause academic palliative care institution. Our re- in Germany a challenging dilemma. In order to investigate search aims at the development, evaluation, Project managers: Prof. Dr. C. Ostgathe, Dr. S. the motivations and expectations of patients and improvement of palliative and hospice Stiel asking for hastened death, we conducted a care services and structures and at specific The discussion about suitable quality indicators qualitative study using Grounded Theory (GT). treatment approaches for seriously ill and in palliative care and nationwide quality man- b) To be able to study DhD in patients receiv- dying patients. Although research in this vul- agement is a current research topic in Germany. ing palliative care, research tools reflecting the nerable population of patients is limited by Since 1996, a working group has developed a thoughts of patients are needed. The German patient characteristics, research projects tak- standardized basic documentation tool (Hos- version of the assessment tool „Schedule of ing these limitations into account are ethical pice and Palliative Care Evaluation (HOPE)) for Attitudes towards Hastened Death” (SAHD) and justifiable. palliative care patients in Germany. was validated. We investigated whether the

58 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) SAHD-D is appropriate to assess (1) DhD in pa- Teaching Selected Publications tients with little burden, (2) the characteristics Ostgathe C, Alt-Epping B, Golla H, Gaertner J, Lindena G, and intensity of DhD, and (3) the desire in fol- Our goal in teaching palliative care is to relate Radbruch L, Voltz R, the Hospice and Palliative Care Evalu- ation (HOPE) Working Group (2011) Non-cancer patients low-up sessions. medical knowledge in specific aspects of palli- in specialized palliative care in Germany: What are the The validation of the SAHD-D illustrates good ative medicine (symptom control, communica- problems? Palliat Med, 25: 148-152 discriminant validity, demonstrating that de- tion skills, weighing possible therapeutic goals Voltz R, Galushko M, Walisko J, Karbach U, Ernstmann N, pression, anxiety, physical state, and DhD are and treatment regimens in advanced disease, Pfaff H, Nauck F, Radbruch L, Ostgathe C (2011) Issues of ethical decisions). We also try to create a set- “life” and “death” for patients receiving palliative care - separate constructs. The unidimensionality of comments when confronted with a research tool. Support the SAHD could not be reproduced. The cri- ting for our students to support reflecting their Care Cancer, 19: 771-7 terion validity is insufficient. The field notes bearing and values pertaining advanced dis- Raijmakers N, Galushko M, Domeisen F, Beccaro M, Lundh suggest that DhD has to be differentiated into eases, dying, and death. In our way to teach Hagelin C, Lindqvist O, Popa-Velea O, Romotzky V, Schuler palliative medicine, we try to reflect our goals S, Ellershaw J, Ostgathe C; OPCARE9 (2012) Quality indi- actual and non-actual DhD. cators for care of cancer patients in their last days of life: in teaching. Almost exclusively we teach small literature update and experts‘ evaluation. J Palliat Med, Health care research groups of students and our tutors come from 15: 308-16 Project managers: Prof. Dr. C. Ostgathe, Dr. C. all sections of the multidisciplinary team. Stiel S, Pollok A, Elsner F, Lindena G, Ostgathe C, Nauck F, Radbruch L (2012) Validation of the Symptom and Prob- Klein Our teaching scope encompasses: - Mandatory classes in palliative care; lem Checklist of the German Hospice and Palliative Care There are several approaches in health care re- Evaluation (HOPE). J Pain Symptom Manage, 43: 593-605 - Voluntary course (symptom control, measures search that aim at implementing recommenda- Stiel S, Krumm N, Pestinger M, Lindena G, Nauck F, Ost- in dying patients, hospice work in Germany, tions of the World Health Organisation (WHO) gathe C, Radbruch L, Elsner F (2012) Antibiotics in palli- ethical questions, nursing in palliative care, ative medicine-results from a prospective epidemiological into palliative care practice. The feasibility and psychology in palliative care); investigation from the HOPE survey. Support Care Cancer, benefit of integration of palliative care early 20: 325-33 - Voluntary course (treatment of two virtual pa- within patients' disease trajectories as recom- tients in a setting of case-based learning); Stiel S, Pastrana T, Balzer C, Elsner F, Ostgathe C, Radbruch mended by the WHO was investigated. L (2012) Outcome assessment instruments in palliative - Voluntary classes (talks on different aspects of and hospice care - a review of the literature. Support Care Although a better utilization and understanding palliative care); Cancer, 20: 2879-93 of palliative care could be demonstrated with - Voluntary participation in rounds and team the "early integration" approach, the adoption meetings; International Cooperations of the WHO recommendation was not enough - Talks on contemporary aspects of palliative OPCARE9: an EU 7th Framework Collaboration & Support to integrate palliative care into routine cancer care medicine (students, health professionals, Action grant to optimise research for the care of cancer patients in the last days of life: Europe care early in the course of the illness. Therefore, and open to the public); the development of disease specific guidelines - Colloquium on scientific approaches in med- Meetings and International Training is advocated. icine. Courses A central project of the Division (funded by Mandatory and voluntary teaching by our Divi- ELAN) is the attempt that aims at generating 12.02.2011: 11. Erlanger Schmerz- und Palliativtag, UK sion is continually evaluated both, in regard to Erlangen, Erlangen an image of the clinical practice of palliative se- formative as well as academic aspects. 10.-11.02.2012: 12. Erlanger Schmerz- und Palliativtage, dation (PS) in Germany which may enable the In addition to classes held exclusively by our UK Erlangen, Erlangen development of a national guideline based on Division, we take part in classes held by other 16.-20.07.2012: Ausrichtung einer Präsenzwoche für den the framework for PS of the EAPC. Therefore, medical faculties (e.g. anesthesiology, medical Studiengang Master in Palliative Care der Dresden Inter- all palliative care institutions listed in official sociology, medical psychology, anatomy) and national University (DIU), UK Erlangen, Erlangen address registers were asked by questionnaire other specialties (medical process manage- about their clinical practice of PS. ment, psychogerontology) at the FAU.

Silence room

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 59 UNIVERSITY HOSPITAL

Department of Cardiac Surgery Chair of Cardiac Surgery

Address the abdominal aortic allograft model as a suit- onary blood flow and reduce the coronary re- Krankenhausstraße 12 able tool to study the development of trans- sistance and the mean arterial blood pressure. 91054 Erlangen plant arteriosclerosis. Ongoing projects involve Furthermore, CGRP was demonstrated to be Phone: +49 9131 8533319 the role and importance of chemokines and cardio-protective and reduce the infarct size of Fax: +49 9131 8532768 chemokine-receptors, in particular CCR7 and myocardial infraction. www.herzchirurgie.med.uni-erlangen.de CXCR5, in the development of transplant arte- The aim of our project (cooperation with Prof. riosclerosis. CCR7, the major homing receptor Dr. K. Messlinger, Institute of Physiology and Head of Department for trafficking of T and B cells, plays a crucial Pathophysiology) is to develop an experimen- Prof. Dr. med. Michael Weyand role in leukocyte homing. Experiments using tal mouse model in order to investigate the ef- CCR7-/- mice as recipients of aortic allografts fects and kinetics of CGRP production in great- Contact showed increased amounts of transplant arte- er detail. In addition, analyses of human CGRP Prof. Dr. med. Michael Weyand riosclerosis during the absence of this receptor production are planned by using tissue from Phone: +49 9131 8533319 and suggest an interesting role of this recep- the right ventricle or ascending aortic tissue. Fax: +49 9131 8532768 tor in this disease. Recent findings implicate [email protected] an important role of human cytomegalovirus Hospital-economics and management infection (HCMV) for the development of in- Project managers: PD Dr. R. Feyrer, U. Kunz- Research Focus flammatory-proliferative vascular lesions in mann •• Chronic rejection of allografts transplanted vascularised allografts. Therefore, This group is a collaboration between the •• Therapy of end-stage heart failure: Heart the major aim of this project is to develop a Department of Cardiac Surgery and the com- transplantation or support with a left or right human peripheral blood lymphocyte (hu-PBL)/ petent office of Healthcare Resource Groups ventricular assist device severe combined immunodeficiency (SCID) (DRGs). One of the main tasks of this group •• Neuropeptide release of the heart mouse xenograft-model to investigate the im- since the introduction of the DRGs has been •• Hospital-economics and management munological and pathological mechanisms of to face the changes in hospital reimbursement •• The arterialization of cardiac veins as an al- HCMV in the modulation and progression of from retrospective payment to a prospective ternative myocardial revascularization strate- transplant arteriosclerosis. flat rate payment. Other current projects in- gy in an experimental long term model in volve the development of the so called ‘clin- pigs Therapy of end-stage heart failure: ical pathways’ in order to improve cost unit •• Tissue engineering of cardiovascular im- Heart transplantation or support with calculations and enable us to create comput- plants a left or right ventricular assist device er-simulated scenarios of complex problems of Orthotopic cardiac transplantation is the ther- hospital cost management. In cooperation with Structure of the Department apy of choice for cardiac insufficient patients. the Department of Anesthesiology, we perform Due to an increasing shortage of donor organs, a study analyzing the costs involving intensive 20 medical doctors work in the Department of a considerable number of patients dies. If nec- care patients, and together with the German Cardiac Surgery. The research is accomplished essary, these patients can be bridged with an Heart Center in Berlin, we are trying to set up a by all medical doctors, seven graduate stu- implantable ventricular assist device until a database regarding long-term costs of patients dents, and two technical assistants. suitable donor organ is available. In some cases on cardiac assist devices. heart disease has already progressed to such an Research extent that the patients need to be stabilized The arterialization of cardiac veins as with a left ventricular assist device or - in case an alternative myocardial revascula- Chronic rejection of allografts of additional right heart failure - with a biven- rization strategy in an experimental Today transplant arteriosclerosis represents tricular assist device. long term model in pigs the major obstacle for indefinite graft survival In ischemic hearts, venous retroperfusion is a and has become the leading cause of death Neuropeptide release of the heart potential myocardial revascularization strategy. in cardiac transplant recipients who survive Project manager: PD Dr. T. Strecker The goal underlying retrograde coronary sinus beyond the third year after transplantation. Calcitonin-Gene Related Peptide (CGRP) is a (CS) perfusion is perfusion of the ischemic myo- Pharmacological agents that effectively prevent neuropeptide consisting of 37 amino acids and cardium proximal to the occlusion or steno- acute graft rejection have proven inadequate its biological action results in a strong vasodil- sis. The lack of suitable target vessels remains for averting late graft loss caused by transplant atation. CGRP is mainly produced by the sen- a challenge for aortocoronary bypass grafting arteriosclerosis. Transplant arteriosclerosis is the soric A-d- and C-fibres. Recent data suggested in end stage coronary heart disease. This study main reason for late graft failure and develops that it may play an important role in myocar- aimed at investigating the arterialization of car- in all other vascularized organ transplants, such dial ischemia. Neural fibres with a high CGRP diac veins as an alternative myocardial revascu- as liver and kidney. In order to develop effec- content are found in both atria, the pericar- larization strategy in an experimental long term tive therapeutical strategies and translate them dium and within the adventitia of coronary ar- model in pigs. into clinical success, a detailed understanding teries. Changes in CGRP production correlate In a pig model of myocardial ischemia, selective of the mechanisms responsible for the develop- with increased activity within cardiac afferent retrograde perfusion of a coronary vein (aorta ment of transplant arteriosclerosis is essential. fibres. It was shown in vitro that elevated CGRP to coronary vein bypass, retrobypass) was per- We have recently established and characterized concentrations were able to increase the cor- formed. A ligation of the ramus interventricu-

60 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) laris paraconalis (equivalent to the left ante- on RGD-PEG hydrogels, both cell lines showed rior descending artery (LAD) in humans) was a reduced cell speed on RGD plus RYVVLPR performed in 20 German landrace pigs (Sus and RGD plus DGEA (MVEC: -22% on RYVVL- scrofa domestica). Retroperfusion (RP) of the PR+RGD, -21% on DGEA+RGD; SMC: -27% on concomitant vein of the LAD was performed in RYVVLPR+RGD, - 22% on DGEA+RGD). For the four pigs (RP+), but not in the other four (RP-), combination of SIKVAV and RGD, only MVEC and the vena cordis magna (VCM) was ligated showed a small, but not significant increase in (L+) in four pigs in each of these groups, but mobility whereas SMC did not show any dif- left open (L-) in the remaining animals. ference. Hemodynamic performance (e.g. cardiac output) was significantly better in RP+L+ (4.1 L/ Teaching min) pigs that underwent selective retroperfusion with proximal ligation of vena cordis mag- Beside the traditional teaching forms (main na as compared to all other animals (RP+L-, lecture and practical courses), hospitations and 2.5 L/min), (RP-L+, 2.2 L/min), (RP-L-, 1.9 L/ fellowships can be undertaken anytime. min). Long term survival was significantly better in RP+L+ pigs (112 +16 d) than in all other Selected Publications groups. Histological follow-up studies showed Harig F, Schmidt J, Hoyer E, Eckl S, Adamek E, Ertel D, significantly smaller area of necrosis in all ani- Nooh E, Amann K, Weyand M, Ensminger SM (2011) mals of the RB+L+ group. Long-term evaluation of a selective retrograde coronary venous perfusion model in pigs (Sus scrofa domestica). Venous retroperfusion is an effective technique Comp Med, 61: 150-7 to achieve long term survival after acute LAD Heim C, Eckl S, Abele-Ohl S, Ramsperger-Gleixner M, occlusion in a pig model. In this setting, prox- Mahmoudian S, Stamminger T, Weyand M, Ensminger SM imal ligation of V. cordis magna is mandatory. (2011) Murine Cytomegalovirus Infection Is Associated with Increased Number of T- and Dendritic Cells in Murine Aortic Allografts J Heart Lung Transplant, 30 S: S138-S138 Tissue engineering of cardiovascular Ramsperger-Gleixner M, Spriewald BM, Tandler R, Kon- implants druweit M, Amann K, Weyand M, Ensminger SM (2011) The background for these studies is the devel- Increased transcript levels of TNF-a, TGF-b, and granzyme opment of an ingrowth matrix within the tissue B in endomyocardial biopsies correlate with allograft rejection. Exp Clin Transplant, 9: 387-92 engineering of cardiovascular grafts. The purpose of these investigations is to show whether Strecker T, Munch F, Weyand M (2012) One hundred ten days of extracorporeal membrane oxygenation in a young it is possible to influence the mobility of en- women with postpartum cerebral venous thrombosis and dothelial cells, smooth muscle cells, and fibro- acute respiratory distress syndrome. Heart Surg Forum, blasts within a fully synthetic matrix by incor- 15(4): 180-E181 porating bioactive peptides. The purpose is to Abele-Ohl S, Leis M, Wollin M, Mahmoudian S, Hoffmann define a matrix which provides optimal mobili- J, Müller R, Heim C, Spriewald BM, Weyand M, Stam- minger T, Ensminger SM (2012) Human cytomegalovirus ty for those cells needed for a functional cardio- infection leads to elevated levels of transplant arterioscle- vascular implant. Such a matrix could be inte- rosis in a humanized mouse aortic xenograft model. Am J grated into a cardiovascular prosthesis in order Transplant, 12: 1720-9 to facilitate and direct the ingrowth of the pa- Abele-Ohl S, Heim C, Eckl S, Weyand M, Stamminger T, tient’s own tissue. A single cell migration model Ensminger SM (2012) Procurement regimens to reduce ischemia reperfusion injury of vascular grafts. Eur Surg Res, was used to compare the influence of different 49: 80-7 cell interactive peptides on the mobility of vascular cell lines as microvascular endothelial cells (MVEC) and aortic vascular smooth muscle cells (SMC). In previous studies it could already be shown that selectively MVEC, but not SMC accelerate on a PEG matrix covered with RGD (fibronectin) and YIGSR (laminin) in comparison to a matrix covered only with RGD. These experiments were extended to the peptide sequences SIKVAV, RYVVLPR (both laminin), and DGEA (collagen) also known from the literature as being vascular cell interactive. For sufficient cellular adhesion, RGD was added to the matrix again. At an average migration speed of 21.1 µm/h for MVEC and 26.9 µm/h for SMC

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 61 UNIVERSITY HOSPITAL

Department of Cardiac Surgery Division of Pediatric Cardiac Surgery

Address aortic arch surgery is currently performed in hy- cardioprotective qualities. Surgical standard Loschgestraße 15 pothermic low-flow perfusion, avoiding deep for newborns and children is the use of cold 91054 Erlangen hypothermic circulatory arrest. Our research christalloid cardioplegic solutions. In the field Phone: +49 9131 8534010 in this topic was awarded with the highest sci- of adult cardiac surgery, blood cardioplegia Fax: +49 9131 8534011 entific award of the German Society for Tho- has been established for a long time especially www.kinderherzchirurgie.uk-erlangen.de racic and Vascular Surgery. Other parts of the for critically ill patients. The myocardial study research project received the "Congenital Heart group aims at optimal cardioprotection for chil- Head of Division Surgery Award" from the EACTS (European As- dren with congenital heart disease through use Prof. Dr. med. Robert Cesnjevar sociation for Cardio-Thoracic Surgery). Current of a modified blood cardioplegia. Therefore ex- animal experiments are validating the practi- tensive blood and hemodynamic analyses are Contact cability of hypothermic low-flow perfusion in being collected and documented in a detailed Prof. Dr. med. Robert Cesnjevar combination with a beating-heart technique. patient register. Phone: +49 9131 8534010 The experimental setup is funded by the ELAN- Fax: +49 9131 8534011 Fond of the Faculty of Medicine. Reconstruction of the right ventricular [email protected] outflow tract Biomaterial bank for congenital A large number of congenital heart defects Research Focus heart disease require surgical reconstruction of the right •• Aortic arch surgery In cooperation with the Division of Pediatric ventricular outflow tract with or without place- •• Biomaterial bank for congenital heart disease Cardiology (Dr. O. Toka), a database and stor- ment of a pulmonary valve. Biological valved conduits are often used although they have •• Development of new surgical procedures age option for tissue samples was established to be replaced over time. Major problems are and treatment of strategies for the univen- in September 2008. Tissue samples routinely the lack of growth and valvar degeneration. tricular heart removed and resected during surgery are sys- Implantation of decellularized valves is widely •• Myocardial protection - comparative study tematically collected for examination in co- propagated as being the ultimate solution to of variant cardioplegic solutions operation with the Institute of Pathology and this dilemma. In collaboration with the De- •• Reconstruction of the right ventricular out- preserved for further studies afterwards. Erlan- partment of Medicine 2 - Cardiology and An- flow tract gen has the largest tissue sample database for giology (Prof. Dr. C. Garlichs, PD Dr. Y. Cicha), •• Role of thymic tissue in immune cell differ- children with congenital heart disease. Dr. O. explanted decellurized tissue valves were sys- entiation Toka has been awarded for this project by the tematically examined. It could be shown that •• Migration of plasticizers into patients blood ”German Foundation for Cardiac Research”. pathological mechanisms responsible for degeneration of decellularized valves are similar Structure of the Department Development of new surgical proce- to those of other valved conduits (xenografts, dures and treatment of strategies for homografts). Four doctors cover the medical service in the the univentricular heart However, tissue engineering will hopefully re- newly established Division of Pediatric Cardiac One of the most hazardous defects in congen- sult in the production of implantable, non-an- Surgery. Patient care is provided in close co- ital heart disease is the hypoplastic left heart tigenic and growing bioimplants in the near operation with the Division of Pediatric Cardi- syndrome. Staged treatment requires three future. Thus, further research in this field makes ology. In May 2009, the ”expert network for operations, each of them carrying a substan- a lot of sense. patients with congenital heart disease in north- tial risk of mortality. The aim of our Division is ern Bavaria” was founded by both divisions in to lower the operative risk to the level of stan- Role of thymic tissue in immune cell cooperation with all pediatric cardiologists in dard neonatal operations. The first surgical step differentiation the north Bavarian region. Using a new tele- (Norwood I) carries a mortality risk of about In cooperation with the Department of Der- medicine platform, optimal patient care after 30% in Europe. In conjunction with the Division matology (Prof. Dr. D. Dudziak) and the De- surgical or interventional procedures is much of Pediatric Cardiology, we have established partment of Medicine 5 - Hematology and easier to achieve. Currently, eight medical stu- processes to lower the risk of mortality below Oncology (Prof. Dr. E. Ullrich), a project about dents are involved in scientific projects. 15% for hypoplasts. In parallel, we have devel- differentiation of immunocompetent cells of oped a novel surgical technique for the first step children with congenital heart defects was Research in the treatment of patients with hypoplastic started. Routinely removed thymus tissue is left heart syndrome in December 2010 which processed systematically in order to examine its Aortic arch surgery was approved by the ethics committee. immune-competent cells. The same character- Surgery of the aortic arch has been a research izations are carried out in the peripheral blood focus of the Division of Pediatric Cardiac Sur- Myocardial protection - comparative of patients. Research is focused on thymus sub- gery for a long time and several organ protec- study of variant cardioplegic solutions populations in order to gain information about tive perfusion methods have been introduced One project investigates myocardial protection the natural maturation of the immune system. by the research group into clinical practice. during routine operations. Variant cardioplegic The project is funded by the ELAN-Fond of the Based on our own research results, pediatric solutions are being investigated concerning Faculty of Medicine.

62 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Migration of plasticizers into International Cooperations patients blood Prof. Dr. M.R. de Leval, Cardiothoracic Unit, Great Or- Current studies focus on migration of phthalate mond Street Hospital, London: UK plasticizers (DEHP) from the cardiopulmonary Prof. Dr. A. Philips, Cincinnati Children´s, Cincinnati: USA bypass circuit into the patients blood. These Prof. Dr. J. Cheatham, Nation Wide Children´s Hospital, plasticizers are toxic, especially in children. Columbus: USA In cooperation with the Institute and Outpatient Clinic of Occupational, Social, and Environmen- tal Medicine (Prof. Dr. T. Göen), the Division of Pediatric Cardiac Surgery investigates leaching of alternative plasticizers and investigates alternative materials which do not contain plasticizers. The topic is of paramount importance. In the past years phthalate contaminants were repeatedly found in plastic toys, baby bottles, and soothers. It has been proven that phthalate plasticizers are endocrinal disruptors and provoke change in the development of reproductive organs and fertility which is of particular interest in children.

Teaching Heart with hypoplastic left heart syndrome in comparison to the surgeon’s hand Main lecture, internship, and clinical trainee- ship are being held throughout the year. Special operative techniques, anatomic considerations, and pathogenesis of congential heart disease are being taught in separate student tutorials in small groups. Teaching is supported by modern technical equipment. All operative steps could be followed on additional screens in the operating theatre.

View in the operating theater Selected Publications Cicha I, Rüffer A, Cesnjevar R, Glöckler M, Agaimy A, Dan- iel WG, Garlichs CD, Dittrich S (2011) Early obstruction of decellularized xenogenic valves in pediatric patients: involvement of inflammatory and fibroproliferative processes. Cardiovasc Pathol, 20: 222-31 Dragu A, Birkholz T, Kleinmann JA, Schnürer S, Münch F, Cesnjevar R, Schmidt J, Taeger C, Kneser U, Horch RE (2011) Extracorporeal perfusion of free muscle flaps in a porcine model using a miniaturized perfusion system. Arch Orthop Trauma Surg, 131: 849-55 Ruffer A, Cicha I, Dittrich S, Cesnjevar RA (2011) Re: Ear- ly failure of xenogenous de-cellularised pulmonary valve conduits: a word of caution! Reply. Eur J Cardiothorac Surg, 39: 284-284 Rüffer A, Arndt F, Potapov S, Mir TS, Weil J, Cesnjevar RA (2011) Early Stage 2 Palliation Is Crucial in Patients With a Right-Ventricle-to-Pulmonary-Artery Conduit. Ann Thorac Surg, 91: 816-22 Rüffer A, Wittmann J, Potapov S, Purbojo A, Glöckler M, Koch AM, Dittrich S, Cesnjevar RA (2012) Mid-term experience with the Hancock porcine-valved Dacron conduit for right ventricular outflow tract reconstruction. Eur J Car- diothorac Surg, 42: 988-95 Rüffer A, Webinger J, Glöckler M, Purbojo A, Dittrich S, Cesnjevar RA, Carbon R (2012) Pericardial cyst or terato- ma? Change of strategy during mediastinal tumor surgery. Thorac Cardiovasc Surg, 60: 488-90

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 63 UNIVERSITY HOSPITAL

Department of Dermatology Chair of Skin and Venereal Diseases

Address The production and clinical testing of inno- low for the clinical application of CAR-transfect- Ulmenweg 18 vative cellular therapies is the task of the Ex- ed T cells. 91052 Erlangen perimental Immunotherapy Unit which is or- Phone: +49 9131 8533661 ganized into the GMP laboratory and a clinical Functional role of dendritic cell sub- Fax: +49 9131 8536175 trial unit. Close interaction with the Derma- populations and antigen presentation www.hautklinik.uk-erlangen.de tooncology and the FACS and Immunomon- Project manager: Prof. Dr. D. Dudziak itoring Core Unit is essential. Metastasized The Emmy-Noether and BayGene research Head of Department melanoma patients have been vaccinated with group ‘Dendritic Cell Biology’ focuses on Prof. Dr. med. Gerold Schuler autologous ex vivo generated tumor-peptide the characterization of murine and human loaded DCs, and more recently with DCs DC subsets. DCs as most important antigen Contact electroporated with mRNAs coding for de- presenting cells direct immune responses Prof. Dr. rer. nat. Diana Dudziak fined tumor antigens (Mage-A3, MelanA, and tolerance. By antigen-coupled antibod- Phone: +49 9131 8539346 and survivin). This strategy not only allows a ies murine DC can be loaded with antigens Fax: +49 9131 8539347 broader immune response, but alleviates the in vivo. Depending on the DC subpopulation [email protected] restriction to certain HLA haploytpes inherent the group found that T cell responses could to the use of peptides. This RNA-DC approach be directed and were either CD4+ T-helper Research Focus is now optimized for vaccination against mu- responses when CD11c+CD8– DC presented •• Cellular Immune Intervention tated antigens of a given tumor. A randomized the antigen or prominent cytotoxic T cell re- •• RNA electroporation to improve DC vaccines multicenter phase III trial using DCs transfec- sponses, when CD11c+CD8+ DC were target- and to generate antigen-specific T cells ted with autologous tumor-RNA (DCaT-RNA) ed. Recently, in close collaboration with Prof. •• Functional role of dendritic cell subpopula- starts in 2013 in uveal melanoma patients Dr. M. Karlsson (Karolinska-Institute), it could tions and antigen presentation whose tumor cells have lost one chromosome be shown that the Autoimmune regulator •• Generation, composition, and function of 3 indicating an unfavorable prognosis. Based gene (AIRE) is expressed on peripheral CD- extracellular vesicles (EV) on respective clinical work (see below), we 11c+CD8- DC in murine spleens and not only •• Characterization of the toponome of tissue plan the adoptive transfer of T cells repro- in thymic stroma. These results suggest that and cells by multi-epitope-ligand-cartogra- grammed by RNA electroporation as well as AIRE expression in CD11c+CD8- DC might be phy (MELC) the adoptive transfer of autologous regulatory necessary for the maintenance of peripheral •• Identification of biomarkers in malignant T cells. tolerance. At the moment the group focuses melanoma on the translation of the concept of antigen •• Regulatory T cells for cell-based therapy in RNA electroporation to improve DC targeting from the murine into the human inflammatory bowel disease vaccines and to generate antigen-spe- system. In close collaboration with various •• Identification and modulation of allergenic cific T cells clinical institutions (Erlangen, Bamberg), DC structures Project managers: PD Dr. N. Schaft, Dr. J. Dörrie subpopulations and other antigen presenting Structure of the Department The RNA-group focuses its research on two dis- cells from human tissues are characterized tinct topics: and human antigen targeting antibodies are 1) the optimization of vaccination against mel- generated. More than 200 people are employed at the Chair anoma by modulation of mRNA-transfected of Skin and Venereal Diseases, among them 39 medical doctors and 26 scientists. In the differ- DCs and Generation, composition, and function ent working groups clinically-relevant questions 2) the generation of tumor specific T cells by of extracellular vesicles (EV) are addressed in the areas of dendritic cell (DC) transfer of T cell- and chimeric antigen specific Project manager: PD Dr. A. Baur biology, DC-based vaccine development, oncol- receptors (TCR, CAR). This group investigates the molecular mecha- ogy with a focus on malignant melanoma, and 1) In vitro, our group found MelanA-specific nisms leading to the generation of EV, but is allergy. The Department of Dermatology focuses CD8+ T cells to be exhausted after re-stimula- also interested in their composition and func- on the development and clinical validation of in- tion with the DC vaccine. The transfection of tion in the microenvironment of malignant novative cellular therapies with an emphasis on mRNAs coding for CD40L, CD70, and con- melanoma and in HIV-infected cells. It could be ex-vivo generated DC-based vaccines. For this, a stitutively active TLR4 led to an improvement demonstrated that EV play an important role modern GMP-facility is available. The projects at of the DC immunogenicity. In addition, in in in the differentiation of monocytes into DC. In- the Department are all third-party funded, e.g. vitro culture experiments it could be shown terestingly, in HIV and cancer patients a higher by the SFB 643 ”Strategies of cellular immune that CD4+ T cells, CD8+ T cells, and DCs must proportion of EV could be detected. In melano- intervention” (see own report). concomitantly interact to allow repetitive CTL ma as well as HIV-infected cells, EV secretion is stimulation. initiated by an integrin-dependent mechanism Research 2) Chimeric HIV, CMV, or Ewing’s sarcoma spe- in which the signaling proteins Paxilin, Pak1, cific TCR/CAR were transfected into T cells, thus and Pak2 play crucial roles. Interestingly, sev- Cellular Immune Intervention leading to an improved recognition of HIV-, eral of the identified micro-RNAs in those EV Project managers: PD Dr. B. Schuler-Thurner, CMV-infected, or tumor cells. Furthermore, point to a single signaling pathway, known to Prof. Dr. E. Kämpgen, Dr. S. Groß, Prof. Dr. G. a protocol for the expansion of T cells under play an important role in the pathogenesis of Schuler GMP conditions was developed which will al- cancer.

64 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Characterization of the toponome of been established for the optimized in vitro ex- Selected Publications tissue and cells by multi-epitope- pansion of Treg cells of colitis ulcerosa patients. Biburger M, Aschermann S, Schwab I, Lux A, Albert H, ligand-cartography (MELC) Such cells will be intravenously administered in Danzer H, Woigk M, Dudziak D, Nimmerjahn F (2011) Project manager: Dr. A. J. Pommer an upcoming clinical trial to mitigate disease Monocyte subsets responsible for immunoglobulin G-dependent effector functions in vivo. Immunity, 35: 932-44 The Toponome group deals with the char- activity (collaboration Prof. Dr. M.F. Neurath, Department of Medicine 1). Hofmann C, Höfflin S, Hückelhoven A, Bergmann S, Harrer acterization of cell cultures and tissues by E, Schuler G, Dörrie J, Schaft N, Harrer T (2011) Human T means of the innovative MELC technology cells expressing two additional receptors (TETARs) specific which permits to stain 100 antigens on one Identification and modulation of aller- for HIV-1 recognize both epitopes. Blood, 118: 5174-7 and the same tissue section. This method was genic structures Paulus KE, Schmid B, Zajic D, Schäfer A, Mahler V, Son- used to identify a large panel of murine leu- Project manager: Prof. Dr. V. Mahler newald U (2012) Hypoallergenic profilin - a new way to identify allergenic determinants. FEBS J, 279: 2727-36 kocyte subpopulations in a whole frozen sec- This group focuses on the elucidation of rel- tion of a peripheral lymph node (see figure) evant allergenic structures in plants and Eckhardt J, Ostalecki C, Kuczera K, Schuler G, Pommer AJ, Lechmann M (2013) Murine whole-organ immune cell as well as non-inflamed versus inflamed tissues plant-derived food and their modification populations revealed by multi-epitope-ligand cartogra- of brain and spinal cord in an experimental with the aim to obtain hypoallergenic crops phy. J Histochem Cytochem, 61: 125-33 autoimmune encephalomyelitis model. Fur- as proof of principle [in collaboration with Lee JH, Wittki S, Bräu T, Dreyer FS, Krätzel K, Din- thermore, the Toponome group tries to ex- the Division of Biochemistry, FAU (Prof. Dr. dorf J, Johnston IC, Gross S, Kremmer E, Zeidler R, Schlötzer-Schrehardt U, Lichtenheld M, Saksela K, Harrer tend the MELC-technology to formalin-fixed U. Sonnewald); Paul-Ehrlich-Institute, Langen T, Schuler G, Federico M, Baur AS (2013) HIV Nef, paxil- paraffin-embedded (FFPE) tissue sections. (Prof. Dr. S. Vieths); Institute of Phytopatho- lin, and Pak1/2 regulate activation and secretion of TACE/ The MELC-technology has great potential in logy, Giessen (Prof. Dr. K.H. Kogel)]. After the ADAM10 proteases. Mol Cell, 49: 668-79 different key research areas and can be used identification of allergic target-structures and Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh in cooperation with other groups to answer the use of RNAi-constructs, relevant allergens E, Adams WC, Loré K, Winqvist O, Chambers BJ, Karlsson could be silenced in planta resulting in a re- MC (2013) AIRE expressing marginal zone dendritic cells questions in basic research, applied medicine, balances adaptive immunity and T-follicular helper cell re- and diagnostic. duced allergen content in tomato fruits and cruitment. J Autoimmun, 42: 62-70 carrot roots. Identification of biomarkers in International Cooperations Teaching malignant melanoma Prof. P.G. Coulie, de Duve Institute, Université catholique Project manager: Prof. Dr. L. Heinzerling de Louvain, Brussels: Belgium The Chair of Dermatological and Venereal Dis- The Biomarker research group focuses on Prof. M.C. Nussenzweig, Rockefeller University, Rockefel- predictive and therapeutic biomarkers in eases teaches students of human medicine, ler University, Laboratory of Molecular Immunology, New York: USA melanoma to optimize selection of therapeu- dental medicine, molecular medicine, and Bi- tic options. With a semi-automated mRNA ology in molecular and cellular immunology Prof. J.V. Ravetch, Rockefeller University, Rockefeller Uni- versity, Laboratory of Molecular Genetics and Immunolo- extraction from formalin fixed paraffin-em- in combination with translational applications (GMP-laboratory). The educational program is gy, New York: USA bedded (FFPE) sections of primary melano- organized in seminars, practical training cour- mas and melanoma metastases, a set of 20 ses in the clinic and the laboratories, lectures Meetings and International Training indicator genes, previously identifiedby array as well as bachelor, master, and medical theses. Courses analyses, was evaluated. The comparison of The clinic is responsible for the organization of 24.-25.03.2011: 6th International Symposium on the responders and non-responders for different Clinical Use of Cellular Products, Erlangen dermatological advanced training courses for immunotherapy options (DC-vaccination, physicians. 23.11.2011: DCs, T cells and beyond, Erlangen anti-CTLA-4 antibody ipilimumab) resulted in differential gene expression signatures. Furthermore, a large biobank of melanoma patients (including tumor mutations) is established (in collaboration with the Institute of Pathology).

Regulatory T cells for cell-based therapy in inflammatory bowel disease Project managers: Dr. C. Bosch-Voskens, Prof. Dr. G. Schuler The focus of this project funded by KFO 257 (see own report) is on regulatory T cells (Treg). They play a key role in the maintenance of peripheral tolerance by suppression of proliferat- ing effector T cells. In inflammatory bowel disease, it is postulated that insufficient numbers of Treg cells expand to attenuate local proliferation of effector T cells in the gut. A protocol has

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 65 UNIVERSITY HOSPITAL

Department of Dermatology Division of Immune Modulation

Address el for the early, inflammatory phase of Multi- Intracellular signal transduction of Hartmannstraße 14 ple Sclerosis in a prophylactic as well as in a CD83 in DC 91052 Erlangen therapeutic setting. Furthermore, also the re- Project managers: Dr. M. Stein, K. Blume Phone: +49 9131 8536725 jection of heart-, skin-, and cornea-transplants The main research focus of the project con- Fax: +49 9131 8535799 could be prevented by the use of sCD83. centrates on structural- and signal trans- www.immunmodulation.uk-erlangen.de Regarding the mode of action of sCD83, we duction pathway analyses of the membrane could show that it induces regulatory T cell bound CD83 molecule. Specific binding Head of Division (Tregs) and that indoleamine 2,3-dioxygen- domains/-partners have been identified us- Prof. Dr. phil. Alexander Steinkasserer ase (IDO) plays a major role. Interestingly, a ing a yeats two hybrid screen. Site directed naturally occurring sCD83 molecule has been mutagenesis-, transfection-, immune-precip- Contact identifiedin the serum of tumor patients, itation-, and co-immunofluorescence-studies Prof. Dr. phil. Alexander Steinkasserer whereby high concentrations of sCD83 cor- have been used to further characterize the Phone: +49 9131 8536725 related with a reduced treatment free survival protein-protein interaction, the N-linked gly- Fax: +49 9131 8535799 in CLL patients, indicating its relevance also in cosylation, and the activation of mCD83 on [email protected] tumor patients. In the long run, sCD83 will be a molecular level. To identify possible bind- developed as a new therapeutic option also ing motifs in silico, a bioinformatic modeling Research Focus for humans. study has been performed. The elucidation •• Immune-modulation in autoimmunity and of the mCD83 signaling pathway in mature transplantation by soluble CD83 Transcriptional in vivo targeting of human DC will open new and specific thera- •• Transcriptional in vivo targeting of dendritic dendritic cells (DC) using the human peutic targets. cells (DC) using the human CD83 promoter CD83 promoter •• Intracellular signal transduction of CD83 in Project manager: Dr. I. Knippertz Interaction of DC und viruses DC The major aim of the research group is the Project manager: Dr. M. Kummer •• Interaction DC cells und viruses functional characterization of the human The project group ”DC and viruses” analy- DC-specific CD83 promoter. The mem- zes the interaction between DC and viruses. Structure of the Department brane-bound CD83 molecule is a 45 kDa Particular attention has been given to HSV-1 glycoprotein expressed on the surface of ma- and HCMV infections. In this respect, the In the Division of Immune Modulation, head- ture DC and is to date one of the best known group was able to identify several new im- ed by Prof. Dr. A. Steinkasserer, more than 20 markers for human mature DC. Since CD83 mune-escape mechanisms. For instance, the researchers are working. Five research groups is not expressed on immature DCs, its regu- infection of DC with HSV-1 leads to a com- concentrate on basic immunological questions, latory DNA region, the CD83 promoter, is of plete degradation of CD83 which correlates whereby the translation of basic results into high interest in the context of a DC-media- with a reduced immuno-stimulatory capaci- clinically applicable therapeutic strategies is a ted vaccination strategy for the modulation ty of these infected DC. This degradation is major goal. Especially autoimmune disorders of mature DC by the targeted in vivo gene ex- mediated by the viral immediate early protein and the transplantation studies are in the fo- pression of different therapeutic transgenes. ICP0 and the cellular proteasome. The exact cus of our research activities. The interaction For this purpose, different immune-modula- between viruses and dendritic cells (DC) repre- mechanism of this degradation is subject of sents the second major research area of the Di- tory and therapeutic transgenes will be ex- current research. Interestingly, infection of vision. The identification and characterization pressed in vivo (directly in patients) under mature DC with HCMV induced the shed- of specific viral immune escape strategies will the control of the cell type- and stadium ding of a soluble CD83 molecule from the cell be exploited to develop new antiviral strate- specific CD83 promoter. Initially, the charac- surface which has immune-suppressive activ- gies. This research work is mainly supported by terization of the human CD83 promoter was ities. Moreover, it could be shown that the research grants funded by the DFG, SFB, GK, accomplished by a ChIP-chipTM Microarray infection of mature DC with HSV-1 leads to and scientific foundations. analysis, by which, in addition to the min- an inhibition of STAT1 signaling, presumably imal promoter, a short enhancer sequence via loss of the IFNg-receptor 1. Furthermore, Research was identified. Further, bio-informatical anal- the group is also interested in the replication ysis identified an additional promoter region of HSV-1 in mature DC. In contrast to earlier Immune-modulation in autoimmunity which was shown to build a ternary pro- reports, recently the replication of HSV-1 in and transplantation by soluble CD83 moter-complex together with the minimal mature DC could be reported. Although this Project manager: Dr. E. Zinser promoter and the enhancer. Moreover, we replication is very inefficient, it could very The project group focuses on the immu- have demonstrated that this ternary promot- well be of biological importance in vivo, since no-suppressive properties of soluble CD83 er-complex is not only highly inducible, but progeny virus could be passed on to primary (sCD83). Using a recombinantly expressed it is also cell type- and maturation specific. keratinocytes. During this cell-to-cell mediat- sCD83 molecule, it was possible to inhibit the Finally, we have identified the transcription ed infection, the viral glycoprotein gE plays a paralyses associated with EAE, an animal mod- factors involved in this process. major role.

66 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) An additional project deals with the HSV-1 mediated modulation of DC migration. It could be shown that HSV-1 interferes with the chemokine mediated DC-migration which is an abso- lutely essential step in order to induce potent antiviral immune responses.

Teaching

The co-worker of the Division teach students of molecular medicine and biology in the field of molecular and cellular immunology. The training takes place in form of lectures, seminars, practical courses as well as bachelor, master, and PhD theses. In addition, the Collaborative Research Centre/SFB 643 (strategies of cellular immune intervention; compare own report) is coordinated together with the Department of Dermatology.

Selected Publications Goldwich A, Prechtel AT, Mühl-Zürbes P, Pangratz NM, Stössel H, Romani N, Steinkasserer A, Kummer M (2011) Herpes simplex virus type I (HSV-1) replicates in mature dendritic cells but can only be transferred in a cell-cell contact-dependent manner. J Leukoc Biol, 89: 973-9 Knippertz I, Stein MF, Dörrie J, Schaft N, Müller I, Deinzer A, Steinkasserer A, Nettelbeck DM (2011) Mild hyperthermia enhances human monocyte-derived dendritic cell Immune-fluorescence staining of mature dendritic cells functions and offers potential for applications in vaccination strategies. Int J Hyperthermia, 27: 591-603 Seifarth C, Littmann L, Resheq Y, Rössner S, Goldwich A, Pangratz N, Kerek F, Steinkasserer A, Zinser E (2011) MCS- 18, a novel natural plant product prevents autoimmune diabetes. Immunol Lett, 139: 58-67 Theodoridis AA, Eich C, Figdor CG, Steinkasserer A (2011) Infection of dendritic cells with herpes simplex virus type 1 induces rapid degradation of CYTIP, thereby modulating adhesion and migration. Blood, 118: 107-15 Schierer S, Hesse A, Knippertz I, Kaempgen E, Baur AS, Schuler G, Steinkasserer A, Nettelbeck DM (2012) Human dendritic cells efficiently phagocytose adenoviral onco- lysate but require additional stimulation to mature. Int J Cancer, 130: 1682-94 Zinser E, Rössner S, Littmann L, Pangratz N, Schuler G, Steinkasserer A (2012) The IL-2 diphtheria toxin fusion protein denileukin diftitox modulates the onset of diabetes in female nonobese diabetic animals in a time-dependent manner and breaks tolerance in male nonobese diabetic animals. J Immunol, 189: 1173-81

International Cooperations Prof. Dr. H. Wang, Lawson Health Research Institute, Uni- versity of Western Ontario, London: Canada Prof. Dr. Carl C. Figdor, Nijmegen Center for Molecular Life Sciences, Nijmegen: The Netherlands Prof. Dr. R.D. Everett, MRC-Center for Virus Research, Uni- versity of Glasgow, Glasgow: UK Prof. Dr. N. Romani, Department of Dermatology, Medical University Innsbruck, Innsbruck: Austria Prof. Dr. U. Grohmann, University of Perugia, Perugia: Italy HSV-1 and HCMV specifically target CD83 to evade immune responses

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 67 UNIVERSITY HOSPITAL

Department of Medicine 1 – Gastroenterology, Lung Diseases, and Endocrinology Chair of Internal Medicine I

Address Research Immunomodulatory strategies for the Ulmenweg 18 treatment of chronic inflammatory 91054 Erlangen Intestinal diseases diseases Phone: +49 9131 8535000 Project managers: Dr. C. Neufert, Dr. M. Waldner Project manager: Dr. I. Atreya Fax: +49 9131 8535209 We are interested in the molecular mechanisms Our research group is interested in immuno- www.medizin1.uk-erlangen.de driving intestinal inflammation and colitis-as- modulatory strategies for the treatment of sociated tumorigenesis. Current topics are cy- chronic inflammatory diseases. Innovative ther- Head of Department tokine research in colitis and investigations into apeutic approaches are evaluated preclinically Prof. Dr. med. Markus F. Neurath growth factors that are differentially regulated in order to define their immunomodulatory between different tumor entities in the large capacity and to potentially pave the way for Contact intestine. Moreover, our studies have a closer clinical trials. Prof. Dr. rer. nat. Christoph Becker look at the molecular crosstalk between stro- New as well as clinically established immuno- Phone: +49 9131 8535886 mal cells, such as cancer-associated fibroblasts suppressive compounds are monitored in order Fax: +49 9131 8535959 and intestinal epithelial cells. The research per- to describe their interaction with specific intra- [email protected] formed by our group may help to improve fu- cellular signaling cascades and their resulting ture therapeutic options for various intestinal impact on pro-inflammatory immune cell func- Research Focus diseases. tion. Through a more detailed understanding of •• Intestinal diseases the underlying mechanism of action, we intend •• Endocrinology Endocrinology to optimize immunosuppressive strategies or •• Experimental hepatology Project manager: Prof. Dr. C. Schöfl even to identify new therapeutic target structures. •• Immunomodulatory strategies for the treat- The Calcium-Sensing-Receptor (CaSR) is pivotal ment of chronic inflammatory diseases for calcium homeostasis. Mutations of the CaSR Division of clinical and experimental •• Division of clinical and experimental pulmo- cause hyper- and hypocalcemic disorders. Our pulmonology nology group characterizes inactivating and activating Project managers: Dr. F. Fuchs, Prof. Dr. K. Hild- •• Molecular endoscopy CaSR mutations and tests how the detrimen- ner •• Molecular gastroenterology tal effects of these mutations can be corrected Our clinical research attempts to evaluate new •• Patient-oriented research in IBD pharmacologically. imaging methods during bronchoscopy. Our •• Ultrasound Treatment of patients suffering from hypocalce- data highlight in vivo confocal laser-endomi- •• Cytokines and transcription factors in IBD mia due to activating mutations of the CaSR is croscopy as a real time and safe method to unsatisfactory and often has side effects. Recent visualize malignant lesions. Furthermore, we Structure of the Department results from our group indicate that novel cal- perform feasibility and surplus studies of chro- cilytics currently in clinical testing may offer a mo-bronchoscopy in vivo. The Department of Medicine 1 covers research superior treatment option for patients suffering Our preclinical studies try to shed light on the in the fields of gastroenterology, hepatology, from Autosomal Dominant Hypocalcemia and immunopathogenesis of lung cancer both, in endocrinology, pneumology, intensive care Bartter-Syndrome Type V. murine model systems and in patients. We are medicine, infectious diseases as well as endos- establishing clinically relevant mouse tumor copy and ultrasound. Several research groups Experimental hepatology models and started to bank human lung tissue cover these fields in clinical and basic research. Project manager: Dr. S. Wirtz for further molecular analysis. In the past two years, the research division of In this research focus, we are particularly the Department of Medicine 1 has continuous- interested in the role of the novel pro- and Molecular endoscopy ly expanded. This has become possible due to anti-inflammatory cytokines IL-28, IL-33, and Project manager: Prof. Dr. H. Neumann the successful raising of financial means from IL-27 in the context of acute and chronic liver Molecular endoscopy offers the unique po- public bodies, including the DFG and the Euro- diseases. We have observed that the expres- tential to significantly impact on current diag- pean Community. sion of these factors is upregulated early dur- nostic and therapeutic approaches based on A special highlight was last year’s establishment ing hepatocellular stress and inflammatory in vivo minimally invasive visualization of dis- of a Clinical Research Unit on the topic of in- liver diseases. Preclinical studies showed that ease-specific morphologic or functional tissue flammatory bowel disease (KFO 257, CEDER, they significantly contributeto gradual accu- alterations. In this context, recent data indicate compare own report). mulation of extracellular matrix components the potential of molecular endoscopy for in The laboratories of the Department of Medi- and hepatic tissue remodeling. In the long vivo molecular imaging of therapeutic targets cine 1 are located at the Kussmaulcampus for run, we want to identify in these translational of gastrointestinal cancers. Medical Research. In these laboratories, ten research projects new molecular mechanisms Main emphasis of this research project is the research groups with overall 80 staff members of liver pathophysiology and identify potential identification and investigation of highly spe- investigate the cause of different diseases and prognostic markers or therapeutic targets in cific markers to recognize lesions at risk and to develop new therapeutical strategies. liver disease. predict response to targeted treatment.

68 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Molecular gastroenterology • ARFI of extrahepatic disorders (pancreas, gas- A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor Project manager: Prof. Dr. C. Becker trointestinal tract) b signaling. Gastroenterology, 142: 1183-1194.e4 The research group focuses on the immuno- • Sonographically guided abdominal interven- Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hild- logical and molecular mechanisms that lead to tions (multicenter trial German Society for Ul- ner K, Guachalla LM, Gompf A, Hartmann D, Schambach the development of infection, chronic inflam- trasound in Medicine). A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL mation, and cancer within the gut. In the past (2012) A differentiation checkpoint limits hematopoietic two years, this group has developed a new Cytokines and transcription factors stem cell self-renewal in response to DNA damage. Cell, concept for the pathogenesis of chronic in- in IBD 148: 1001-14 flammatory bowel disease (IBD). The research- Project manager: Dr. B. Weigmann ers could show that the molecule caspase-8 Crohn’s disease and ulcerative colitis are clas- plays an important role for regulating cell sur- sic defined entities of IBD which have a char- vival and cell death in the gut. If caspase-8 lev- acteristic profile of cytokines. Crohn’s disease els or the function of the protein is insufficient is characterized by Th1 cytokines as well as IL- in epithelial cells, these cells become highly 23 and IL-17 producing cells, whereas in pa- susceptible to necroptosis, a new mode of pro- tients suffering from ulcerative colitis a more grammed cell death. Particularly affected are Th2-mediated cytokine profile is observed. Paneth cells, specialized epithelial cells which In former studies, a key regulatory role of the produce substances to control or even kill bac- Th1 associated transcription factor t-bet, reg- teria. As a consequence, bacteria can penetrate ulating IFN-g, could be found. Actually, the the intestinal wall and trigger inflammatory re- function of Th2-associated transcription fac- actions such as those in patients with chron- tors, like c-maf, GATA-3 and NFAT, is in the Hepatic Stellate Cells ic IBD. On the basis of these research results, focus of our research. Likewise, influence of new treatment methods allowing the targeted these transcription factors in the pathogene- manipulation of such cellular processes will be sis of colorectal carcinoma is currently being developed in order to better treat patients with analyzed. chronic IBD. Teaching Patient-oriented research in IBD Project manager: Prof. Dr. R. Atreya The Department of Medicine 1 contributes to Aim of our research group is the characteri- curricular teaching for medical students from zation on the immunpathogenesis of IBD and second to final year. The necessary skills are especially the molecular mechanism of action taught in practical courses (introduction to In 2010, the Department of Medicine 1 moved into the of immunosuppressive therapies. Another aim clinical medicine, physical examination course, laboratories of the new research building at the Hart- is the establishment of therapy-specific predic- internal medicine) and with models and simu- mannstraße. tors of response. These predictors are derived lators. Several lectures deal with general inter- from cytokine mediated signaling pathways nal medicine and the different foci of the clinic. and transcription factors. The use of endoscopic molecular imaging for the individual predic- Selected Publications tion of therapeutic response in IBD represents Atreya R, Zimmer M, Bartsch B, Waldner MJ, Atreya I, another field of our research group. Neumann H, Hildner K, Hoffman A, Kiesslich R, Rink AD, Rau TT, Rose-John S, Kessler H, Schmidt J, Neurath MF (2011) Antibodies against tumor necrosis factor (TNF) in- Ultrasound duce T-cell apoptosis in patients with inflammatory bowel Project manager: Prof. Dr. D. Strobel diseases via TNF receptor 2 and intestinal CD14+ macrophages. Gastroenterology, 141: 2026-38 Research includes contrast enhanced ultra- Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, sound (CEUS), elastography, acoustic radiation Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath force imaging (ARFI), and interventional ultra- MF, Becker C (2011) Caspase-8 regulates TNF-a-induced sound. epithelial necroptosis and terminal ileitis. Nature, 477: 335-9 • CEUS for the detection of liver metastasis in Neumann H, Vieth M, Neurath MF, Fuchs FS (2011) In colorectal cancer (multicenter trial German So- vivo diagnosis of small-cell lung cancer by endocytoscopy. ciety for Ultrasound in Medicine) J Clin Oncol, 29: e131-2 • CEUS for the characterization of hepatic tum- Wirtz S, Billmeier U, McHedlidze T, Blumberg RS, Neur- ors and monitoring of antiangiogenetic therapy ath MF (2011) Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. • CEUS in IBD Gastroenterology, 141: 1875-86 • CEUS quantification Dornhoff H, Becker C, Wirtz S, Strand D, Tenzer S, Rosfa S, • ARFI of chronic hepatic diseases and tumors Neufert C, Mudter J, Markl J, Siebler J, Neurath MF (2012)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 69 UNIVERSITY HOSPITAL

Department of Medicine 2 – Cardiology and Angiology Chair of Internal Medicine II

Address The project IS 08b is funded by the BMBF. Its opment of prostheses for transcatheter aortic Ulmenweg 18 aim is to develop an algorithm which predicts valve implantations (TAVI). The Department 91054 Erlangen the worsening of the clinical condition of heart of Medicine 2 was one of the centers where Phone: +49 9131 8535301 failure patients. Implantable cardioverter defi- the study for the regulatory approval of the Fax: +49 9131 8535303 brillators with new developed sensors and the JenaValve® prosthesis was conducted. The http://www.medizin2.uk-erlangen.de Home-Monitoring platform from BIOTRONIC Department participates also in international are applied for this study. In the iChart-study, multicenter trials for the evaluation of ballon Head of Department confounding factors that influence the mea- expandable prosthesis (Prevail, Edwards life- Prof. Dr. med. Stephan Achenbach surement of the intrathoracic impedance sciences) and an international registry for the were identified. The measurement of the int- documentation of the long term performance Contact racardiac impedance is the main focus of the of the Edwards-sapein-XT prosthesis® (source Dr. med. Lutz Klinghammer iGraph-study (figure 1). Acute hemodynam- XT registry). Phone: +49 9131 8535393 ic changes in patients are correlated to mea- Fax: +49 9131 8535303 surements of the intracardiac impedance. In an Echocardiography [email protected] accompanying registry, again potentially con- Project manager: PD Dr. O.A. Breithardt founding factors for the intracardiac imped- This research group focuses on tissue Doppler Research Focus ance are documented. and deformation (”strain”, ”2D strain”) ima- •• Electrophysiology ging, especially in the field of ischemia detec- •• Interventional cardiology Interventional cardiology tion, the identification of heart failure patients •• Echocardiography Project managers: Prof. Dr. J. Ludwig, PD Dr. H. who benefit from cardiac resynchronization •• Cardiac magnetic resonance tomography Rittger, Dr. M. Arnold therapy, and myocardial deformation charac- •• Cardiac computed tomography Main focus of the working group was the in- teristics in patients with aortic valve disease •• Molecular and experimental cardiology terventional therapy of coronary artery disease before and after valve replacement. (CAD), especially new treatment modalities Structure of the Department and specific aspects of the interventional treat- Cardiac magnetic resonance tomogra- ment of stable CAD and acute coronary syn- phy The Department of Medicine 2 focuses on dromes in elderly patients. Projekt managers: Dr. M. Schmid, Prof. Dr. S. cardiology and angiology. Together with the One main topic was the specific therapy of In- Achenbach Department of Cardiac Surgery, the Division stent-Restenosis (ISR) especially in drug elut- In collaboration with the Institute of Radiology of Pediatric Cardiology, and the Division of ing stents (DES). In a multicentric, randomized (head: Prof. Dr. M. Uder) and Siemens Health- Pediatric Cardiac Surgery, the Department of study, we demonstrated that the interventional care, Erlangen, the research group focuses on Medicine 2 forms the University Heart Center therapy of DES-ISR with drug coated balloons the development and validation of new cardi- of Erlangen. The Department is a tertiary refer- (DCB) is significantly better than balloon angi- ac magnetic resonance techniques in clinical ral center offering the full array of inpatient and oplasty alone regarding angiographic and clin- studies. One field is the prognostic impor- outpatient diagnostic and therapeutic options ical endpoints. tance of T2 weighted and contrast-enhanced for cardiovascular diseases. The Department Based on these results, the working group is imaging after myocardial infarction and the employs 39 physicians, eight of them with developing algorithms for the treatment of determination of infarct size as a surrogate permanent teaching positions at the Faculty DES-ISR, since the impact of restenosis patterns endpoint for research studies. Studies of myo- of Medicine (“Habilitation”), three biologists, on the success of a therapy with drug-eluting cardial perfusion with adenosine stress using and 122 non-physician nursing or supporting balloons (DEB) for DES-ISR has important new high-resolution sequences are another staff. It harbors two large normal care wards, prognostic significance for the success rate focus of interest. Furthermore, in suspected an coronary care unit, two cath lab suites, one of the repeated intervention and restenosis perimyocarditis, so-called edema-sequences hybrid-lab and an outpatient department with after DES implantation, making it particularly are evaluated to detect the acute inflamma- several specialized clinics for heart failure, con- challenging to treat. Aim is the development tory process and the extent of myocardial genital heart disease in adults, arrhythmias, of a new classification of DES-ISR and therapy involvement. Additional research topics are and pacemakers/defibrillators. Furthermore, recommendations for the treatment of DES- the non-invasive quantitation of valvular heart the Department disposes of a large basic-sci- ISR with the DCB. Another study evaluates the disease with comparison to established stan- ence laboratory. In October 2012, Prof. Dr. S. restoration of endothelial function after DCB dards, morphologic and functional MRI ima- Achenbach became Prof. Dr. W.G. Daniel’s suc- treatment. ging in stress cardiomyopathy, and character- cessor as the director of the Department. Of further interest is the outcome of elderly ization and localization of myocardial fibrosis patients after interventional treatment of CAD. in dilated cardiomyopathy. Research Based on data of the German ALKK-registry, we showed that there are only minor differences Cardiac computed tomography Electrophysiology in outcome as compared to younger patient Project manager: PD Dr. T. Pflederer Project manager: Dr. M. Arnold cohorts. The major focus of the working group Car- The electrophysiology research group is part In cooperation with the Chair of Cardiac Sur- diac Computed Tomography is non-invasive of the Leading Edge Cluster „Medical Valley”. gery, our Department participates in the devel- coronary CT angiography and imaging of cor-

70 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) onary atherosclerosis. Several research pro- a4) Which influence does sodium have on the International Cooperations jects receive funding - among others - by the development of atherosclerotic plaques? Dr. U. Hoffmann, Massachusetts General Hospital, Boston: BMBF. One research focus is the development With regard to biomarkers in cardiovascular USA and validation of techniques for reducing the diseases, we focus on questions such as: Dr. S. Voros, Health Diagnostic Laboratory, Richmond: associated radiation exposure. Advances in b1) Which multimarker-profile correlates with USA hard- and software now allow non-invasive atherogenesis, heart failure, or arterial hyper- D. Dey, PhD, D.S. Berman, MD, Cedars Sinai Medical Center, Los Angeles: USA assessment of coronary arteries in daily rou- tension? tine with effective radiation doses between b2) Which multimarker-profile correlates with Research Equipment 1.0 and 2.0 mSv (see figure 2). Furthermore, coronary calcifications as seen in heart comput- for the first time, recent studies could achieve ertomography? Siemens Healthcare, Cardiac catheterization lab - angiography (three labs) - in selected patients - a reduction of effec- Additional projects envision the creation of St. Jude Medical, OCT-System tive radiation dose to values less than 0.1 mSv biological, artificial vessels. As part of the ‘Emer- (the average natural background radiation ging Field Initiative’ at the FAU, we currently Biosense Webster (Johnson & Johnson), Carto 3 Biosense Webster Electroanatomical Mapping System dose in Germany in 2009 was 2.35 mSv per establish cell lineages as well as culture tech- person). Another research focus is the valida- niques allowing the construction of three-lay- tion of techniques aiming at improving im- ered, biological active vessels. age quality. Advances in the field of "Iterative With our projects and biobanks, we participate Reconstruction" allowed reduction of noise in national and international projects (e.g. na- and thus a more accurate assessment of the tional projection about gen-polymorphisms in coronary arteries and coronary stents. All the coronary artery disease). same, studies assessing automated software programs could show a potential benefit in Teaching planning the CT scan itself - again for the Figure 1: Schematic representation of measurement of intrathoracic impedance (left) and of intracardial imped- reduction of radiation exposure - as well as The Department provides 32 teaching activities ance (right). in the subsequent evaluation of coronary ar- (from lecture to practical exercise) per term. tery concerning significant stenoses. In the Members of the Department repeatedly won field of CT-guided planning of transcatheter the first prize for good teaching of the Faculty aortic valve implantation (TAVI), international of Medicine. standards regarding measurement methodology and procedural planning have been es- Selected Publications tablished. Moreover, the CT working group cooperates with major national and interna- Achenbach S (2011) Anatomy meets function. Modeling coronary flow reserve on the basis of coronary computed tional registries to further evaluate the prog- tomography angiography. J Am Coll Cardiol, 58: 1998- nostic value of CT coronary angiography and 2000 is involved as a Core-Lab in international mul- Cicha I, Wörner A, Urschel K, Beronov K, Goppelt-Struebe Figure 2: Cardiac computed tomography with an effec- ticenter studies. M, Verhoeven E, Daniel WG, Garlichs CD (2011) Carotid tive dose of 0.6 mSv. The curved multiplanar reconstruc- plaque vulnerability: a positive feedback between hemod- tion allows to reliably exclude an obstructive coronary ynamic and biochemical mechanisms. Stroke, 42: 3502-10 artery disease. (*) indicates non-obstructive atheroscle- Molecular and experimental cardiology rotic plaques. Project manager: Prof. Dr. C. Garlichs Gauss S, Achenbach S, Pflederer T, Schuhbäck A, Daniel WG, Marwan M (2011) Assessment of coronary artery re- The research projects of the group concentrate modelling by dual-source CT: a head-to-head comparison on with intravascular ultrasound. Heart, 97: 991-7 a) Pathomechanisms of atherosclerosis, Marwan M, Taher MA, El Meniawy K, Awadallah H, b) Biomarkers in cardiovascular diseases, and Pflederer T, Schuhbäck A, Ropers D, Daniel WG, Achen- c) The construction of new vessels. bach S (2011) In vivo CT detection of lipid-rich coronary artery atherosclerotic plaques using quantitative histo- Research questions focus on: gram analysis: a head to head comparison with IVUS. Ath- a1) Which role do flow patterns of blood have erosclerosis, 215: 110-5 on atherogenesis and plaque rupture, respec- Raaz-Schrauder D, Klinghammer L, Baum C, Frank T, tively? How do blood flow patterns interact Lewczuk P, Achenbach S, Cicha I, Stumpf C, Wiltfang J, with inflammatory mechanisms? What specific Kornhuber J, Daniel WG, Garlichs CD (2012) Association of systemic inflammation markers with the presence and pathways act in vessel bifurcations? extent of coronary artery calcification. Cytokine, 57: 251-7 a2) Which role does the receptor of CRP (c-re- Rittger H, Brachmann J, Sinha AM, Waliszewski M, Ohlow active protein) play within atherogenesis? M, Brugger A, Thiele H, Birkemeyer R, Kurowski V, Breit- a3) Which role play dendritic cells and regula- hardt OA, Schmidt M, Zimmermann S, Lonke S, von tory T cells in the development of atherogene- Cranach M, Nguyen TV, Daniel WG, Wöhrle J (2012) A sis and plaque rupture? The recent work of our randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon group suggests a strong influence of these cells angioplasty in drug-eluting stent restenosis: the PEP- on atherogenesis. CAD-DES study. J Am Coll Cardiol, 59: 1377-82

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 71 UNIVERSITY HOSPITAL

Department of Medicine 3 – Rheumatology and Immunology Chair of Internal Medicine III

Address efficient mesenchymal stem cell based therapy One research area in collaboration with the ex- Krankenhaussstraße 12 for the treatment of the osteoarthritis, the most perimental cardiac surgery unit is the induction 91054 Erlangen common form of arthritis. Our task is to test of transplantation tolerance and the modulation Phone: +49 9131 8533363 the improvement of the treatment efficacy by of transplant arteriosclerosis through the appli- Fax: +49 9131 8534770 genetically modifying adipose-derived mesen- cation of donor alloantigen and co-stimulation www.med3.med.uni-erlangen.de chymal stem cells in mice. blockade. An important contribution to clinical research is the detection and differentiation of an- Head of Department Activation of synovial fibroblasts by mi- ti-HLA alloantibodies. Imunogenetic studies ana- Prof. Dr. med. Georg Schett croparticles in rheumatoid arthritis (RA) lyze polymorphisms of several cytokines and T cell Project manager: PD Dr. J. Distler regulatory genes and their association with rheu- Contact Microparticles, released from cytokine activated matic, malignant, and endocrinological disorders. Prof. Dr. med. Georg Schett and apoptotic leukocytes, accumulate in high Phone: +49 9131 8539133 numbers in the involved joints in patients with Immunomodulatory effects of Fax: +49 9131 8534770 RA. The group could demonstrate that micropar- apoptotic and necrotic cells [email protected] ticles represent a novel mechanism for inter-cel- Project managers: Dr. M. Hoffmann, Prof. Dr. lular communication. Microparticles might thus Dr. M. Herrmann Research Focus play an important role in the pathogenesis of During the execution of apoptosis and necrosis, •• Adipose derived stromal cells for osteoarthritis RA by triggering a vicious circle of inflammation the cellular surfaces get modified. These chan- •• Activation of synovial fibroblasts by mi- and bone-erosion. The mechanisms by which ges are the basis for the clearance of the dying croparticles in rheumatoid arthritis (RA) microparticles activate synovial fibroblasts are cells in vivo. In contrast to the pro-inflammato- •• Analysis of risk factors and long-term outcome in currently a major focus of the group. ry clearance of necrotic cells, apoptotic cells are patients with systemic lupus erythematosus (SLE) eliminated without inflammation and immune •• National and international clinical trials Analysis of risk factors and long-term response. This fact has important consequences •• Immunogenetics and transplantimmunology outcome in patients with systemic for both, the etiopathogenesis of autoimmunity •• Immunomodulatory effects of apoptotic and lupus erythematosus (SLE) and the development of tumor vaccines. necrotic cells Project manager: Prof. Dr. B. Manger •• Immunodeficiencies and infectious diseases In a cohort of 410 SLE patients, genetic, sero- Immunodeficiencies and infectious •• Mechanisms for the activation of fibroblasts logical, and clinical predictors for long-term diseases in systemic sclerosis (SSc) outcome are analyzed in retrospective and pro- Project manager: Prof. Dr. T. Harrer •• Molecular signaling pathways in RA spective studies. One focus is on the investiga- The Department of Medicine 3 is an important •• Pathogenesis of RPGN in ANCA-associated tion of premature atherosclerosis and ovarian treatment center for patients with immuno- systemic vasculitides failure in SLE. deficiencies, a variety of infectious diseases. •• Pathomechanisms of bone destruction in RA The major interest of research of the group •• The role of 12/15-lipoxygenase (12/15-LO) in National and international clinical are various aspects of HIV-infection, such as the regulation of innate and adaptive immunity trials immunology of HIV-infection, drug resistance, •• Analysis of inflammatory mechanisms in Project managers: Dr. J. Rech, Dr. M. Ron- and basic and clinical research on develop- adult onset Still’s disease neberger, Dr. A. Reisch, Dr. S. Finzel ment and evaluation of new therapeutic and Various national and international phase Ib-IV diagnostic procedures, such as T cell receptor Structure of the Department studies are conducted, primarily to investigate transfer and immunomonitoring using mRNA new treatment approaches in rheumatic disea- electroporation. The Department is working on The Department of Medicine 3 covers the fields ses. The major focus of the therapeutic trials are the development of immunotherapies, such as of rheumatology, immunology, and allergol- on treatments with ”biologicals and small mol- therapeutic vaccines and immunomodulators. ogy. It involves the diagnosis and therapy of ecules” e.g. therapeutic principles which block The Department participated in clinical studies rheumatologic and immunologic diseases. For the proinflammatory cytokine tumornecrosis including studies for the evaluation of new in- the treatment of patients, the Department of factor a, IL-6, IL-17, IL-12/23, JAK3-kinase. novative therapeutics of HIV-infection, such as Medicine 3 is supplied with inpatient and out- Another focus is the initiation and conduction new antiretroviral drugs and therapeutic vac- patient wards where patients are cared for. of a multicenter phase II trial in patients ero- cines. Other projects are investigating further Our physicians are specialized in recognizing and sive finger osteoarthritis. In the course of inter- infectious and immunologic diseases, such as treating these hard to diagnose diseases. The De- national multicenter trials, we are conducting Borrelia burgdorferi infection, chronic fatigue partment of Medicine 3 is among the few Europe- standardization seminars for examination tech- syndrome, and humoral immunodeficiencies. an ”Centers of Excellence” according to the guide- niques in patients with RA. lines of the European League Against Rheumatism Mechanisms for the activation of (EULAR) which mirrors its expertise on these fields. Immunogenetics and fibroblasts in systemic sclerosis (SSc) transplantimmunology Project manager: PD Dr. J. Distler Research Project manager: PD Dr. B. Spriewald SSc is characterized by a progressive accumu- The laboratory provides service for the lation of extracellular matrix components with Adipose derived stromal cells for Eurotransplant area Northern Bavaria with the progressive fibrosis of the involved organs. The osteoarthritis transplant centers Erlangen-Nürnberg, Würzburg, fibrosis is mediated by an excessive, uncon- Project managers: Prof. Dr. G. Schett, J.-P. David and Regensburg. The laboratory is accredited trolled production of extracellular matrix by fi- The FP7-EU-funded ADIPOA wishes to develop by the European Federation of Immungenetics. broblasts. However, therapies to inhibit selective-

72 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) ly the overproduction of extracellular matrix and elucidate the molecular role of 12/15-LO and Prof. Dr. S. Kiechl, Prof. Dr. L. Wildt, Innsbruck Medical prevent fibrosis are lacking. The research group its metabolites in macrophages and dendritic University, Innsbruck: Austria investigates novel signaling cascades that lead cells (DC). Moreover, a potential involvement Dr. D. McIlroy, Université de Nantes, Nantes: France to activation of fibroblasts and studies potential of this enzyme in the phagocytosis of apopto- Prof. Dr. C. Jorgensen, CHU Montpellier, Montpellier: therapeutic approaches to inhibit the overpro- tic cells and during the interaction between France duction of extracellular matrix by SSc fibroblasts. DC and T-lymphocytes will be investigated. In Prof. Dr. S. Muller, Institut de Biologie Moléculaire et Cel- addition, the role of 12/15-LO during chronic lulaire du CNRS, Strasbourg: France Molecular signaling pathways in RA inflammatory diseases is studied in vivo using Prof. Dr. B. Autran, Hôpital Pitié-Salpêtrière, Paris: France Project managers: Prof. Dr. G. Schett, Dr. M. Stock 12/15-LO deficient mice and various disease Prof. Dr. D. Isenberg, Center for Rheumatology Research, RA is characterized by perpetuating synovial models (TNF-transgenic mice, collagen-in- London: UK inflammation and progressive joint destruction duced arthritis). Prof. Dr. J. Savill, Prof. Dr. I. Dransfield, The University of based on cartilage damage and bone erosion Edinburgh, Edinburgh: UK as a result of an imbalance of formation and Analysis of inflammatory mechanisms Prof. Dr. A. Manfredi, Immunologia Clinica, Milano: Italy resorption of cartilage and bone. Wnt signals in adult onset Still’s disease Prof. Dr. A. Tincani, Hospital and University of Brescia, appear to link inflammation to this structural Project managers: Dr. J. Rech, Prof. Dr. B. Manger Brescia: Italy damage in arthritis and therefore may play a Inflammatory mechanisms and cytokine pro- Prof. Dr. O.-P. Rekvig, University of Tromso, Tromso: Nor- major role in the pathogenesis of RA. Thus, the files in patients with adult onset Still’s disease way group is focused on the Wnt signaling network are analyzed with respect to clinical presenta- Prof. Dr. I. Mcinnes, University of Glasgow, Glasgow: Scot- in rheumatic diseases. In particular the regulation and outcome to identify therapeutic strat- land tion of Wnt signaling is investigated and poten- egies for this rare disease. Prof. Dr. L. Klareskog, Karloniska Institutet, Stockholm: tials to interfere with cartilage damage caused Sweden by dysregulated Wnt signaling are evaluated. Teaching Prof. Dr. P.-P. Tak, Academic Medical Center, University of Amsterdam, Amsterdam: The Netherlands Pathogenesis of RPGN in ANCA- The education offered by the Department of Prof. Dr. J. van de Winkel, University Medical Center associated systemic vasculitides Medicine 3 is embedded into the master plan Utrecht, Utrecht: The Netherlands Project manager: PD Dr. J. Zwerina of teaching in the internal medicine with lec- Prof. Dr. A. Vandamme, Prof. Dr. R. Lories, Katholieke Uni- The group investigates the mechanisms of the tures, courses, and internships. versiteit Leuven, Leuven: The Netherlands activation of intrinsic renal cells and infiltrating The Graduate School of the SFB 643 is engaged Prof. Dr. T. Huizinga, University Medical Center, Leiden: immune cells that lead to a massive up-regu- with strategies of cellular immune intervention The Netherlands lation of pro-inflammatory cytokines and pro- (see own report). Prof. Dr. L. Joosten, Radboud University, Nijmegen: The liferation leading to the crescent formation in Netherlands affected glomeruli. Potential candidate mole- Selected Publications Prof. Dr. T. Swaak, Erasmus Universiteit Rotterdam, Rotter- cules responsible for this deregulation are in- dam: The Netherlands vestigated in kidney biopsies of patients with Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkon- taite I (1997) Immunosuppressive effects of apoptotic Prof. Dr. D.S. Pisetzky, Durham University, Durham: UK a RPGN as well as experimental RPGN models. cells. Nature, 390: 350-1 Prof. Dr. B. Walker, Boston Medical Center, Boston: USA Kiechl S, Willeit J, Schett G (2009) Denosumab, osteo- Pathomechanisms of bone destruction Prof. Dr. G. Firestein, University of California, San Diego: porosis, and prevention of fractures. N Engl J Med, 361: USA in RA 2188-9; author reply 2190 Project managers: Prof. Dr. G. Schett, PD Dr. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler Meetings and International Training J. Zwerina H, Gaipl US, Voll RE, Springer E, Munoz LE, Schett G, Herr- RA is one of the most common inflammato- mann M (2011) Sodium overload and water influx acti- Courses ry rheumatic joint diseases with an estimated vate the NALP3 inflammasome. J Biol Chem, 286: 35-41 23.-26.03.2011: Fachkongress für Osteologie, Fürth prevalence of 1%. Chronic arthritis, if poorly Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossi- 18.-19.10.2011: Retreat des GRK des SFB 643, Heiligen- controlled, typically provokes extensive joint pova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E, stadt damage with the emergence of bone destruc- Sarmay G, Krumbholz G, Neumann E, Toes R, Scherer HU, Catrina AI, Klareskog L, Jurdic P, Schett G (2012) Induction 10.11.2011: Science meets companies, Erlangen tion associated with significantly decreased of osteoclastogenesis and bone loss by human autoanti- 05.-07.11.2012: Retreat des GRK des SFB 643, functional capacities. Hence, the project group bodies against citrullinated vimentin. J Clin Invest, 122: Garmisch-Partenkirchen focuses on the pathophysiology of bone de- 1791-802 struction by the use of experimental arthri- Schett G, Gravallese E (2012) Bone erosion in rheumatoid Research Equipment tis models. They investigate the mechanisms arthritis: mechanisms, diagnosis and treatment. Nat Rev Beckman Coulter GmbH, Flow Cytometer Gallios 3L/10C leading to increased synovial activation of os- Rheumatol, 8: 656-64 teoclasts and decreased ability to repair bone Uderhardt S, Herrmann M, Oskolkova OV, Aschermann Scanco Medical AG, XtremeCT in vivo MicroCT Scanner destruction with the help of osteoblasts. S, Bicker W, Ipseiz N, Sarter K, Frey B, Rothe T, Voll R, Scanco MEDICAL samples 1ccm-20ccm, Micro-CT 40 Nimmerjahn F, Bochkov VN, Schett G, Krönke G (2012) 12/15-lipoxygenase orchestrates the clearance of apopto- The role of 12/15-lipoxygenase tic cells and maintains immunologic tolerance. Immunity, (12/15-LO) in the regulation of innate 36: 834-46 and adaptive immunity Project manager: Dr. G. Krönke International Cooperations 12/15-LO is a central arachidonic acid-meta- Prof. Dr. J. Penninger, Prof. Dr. K. Redlich, Prof. Dr. J. Smo- bolizing enzyme. The aim of this project is to len, Institut of Molekular Biotechnology, Vienna: Austria

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 73 UNIVERSITY HOSPITAL

Department of Medicine 3 – Rheumatology and Immunology Division of Molecular Immunology

Address ronment through its central location in the NFZ es, such as multiple myeloma or EBV (Epstein-Barr Glückstraße 6 and through its leading role in research groups virus) infection. MiRNAs are small, 22-nt long, 91054 Erlangen and research training groups (e.g. Research non coding RNAs that control the expression of Phone: +49 9131 8535913 Unit (FOR 832) and GK 1660). Nationally, the specific target genes at the post-transcriptional Fax: +49 9131 8539343 Division of Molecular Immunology is an impor- level (figure 2). MiRNAs bind to the 3’-untrans- www.molim.uni-erlangen.de tant part of the working committee on Biology lated region of mRNAs which results either in of B lymphocytes within the DGfI (Deutsche a block of translation or an acceleration of the Head of Division Gesellschaft für Immunologie). degradation of the target mRNA. MiRNAs play a Prof. Dr. rer. nat. Hans-Martin Jäck The overall research activities of the Division central role in the regulation of cell fate and cell of Molecular Immunology focus on molecular differentiation processes in animals and plants. Contact aspects of maturation and activation of anti- Dysregulation of miRNA expression was detect- Prof. Dr. rer. nat. Hans-Martin Jäck body-producing B cells as well as the pathogen- ed in various tumors. Therefore, we are current- Phone: +49 9131 8535912 esis of B cell leukemia and autoimmune diseases. ly investigating the function of miRNAs during Fax: +49 9131 8539343 B-Lymphocytes express immunoglobulin (Ig) re- development of normal B cells as well as the [email protected] ceptors on their surface which allow to recognize pathogenesis of Multiple Myeloma and B cell au- foreign antigens and pathogens. Ig receptors toimmune diseases. Currently, we are analyzing Research Focus consist of two covalently associated identical im- miRNA expression profiles in different B cell sta- •• The role of miRNAs in B cell maturation and munoglobulin heavy (IgH) and two identical im- ges and myeloma as well as lymphoma cells by pathogenesis of multiple myeloma munoglobulin light (IgL) chains which differ from high-throughput-sequencing of miRNA libraries •• Nonsense-codon mediated decay of non- cell to cell in their variable regions. When B cells which will serve as a platform for further func- functional mRNA are activated by contact to pathogen, they devel- tional analysis of specific miRNAs involved in the •• Molecular control of early B cell differenti- op into either memory B cells or so-called plas- B cell maturation and the generation of multiple ation ma cells, the latter of which then produce huge myeloma or B cell lymphoma (figure 2). •• Molecular control of peripheral B cell and amounts of soluble antibody molecules. These plasma cell differentiation antibodies then bind to the pathogen, leading to Nonsense-codon mediated decay of •• Selection of B cells its elimination and/or destruction (figure 1). non-functional mRNA B cells emerge from hematopoietic stem cells in Project managers: Prof. Dr. H.-M. Jäck, Dr. J. Structure of the Department the bone marrow. During their maturation pro- Wittmann cess, B cells pass different developmental stages Another major focus of research is the molec- The Division of Molecular Immunology was characterized by the rearrangement of Ig gene ular control of recognition and decay of non founded as an independent section within the segments which starts at the IgH locus and later functional Ig-mRNAs, a pathway that is termed Department of Medicine 3 in 1997. The labo- at the IgL locus. Each of these processes need nonsense-codon mediated decay (NMD) of ratories reside in the NFZ and the Division is to be carefully and tightly controlled to avoid non-functional mRNA (mRNA surveillance). Non- headed by Prof. Dr. H.-M. Jäck together with the generation of self-reactive or leukemic B sense Ig mRNA is encoded from non-productively a Professor emeritus (Prof. Dr. Dr. h.c. J.R. cells. One part of the first critical checkpoint in rearranged Ig genes during B cell development Kalden), eight senior postdoctoral scientists early B cell development is the expression of the as a consequence of a defective VDJ recombina- who supervise currently four PhD students, five pre-B cell receptor (pre-BCR) in early progenitor tion. As faulty mRNAs can be translated into po- technicians, and various rotation students. The B cells. Only cells that express a functional IgH tentially toxic proteins, the elucidation of control main scientific focus of the Division concen- chain can assemble a pre-BCR and subsequent- mechanisms and factors involved in mRNA decay trates on the humoral immune response with a ly receive signals for survival, proliferation, and is of particular interest for B and T cell matura- special emphasis on B cell biology. In addition, differentiation. During the next developmental tion. The role of NMD in central B cell maturation members of the Division participate in teach- stage, rearrangement takes place at the IgL lo- is currently analyzed in a mouse line in which a ing at undergraduate, graduate, and doctoral cus, leading to the synthesis of an IgL chain that specific NMD factor which was discovered in our levels which is reflected by a broad offer of lec- is then assembled with the IgH chain to form the lab can be conditionally deleted in developing B tures, seminars, and lab courses. B cell receptor (BCR). The BCR is then controlled cell progenitors. In parallel, immunprecipitation Several research groups within the Division ex- for binding to self structures in the bone marrow analyses followed by mass spectrometry analyses amine molecular mechanisms of development, environment. B cells with a non-self BCR leave are carried out to identify novel interaction part- activation, and differentiation of B cells in cell the bone marrow and differentiate via transition- ners and their role in the degradation of faulty culture systems and transgenic mouse lines. al stages into mature antigen-responsive B cells. mRNAs and early B cell maturation. Methods include state of the art molecular biology, cultivation of primary B cells, flow cyto- Research Molecular control of early B cell metry with cell sorting, and mouse immunol- differentiation ogy. Cell culture systems are being used to The role of miRNAs in B cell maturation Project managers: Prof. Dr. H.-M. Jäck, Dr. W. identify new regulatory factors, e.g. miRNAs, and pathogenesis of multiple myeloma Schuh adaptor proteins, and transcription factors. Project managers: Prof. Dr. H.-M. Jäck, Dr. J. One major focus is the analysis of mechanisms Subsequently, new mouse models are estab- Wittmann that control early B cell development and sig- lished by homologous recombination in ES cells One research focus is on the role of microRNAs naling of the pre-B cell receptor. For example, and blastocysts as well as by pronucleus injec- during central and peripheral development of B the interaction of the pre-BCR with structures tions. The Division of Molecular Immunology is cells, the antigen-induced differentiation of ma- and ligands in the bone marrow microenvi- well integrated into the Erlangen research envi- ture B cells, as well as the pathogenesis of diseas- ronment and its impact on survival and pro-

74 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) liferation of progenitor B cells is studied using Teaching hibition of the RNaseIII enzyme Drosha. Eur J Immunol, different mouse models. Using transcriptome- 41: 549-51 and proteome analyses, we identified various The Division participates in undergraduate and Lutz J, Heideman MR, Roth E, van den Berk P, Müller W, cellular components of the pre-BCR signaling Raman C, Wabl M, Jacobs H, Jäck HM (2011) Pro-B cells graduate education within the bachelor and sense productive immunoglobulin heavy chain rearrange- cascade, for example the transcription factor master programs in biology, life science en- ment irrespective of polypeptide production. Proc Natl Krüppel-like factor 2 (KLF2) and a number of gineering, and molecular medicine. Students Acad Sci U S A, 108: 10644-9 small non-coding microRNAs (miRNAs). How- have the opportunity to work on their bachelor Vettermann C, Castor D, Mekker A, Gerrits B, Karas M, Jäck ever, investigations of the function of KLF2 in and master theses embedded in the research HM (2011) Proteome profiling suggests a pro-inflamma- B cell maturation and activation showed that tory role for plasma cells through release of high-mobility focus of the Division. Furthermore, the Division KLF2 cannot be solely responsible for termina- group box 1 protein. Proteomics, 11: 1228-37 engages in educating and training doctoral stu- tion of pre-BCR induced proliferation. In future Winkelmann R, Sandrock L, Porstner M, Roth E, Mathews dents from GK 1660 and the research group studies, we will analyze further potential target M, Hobeika E, Reth M, Kahn ML, Schuh W, Jäck HM (2011) FOR 832 by offering numerous workshops and B cell homeostasis and plasma cell homing controlled by genes of pre-BCR signaling and their role in Krüppel-like factor 2. Proc Natl Acad Sci U S A, 108: 710-5 pre-B cell differentiation. seminars, like journal clubs or scientific writing and presentation workshops. Metzner M, Jäck HM, Wabl M (2012) LINE-1 retroele- ments complexed and inhibited by activation induced Molecular control of peripheral B cell cytidine deaminase. PLoS ONE, 7: e49358 Selected Publications and plasma cell differentiation Thiele S, Wittmann J, Jäck HM, Pahl A (2012) miR-9 en- Project managers: Prof. Dr. H.-M. Jäck, Dr. W. Brandl A, Wittmann J, Jäck HM (2011) A facile method hances IL-2 production in activated human CD4(+) T cells Schuh to increase titers of miRNA-encoding retroviruses by in- by repressing Blimp-1. Eur J Immunol, 42: 2100-8 Immune responses are strictly dependent on proper positioning of effector cells. KLF2, a target gene of the pre-BCR, plays a dominant role in proper positioning of B cells in peripheral com- partments. Furthermore, analyses of a B cell-specific KLF2 deletion showed that KLF2 is essential for the migration of plasma cells to their survival niches in the bone marrow. Future studies should identify the underlying mechanisms by analyses of new and/or known target genes of KLF2.

Selection of B cells Project manager: PD Dr. D. Mielenz The unique passport of each single B cell is the B cell receptor (BCR). The BCR allows a specific antigen to select its cognate B cells via binding to the BCR from a pool of billions of B cells. On one hand, this permits an effective and specific immune response; on the other hand, it prevents the activation of potentially dangerous B cells Figure 1: Overview Humoral Immunity with self-antigens. The specificity of a BCR may furthermore decide which anatomic niche will be populated by a given B cell. Since expression of the BCR per se controls B cell survival, newly formed B cells are positively selected for proper surface expression of the BCR and negatively for self-reactivity. The selected B cell pool, however, should recognize any kind of antigen presented in the blood or on antigen-presenting cell. The diverse requirements that are imposed upon the BCR require thus a fine-tuned intracellular signal transduction machinery whose elements are not fully characterized yet and that are also employed by other receptors on B cells, such as CD40 or toll-like receptors. Therefore, the main goal of this project is to identify new signal elements in B cells. So far, three new adaptor proteins have been identified. The function of these proteins in the proximal and distal signaling pathways of the BCR and CD40 is currently being investigated in cell culture systems and transgenic as well as knock-out mouse lines. Figure 2: RNA interference by endogenous microRNA

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 75 UNIVERSITY HOSPITAL

Department of Medicine 4 – Nephrology and Hypertension Chair of Internal Medicine IV

Address secondary hypertension, renal transplantation, inhibitors of HIF degradation result in a marked Ulmenweg 18 sepsis, and multiorgan failure. nephroprotection. This approach is potentially 91054 Erlangen transferable into the clinic in order to prevent Phone: +49 9131 8539002 Research acute kidney injury and reduce ischemia re- Fax: +49 9131 8539209 perfusion injury in the context of kidney trans- www.medizin4.uk-erlangen.de Development and progression of plantation. In parallel, the potential long term chronic kidney disease consequences of hypoxia on renal structure are Head of Department In order to better understand the course of being analyzed, in particular fibrogenesis, epi- Prof. Dr. med. Kai-Uwe Eckardt chronic kidney disease and to identify novel thelial mesenchymal transition, and the growth risk factors and molecular markers, a national of renal cysts. Contact prospective cohort study, the German Chronic Prof. Dr. med. Kai-Uwe Eckardt Kidney Disease (GCKD) Study, has been initi- Pathogenesis of arterial hypertension Phone: +49 9131 8539002 ated. Nine regional centers and several insti- and hypertensive endorgan damage Fax: +49 9131 8539209 tutes at other universities collaborate with the A further important research area relates to [email protected] coordinating center in Erlangen to study 5,000 studies of arterial hypertension. A specific fo- patients with chronic kidney disease and to fol- cus in this area lies on target organ damage Research Focus low them for up to ten years. This large consor- induced by hypertension in kidneys, heart, eye, •• Development and progression of chronic tium is funded by the BMBF and the Founda- and vasculature. In addition, the etiology and kidney disease tion for Preventive Medicine of the Kuratorium pathogenesis of arterial hypertension are being •• Pathophysiologic relevance of hypoxia-in- für Heimdialyse. Studies of the genetic causes investigated. ducible gene expression of kidney disease play an increasing role. This research includes studies on sodium ho- •• Pathogenesis of arterial hypertension and hy- Besides the observational studies, intervention- meostasis which test the hypothesis that stores pertensive endorgan damage al clinical trials are performed in patients with of non-osmotically active sodium exist in the •• Acute and chronic renal allograft failure kidney disease of different etiologies, in par- body and that their capacity has an important •• Systemic consequences of kidney disease ticular with certain forms of glomerulonephritis impact on blood pressure regulation. Mecha- and renal replacement therapy and polycystic kidney disease. nisms in the skin where alterations in sodium Experimental projects in this research area aim content influence lymph-angiogenesis appear Structure of the Department at determining changes in the kidney in con- to be of particular relevance in this context. junction with the initiation of kidney injury and Using sodium balance studies during the Mars The Department of Medicine 4 comprises the at identifying the mechanisms which result in mission project (MARS 500) and innovative Department of Medicine 4 - Nephrology and regeneration or progressive loss of function. To imaging techniques (sodium-MRI), changes in Hypertension at the UK Erlangen and the Com- this end, analyses are being performed in iso- sodium homeostasis and tissue sodium content munity Hospital in Nürnberg. Together they lated cells, human kidney tissue, and animals. are analyzed in humans. represent the largest research and treatment Another focus comprises studies determining Additional experimental projects deal with the center for kidney disease and hypertension in the influence of renal autonomous innervation role of the renin-angiotensin system and the Germany. on inflammatory processes in the kidney. Pro- sympathetic nervous system for the patho- More than 90 physicians and basic scientists jects primarily related to the renal vasculature genesis of hypertension and kidney injury. work in the Department of Medicine 4. include studies of the role of oxidative stress in These studies include electrophysiological in- Patient related and experimental research aims diabetic nephropathy. vestigations of ganglion cells, measurements at better understanding the pathogenesis of of tissue hormones, and studies in transgenic kidney disease and hypertension and their pro- Pathophysiologic relevance of mice as well as tissue analyses. Electrophysio- gression and adverse consequences, at identi- hypoxia-inducible gene expression logical measurements of sympathetic nerve fying novel therapeutic strategies, and at eval- One pathomechanism which is intensively in- activity are not only being conducted in an- uating therapeutic options. Research projects vestigated concerns hypoxia and its relevance imal models, but - using microneurography at this Department have played a major role in for kidney disease. Focus of these studies is the - also in humans. In addition, symphathetic research networks, such as the Clinical Research regulation and functional role of the hypoxia outflowto the kidney and endothelial func- Group 106 (Endorgan Damage in Arterial Hy- inducible transcription factors HIF-1 and HIF-2. tion of renal vessels are indirectly measured pertension) and the SFB 423 (Kidney Injury: Based on studies of the physiological expres- through determination of renal perfusion Pathogenesis and Regenerative Mechanisms) sion of these factors and their regulating en- and sodium excretion. Additional studies in and contribute significantly to the research fo- zymes, the activity of the HIF system is being patients are dealing with the regulation of cus ”Kidney and Circulation Research” of the investigated in different types of kidney disease. endothelial function and in particular the in- Faculty of Medicine. In addition, experiments are performed to test fluence of lipids and hormones. In coopera- The main clinical areas comprise diagnosis if kidney disease can be influenced by modulation with the Department of Ophthalmology, and therapy of kidney diseases, essential and tion of the HIF system. It could be shown that perfusion, structure, and endothelial function

76 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) of retinal vessels in patients with hypertension does not cross react with the antibodies has International Cooperations are being analyzed. been initiated. For further information, please visit our homepage: The AURORA trial and the SHARP trial have www.medizin4.uk-erlangen.de. Acute and chronic renal allograft been conducted to address the question as to failure where statins improve the poor cardiovascular Meetings and International Training Courses In cooperation with the Departments of Urolo- prognosis of patients on dialysis. gy and Surgery, approximately 100 kidney and Additional clinical research deals with acute 26.02.2011: Intensivsymposium, Klinikum Nürnberg Süd combined kidney-pancreas transplantations kidney injury, in particular in the context of 26.11.2011: Post ASN Fortbildung, Nürnberg are performed per year, including living donor sepsis and multiorgan failure. The North Ba- 03.03.2012: Intensivsymposium, Klinikum Nürnberg Süd transplantations. Blood group incompatible liv- varian SepNet Regional Center, located at the 22.-24.06.2012: Symposium: Molecular Targets in Renal ing donation is a particular focus. Department of Medicine 4 in Erlangen and Disease, Bamberg The research program in this field aims at op- Nürnberg, participates in several observational 24.11.2012: Post ASN Fortbildung, München timizing long term graft function with particu- and treatment trials. lar emphasis on grafts from marginal donors. Several multicenter trials are being conducted Teaching to evaluate novel immunosuppressive drugs or their combination. The Department of Medicine 4 with its clinical In parallel to the clinical trials, experimental units in Erlangen and Nürnberg contributes to studies are being performed in a rat transplant the entire spectrum of curricular teaching in in- model in order to identify novel strategies for ternal medicine, including main lectures, differ- the improvement of organ function. ent courses, and training of final year medical students. In addition, several specialized semi- Systemic consequences of kidney dis- nars are being offered as well as optional cour- ease and renal replacement therapy ses in intensive care medicine, transplantation, More than 10% of the population suffer from kidney and vascular system. chronic kidney disease, as defined by reduced There is also the opportunity for clerkships and Magnetic resonance imaging with arterial spin labeling kidney function and/or increased urinary pro- short term visits. (MRI-ASL): Calculated perfusion map with color enco- tein excretion. Kidney disease is associated with ding. the risk of progressive loss of renal function as Selected Publications well as a marked increase in cardiovascular risk. O‘Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, Research projects at the Department of Medi- McQueen M, Sleight P, Sharma AM, Dans A, Probstfield J, Schmieder RE (2011) Urinary sodium and potassium cine 4 in this context deal with epidemiological excretion and risk of cardiovascular events. JAMA, 306: questions, aspects of public health care, the 2229-38 causes of an increased cardiovascular risk, and Schley G, Klanke B, Schödel J, Forstreuter F, Shukla D, Kurtz A, Amann K, Wiesener MS, Rosen S, Eckardt KU, the optimization of renal replacement therapy. Maxwell PH, Willam C (2011) Hypoxia-inducible tran- Partly in collaboration with the Department of scription factors stabilization in the thick ascending limb Medicine 2, mechanisms of atherogenesis are protects against ischemic acute kidney injury. J Am Soc Nephrol, 22: 2004-15 being investigated as well as the specific con- Schmieder RE, Mann JF, Schumacher H, Gao P, Mancia G, sequences of impaired renal function on vascu- Weber MA, McQueen M, Koon T, Yusuf S, on behalf of the lar pathology. This includes e.g. experimental ONTARGET Investigators (2011) Changes in albuminuria studies of the role of asymmetric Dimethy- predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol, 22: 1353-1364 larginin (ADMA) and of impaired angiogenesis Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T, in kidney disease. Schöfl C, Renz W, Santoro D, Niendorf T, Müller DN, Nei- The characteristic systemic consequences of ninger M, Cavallaro A, Eckardt KU, Schmieder RE, Luft FC, chronic kidney disease include also anemia and Uder M, Titze J (2012) (23)Na magnetic resonance imaging of tissue sodium. Hypertension, 59: 167-72 disturbances in bone and mineral metabolism Ritt M, Harazny JM, Ott C, Raff U, Bauernschubert P, Le- which have both been identified as cardiovas- hmann M, Michelson G, Schmieder RE (2012) Impaired cular risk factors. The Department participates increase of retinal capillary blood flow to flicker light exposure in arterial hypertension. Hypertension, 60: 871-6 in several multicenter trials aiming at optimizing management of these complications. A rare Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, complication of treatment with recombinant Koesters R, Bachmann S, Betz P, Schley G, Schödel J, human EPO is the development of neutralizing Willam C, Winkler T, Amann K, Eckardt KU, Maxwell P, Wiesener MS (2012) Renal tubular HIF-2a expression re- antibodies leading to pure red cell aplasia. A quires VHL inactivation and causes fibrosis and cysts. PLoS therapeutic trial with a novel EPO-mimetic that ONE, 7: e31034

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 77 UNIVERSITY HOSPITAL

Department of Medicine 5 – Hematology and Oncology Chair of Hematology and Oncology

Address project is to establish a protocol for the expan- II restricted MiHA, we could identify a group Ulmenweg 18 sion and differentiation of highly functional tu- of antigens whose presentation is dependent 91054 Erlangen mor-specific T cells. The population of human on expression of the non-classical HLA mole- Phone: +49 9131 8535955 TCRa/b+ CD4- CD8- double-negative (DN) cule HLA-DO. Based on the selective expression Fax: +49 9131 8535958 T cells plays a special role in the regulation of profile of HLA-DO, these results could open the www.medizin5.uk-erlangen.de immune responses. In this project, the group possibility to separate GvL effect and GvHD. investigates the immunoregulatory function of In an additional project, we analyze the CD4+ Head of Department human DN T cells. In addition, the role of DN T cell mediated eradication of HLA class II neg- Prof. Dr. med. Andreas Mackensen T cells under pathologic conditions as auto- ative tumors via indirect antigen presentation immunity and transplant rejection is currently in mice and involved intracellular mechanisms. Contact determined. The long-term goal is to develop These projects are funded by ELAN, IZKF, and Prof. Dr. med. Andreas Mackensen a clinical strategy for using DN T cells to treat Jung-Stiftung. Phone: +49 9131 8535955 graft-versus-host disease after allogeneic stem Fax: +49 9131 8535958 cell transplantation. The projects are funded by Immunoregulation of alloSCT [email protected] DFG and ELAN. Project managers: Prof. Dr. E. Ullrich, K. Mein- hardt, S. Krieg, J. Rothamer Research Focus Adoptive cell therapy with memory This research group focuses on immunoreg- •• T cell based immunotherapy B-lymphocytes for patients after Stem ulation of GvL and GvH effects in alloSCT. •• Adoptive cell therapy with memory B-lym- Cell Transplantation (alloSCT) Clinical studies exploiting the impact of innate phocytes for patients after Stem Cell Trans- Project managers: J. Winkler, Prof. Dr. T. Win- effector cells on GvHD lead to the suggestion plantation (alloSCT) kler, Prof. Dr. M. Mach, Prof. Dr. A. Mackensen that allogeneic donor NK cells mediate GvL •• CD4+ T cell based immunotherapy The aim of our project is the preclinical devel- while preventing GvHD. It has been shown •• Immunoregulation of alloSCT opment of a new, first-in-man cell based ther- that NK cells represent a heterogeneous pop- •• Immunregulation in cancer biology and SCT apy for the improvement of humoral immune ulation of different subsets. Current projects •• Immunotherapy and Magnetic Flowcytome- responses in patients after alloSCT. The devel- of the research group analyze the specific try with CD4+ T cells opment of the technology under GMP-condi- function of murine and human NK subsets in •• Tumor immune escape tions showed that only two-step separations tumor models and GvHD. The aim of these •• Cellular immunotherapy with an CD3-depletion and an enrichment of studies is to further develop NK cell immu- •• HLA-laboratory CD19-B-cells was sufficient for the required notherapeutic concepts in malignant disea- purity of B-cells in the cellular product. We ses. The preclinical research is funded by the Structure of the Department showed that B-cells in the product were func- Max Eder Program of the German Cancer Aid tional in vitro. In May 2012, we obtained the and the IZKF. In addition, the Wilhelm Sander The Department of Medicine 5 is the clinic of GMP-certificate for the B-cell product from the foundation supports another project that aims Hematology and Oncology. As maximum-care regulatory authorities. In the second part of the at dissecting the polarization of T-helper cell hospital, the complete range of diagnostic and project, we developed a study protocol for a populations during GvHD. therapeutic options for malignancies of the phase I/IIa clinical trial for the adoptive transfer blood, lymphnodes, and solid tumors are of- of allogeneic donor B-lymphocytes for patients Immunregulation in cancer biology fered for both, ambulatory and stationary pa- five months after alloSCT according to GCP. and SCT tients. The clinic focuses on the transplantation All necessary documents have been delivered Project manager: Dr. D. Mougiakakos of allogeneic and autologous bone marrow to the Paul-Ehrlich-Institute in February 2013. Our research group is mainly interested in stud- stem cells in adults. Funded by BayimmuNet, GCP-Fonds „Clinical ying the alterations of the immune system due The Department has a total of 81 employees Studies” 2009 - 2012. to cancer and after stem cell transplantation. A (24 on extra-departmental funding). The sci- better understanding regarding the tumor-as- entific section counts twelve post-doctoral CD4+ T cell based immunotherapy sociated strategies contributing to an immu- fellows, ten graduate students, and ten tech- Project managers: Dr. A. Kremer, S. Kretsch- nosuppression will support the development nicians. mann of novel therapeutic strategies. Furthermore, In HLA-matched stem cell transplantation, the we aim at ”learning” from tumors how they Research beneficial graft versus leukemia (GvL) effect specifically weaken immune responses in order is mediated by donor-derived T-lymphocytes to translate these findings into potential exper- T cell based immunotherapy which recognize patient-derived polymorphic imental approaches for the treatment of rejec- Project managers: Prof. Dr. A. Mackensen, Dr. peptides. These so-called minor histocompat- tion reactions (GvHD) following SCT. Our main M. Aigner, Dr. S. Völkl ibility antigens (MiHA) also play an important research interests include studies regarding (I) The group develops new approaches to gen- role in the induction of detrimental graft versus oxidative stress associated immunosuppression erate and improve adoptive T cell therapy host disease (GvHD). By characterization of the in leukemias, (II) myeloid derived suppressor against malignant diseases. Main focus of this intracellular processing pathways of HLA class cells in various tumor entities and following

78 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) stem cell transplantation, and (III) the suppres- the development of virus specific T cells for Aigner M, Feulner J, Schaffer S, Kischel R, Kufer P, Schnei- sive effects exerted by human mesenchymal adoptive transfer in patients after allogeneic der K, Henn A, Rattel B, Friedrich M, Baeuerle PA, Mack- ensen A, Krause SW (2013) T lymphocytes can be effec- stem cells. Supported by ELAN, IZKF, SFB 643, stem cell transplantation. Parallel to the de- tively recruited for ex vivo and in vivo lysis of AML blasts and Deutsche Krebshilfe. velopment of a GMP grade T cell product, the by a novel CD33/CD3-bispecific BiTE antibody construct. group established an extended immunomon- Leukemia, 27: 1107-15 Immunotherapy and Magnetic itoring of patients. Within the collaborative International Cooperations Flowcytometry with CD4+ T cells research center SFB 643, the immunomonitoring was extended in collaboration with R. Kiessling, Cancer Centre Karolinska, Karolinska Institu- Project manager: Dr. J. Bosch tet, Stockholm: Sweden The main focus of our research group is to de- the Institute of Pathology (Charité Berlin) by J.H.F. Falkenburg, Department of Hematology, Leiden Uni- velop immunotherapy with CD4+ T cells for single cell TCR analysis using Next Generation versity, Leiden: The Netherlands Sequencing. treatment of ocular melanoma and to develop L. Zitvogel, Institut Gustave Roussy, Paris: France Funded by DFG, Deutsche Krebshilfe, ZIM, and a novel magnetic flowcytometry technique. B.R. Ksander, The Schepens Eye Research Institute and Current research aims at determining which BayImmuNet. Department of Ophthalmology, Harvard Medical School, immune cells infiltrate the primary tumor in the Boston: USA immune-privileged eye and if uveal melanoma HLA-laboratory vaccines activate different subpopulations of Project manager: PD Dr. B. Spriewald Research Equipment In recent years, the laboratory was interested CD4+ T cells. The studies on magnetic flowcy- Applied Biosystems, Sequencer AB Genetic Analyser 3130 in new methods for the detection of various tometry focus on a novel technique which ap- Becton Dickinson, FACS Canto II subclasses of anti-HLA antibodies in solid organ plies magnetophoresis to perform cell enrich- Seahorse Bioscience, XFe96 Analyzer transplantation. Our immunogenetic studies ment, focusing, and background elimination look into polymorphisms of several cytokines in a single step. Time-of-flight measurements and T cell regulatory genes and their associa- are performed with integrated magnetic sen- tion with rheumatic and malignant disorders. sors to detect specifically cancer cells and cell Another focus is on experimental studies for diameters in whole blood. Funded by DFG and the induction of transplantation tolerance and WING-program of the BMBF. reduction of chronic rejection. These studies are performed in close collaboration with the Tumor immune escape group of experimental heart surgery. Project managers: Prof. Dr. A. Mackensen, Dr. M. Aigner Teaching In the last years, the study of tumor metabolites Human M1 macrophages attack Lymphoma-Cells. (A) One M1 macrophage secretes a cytotoxic peptide and their effects on the adaptive immune sys- A traditional teaching program (lectures, semi- (red), directed against a lymphoma cell (green). tem moved into the center of interest of tumor nars, practica) covering all subjects in the field (B) M2 macrophages show no expression of this peptide. immunology. By modulation of their metabo- of hematology and oncology is being offered lism, tumors are able to generate advantages by qualified staff in an integrated and interdis- for growth and proliferation for themselves. ciplinary fashion. A new internal medicine pro- Our group focuses on the functions of 5’-De- gram in hematology and oncology was intro- oxy-5’-methylthioadenosine (MTA) and its deduced. In this comprehensive program, small grading enzyme MTAP, as it is known that these groups of medical students learn the basics of molecules play a role in many malignacies. The hematology and oncology in a patient-oriented influence of MTA produced by tumors on the setting. activation, proliferation, and various effector functions of cytotoxic CD8+ T cells is studied Selected Publications by the research unit in cooperation with the Bosch JJ (2012) Immunotherapy of uveal melanoma. Dev Universitätsklinikum Regensburg and funded Ophthalmol, 49: 137-49 by the DFG. Gerbitz A, Sukumar M, Helm F, Wilke A, Friese C, Fahren- waldt C, Lehmann FM, Loddenkemper C, Kammertoens T, Mautner J, Schmitt CA, Blankenstein T, Bornkamm GW Cellular immunotherapy (2012) Stromal interferon-g signaling and cross-presenta- Project managers: Prof. Dr. A. Gerbitz, Dr. M. tion are required to eliminate antigen-loss variants of B cell lymphomas in mice. PLoS ONE, 7: e34552 Aigner, Dr. H. Bruns, Dr. R. Gary Kremer AN, van der Meijden ED, Honders MW, Goeman JJ, The ”Cellular Immunotherapy” group works Wiertz EJ, Falkenburg JH, Griffioen M (2012) Endogenous on the development of T cell therapies direct- HLA class II epitopes that are immunogenic in vivo show ed against B-cell specific self antigens, such distinct behavior toward HLA-DM and its natural inhibitor HLA-DO. Blood, 120: 3246-55 as CD19. Main goal is the development of Le Blanc K, Mougiakakos D (2012) Multipotent mesenchy- lymphoma specific T cell therapies in murine mal stromal cells and the innate immune system. Nat Rev models. In addition, the group focuses on Immunol, 12: 383-96

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 79 UNIVERSITY HOSPITAL

Department of Neurology Chair of Neurology

Address On the basis of this specialized know-how, the ing specialist care for patients with epilepsy in Schwabachanlage 6 Department is able to provide up to date and Northern Bavaria will be launched and scientif- 91054 Erlangen competent diagnosis and treatment as well as ically evaluated. Phone: +49 9131 8534563 scientific work within all areas of modern clini- Fax: +49 9131 8536597 cal neuroscience. Epilepsy www.neurologie.uk-erlangen.de Project manager: Prof. Dr. H.M. Hamer Research The Erlangen Epilepsy Center ranks among the Head of Department top five University Epilepsy Centers in Germa- Prof. Dr. med. Dr. h.c. Stefan Schwab Intensive care, stroke, emergency care ny. Scientific hot spots in 2011/2012 included: Project managers: PD Dr. M. Köhrmann (Stroke- 1) Changes of the innate immune-system in Contact Unit), PD Dr. H. Huttner (neurocritical care unit), epilepsy; 2) Epilepsy in CNS-malformations; Dr. med. Axel Schramm PD Dr. Dr. L. Marquardt (emergency room) 3) Pathophysiology of epilepsy: Studies corre- Phone: +49 9131 8546018 Neurointensive care: Clinical and translational lating clinical parameters, e.g. neuropsycholo- Fax: +49 9131 8536589 research are major columns of neurointensive gy, with hippocampal pathology; 4) Magneto- [email protected] care research in Erlangen. Examples include encephlography; the new multichannel MEG brain edema treatment after ICH, temperature system is running; 5) Neuropsychology/Cogni- Research Focus management in subarachnoid hemorrhage tion; 6) Quantitative EEG in epilepsy and en- •• Intensive care, stroke, emergency care cerebral ischemia, intraventricular fibrinoly- cephalopathy; 7) Drug monitoring; 8) Histori- •• Telemedicine and health services sis and lumbar drainage after intraventricular cal aspects of epileptology; 9) Socio-economic •• Epilepsy hemorrhage as well as multimodal monitoring aspects of epilepsy. •• Neuroimmunology for patients with intracranial pressure. Funding sources are DFG and the Bavarian •• Pain and functional imaging Emergency room: Each year the initial assessment State Ministry of the Environment and Public •• Autonomic nervous system of about 6,000 patients takes place in the emer- Health. •• Neuromuscular diseases gency room. After an immediate clinical exam- •• Cognitive neurology ination, adequate diagnostic procedures and Neuroimmunology prompt specificemergency treatment is initiated Project manager: Prof. Dr. R. Linker Structure of the Department if necessary. For a multitude of clinical studies, Activities in the area have been further pro- especially vascular ones, screening and inclusion moted by the establishment of a W2 endowed The Department of Neurology is one of the is managed directly in the emergency room. chair now held by Prof. Dr. R. Linker. Conse- largest neurological centers in Germany treat- Stroke-unit: We treat more than 1,000 in-hos- quently, the main focus of our interest is a ing 4,500 in-patients and more than 15,000 pital patients on our 14-bed stroke-unit. An translational approach, bringing experimental outpatients each year. Thereby, the Department extremely high level of medical care (iv-throm- knowledge to the patient and vice versa. Apart maintains close collaborations with the Division bolysis rate > 25%) is combined with state- from the participation in several multicenter of Molecular Neurology and the Departments of-the-art research, including e.g. MRI-based trails concerning immunmodulatory therapy of Neurosurgery and Neuroradiology. interventions, ECG-monitoring and new oral of MS, three experimental workgroups have Particularly the emergency unit of the ”Kopf- anticoagulants. Residents are part of an educa- been established very successfully: 1) Im- klinik”, coordinated by our Department, guar- tional curriculum for stroke-care. munregulation and new human biomarkers, antees immediate and best medical treatment 2) Neuroprotection and neurodegeneration in and is directly linked to the Department of Telemedicine and health services the experimental model, as well as 3) T cell im- Neuroradiology. For treatment of in-patients, Project manager: PD Dr. Dr. L. Marquardt munology and regulation of sodium and water the Department provides 78 beds altogeth- For more than five years, the Department of balance. Recent work deals with the regulation er. 14 beds are located at one of the largest Neurology has been running and coordinating of pathogenic Th-17 cell responses by sodium Stroke-Units in Germany and twelve on the in- the Stroke Network with Telemedicine with chloride intake. Our group is supported by the tensive care unit which has been completely re- three stroke centers and 17 regional hospitals. Else-Kröner Forschungsstiftung and by several modeled in 2012. The center of Epilepsy (EZE) Since 2011 the Network has, as the only one industrial grants. represents another outstanding facility includ- of its kind, been certified to the international ing a monitoring unit and an interdisciplinary ISO standard for its rigorous quality manage- Pain and functional imaging team for surgery in epilepsy. Last but not least ment system. The Network is responsible for Project manager: Prof. Dr. C. Maihöfner a telemedical network for stroke care (STENO) state-of-the-art stroke care and management in Our research team investigates mechanisms of and a number of specialized outpatient services Northern Bavaria and South Thuringia and is adaptive and maladaptive sensorimotor plas- provides university neurological treatment be- part of the regular health care system. Impact ticity in several diseases (neuropathic pain, yond the borders of our region. and effect of the Network are investigated in headache, and stroke). Employed methods are The establishment of two endowed chairs for scientific studies and the technology is subject non-invasive functional brain imaging tech- Neuroimmunology and Neurorehabilitation as to continuous improvement. Amongst other niques (fMRI, MEG), neuropsychology, psycho- well as efforts in many other areas further pro- projects with multiple industry and medical physics, and repetitive transcranial magnetic moted our research activities. collaborators, a very innovative project regard- stimulation (rTMS). Work done by the group

80 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) has been awarded several times. Main funding to develop and evaluate new treatment ap- Meetings and International Training sources are BMBF (”German Research Network proaches for patients with hemi-blindness and Courses on Neuropathic Pain”) and DFG (”Determi- hemispatial neglect. In cooperation with the 12.02.2011: Erlanger Schmerz- & Palliativtag, Erlangen nants and modulators of postoperative pain”, neuroimmunological group, we examine the 08.-09.07.2011: Symposium Herz & Hirn 2011, Coburg KFO 130; see own report). cognitive consequences of neuroimmunologi- 13.10.2011: 3. Erlanger Telemedizin-Symposium, Erlangen cal disorders. In cooperation with the Institute 10.-11.02.2012: Erlanger Schmerz- & Palliativtage, Erlan- Autonomic nervous system of Psychiatry, London, we examine the role of gen Project manager: Prof. Dr. M.J. Hilz the post-traumatic stress disorder in patients’ 13.-14.04.2012: Comprehensive Epilepsy Course, Erlan- The autonomic research laboratory evaluates ability to recover after a neurological disease. gen cardiovascular autonomic functions of various 28.-29.09.2012: Comprehensive Epilepsy Course, Erlangen medical disorders, involving the central and pe- Teaching 15.-16.06.2012: Symposium MS-Zentrum Franken 2012, ripheral autonomic network. Moreover, we per- Between everyday clinical practice and the Nürnberg form quantitative sensory testing (vibration and teachings segment of our Department, the 11.12.2012: 4. Erlanger Telemedizin-Symposium, Erlan- temperature sensation) to evaluate polyneuropa- block training gained widespread recognition gen thy, especially small fiber neuropathy. We investi- by the students. Also the clinical course „Ein- gate the influence of enzyme replacement thera- führung in die klinische Medizin” (EKM), giv- py in lysosomal storage disorders, such as Fabry ing a short introduction in the everyday clinical and Pompe disease, on disease progression. practice, as well as the main lecture are ap- In patients with familial dysautonomia, we per- preciated by many students. Due to increased formed polysomnographic sleep recordings in demand, we were not able to integrate all can- cooperation with the New York University. Fur- ditates for the final year. A detailed evaluation thermore, we evaluated autonomic cardiovascu- on scientific basis of teaching activities demon- lar modulation in patients with stroke, traumatic strated positive results. brain injury, epilepsy, multiple sclerosis, and in professional soccer players after header training. Selected Publications Hilz MJ, Koehn J, Kolodny EH, Brys M, Moeller S, Stemper Kopfklinikum Neuromuscular diseases B (2011) Metronomic breathing shows altered parasym- pathetic baroreflex function in untreated Fabry patients Project managers: Prof. Dr. R. Linker (spokes- and baroreflex improvement after enzyme replacement man), Prof. Dr. R. Schröder therapy. J Hypertens, 29: 2387-94 The Neuromuscular Disease Center is an in- Kiphuth IC, Huttner HB, Struffert T, Schwab S, Köhrmann terdisciplinary institute, providing a special- M (2011) Sonographic monitoring of ventricle enlarge- ment in posthemorrhagic hydrocephalus. Neurology, 76: ized outpatient clinic and a neuropathological 858-62 laboratory for diagnostic biopsies and for the Nowak M, Bauer S, Haag A, Cepok S, Todorova-Rudolph investigation of neuromuscular diseases. The A, Tackenberg B, Norwood B, Oertel WH, Rosenow F, neuromuscular research is composed of three Hemmer B, Hamer HM (2011) Interictal alterations of cytokines and leukocytes in patients with active epilepsy. task forces with the following key aspects: 1) Brain Behav Immun, 25: 423-8 Examination in immunopathogenesis of au- Staykov D, Wagner I, Volbers B, Hauer EM, Doerfler A, toimmune myositis and Myasthenia gravis, 2) Schwab S, Bardutzky J (2011) Natural course of perihem- Studies for pathogenesis of myofibrilar myopa- orrhagic edema after intracerebral hemorrhage. Stroke, 42: 2625-9 thy, 3) Works to genetic respectively pathogenesis of hereditary as well as inflammatory neu- Birklein F, Maihöfner C (2012) Neglect your back to control your pain? Neurology, 79: 300-1 ropathy. A special success was achieved with Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, the extrapolation of the research group FOR Linker RA, Muller DN, Hafler DA (2013) Sodium chloride 1228, supported by DFG (see own report). The drives autoimmune disease by the induction of pathogen- group is managed by Prof. Dr. R. Schröder, not ic TH17 cells. Nature, 496: 518-22 bound to a location. International Cooperations Cognitive neurology X. Wang, Fudan University, Shanghai: China Project manager: Prof. Dr. T. Schenk L. MacDonald, T. Schweizer, Department of Neurosurgery, We are interested in visual and movement University of Toronto, Toronto: Canada disorders that occur after selective damage to Department of cell and molecular biology, Karolinska Insti- tute, Stockholm: Sweden the brain. We use 3D movement recordings and detailed psychophysicial experiments to A. Noble, Institute of Psychiatry, King’s College, London: UK gain a better understanding of how the brain New York University, New York: USA uses sensory information to guide our move- D. Hafler, Yale University, New Haven: USA ments. The same techniques are also applied B.S. Chang, BIDMC Harvard, Boston: USA

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 81 UNIVERSITY HOSPITAL

Department of Neurology Division of Molecular Neurology

Address degenerative mechanisms in synucleinopa- entire spectrum of therapies for movement dis- Schwabachanlage 6 thies are analyzed in order to understand the orders. 91054 Erlangen molecular mechanisms in the development of Automated motion and gait analysis systems Phone: +49 9131 8539324 Parkinson's disease and Lewy body dementia. for stationary and mobile diagnostics are de- Fax: +49 9131 8536597 The interaction between neurodegenerative veloped in collaboration with the Faculty of En- www.molekulare-neurologie.uk-erlangen.de processes and inflammatory pathomechanisms gineering (Pattern Recognition Lab) and with within the CNS has become an additional main local industry partners (IT Astrum). The goal is Head of Division focus within the Division. to support patients using objective assessment Prof. Dr. med. Jürgen Winkler of movement deficits during daily life at home Translational neuroscience in order to achieve an optimal treatment. Contact The Division is interested in the molecular and PD Dr. med. Jochen Klucken cellular biology of adult neural stem and pro- Teaching Phone: +49 9131 8539324 genitor cells in two regions of the adult brain, Fax: +49 9131 8536597 the subventricular zone and the hippocampus The Division of Molecular Neurology is involved [email protected] where new neurons are generated throughout in the curricular teaching of Medicine (Depart- the whole life span. Adult neurogenesis is se- ment of Neurology) and Molecular Medicine. Research Focus riously altered in the context of neurodegen- In addition, internships, bachelor and master •• Neurodegenerative diseases erative diseases. Numerous findings indicate thesis as well as medical and natural scientific •• Translational neuroscience that impaired adult neurogenesis may be one doctoral theses are supervised. •• Clinical research and development of the underlying pathophysiological events in the development of non-motor symptoms, like Selected Publications Structure of the Department depression, cognitive impairment, and olfacto- Klucken J, Barth J, Maertens K, Eskofier B, Kugler P, Steidl R, ry dysfunction. These symptoms are likely to Hornegger J, Winkler J (2011) Mobile biosensor-based gait analysis: a diagnostic and therapeutic tool in Parkinson’s The Division of Molecular Neurology aims at reflect the compromised ability of the brain to disease. Nervenarzt, 82: 1604-11 establishing a link between daily patient care generate new neurons in the hippocampus as Moessnang C, Frank G, Bogdahn U, Winkler J, Greenlee towards the neuroscientific development for well as the olfactory bulb. Moreover, cell and MW, Klucken J (2011) Altered activation patterns within novel therapies in the field of neurodegenera- molecular techniques have been established the olfactory network in Parkinson’s disease. Cereb Cortex, tive diseases. The main focus of the Division is to delineate and modify pathological mecha- 21: 1246-53 on neurodegenerative diseases, such as Parkin- nisms associated with protein aggregation of Klucken J, Poehler AM, Ebrahimi-Fakhari D, Schneider J, son‘s disease, Huntington‘s disease, and hered- a-synuclein in Parkinson’s disease and atypical Nuber S, Rockenstein E, Schlötzer-Schrehardt U, Hyman BT, McLean PJ, Masliah E, Winkler J (2012) a-synuclein ag- itary spastic paraplegia. In addition, the Divi- parkinson syndromes. This strategy may lead to gregation involves a bafilomycin A 1-sensitive autophagy sion intends the integration of ongoing clinical a causal therapy of synucleinopathies. pathway. Autophagy, 8: 754-66 projects with the neighboring Departments. These concepts are currently translated into the Kohl Z, Winner B, Ubhi K, Rockenstein E, Mante M, Münch Clinically, a large outpatient clinic for move- generation and characterization of patient de- M, Barlow C, Carter T, Masliah E, Winkler J (2012) Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic ment disorders is established where the entire rived stem cells that can be isolated from the A53T synuclein mouse model. Eur J Neurosci, 35: 10-9 spectrum of clinical, electrophysiological, im- skin and differentiate into neurons. Based on May VE, Nuber S, Marxreiter F, Riess O, Winner B, Winkler aging, and genetic diagnostics is provided for the initial findings, these patient derived neu- J (2012) Impaired olfactory bulb neurogenesis depends on patients affected with these diseases. Another rons provide for the first time an important tool the presence of human wild-type alpha-synuclein. Neuro- focus of the movement disorder outpatient to study disease processes and define novel in- science, 222: 343-55 clinic is to assess movements using embedded terventions. Winner B, Regensburger M, Schreglmann S, Boyer L, Prots biosensor systems. This project is jointly devel- I, Rockenstein E, Mante M, Zhao C, Winkler J, Masliah E, Gage FH (2012) Role of a-synuclein in adult neurogenesis oped with an industry partner and the Pattern Clinical research and development and neuronal maturation in the dentate gyrus. J Neurosci, Recognition Lab. The outpatient clinic for movement disorders 32: 16906-16 (in particular Parkinson's disease, Huntington's Research disease, and hereditary spastic paraplegia) International Cooperations is offering state of the art diagnostic proce- Prof. Dr. L. Aigner, Institute of Molecular Regenerative Neurodegenerative diseases dures and long-term care for patients and their Medicine, Paracelsus Medical University, Salzburg: Austria The scientific focus of the Division emphasizes caregivers. Furthermore, the integration of sci- Dr. T.F. Outeiro, Institute for Molecular Medicine - Cellular on adult neurogenesis and neurodegenerative entific projects will be consequently followed and Molecular Neuroscience Unit, University of Lisbon, Lisbon: Portugal mechanisms in Parkinson's disease, Hunting- up in close cooperation with the Department Prof. Dr. E. Masliah, Department of Neurosciences, Univer- ton's disease, and hereditary spastic paraplegia. of Neurology which provides the care for in- sity of California San Diego, San Diego: USA Neuroregenerative processes with emphasis on patients. Prof. Dr. B.T. Hyman, Massachusetts General Hospital - adult neurogenesis (generation of new neurons In addition to the clinical and neurobiologi- MIND, Harvard University, Boston: USA in the adult brain) are assessed in movement cal activities, deep brain stimulation (DBS) for Prof. Dr. G. Wenning, Universitätsklinikum Innsbruck, disorders, using cell culture and transgenic movement disorders will be established in close Neurologische Universitätsklinik, Innsbruck: Austria models of Parkinson's and Huntington's dis- cooperation with the Departments of Neurolo- Prof. Dr. T. Wyss-Coray, Stanford School of Medicine, Neu- ease. In a complementary approach, neuro- gy and Neurosurgery in order to provide the ro Immunology and Degeneration, Stanford: USA

82 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Meetings and International Training Courses 01.01.2011.-31.12.2012: Fortbildungsveranstaltungen im Fortbildungsprogramm der Neurologie, Erlangen Biopsy Repro- Differen- graming tation 27.-29.10.2011: Jahrestagung der Deutschen Gesellschaft für Neurogenetik, Erlangen 07.12.2012: AMASE: 3. Automated Mobility Analysis Sym- posium Erlangen, Erlangen Biopsy derived skin fibroblasts can be reprogrammed into induced pluripotent stem cells and further differentiated into different neural cell types.

Data derived from different body sensors are transferred via IT-network, analyzed server-based, and made available to the patient and therapists.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 83 UNIVERSITY HOSPITAL

Department of Neurosurgery Chair of Neurosurgery

Address Subgroup I (intraoperative imaging): ment of growth hormone secreting pituitary Schwabachanlage 6 A major effort of this group is the acquisition adenoma represent a central part. Our clinical 91054 Erlangen of all parameters that are connected to intra- and laboratory chemical analysis and screening Phone: +49 9131 8534566 operative imaging of pituitary and suprasellar studies are supported by Pfizer and Novartis. Fax: +49 9131 8534476 tumors, intra- and extraaxial brain tumors, and The efficacy of novel intra-operative technolo- www.neurochirurgie.uk-erlangen.de epilepsy-associated procedures. The analysis gies in pituitary adenoma surgery and cranio- of these data is currently in progress. In ad- pharyngiomas is evaluated. Novel procedures Head of Department dition, the group worked on the visualization include endoscopic surgery, such as endoscop- Prof. Dr. med. Michael Buchfelder of important eloquent brain areas with the ic assisted microsurgery and intraoperative implementation of diffusion-tensor-imaging, MRI. These techniques allow the possibility of Contact functional MRI and magnetoencephalography. control of resections in cases of intrasellar and PD Dr. med. Ilker Y. Eyüpoglu Moreover, studies of implementation of trac- suprasellar tumors. Goal of these clinical long Phone: +49 9131 8544756 tography data in the surgical treatment of brain term studies is to define the relapse frequencies Fax: +49 9131 8534569 stem lesions were completed. Two important of sellar tumors including different prognostic [email protected] studies analyzed the connectivity of eloquent factors. brain areas with different DTI algorithms using The field of neuroendocrinology in the De- Research Focus probabilistic fiber tracking and investigated the partment of Neurosurgery was established •• Functional Neuronavigation and Intraopera- amount of susceptibility artifacts in linear regis- in 2007 in the framework of an endowed tive Imaging tration of fiber tracts. professorship for clinical and experimental •• Neuroendocrinology Subgroup II (functional imaging): neuroendocrinology. In cooperation with the •• Neurooncology This group made correlative studies for cor- Institute of Radiology, body composition, tical plasticity after resection of gliomas. Also liver and muscle fat content are determined Structure of the Department the connectivity of receptive and expressive by MRI in patients with various hypothalam- language areas was investigated with fMRI and ic-pituitary diseases (e.g. pituitary deficiency, The Department of Neurosurgery of the FAU is DTI following reports of other groups with elec- acromegaly, and M. Cushing). The results are one of the largest in Germany. There is a total trical stimulation. correlated with various metabolic characteris- of 78 beds for inpatients, including ICU beds. Subgroup III (metabolic imaging): tics and with novel parameters involved in the The number of outpatients is 4,000 per year. Major efforts were studies of metabolic imag- metabolic control. The aims of these studies Up to 2,600 patients get inpatient treatment. ing for the characterization of the infiltration of are to obtain novel insights in the neuroen- Caseloads include approximately 2,200 major gliomas with proton MR spectroscopy and FET- docrine control of metabolic and energetic neurosurgical procedures per year. The range PET. Furthermore, studies of the tumor invasion processes. Another translational scientific proof operations covers the whole spectrum of into fiber tracts and its influence on their recon- ject involves the functional characterization of neurosurgery with a focus in the microsurgical struction and neurologic symptoms and studies mutations of the metabotropic calcium-sens- treatment of processes of the skull base, par- of metabolic changes in temporal lobe lesions ing receptor (CaSR) that occur in patients with ticularly in the sellar region, in eloquent brain with 1H MR spectroscopy were investigated. specific disorders of calcium homeostasis. The areas (e.g. central region, brain stem), the Further, we investigate the following topics: CaSR is also expressed in pituitary cells and in vascular neurosurgery, spine surgery, pediatric Correlation of fluorescence-guided resection of hypothalamic nuclei involved in the control of neurosurgery, and epilepsy surgery. Aside of malignant gliomas, utilizing five-aminolevulinic endocrine systems. In this project the patients modern microsurgical techniques, endoscopic acid (5-ALA) and intraoperative MR imaging, are screened for clinical evidence of neuroen- procedure, intraoperative electrophysiological studies of cortical plasticity after gliome resec- docrine dysfunction, and clinical and in-vitro monitoring, neuronavigation, and intraopera- tion adjacent to eloquent brain areas and intra- data are correlated to define a potential ge- tive MRI are used. A molecular biological lab- operative MR spectroscopy in gliomas. notype-phenotype relation. Furthermore, ag- oratory with an integrated cell culture and a onists and antagonists of the CaSR are tested wide range of cellular and molecular biological Neuroendocrinology in vitro whether they can rescue the molecu- methods is available for basic scientific issues. The Department of Neurosurgery represents a lar defect of the mutated CaSR. This poten- nationally and internationally specialized center tially offers a therapeutic approach specifically Research for the whole spectrum of sellar pathologies. tailored to patient´s molecular CaSR defect Clinically we investigate the influence of in- (individualized medicine). Further projects in- Functional Neuronavigation and Intra- terventional/operative, radiotherapeutic, and vestigate various aspects of growth-hormone operative Imaging pharmacological approaches on normal and secreting human adenoma cells in vitro, like The research group ”functional neuronaviga- hypersecretory pituitary gland function in the the expression of certain membrane receptors tion and intraoperative imaging” is divided in course of the ”Acrostudy” (treatment and MRI (e.g. somatostatin receptors) and the char- three subgroups that work in part independent- follow-up of the medicinal therapy with So- acteristics of signaling cascades (cAMP- and ly, but use the intraoperative 1.5 T MRI-scanner mavert). Also, investigations on Somatostatin Ca2+-PI-signaling pathway). The in vitro data as a common interface. analoga and their clinical relevance in the treat- are related to various clinical data in order to

84 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) extract potential prognostic factors concern- Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. ing therapeutic outcome and to define poten- Nat Med, 14: 629-32 tial new therapeutic targets. Brandner S, Kleindienst A (2011) Neuroprotection and neuroregeneration: what to expect from a stem cell-based Neurooncology therapy of acute brain injury. Crit Care Med, 39: 2577-8 Gliomas are the most common primary tumors Savaskan NE, Seufert S, Hauke J, Tränkle C, Eyüpoglu IY, of the brain, and about 70% of these tumors Hahnen E (2011) Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant are malignant gliomas. Currently, there is no gliomas. Oncogene, 30: 43-53 promising therapy for the treatment of ma- Buchfelder M, Schlaffer SM (2012) Intraoperative magnet- lignant tumors which targets the high prolific resonance imaging during surgery for pituitary adeno- eration and diffuse brain invasion. Therefore, mas: pros and cons. Endocrine, 42: 483-95 Neurooncology investigation and characterization of the mo- Eyüpoglu IY, Hore N, Savaskan NE, Grummich P, Roessler K, Buchfelder M, Ganslandt O (2012) Improving the ex- lecular mechanisms of glioma growth and in- tent of malignant glioma resection by dual intraoperative vasion are essential steps in developing novel visualization approach. PLoS ONE, 7: e44885 therapeutic strategies. The neurooncology re- Eyüpoglu IY, Buchfelder M, Savaskan NE (2013) Surgical search group deals with the biology and thera- resection of malignant gliomas-role in optimizing patient outcome. Nat Rev Neurol, 9: 141-51 py of brain tumors and could demonstrate that malignant gliomas secrete high amounts of the International Cooperations neurotransmitter glutamate which results in Prof. Dr. T. Lei, Department of Neurosurgery, Huazhong neuronal cell death in the peritumoral brain pa- University of Science and Technology, Tongji Medical Col- renchyma and induces perifocal edema. These lege, Wuhan: China data correlate with a reduced quality of life Prof. Dr. A. Devin, Cell energy metabolism laboratory, Uni- versité Bordeaux, Bordeaux: France of patients suffering from malignant gliomas. Another focus of the group is to decipher the Prof. Dr. I. Shachar, Weizmann Institute of Science, Rehov- ot: Israel interaction of different brain cells and glioma Prof. Dr. R. Bucala, Department of Medicine, Yale Universi- proliferation. One candidate molecule for tu- ty School of Medicine, New Haven: USA Functional neuronavigation mor-associated cell interaction represents the Prof. Dr. D.L. Kleinberg, Department of Endocrinology, protein MIF. This cytokine is secreted by glioma New York University Langone Medical Center, New York: cells and interacts with the adjacent parenchy- USA ma. The aim of this project is the analysis of MIF effects on immune competent cells in the brain, such as microglial cells, and its role in glioma proliferation and invasion. Moreover, the preliminary data indicate that microglial cells participate at edema formation surrounding malignant gliomas. The presented studies are funded by a grant from the ”Wilhelm San- der-Stiftung” and from the ”Institut Danone Ernährung für Gesundheit e.V.”.

Teaching The Department of Neurosurgery

Aside of the neurosurgical main lecture with case demonstrations and live broadcasts from the operating theater, neurosurgical diseases are also discussed in smaller groups. As part of the practical course, students learn how to examine neurosurgical patients. Moreover, they have the possibility to participate on clinical routines, such as examination of outpatients, inpatients, and visit the operating theater.

Pituitary surgery Selected Publications Savaskan NE, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Ganslandt O, Nimsky C, Buchfelder M, Eyüpoglu IY (2008)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 85 UNIVERSITY HOSPITAL

Department of Nuclear Medicine Chair of Clinical Nuclear Medicine

Address already existing methodology. However, the development of Ga-68-labeled peptides for Ulmenweg 18 complexity of the diagnostic process has corre- the transferrin receptor, the characterization 91054 Erlangen spondingly also increased. Therefore, the inte- of superagonists of the thyroid TSH receptor Phone: +49 9131 8533411 gration of information from different imaging in vitro and in vivo, and the translation of [18F] Fax: +49 9131 8539262 modalities has become an important issue. Ide- fluoroethyl tyrosine into the clinic for patients www.nuklear.med.uni-erlangen.de ally, image datasets from two different modal- with epilepsy. Based on our recent develop- ities are registered to one common coordinate ment of a highly effective radiochemical labe- Head of Department system to allow for true correlative imaging. ling method for the glycosylation of biomol- Prof. Dr. med. Torsten Kuwert The manufacturers of medical imaging devices ecules that is compatible to the short half life have developed two different solutions to this of the positron emitters, a variety of F-18-la- Contact problem: On the one hand, devices have been beled glycoconjugates is studied in our lab in Prof. Dr. med. Torsten Kuwert designed that unify two cameras of different search for new radiopharmaceuticals. These Phone: +49 9131 8533411 modalities, the so-called hybrid systems. In studies include the development of tracers Fax: +49 9131 8539262 particular, hybrid systems combining emission for imaging angiogenesis with a special focus [email protected] tomographic cameras with X-ray computerized on the evaluation of the PET method for early tomographs (CTs) are currently commercially detection of therapy response in the preclin- Research Focus available. On the other hand, user platforms ical setup. This project is processed in coop- •• Correlative Imaging and data structures have been homogenized eration with the Chair of Pattern Recognition •• Molecular Imaging and Radiochemistry so that the exchange of image data between of the FAU (Prof. Dr.-Ing. J. Hornegger) with different modalities and also the registration a special interest in small-animal PET imaging Structure of the Department of independently acquired images have been and was supported by the BMBF. facilitated a lot. In cooperation with the Chair In cooperation with the Chair of Pharmaceuti- At the Department of Nuclear Medicine, the of Pattern Recognition of the FAU and Siemens cal Chemistry of the FAU (Prof. Dr. P. Gmeiner), Chair of Clinical Nuclear Medicine and the Healthcare, the Department of Nuclear Medi- this methodology has supported and accelera- Professorship of Radiochemistry and Molecular cine develops a new methodology of correlated the development of tracers for various mo- Imaging, founded in 2010, are established. For tive imaging and investigates its clinical value. lecular targets suitable for PET imaging stud- patient-oriented clinical research, the hybrid Currently investigated combinations of modali- ies. Moreover, radioligands for the D3 and D4 cameras SPECT/spiral-CT and PET/CT are be- ties are SPECT/CT, PET/CT, and MR/PET. subtype of the dopamine receptor have been ing used in an interdisciplinary setting. Since October 2010, owing to a research coopera- evaluated. As yet, radiopharmaceuticals suited Molecular Imaging and Radiochemis- tion with Siemens Healthcare, the Department to study these receptor subtypes supposed to try has had access to a simultaneous whole-body be implicated in the pathogenesis of several Diagnostic nuclear medicine images the dis- MR/PET hybrid system that is being operated neuropsychiatric disorders are lacking so that tribution of radioactively labeled substances together with the Institutes of Radiology and this project may be considered to be truly in- within the body of patients. This distribution Medical Physics. The radiochemical laboratory novative. In 2011 and 2012, this project was is a consequence of the interaction of the ra- of the Department is equipped with synthesis supported by the DFG (PR 677/2-3). Further diopharmaceuticals with functionally relevant modules for synthesizing radiotherapeutics and radiopharmaceutical chemistry projects include by a further module for producing PET tracers proteins. By visualizing this interaction and the development of radiopeptides addressing which is operated under good-manufactur- thus the expressing and activating the proteins, the neuropeptide-Y receptor and neurotensin ing-practice (GMP) conditions in cooperation nuclear medicine can bridge the gap between receptor that are studied as targets for imag- with the PETNET GmbH. In the laboratory of molecular biology and clinical imaging and can ing of mamma and prostate carcinoma in the molecular imaging of the Department new ra- correlate imaging results to the specific reason preclinical setup by small-animal PET. In 2011 diopharmaceuticals are being developed and of disease or metabolic disorder. Following this and 2012, this research was supported by the evaluated. The methodology implemented for idea and the use of molecular tracers in func- DFG (clinical research unit FOR 661, see own this purpose includes chemical, radiochemical, tional imaging, the term molecular imaging report). and cell biological facilities. In addition, the lab- has recently been implemented in this field of oratory operates a highly resolving autoradio- research. Teaching graphic detector system and a micro-PET. The main research area of the professorship of molecular imaging and radiochemistry is The head of the Department teaches nuclear Research the development of new radiochemical la- medicine to students of medicine. Further- beling methods for the production of radio- more, the head of the Department organizes Correlative Imaging pharmaceuticals, the preclinical evaluation of the course on radiation safety for students of The tremendous progress of technology has novel radiotracers in vitro and in vivo, and the molecular medicine. He also participates in created a wide array of new ways to image translation of the research results into the clin- teaching physiology, pharmacology, and com- the human body and considerably improved ic. Recent examples for these studies are the puter sciences. In a broad fashion, the head of

86 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) the Department performs postgraduate teaching for physicians in Middle and Upper Franco- nia. The Professor for Molecular Imaging and Radiochemistry offers practical trainings for students of molecular medicine and provides lectures for students of molecular sciences in the scientific faculty.

Selected Publications Kasper BS, Struffert T, Kasper EM, Fritscher T, Pauli E, Weigel D, Kerling F, Hammen T, Graf W, Kuwert T, Prante O, Lorber B, Buchfelder M, Doerfler A, Schwab S, Stefan H, Linke R (2011) (18) Fluoroethyl-l-tyrosine-PET in long- term epilepsy associated glioneuronal tumors. Epilepsia, 52: 35-44 Kügler F, Sihver W, Ermert J, Hübner H, Gmeiner P, Prante O, Coenen HH (2011) Evaluation of 18F-labeled benzo- dioxine piperazine-based dopamine D4 receptor ligands: lipophilicity as a determinate of nonspecific binding. J Med Chem, 54: 8343-52 Merhof D, Markiewicz PJ, Platsch G, Declerck J, Weih M, Kornhuber J, Kuwert T, Matthews JC, Herholz K (2011) Optimized data preprocessing for multivariate analysis applied to 99mTc-ECD SPECT data sets of Alzheimer’s patients and asymptomatic controls. J Cereb Blood Flow Metab, 31: 371-83 Reinfelder J, Maschauer S, Foss CA, Nimmagadda S, Fre- mont V, Wolf V, Weintraub BD, Pomper MG, Szkudlinski MW, Kuwert T, Prante O (2011) Effects of recombinant human thyroid-stimulating hormone superagonists on thyroidal uptake of 18F-fluorodeoxyglucose and radio- iodide. Thyroid, 21: 783-92 Wängler C, Nada D, Höfner G, Maschauer S, Wängler B, Schneider S, Schirrmacher E, Wanner KT, Schirrmacher R, Prante O (2011) In Vitro and Initial In Vivo Evaluation of (68)Ga-Labeled Transferrin Receptor (TfR) Binding Pep- tides as Potential Carriers for Enhanced Drug Transport 55-year-old patient four months after bullet injury Focal area with increased uptake indicating an inflammatory lesion into TfR Expressing Cells. Mol Imaging Biol, 13: 332-41 (Osteomyelitis) in the Os naviculare. Menges M, Uder M, Kuwert T, Schmidt D (2012) 131I SPECT/CT in the follow-up of patients with differentiated thyroid carcinoma. Clin Nucl Med, 37: 555-60

International Cooperations Dr A.H. Vija, Molecular Imaging, Siemens Medical Solu- tions, Hoffman Estates, Chicago: USA Dr. R. Haubner, Department of Nuclear Medicine, Inns- bruck Medical University, Innsbruck: Austria

Research Equipment Siemens, mCT (PET/CT) Siemens, SPECT/CT Symbia T6 Siemens, SPECT/CT Symbia T2 Siemens, mMR (PET/MR) Siemens, Animal PET

This image depicts the 18F-labeled cyclic glycopeptide bearing the RGD amino acid sequence that displays high specific binding to newly built blood vessels. Thus, this radiotracer could in principle visualize the process of angiogenesis, e.g. in tumors. This radiopharmaceutical will be further evaluated in preclinical studies in our research laboratory.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 87 UNIVERSITY HOSPITAL

Department of Obstetrics and Gynecology Chair of Obstetrics and Gynecology

Address in the hospital clinically and scientifically. They pre-stages as compared to control tissues. In Universitätsstraße 21-23 are supported by two mathematicians, two sci- close cooperation with the Institute of Medical 91054 Erlangen entists, and seven study nurses. Physics (head: Prof. Dr. B. Fabry), a cell invasion Phone: +49 9131 8533451 The clinic has an approval of the European analysis system was established on the basis of Fax: +49 9131 8533456 Board and College of Obstetrics and Gynecol- collagen. Other preclinical studies in endome- www.frauen.med.uni-erlangen.de ogy (EBCOG) as a training clinic for the Euro- trial and breast cancer cells showed that the pean physician. (de)phosphorylation of AKT and mTOR were Head of Department differentially activated in these cells. Prof. Dr. med. Matthias W. Beckmann Research In an analysis of endometriosis tissue samples, the same cell invasion analysis system was used Contact Gynecological oncology (Laboratory to examine the different invasion capabilities Prof. Dr. med. Matthias W. Beckmann for Molecular Medicine, LMM) of fractionated endometriosis versus control Phone: +49 9131 8533451 Project managers: PD Dr. R. Strick, Prof. Dr. endometrium cells. First results show that en- Fax: +49 9131 8533456 P.A. Fasching, Dr. A. Hein, Dr. C. Rauh, Dr. M. dometriosis cells have a higher ability to invade [email protected] Schrauder, PD Dr. P. Strissel, PD Dr. S.P. Renner matrices. Additional studies are planned to in- In the LMM, the DNA and tissue bank has been vestigate the correlation of invasion and pain. Research Focus expanded. End of 2012, more than 65,000 •• Gynecological oncology (Laboratory for Mo- blood and DNA samples and more than 41,000 Specialized obstetrics and perinatal lecular Medicine, LMM) serum samples and - in cooperation with the medicine •• Specialized obstetrics and perinatal medicine Institute of Pathology, FAU (Head: Prof. Dr. A. Project managers: Prof. Dr. T.W. Goecke, Dr. F. •• Clinical Trials (Clinical Trial Center, CTC; In- Hartmann) - more than 10,100 tissue samples Faschingbauer, Prof. Dr. P.A. Fasching, PD Dr. stitute for Women’s Health, IFG©) of benign and malignant tumors have been S. Kehl •• Gynecological endocrinology and reproduc- stored. These samples are utilized for in house This group together with the LMM was award- tive medicine research and participation in international ed two DFG-projects to investigate the func- consortia, such as the Breast Cancer Associ- tional role of specific envelope proteins of Structure of the Department ated Consortium (BCAC), the Ovarian Can- human endogenous retroviruses (HERV-family) cer Association Consortium (OCAC), and the in the placenta. It was shown that changes of Following an extensive structural change in NIH-funded networks, like the Genomics and the HERV proteins Syncytin-1, -2, and -3 signif- the Department of Obstetrics and Gynecology, Randomized Trials Network (GARNET) and the icantly affected the formation of placental dis- the three traditional pillars of the field (Gyne- Pharmacogenetics Research Network (PGRN). orders, such as HELLP-syndrome, preeclampsia, cology, Gynecologic Oncology, Obstetrics and Cancer research focused on gene variations and intrauterine growth retardation (IUGR). Perinatal Medicine, and Endocrinology and Re- and their possible correlation with disease In a multicenter study planned with 10,000 productive Medicine) are represented clinically risk, detection, and prognosis. Within the pregnant women (Clinical Gravidity Associ- and scientifically in the following organization- BMBF-funded Cluster of Excellence (Spitzen- ation Trials and Evaluation Program, CGATE) al units: cluster) ”Integrated Breast Care”, a study over a longer observation period, possible as- • University Breast Center Frankonia (UBF), (Imaging and Molecular Detection in Breast sociations of different factors in pregnancy (in- • Gynecological University Cancer Center Fran- Cancer; iMODE-B) has been conducted that cluding health problems, lifestyle) with the eti- konia (GKF), aims at risk prediction and early detection of ology of diseases in later life of the mother and • University Perinatal Center Frankonia (UPF), breast cancer. With regard to molecular detec- child are studied. One of the study objectives • University Center for Reproductive Medicine tion markers, miRNA in healthy and diseased is the detection of valid risk factors that could Frankonia (UFF), women have been studied. Using miRNA chips, constitute a basis for preventive measures. Cur- • University Endometriosis Center Frankonia several miRNA could be identified that are rently, the study has recruited 453 patients and (UEF). associated with breast cancer. Further cancer therefore nearly completed the pilot phase. Fol- These centers are certified by the appropriate detection studies include the development of lowing a futility analysis, the design of further national and international professional societies new imaging methods based on 3D imaging targets is planned. and by quality management. methods (ultrasound, tomosynthesis, MRI) in In the clinic, two W2 Professorships for Transla- collaboration with the Institute of Radiology, Clinical Trials (Clinical Trial Center, tional Gynecology and Obstetrics (Prof. Dr. P.A. SIEMENS, and the Erlangen Center for As- CTC; Institute for Women’s Health, Fasching) and Experimental Reproductive Med- troparticle Physics. IFG©) icine (Prof. Dr. R. Dittrich) were established. In- In addition, the role of 21 envelope genes of Project managers: Prof. Dr. P.A. Fasching, PD terfaces of the scientific work are provided by human endogenous retroviruses (HERV) as a Dr. F. Thiel, PD Dr. C. Löhberg the Laboratory for Molecular Medicine (LMM) oncologic risk factor and their importance for Until 2012, over 161 research projects have and the associated center for clinical studies cell invasion and cell-cell fusion was examined. been carried out in the IFG®. These include (Study Center, Institute for Women's Health, Seven of these envelope genes were significant- clinical phase I-IV studies as well as research on IFG®). In total, more than 40 physicians work ly overexpressed in endometrial cancer and new surgical techniques. The clinical studies

88 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) pursue innovative approaches to the etiology, sue. Meanwhile, not only the ovary, but also Ruebner M, Langbein M, Strissel PL, Henke C, Schmidt D, Goecke TW, Faschingbauer F, Schild RL, Beckmann MW, diagnosis, and therapy of breast, ovarian, en- the uterus and the kidneys are a focal point Strick R (2012) Regulation of the human endogenous dometrial, and cervical cancer. In addition to of experiments aimed at cryopreservation of retroviral Syncytin-1 and cell-cell fusion by the nuclear genetic testing and chemotherapy protocols, whole organs. hormone receptors PPARg/RXRa in placentogenesis. J Cell Biochem, 113: 2383-96 the current "target therapies" are examined. In Experiments with an ex-vivo uterus-model line with studies which include both, curative showed that seminal plasma from different International Cooperations and palliative therapies, so far 1,389 patients patients has different potency to induce rhyth- Prof. B. Ponder, Prof. D. Easton, Breast Cancer Consorti- received a treatment. mical contractions. This capability may be an um, Cambridge, Cambridge: UK Noteworthy for breast cancer is the Preface additional male factor influencing the fertility Prof. D. Slamon, MD, PhD, David Geffen School of Medi- study which recruitment phase has ended and rate. Thus, the supplementation of substanc- cine, UCLA, Los Angeles: USA was carried out throughout Germany under es inducing muscular contractions in sperm R. Weinshilboum, MD; L. Wang, MD; J. Ingle, MD, Mayo the guidance of Erlangen. A total of 3,500 pa- preparations for assisted reproductive treat- Clinic, Rochester: USA tients were included from more than 220 study ments may increase the pregnancy rate. centers. The Phase-IV study examines phar- Meetings and International Training Courses macogenetic markers which should predict Teaching treatment effects and side effects of aromatase 14.01.2011: Erlanger OP-Workshop Endometriose, Erlan- gen inhibitors. Initial analyses of toxicity have been Since the end of 2010, the specific function- 25.-28.05.2011: Gemeinsame Tagung der Bayerischen presented at scientific meetings. With regard al area for undergraduate teaching has been Gesellschaft für Geburtshilfe und Frauenheilkunde (BGGF) to genital cancers, the Department of Obstet- among the first university clinical institutions und der Österreichischen Gesellschaft für Geburtshilfe und Gynäkologie (OEGGG), Erlangen rics and Gynecology headed the AGO-cervix-1 in Germany to acquire a quality management 22.10.2011: Expertenmeeting: Das fetale Herz, Erlangen study. This Phase-III study was designed to system especially for medical education. In compare the chemotherapy regimens paclitax- 2011 and 2012, the structures of practical 15.02.2012: Fertilititätsprotektion bei Kindern, Frauen und Männern, Erlangen el plus topotecan and topotecan plus cisplatin clinical courses (Blockpraktika) were further im- in patients with recurrent, persistent, or meta- 02.05.2012: Neue Perspektiven in der Primärtherapie der proved on this basis and evaluated in respect Patientin mit Endometrium- oder Ovarialkarzinom, Erlan- static cervical cancer. However, in April 2012 to the resulting innovations. Aside from this, a gen following an analysis of intermediate results, study reviewed the efforts to improve medical 19.09.2012: Abnorme uterine Blutungen und neue Be- the study was stopped because of sagging re- handlungsoptionen des Uterus myomatosus, Erlangen education at all German university hospitals cruitment and doubts in reachability of suffi- for Obstetrics and Gynecology. The published 27.10.2012: Das fetale ZNS; Grundlagen und Experten- cient statistical power. wissen der interdisziplinären Pränataldiagnostik, Erlangen results and their discussion are expected to en- The work of the clinical trials center is comple- courage further development. mented by a preclinical research program with the same substances. Using the breast cancer Selected Publications xenograft mouse models, we could show that Fasching PA, Heusinger K, Haeberle L, Niklos M, Hein the combination with the anti-malaria drug A, Bayer CM, Rauh C, Schulz-Wendtland R, Bani MR, chloroquine activated p53 and weakened the Schrauder M, Kahmann L, Lux MP, Strehl JD, Hartmann RAD001-induced AKT phosphorylation and A, Dimmler A, Beckmann MW, Wachter DL (2011) Ki67, chemotherapy response, and prognosis in breast cancer could abrogate the resistance mechanism in patients receiving neoadjuvant treatment. BMC Cancer, cancer cells. 11: 486 Nik-Zainal S, Strick R, Storer M, Huang N, Rad R, Willatt Gynecological endocrinology and L, Fitzgerald T, Martin V, Sandford R, Carter NP, Janecke AR, Renner SP, Oppelt PG, Oppelt P, Schulze C, Brucker reproductive medicine S, Hurles M, Beckmann MW, Strissel PL, Shaw-Smith C Project manager: Prof. Dr. R. Dittrich (2011) High incidence of recurrent copy number variants The research in the University Reproductive in patients with isolated and syndromic Müllerian aplasia. J Med Genet, 48: 197-204 Center (UFF) includes the cryo-preservation of Schaefer J, Beckmann MW, Frobenius W (2011) Marked germ cells, the physiology of movements of Improvements in Training for Students in their Practical the non-pregnant uterus, and the pathology of Year Developments in German Gynecology Teaching genital malformations. From 2006 to 2010 and the Prospects Geburtsh Frauen- heilk, 71: 956-966 Most important, the efforts to restore fertility in young cancer patients after chemotherapy Dittrich R, Lotz L, Keck G, Hoffmann I, Mueller A, Beck- mann MW, van der Ven H, Montag M (2012) Live birth and/or radiotherapy have been crowned with after ovarian tissue autotransplantation following over- success: In 2011 and 2012, the first two wom- night transportation before cryopreservation. Fertil Steril, en in Germany gave birth to healthy children at 97: 387-90 the University Hospital after pregnancies which Faschingbauer F, Beckmann MW, Goecke TW, Yazdi B, Sie- mer J, Schmid M, Mayr A, Schild RL (2012) A new formula In 2011 and 2012, the first two babies in Germany after developed following homologous endoscopic for optimized weight estimation in extreme fetal macroso- homologous transplantation of ovarian tissue were given transplantation of cryo-preserved ovarian tis- mia (>= 4500 g). Ultraschall Med, 33: 480-8 birth.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 89 UNIVERSITY HOSPITAL

Department of Ophthalmology Chair of Ophthalmology

Address intraocular lenses, and intraocular injections of identify different signal pathways in the retina Schwabachanlage 6 compounds to treat age related macular de- and the changes caused by a disease. The re- 91054 Erlangen generation (AMD). sults of the animal and human experiments are Phone: +49 9131 8534478 In the field of the conservative medicine, spe- related with each other so that the pathophys- Fax: +49 9131 8536435 cial consultation areas are established. Special iological processes can be better understood. www.augenklinik.uk-erlangen.de departments (optometry, fluorescence angiography and laser, outpatients department, and Clinoco-pathologic concepts in diagno- Head of Department the cornea bank) are present. In addition, there sis and management of ocular diseases Prof. Dr. med. Friedrich E. Kruse is support from different laboratories. Project managers: Prof. Dr. L. Holbach, Prof. Dr. F.E. Kruse, Prof. Dr. G. Gusek-Schneider, Prof. Contact Research Dr. A. Bergua Prof. Dr. med. Friedrich E. Kruse 1. Diagnosis and management of orbital dis- Phone: +49 9131 8534478 Biomorphometry of the optic nerve eases - a multidisciplinary approach. Fax: +49 9131 8536435 Project managers: Prof. Dr. C. Mardin, PD Dr. R. 2. Surgical management of periocular malig- [email protected] Lämmer, Dr.-Ing. R. Tornow nant tumors using frozen section control and Main focus of the research is the development plastic reconstruction - indications, methods, Research Focus and application of imaging methods for early and results. •• Biomorphometry of the optic nerve detection of glaucoma and to quantify progres- The aim of this study is the long-term evalua- •• Functional aspects of retinal neurodegener- sion. Especially the possibilities of the spectral tion of surgical results following intraoperative ation domain OCT to measure retinal layers will be frozen section control and immediate plastic •• Retinal physiology optimized. The developed imaging methods repair regarding recurrence rates and adequacy •• Clinoco-pathologic concepts in diagnosis are complemented by functional tests. The of reconstructive techniques. and management of ocular diseases findings are also applied to other diseases, like 3. Diagnosis and surgical management of •• Corneal stem cells diabetic retinopathy and age related macular epibulbar lesions. •• Pseudoexfoliation syndrome/glaucoma degeneration. The purpose of this study is to establish corre- •• Improvements in corneal transplantation lations between morphologic, biomicroscopic, •• Circulation of the eye and the visual path- Functional aspects of retinal histologic, and molecular genetic criteria and way and computer-aided-diagnosis & virtual neurodegeneration the long-term results of surgical excision and education Project managers: Prof. Dr. A. Jünemann, Prof. plastic reconstruction. Dr. J. Kremers, Dr.-Ing. F. Horn Structure of the Department In this research center, new electrophysiologi- Corneal stem cells cal and psychophysical techniques are devel- Project managers: Prof. Dr. U. Schlötzer-Schre- In total 169 persons are employed at the De- oped to study the functional aspects of reti- hardt, Prof. Dr. F.E. Kruse partment of Ophthalmology. Of these, 43 are nal degeneration, especially in glaucoma. The The maintenance of a healthy corneal epithe- physicians and ten scientific staff members. responses from different retinal pathways are lium and transparent cornea is achieved by a Nine of these are employed as professors. In separated by appropriate stimuli. The stimula- population of stem cells located at the corneal addition, 78 persons are employed for nursing tion of non-redundant systems allows the early limbus. This research project explores the mo- service and 38 as non-scientific staff (techni- detection of functional glaucomatous damage. lecular characteristics of corneal stem and pro- cians etc.). Electrophysiological tests have the advantage of genitor cells together with their specific niches The clinical expertise of the Department of objectivity, but they are less sensitive in compar- and their utilization for novel stem cell based Ophthalmology includes the complete spec- ison to the psychophysical tests. The multifocal therapies for ocular surface reconstruction in trum of surgical and conservative ophthalmol- stimulation, the full-field flash ERG with colored patients with limbal stem cell deficiency. The ogy. stimuli and temporal contrastsensitivity in peri- applicability of alternative autologous stem cell In the surgical ophthalmology, a diverse spec- metric tests are new developments to improve sources for corneal epithelial tissue engineering trum of operations is performed, including sur- sensory testing of retinal degeneration. strategies is investigated. gery of the frontal eye, cornea surgery, reconstructive surgery of the frontal eye, glaucoma Retinal physiology Pseudoexfoliation syndrome/ surgery, oculoplastic, orbita, tumor, tear gland, Project managers: Prof. Dr. J. Kremers, Prof. Dr. glaucoma and vitreo-retinal surgery. A. Jünemann Project manager: Prof. Dr. U. Schlötzer-Schre- In the surgical area, innovative surgical proce- The goal of this topic is to study the function of hardt dures are developed and evaluated. These de- the normal and diseased retina. To reach that The focus of this research project is the molec- velopments include seamless transconjunctival goal, we record electrophysiological responses ular analysis of the generalized matrix process retinal-vitreal surgery (23-gauge-vitrectomy), of the retina of rodent models of human dis- and its causally related glaucoma development. minimal invasive glaucoma surgery employing eases. In addition, we perform electrophysio- These investigations resulted in new findings implants, refractive surgery with the femto- logical and psychophysical experiments with contributing significantly to an elucidation of second laser, cataract surgery with innovative normal human test persons and patients to pathogenesis, an improved understanding of

90 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) the symptoms, an earlier diagnosis, a reduction leader and research fellows are involved in the of surgical complications, and the identification regular student education and practical cour- of novel therapeutic targets. These findings es- ses. Moreover, they are involved in doctorates’ tablished the group’s leading position in basic education and training. research on PEX syndrome/glaucoma. Owing to the extensive contacts with colleagues abroad, many foreign students come to Improvements in corneal the Department of Ophthalmology for at least transplantation a part of their study (graduate or post-gradu- Project managers: Prof. Dr. F.E. Kruse, Dr. B. ate) and for further education. Bachmann The working group seeks for improvements in Selected Publications different surgical techniques for corneal trans- Kruse FE, Laaser K, Cursiefen C, Heindl LM, Schlötzer-Schre- plantation. Clinical research has lead to an in- hardt U, Riss S, Bachmann BO (2011) A stepwise approach to donor preparation and insertion increases safety and crease in safety, reproducibility, and functional outcome of Descemet membrane endothelial keratoplas- outcome after corneal transplantation by utiliz- ty. Cornea, 30: 580-7 ing the lamellar structure of the cornea for the Meyer-Blazejewska EA, Call MK, Yamanaka O, Liu H, lamellar replacement of diseased corneal tissue. Schlötzer-Schrehardt U, Kruse FE, Kao WW (2011) From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell Circulation of the eye and the deficiency. Stem Cells, 29: 57-66 visual pathway and computer-aided- Michelson G, Engelhorn T, Dörfler A (2011) Retinal mi- diagnosis & virtual education croangiopathy in arterial hypertension as an early marker Project manager: Prof. Dr. G. Michelson of a cerebral macroangiopathy. Dtsch Med Wochenschr, 136: 2355-8 1. Ocular circulation of the eye and the visual Schrems WA, Laemmer R, Hoesl LM, Horn FK, Mardin CY, pathway Kruse FE, Tornow RP (2011) Influence of atypical retarda- The tissues and vessels of the eye reflect sys- tion pattern on the peripapillary retinal nerve fibre distri- Top: Old technique corneal transplantation where the temic diseases and are a perfect system for the bution assessed by scanning laser polarimetry and optical coherence tomography. Br J Ophthalmol, 95: 1437-41 graft becomes sutured into the recipients bed. visualization of physiologic processes of the Bottom: New sutureless technique for corneal transplan- body. Immunological processes, diabetes, and Horn FK, Kaltwasser C, Jünemann AG, Kremers J, Tornow tation. The lamellar graft becomes attached to the back- RP (2012) Objective perimetry using a four-channel multi- side of the recipient’s corena by a temporary air fill of the arterial hypertension can be evaluated quanti- focal VEP system: correlation with conventional perimetry anterior chamber. tatively in the eye. and thickness of the retinal nerve fibre layer. Br J Ophthal- 2. Computer-aided-diagnosis & virtual educa- mol, 96: 554-9 tion Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE (2012) Descemet membrane endothelial keratoplasty ver- Ophthalmology needs new methods for med- sus descemet stripping automated endothelial keratoplas- ical information processing to optimize di- ty. Am J Ophthalmol, 153: 1082-90.e2 agnosis and therapy. Automated analysis of ophthalmic images combined with automated International Cooperations classification leads to a fast and bias-free eval- Prof. D.S. Fix Ventura, University of Sao Paulo, Sao Paulo: uation which is an important prerequisite for Brazil screening. Dr. N. Parry, Royal Eye Hospital, University of Manchester, Manchester: UK 3. Diffusion measurement of the visual pathway based on magnetic resonance images Department of Ophthalmology, Medical University, Lub- lin: Poland Neurodegenerative eye diseases often involve Department of Ophthalmology, University of Cincinnati, the entire visual system. In some cases, they Cincinnati: USA are induced by a cerebral macro- and micro- Dr. S. Kinoshita, Kyoto Prefectural School of Medicine, angiopathy with subsequent ischemic changes Kyoto: Japan and degeneration of the visual pathway. The Kunming University of Science and Technology, Kunming: new non-invasive technique based on mag- China netic-resonance imaging provides information about the integrity and orientation of the visual pathway.

Teaching

Results of research are directly implemented in medical student and postgraduate teaching. In the course of the standard curriculum, project

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 91 UNIVERSITY HOSPITAL

Department of Oral and Cranio-Maxillofacial Surgery Chair of Dental, Oral, and Maxillofacial Medicine - especially Oral and Maxillofacial Surgery

Address cial skeleton, esthetic surgery as well as dental diagnosed with oral squamous cell carcinoma Glückstraße 11 implantology. of the oral cavity is a prime focus. 91054 Erlangen Oral cancer and its therapy can heavily influ- Phone: +49 9131 8533601 Research ence speech intelligibility. An interdisciplinary Fax: +49 9131 8536288 work group, headed by the Department of www.mkg-chirurgie.uk-erlangen.de Infection and inflammation Oral and Cranio-Maxillofacial Surgery, FAU, ex- Research adresses etiology, pathogenesis, and plores the impact of oral cancers and different Head of Department therapeutic options in inflammatory reactions treatment modalities on speech quality using a Prof. Dr. med. Dr. med. dent. Dr. h.c. Friedrich of the facial skeleton. Also the osseous regen- special automatic speech analysis system. Tech- W. Neukam eration of bone defects in sites displaying com- nical enhancements of the automatic system, promised wound healing is being investigated. performed by the Division of Phoniatrics and Contact A relevant focus is on the bisphosphonate-asso- Pediatric Audiology together with the Chair of Prof. Dr. med. Dr. med. dent. Dr. h.c. Friedrich ciated osteonecrosis of the jaw (BONJ). Pattern Recognition, FAU, now allow for an ob- W. Neukam As BONJ is restricted to craniofacial bone struc- jective measurement of the word recognition Phone: +49 9131 8533601 tures, research focuses on jaw bone specific rate of each patient which is automatically ana- Fax: +49 9131 8536288 signal transduction processes during develop- lyzed by a computer system. A further develop- [email protected] ment, bone remodeling, and disease. Cranial ment the researchers’ group is heading for is neural crest derived pluripotent progenitor cells the analysis of single distorted phonems. This Research Focus are of scientific and clinical interest in exper- innovative method will enable the surgeon to •• Infection and inflammation imental approaches to develop regeneration identify subtle operation techniques which will •• Tumor research strategies in craniofacial bone structures. In preserve function at its best, to support speech •• Biomedical technics addition, patient-related factors are being eval- quality as elementary part of patients’ social life uated which may promote onset and course even after the treatment of severe oral cancer. Structure of the Department of bisphosphonate-associated osteonecrosis There is increasing evidence that maintenance, of the jaw. An animal model in pigs serves a growth, and spread of cancers is driven by a small The Department of Oral and Cranio-Maxillo- study to answer the question whether there is subpopulation of cancer stem cells (CSC) which facial Surgery is responsible for teaching oral an influence of bisphosphonate exposed bone are the only cells that are capable of long-term and maxillofacial surgery, including dental in osseointegration of dental implants. self-renewal. Also current failure of cancer ther- surgery and dental radiology, research as well For functional and esthetic long-term success apies may be due to postulated drug resistance as patient care. The Department employs 15 of dental implants, a sufficient amount of and potential quiescence of these cells, because medical doctors/dentists and two biologists. peri-implant hard and soft tissues is indispensi- they will remain vital and may be able to repopu- Research mainly focuses on biomedical tech- ble. The research especially focuses on modula- late the tumor. Therefore, new therapeutic strat- nology, infection, and inflammation as well as tion and optimization of peri-implant tissues in egies, like the immune therapies which are aimed tumors of the head and neck. Topics of particu- the context of rehabilitation of severe atrophic at the destruction of the CSC, are urgently need- lar interest are augmentation of osseous de- edentulous jaw and jaw segments with implant ed. Attractive targets for immunotherapy are fects by transplantation of autogenous tissues fixed dentures. This refers particularly to pre- Cancer/Testis antigens because of their restricted or specific bone substitutes, the pathoetiology clinical and clinical examination of new tech- expression and their high immunogenetic fea- of osteonecrosis of the jaw as well as the evalu- niques and materials for the augmentation of tures. Whether oral CSC express these antigens ation of therapeutic options in sites displaying non-space making vertical bony defects and and whether CSC can be eliminated by such compromised healing, and the identification the long-term stability of vertical bone grafts. therapies in the long run is unknown. of indicators of prognosis in patients undergo- Furthermore, research focuses on the regener- Aim of another research project is to analyze ing resection of oral squamous cell carcinoma. ation of peri-implant soft tissues and their im- the expression of known stem cell markers in Innovative research focuses on the evaluation pact on peri-implant health. oral tumor cell lines and tissues of OSCC us- and development of laser-assisted surgery. The For modeling compromised osseous healing, a ing immunohistochemistry, RTPCR, and flow research laboratory (S1-facility) of the Depart- diabetic pig model was established. This animal cytometry. Additionally cell populations with ment allows a wide range of immunohisto- model is currently used for an assessment of re- stem cell characteristic features will be enriched chemical and molecular biological techniques. generative options, using BMP-2 transfected by using cell surface markers, e.g. CD133 and For experimental trials concerning bone histol- bone substitute in critical size defects. a magnetic activated cell sorting system, the ogy and biomedical technology, a specialized efflux of Hoechst dye or the sphere culture sys- facility is shared with the Department of Pros- Tumor research tem. Afterwards the populations will be char- thodontics. The clinical focus is on the surgery Research aims at improving function as well as acterized on the biomolecular level. Most no- of malformations of the head/neck and cleft lip facial esthetics following resection of tumors tably the expression of stem cell markers and palate in particular, oncologic and reconstruc- of the head and neck. In addition, the identi- CT antigens is to be examined. In the future tive surgery for tumors of the head and neck, fication of clinical, immunohistochemical, and these studies could lead to more gene specific orthognathic surgery, traumatology of the fa- molecular indicators of prognosis in patients therapies aimed at the destruction of CSC.

92 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) The diagnosis of carcinoma of the oral cavity Oral and Cranio-Maxillofacial Surgery provides Ries J, Agaimy A, Vairaktaris E, Gorecki P, Neukam FW, needs invasive surgery for histopathological compulsory and elective courses for medical Straßburg LH, Nkenke E (2012) Detection of MAGE-A expression predicts malignant transformation of oral leuko- examination. Hence, it is the goal of a inter- and dental students during clinical education. plakia. Cancer Invest, 30: 495-502 disciplinary project to develop an optical, In clinical dentistry, these involve oral and max- Stockmann P, Park J, von Wilmowsky C, Nkenke E, Felsze- non-invasive biopsy for oral cancer detection. illofacial surgery, dental surgery, and dental ghy E, Dehner JF, Schmitt C, Tudor C, Schlegel KA (2012) Guided bone regeneration in pig calvarial bone defects The research is based on three technical pillars: radiology. Apart from traditional methods of using autologous mesenchymal stem/progenitor cells - A Diffuse Reflection Spectroscopy, Autofluores- teaching (lectures, lectures with case demon- comparison of different tissue sources. J Craniomaxillofac cence Spectroscopy, and Raman-Spectrosco- strations, practical training for medical and Surg, 40: 310-20 py. First results demonstrate a high potency of dental students), problem based and interdis- Lutz R, Prechtl C, Nonhoff J, Weisel T, Damien CJ, Schlegel KA (2013) Biofunctionalization of the implant surface with differentiation between normal and malignant ciplinary approaches are also used. Topics of in- different concentrations of a synthetic peptide (P-15). Clin oral mucosa. Further research will focus on the terdisciplinary education include among others Oral Implants Res, 24: 781-786 optical identification of different grades of tis- emergency medicine, electivum implantology sue dysplasia to further enhance early cancer for dental students (I-LECT), classes as part of International Cooperations detection by monitoring premalignant lesions the Graduate School in Advanced Optical Tech- Dr. E. Felzshegy, Gerichtsmedizinisches Institut, Semmel- using the optical biopsy. nologies (SAOT), and automated analysis of weiss-University, Budapest: Hungary speech disorders in cooperation with the Chair Prof. Dr. Dr. E. Vairaktaris, Department of Oral and Maxil- lofacial Surgery, University of Athens, Athens: Greece Biomedical technics of Pattern Recognition of the Technical Faculty. The focus ”biomedical technology” comprises Dr. J. Wolfaardt, PhD, Division of Otolaryngology Head and Neck Surgery, Faculty of Medicine and Dentistry, Uni- research projects on regeneration of soft and Selected Publications versity of Alberta, Alberta: Canada hard tissues, intraoperative imaging, and laser Wehrhan F, Hyckel P, Guentsch A, Nkenke E, Stockmann applications. P, Schlegel KA, Neukam FW, Amann K (2011) Bisphospho- Meetings and International Training nate-associated osteonecrosis of the jaw is linked to sup- Bone substitutes promote formation of new pressed TGFb1-signaling and increased Galectin-3 expres- Courses bone in pre-existing osseous defects by dif- sion: a histological study on biopsies. J Transl Med, 9: 102 15.-18.06.2011: 61. Jahrestagung der Deutschen Ge- ferent biologic mechanisms, including inflam- von Wilmowsky C, Stockmann P, Harsch I, Amann K, sellschaft für MKG-Chirurgie, Bamberg matory and proliferative cellular reactions. As Metzler P, Lutz R, Moest T, Neukam FW, Schlegel KA (2011) Diabetes mellitus negatively affects peri-implant Research Equipment opposed to autogenous bone, the application bone formation in the diabetic domestic pig. J Clin Per- of anorganic bone substitutes results in a pro- iodontol, 38: 771-9 BrainLab, Heimstetten, Neuronavigations system Vector Vision II longation of the inflammatory phase. Nkenke E, Vairaktaris E, Bauersachs A, Eitner S, Budach A, The project aims at creation, application, and Knipfer C, Stelzle F (2012) Acceptance of technology-en- Kavo, digital volume tomograph (DVT) hanced learning for a theoretical radiological science 3DSYSTEMS, 3D-printer evaluation of biomimetic materials and bio- course: a randomized controlled trial. BMC Med Educ, functional surfaces in implant dentistry. Mod- 12: 18 KLS-Martin, CO2-Laser (MCO 50+) ification of titanium surfaces for adsorption of several cell populations, poly-ether-ether-ke- tone (PEEK), as well as ceramic materials were applied in in vitro and in vivo experiments. In cooperation with the Bavarian Laser Center, a sensor-assisted laser system for selective bone ablation was tested in cadaver bone as well as in an in vivo setting. By connecting the Er:YAG laser to a process control for material-specific ablation, the system is able to differentiate cortical and cancellous bone as well as soft tissues. In oral and maxillofacial surgery the selective bone ablation offers a new perspective to preserve nerval structures during surgery, such as the nervus mandibularis during osteotomy of the lower jaw. A second research approach is to transfer the system of optical tissue differentiation towards tumor tissue to allow high selectiv tumor resection in the future.

Teaching

Oral and maxillofacial surgery is a part of both, Project manager PD Dr. Dr. F. Stelzle (left) and project team member Dr. C. Knipfer (right) during implementation of medical and dental curriculum. The Chair of an optical non-invasive biopsy to identify oral cancer.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 93 UNIVERSITY HOSPITAL

Department of Otorhinolaryngology – Head and Neck Surgery Chair of Otorhinolaryngology

Address grading sytem was established enabling dis- The emphasis of the neurotology/vestibular Waldstraße 1 ease classification and estimation of prognosis. laboratory was in particular on the pre- and 91054 Erlangen Salivary duct and gland endoscopy therefore is postoperative diagnostics concerning cochlear Phone: +49 9131 8533156 now finding a growing positive resonance also implants and octavusneurinomas. Furthermore, Fax: +49 9131 8533833 in the Northern United States where a cooper- the computerized dynamic posturography was www.hno-klinik.uk-erlangen.de ation (Prof. M.B. Gillespie, MUSC, Charleston, used not only to improve the diagnostics of USA) led to interesting aspects of different vestibular disturbances, but also very successful Head of Department treatment regimes in salivary gland disease. regarding the respective therapy of these dis- Prof. Dr. med. Dr. h.c. Heinrich Iro The international academic workshops in ultra- eases in cooperation with physiotherapists. sound and salivary gland surgery again showed Contact growing numbers of participants confirming us Neurophysiology Prof. Dr. med. Christoph Alexiou to endeavour education and academic projects. The neurophysiology and electromyography Phone: +49 9131 8533142 (EMG) laboratory focuses on diagnosis and Fax: +49 9131 8534828 Computer aided surgery/robotics therapy of cranial nerves involved in ENT-pro- [email protected] The group of computer aided surgery and ro- cedures. botics focused its research on the advancement In paresis or during accordant operations, the Research Focus of clinical navigation and robotic procedures. A function of the facial nerve or the inferior laryn- •• Ultrasound and endoscopy new software for intraoperative image-update geal nerve is controlled. •• Computer aided surgery/robotics was evalutated and its applicability tested in a •• Individual speech processor programming in clinical setting. Possible errors, misleading pro- Allergology/clinical immunology cochlear implant users cedures as well as advancements were docu- and rhinology •• Neurootology/vestibular laboratory mented. A so far underrepresented field of nav- In patients with ASA intolerance, therapeutic •• Neurophysiology igation was evalutated by applying navigation options are the endoscopic sinus surgery and •• Allergology/clinical immunology and rhino- techniques to soft tissues areas of the head and adaptive desensitization to ASA. The diagnos- logy neck. Foreign bodies were removed using nav- tic value of a functional blood test (FET-AIT®) •• Experimental otorhinolaryngology igation procedures. In collaboration with the for measuring the eicosanoid dysbalance in pa- •• Nanomedicine Department of Neurosurgery, a modification tients with sensitivity to ASA is tested. A dou- •• Laboratory for sleep disorders/somnology of the Erlangen robot A73 was developed and ble-blind, randomized, placebo-controlled trial tested in a preclinical setting. on clinical and biological effects of oral corti- Structure of the Department costeroids or doxycycline in patients with nasal Individual speech processor program- polyps focuses on clinical and biological mark- In the Department, altogether 286 people are ming in cochlear implant users ers. The stimulation of functional intact nasal employed, out of these 86 are engaged in the Today cochlear implants (CI) provide an effi- tissue under in-vitro conditions with the biopsy clinical-scientific and medical-technical area, cient treatment of profound hearing loss and mucosa oxygenator is used for investigating rel- 13 exclusively within basic research, and 187 in inner ear deafness. However, individual results evant mediators of inflammation which are then nursing and administration. vary substantially. The aim of this project is to modifiedpharmacologically . In a multi-cen- Within different scientific groups, clinical-rele- identify the individual differences by means tered, double-blind, placebo-controlled study, vant research concerning neurootology, som- of cortical auditory potentials and enhance patients' oral corticosteroids post-operative are nology, oncology, ultrasound and endoscopy, speech and music perception by individual evaluated, looking at the rate of recurrences. allergology, and neurophysiology is performed. speech processor adjustments. Study centers: Departments of Otolaryngology, Head- and Neck-Surgery in Kiel, Regensburg, Research Neurootology/vestibular laboratory Berlin Charité, Marburg, and Stuttgart. In addi- The neurotology/vestibular laboratory with its tion, a clinical study concerning subcutaneous Ultrasound and endoscopy up to date equipment inclusive computerized immunotherapy is performed. Studies in imaging of head and neck cancer dynamic posturography (Smart Equi Test®, with the help of high resolution ultrasound NeuroCom International), videooculography Experimental otorhinolaryngology remain a key issue. Identification and classifi- combined to computernystagmography, laser The research lab experimental otorhinolaryn- cation of tissue by visualization techniques (Tis- target projector, rotary-/pendularchair system, gology focused its research on projects on sues Harmonic Imaging) were further investi- and static posturography was upgraded at the 1. Central tinnitus and gated in their use in the head and neck area. end of 2010 with a video head-impulse test. 2. Neuronal plasticity after brain damage in an- The Department was able to move into brand This newly developed system allows the physi- imal models as well as new ultrasound and endoscopy facilities. Min- cian to objectify a pathologic vestibulo-ocular 3. Ex vivo tissue cultures of human nasal mu- imally invasive interventions of the salivary reflex, even in well compensated patients with cosa. glands and their adjacent duct systems are not so called ”covert saccades” which are normal- Results yielded e.g.: only part of the daily routine, but were system- ly not visible with the pure eye. This helps to 1. Demonstration of the existence of a central atically analyzed regarding clinicial outcome differentiate between peripheral and central predisposition for the development of subjec- of obstructive gland disease. An endoscopic vestibular disorders. tive tinnitus in an animal model.

94 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 2. The description of subcortical reorganization Teaching 13.-15.06.2012: Internationaler Kurs für Ultraschall und after unilateral lesion of the auditory cortex Speicheldrüsenchirurgie, Erlangen that enables subcortical regions to replace cor- Traditional instruction forms (main lecture with 29.-30.06.2012: Allergologie Grund- und Aufbaukurse, Erlangen tical functions. case-demonstration and live transmission of 3. Using oxygenation, we obtained cytokine operations, block practical courses) are supple- 13.-14.10.2012: Sonographie der Kopf-Hals-Region, Er- langen expression data from ex vivo tissue cultures mented by interdisciplinary meetings. Further- of human nasal mucosa stimulated with phy- more the possibility for hospitation in the out- to-therapeutics, cortisone compounds, or con- patient clinic and the operating theater exists ventional antihistamines. althrough the year.

Nanomedicine Selected Publications Project manager: Prof. Dr. C. Alexiou Gillespie MB, Koch M, Iro H, Zenk J (2011) Endoscopic-as- The Section for Experimental Oncology and sisted gland-preserving therapy for chronic sialadenitis: a Nanomedicine (SEON) focuses on the targeted German and US comparison. Arch Otolaryngol Head Neck Surg, 137: 903-8 local chemotherapy employing magnetic nan- Hornung JA, Brase C, Zenk J, Iro H (2011) Results obtained oparticles (Magnetic Drug Targeting). Magnet- Ultrasound image using ultrasound elastography for with a new superelastic nitinol stapes prosthesis in stapes ic nanoparticles bound to cytostatic drugs are surgery. Otol Neurotol, 32: 1415-21 measurement of tissue stiffness in different tumor entities. injected intraarterially close to the tumor and Tietze R, Rahn H, Lyer S, Schreiber E, Mann J, Odenbach enriched in the tumor region under the pres- S, Alexiou C (2011) Visualization of superparamagnetic ence of an external magnetic field. The research nanoparticles in vascular tissue using XmCT and histology. Histochem Cell Biol, 135: 153-8 project is supported by the Else Kröner-Frese- nius-Foundation and by the BMBF Leading Ahlf S, Tziridis K, Korn S, Strohmeyer I, Schulze H (2012) Predisposition for and prevention of subjective tinnitus de- Edge Cluster initiative „Exzellenzzentrum für velopment. PLoS ONE, 7: e44519 Medizintechnik”. In 2012, two new research Koch M, Künzel J, Mantsopoulos K, Zenk J, Iro H (2012) projects started: In the project ”Nanotoxicolo- Defect closure after oral and pharyngeal tumor resection gy”, supported by the Bayerisches Staatsminis- with the superiorly pedicled myocutaneous platysma flap: indications, technique, and complications. Eur Arch terium für Umwelt und Gesundheit, systematic Otorhinolaryngol, 269: 2111-9 toxicological analyses for medical nanoparticles Tietze R, Lyer S, Durr S, Alexiou C (2012) Nanoparticles will be performed and risk profiles will be gener- for cancer therapy using magnetic forces Nanomedicine, ated. Furthermore, magnetic nanoparticles can 7: 447-457 SEON research laboratory (Angiography system Artis zee, Siemens and electromagnet) be applied to magnetize living cells. Magnetic cells give promise for effective tissue engineer- International Cooperations ing, since they can be grown into three-dimen- Prof. C. Bachert, Department of Otorhinolaryngology - sional structures by application of an external Head & Neck Surgery, Ghent University, Ghent: Belgium magnetic field which will be done in the pro- Prof. M. Mc Gurk, Salivary Research Unit, Maxillofacial ject ”TOPbiomat” which is supported by the Surgery, Guy’s, King’s and St. Thomas’ Dental Institute, King’s College, London: UK Emerging Fields Initiative (EFI) of the FAU. Such Prof. D.A. Sherris, Department of Otolaryngology, Univer- cellular structures are the basic components of sity of Buffalo, Buffalo: USA multicellular organs and a prerequisite for the Prof. E.J. Moore, Department of Otorhinolaryngology - engineering of functional tissue. Head & Neck Surgery, Mayo Clinic, Rochester: USA

Laboratory for sleep disorders/ Meetings and International Training somnology Courses The projects focus on a surgical treatment of 13.-14.01.2011: Erlanger Ohroperationskurs, Erlangen primary snoring and obstructive sleep apnea. 05.02.2011: Jährliche HNO-Fortbildung, Erlangen Besides the well known nCPAP therapy in obstructive sleep apnea, we try to find alternative 17.-20.05.2011: International Course on Aestetic and Re- constructive Rhinoplasty and Otoplasty, Blepharoplasty treatment options. Therefore we have invent- and Face Lift, Erlangen ed a special nasopharyngeal stent in order to 01.-02.07.2011: Allergologie Grund- und Aufbaukurse, prevent obstruction in patients suffering of ob- Erlangen structive sleep apnea. Results are to be com- 22.-23.10.2011: Sonographie der Kopf-Hals-Region, Er- pared to nCPAP therapy. Furthermore we de- langen velop a method for wireless sleep stage analysis 12.-13.01.2012: Erlanger Ohroperationskurs, Erlangen based on unobtrusive motion sensors. More- 11.02.2012: Jährliche HNO-Fortbildung, Erlangen over we analyze pharyngeal tissue reactions 13.-16.03.2012: International Course on Aesthetic and and modification of saliva caused by obstruc- Reconstructive Rhinoplasty and Otoplasty, Blepharoplasty tive sleep apnea. and Face Lift, Erlangen

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 95 UNIVERSITY HOSPITAL

Department of Otorhinolaryngology – Head and Neck Surgery Division of Phoniatrics and Pediatric Audiology

Address auditory control. The feedback mechanisms tions between dynamics as well as tissue struc- Bohlenplatz 21 can be affected by voice and speech disorders tures and the quality of the resulting acoustic 91054 Erlangen in different ways. signal. High-speed recordings in combination Phone: +49 9131 8533146 This project investigates the feedback mecha- with a newly developed laser grid projection Fax: +49 9131 8539272 nisms of phonation and articulation of healthy system are applied. This combination allows a www.phoniatrie.uk-erlangen.de test persons and compares their performance quantitative registration of occurring dynam- with patients suffering from voice disorders ics. The dynamics are adopted by numerical bi- Head of Division (hyper-, hypotension dysphonia (MTD)) and omechanical models. The resulting parameters, Prof. Dr. med. Dr. rer. nat. Ulrich Eysholdt speech disorder (Apraxia of Speech (AOS)). like damping and swinging masses, are further The synchronous data acquisition (visual and analyzed and interpreted. Contact EEG) enables for the first time the analysis of Prof. Dr.-Ing. Michael Döllinger the connection between kinesthetic and audi- Phonovibrography - objective analysis Phone: +49 9131 8533814 tory feedback processes. Current methods of of vocal fold vibrations Fax: +49 9131 8539272 electrophysiology and quantitative endoscopy The causes of hoarseness are not yet complete- [email protected] are used simultaneously. ly understood. The presumed irregularities of The goal of the study is a first understanding of vocal fold oscillation cannot be proven with the Research Focus the cooperating auditory and kinesthetic feed- conventional investigation instrument (strobos- •• Kinesthetic and auditory feedback during back control. copy), because this is only designed for periodic phonation and articulation events. Owing to funding of the DFG, the novel •• Biomechanical parameterization of vocal fold Biomechanical parameterization approach of phonovibrography was developed vibrations of vocal fold vibrations which enables a visualization and analysis of •• Modeling of tracheoesophageal voice Vocal fold vibrations are captured by apply- vocal fold dynamics. In this approach, digital •• Phonovibrography - objective analysis of vo- ing high speed recordings. Including a laser high-speed recordings of vocal fold vibrations, cal fold vibrations projection system, the three dimensional dis- captured at a frame rate of 4000 Hz, are ana- •• Differentiated objective analysis of the placements can be extracted. By segmentation lyzed. For an objective analysis, a specialized speech quality of chronically hoarse patients algorithms, the three dimensional vocal fold image segmentation algorithm was developed to enhance evidence-based diagnostics trajectories can be determined. The segment- which extracts the vibrating vocal fold edges •• Fluid Mechanical Basis of the Human Voice ed vocal fold oscillations can be analyzed with from the high-speed recordings. The results of means of non-linear dynamics by simulating the procedure were extensively evaluated in a Structure of the Department vocal fold motion curves with a biomecha- clinical trial. To visualize the relevant vibration nical multi-mass model of the vocal folds. The information within a single image, the so-called Phoniatrics and Pediatric Audiology is a medi- model simulates the principle properties of vo- phonovibrogram (PVG) was developed. A PVG cal field which addresses diseases and disorders cal fold vibrations with a system of differential image contains the entire vocal fold oscilla- of voice, speech, language, hearing, and swal- equations which establish the temporal process tion pattern and enables a novel classification lowing. Research deals basically with commu- of the vocal fold oscillations. By adapting the of vocal fold vibrations. First studies show the nication disorders on the perception side (hear- model oscillations to the extracted vocal fold robustness as well as the reliability of the new ing research) and the production side (speech vibrations, the asymmetry of vibration patterns suggested approach. For further quantification, and voice research). The principle contents of as well as tissue properties can be quantified a laser-line projection device was developed the research projects connect the medical field within a 3D parameter domain. In future, dif- which enables a two-dimensional quantifica- with applied natural sciences and technology. ferent kinds of dysphonia can be quantified tion of the image data. Thus, absolute mea- The head of the Division is also member of the within the parameter domain of the biome- sures of vocal fold elongation and velocities can Technical Faculty of the FAU and is supervising chanical model. So far, experiments are per- be performed. In this research area, we closely scientific works in all of these fields. Totally, 21 formed only in vitro models. collaborate with colleagues from the USA. employees work at the Division, five of them are financed via third-party funds. Modeling of tracheoesophageal voice Differentiated objective analysis of the After laryngectomy, the loss of natural voice is speech quality of chronically hoarse Research the most prominent functional defect. It can be patients to enhance evidence-based rehabilitated best by means of shunt valves. So diagnostics Kinesthetic and auditory feedback far, there is no consensus on how to evaluate For differentiated diagnostics of functioning during phonation and articulation tracheoesophageal voice. and evaluation of distorted voice and speech The precision of the human speech signal is In a study funded by the German Cancer Aid production, there are currently no validated controlled by parallel working feedback pro- Foundation, we objectively analyze the dynam- objective approaches. Voice and speech disor- cesses while speaking. The feedback mecha- ics and the resulting acoustical signal of the ders are usually assessed by perceptive evalua- nisms are developed during language acqui- remaining pharyngoesophageal segment after tions with only restricted reliability for clinical sition and can be divided into kinesthetic and total laryngectomy. The goal is to find correla- or scientific use.

96 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Perceptual evaluations are very time consuming proach is another important step towards evi- Schmidt B, Stingl M, Leugering G, Berry DA, Döllinger M and are of limited suitability in clinical routine. dence-based diagnostics in phoniatrics. (2011) Material parameter computation for multi-layered vocal fold models. J Acoust Soc Am, 129: 2168-80 For a differentiated, objective analysis, auto- This project is a cooperation with the Pattern Yang A, Stingl M, Berry DA, Lohscheller J, Voigt D, Eysholdt matic methods are developed which take this Recognition Lab (Head: Prof. Dr.-Ing. J. Horneg- U, Dollinger M (2011) Computation of physiological hu- into account. Subjective clinical evaluation ger) of the FAU as well as with the Department man vocal fold parameters by mathematical optimization criteria are described by objectively computed of Oral and Cranio-Maxillofacial Surgery (Head: of a biomechanical model. J Acoust Soc Am, 130: 948-64 parameters. The involved patient groups in- Prof. Dr. Dr. F.W. Neukam). Döllinger M, Berry DA, Luegmair G, Hüttner B, Bohr C (2012) Effects of the epilarynx area on vocal fold dynamics clude patients with voice disorders, e.g. chron- and the primary voice signal. J Voice, 26: 285-92 ic hoarseness, partial and total laryngectomy, Fluid Mechanical Basis of the Döllinger M, Dubrovskiy D, Patel R (2012) Spatiotempo- and patients with articulation disorders, e.g. Human Voice ral analysis of vocal fold vibrations between children and children with cleft lip and palate and patients More detailed information is given in the sepa- adults. Laryngoscope, 122: 2511-8 with oral squamous cell carcinoma. rate report of FOR 894, supported by DFG. The automatic methods analyzed voice para- International Cooperations meters as well as speech aspects with a strong Teaching Prof. J.G. Švec, PhD, Department of Experimental Physics, focus on a detailed (phoneme) analysis. In this Palacký University, Olomouc: Czech Republic way, the communication problem is not de- Our Division is dedicated to a first-class aca- Y.J. Moon, PhD, School of Mechanical Engineering, Korea University, Seoul: South Korea scribed as one single unit, but phone classes demic teaching which is of the same value as Prof. Dr. R.E. Hillman, Voice Center Research Laboratories, have been identified which are specifically af- patient care and scientific research. The offer Massachusetts General Hospital, Boston: USA fected by the distortion. of lectures follows the clinical focus of the area. Prof. D.A. Berry, PhD, Laryngeal Dynamics Laboratory, Di- Systems for a detailed phoneme analysis in Phoniatrics and pediatric audiology is teached vision of Head and Neck Surgery, University of California children with cleft lip and palate and patients during both, the pre-clinical and clinical phase. Los Angeles: USA with oral squamous cell carcinoma were also Complementarily, practical trainings on voice, Prof. T.T. Truscott, PhD, Prof. S.L. Thomson, PhD, Depart- established. These systems are based on auto- swallowing, speech, and hearing impairments ment of Mechanical Engineering, Brigham Young Univer- sity, Provo: USA matic speech processing techniques, prosodic are given. Additionally, lectures and trainings Prof. M. Kunduk, PhD, Department of Communication analysis, phonemic and phonological features. are given in physiology: ”auditory system”, Science & Disorders, Louisiana State University, Baton Additionally, the current topic is the quantifi- ”voice, speech, and language” and medical Rouge: USA cation of hoarseness which will also include psychology and sociology: ”language develop- Prof. R. Patel, PhD, Department of Otolaryngology Vocal speech-related parameters for the first time. ment in children” and ”rehabilitation”. Physiology and Imaging Laboratory, Indiana University, Bloomington: USA The objective measurement of nasality without The training of speech therapists takes place at complex and expensive equipment is also part the full-time vocational school speech therapy. of the research project. In this way, an objective clinical evaluation is created. Selected Publications The automatic analysis is the basis for future Dollinger M, Berry DA, Huttner B, Bohr C (2011) Assess- telemedical applications for the control of the ment of local vocal fold deformation characteristics in an progress of voice and speech therapy. Further- in vitro static tensile test. J Acoust Soc Am, 130: 977-85 more, this analysis will serve as objective ad- Huttner B, Sutor A, Luegmair G, Rupitsch SJ, Lerch R, Döllinger M (2011) Optical 3-D metric measurements of dition to the established subjective voice and local vocal fold deformation characteristics in an in vitro speech evaluation in clinical practice. The ap- setup. IEEE Trans Biomed Eng, 58: 2758-66

(a) Single frame of an in vivo high-speed recording of human vocal folds with projected laser dot grid. (b) Segmented laser dots of the left (blue) and right (red) vocal fold. (c) Reconstructed vocal fold surface basing on the 3D coordinates of the segmented laser dots.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 97 UNIVERSITY HOSPITAL

Department of Pediatrics and Adolescent Medicine Chair of Pediatrics

Address bring novel research to the bedsite. Patient care As progression of kidney disorders also depends Loschgestraße 15 is based on close collaboration with the Divi- on the congenital endowment with functional 91054 Erlangen sions of Pediatric Cardiology, Pediatric Surgery, renal tissue that is capable of self-regeneration, Phone: +49 9131 8533118 and Cardiac Surgery as well as with various we attempt to characterize the impact of pre- Fax: +49 9131 8533113 subspecialities, often planned and carried out natal conditions on kidney function and disease http://www.kinderklinik.uk-erlangen.de by interdisciplinary teams (Center for Perinatal progression (fetal programming). Medicine, Center for Epilepsy, Heart Center, Head of Department Cleft Lip and Palate Center, Transplantation Genetic diseases of the neonate Prof. Dr. med. Dr. h.c. Wolfgang Rascher Center). Project manager: Prof. Dr. H. Schneider Our primary research goal is to identify patho- Contact Research genetic mechanisms underlying genoderma- Prof. Dr. med. Holm Schneider toses (hereditary disorders of the skin and its Phone: +49 9131 8533775 Medication safety appendages) at a molecular level and to devel- Fax: +49 9131 8533013 Project managers: PD Dr. A. Neubert, Prof. Dr. op appropriate therapeutic approaches. These [email protected] W. Rascher diseases are rare, but may be associated with Newborns and infants are particularly at risk life-threatening complications already in the Research Focus for adverse drug reactions and medication first weeks after birth. In addition to the skin, •• Medication safety errors due to common off-label use and lack other organs, such as eye, ear, and lung, are •• Determinants of kidney disorders of age-appropriate formulations. We have frequently affected by the pathogenetic pro- •• Genetic diseases of the neonate been working for many years on methods to cesses. First systematic studies of patients of •• Genomic aberrations in childhood malignan- improve medication safety. To this purpose, different age groups allowed the characteriza- cies data on adverse drug reactions (ADR) have tion of genotype-phenotype relationships as a •• Pediatric cell therapy been collected systematically in various mono- prerequisite for specific therapeutic attempts. •• Perinatal hypoxic brain injury and neuropro- and multicenter prospective studies. High-risk In mouse models of epidermolysis bullosa, tection medications were detected and particularly lamellar ichthyosis, and hypohidrotic ectoder- vulnerable groups of patients were identified. mal dysplasia, we have been investigating the Structure of the Department Furthermore, we evaluated computerized ADR feasibility of gene therapy in utero or perinatal detection and tested methods to improve the protein replacement therapy. The Department of Pediatrics and Adolescent specificity of this system. We are currently in- Currently, the first clinical trial in neonates with Medicine comprises five specialized divisions vestigating the impact of electronic prescrip- hypohidrotic ectodermal dysplasia is being pre- (Neonatology, Neuropediatrics and Social Pedi- tion on medication safety, aiming at developing pared, a multicenter interventional study based atrics, Pediatric Oncology/Cell Therapy, Ne- evidence-based, structured dosing-information on the promising preclinical data collected over phrology, and Molecular Pediatrics), an en- to be integrated into the system. In addition, the last years. dowed professorship for Pediatric Endocrinol- we actively participate in two EU-funded mul- ogy and Diabetology, and a number of spe- ticenter pharmacovigilance studies (long-term Genomic aberrations in childhood cialized outpatient clinics. Academic staff of safety of the iron-chelating agent deferiprone malignancies the Department includes 98 physicians and and long-term safety of methylphenidate in Project managers: PD Dr. M. Metzler, Prof. Dr. scientists. Of these, 13 positions are financed children with ADHD). T. Langer by external funds. Modern molecular biology has advanced un- Research is focused on the field of perinatal Determinants of kidney disorders derstanding of the impact of both, heritable medicine with particular emphasis on molecu- Project managers: Prof. Dr. A. Hartner, PD Dr. and acquired genetic alterations on the devel- lar and developmental biology. Project coordi- K. Benz opment and progression of pediatric tumors. nation and scientific guidance are provided by Typical features of progressive kidney diseases We have been trying to exploit such new infor- a professorship for experimental perinatal med- are fibrotic changes due to extracellular matrix mation for diagnostic purposes and novel ther- icine. Other main research activities are relat- accumulation and hyperplasia. In this connec- apeutic approaches, placing emphasis on acute ed to pediatric oncology, neuropediatrics, and tion, integrins as matrix receptors are known and chronic childhood leukemia, non-Hodgkin nephrology. In addition, clinical trials are con- to play a pivotal pathogenetic role. Therefore, lymphoma, Ewing's sarcoma, and other fre- ducted by all five divisions of the Department we investigate the function of integrins and quent pediatric malignancies. Methods to de- and by the section of endocrinology/diabetolo- their ligands which are relevant to the kidney. tect patient-specific aberrations of the tumor gy (e.g. interventional trials, studies on genetic We were able to show that a8-integrin can genome have been established and employed conditions, infection epidemiology or medi- regulate cell adhesion, migration, differenti- for quantifying the minimal residual disease, a cation safety, studies investigating long-term ation and proliferation, thereby contributing significant prognostic factor indicating the re- effects of surgical interventions, anti-cancer significantly to the maintenance of renal tissue sponse to therapy. therapy or growth hormone application during homeostasis. Further studies aim at clarifying In addition to acquired mutations in the tumor childhood). The clinical studies are supported whether these results may provide a basis for genome, the impact of hereditary single nucle- by the hospital’s site management organiza- the development of new strategies for diagno- otide polymorphisms on the development of tion. Many medical experts work together to sis and therapy of renal diseases. late adverse effects of current cancer therapy,

98 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) such as hearing loss or cardiomyopathy, is be- staff give lectures and practical courses for International Cooperations ing investigated (LESS study). students enrolled in the Graduate Programs Dr. E. Griesmeier, Department of Pediatrics, Innsbruck in Molecular Medicine and Medical Process Medical University, Innsbruck: Austria Pediatric cell therapy Management. An "emergency care simula- Prof. Dr. I. Wong, Department of Pharmacology & Phar- Project managers: Prof. Dr. W. Holter, Prof. Dr. tor" adapted to the needs of neonatology and macy, University of Hongkong, Hongkong: China H. Schneider pediatric intensive care enables the training of Prof. Dr. M. Ohlin, Department of Immunotechnology, Our main goal is to develop immunotherapies emergency medical procedures and team-work Lund University, Lund: Sweden directed towards viral infections and malignant analysis of the management strategies applied. Prof. Dr. M. Gassmann, Center for Integrative Human disease. Experimental approaches are based on This includes regular reviews of real emergency Physiology, University of Zurich, Zurich: Switzerland antigen presentation by TLR-matured dendritic situations experienced in our clinic. Dr. C. Tuleu, Centre for Paediatric Pharmacy Research, University College London School of Pharmacy, London: cells, the expansion of peptide-specific T cells, UK and the transfer of chimeric receptors (derived Selected Publications Prof. Dr. T.H. Rabbitts, Institute of Molecular Medicine, from monoclonal antibodies and NKG2D) into Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton University of Leeds, Leeds: UK effector cells by RNA-based and lentiviral gene JM, Sato Y, Hartner A, Sekiguchi K, Reichardt LF, Watt FM (2011) The basement membrane of hair follicle stem cells Prof. Dr. A. Clarke, Institute of Cancer & Genetics, Cardiff transfer. Furthermore, we study the regulation is a muscle cell niche. Cell, 144: 577-89 University School of Medicine, Cardiff: UK of apoptosis in dendritic cells and differentiated Kuster L, Grausenburger R, Fuka G, Kaindl U, Krapf G, Prof. Dr. M. Gibson, Biochemical Genetics Laboratory, Uni- T cells under the influence of cytokines. Inthal A, Mann G, Kauer M, Rainer J, Kofler R, Hall A, Metz- versity of Pittsburgh, Pittsburgh: USA ler M, Meyer LH, Meyer C, Harbott J, Marschalek R, Strehl Another research project is focused on the Dr. K. Huttner, Edimer Pharmaceuticals Inc., Cambridge: S, Haas OA, Panzer-Grümayer R (2011) ETV6/RUNX1-posi- controlled differentiation of cord blood-de- USA tive relapses evolve from an ancestral clone and frequently rived mesenchymal stem cells into osteoblasts, acquire deletions of genes implicated in glucocorticoid chondrocytes, and myocytes. These cells could signaling. Blood, 117: 2658-67 Meetings and International Training be used for autografts, e.g. in the treatment Nüsken KD, Schneider H, Plank C, Trollmann R, Nüsken E, Courses Rascher W, Dötsch J (2011) Fetal programming of gene of cleft lip and palate (the most common con- 23.01.2012: Spätfolgen und Nachsorge, Erlangen expression in growth-restricted rats depends on the cause genital malformation) to reduce the number of of low birth weight. Endocrinology, 152: 1327-35 17.-18.02.2012: Jahrestagung der DEGUM-Sektion Pädi- surgical interventions required. atrie, Erlangen Pacho F, Zambruno G, Calabresi V, Kiritsi D, Schneider H (2011) Efficiency of translation termination in humans 01.-03.06.2012: 5th International Conference on Ectoder- Perinatal hypoxic brain injury and is highly dependent upon nucleotides in the neighbour- mal Dysplasia, Erlangen neuroprotection hood of a (premature) termination codon. J Med Genet, 48: 640-4 23.-25.11.2012: JA-PED-Tagung, Erlangen Project manager: Prof. Dr. R. Trollmann Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis Aiming at an early detection and prevention P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider Research Equipment of perinatal brain injury caused by acute or H, Sadowski A, Riener MO, MacDougald OA, Distler O, Beckman Coulter, DNA-Sequenzer chronic hypoxia, we have been analyzing the Schett G, Distler JH (2012) Activation of canonical Wnt signalling is required for TGF-b-mediated fibrosis. Nat Becton Dickinson, FACS Calibur regulation and function of hypoxia-inducible Commun, 3: 735 Applied Biosystems, 2 Tandem-mass spectrometer transcription factors (HIF) in the immature Oehme AK, Rashed AN, Hefele B, Wong IC, Rascher W, Tecan, analyze platform EVO 150 brain. HIF-regulated factors with strong im- Neubert A (2012) Adverse drug reactions in hospitalised pact on the adaptation to hypoxic conditions children in Germany are decreasing: results of a nine year Carl Zeiss, Inverse microscope Axio Observer (Live cell have been characterized as placental indica- cohort-based comparison. PLoS ONE, 7: e44349 imaging) tors of severe hypoxic-ischemic CNS injury in term neonates. In a mouse model of perinatal brain hypoxia, gestational age-dependent and cell-specific molecular effects of hypoxia on endogenous neuroprotective mechanisms have been demonstrated. Furthermore, the impact of perinatal hypoxia on early neuronal migration, astrocytic, and blood-brain barrier function has been investigated - as well as experimental approaches to stabilize HIF by pharmacological means.

Teaching

Besides traditional forms of teaching (compulsory lecture series with case presentations, revision course, and hands-on training in pediatrics), special lectures, research seminars, and interdisciplinary courses are offered to medical Childhood leukemia typically arises from a prenatally established pre-leukemic cell clone. The initial prenatal lesion re- students. Individual members of the research presents a first, albeit insufficient hit which is followed by additional genetic damage that ultimately leads to leukemia.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 99 UNIVERSITY HOSPITAL

Department of Pediatrics Division of Pediatric Cardiology

Address Research eter interventions or operations. In addition, Loschgestraße 15 this three-dimensional model can be used as a 91054 Erlangen B-type natriuretic peptide (BNP) in three-dimensional map for navigation during Phone: +49 9131 8533750 congenital heart disease and acquired interventional procedures. By a 3D-3D-fusion, Fax: +49 9131 8535987 heart disease the data from pre-procedural MRI- or CT-scans http://www.kinderkardiologie.uk-erlangen.de/ After our own assessment of normal age- and can be implemented in the current angio- gender-related values for BNP and the N-termi- graphic examination. Head of Division nal fragment of its prohormone (NT-proBNP) We evaluate the application of this technique Prof. Dr. med. Sven Dittrich in healthy children, we now evaluate the diag- mainly in complex anatomy and complicated nostic value of this biomarker in children with interventions for the optimal use of the poten- Contact congenital heart disease and acquired heart tial of this imaging modality of reduction of Prof. Dr. med. Sven Dittrich disease. There is a special focus on the diagnos- radiation exposure, use of contrast dye, and Phone: +49 9131 8533750 tic value in the longterm outcome of patients fluoroscopy time. Fax: +49 9131 8535987 after corrective and palliative heart surgery and [email protected] children suffering from cardiomyopathies. Molecular cardiology Project manager: Dr. O. Toka Research Focus 3D-Imaging The investigations of the Molecular Cardiolo- •• B-type natriuretic peptide (BNP) in congen- Our objective is the processing of pre-proce- gy team focuses on the evaluation of genetic ital heart disease and acquired heart disease dural data of magnetic resonance imaging factors and subcellular mechanisms respon- •• 3D-Imaging (MRI) or computed tomography (CT) for inter- sible for congenital heart malformation. With •• New imaging possibilities in the catheteriza- ventions, especially for cardiac interventional good clinical practice, we could establish a comprehensive biomaterial bank for individuals tion laboratory procedures. For an optimal planning of safe with congenital heart defects which currently •• Molecular cardiology and effective procedures, the pediatric cardiac counts about 1,500 DNA samples and about •• Duchenne muscular dystrophy surgeon as well as the pediatric cardiologist are provided with three-dimensional volume-ren- 1,500 cardiac tissue samples of all four cham- •• Neutrophil gelatinase-associated lipocalin dered images from the cardiac catheterization bers of the heart. Thus, the biomaterial bank (NGAL) as a new biomarker for diagnosis of laboratory. Thus, individually different possibil- in Erlangen represents one of the largest bio- acute kidney damage ities to imagine a three-dimensional situs with banks for patients with congenital heart defects Structure of the Department the help of two-dimensional sectional images in the country. Since 2009, a close cooperation can be avoided. and funding through the National Compe- 3D-models are generated by different 3D-re- tence-Network has been existing for congeni- The independent Division of Pediatric Cardiol- construction programs in addition to conven- tal heart disease. The research projects include ogy was established in July 2007. Clinical work tional 2D-sectional images to provide the sur- mutation detection and expression analysis in and research activities are performed in close geons with information for surgical planning. familial and sporadic cases of congenital heart cooperation with the Department of Pediatrics Furthermore, these models can be used for disease which are realized by the local research and the Division of Pediatric Cardiac Surgery, 3D-navigation in catheter-based interventions team or national and international cooperation. founded in September 2008. A total of 19 em- by a registered fluoroscopic overlay on a mon- Another research focus involves comprehensive ployed medical doctors are splitting clinical itor. We evaluate the benefit over convention- clinical and molecular-biological investigations work, teaching, and research. At the moment, al imaging techniques. The ideal acquisition on the pathogenesis of the Failing-Fontan there are eleven graduate students studying for techniques for subsequent 3D-reconstructions physiology. Our collaborators are the Institute a doctorate. Several projects were established of the different sectional imaging methods are for Human Genetics (FAU), the Department of to study the genetic mechanisms responsible developed in collaboration with the Institute of Cardiovascular Genetics (Harvard University, for congenital heart disease. There is a col- Radiology. Boston, USA), the Experimental and Clinical laboration with the Competence Network for Research Center (Charité and MDC Berlin), and Congenital Heart Defects in multicenter clinical New imaging possibilities in the the Department for Medical Genetic and Hu- trials, additionally, we prepare an own multi- catheterization laboratory man Genetic (Charité Berlin). center study to evaluate the efficiency of drug Flat detector computed tomography is an in- Current projects are: treatment for cardiac failure in patients with novative three-dimensional imaging technique 1. Expression analyses of vasocactive signaling Duchenne muscular dystrophy. generating CT-like images by an interventional cascades in human aortic tissue of patients with The clinical focus is on interventional therapy angiography system. 3D-data are generated congenital coarctation of the aorta; of congenital heart defects in the catheter lab- from a rotational angiography with contrast 2. Exomsequencing in mendalian traits of com- oratory, on surgical therapy of congenital heart injection during imaging acquisition over five plex cardiac malformations; defects in close cooperation with the Division seconds. This data can now be used for recon- 2.1 Exomesequencing and pathway mapping of Pediatric Cardiac Surgery, and on intensive struction of a cardiovascular model allowing in a cohort of sporadic cases of complex cardi- care after cardiac surgery. for diagnostic purposes and planning of cath- ac malformations;

100 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 3. CNV-Analyses in patients with coarctation renal injury in infants and children early after Glöckler M, Koch A, Halbfaß J, Greim V, Rüffer A, Cesnje- of the aorta. Do chromosomal rearrangements cardiopulmonary bypass. var R, Achenbach S, Dittrich S (2012) Assessment of cav- opulmonary connections by advanced imaging: value of matter? flat-detector computed tomography. Cardiol Young, 1-9 4. Systemic inflammation as a relevant patho- Teaching Glöckler M, Halbfaß J, Koch A, Achenbach S, Dittrich S mechanism of the Failing-Fontan physiology. (2013) Multimodality 3D-roadmap for cardiovascular in- The Division of Pediatric Cardiology takes part terventions in congenital heart disease-A single-center, retrospective analysis of 78 cases. Catheter Cardiovasc Duchenne muscular dystrophy in the general teaching program of the Depart- Interv: DOI 10.1002/ccd.24646 In our study „Effect and safety of preventive ment of Pediatrics (traditional main lecture, Koch AM, Hammersen G, Rüffer A (2012) Aortopulmonary treatment with ACE inhibitors and b blockers compulsory lecture series with case presenta- window. Eur Heart J, 33: 1200 on the onset of left ventricular dysfunction in tions, seminars, hands-on training in pediatrics, Tagariello A, Breuer C, Birkner Y, Schmidt S, Koch AM, Duchenne muscular dystrophy”, we are in- practical training courses). Additionally, med- Cesnjevar R, Ruffer A, Dittrich S, Schneider H, Winterpacht A, Sticht H, Dotsch J, Toka O (2012) Functional null muta- ical students are taught pediatric cardiology vestigating the start of cardiomyopathy and tions in the gonosomal homologue gene TBL1Y are asso- the changes in quality of life in patients with within a specialized training course ”optional ciated with non-syndromic coarctation of the aorta. Curr confirmed diagnosis of Duchenne muscular subject pediatrics”. Furthermore, we offer the Mol Med, 12: 199-205 dystrophy. These patients, aged 10 to 14, are possibility to perform clinical electives or in- Seitz S, Rauh M, Gloeckler M, Cesnjevar R, Dittrich S, Koch so far without any signs of impaired left ven- ternships in our Division. AM (2013) Cystatin C and neutrophil gelatinase-associated lipocalin: biomarkers for acute kidney injury after con- tricular function. The study is sponsored by the genital heart surgery. Swiss Med Wkly, 143: w13744 BMBF and has been initiated in march 2010. Selected Publications The drugs Enalapril and Metoprolol are used Koch AM, Dittrich S, Cesnjevar R, Rüffer A, Breuer C, Meetings and International Training in a randomized double-blinded study design Glöckler M (2011) Plasma neutrophil gelatinase-asso- Courses ciated lipocalin measured in consecutive patients after and tested against placebo. In current clinical congenital heart surgery using point-of-care technology. 16.11.2012: 3D-Bildgebung in der Kinderkardiologie, Er- practice, only patients with already impaired Interact Cardiovasc Thorac Surg, 13: 133-6 langen ventricular function are treated with anticon- gestive therapy. The objective of the study is to examine if the time of onset of cardiomyopathy can be postponed by a preventive treatment with ACE inhibitors and beta blockers. Possibly, quality of life for these patients would improve, and perhaps even a prolonged life expectancy may result. This is a nationwide multi-center study with the involvement of eleven centers within the German network of congenital heart disease (Kompetenznetz AHF). Until December 2013, more patients will be included. Method- ically, we are using the standard measurements in echocardiography, tissue Doppler, ECG, and Holter ECG and standardized questionnaires for the assessment of quality of life.

Neutrophil gelatinase-associated lipocalin (NGAL) as a new biomarker for diagnosis of acute kidney damage NGAL has emerged as a new biomarker for early diagnosis of acute renal injury. Impairment of the renal function due to ischemia is a common risk after cardiopulmonary bypass. In a prospective study, we evaluate the significance of this new biomarker in addition to Cystatin C in children with congenital heart disease. Fur- thermore, we compare the diagnostic impact of these parameters early postoperatively in pediatric patients after cardiac surgery. In the future, primarily the evaluation of Cystatin C Hypoplastic left heart syndrome after Norwood I-Procedure. Examination with spontaneous breathing, contrast medi- and NGAL in the urine might be a helpful diag- um administration of 2 ml/kg. Demonstration of the right ventricle, the Sano-Shunt connecting the right ventricle to nostic tool to improve the assessment of acute the pulmonary artery, and the reconstructed aorta.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 101 UNIVERSITY HOSPITAL

Department of Plastic and Hand Surgery

Address models have been established. With these in Evaluation of quality of life in postbar- Krankenhausstraße 12 vivo studies, many key questions are addressed iatric plastic surgery patients in pre- 91054 Erlangen in the field of plastic and reconstructive sur- and post-surgery Phone: +49 9131 8533277 gery, especially concerning angiogenesis and Project manager: PD Dr. A. Dragu Fax: +49 9131 8539327 tissue engineering. The S3 Guideline: „Surgery in Adipose Pa- www.plastische-chirurgie.uk-erlangen.de tients” emphasizes the importance of an in- Research terdisciplinary approach of the treatment of Head of Department bariatric patients and discusses the relevance Prof. Dr. med. Raymund E. Horch Artificial dermis for coverage of silicon of the contribution provided by postbariatric implants to prevent capsular fibrosis plastic surgery. In order to generate a high Contact Project manager: Dr. M. Schmitz level of evidence, publications are needed pro- Prof. Dr. med. Raymund E. Horch Capsular fibrosis represents a significant com- viding the development of postbariatric plastic Phone: +49 9131 8533277 plication following implantation of silicone surgery treatment strategies. In the context of Fax: +49 9131 8539327 breast implants, necessitating further surgical this prospective clinical research work, patients [email protected] intervention. Numerous studies investigating will be evaluated using the SF-36 (Short-Form- methods to prevent capsular fibrosis have been 36-Questionnaire) at defined time points after Research Focus carried out without success so far. In order to their postbariatric plastic surgery procedure. •• Artificial dermis for coverage of silicon im- reduce foreign body reaction of the surround- The SF-36 evaluates health-associated quali- plants to prevent capsular fibrosis ing tissue, coverage of silicone implants with ty of life, enabling short term as well as long •• The impact of syngenic endothelial progen- acellular dermis has recently been investigated. term effects of plastic surgical procedures on itor cells on de novo vascular network for- An experimental animal study will be conduct- the quality of life of this patient cohort as com- mation ed to investigate if acellular dermis can be used pared to their situation before plastic surgery. •• Establishment and modulation of a lymphat- as an envelope for subcutaneous or submuscu- ic network in the AV loop model lar silicon implants. Clinical observation as well Molecular analysis of ischemia-associ- •• Evaluation of quality of life in postbariatric as histochemistry and immunohistochemistry ated phenomena in extracorporal tis- plastic surgery patients in pre- and post-sur- will be used for evaluation over a period of sue perfusion in a large animal model gery twelve months. Project managers: Dr. S. Schnürer, PD Dr. A. Dragu •• Molecular analysis of ischemia-associated This research project explores the tolerance phenomena in extracorporal tissue perfusion The impact of syngenic endothelial of the M. rectus Abdominis to ischemia and in a large animal model progenitor cells on de novo vascular how it may be improved and increased. A po- •• Optimizing extracorporal tissue preservation network formation tential relationship with genes associated with by adaptation of conservation parameters in Project manager: Dr. O. Bleiziffer apoptosis, inflammation, and adaptation to reconstructive plastic surgery The aim of this project is to establish and char- ischemia will be investigated in muscle tissue •• A retrospective analysis of the operative ther- acterize syngenic endothelial progenitor cells samples harvested at different time points. apy of advanced Dupuytren's contracture (EPC) derived from rat bone marrow. Further- with the Erlangen Distraction Device versus more, their angiogenic potential and their in- Optimizing extracorporal tissue other treatments tegration into a newly formed vascular network preservation by adaptation of conser- •• Tissue Engineering of axially vascularized are being investigated in the AV loop model in vation parameters in reconstructive bone in a small animal model the rat. plastic surgery •• Tissue Engineering: Skeletal muscle Project managers: Dr. C.D. Taeger, PD Dr. A. •• Tissue engineering: Generation of axially vas- Establishment and modulation of a Dragu cularized tissue in the large animal arterio- lymphatic network in the AV loop The aim of this study is to investigate which venous loop model model physiological parameters, including temper- Project managers: Dr. A.M. Boos, PD Dr. J.P. ature and oxygen tension, have a significant Structure of the Department Beier impact on tissue preservation. Muscle tissue of An autonomous lymphatic network will be pigs will be connected to an extracorporal main- Under the auspices of the head of the Depart- generated in the AV loop model in the rat using tenance system to adress how adjustment of the ment of Plastic and Hand Surgery, Prof. Dr. R. lymphatic enddothelial cells and mesenchymal above parameters can improve tissue viability. Horch, and four attending plastic surgeons, stem cells in combination. This lymphatic net- eight residents, two lab technicians, two vet- work may connect to the vascular network and A retrospective analysis of the opera- erinarian doctors, two scientists, and 16 med- provide lympathic drainage from the artificially tive therapy of advanced Dupuytren's ical students are working in different groups generated tissue. Stimulation by growth factors contracture with the Erlangen Distrac- on various projects including basic science and and transgenic lympathic enddothelial cells tion Device versus other treatments clinical research. Besides clinical studies and re- may provide the opportunity for therapeu- Project manager: Dr. M. Schmitz search based on in vitro investigations of clin- tic modulation of the lympathic network and Dupuytren's contracture may be associated ical samples, different large and small animal thereby lympathic metastasis in tumor therapy. with extreme flexion contractures of the finger

102 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) joints that canot be treated with arthrolysis in AV-loop model in order to allow the generation International Cooperations a satisfactory fashion on the long run. A slow of transplantable bone tissue in a very short pe- Prof. Dr. D. Hutmacher, Institute of Health and Biomedical distraction therapy may be a promising alterna- riod of time. Innovation, Queensland University of Technology, Bris- tive. We performed a retrospective study over bane: Australia ten years to evaluate this treatment regimen Teaching Prof. E. Eriksson, MD, PhD, Plastic Surgery Division, Har- vard Medical School, Boston: USA in comparison with other operative regimens Prof. J. Sun, Department of Plastic and Cosmetic Surgery, for the treatment of advanced M. Dupuytren of According to the German ”Statutes of the Union Hospital, Hubei: China Grade III-IV according to Iselin's classification. medical act (ÄAppO)”, a lecture series of 25 academic hours per term (AHS) is held as part Research Equipment Tissue Engineering of axially vascular- of the general surgery lecture series. It covers Zeiss, 2 Zeiss Surgical Microscopes ized bone in a small animal model general principles of Plastic and Hand Surgery. Leica, 1 Leica Surgical Microscope Project managers: PD Dr. A. Arkudas, PD Dr. U. Additionally, the following teaching courses are Kneser conducted regularly by the Department of Plas- Several cooperations have adressed the combi- tic and Hand Surgery: nation of extrinsic and intrinsic vascularisation - Lecture series on ”Specific Issues in Plastic and in the AV loop model using porous titanium Hand Surgery” chambers, and axially vascularized bone tissue - Tutorial ”Tissue Engineering” was succesfully generated using autologous - Clinical Ward Round of Department of Plastic mesenchymal stem cells (MSCs) in combi- and Hand Surgery nation with BMP-2. A femur defect model in - Surgical Anatomy of the Hand and Techniques combination with a titanium chamber with an of Hand Examination integrated plate osteosynthesis was successfully - Interdisciplinary Consultation Hour in ”Breast established to investigate bone formation with Reconstruction” the help of transplantation of a pedicled pre- - Teaching Ward Round and Advanced Course vascularized bone construct. in Plastic Surgery Newly designed bioartificial matrices were in- - Microsurgical Suture Techniques vestigated within the Emerging Fields Initiative - Teaching Ward Round and Advanced Course Project (EFI) TOPbiomat. in Reconstructive Microsurgery - Postbariactric Plastic Surgery Consultation Tissue Engineering: Skeletal muscle Hour. Project manager: PD Dr. J. Beier We use specially designed functional 3D-scaf- Selected Publications folds via electrospun PCL(poly-e-Caprolacton)/ Beier JP, Horch RE, Bach AD (2009) Breast reconstruction collagen nanofibers. after breast-cancer surgery. N Engl J Med, 360: 418-9; au- In a rat model, additional vascularization and thor reply 420-1 muscle outgrowth of previously raised muscle Bleiziffer O, Hammon M, Naschberger E, Lipnik K, Arku- cells is stimulated by a further development das A, Rath S, Pryymachuk G, Beier JP, Stürzl M, Horch RE, Kneser U (2011) Endothelial progenitor cells are in- of our established AV loop rat model, i.e. by tegrated in newly formed capillaries and alter adjacent secondary insertion of an adjacent motor nerve fibrovascular tissue after subcutaneous implantation in a fibrin matrix. J Cell Mol Med, 15: 2452-61 branch for neurotisation. The goal of this combined approach is de novo developing axially Boos AM, Loew JS, Deschler G, Arkudas A, Bleiziffer O, Gulle H, Dragu A, Kneser U, Horch RE, Beier JP (2011) Di- vascularized innervated skeletal muscle tissue. rectly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic Tissue engineering: Generation of sheep model. J Cell Mol Med, 15: 1364-78 axially vascularized tissue in the large Arkudas A, Pryymachuk G, Beier JP, Weigel L, Körner C, Singer RF, Bleiziffer O, Polykandriotis E, Horch RE, Kneser animal arteriovenous loop model U (2012) Combination of extrinsic and intrinsic pathways Project managers: Dr. A.M. Boos, Dr. A. Weigand significantly accelerates axial vascularization of bioartificial Using two clinically approved bone substitutes tissues. Plast Reconstr Surg, 129: 55e-65e in combination with osteoinductive growth Dragu A, Kleinmann JA, Taeger CD, Birkholz T, Schmidt factors as well as autologous mesenchymal J, Geppert CI, Präbst K, Unglaub F, Münch F, Weyand M, Kneser U, Horch RE (2012) Immunohistochemical eval- stem cells, de novo formation of axially vascu- uation after ex vivo perfusion of rectus abdominis mus- larized tissue has already been demonstrated in cle flaps in a porcine model. Plast Reconstr Surg, 130: the large animal sheep model. Ongoing stud- 265e-273e ies are evaluating a load-stable nanocrystalline Horch RE, D’Hoore A, Holm T, Kneser U, Hohenberger W, Arkudas A (2012) Laparoscopic Abdominoperineal Resec- bone augmentation material and are focused tion with Open Posterior Cylindrical Excision and Primary on the acceleration of the vascularization in the Transpelvic VRAM Flap. Ann Surg Oncol, 19: 502-3

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 103 UNIVERSITY HOSPITAL

Department of Psychiatry and Psychotherapy Chair of Psychiatry and Psychotherapy

Address being integrated into the routine treatment of Therapeutically active compounds are accumu- Schwabachanlage 6 alcohol addiction. Similarly, results from the nic- lated and then released in high concentrations 91054 Erlangen otine research projects are now part of the quit like neurotransmitters by nerve endings during Phone: +49 9131 8534166 smoking courses. The Department of Psychiatry signal transmission. A paper discussing the fun- Fax: +49 9131 8534862 and Psychotherapy incorporates the Laboratory damentals of this subject has been published in www.psychiatrie.uk-erlangen.de for Clinical Neurochemistry and Neurochemical a leading specialist journal. On the basis of this Dementia Diagnostics, the National Reference highly promising work, the existing research Head of Department Center for Neurochemical Dementia Diagnos- premises now form the Laboratory for Neuro- Prof. Dr. med. Johannes Kornhuber tics within the KND. In addition, the Laborato- photonics. This laboratory is associated with ries for Molecular Neurobiology, the Neuropho- the Optical Imaging Center Erlangen and net- Contact tonics Laboratory, and a Sensor Laboratory are works on an interdisciplinary basis with groups Beatrix Jauch part of the Department. from the Max-Planck-Institute for the Physics of Phone: +49 9131 8544166 Light and Medical Fundamentals. The laborato- Fax: +49 9131 8534123 Research ry is due to expand in size in the near future in [email protected] order to enable continuing work to be carried Dementia out (e.g. by the Else-Kröner-Fresenius Founda- Research Focus The focus of research work is on improving the tion with more than 200,000 Euro). •• Dementia early and progressive diagnosis of disorders sur- •• Neurophotonics rounding dementia. In the psychometrics branch, Schizophrenia •• Schizophrenia a new version of the Resource Utilization in De- Following the appointment of Prof. Dr. S.G. •• Addictive behavior mentia (RUD) for use in care homes has been de- Schwab as W2 Chair for Molecular Psychiatry •• Clinical neurochemistry and neurochemical veloped. This is an instrument which covers the in September 2010, research in the branch of dementia diagnosis time required to support patients in a care home schizophrenia has been considerably enhanced. for helping with activities related to day-to-day In cooperation with colleagues in Perth, Austral- Structure of the Department issues and supervision and which is suitable for ia, and Jakarta, Indonesia, it has been possible to use in health care research studies. In the branch characterize a sample with more than 1,000 pa- The Department of Psychiatry and Psychother- of psychometrics, work is being carried out under tients with schizophrenia and more than 1,000 apy combines all psychosocial faculties under the sponsorship of the DFG to further develop control persons from Indonesia for chromosomal one roof regarding organization and location. a performance test for measuring daily activities genomes which had already caused a sensation The clinic encompasses the divisions Psychoso- on an objective, valid, and economical basis even in conjunction with other genome-wide studies. matic Medicine, Child Psychiatry, Medical Psy- for mild forms of dementia. It covers tasks from It is evident that these genomes not only play a chology, and the Medical Sociology. Content- aspects of life including communication, mobili- role in the origins of schizophrenia in European related networking is supported by the DIN EN ty, self-care, and domestic life. So far, only exter- populations, but also in Asian populations such ISO 9001:2008 certified quality management nal assessments exist. This test, in contrast, will as the Indonesian population. Furthermore, by system. Medical treatment at our clinic is ad- provide more accurate measurements of therapy cooperating with groups from Europe, the USA, ministered by a highly qualified interdiscipli- success in dementia disorders. The participation and Australia, it has been possible to obtain for nary team whose dedication and competence of the immune system in mental illnesses with the first time clear signs of genes that play a role assures a speedy recovery of our patients. The the focus on Alzheimer’s dementia is being in- in the origin of schizophrenia. This work has been cooperation between doctors, care staff, psy- vestigated in cooperation with the Division of published in leading specialist journals. chologists, social education workers, occupa- Molecular Immunology within the Department tional therapists, and physiotherapists allows of Medicine 3 - Rheumatology and Immunology. Addictive behavior for comprehensive diagnoses and selective In a further project in cooperation with the De- In the research work focusing on addiction, treatments. Patients may receive treatment on partment of Medicine 4 - Nephrology and Hyper- significant findings have been obtained on ge- a full or partial inpatient basis or as outpatients. tension, the occurrence of affective and cognitive netic fundamentals, biomarkers, and molecular Various stimulatory methods represent a special disorders is being investigated on patients who changes in alcohol and nicotine addiction. In form of clinical treatment. The research activities have undergone a kidney transplant and who are the field of alcohol research, the focus was on of the clinic have a special focus on affective dis- suffering from a suppressed immune system and genetic and molecular mechanisms in the devel- orders, addiction, schizophrenia, and dementia. its connection with soluble and cellular immuno- opment of addiction. Here, new genetic muta- The clinic is part of the competence network De- logical biomarkers. tions and downstream molecular circuits have menzen e.V. (KND) where it assumes a leading been discovered and described which clearly role as diagnostics center with the focus on early Neurophotonics increase the risk of developing an addiction. In a and differential diagnosis. It further participates This area of research has seen a number of suc- further focal point, the role of sexual hormones in ongoing projects on neurodegenerative dis- cessful developments during the report period. in association with craving has been investigated orders in Germany and Europe. In the area of Thus, it has been possible to show that the drug during alcohol withdrawal. Thus, various poly- addiction research, the FARS (Franconian Alco- levels of psychopharmaceuticals (e.g. neurolep- morphisms were identified in the genes of the holism Research Studies) investigated the neu- tics) are not constant in the brain during chron- sexual hormone axis which are associated with robiological base of alcoholism in a large patient ic treatment (contrary to earlier assumptions), the strength of the craving. Research in the field cohort. The results of this study are currently but fluctuate with the activity of the nerve cells. of nicotine dependence has shown that the con-

104 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) sumption of nicotine leads to enhanced activa- the doctor/patient interaction. The performance narson H, Gao C, Citri A, Hansen M, Ripke S, Schizophre- tion of intracellular signal cascades. These signal record of this training is assessed by a compe- nia Psychiatric GWAS Consortium, Dudbridge F, Holmans PA (2012) Genome-wide association study of multiplex cascades play an essential role in the establish- tence-oriented test, a portfolio. This can be pre- schizophrenia pedigrees. Am J Psychiatry, 169: 963-73 ment of addictive behavior. In addition, the ef- pared by the students in a flexible time window, Tischbirek CH, Wenzel EM, Zheng F, Huth T, Amato D, fects of nicotine consumption were investigated thus reducing the work load at the end of the Trapp S, Denker A, Welzel O, Lueke K, Svetlitchny A, Rauh for the EEG activity and for a modified sensory term. It promotes process-based learning thanks M, Deusser J, Schwab A, Rizzoli SO, Henkel AW, Müller CP, evaluation of the attractions of nicotine. Smokers to individual feedback and an intensive support Alzheimer C, Kornhuber J, Groemer TW (2012) Use-dependent inhibition of synaptic transmission by the secre- were found to have a more positive assessment by tutors. In 2011, the Erlangen students ranked tion of intravesicularly accumulated antipsychotic drugs. of S nicotine versus R nicotine. The changes with first in the subject Medical Psychology and Medi- Neuron, 74: 830-44 regard to hedonics were explained by condition- cal Sociology in Part One of the National Medical Wagner M, Wolf S, Reischies FM, Daerr M, Wolfsgruber ing mechanisms. On a human/experimental ba- Licensing Exam in a country-wide comparison. S, Jessen F, Popp J, Maier W, Hüll M, Frölich L, Hampel sis, it was possible to show an inverse correlation H, Perneczky R, Peters O, Jahn H, Luckhaus C, Gertz HJ, with hedonic estimates in the EEG following ol- Selected Publications Schröder J, Pantel J, Lewczuk P, Kornhuber J, Wiltfang J factory stimulation for the P2 component of the (2012) Biomarker validation of a cued recall memory defi- Graessel E, Stemmer R, Eichenseer B, Pickel S, Donath C, cit in prodromal Alzheimer disease. Neurology, 78: 379-86 evoked potentials. In cooperation with the Crim- Kornhuber J, Luttenberger K (2011) Non-pharmacologi- inological Research Institute Lower Saxony (KFN) cal, multicomponent group therapy in patients with de- International Cooperations and the Hannover Medical School, the problem generative dementia: a 12-month randomzied, controlled trial. BMC Med, 9: 129 behavior of binge drinking was investigated in- Prof. Dr. D.B. Wildenauer, School of Psychiatry and Clinical Neurosciences University of Western Australia, Crawley: volving 45,000 youths in a representative study Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Australia in Germany. Epidemiological data were evaluat- Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Prof. Dr. O.M. Lesch, Universität Wien, Wien: Austria ed with respect to town and country differences Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone as well as sample differences in consumption as a S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Prof. Dr. M. Barros, Institute of Pharmacology, Brasilia: Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig Brazil function of migration background of the youths. D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Prof. Dr. S. Trapp, Technical University of Denmark: Den- Using a theoretical approach, a predictor analysis Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, mark of binge drinking was carried out which resulted Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, in two statistical and content-relevant protective Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun Prof. Dr. G. Schumann, Institute of Psychiatry, London: UK R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, factors and four risk factors. Later evaluations Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, are planned with respect to the relationships be- Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cru- tween mental instability and binge drinking. The chaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bet- tens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, project is sponsored by external funding (ERAB). Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton Clinical neurochemistry and neuro- AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, chemical dementia diagnosis Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Project manager: Prof. Dr. P. Lewczuk Graff-Radford NR, Petersen RC, Alzheimer’s Disease Neuro- The ISO 9001:2008-certified laboratory is an imaging Initiative, van Duijn CM, Breteler MM, Ikram MA, internationally recognized center for neu- DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, CHARGE consortium, Berr C, Campion D, Epelbaum J, rochemical dementia diagnosis (NDD). The Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, EADI1 analysis of cerebrospinal fluid offers excellent consortium, Feulner TM, Friedrich P, Riehle C, Krawczak M, diagnostic options in several neurological and Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Stein- psychiatric diseases, such as neurodegenerative berg S, Stefansson H, Stefansson K, Snaedal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soini- disorders, stroke, multiple sclerosis and other nen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, neuroinflammatory diseases. The head of the Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, A: Axon terminals visualized using fluorescence microsopy laboratory, published two special journal edi- Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio tions as a guest editor in renowned scientific B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, journals in 2012. Furthermore, he received a Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jons- grant from the BMBF as part of the EU project son T, Riemenschneider M, Morgan K, Younkin SG, Owen "BiomarkAPD" of the JPND and coordinates the MJ, O’Donovan M, Amouyel P, Williams J (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and work package "Certified Reference Material". CD2AP are associated with Alzheimer’s disease. Nat Genet, 43: 429-35 Teaching Lenz B, Müller CP, Stoessel C, Sperling W, Biermann T, Hillemacher T, Bleich S, Kornhuber J (2012) Sex hormone The Department offers a wide spectrum of cours- activity in alcohol addiction: integrating organizational and activational effects. Prog Neurobiol, 96: 136-63 es for students of human and molecular medicine Levinson DF, Shi J, Wang K, Oh S, Riley B, Pulver AE, Wilde- as well as the MPM study program. Evaluation nauer DB, Laurent C, Mowry BJ, Gejman PV, Owen MJ, of training regularly places psychiatry among Kendler KS, Nestadt G, Schwab SG, Mallet J, Nertney D, the best clinical subjects. Planning and evalua- Sanders AR, Williams NM, Wormley B, Lasseter VK, Albus tion of the exams is carried out in accordance M, Godard-Bauché S, Alexander M, Duan J, O’Donovan MC, Walsh D, O’Neill A, Papadimitriou GN, Dikeos D, with scientific principles. Particular attention is Maier W, Lerer B, Campion D, Cohen D, Jay M, Fanous A, B: Corresponding cytoskeleton visualized using fluores- focused on training of communication skills in Eichhammer P, Silverman JM, Norton N, Zhang N, Hako- cence microsopy

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 105 UNIVERSITY HOSPITAL

Department of Psychiatry and Psychotherapy Division of Child and Adolescent Mental Health

Address Research comparing children with and without ADHD, Schwabachanlage 6 und 10 altered inhibitory patterns were obtained for 91054 Erlangen Neurofeedback children with ADHD depending on the level Phone: +49 9131 8539122 In neurofeedback training, participants learn of hyperactivity/impulsivity. Combining TMS Fax: +49 9131 8539126 to gain self-control over certain brain activity and ERPs revealed a compensatory pattern in www.kinderpsychiatrie.uk-erlangen.de patterns. In this way, children with ADHD are children with ADHD. Neurophysiological mark- trained to develop strategies that enable them ers allowed to classify 90% of the children cor- Head of Division to improve their attention abilities as well as rectly. In further studies attentional processes Prof. Dr. med. Gunther H. Moll to better regulate their behavior. In the up to and their modulation by methylphenidate and now largest randomized controlled trial that atomoxetine (medications for the treatment of Contact had been conducted in cooperation with the ADHD) were examined in children with ADHD. Gunda Gstettner Child and Adolescent Psychiatry at the Univer- While both medications led to a comparable Phone: +49 9131 8539122 sity Clinic of Göttingen and the Heckscher-Klin- reduction of the severity of ADHD symptoms, Fax: +49 9131 8539126 ik in München, the clinical effectiveness of a methylphenidate exerted more pronounced ef- [email protected] neurofeedback training in children with ADHD fects on attentional processes (with respect to could be demonstrated and evidence for the reaction time variability and contingent nega- Research Focus mechanisms of action of the standard protocols tive variation). •• Neurofeedback theta/beta and SCP training was obtained. In •• Attention and inhibition processes in chil- the report period, invited reviews including this Neural processing of emotional and dren with ADHD study were published and perspectives for the disorder specific stimuli in girls with •• Neural processing of emotional and disorder application of neurofeedback in ADHD have eating disorders specific stimuli in girls with eating disorders been discussed. In adolescent girls with eating disorders (an- •• Behavioral and neural consequences of pre- In a small-scale study on SCP training in chil- orexia nervosa, bulimia nervosa) and typical- dren with ADHD, associations of SCP self-reg- natal trauma in an animal model ly developing girls, gaze behavior and central ulation skills and clinical reductions of ADHD nervous and peripheral physiological responses symptomatology were found. Moreover, to- Structure of the Department were studied, e.g. when viewing body scheme mographic analyses (sLORETA) confirmed that pictures of underweight, normal weight, and fronto-parietal networks are involved in SCP The Division of Child and Adolescent Mental overweight women. Eating disordered patients generation. Health at the Department of Psychiatry and showed longer fixation times for unclothed A further study in students examined the ef- Psychotherapy is a self-contained division of body regions (visual attentional bias towards fects of different variants of neurofeedback the UK Erlangen. It is subdivided in the areas body shape-related information). At the cen- training on attentional processes, the motor research, outpatient division/policlinic, day tral nervous level (event-related potentials in system and well-being in comparison to a con- hospital, and inpatient division. Furthermore, the EEG), anorectic patients showed largest trol training. For the different neurofeedback in cooperation with the Fürth City Hospital, an- responses for pictures of underweight women. protocols, some specific effects, even though other child psychiatric day hospital is operated In a further study, an assessment battery in- smaller than expected, could be observed. For and professionally directed by Prof. Dr. G. Moll cluding standardized pictures of underweight, example, hints were obtained for associations which has been extended to include a family normal weight, and overweight women as well of successful self-regulation of negativity during day care for families with children between one SCP training and increased amplitudes of the as pictures of low- and high-caloric food was and four years. contingent negative variation during an atten- developed and evaluated in healthy female pu- The clinical focus lies on: Attention deficit/ tion task. In addition, hints for increased intra- pils. The results indicated that especially female hyperactivity disorder (ADHS), tic disorders, cortical inhibition and facilitation in the motor adolescents in the age of 16 to 18 years rated obsessive-compulsive disorders, anxiety disor- system were observed after theta/beta training. underweight women as more attractive than ders, depressive disorders, posttraumatic stress Hence, these studies could contribute to a bet- normal weight women. disorders, eating disorders, autistic disorders, ter understanding of the mechanisms of differ- reduced intelligence with psychiatric comor- ent neurofeedback protocols. Behavioral and neural consequences of bidity, and regulation and behavior disorders in prenatal trauma in an animal model early childhood. Attention and inhibition processes in We have established an animal model for pre- The different research projects of the division children with ADHD natal trauma which enables us to further ex- aim at better understanding of developmental Children with ADHD show an inhibitory deficit amine the mechanisms which lead to a higher processes and of the neurobiological basis of in the motor system. In order to examine this risk of developing a psychiatric disorder in chil- emotional and behavioral disorders in children deficit at the neuronal level in more detail, we dren having suffered from a prenatal trauma. and adolescents as well as gaining further in- developed a methodological approach com- In our mouse model, we examine the effects of sights into the neural mechanisms underlying bining transcranial magnetic stimulation (TMS) a prenatal trauma on processes of learning and therapeutic interventions. and event-related potentials (ERPs). In a study memory, anxiety and fear, as well as on depres-

106 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) sion-like behavior. We measure changes in the Medicine despite its immense importance for Hoegl T, Heinrich H, Barth W, Lösel F, Moll GH, Kratz O neuronal activity of brain structures involved in the field. However, practical training and sem- (2012) Time course analysis of motor excitability in a response inhibition task according to the level of hyperac- these processes as well as changes in the ac- inar are a fixed component of the constantly tivity and impulsivity in children with ADHD. PLoS ONE, tivity of the hypothalamic-pituitary-adrenal axis very successfully evaluated lecture of the De- 7: e46066 (HPA). Moreover, correlations of the effects of partment of Psychiatry and Psychotherapy. Horndasch S, Heinrich H, Kratz O, Moll GH (2012) The late maternal behavior and the phenotype of their Moreover, the subject ”Child and adolescent positive potential as a marker of motivated attention to underweight bodies in girls with anorexia nervosa. J Psy- offspring are correlated and a differentiation psychiatry and psychotherapy” is offered as chosom Res, 73: 443-7 between in utero and postnatal environmental a compulsory optional subject for students of Kratz O, Studer P, Baack J, Malcherek S, Erbe K, Moll GH, effects is examined. medicine (clinical/preclinical term) and as an Heinrich H (2012) Differential effects of methylphenidate optional lecture with accompanying seminar and atomoxetine on attentional processes in children with ADHD: An event-related potential study using the Atten- Teaching within the course of studies in Psychology tion Network Test. Prog Neuropsychopharmacol Biol Psy- (Bachelor/Master). Since the summer term chiatry, 37: 81-9 The teachings in the field of child and adoles- 2012, the seminar „school related psychiatric Sauerhöfer E, Pamplona FA, Bedenk B, Moll GH, Dawirs cent psychiatry and psychotherapy are com- disorders” has offered as an interdisciplinary RR, von Hörsten S, Wotjak CT, Golub Y (2012) General- posed of lectures, seminars, case presentations ization of contextual fear depends on associative rather lecture for both, students and professionals, than non-associative memory components. Behav Brain as well as block seminars. These comprise di- in the fields of education science, psychology, Res, 233: 483-93 agnostics and therapy of the clinical disorders and medicine. as well as the research methods applied in this International Cooperations field. ear-roundY students of medicine, psy- Selected Publications Prof. Dr. D. Brandeis, Dr. R. Drechsler, Department of Child and Adolescent Psychiatry, University of Zurich, Zurich: chology, education science, and social peda- Golub Y, Kaltwasser SF, Mauch CP, Herrmann L, Schmidt Switzerland gogy are being educated and supervised. The U, Holsboer F, Czisch M, Wotjak CT (2011) Reduced hip- main lecture ”Child and adolescent psychiatry pocampus volume in the mouse model of Posttraumatic Stress Disorder. J Psychiatr Res, 45: 650-9 and psychotherapy” is attended by numer- Gevensleben H, Rothenberger A, Moll GH, Heinrich H ous students even though it has not yet been (2012) Neurofeedback in children with ADHD: validation included in the curriculum of the Faculty of and challenges. Expert Rev Neurother, 12: 447-60

Event-related EEG curve (“late positive potential”, electrode Pz, left) and “Attention map” (visualization of fixations, right)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 107 UNIVERSITY HOSPITAL

Department of Psychiatry and Psychotherapy Division of Psychosomatics and Psychotherapy

Address and suffering. Our research addresses epidemi- and healthy controls. Another project aims at Schwabachanlage 6 ology, diagnostic procedures, and etiological investigating selective visual attention in indi- 91054 Erlangen aspects of somatoform disorders as well as the viduals with BDD. Phone: +49 9131 8534596 development and evaluation of psychological Fax: +49 9131 8534153 treatment approaches. Eating disorders www.psychosomatik.uk-erlangen.de 1) In cooperation with the Universities of Mar- Project managers: Prof. Dr. M. de Zwaan (until burg and Leipzig (DFG grant), a longitudinal October 2011), Dr. H. Graap Head of Division survey aiming at clarifying predictors of symp- Prof. Dr. M. de Zwaan coordinates the ”Re- Prof. Dr. (TR) Yesim Erim tom persistence in somatoform disorders was search consortium on psychotherapy of eating completed and results on the validity of current disorders (EDNET)”, funded by the BMBF. The Contact classification proposals have been published. funding period runs from 2007 to 2013. With- Heike Dahlem 2) Unspecific chest pain: More than 50% of in the consortium, five large randomized mul- Phone: +49 9131 8534596 patients in cardiology are found to have no ti-center psychotherapy trials are conducted, Fax: +49 9131 8534153 cardiac basis for their persisting chest pain. As all of which represent international milestone [email protected] a result, patients often suffer from emotional studies. Until the end of 2011, the Division of distress and significant restrictions in daily life, Psychosomatics and Psychotherapy was the Research Focus both leading to an increased health care utiliza- coordinating center of a trial for the treatment •• Somatoform disorders tion. To prevent chronic manifestations of chest of Binge-Eating-Disorder, initiated in 2010. The •• Body dysmorphic disorder pain, a brief and early cognitive-behavioral in- efficacy of an internet-based, therapist-guided •• Eating disorders tervention has been developed and evaluated intervention will be compared with individual •• Obesity in a randomized controlled trial. The study has cognitive-behavioral therapy. As adjunct pro- •• Behavioral medicine received a grant by ELAN-Fond and is conduct- jects to the psychotherapy trials within EDNET, •• Psycho-oncology ed in cooperation with the Departments of Car- genetic, epigenetic, and endocrinological stud- diology of the UK Erlangen and the clinic Mar- ies are conducted. Structure of the Department tha-Maria in Nürnberg. Our analyses show that Besides the engagement in EDNET, we conduct cognitive processes are relevant in non-cardiac a study concerning an intervention to support The independent Division could considerably chest pain and that our intervention was well the carers of patients with eating disorders. A expand its services during the last years. We accepted. Results on the longitudinal course skills training for carers and reading a selfhelp- offer inpatient, day-patient and outpatient of the complaints as well as of the randomized guide are compared regarding their impact on treatment, as well as a psychosomatic con- clinical trial can be expected in 2013. In addi- carers' quality of life, relationship to the patient, sultation-liaison service for the patients of the tion, we have developed an experimental de- and the course of the eating disorder. UK Erlangen with a major focus on psycho-on- sign in cooperation with the university of Co- cology. The main clinical focus of the Division logne to investigate cognitive factors in chest Obesity surrounds eating disorders. Other areas of ac- pain patients. Project managers: Prof. Dr. M. de Zwaan (until tivity include obesity, somatoform disorders, October 2011), PD Dr. Dr. A. Müller pain treatment, and psycho-oncology. The Body dysmorphic disorder Prof. Dr. M. de Zwaan is a board member of the treatment focuses on multimodal and multidis- Project manager: Prof. Dr. A. Martin Competence Network Obesity which was fund- ciplinary evidence-based psychotherapy. Prof. Individuals with body dysmorphic disorder ed in August 2008 by the BMBF. In addition, Dr. A. Martin, who filled a faculty professorship (BDD) are preoccupied with perceived defects she is deputy speaker of the entire Competence in ”Psychotherapy Research” until 30.09.2012, or flaws in their physical appearance. These Network. The Division of Psychosomatics and strengthened the field of behavioral medicine defects or flaws are not observable by others Psychotherapy in Erlangen has successfully and collaborated successfully with the oth- or appear slight to others. BDD is frequently established the German Weight Control Reg- er departments of the UK Erlangen. With her accompanied by feelings of shame and low istry (GWCR) with the goal to determine and work, she underlined the importance and im- self-esteem, compulsive checking behaviors examine factors that support better long-term pact of psychosomatic medicine as an interdis- (e.g. mirror checking), or attempts to hide the weight loss maintenance. This is taken as a ba- ciplinary medical field. imagined defect (e.g. cosmetic camouflage). sis for more focused treatments. The registry The preoccupation with appearance is exces- includes primarily volunteers from the general Research sive and causes significant distress or impair- population who have intentionally lost at least ment in functioning. 10% of their initial body weight and have kept Somatoform disorders We aimed at identifying disorder-specific charit off for at least one year. All participants are Project manager: Prof. Dr. A. Martin acteristics of BDD in comparison with a clinical subsequently followed-up annually. For data The common feature of the somatoform disor- control group (eating disorders) and healthy capture, a participant-centered approach with ders is the presence of physical symptoms that controls. Furthermore, we examined body im- secure data entry directly by the participants cannot fully be explained by a general medical age variables in individuals with BDD in com- is planned. A requirement specification for en- condition, resulting in considerable impairment parison to individuals with major depression hancing existing remote data entry (RDE) sys-

108 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) tems to cover for such aspects will be produced year rotation (”Praktisches Jahr”). The Division by Prof. Dr. H.U. Prokosch and his team from also offers courses for advanced training in psy- the Chair of Medical Informatics at the FAU. chotherapy for psychotherapist with a universi- Another project focused on executive functions ty degree in psychology. In the study program in grade 3 obesity. The study examined execu- Medical Process Management, the Division of tive functioning in 150 morbidly obese patients Psychosomatics and Psychotherapy is respon- with and without binge eating. The findings sible for a seminar on ”communication and suggest a tendency to disadvantageous, risky cooperation aspects within the health care sys- decisions in obese individuals with regular tem”. The Division regularly receives high rat- binge eating. ings for the lecture and practical courses based on the evaluation of the medical students. Behavioral medicine Project manager: Prof. Dr. A. Martin Selected Publications Psychosocial factors in congenital chest wall Mueller A, Holzapfel C, Hauner H, Crosby RD, Engel SG, deformity: Patients with funnel or pigeon chest Mühlhans B, Kolotkin RL, Mitchell JE, Horbach T, Zwaan MD (2011) Psychometric evaluation of the German suffer not only from physical restrictions, but version of the impact of weight on Quality of Life-Lite also from psychological distress. In a project (IWQOL-Lite) questionnaire. Exp Clin Endocrinol Diabe- tes, 119: 69-74 supported by the ELAN-Fond and in cooperation with the Division of Pediatric Surgery, we de Zwaan M, Gruß B, Müller A, Philipsen A, Graap H, Mar- tin A, Glaesmer H, Hilbert A (2011) Association between have shown that patients with a chest wall de- Obesity and Adult Attention-Deficit/Hyperactivity Disor- formity suffer from an impaired body image, der in a German Community-Based Sample. Obes Facts, 4: 204-211 strongly influencing the self-esteem. The surgical correction of the chest wall deformity re- Kollei I, Brunhoeber S, Rauh E, de Zwaan M, Martin A (2012) Body image, emotions and thought control strate- sults - as expected - in physical improvements, gies in body dysmorphic disorder compared to eating dis- but also in a better body image. Currently, the orders and healthy controls. J Psychosom Res, 72: 321-7 maintenance and predictors of post-surgical Krille S, Müller A, Steinmann C, Reingruber B, Weber P, Martin A (2012) Self- and social perception of physical ap- course are further investigated. pearance in chest wall deformity. Body Image, 9: 246-52 Schroeder S, Achenbach S, Körber S, Nowy K, de Zwaan Psycho-oncology M, Martin A (2012) Cognitive-perceptual factors in non- Project manager: H. Sinzinger cardiac chest pain and cardiac chest pain. Psychosom Med, 74: 861-8 The establishment of the Comprehensive Can- cer Center Erlangen-Nürnberg (CCC), funded de Zwaan M, Gruß B, Müller A, Graap H, Martin A, Glaes- mer H, Hilbert A, Philipsen A (2012) The estimated preva- by the German Cancer Aid, increases the rel- lence and correlates of adult ADHD in a German commu- evance and importance of research in the area nity sample. Eur Arch Psychiatry Clin Neurosci, 262: 79-86 of psycho-oncology. In collaboration with the psycho-oncology services of the other funded International Cooperations CCCs, we intend to investigate the needs and Prof. Dr. L. Claes, Department of Psychology, Katholieke Universiteit Leuven, Leuven: Belgium demands of the patients as well as the utilization of psychosocial services. PD Dr. J. Gaab, Clinical Psychology and Psychotherapy, University of Zurich, Zurich: Switzerland Prof. Dr. J.E. Mitchell, Neuropsychiatric Research Institute Teaching and University of North Dakota School of Medicine and Health Sciences, University of North Dakota, Fargo: USA The Division is significantly involved in the curriculum of the Faculty of Medicine. We test new methods of instruction and teaching formats within the practical course offered by the Divi- sion in order to teach students basics aspects of a professional doctor-patient-relationship. The Division also participates in several cross dis- cipline teaching efforts (”Querschnittsfächer”) within the curriculum of the Faculty of Med- icine and also offers courses for psychology students. Medical students can choose Psycho- somatic Medicine as a clinical elective (”Fam- ulatur”) and as an internship during their final

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 109 UNIVERSITY HOSPITAL

Department of Radiation Oncology Chair of Radiotherapy

Address therapy. The latter is one of the most modern 7. Multi-institutional Phase I/II Study: Neoad- Universitätsstraße 27 and biggest departments for interventional ra- juvant chemoradiation with 5-FU (or capeci- 91054 Erlangen diotherapy in Germany. Translational and basic tabine) and oxaliplatin combined with deep Phone: +49 9131 8533405 radio(immune)-biological research is carried out regional hyperthermia in locally advanced or Fax: +49 9131 8539335 by two groups, the classical radiation biology recurrent rectal cancer. www.strahlenklinik.uk-erlangen.de group and the radiation immune biology group. 8. Dose-painting-Image-guided interstital The whole laboratory team consist of two assis- PDR-brachytherapy based on HistoScanning in Head of Department tant professors, two postdoctoral fellows, three patients with prostatic cancer - Phase II-Study. Prof. Dr. med. Rainer Fietkau technicians as well as six PhD students and nu- The Department further participates in the fol- merous medical doctoral candidates. The ”Med- lowing externally led phase-III trials: Contact ical Radiation Physics” group consists of seven 1. Radiation dose intensity study in breast can- Prof. Dr. med. Rainer Fietkau doctorate holding co-workers, five doctoral cer of young women: Randomized phase-III Phone: +49 9131 8533405 candidates, and three technicians. Since Octo- trial of additional dose to the tumor bed. Prin- Fax: +49 9131 8539335 ber 2012, the head of this group has been the cipal investigator (PI): Prof. Dr. H. Bartelink, [email protected] newly appointed full professor Dr. C. Bert who Amsterdam, Netherlands. wants to intensify the physico-medical research. 2. Multicenter Trial: Effectiveness of Adjuvant Research Focus The ”Medical Radiation Physics” group prioritiz- Radiotherapy in Patients With Oropharyngeal •• Clinical Trials es the power of clinical radiation therapy. and Floor of Mouth Squamous Cell Carcinoma •• Radiation Biology and Concomitant Histological Verification of •• Physical Aspects of Radiation Oncology Research Singular Ipsilateral Cervical Lymph Node Me- •• Radiation Immunobiology tastasis (pN1-state). PI: Prof. Dr. Dr. W. Wagner, Clinical Trials Mainz Structure of the Department Project managers: Prof. Dr. R. Sauer, Prof. Dr. V. 3. A randomized two-armed open study on Strnad, Prof. Dr. R. Fietkau, PD Dr. O. Ott the adjuvant therapy in patients with R0/R1 The Department of Radiation Oncology offers 1. Phase-III multicenter trial: Preoperative radio- resected pancreatic carcinoma with Gemci- the entire spectrum of modern Radiotherapy at chemotherapy and adjuvant chemotherapy tabine alone versus Gemcitabine plus Cisplatin the highest level. Clinical, biological, and phys- with 5-fluorouracil versus preoperative radio- with regional hyperthermia. PI: Prof. Dr. R. Is- ical aspects of radiation oncology are scientifi- chemotherapy and adjuvant chemotherapy sels, München. cally analyzed. A multimodal radiooncological with 5-fluorouracil combined with oxaliplatin 4. German Hodgkin trials, coordinated by: therapy from one source is applied. The treat- in patients with locally advanced UICC stage Deutsche Hodgkin Lymphom Study Group ment spectrum compasses intensity modulated II and III rectal cancer. Funded by Deutsche (DHSG), Köln. radiotherapy (IMRT), image guided radiothera- Krebshilfe. In addition, the Department runs a number of py (IGRT), radiochemotherapy, brachytherapy 2. Phase-III multicenter trial: Comparison of phase I and II trials. with its whole spectrum of indications, inten- partial breast interstitial brachytherapy with sity modulated brachytherapy (IMBT), image external whole breast beam radiotherapy in Radiation Biology guided brachytherapy (IGBT), radiosurgery, patients with low risk invasive and in situ breast Project manager: PD Dr. L. Distel hyperthermia (including two deep regional de- carcinomas. Cooperation with C. Polgár, Buda- 1. Individual sensitivity to radiation. Funded vices, one of it with MR guided thermometry), pest, Hungary; funded by Deutsche Krebshilfe. by: Deutsche Krebshilfe. Individual differenc- palliative multimodal concepts, and supportive 3. Phase-III multicenter trial: Reducing total ra- es in the sensitivity of normal tissues to radi- therapies. Clinical aspects of radiation oncolo- diation dose in the context of a simultaneous ation are the most important determinant for gy are predominantly examined within phase I, radiochemotherapy of head and neck tumors. the occurrence of dose-limiting side effects of II, and III trials. This takes place on the ward, Cooperation with Prof. Dr. H. Iro, Depart- radiotherapy. In a project run jointly with the in the outpatient department, the therapeutics ment of Otorhinolaryngology, FAU; funded by University of Würzburg (PD Dr. T. Djuzeno- department as well as the treatment planning Deutsche Krebshilfe. va), the usefulness of a bed-side test in deter- department and hyperthermia unit. A total of 4. Phase-III multicenter trial: Nutritional ther- mining the b-H2AX phosphorylation status is five senior physicians and 16 residents treat apy of patients with head and neck tumors. compared to the established assay based on patients and are involved in running the var- Funded by Fresenius Kabi AG. the analysis of chromosomal aberrations in ious trials and clinical studies. Coordination of 5. Phase II-Study: PDR/HDR interstitial brachy- peripheral blood lymphocytes. Patients with the clinical trials is carried out by the in-house therapy alone in patients with pT1/pT2 pN0 rectal and breast tumors serve as study pop- clinical trials office. Besides the administration breast carcinomas after breast conserving sur- ulation. by three scientific employees, three assistant gery. 2. Tumor infiltrating lymphocytes. The role study nurses as well as a secretary are respon- 6. Phase II-Study: 3D conformal, external par- played by tumor infiltrating lymphocytes in sible for this work. Radiotherapy treatments are tial breast irradiation in patients with pT1/2 determining the efficacy of a course of radio- carried out at one of four linear accelerators and pN0 breast carcinomas after breast conserving therapy is still largely unknown. In a project run in the department of interventional radiation surgery. jointly with the Department of Pathology at

110 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) the FAU (PD Dr. M. Büttner-Herold), the role of 4. Role of interaction of therapy induced dead Frey B, Stache C, Rubner Y, Werthmöller N, Schulz K, Sie- CD4, CD8, B-cells, macrophages, and the influ- tumor cells with dendritic cells for the induction ber R, Semrau S, Rödel F, Fietkau R, Gaipl US (2012) Com- bined treatment of human colorectal tumor cell lines with ence of regulatory T cells is studied in patients of tumor immunity; funded by DFG, GK 1660. chemotherapeutic agents and ionizing irradiation can in with head and neck tumors, gastric cancer, and 5. Induction of anti-tumor immunity by ionis- vitro induce tumor cell death forms with immunogenic potential. J Immunotoxicol, 9: 301-13 carcinoma of the rectum. ing radiation in combination with the adjuvant Lettmaier S, Lotter M, Kreppner S, Strnad A, Fietkau R, AnnexinA5; funded by DFG. Strnad V (2012) Long term results of a prospective dose Physical Aspects of Radiation Oncology 6. Analyses of surface changes of cells after low escalation phase-II trial: interstitial pulsed-dose-rate Project manager: Prof. Dr. C. Bert dose radiation that are relevant for phagocy- brachytherapy as boost for intermediate- and high-risk prostate cancer. Radiother Oncol, 104: 181-6 1. Dosimetric verification and Monte-Carlo tosis within inflammatory reactions; funded by based simulation of inhomogeneities in treat- Doktor Robert-Pfleger Foundation. International Cooperations ment planning for interstitial brachytherapy. For further information, please visit our homepage: 2. MR-spectroscopy for absolute thermometry Teaching http://www.strahlenklinik.uk-erlangen.de in hyperthermia; Funding: ZIM, partner: Dr. Sennewald GmbH. Apart from the traditional radiotherapy teaching Meetings and International Training 3. Evaluation of a fixed-anode computed to- sessions embedded in the course covering the Courses mography concept by multiphysical simula- related fields of medical imaging, radiotherapy 08.-09.04.2011: Grundlagen der Brachytherapie - Inter- tions. treatment, and radiation protection, the Depart- ventionelle Radioonkologie, Erlangen 4. Development of a treatment plan verifi- ment organizes an interdisciplinary lecture series 15.-17.09.2011: 14. Interdisziplinäres Symposium, Rothen- cation method by electronic portal imaging in collaboration with the Comprehensive Cancer burg (EPID). Center Erlangen-EMN (CCC). In these lectures, 07.-10.06.2012: 18. Jahrestagung der Deutschen Ge- sellschaft für Radioonkologie “Qualität schafft Sicherheit”, tumors from different organs are considered 5. Developments of algorithms for quality Wiesbaden assurance of the treatment geometry via on- from different perspectives (surgery, chemother- 09.-10.11.2012: Interdisziplinäre Behandlung, Mam- board imaging devices. apy, pathology, epidemiology, medical imaging, makarzinom, Oligometastasierung, Palliative Radiothera- 6. Voxel-based modeling of normal tissue radiooncology) or an interdisciplinary discussion piekonzepte, Erlangen complication rates for treatment planning. revolving around defined tumor settings is held. 12.-13.12.2012: 4D Treatment Planning Workshop 2012, Erlangen 7. Scattering of g Rays from Concrete Walls in In the context of this course, a database is being Radiation Treatment Facilities. generated that will allow students to familiarize 8. Development and prototyping of an optical themselves with the interdisciplinary approach patient-positioning-system (TOPOS), Patents: by doing clinical case studies. A course in ra- D, EU, US; partner: cybertechnologies GmbH, diation protection including practical teaching Ingolstadt. sessions for students that is recognized by the BLAEK is held semi-annually. For students do- Radiation Immunobiology ing practical clinical work in their pre-registra- Project managers: PD Dr. U. Gaipl, Dr. B. Frey tion year, a complementary teaching program The aim of the Radiation Immunobiology Group is offered. A new teaching course ”prevention, is to understand the relationship between tar- diagnostics, therapy, and after-care of cancer” geted (classical radiobiology) and non-targeted was offered to the students of the Medical Pro- (immune mediated) abscopal effects of ionising cess Management Masters Degree program. radiation alone and especially in combination Furthermore, lectures and seminars dealing with with further immune activation and to identify problems of tumor immunology are offered. the underlying immune mechanisms. The practical and theoretical training of Bach- The following third-party supported projects elor and Master students takes place within the are currently handled: basic training ”Infections Immunology” and the 1. Modulation of inflammation in inflammatory specialization module ”Immunobiology”. Lab mouse models and in patients with inflamma- rotations are offered for fast track students of tory diseases after therapy with low dose of ion- GK 1660. ising radiation (LDRT) or exposition to radon; funded by BMBF, GREWIS network. Selected Publications 2. Modulation of inflammation by low and Brockmann S, Grummich P, Ganslandt O, Fietkau R, Sem- rau S (2011) Reorganization of functional areas of the moderate dose of ionising radiation; ModInIr; brain after brain irradiation. J Clin Oncol, 29: e321-3 funded by EU, DoReMi network of excellence. Schildkopf P, Frey B, Ott OJ, Rubner Y, Multhoff G, Sauer 3. Determination of immune and tumor mark- R, Fietkau R, Gaipl US (2011) Radiation combined with ers in sera of tumor patients; funded by BMBF, hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines Leading Edge Cluster m4 personalized medi- by dendritic cells and macrophages. Radiother Oncol, cine. 101: 109-15

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 111 UNIVERSITY HOSPITAL

Department of Surgery Chair of Surgery

Address postgraduates). Over 80% of funding came side-to-side anastomosis respectively function Krankenhausstraße 12 from grants from DFG, EU, BMBF, German and quality of life in rectal carcinoma patients”, 91054 Erlangen Cancer Aid, IZKF, and ELAN-awards from the PANTER-study (perioperative chemotherapy Phone: +49 9131 8533201 UK Erlangen for equal opportunity for women. for liver metastases in colorectal carcinoma), Fax: +49 9131 8536595 The division is heading the colorectal carcino- COMBATAC-study (HIPEC for peritoneal carci- www.chirurgie.uk-erlangen.de ma research group within the framework of the nomatosis in colorectal carcinoma), HERFLOT/ BMBF-core program for molecular diagnostics. NEOFLOT (perioperative chemotherapy for Head of Department Subprojects are embedded in cooperative re- gastric cancer). Patients were screened during Prof. Dr. med. Dr. h.c. Werner Hohenberger search programs of the DFG, including the core the interdisciplinary tumorboard for gastro- program 1130 ”Infection of the endothelium”, intestinal tumors, assigned to the studies and Contact the GK 1071 ”Viruses of the immune system”, further attended by the study team (e.g. timely Prof. Dr. med. Dr. h.c. Werner Hohenberger the clinical research group 257 „Moleculare sending of quality of life questionnaires). The Phone: +49 9131 8533201 pathogenesis and optimized therapy of chron- trial ”Neoadjuvant chemoradiation in resecta- Fax: +49 9131 8536595 ic inflammatory bowel dieseases”, and the SFB ble pancreatic cancer” was evaluated. The trial [email protected] 796 ”Reprogramming of host cells by microbial ”Evaluation of lymphnode dissection for micro- effectors”. The results of our research ultimate- metastasis in sentinel node biopsy in malignant Research Focus ly generated revenue following the issuing of a melanoma” was performed together with the •• Evaluation of prognosis of gastrointestinal licence for an ELISA by two companies in the Department of Dermatology. tumors USA (Genway Biotech, Quest Diagnostics). •• Randomized trials for gastrointestinal tumors Anorectal dysfunction •• Anorectal dysfunction Research Project manager: Prof. Dr. K. Matzel •• Sensitive Polyprobe-method for improved In 1994, the world’s first sacral nerve stimulator prediction of therapy response and determi- Evaluation of prognosis of gastrointes- for treatment of fecal incontinence was implant- nation of prognosis in patients with colorec- tinal tumors ed at this Department. Since then, the method tal carcinoma Project managers: Prof. Dr. Dr. h.c. W. Hohen- has been continuously improved. Our patients •• Molecular mechanisms of inflammatory re- berger, Prof. Dr. S. Merkel are participating in an extensive post-operative lated angiogenesis Since 1978, a Clinical Cancer Registry has review program which for the first time allows •• Molecular mechanisms of infection related been prospectively maintained for organ spe- to document long term follow-up and the sus- angiogenesis cific tumor documentation. At present, more tainability of the therapeutic effects. We repeat- than 27,000 patients are registered. The main edly run workshops on a national and interna- Structure of the Department focus is on colorectal cancer with over 11,500 tional level which are dedicated to conveying documented cases. Patients are followed for innovative therapeutic methods and initiating Research activities are structured into clinical life with only 1% of patients lost to follow-up. international cooperation. Various international research (clinical trials, clinical diagnosis, and The scientific evaluation of this data focuses studies for the development and evaluation of therapy research) and fundamental molecular on health services research, quality manage- new treatment procedures for anorectal dys- research (molecular mechanisms of angiogen- ment, the improvement of tumor classifica- function (e.g. constipation and incontinence), esis and tumor diagnostic). The clinical trials of tion, the identification of prognostic factors, e.g. the NASHA/Dx study, have been devel- the Department of Surgery are largely super- the definition of quality indicators, and quality oped and conducted. vised by the Clinical Trials Office (CCS; see own of life research. The documentation of specific report) which efficiently initiates and monitors diagnostics and multimodal treatment strate- Sensitive Polyprobe-method for im- the clinical trials. Since then, numerous trials gies in many patients results from an interdis- proved prediction of therapy response aiming at improving cancer therapy and sur- ciplinary cooperation of clinicians and scien- and determination of prognosis in gical techniques and also at establishing new tists of numerous medical departments of the patients with colorectal carcinoma surgical approaches have been conducted. UK Erlangen. Project managers: Prof. Dr. M. Stürzl, Prof. Dr. The fundamental molecular research has been R. Croner conducted at the Division of Molecular and Ex- Randomized trials for gastrointestinal The Polyprobe study is a multicentric inter- perimental Surgery (AMEC; head: Prof. Dr. M. tumors disciplinary approach of the Medical Centers Stürzl) which was also founded in 2003. The Project managers: Prof. Dr. Dr. h.c. W. Hohen- Erlangen and Frankfurt in cooperation with main focus of AMEC´s research is molecular on- berger, Dr. H. Golcher, Dr. K. Öckl, Prof. Dr. J. the industrial partner Siemens Healthcare Di- cology with particular focus on novel markers Göhl agnostics GmbH. It is the goal of the study of prognosis and the molecular regulation of The Department of Surgery respectively the in- to provide new biomarkers for the initiation inflammation-associated angiogenesis in ma- terdisciplinary Colorectal Cancer Centre/Modul of combination therapy in the treatment of lignant and infectious diseases. In the reported Pancreas cancer took part in different mul- colorectal carcinoma. 650 patients will be re- period, the Department consisted of twelve sci- ticenter trials about gastrointestinal tumors, cruited in the study (presently 450 patients are entific researchers (four post-doctorates, eight inter alia ”Comparison of colon-pouch versus included). The specific target of the Polyprobe

112 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) project is the validation of 60 previously iden- targeted by this modification in infected cells. International Cooperations tified biomarkers at the mRNA level in order to Moreover, experimentally induced O-Glyc- Prof. S. Laurberg, Department of Surgery, University of predict tumor stage, survival, and response to NAcylation was found to be associated with Aarhus, Aarhus: Denmark chemo- and radiotherapy of the individual pa- inhibition of virus production in infected cells. Prof. Dr. M. Gariglio, University of Piemonte Orientale, Novara: Italy tients (predictive and prognostic molecular di- This suggests that O-GlycNAcylation mediates agnosis, prospective diagnostics study). In this metabolic effects in KSHV virus replication. In Prof. Dr. S. Indraccolo, University of Padova, Padova: Italy framework, a novel technical platform is used cooperation with the Institute of Clinical and Prof. T. Holm, Colorectal Surgical Unit, Karolinska Institu- tet, Solna, Stockholm: Sweden which allows automated extraction of RNA Molecular Virology, ephrin A2 was identified from formalin-fixed paraffin-embedded tissue Prof. Dr. M. Heikenwälder, Institut für Neuropathologie, as a cellular receptor of KSHV. Moreover, in Universitätshospital Zürich, Zurich: Switzerland (FFPE). The commercial exploitation of the val- the framework of routinely applied quality Prof. P. Quirke, Institute of molecular medicine and pa- idated markers will be addressed together with control analyses, our laboratory could show thology, Leeds: UK Siemens. that the worldwide commonly used model Prof. Dr. D. Ganem, Novartis Institutes for Biochemical Re- cell line for KS (SLK) is not derived from KS, search, St Emeryville: USA Molecular mechanisms of inflammato- but is instead a contamination of a renal cell Prof. Dr. A. Nusrath, Emory University School of Medicine, ry related angiogenesis carcinoma cell line. This clearly demonstrates Atlanta: USA Project manager: Prof. Dr. M. Stürzl the importance of routinely applied safe qual- Meetings and International Training In previous studies, the group succeeded in ity control analyses in the framework of trans- Courses identifying the large GTPase guanylate bind- lationally oriented research work. ing protein-1 (GBP-1) as a central regulator of 23.-24.05.2011: 6th Advanced Course in Colorectal Can- cer Surgery, Erlangen inflammation-associated angiostasis. It could Teaching be shown that GBP-1 can inhibit epithelial 16.-17.06.2011: Interstim Neuromodulation Academy Colorectal Surgeons & Urologists, Fundamental Training, cell proliferation via inhibition of b-catenin/ In the context of the main course, live broad- Erlangen TCF-signal pathways which might be of high casts of operations into the lecture hall are 18.10.2011: Das kolorektale Karzinom - Interdisziplinäre relevance for the pathogenesis of colorectal arranged for visualization. Moreover, a bed Behandlung in onkologischen Darmzentren, Erlangen carcinoma. In addition, it could be shown side teaching is included in the internships. To 03.12.2011: Arzt-Patienten-Seminar zu Lebertransplanta- tion, Erlangen that GBP-1 acts as a tumor suppressor pro- further deepen the acquired knowledge from tein in colorectal carcinoma cell lines which the main course, we run among other meas- 21.-22.05.2012: 7th Advanced Course in Colorectal Can- may be of relevance for immune evasion in cer Surgery, Erlangen ures intensive preparatory classes. In order colorectal carcinoma. Moreover, an impor- to gain a realistic perspective of the clinical tant role of GBP-1 in chronic inflammato- Research Equipment routine, small supervised groups are allowed ry diseases could be substantiated. In this Bio-Rad Laboratories GmbH, VERSARRAY CHIPWRITER PRO to visit the operating room and the intensive framework, it could be shown that GBP-1 lev- Leica, TCS-SPE care unit. The Division of Molecular and Ex- els are increased in tissues and serum of pa- Fuji, FLA 5000 perimental Surgery offered during the period tients with autoimmune diseases, including under report in total 18 different teaching lupus erythematosus, systemic sclerosis, and courses. Among these, a two-week cell bio- rheumatoid arthritis. The observed increased logical ground course and a scientific project levels of GBP-1 were associated with vascular developing seminar were conducted in the defects in accordance with the biologic func- study course molecular medicine. Additional tion of GBP-1. alternating exchange of basic researchers and medical scientists is meant to improve trans- Molecular mechanisms of infection lational research. related angiogenesis Project manager: Prof. Dr. M. Stürzl Selected Publications The research on infection-associated angiogenesis focuses on the pathogenesis of AIDS- Mulsow J, Merkel S, Hohenberger W (2011) Right colonic transposition technique for pelvic anastomosis. Dis Colon associated Kaposi’s sarcoma (KS), a tumor of Rectum, 54: e245 endothelial cell origin which is etiologically Langheinrich MC, Schellerer V, Perrakis A, Lohmüller C, connected with Kaposi’s sarcoma-associated Schildberg C, Naschberger E, Stürzl M, Hohenberger W, herpes virus (KSHV). In the research period Croner RS (2012) Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract. Int to be reported about, it was systematically J Clin Exp Pathol, 5: 614-23 analyzed which of the 86 gene products of West NP, Kobayashi H, Takahashi K, Perrakis A, Weber KSHV are targeted by the regulatory post- K, Hohenberger W, Sugihara K, Quirke P (2012) Under- translational modification O-GlycNAcylation. standing optimal colonic cancer surgery: comparison of Japanese D3 resection and European complete mesocolic It could be shown that predominantly regula- excision with central vascular ligation. J Clin Oncol, 30: North/east view of the new Surgical Center. Moving in tory proteins involved in virus replication are 1763-9 July 2013.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 113 UNIVERSITY HOSPITAL

Department of Surgery Division of Pediatric Surgery

Address outstanding experiences in minimally invasive days. The evaluation of functional and cosmetic Krankenhausstraße 12 pediatric surgery (laparoscopy, thoracoscopy, features showed unsatisfactory results (pain, in- 91054 Erlangen rendez-vous procedures) with high-end tissue stability, loosening of implants, secondary pro- Phone: +49 9131 32923 management and wide-area indications. cedures) in 82.6%. Fax: +49 9131 34432 The preliminary results show the impact of www.kinderchirurgie.uk-erlangen.de Research programmed strategy with gaining sterile con- www.kinderoperatives-zentrum.uk-erlangen.de ditions with the aid of local antiseptic instilled Chest wall repair and deficiency in agents in combination with a vacuum wound Head of Division wound healing. Creating an algorithm dressing (V.A.C.). Prof. Dr. med. Roman T. Carbon Project manager: Dr. S. Schulz-Drost Deficiencies in wound healing are present in Embryonic remnants and appendicitis. Contact open chest wall repair (pectus excavatum, pec- Prospective study Prof. Dr. med. Roman T. Carbon tus carinatum) in up to 10% and represent a Project manager: Prof. Dr. R.T. Carbon Phone: +49 9131 8533296 severe complication. Healing of cartilage and In human development, the gastrointestinal Fax: +49 9131 8534432 bone structures is compromised by microbial tract has a double-curtain mounting with the [email protected] structures. Materials for reconstruction, e.g. mesenteric structures: Along the persistent metal bars and locking titanium plates, have to dorsal mesentery, there is a ventral suspenso- Research Focus be removed in case of an inflammatory event ry which should be regressing in utero. From •• Chest wall repair and deficiency in wound with the result of a functional and cosmetic embryonic pathology, peritoneal ligaments are healing. Creating an algorithm loss. wellknown, e.g. LADD's ligaments, arising from •• Embryonic remnants and appendicitis. Pro- Prospectively, patients with deficiencies in the transverse colon to the right edge of the spective study wound healing were treated by a vacuum-in- peritoneal space or connected to the edge of •• Implementation of sacral nerve stimulation stillation therapy (V.A.C. instill). At the first the liver with consecutive compression of small (SNS) in pediatric surgery step, hard-coded programmed operative re- bowel with relevant effects on gastrointesti- visions and application of periodic instillation nal passage. Other ligaments are known from Structure of the Department with local antiseptic agents (Polihexanid) are Waldschmidt 1990 and are registered at the il- achieved. In primary procedures, a standard- eocaecal pole and, depending on position and The Division of Pediatric Surgery is a self-con- ized strategy takes place: latitude, they are responsible for perturbance in tained division in the Department of Surgery 1. Debridement and necrosectomy, gastrointestinal transport. of the UK Erlangen. Facilities are settled down 2. Rinsing with local antiseptic agents, From 1992 to 2012, 1,552 pediatric laparos- in the Department of Pediatrics and Adolescent 3. Setting up an instillation system. copies (aged 1.5 to 21 years, mean 9.2 years) Medicine (Prof. Dr. Dr. h.c. W. Rascher) with At the second step, the programmed revision were performed because of "acute lower abdo- ward CK 4 and the Department of Surgery with with men/appendicitis" (982 girls, 570 boys). Each ward U2, closely connected to the Department 1. Vacuum-wound dressing with instillation un- case had an appendicectomy and a peritoneal of Urology (Prof. Dr. B. Wullich). til gaining a two-fold negative microbial result exploration. There were 54 MECKEL's divertic- There is also a membership in the expert-net- of the specimen. Revisions are accomplished ula, 485 hydatides at the fimbrial stem, 232 work of the Perinatal Center of Franconia, lo- repeatedly from three to five days. cystic ovarian structures, 18 carcinoids at the cated at the Department of Obstetrics and 2. Debridement, sampling; appendix, and 14 embryonic vessels (A. vitelli- Gynecology (Prof. Dr. M.W. Beckmann) and in 3. If applicable, conventional vacuum wound na dextra et sinistra). the Pediatric Operative Center (KIOZ). There dressing is accomplished until gaining sterile Persistent, ventral mesenteries were evident in is a close connection, including operative co- wound situations and sufficient conditioning of variable expressions in 1,223 patients: Colopa- operation, to the university teaching hospitals wounds; rietal ligaments were present at the right colon in Bamberg (Prof. Dr. K.-H. Deeg), Bayreuth 4. Downsizing the wound. in 1,118 patients, in 84 patients at the colon (Prof. Dr. T. Rupprecht), Schweinfurt (Dr. J. In a third step, the final wound closure occurs: descendens/sigmoideum, and in 21 patients Herrmann) and Fürth/B. (Prof. Dr. J. Klinge). 1. Final stabilization of wounds, if applicable in on both sides. Kinking, warping, compres- The medical spectrum comprises the surgical a second procedure; sion, and constipation were present in 1,178 treatment of congenital malformations, espe- 2. Wound closure with a secondary single knot patients. At any case, there always existed a cially in the thoracic, abdominal, skeletal, and suture. phlegmoneous finding or a higher grade of ap- integumental areas in newborn and children. Until today, open chest wall repair shows early pendix's inflammation. "Appendix bags" were Acute and chronical diseases are treated in all inflammation after 14-30 days postoperatively. discovered in 144 patients - in that situation age groups in cooperation with the pediatrics. With the aid of instillation of local antiseptic at least an ulcero-phlegmoneous appendicitis Strongest importance is placed on consistent agents, all cases showed sterile wound condi- with perforations was present in 88 patients. after-care. Traditionally, excellent expertise is tions and preservation of implants. Secondary The preliminary overview shows a high sig- known in minimally invasive surgical treatment sutures for wound closure were accomplished nificance (p <0.001) of correlation "appendix of chest deformities (Pectus excavatum et car- after an average of 12.6 days. Conventionally, a bag"/perforation, because kinking of the ap- inatum) and in special techniques to resolve prolonged wound healing was evident, the sec- pendix leads to consecutive coprostasis and recurrences after chest wall repair. There are ondary closure took place in average after 52.6 induces inflammation. In comparison to lapa-

114 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) roscopic procedures done for the upper abdo- ing of the rectum is noticed. Furthermore, the and hands-on courses). An increasing number men and/or elective reasons, there are highly increase of the tonus of the internal sphincter of trainees and interns (non-local students, significant differences in the existence of emis evident. It is the belief that neuromodulation ERASMUS-students, students of cooperative bryonic remnants of the ventral mesenteries. changes the function of afferent sensoric nerve universities) is embedded into the curriculum. Those remnants caused by the vental mesen- filaments, spinal reflexes, and sympathonic teries induce higher-grade inflammation at and parasympathonic activity. The main goal Selected Publications the appendix related to local constipation. No of SNS is that success of treatment can be es- Agaimy A, Stachel KD, Jüngert J, Radkow T, Carbon R, high-frequency or radiologic diagnostic device timated after the minimally invasive testing of Metzler M, Holter W (2011) Malignant Epithelioid Pe- is able to detect such ligaments, so laparosco- stimulation. SNS is administered in three steps: ripheral Nerve Sheath Tumor With Prominent Reticular/ Microcystic Pattern in a Child: A Low-grade Neoplasm pic exploration is the choice for both, diagnosis 1. Intraoperative test-stimulation. The sacral fo- With 18-years Follow-up. Appl Immunohistochem Mol and therapy. ramina are punctured with needles. An electric Morphol: DOI 10.1097/PAI.0b013e318224751f stimulation is maintained. In case of adequate Steinmann C, Krille S, Mueller A, Weber P, Reingruber B, Implementation of sacral nerve stimu- motor response, a test probe is put into the sa- Martin A (2011) Pectus excavatum and pectus carinatum lation (SNS) in pediatric surgery cral foramen and is fixed by a patch; patients suffer from lower quality of life and impaired body image: a control group comparison of psychological Project manager: Dr. M. Besendörfer 2. External pacemaker: Subchronical phase of characteristics prior to surgical correction. Eur J Cardio- The sacral nerve stimulation (SNS) is a low-fre- stimulation; Evaluation and writing a stool-diary; thorac Surg, 40: 1138-45 quency (15-25 Hz) electric long-time stimula- 3. After successful test-phase, the implantation Brecht IB, Agaimy A, Besendörfer M, Carbon R, Thiel FC, tion of sacral ganglion cells - mostly segment S3. of an internal pacemaker is to be designed. Rompel O, Osinski D, Langer T, Metzler M, Holter W (2012) The impact of this principle was founded in urol- Aim of the study: Instruments of application Malignant peritoneal mesothelioma in a 16-year-old girl: presentation of a rare disease. Klin Padiatr, 224: 170-3 ogy and is a therapeutic option in neurogenic adapted to children. Topographic anatomical Naumann-Bartsch N, Carbon R, Klein P, Agaimy A, Holter aconuresis. As a side effect in those studies, anal studies of sacral anatomy and its changing W, Jüngert J (2012) An unusual thyroid mass in a 5-year- incontinence and constipation were treated just character depending on age. old girl. J Pediatr, 161: 565 as well. The side effects put focus on an increase Rüffer A, Webinger J, Glöckler M, Purbojo A, Dittrich S, of pressure of the anal sphincteric structures and Teaching Cesnjevar RA, Carbon R (2012) Pericardial cyst or terato- improvement of colonic movement. So it stands ma? Change of strategy during mediastinal tumor surgery. Thorac Cardiovasc Surg, 60: 488-90 to reason to implement SNS in incontinence, Pediatric surgery is a self-contained surgical constipation, and colon irritable. speciality and is presented academically as fol- Weikert E, Kraske S, Schott GE, Wullich B, Hirsch K (2012) Umbilical rotation: A new technique for the cutaneous fix- Disorders in fecal evacuation in pediatric pa- lows: ation of continent catheterizable vesicostomies. J Pediatr tients are mostly dismissed and frequently in- 1. Curricular in the course of IMPP (gener- Urol, 8: 87-91 duce psychiatric treatment. That leads to social al guidelines for medical studies in Germany: isloation and disorders in personal develop- general and special pediatric surgery in theory Meetings and International Training ment. Especially in children, a high potential and practice) in individual lectures, partly inte- Courses of developmental improvement of ganglion grated in main lectures on surgery and pediat- 25.07.2012.-27.07.2015: Zystisches Lymphangiom - aku- activity is evident. "Learning by test-stimula- rics. Cooperative academic events in the course tes Abdomen beim Säugling, Regensburg tion" gives rise to a long term improvement of of technical schools at FAU (pediatric nursing, 25.-27.07.2012: Ausgusspräparat des Magens. Rapun- quality of life and implantation of a pacemaker pediatric intensive care medicine, School for zel-Syndrom, Regensburg is omitted. operational and technical assistents, physio- 12.-16.09.2012: Bezoar des Magens - Ein Fallbericht, The effect of this method is partly explained therapy, massage) Hamburg by the direct stimulation of efferent nerve fil- 2. Interdisciplinary (lecture series "Emergency", 12.-16.09.2012: Mesenteriales Lymphangiom beim Säugling, Hamburg aments. In addition to improvement of direct seminars, boards) measurable contractions of the sceletal muscles 3. Special (postgraduate/diploma students, 28.-30.11.2012: Stabilizing of the anterior chest wall in recurrent pectus excavatum with sternocostal pseudar- of the anal sphincter, an improvement of the practical education in phantom-courses for throsis by elastic stable chest repair (ESCR): an innovative sensor system and the state of feeling the fill- minimally invasive pediatric surgery in skills lab fixation device, Dubai, U.A.E.

Fan-like, connective tissue canvas producing warping of “Stairway-phenomenon” (sternocostal instability and the bowel and inducing constipation and inflammation Prototypes of 1.9 mm-instruments, suitable for pediatric pseudarthrosis) following open chest wall repair. Implan- of the appendix. laparoscopy and thoracoscopy. tation of locking-titanium-plates.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 115 UNIVERSITY HOSPITAL

Department of Surgery Division of Thoracic Surgery

Address Nuclear Medicine, we have founded the Lung method in deep infected wounds, e.g. pleural Krankenhausstraße 12 Center Erlangen. empyema. 91054 Erlangen Emphasis of our clinical activity concentrates on Phone: +49 9131 8532047 minimally invasive lung resections (VATS-sur- Using tracking dogs in early diagnosis Fax: +49 9131 8532048 gery) and also on interdisciplinary therapy for lung cancer www.thoraxchirurgie.uk-erlangen.de concepts for the advanced lung cancer and Project managers: Prof. Dr. H. Sirbu, Dr. M. other chest diseases. The intensive cooperation Würfel*, P. Stapel Head of Division with all other oncological field unities and the By using standardized collected breath sam- Prof. Dr. med. Horia Sirbu connection with our Comprehensive Cancer plings of patients with lung cancer, tracking Center (CCC; see ower report) is assuring the dogs of Johanniter Unfallhilfe are trained in dif- Contact best therapy for our patients. ferent stages to prove how an early detection Dr. med. Waldemar Schreiner The Division of Thoracic Surgery is actively par- of lung cancer is possible. The main objective is Phone: +49 9131 8532047 ticipating and organizing the activities of the to provide foundations for a technical gas anal- Fax: +49 9131 8532048 academical study group of the German Society ysis (”electronic nose”) as well as the chemical [email protected] of Thoracic Surgery. identification of gas markers with their characteristic ratio in the different stages of cancer. Research Focus Research *Krankenhaus Martha-Maria, Nürnberg •• Surgical therapy of hyperhidrosis - a prospective quality control study Surgical therapy of hyperhidrosis - a Imunological and molecular charac- •• Surgical management of pulmonary metas- prospective quality control study terization of malignant lung tumors tases from colorectal cancer Project manager: A. Zdrojek Project managers: Prof. Dr. H. Sirbu, Prof. Dr. S. •• Deep intrathoracic vacuum therapy for Videoscopic assisted thoracic sympathectomy Finotto, Dr. D. Trufa chronic empyema is a widely accepted approach in the therapy The aim of this research project is to investigate •• Using tracking dogs in early diagnosis for of palmar and axillary hyperhidrosis. Long term immunological and molecular basis. The focus lung cancer postoperative results are very heterogenous. within this project are the malignancies that •• Imunological and molecular characterization In this trial, we are analyzing the long term become visible in the lung, especially non-small of malignant lung tumors patient satisfaction with a specially designed cell lung cancer (NSCLC). These parameters are •• Hyperthermic intrathoracic chemotherapy questionnaire by the Division of Psychosomat- then correlated with the clinical findings. after pleurectomy/decortication in pleural ics and Psychotherapy. Before the surgery, the clinical data (age, mesothelioma - a phase I study height, weight, sex, nutritional status, smoking •• Neoadjuvant therapy of locally advanced Surgical management of pulmonary and occupational history, family history, etc.) non-small cell lung carcinoma IIIA; concur- metastases from colorectal cancer are acquired. After the surgery, some samples rent radiochemotherapy followed by surgery Project managers: Dr. W. Schreiner, Dr. O. from resected lung tissue and from removed •• Trimodal therapy of malignant mesothelio- Oster lymph nodes are analyzed in the laboratory. ma Although resection of solitary lung metastases From the single cell suspension, various cell •• The value of the systematic extensive lymph has been widely accepted, pulmonary resec- subpopulations, such as isolated CD4 + or CD8 node dissection in the operative treatment in tion for multiple or bilateral metastases is still + T cells, are taken in culture. The cultured cells non-small cell lung carcinoma under discussion. This monocentric, retrospec- are then analyzed in different ways (e.g. FACS tive study analyzes clinical data, prognostic analysis, ELISA, PCR, etc.). RNA and DNA are Structure of the Department factors, and long term follow-ups after surgi- isolated, too, which can then be used for epi- cal treatment of pulmonary metastases from genetic studies, microarray analysis, and RNA The Division of Thoracic Surgery was founded colorectal cancer. expression analysis. Finally, the proteins can be in 2008 and is offering the complete diagno- The Division of Thoracic Surgery is actively or- isolated and analyzed. sis and therapy of lung, mediastinal, and chest ganizing and participating in the activities of diseases. Our division is nationwide one of the the academical study group of the German So- Hyperthermic intrathoracic chemo- first academic thoracic surgical divisions. Under ciety of Thoracic Surgery. therapy after pleurectomy/decortica- the auspices of the head of the Division, Prof. tion in pleural mesothelioma - a phase Dr. H. Sirbu, who is Extraordinarius for thoracic Deep intrathoracic vacuum therapy for I study surgery, there are working two consultant tho- chronic empyema Project managers: Dr. W. Schreiner, M. Hanika racic surgeons, four residents, and a number of Project managers: Dr. W. Schreiner, Dr. O. The end point of this prospective trial is the medical students. Oster survival and the disease free interval through In cooperation with the Departments of Medi- Vacuum therapy leads to a significant improve- the combination of the intrathoracic hyperther- cine 1 and 5, the Department of Radiation On- ment in the local therapy of infected wounds. mic cisplatin with pleurectomy/decortication cology, the Institute of Pathology, the Division The aim of this study is to examine the clinical in patients with stage I pleural mesothelioma. of Palliative Medicine, and the Department of long and short time results of this therapeutical Through radical pleurectomy/decortication,

116 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) an operative tumor reduction is possible. This thoracic surgical teaching during the main lec- cytoreduction is improving the efficacy of the tures, the lecture of emergency organized by intrathoracic chemotherapy. The combination the Chair of Anesthesiology, and/or lectures of the intrathoracic perfusion with cisplatin and during hands-on training. hyperthermia is improving the needed cytotox- For advanced students, we additionally offer ic effect locally. This trial is including patients practical patient bases exercises on thoracic with advanced age and co-morbidity, resecta- diseases in practical training. ble mesothelioma masses without lymph node metastasis. Selected Publications Fuchs P, Schreiner W, Wolter TP, Autschbach R, Sirbu H, Neoadjuvant therapy of locally ad- Pallua N (2011) A four-muscle-flap for thoracomyoplasty in patients with sacrificed thoracodorsal vessels. J Plast Re- vanced non-small cell lung carcinoma constr Aesthet Surg, 64: 335-8 IIIA; concurrent radiochemotherapy Scholz GA, Sirbu H, Semrau S, Anders K, Mackensen A, followed by surgery Spriewald BM (2011) Persisting right-sided chylothorax in Project managers: Prof. Dr. H. Sirbu, Prof. Dr. a patient with chronic lymphocytic leukemia: a case report. J Med Case Reports, 5: 492 R. Fietkau In this trial, we compare the therapy concept Spillner J, Amerini A, Hatam N, Rex S, Pott F, Goetzenich A, Menon A, Repas T, Steiner F, Autschbach R, Carpi A, of neoadjuvant radiochemotherapy (45Gy/ Oster O (2011) Pulmono-atrial shunt and lung assist to Cisplatin, Etoposide), followed by surgery with treat right ventricular failure. Front Biosci, 16: 2342-51 the concept of definitive radiochemotherapy in Schmidt J, Irouschek A, Heinrich S, Oster O, Klein P, Birk- patients with locally advanced, non-small cell holz T (2012) Recurrent Laryngeal Nerve Monitoring during Esophagectomy and Mediastinal Lymph Node lung carcinoma stadium IIIA. Dissection: A Novel Approach Using a Single-lumen En- dotracheal EMG Tube and the EZ-blocker. World J Surg, Trimodal therapy of malignant 36: 2946-7 mesothelioma Schreiner W, Oster O, Stapel P, Sirbu H (2013) V. A. C. INSTILL® therapy - new option in septic thoracic surgery. Project managers: Dr. W. Schreiner, M. Hanika Zentralbl Chir, 138: 117-20 The trial is including patients in good clini- Ubel C, Mousset S, Trufa D, Sirbu H, Finotto S (2013) Es- cal condition, younger than 60 years without tablishing the role of tyrosine kinase 2 in cancer. Oncoim- significant co-morbidity, a resectable tumor munology, 2: e22840 mass, and without lymph node involvement. After neo-adjuvant chemotherapy, extended Meetings and International Training operative tumor resection (pleuropneumecto- Courses my with pericardectomy and resection of di- 26.03.2011: 2. Workshop “Arbeitsgemeinschaft Universi- täre Thoraxchirurgie” der Deutschen Gesellschaft für Tho- aphragma) is performed. Postoperatively, the raxchirurgie, Erlangen radiotherapy of the hemithorax is added. The 16.11.2011: Erlanger Thorax-Kolloquien: Aktuelle Aspekte end point of the study is the survival and the in der Äthiologie und Behandlung des Pleuraempyems, disease free interval. Erlangen 29.02.2012: Erlanger Thorax-Kolloquien: Der Pneumotho- The value of the systematic extensive rax, Erlangen lymph node dissection in the opera- 18.07.2012: Erlanger Thorax-Kolloquien: Die Thorakoskopie, Erlangen tive treatment in non-small cell lung carcinoma Project manager: Dr. W. Schreiner The purpose of the study is the investigation of the extensive lymph node dissection under consideration of the lymphatic metastasis pathways and the improvement of the lymph node staging. In this study, we have included about 500 patients over a 20 years period.

Teaching

University teaching was completed with the establishment of a professorship for thoracic surgery at the Chair of Surgery. We offer a wide LASER asissted thoracic surgical procedure

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 117 UNIVERSITY HOSPITAL

Department of Surgery Division of Transfusion Medicine and Hemostaseology

Address Research formed several series of PLT preparations using Krankenhausstraße 12 the TRIMA separator by Caridian. PLT concen- 91054 Erlangen Preparation and characterization of trates in the additive solutions PAS II, PAS III, and Phone: +49 9131 8536972 white cell-poor platelet concentrates PAS III M were compared with each other and Fax: +49 9131 8536973 by apheresis with platelets in plasma by analyses of the in vit- www.transfusionsmedizin.uk-erlangen.de Project managers: PD Dr. J. Zingsem, Prof. Dr. ro quality of fresh and stored PLT concentrates. J. Ringwald Head of Division Platelet apheresis processing large blood vol- Clinical research related to Prof. Dr. med. Reinhold Eckstein umes to produce platelet-rich plasma has be- hemostaseology come a standard procedure. A major research Project managers: Prof. Dr. J. Ringwald, Prof. Contact focus is the preparation of extremely white cell- Dr. E. Strasser Prof. Dr. med. Robert Zimmermann poor platelet concentrates making additional Other research interests include thrombophil- Phone: +49 9131 8542110 filtration unnecessary. Apheresis procedures ia, traveller’s thrombosis, and hemostasis dys- Fax: +49 9131 8536973 were developed for producing concentrates functions resulting in bleeding disorders. Other [email protected] with standardized platelet content, but concurrent study objectives are preanalytical deter- taining almost no residual white cells. Anoth- minants of fibrinolysis tests, hemostasis tests in Research Focus er research interest is the evaluation of quality systemic lupus erythematodes, and other cur- •• Preparation and characterization of white control-procedures detecting very low white rently relevant topics. cell-poor platelet concentrates by apheresis cell-contaminations of cellular blood compo- •• Collection of monocytes for the generation nents. Additionally, the influence of different Clinical research related to of dendritic cells (DC) blood bags and of component volumes on the hemotherapy Project managers: Prof. Dr. V. Weisbach, Prof. •• Preparation of dry platelet concentrates and quality of stored platelets is examined. Dr. R. Zimmermann, Prof. Dr. J. Ringwald, Prof. platelet storage in additive solutions Dr. E. Strasser •• Clinical research related to hemostaseology Collection of monocytes for the Other research interests are the examination of •• Clinical research related to hemotherapy generation of dendritic cells (DC) Project manager: Prof. Dr. E. Strasser antibodies against red cell antigens, the char- •• Mesenchymal stromal cells (MSC) Circulating monocytes are precursors of DC acterization of factors influencing the quality of •• Optimization of collection procedures to get which play a key role in the immune system's stored red cell concentrates, and complex dys- regulatory T cells (Tregs) function by presenting antigens to specific functions of the coagulation system. •• Legislation of transfusion lymphocytes. The collection and cultivation •• Platelet-derived growth factors for wound of these cells enables the development of new Mesenchymal stromal cells (MSC) healing and angiogenesis strategies in the treatment of malignant dis- Project managers: Prof. Dr. V. Weisbach, Dr. C. eases. Members of the Division of Transfusion Klein Structure of the Department Medicine and Hemostaseology cooperate with Mesenchymal stromal cells (MSC) are the pre- colleagues from the Department of Dermatolo- decessors of osteoblasts, chondrocytes, and The Division of Transfusion Medicine and He- gy to adjust the collection procedures optimal- adipocytes. The term ”MSC” especially covers mostaseology is located at the Department of ly to the specific clinical and experimental de- cells cultivated and expanded ex vivo. These Surgery of the UK Erlangen. The head of the mands of procedures aimed at the cultivation, cells are a mixture of stem and progenitor cells Division is Extraordinarius for Transfusion Med- expansion, and priming of DC. up to mature stroma cells and are named MSC icine and Hemostaseology. according to a definition of the International The Division produces pharmaceutical prod- Preparation of dry platelet concen- Society of Cellular Therapy. It is excpected that ucts from blood and has a widespread manu- trates and platelet storage in additive MSC will play a major role in future applica- facturing permit from the local and the federal solutions tions of regenerative medicine. The main focus authorities. Project manager: Prof. Dr. J. Ringwald of the working group is the preparation, char- The division offers all laboratory methods in the The preparation of platelet (PLT) concentrates acterization, and expansion of MSC especially fields of immunohematology and hemostase- in additive solutions attracts growing attention from placentar tissues. ology, organizes the depots of blood preserva- since there is the possibility to inactivate path- tions and plasma derivates for the treatment of ogens that contaminate cellular blood compo- Optimization of collection procedures coagulation disorders and the cord blood and nents. Such inactivation procedures presuppose to get regulatory T cells (Tregs) stem cell bank of the UK Erlangen. the reduction of the plasma portion in platelet Project managers: Prof. Dr. E. Strasser, Dr. J. The quality management system of the Divi- concentrates. Clinically, the reduction of the Strobel sion has been certified according to the DIN plasma portion in PLT components may reduce T cells play an important role in adoptive im- EN ISO 9001:2008 standard. Laboratories of the frequency of adverse reactions, e.g. of aller- mune response in many diseases (infectious the Division have been accredited by the Euro- gic reactions. The resuspension of PLT in addi- and inflammatory diseases, tumors). DC act pean Federation for Immunogenetics (EFI) and tive solutions requires the production of ”dry as antigen presenting cells for specific T cells according to the DIN EN ISO 15189 standard platelets” - concentrates containing more than activation. The collection of circulating T cells by the DAkkS. 3000 x 10e+3 per myl. For this purpose, we per- as well as the culture and expansion of T cells,

118 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) especially regulatory T cells (Tregs), enables • Participation in the practical training course the development of new strategies for the an- in surgery; ti-inflammatory and immunosuppressive ther- • Further lectures, seminars, and practical train- apies. Members of the Division of Transfusion ings according to the university calendar; Medicine and Hemostaseology cooperate with • Regular seminars for the Bavarian Medical colleagues from the Departments of Medicine Council; 1, Dermatology, and Medicine 5 of the UK Er- • Teaching at the school for assistant medical langen to optimally adjust the collection proce- technicians; dures to the specific clinical and experimental • Teaching for assistant medical technicians demands of procedures aimed at the cultiva- and nurses. tion and expansion of Tregs. In the context of cell preparation, analysis of factors responsible Selected Publications for cell damage (cell apoptosis and necrosis) is Strasser EF, Weidinger T, Weiss DR, Strobel J, Zimmermann relevant to optimize the quality of leukocyte R, Eckstein R (2011) Storage induced apoptosis of peripheral blood mononuclear cells obtained from leucoreduc- products. tion system chambers. Vox Sang, 101: 106-11 Hauck-Dlimi B, Hammon K, Eckstein R, Ott S, Zimmer- Legislation of transfusion mann R, Dengler T, Ringwald J (2012) Human platelet Project manager: Prof. Dr. R. Zimmermann antigen genotypes in Turkish and Caucasian blood donors Under the auspices of the Legal Counsel and in Germany. Tissue Antigens, 80: 214-8 Deputy Commercial Director of the UK Erlan- Ringwald J, Tully S, Geier C, Hauck B, Weiss D, Callaert M, gen, Dr. A.W. Bender, the Division of Transfu- Eckstein R (2012) Effects of immediate or delayed addition of platelet additive solution on the in vitro quality of sion Medicine and Hemostaseology is involved apheresis platelets. Transfusion, 52: 1237-44 in publications on the legislation and law of Strobel J, Jörns H, Weisbach V, Ganslandt T, Zimmermann blood transfusion in Germany. The focus of R, Eckstein R (2012) Audit on the usage of plasma derived/ the results is the book ”Transfusion Law” that recombinant coagulation factor concentrates at a German university hospital. Vox Sang, 103: 122-9 has been published by the ”Wissenschaftliche Verlagsgesellschaft Stuttgart”. The book has Weiss DR, Eiche C, Hupke C, Schellerer VS, Keller AK, Strasser EF, Ringwald J, Zimmermann R, Eckstein R (2012) become the benchmark in this field of law and The structure of the von Willebrand factor is not altered has found its way into the jurisdiction of the in patients with colorectal carcinoma. Colorectal Dis, 14: German Federal High Court of Justice. Along- 1500-6 side, book contributions and articles on differ- Zimmermann R, Weiss DR, Zingsem J, Ringwald J, Eckstein R (2012) Pooled platelet concentrates and the quality of ent aspects of the legislation and law of blood the red blood cell supply. Clin Lab, 58: 1-6 transfusion are published. International Cooperations Platelet-derived growth factors for Prof. Dr. J. Ringwald, BEST group, International Society of wound healing and angiogenesis Blood Transfusion (ISBT), Amsterdam: The Netherlands Project manager: Prof. Dr. R. Zimmermann Platelets contain growth factors which stimu- Meetings and International Training late wound healing, angiogenesis, and possibly Courses bone repair. Thus, these cells do not only ini- 18.-19.11.2011: Fortbildungsveranstaltung der Bayer- tiate coagulation at sites of injury, but induce ischen Landesärztekammer “Qualifikation als Transfusions- the processes of healing, too. Possible clinical verantwortlicher/Transfusionsbeauftragter”, Erlangen application of these findings is the local appli- 09.-10.11.2012: Fortbildungsveranstaltung der Bayer- cation of concentrated platelets as a source of ischen Landesärztekammer “Qualifikation als Transfusions- verantwortlicher/ Transfusionsbeauftragter”, Erlangen growth factors for wound healing and bone repair. Additionally, the phenomenon of growth factor release from activated platelets to plasma during procedures with extracorporeal circulation is a focus of research.

Teaching

The Division offers lectures, seminars, and practical hands-on training for students: • Participation in the principal subject ”Labora- tory diagnostics” of the German regulation on education in medicine; Stem cell isolation in the GMP laboratory

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 119 UNIVERSITY HOSPITAL

Department of Surgery Division of Trauma Surgery

Address ment of the nationwide quality of medical care Mechanisms for the stabilization of Krankenhausstraße 12 of severly injured patients by improved com- the chondrocyte phenotype 91054 Erlangen munication, better coordinated standards of Project manager: PD Dr. K. Gelse Phone: +49 9131 8533272 medical care, and quality-based cooperation. This project focuses on the mechanisms that in- Fax: +49 9131 8533300 duce chondrogenesis and stabilize the unique www.unfallchirurgie.uni-erlangen.de Research phenotype of articular chondrocytes. The identification of these mechanisms is finally of cen- Head of Division Development and validation of a ce- tral importance for the success of cartilage re- Prof. Dr. med. Friedrich Hennig ramic total knee endoprothesis pair strategies and therapy of osteoarthritis. In Project managers: Prof. Dr. F. Hennig, Dr. A a project funded by the DFG, we investigated Contact Mauerer, Dr. M. Blanke, Dr. A. Olk if the factors Chondromodulin-I (Chm-I) and Prof. Dr. med. Friedrich Hennig This interdisciplinary project focuses on the Thrombospondin-1 (TSP-1) mediate a stabi- Phone: +49 9131 8533272 development and validation of a novel total lizing effect on the chondrocyte phenotype. Fax: +49 9131 8533300 ceramic knee endoprothesis. Long-term load Both factors exerted a strong anti-angiogenic [email protected] capacity and the biomechanical properties are effect in vitro and could prevent inadvertent analyzed under experimental conditions. In excessive endochondral ossification in cartilage Research Focus these experiments, the total ceramic endopro- defects in a cartilage repair model. Both factors •• Development and validation of a ceramic to- thesis could meet the standards of established efficiently inhibited the terminal chondrocyte tal knee endoprothesis metal endoprotheses. Under long-term load- differentiation and thus contributed to the sta- •• Analysis of soft tissue trauma following surgi- ing (alternating load test), the ceramic com- bility of the permanent phenotype of articular cal care of spine injury ponents withstood 30 million load changes chondrocytes. Gene expression studies indica- •• Mechanisms for the stabilization of the chon- und displayed high reserves in the mechanical ted that the observed effects may be mediated drocyte phenotype strength which exceeded by far the required by the cell cycle inhibitor p21cip/waf or by in- •• „Molecular” magnetic resonance (MR) im- hibition of the expression of GADD45ß. Over- safety norms. These results demonstrated the aging of cartilage and joint structures expression of Chm-I did not only efficiently sta- applicability of this ceramic material for the •• Gait and motion analysis bilize the chondrocyte phenotype, but was also broad clinical use. •• Biochemical evaluation of cartilage proper- able to induce chondrogenic differentiation. Further experiments focus on the analysis of ties in the knee joints of young athletes Further gene expression analyses (cDNA ar- the formation of biofilm on the surface of dif- rays) demonstrated that a number of inhibito- ferent materials, such as CoCr and Biolox (ce- Structure of the Department ry factors, such as the BMP-inhibitor Grem-1 ramic). This work is based on microbiological, or FRZB1 and WISP3, are significantly higher semiquantitative, and qualitative electronical The Division of Trauma Surgery employs 15 expressed in permanent articular cartilage as microscopy methods. The aim is the estab- physicians. Beside patient care, clinical and ex- compared to the transient type of cartilage lishment and evaluation of antiseptic surfaces perimental research work is performed togeth- (e.g. osteophyte cartilage). These observations which are appropriate for endoprotheses. er with ten doctoral candidates, one post-doc- imply that the generation of hyaline repair toral scientist, and two technicians. cartilage does not solely rely on chondrogen- Analysis of soft tissue trauma follow- The different research groups work on the ic growth factors, but also on inhibitory-acting ing surgical care of spine injury evaluation and development of novel innova- factors which may particularly be of immanent Project managers: Dr. A. Mauerer, N. Renner, tive surgical methods and implants for joint importance to prevent inadvertent ossification Dr. O. Fuchs replacement and treatment of skeletal lesions. of repair cartilage tissue. Thus, in future thera- This project investigates if minimally invasive Furthermore, the research focuses on basic peutic settings, it would be useful to load bio- operative treatment of spine injuries will in- mechanisms of cartilage and bone biology active matrices with a cocktail of specific stimu- which provides the basis for the development duce less soft tissue trauma than treatment by latory and inhibitory factors for the generation of regenerative strategies for the musculoskele- conventional open surgery. Soft tissue trauma of hyaline repair cartilage and for the inhibition tal system. This also includes imaging and func- is monitored by the peri- and postoperative of excessive ossification. tional non-invasive methods for the analysis of monitoring of a set of laboratory parameters, musculoskeletal tissues. including a broad spectrum of established and “Molecular” magnetic resonance (MR) The central research projects are supported by potential markers, such as certain muscle en- imaging of cartilage and joint struc- approved fundings, including the DFG, Baye- zymes, cytokines, or acute phase proteins. For tures rische Forschungsstiftung, and ELAN. their validation, these laboratory markers are Project managers: PD Dr. G. Welsch, Dr. M. Besides the clinical and experimental research correlated with clinical scores in the further Pachowsky, PD Dr. K. Gelse projects, the Division of Trauma Surgery is postoperative clinical course. Besides evalu- This research project of musculoskeletal mag- closely integrated in the ”Trauma Network” ation of the different surgical strategies, this netic resonance imaging is performed in coop- and is actively involved in its further develop- study aims at the establishment of novel specif- eration with the MR Center of the Department ment. The aim of this network is the improve- ic marker molecules for soft tissue trauma. of Radiology of the Medical University of Vien-

120 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) na and particularly focuses on the evaluation vide the opportunity to increase the safety of Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, Hen- of articular cartilage (repair tissues and osteo- endoprotheses and to avoid injury and overuse. nig FF, Klinger P (2012) Molecular differentiation between osteophytic and articular cartilage - clues for a transient arthritis) as well as other joint tissues, such as and permanent chondrocyte phenotype. Osteoarthritis meniscus and cruciate ligament. Biochemical evaluation of cartilage Cartilage, 20: 162-71 Goal of the present DFG and Austrian Science properties in the knee joints of young Welsch GH, Juras V, Szomolanyi P, Mamisch TC, Baer P, Fund (FWF) grant is to validate novel biochemi- athletes Kronnerwetter C, Blanke M, Fujita H, Trattnig S (2012) Magnetic resonance imaging of the knee at 3 and 7 tes- cal MR-techniques, such as dGEMRIC, T2 map- Project manager: PD Dr. G. Welsch la: a comparison using dedicated multi-channel coils and ping, 23Na(sodium) imaging, T2* mapping, The aim of this study is to assess the biome- optimised 2D and 3D protocols. Eur Radiol, 22: 1852-9 T2d mapping, ultra-short echo-time (UTE) im- chanical behavior of knee cartilage together aging, magnetization transfer contrast (MTC), with clinical scoring and gait analysis. In this diffusion-weighted imaging (DWI), and T1r by prospective and longitudinal study, asymp- conventional histomorphology and ultra high- tomatic young professional athletes were en- field MR-microscopy using two established closed. The knee joints were clinically assessed animal models and to implement the findings as well as 3-Tesla-MRI was performed based on into clinical MR-follow-up protocols. In experi- biochemical and biomechanical MRI-applica- mental models, healthy articular cartilage was tions. Measurements also included loading and either compared with degenerated articular unloading as well as gait analyses. The results cartilage or with cartilage repair tissues induced will be implemented in the orthopedic medical by the microfracture technique or autologous care and individual training methods of these chondrocyte transplantation. Additionally, bi- young athletes. Furthermore, senso-motoric ochemical MR methods will be used to assess training is performed with the goal of reducing the associated joint structures, including the injuries and helping to prevent early degener- menisci and anterior cruciate ligament, in a ative problems. multi-parametric approach. The aim is to non-invasively attain detailed in- Teaching formation on the composition of articular cartilage that closely correlates with histology. Thus, The comprehensive education comprises the modern MR-imaging is supposed to acquire a traditional main lecture and the curricular prac- high diagnostic predictive value for the analysis tical courses and additional integrated practical of cartilage tissue. seminars, such as sewing courses and implant So far, ”molecular” MR-imaging allowed ade- workshops, as well as colloquia focusing on in- quate characterization of the ultrastructure of terdisciplinary subjects. Interactive courses are cartilage and cartilaginous repair tissue with also provided as an intensive training for final visualization of the content of proteoglycans, exams. Furthermore, the division offers the op- the alignment of collagen fibres, the hydration portunity to participate in clinical rounds and status of cartilage as well as remodeling pro- observe in emergency wards and operation cesses of repair tissues. rooms. Ongoing studies will assess the correlation to clinical parameters after cartilage therapies Selected Publications with the goal to get a high predictive value Gelse K, Klinger P, Koch M, Surmann-Schmitt C, von der reflecting the potential long-term benefit even Mark K, Swoboda B, Hennig FF, Gusinde J (2011) Throm- bospondin-1 prevents excessive ossification in cartilage after a short term follow-up time period. repair tissue induced by osteogenic protein-1. Tissue Eng Part A, 17: 2101-12 Gait and motion analysis Klinger P, Surmann-Schmitt C, Brem M, Swoboda B, Dis- Project managers: Prof. Dr. F. Hennig, Dr. M. tler J, Carl HD, von der Mark K, Hennig FF, Gelse K (2011) Chondromodulin 1 stabilizes the chondrocyte phenotype Blanke, Dr. S. Krinner, PD Dr. G. Welsch and inhibits endochondral ossification of porcine cartilage The aim of this research group is to identify repair tissue. Arthritis Rheum, 63: 2721-31 the biomechanical forces that interact with the Welsch GH, Apprich S, Zbyn S, Mamisch TC, Mlynarik V, human musculoskeletal system of athletes and Scheffler K, Bieri O, Trattnig S (2011) Biochemical (T2, T2* and magnetisation transfer ratio) MRI of knee cartilage: patients with endoprotheses. Dynamic forces feasibility at ultra-high field (7T) compared with high field are not only associated with high strain for the (3T) strength. Eur Radiol, 21: 1136-43 musculoskeletal system, but also set require- Welsch GH, Mamisch TC, Zak L, Mauerer A, Apprich S, ments for components of endoprotheses. The Stelzeneder D, Marlovits S, Trattnig S (2011) Morphologi- cal and biochemical T2 evaluation of cartilage repair tissue biomechanical analysis of these dynamic strains based on a hybrid double echo at steady state (DESS-T2d) and their integration into proper situations pro- approach. J Magn Reson Imaging, 34: 895-903

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 121 UNIVERSITY HOSPITAL

Department of Urology Chair of Urology

Address able prognostic biomarkers depend upon the common patients. Currently open clinical trials Krankenhausstraße 12 molecular characterization of rather large co- mainly focus on new therapeutic options for 91054 Erlangen horts of tissue samples, since the currently used patients with kidney cancer or prostate cancer: Phone: +49 9131 8533683 morphologic criteria only poorly reflect the Registry for advanced kidney cancer, Fax: +49 9131 8534851 progression behavior of one patient’s specific Registry STAR - TOR, www.urologie.uk-erlangen.de tumor. To facilitate this research, the collec- RCC Switch Study, tion of tissue samples originating from tumors Randomized phase III first line trial to evaluate Head of Department and corresponding non-tumor tissue as well efficacy and safety of sequenced therapy su- Prof. Dr. med. Bernd Wullich as blood, serum, and various body fluids, e.g. nitinib/sorafenib versus sorafenib/sunitinib in urine, is of vital importance for translational metastatic kidneys, Contact research projects. A high quality tissue sample RCC Switch 2 Study, Prof. Dr. rer. nat. Helge Taubert repository demands a standardized logistics for PD-1 CA209-025, Phone: +49 9131 8523373 the sample transportation from the operating Principal Study, Fax: +49 9131 8523374 theater to the Institute of Pathology, as well as Everpro Study, [email protected] the careful and standardized preparation of the Protect VEG113387, sample carried out by an experienced pathol- marC-2 Everolimus Study, Research Focus ogist. In close cooperation with the local Insti- Flipper Study, •• Establishment of an annotated tumor tissue tute of Pathology, a repository of urologic tissue Proselica EFC11785, repository containing urologic tumors samples will be established in which tissue sam- Firstana EFC11784, •• Systemic tumor therapy, clinical trials ples of all surgically treated malignant urologic QoLiTime, •• MRI-guided needle biopsy for the diagnosis tumors are introduced. This tissue repository is JASiMA Study. of prostate carcinoma part of the CCC biobank. For the establishment Information about open or closed clinical trials •• The role of hypoxia and hypoxia-associated of the required Standard Operating Procedures can be found at the homepage of the urologi- signal transduction pathways in solid tumors (SOPs), we have established a close cooper- cal trial registry. •• Tumor genetic research with focus on identi- ation with the German Prostate Carcinoma fication of biomarkers Consortium (DPKK) e.V. and could furthermore MRI-guided needle biopsy for the introduce a web-based tissue database system diagnosis of prostate carcinoma Structure of the Department that relies on the hospital’s established clini- Project manager: Prof. Dr. D. Engehausen cal information system. All incorporated pro- The magnetic resonance imaging (MRI)-guid- UK Erlangen: cedures are consistent with the legal, ethical, ed biopsy technique is a novel procedure for - Outpatients’ Clinic and pediatric urology technical, and organisatoy regulations of tissue the generation of diagnostic evidence in the - Adult renal transplantation unit in coopera- repositories and databases (patients’ informed case of a suspected prostate carcinoma. This tion with the Department of Medicine 4 (Prof. consent, data security, SOPs, and quality man- procedure unites the sophisticated MRI vis- Dr. K.-U. Eckardt) agement). Our tissue database system is part ualization and the guided extraction of pros- - Pediatric renal transplantation unit in coop- of the Central Research Infrastructure for Mo- tate biopsy samples. It is a newly developed eration with the Department of Pediatrics and lecular Pathology (CRIP). CRIP is a supervising interdisciplinary technique that incorporates Adolescent Medicine (Prof. Dr. Dr. h.c. W. Ra- system for the distribution of tissue samples a radiologist (visualization of the target area) scher) hosted by the Institute of Biomedical Technol- and an urologist (targeting the biopsy needle - Uro-oncological outpatients’ unit for systemic ogy (IBMT) of the Fraunhofer-Gesellschaft e.V. and extraction of the sample), with the patient drug therapy (AURONTE) in cooperation with lying comfortable. Two biopsy samples from the Department of Medicine 5 (Prof. Dr. A. Systemic tumor therapy, clinical trials every suspect areal and one reference sam- Mackensen). Project manager: PD Dr. P. J. Goebell ple are extracted, each with visual control of Waldkrankenhaus St. Marien gGmbH: The medical care and treatment of patients the biopsy needle. This procedure is intend- - Adult urology (inpatients’ department), private with uro-oncologic diseases represents an in- ed for patients with persistent suspect for insurance patients (outpatients’ department) tegral part of our urologic expertise. Systemic prostate carcinoma after negative transrectal - Trial documentation center. therapy forms, besides the provision of surgical ultrasound (TRUS)-biopsy and shows a very treatment, are among the fundamental sour- high detection rate in this cohort with 40%, Research ces of competence in urology. For this purpose, in a subcohort of patients even with 60%. the outpatient center for uro-oncologic disea- This procedure which is constantly improved Establishment of an annotated tumor ses (AURONTE) was founded together with the is available in only a few centers worldwide tissue repository containing urologic Department of Urology and the Department of (at this time four, including Erlangen) and tumors Medicine 5 to draw therapeutic decisions based requires the interdisciplinary cooperation be- Project manager: Prof. Dr. B. Wullich on a common interdisciplinary conference. tween urologists and radiologists. Before con- New insights into the occurrence of malignant Thus, it can be assured that all currently acti- ducting this type of examination, the modali- tumors and the identification of new and reli- vated and planned clinical trails are open to all ties of payment should be clarified. Presently,

122 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) the total cost of about 1,350 Euro according Teaching Burger M, Goebell PJ (2012) Bladder cancer: Validity of the 2004 system for grading Ta bladder cancer. Nat Rev to the medical fee schedule are not approved Urol, 9: 126-7 by the statutory health insurances. Medical students are taught in the lecture series Kunath F, Keck B, Antes G, Wullich B, Meerpohl JJ (2012) of emergency medicine and specialized urolo- Tamoxifen for the management of breast events induced The role of hypoxia and hypoxia-asso- gical lectures. Students also conduct a practi- by non-steroidal antiandrogens in patients with prostate cancer: a systematic review. BMC Med, 10: 96 ciated signal transduction pathways in cal course in the Department of Urology or one solid tumors of the associated teaching hospitals. The De- Wach S, Nolte E, Szczyrba J, Stöhr R, Hartmann A, Ørntoft T, Dyrskjøt L, Eltze E, Wieland W, Keck B, Ekici AB, Grässer Project manager: Prof. Dr. H. Taubert partment also allows additional education for F, Wullich B (2012) MicroRNA profiles of prostate carcino- The lack of oxygen (hypoxia) is a situation achievement of the title medical specialist for ma detected by multiplatform microRNA screening. Int J Cancer, 130: 611-21 seen in many solid tumors. Especially locally urology. Additionally, specialized training cours- Keck B, Wach S, Kunath F, Bertz S, Taubert H, Lehmann J, advanced malignancies rapidly outgrow the es are offered for the fields of andrology and Stöckle M, Wullich B, Hartmann A (2013) Nuclear E-cad- blood vessels that supported their growth. systemic drug tumor therapy. For acquisition herin expression is associated with the loss of membra- By this, tumor cells are confronted with a lack and improvement of specialized surgical tech- nous E-cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder. Ann of oxygen and nutrition. As a consequence, niques, the Department of Urology uses patient Surg Oncol, 20(7):2440 more than 70 genes are activated by the HIF- simulators. These include models for practicing 1 transcription factor. Signal molecules are sterile placement of catheters or laparoscopic International Cooperations produced that stimulate the growth of new methods for minimally invasive surgery. In ad- Prof. Dr. G. Yousef, Keenan Research Center, St. Michael’s blood vessels, enzymes are produced that dition, practica for basic and advanced tech- Hospital, Research Center, Toronto: Canada support a survival of cells under hypoxic con- niques in molecular urology are offered. Prof. Dr. T. Ørntoft, Department of Molecular Medicine, Århus University Hospital, Århus: Denmark ditions, and stem cell-associated genes are Selected Publications Dr. P.J. Goebell, International Bladder Cancer Network expressed. We are mainly interested in the (IBCN), Barcelona: Spain regulation of miRNA genes by HIF-1. Because Keller A, Leidinger P, Bauer A, Elsharawy A, Haas J, miRNAs themselves regulate numerous target Backes C, Wendschlag A, Giese N, Tjaden C, Ott K, Werner J, Hackert T, Ruprecht K, Huwer H, Huebers J, Jacobs G, Meetings and International Training genes, it is obvious that hypoxia has a vital in- Rosenstiel P, Dommisch H, Schaefer A, Müller-Quernheim Courses J, Wullich B, Keck B, Graf N, Reichrath J, Vogel B, Nebel A, fluence on any cell. Using cell culture models 17.-19.11.2011: 3. Symposium Urologische Forschung Jager SU, Staehler P, Amarantos I, Boisguerin V, Staehler C, der Deutschen Gesellschaft für Urologie, Jena we examine the functional consequences of Beier M, Scheffler M, Büchler MW, Wischhusen J, Haeusler hypoxia on tumor cells. SF, Dietl J, Hofmann S, Lenhof HP, Schreiber S, Katus HA, Rottbauer W, Meder B, Hoheisel JD, Franke A, Meese E (2011) Toward the blood-borne miRNome of human dis- Tumor genetic research with focus on eases. Nat Methods, 8: 841-3 identification of biomarkers Szczyrba J, Nolte E, Wach S, Kremmer E, Stöhr R, Hart- Project manager: Dr. S. Wach mann A, Wieland W, Wullich B, Grässer FA (2011) Down- The identification and characterization of regulation of Sec23A protein by miRNA-375 in prostate carcinoma. Mol Cancer Res, 9: 791-800 specific biological properties of the prostate carcinoma as well as other malignant tumors, like kidney carcinoma, is the main focus of the biological research projects. By assessing changes in microRNA (miRNA) expression profiles, it is already possible to distinguish between samples of tumor and non-malignant tissue. Furthermore, the prognostic value of miRNA expression profiles is currently examined. MiRNAs directly regulate the expression of numerous other proteins in cells. Therefore, experimental methods for analyzing protein expression are a vital component of our research. The complete spectrum of molecular cytogenetic techniques, including fluorescence in situ DNA and RNA hybridization, is established in the laboratory. The quantification of miRNA and gene expression as well as the determination of gene copy numbers using real time PCR approaches are a central part of the experimental methods. MiRNA Microarray expression data: Differences between tumor and corresponding non-malignant tissue.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 123 UNIVERSITY HOSPITAL

Department of Operative Dentistry and Periodontology Chair of Dental, Oral, and Maxillofacial Medicine - especially Operative Dentistry, Periodontology, and Pediatric Dentistry

Address Research Effects of aging on one-step self-etch Glückstraße 11 adhesives 91054 Erlangen Strategies avoiding chipping fractures Project manager: Dr. M. Taschner Phone: +49 9131 8533632 on zirconia-based frameworks The simplification of adhesive bonding systems Fax: +49 9131 8533603 Project manager: PD Dr. U. Lohbauer are getting more and more advertence in ad- www.zahnerhaltung.uk-erlangen.de Thermal mismatch between veneer and zirco- hesive dentistry. Especially reducing the tech- nia core, substructure, surface conditions, and nique-sensitivity and developing less time-con- Head of Department cooling rate will dictate the load to fracture, suming products is playing a major role today. Prof. Dr. med. dent. Anselm Petschelt fracture mode, and reliability of zirconia-based As part of a grant, the influence of different den- all-ceramic crowns. tin pretreatment-protocols as well as the influ- Contact The purpose of this study was to identify the ence of different aging methods on the adhesive PD Dr.-Ing. Ulrich Lohbauer factors involved in zirconia crown delamina- interface between tooth-structure and adhesive Phone: +49 9131 8543740 tions via fatigue testing in sliding-motion step- systems were evaluated by tensile tests (bond Fax: +49 9131 8533603 stress fatigue and fractrography analysis and strength) and optical evaluation (nanoleakage). [email protected] the interaction between them. Zirconia-based all-ceramic single crowns were HAp nanoparticles as reinforcing fillers Research Focus fabricated using a zirconium-oxide substruc- for dental adhesives Project manager: Dr. A. Wagner •• Strategies avoiding chipping fractures on zir- ture and two veneer ceramics with different In collaboration with the University of Jena, we conia-based frameworks coefficients of thermal expansion in order to evaluated the effect of adding HAp nanofillers •• Study on direct cusp restoration with plastic result in groups with high and low thermal mis- resin composites in the load bearing poste- without or with surface modification by silani- match between veneer and core ceramic. Ve- rior region zation into the adhesive resin of a dental adhe- neer ceramics were sintered onto the zirconia •• Effects of aging on one-step self-etch adhesive (Adper Scotchbond Multi-Purpose (SBMP), substructures as sintered or after being sand- sives 3M ESPE) on dentin bond strength. blasted. The cooling process was set at a fast •• HAp nanoparticles as reinforcing fillers for HAp nanoparticles (20-70 nm) were prepared or slow cooling rate. Specimens of each group dental adhesives either by biomimetic growth or by hydro- were fractured in a single load-to-fracture com- •• Wear analysis of prophylaxis tools on tooth thermal processes and incorporated into the pression. Further specimens are submitted to a and filling surfaces adhesive of the SBMP system in 0.2/1/5/10% sliding-motion step-stress fatigue in a chewing •• The proficiency of nanosized silica fillers in (wt/vol). Control (unfilled) and experimental simulator. Fracture patterns were fractographi- self-etch dental adhesives groups (filled) were applied onto flat mid-coro- cally recorded (funded by Forschungsgemein- •• Prospective clinical study on glassionomerce- nal human dentin and composite crowns were schaft Dental, FG Dental). ments using the A.R.T.-technique built-up. The teeth were cut into beams, frac- •• Antimicrobial dental products with silver tured in tension, and examined with a scanning Study on direct cusp restoration with technology electron microscope (SEM) for fractographic plastic resin composites in the load analysis. µTBS to dentin changed depending Structure of the Department bearing posterior region on the fillers and the concentration used. A Project manager: PD Dr. U. Lohbauer significant increase of the mechanical strength The Department of Operative Dentistry and Within the last decade, the longevity of den- was obtained for 1% (wt/vol) biomimetic and Periodontology employs 56 staff members, tal composite fillings could be significantly im- 5% hydrothermal, silanized HAp particles while thereof six professors and associate professors, proved so that one could think of extending the other particle fractions used did not influ- 14 assistant professors, 21 dental nurses, and the use to the posterior region. The advantages ence µTBS significantly. At high concentrations four dental technicians. The Department of of using resin composites over metal or ceramic (10%), nanofiller incorporation had a negative Operative Dentistry and Periodontology fur- restorations are the preservation of natural den- effect on bond strength irrespective of the par- ther hosts a research laboratory with eleven tal tissue, the minimally invasive application of ticle fraction used. research associates (four by external funding). the materials, the simplicity of this onsite treat- Analysis of nanofiller distribution by transmis- The research is generally conducted by three ment, and the reduced costs involved. sion electron microscopy revealed nanoparticle clinically oriented work groups as well as one The study examined the usability of resin com- dispersion through the adhesive layer, but no dental materials, pre-clinically oriented work posites for the use in load bearing applications deposition on or penetration into the hybrid group. Eight post-doctoral researchers, 55 den- in the posterior region. layer. tal post-graduate and graduate students, and The expected results should define the min- five technical assistants are in charge of the imum requirements for the use of composite Wear analysis of prophylaxis tools on manifold research activities in the lab section. materials, allow for appropriate preparation tooth and filling surfaces The main focus is on dental materials research guidelines, and should provide a perspective Project manager: Prof. Dr. M. Pelka with fields of expertise in basic science of op- on the clinical durability of restored cusps in the Removal of supragingival and subgingival erative and periodontal treatment procedures posterior region. The results of this study will plaque and staining is crucial for maintenance and correlation of experimental findings with be incorporated into the teaching and prac- of gingival and periodontal health. Dental clinical outcome. Independent, pre-clinical as- tical training at the Department of Operative care personnel usually remove supragingival sessment of dental materials is a further area of Dentistry and Periodontology (founded by the stain and plaque by means of methods such interest of the lab section. ELAN-programm of the Faculty of Medicine). as scaling, polishing with rubber cups, and

124 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) using polishing paste. Air-polishing devices creased temperature and integrates the tooth Selected Publications (APD) have come into increased use for easy, component hydroxylapatite into the material. Belli R, Rahiotis C, Schubert EW, Baratieri LN, Petschelt A, fast, and complete removal of supragingival In the course of a prospective clinical study in Lohbauer U (2011) Wear and morphology of infiltrated stain and plaque. Air-polishing systems are close cooperation with our partner university white spot lesions. J Dent, 39: 376-85 widely used for effective removal of stain- in Joinville/Brazil, this innovative glass iono- Lohbauer U, Krämer N, Siedschlag G, Schubert EW, Lau- ing. APDs can remove plaque, but leave the mer cement is examined in comparison to the erer B, Müller FA, Petschelt A, Ebert J (2011) Strength and wear resistance of a dental glass-ionomer cement with a exposed surfaces rougher than before treat- ”gold standard” Fuji IX in proximal defects novel nanofilled resin coating. Am J Dent, 24: 124-8 ment. In vitro test methods were established within deciduous teeth using the ”Atraumatic Belli R, Monteiro S, Baratieri LN, Katte H, Petschelt A, to test the abrasive potential of APDs, pol- restauration technique” (A.R.T.). The treatment Lohbauer U (2012) A photoelastic assessment of residual ishing pastes, and dental prophylaxis instru- phase of this study took place in spring 2009. stresses in zirconia-veneer crowns. J Dent Res, 91: 316-20 ments. The results of these studies showed Evaluations were undertaken after six months, Schwarz S, Lohbauer U, Petschelt A, Pelka M (2012) Ver- that the grain size and the chemical composi- one year, and two and three years. At the mo- tical root fractures in crowned teeth: A report of 32 cases. Quintessence Int, 43: 37-43 tion of the air flow powder have major influ- ment, data are analyzed and an ex-vivo model ence on the amount of wear of the tooth or analysis is carried out. Taschner M, Krämer N, Lohbauer U, Pelka M, Breschi L, filling surfaces. It could be shown that even Petschelt A, Frankenberger R (2012) Leucite-reinforced glass ceramic inlays luted with self-adhesive resin cement: low abrasive substances influence the surface Antimicrobial dental products with A 2-year in vivo study. Dent Mater, 28: 535-40 roughness and maybe the subsequent plaque silver technology Zorzin J, Petschelt A, Ebert J, Lohbauer U (2012) pH accumulation. Project managers: Prof. Dr. A. Petschelt, Dr. J. neutralization and influence on mechanical strength in Zorzin self-adhesive resin luting agents. Dent Mater, 28: 672-9 The proficiency of nanosized silica fill- On restorative materials, adhering biofilms can ers in self-etch dental adhesives cause secondary caries. The objective of this co- International Cooperations Project manager: PD Dr. U. Lohbauer operative project of the Department of Opera- Prof. G. Eliades, University of Athens (UOA), Athens: This study is probing the proficiency of com- tive Dentistry and Periodontology with the De- Greece mercial available nanoscaled silica particles as partment of Dental Prosthetics of the University Dr. S. Scherrer, University of Geneva, Geneva: Switzerland fillers in self-etch adhesives in terms of mechan- Hospital of Regensburg and the company Bio- Prof. P.F. Cesar, University of Sao Paulo (USP), Sao Paulo: ical properties and usability. Gate AG is the development of dental materials Brazil Experimental self-etch adhesives were filled with silver technology based on antimicrobial Prof. R. Braga, University of Sao Paulo (USP), Sao Paulo: with nanoparticles in the concentration of 5, properties. The subproject at the Department of Brazil 10, 15, and 20 percent by weight and tested Operative Dentistry and Periodontology focuses Prof. L.N. Baratieri, University of Santa Catarina, Florian- subsequently. A microtensile test on bovine opolis: Brazil on the production, exploration of the impact, teeth revealed the toughening effect of the and effectiveness of antimicrobial dental adhe- Prof. E.W. Schubert, University of Joinville (Univille), Join- particles: Bond strengths doubled up to 10 ville: Brazil sives and filling materials. It is funded by the percent by weight as compared to the unfilled support program "Leitprojekte Medizintechnik" Prof. J. Powers, University of Texas, Houston: USA adhesive and stayed on the same level when (Bayerisches Staatsministerium für Wirtschaft, filler concentration was further increased. SEM Infrastruktur, Verkehr und Technologie). imaging of the crack plain indicated that the resin tags broke outside of the dentin tubules. The viscosity of the adhesives increased with Teaching increasing filler concentration. For more than 10 percent by weight filler, the adhesives can The main lectures of the Department of Op- be considered as too viscous to perform prop- erative Dentistry and Periodontology focus on erly in clinical applications. Imaging via Confo- basic science in operative dentistry and peri- cal Laser Scanning Microscopy confirmed that odontology as well as on endodontology and despite of the increased viscosity, penetration pediatric dentistry. In the specific lectures, the behavior into dentin was comparable for filled most recent international scientific opinions and unfilled adhesives. Additionally, filler in- and trends are embedded and controversially corporation prohibited swelling during water discussed, resorting to own measured data and uptake. scientific outcome of the dental materials lab. Therefore, it can be concluded that nanosized Besides the conventional lectures, the den- silica particles can be used as reinforcing filler tal education is highly practically oriented. particles for self-etch adhesives up to a certain Therefore, the Department of Operative concentration which was found to be 10 per- Dentistry and Periodontology has estab- cent by weight in this study. lished practical blockseminars in the graduate courses teaching endodontic treatment strat- Prospective clinical study on glassiono- egies (seventh term) and indirect inlay manu- mercements using the A.R.T.-technique facturing skills (tenth term). Students as well Project manager: Dr. J. Ebert as doctoral students are required to report in Glass carbomer cement is taking advantage of special seminars on recent scientific trends in the improvement of mechanical values by in- restorative dentistry.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 125 UNIVERSITY HOSPITAL

Department of Orthodontics and Orofacial Orthopedics Chair of Dental, Oral, and Maxillofacial Medicine – especially Orofacial Orthopedics

Address bies and small children with cleft lip palates Erlangen 3D-model analysis for cleft Glückstraße 11 and syndrome malformation, children and lip and palate newborn - long term 91054 Erlangen adolescents with various tooth misalignments documentation Phone: +49 9131 8533643 and jaw malpositions, also including cranio- Due to the long term and interdisciplinary Fax: +49 9131 8532055 facial malformation, and adults with tooth treatment of CLP patients, it is one of the main www.kieferorthopaedie.uk-erlangen.de misalignment and complex interdisciplinary goals to establish a consistent and well-ar- problems. We offer an extensive spectrum of ranged documentation. The treatment with Head of Department international accepted therapy-concepts and presurgical orthopedic appliances in Erlangen Prof. Dr. med. dent. Ursula Hirschfelder modern appliances for the respective age takes place in four week intervals until surgical groups. palate closure. During this time, plaster models Contact The Department of Orthodontics and Orofacial are made at four defined dates within the first Dr. med. dent. Klaus Hertrich Orthopedics is authoritatively involved in the year and later once yearly. Phone: +49 9131 8536779 Interdisciplinary Center of Cleft Lip and Palate Based on our two dimensional analysis of max- Fax: +49 9131 8532055 of the FAU. In this interdisciplinary center, ther- illary models, a simple and clinically applicable [email protected] apy concepts are continuously updated and minimal documentation analysis for linear and initiated by the team. angular measurements on digitized models Research Focus was developed (company 3D-Shape, GmbH). •• 3D-CT evaluation of the asymmetry index by Research The Erlangen 3D-Model analysis can be ap- Katsumata/Maeda plied routinely, precisely, and clinically prac- •• The applicability of the Frankfurt horizontal 3D-CT evaluation of the asymmetry ticable for three-dimensional documentation as reference plane in CT-scans index by Katsumata/Maeda of changes in growth or treatment. It offers a •• Three dimensional efficiency evaluation of So far, skeletal and facial asymmetries were qualification for standardized documentation aligner treatment difficult to locate in the orthodontic diagnosis and data management. •• Erlangen 3D-model analysis for cleft lip and by using cephalograms (lateral and frontal) be- palate newborn - long term documentation cause of structural superimpositions. Face Scan - Stereophotogrammetry •• Face Scan - Stereophotogrammetry With CT-scans and the use of the CT-software In the field of facial soft tissue diagnostics, our •• Material scientific investigations Voxim®, the significance of the asymmetry in- present focus is on the indirect digital measure- •• Investigation of the reproducibility of skeletal dex by Katsumata/Maeda was evaluated. ment of these structures with three-dimension- maxillary landmarks in CT-scans al photographs (”3D-stereophotogrammetry”, •• MSCT and CBCT comparison - an in vitro The applicability of the Frankfurt hori- Face Scan 3D, company 3D-Shape GmbH) and study zontal as reference plane in CT-scans the comparison of these new diagnostic pro- The Frankfurt horizontal (FH) was already pre- cedures with conventional two-dimensional Structure of the Department ferred by anthropologists to standardize anthro- photography. Clinical relevance is given par- pologic-anatomic measurements on the skull in ticularly for therapy planning of malocclusions The Chair of Dental, Oral, and Maxillofacial Med- the 19th century. The cephalogram-analysis is and craniofacial anomalies. icine - especially Orofacial Orthopedics is inte- based on the orientation of the head according grated in the department of dentistry with regu- to the Frankfurt horizontal during the scan. Material scientific investigations lar, biennial rotation of the head of department. The applicability of a constructed coordi- In order to minimize bracket failure rates during Altogether, 23 employees are working in the nate-reference system using the FH in CT-scans orthodontic treatment, this study investigated Department of Orthodontics and Orofacial Or- of skeletal asymmetries is to be evaluated. the bond strength of orthodontic brackets on thopedics. The research is carried out by ten enamel (n = 500 extracted teeth) using differ- scientists and 18 postgraduates. Technical as- Three dimensional efficiency evalua- ent bonding materials. The influence of differ- sistants are not available. tion of aligner treatment ent polymerization devices (LED light-emitting The prime alignment of our research is the Aim of this study was to demonstrate aligner diode, QTH quartz-tungsten-halogen) and po- 3D-evaluation of dentofacial anomalies with efficiency with Durancasts of the Clear Aligner lymerization times were tested. development of practical 3D-analysis methods. System for orthodontic treatment. There are internal and external university coop- The treatment outcome of an adult patient with Investigation of the reproducibility erations concerning this research focus. upper frontal crowding by using three-dimen- of skeletal maxillary landmarks in CT- Other research projects have their focus on sional superimposition of digitized plaster casts scans morphology orientated and interdisciplinary (initial, intermediate, set up, and treatment The skeletal landmarks anterior and posterior themes involving several disciplines of dentistry outcome) was evaluated with the software nasal spine are showing a high morphological and medicine. Onyx Ceph™ after scanning the models with variability. The clinical main emphasis is the orthodontic the smart optics 3D-Scanner and the activity Aim of the study was to verify the reproducibil- treatment of patients of all age groups: ba- 201 software (company 3D-Shape, GmbH). ity of these and other cephalometric maxillary

126 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) landmarks in CT-scans in the x-y-z-axis (trans- Steinhäuser-Andresen S, Detterbeck A, Funk C, Krumm M, mining material heterogeneities and corrosive potential. J Kasperl S, Holst A, Hirschfelder U (2011) Pilot study on Appl Oral Sci, 20: 478-85 verse, sagittal, and vertical). For this study, the accuracy and dimensional stability of impression materi- Strobel-Schwarthoff K, Hirschfelder U, Hofmann E (2012) CT-examination software Voxim® was applied. als using industrial CT technology. J Orofac Orthop, 72: Individualized Erlanger KS-Impression Trays for Infants 111-24 With Cleft Lip and Palate. Cleft Palate Craniofac J, 49: MSCT and CBCT comparison - an in Hanke S, Hirschfelder U, Keller T, Hofmann E (2012) 3D CT 237-9 based rating of unilateral impacted canines. J Craniomax- Hofmann E, Medelnik J, Fink M, Lell M, Hirschfelder U vitro study illofac Surg, 40: e268-76 The aim of this study was to analyze the im- (2013) Three-dimensional volume tomographic study Holst AI, Holst S, Hirschfelder U, Seckendorff VV (2012) of the imaging accuracy of impacted teeth: MSCT and aging accuracy of CBCT data sets compared Retrieval analysis of different orthodontic brackets: the CBCT comparison--an in vitro study. Eur J Orthod, 35: with MSCT data sets in determining the ex- applicability of electron microprobe techniques for deter- 286-294 act mesio-distal width of unerupted porcine tooth germs and to compare the radiologi- cally obtained results of width measurements with the actual mesio-distal dimension of the tooth germs. In MSCT and CBCT data sets, the largest diameter of 24 tooth germs was determined with the aid of the mesial and distal contact points. The reference method used was mesio-distal width measurement using sliding callipers after the tooth germs had been oste- otomized.

Teaching

E-learning platform: Seminar on orthodontic technique The e-learning platform serves as a complementary support for students of dentistry and A structured-light 3D scan showing soft tissue landmarks Development of a CT-based 3D cephalometric analysis goes along with the laboratory processes for on a subject’s face. preparing stereometric measurements in orthodontics. the production of orthodontic appliances. Vid- eo clips allow individual repetition of dental laboratory technology. Further development and integration, supported by ‘Virtuelle Hoch- schule Bayern (vhb)’, shall be conducted in order to facilitate the basic orthodontic seminars in elementary theory and practice. E-learning platform: Interactive virtual orthodontic case studies The further development of this platform will establish online tests as a self-control option to intensively prepare for exams and improve knowledge in orthodontic case management. The interactive virtual orthodontic case studies are examples for orthodontic analysis, diagnosis, and treatment planning. The system offers options to add further cases by the supervisors. As additional benefit, all examples can be shared by other universities, supported by ‘Vir- tuelle Hochschule Bayern (vhb)’.

Selected Publications Medelnik J, Hertrich K, Steinhäuser-Andresen S, Hirschfelder U, Hofmann E (2011) Accuracy of anatomical landmark identification using different CBCT- and MSCT- Lateral view of the 3D illustration of the image-based CT coordinate system in Voxim® 6.1. The permanent dentition is based 3D images: an in vitro study. J Orofac Orthop, 72: colored blue and the impacted canine red. The illustration shows the reference landmarks, the canine axis (A13-S13), 261-78 and the y- and z-axis with the different reference planes: sagittal (y-z) plane, axial, and coronal plane (x-z).

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 127 UNIVERSITY HOSPITAL

Department of Prosthodontics Chair of Dental, Oral, and Maxillofacial Medicine - especially Prosthetic Dentistry

Address factor for treatment success in that context. The aim of the research group is to estab- Glückstraße 11 However, until now bone quality could only be lish and evaluate full-field three-dimensional 91054 Erlangen roughly estimated by radiographic means or (3D) optical inspection systems for clinical Phone: +49 9131 8533604 by subjective hand feeling during implant site application in biomechanic research. The Fax: +49 9131 8536781 preparation. In order to close this diagnostic system will allow real time quantitative de- www.prothetik.uk-erlangen.de gap, principles of hardness testing as applied in piction of biomechanical influences in the dental materials science have been adapted to oral cavity. 3D-image correlation provides Head of Department fit the situation of an implant surgery. strain measurements in all dimensions which Prof. Dr. med. dent. Manfred Wichmann The resulting diagnostic tool ”BoneProbe” will are critical for accurate strain and loading re- allow surgeons to objectively quantify bone sponse measurements in objects. The results Contact quality during implant surgery by means of of these optical measurements are compati- Claudia Ehrhardt a compressive test and thus enable them to ble with finite element analysis software and Phone: +49 9131 8533604 choose the best surgical protocol, the adequate facilitate verificationand iteration of models Fax: +49 9131 8536781 implant geometry as well as to optimize the that cannot be used solely to draw general [email protected] loading protocol. conclusions regarding specific questions re- Following thorough computer simulations, lated to biomechanics. The system available Research Focus prototypes of the BoneProbe were manufac- in the Department of Prosthodontics uses •• Dental biomechanics tured and tested in bone surrogate materials as photogrammetric principles. Relevant pa- •• Psychogenic influence/quality of life and com- well as in bones. Based on the results obtained, rameters for future in vivo applications were plementary medical procedures in dental application of the BoneProbe in regular pa- identified in current and completed studies, questions tients seems to be realistic. Preliminary trials in and first invivo applications revealed prom- •• Optical 3D-measurement technique in den- an animal model showed that the application ising results. tistry of the BoneProbe did not jeopardize osseointe- •• CAD/CAM research laboratories gration of the implants. CAD/CAM research laboratories With bone quality constituting an important Project managers: Prof. Dr. S. Holst, PD Dr. M. Structure of the Department factor also in orthopedics and traumatology, Karl, PD Dr. J. Schmitt future application of the BoneProbe in these Industrial CAD/CAM manufacturing technol- The Department of Prosthodontics is respon- areas is currently evaluated. ogies have gained significant market share in sible for teaching undergraduate students in producing dental restorations in recent years, several areas of fixed and removable prostho- Psychogenic influence/quality of life primarily due to standardized product quali- dontics, dental laboratory technology, occlu- and complementary medical proce- ty and precision as well as economic process- sion and TMJ dysfunction, dental implants, dures in dental questions ing routine in dental laboratories. To achieve CAD/CAM technology and ceramics, as well as Project manager: Prof. Dr. S. Eitner high quality and precision, product aligned maxillofacial prosthodontics. The Department This area of research is divided in two main fo- process routes are a mandatory prerequisite. is staffed with 20 full-time academics with a cal points. The first focal point evaluates psy- The research group focuses on segmenting wide range of expertise and a total of 50 em- chogenic influence on treatment planning and CAD/CAM processes and assessment of the ployees. The Department is involved in several outcome of dental disease patterns with a psy- impact on the overall quality. In addition areas of research, including dental materials, chogenic background. Among other factors, to recently developed methodologies for biomechanics, dental implants, and CAD/CAM the subject’s appraisal of his own body can in- 3D-display and analysis of microgaps in con- technology. fluence dental questions. Besides, the etiolog- ventional dental restorations, new protocols Due to the high demands and quality stan- ical correlation of gag reflexes during dental are in development for a clinical assessment dards of research projects, synergistic effects of treatment, the influence of stress and clinical of fit of implant retained superstructures. highly qualified specialists are mandatory. This pictures on fear, depressive states, and social The research laboratories are equipped with is reflected in the general orientation and a fo- parameters are evaluated, too. state-of-the-art industrial non-contact scan- cus on future demands as well as in extensive The second focal point concerns the thera- ners and necessary analytical software pro- cooperation with other fields of research. peutic intervention with medical hypnosis and grams. One key focus of research is the aging popu- acupuncture in dental treatment and their in- As high strength oxide ceramics are applied lation and the resulting demographic changes fluence on psycho-social factors as well as pain more frequently as framework materials in den- and the investigation of the relationship be- in above mentioned dental problems. tistry, several research projects assess the clin- tween oral and general health. ical application and factors influencing long- Optical 3D-measurement technique in term success. Research dentistry Project managers: Prof. Dr. S. Holst, PD Dr. M. Teaching Dental biomechanics Göllner Project manager: PD Dr. M. Karl Quantitative assessment of biomechanical ef- The main focus of traditional prosthodontic Dental implants form an integral part of cur- fects in vivo intraorally required highly complex education has shifted from a technically ori- rent prosthodontic treatment concepts. The research set-ups due to lack of adequate mea- ented towards an interdisciplinary treatment patient’s bone quality seems to be a decisive surement technology in the past. approach. Prophylaxis and biology are in the

128 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) focus as well as minimally invasive treatment concepts. Clinically relevant topics are introduced into the preclinical curriculum, focussing on biologic interactions and material properties. While theoretical knowledge remains integral part of dental education, manual manufac- ture of dental restoration will be taught only exemplarily. A unique opportunity for all dental students at the FAU Dental School is the opportunity to participate in a 3-year extra-curricular Clinical situation after implant bed preparation. implant program. The ”iLect” program is funded by third parties and provided in cooperation with the Department of Oral and Cra- nio-Maxillofacial Surgery. The iLect program has become an essential part of the elective and interdisciplinary education of dental students. The first students passed successfully their examination in 2012 and finished their program.

Selected Publications Winter W, Krafft T, Steinmann P, Karl M (2011) Quality of alveolar bone - Structure-dependent material properties Sensing element of the BoneProbe to be inserted in the and design of a novel measurement technique. J Mech implant bed for conducting a compressive test. Behav Biomed Mater, 4: 541-8 Bauer JS, Beck N, Kiefer J, Stockmann P, Wichmann M, Eitner S (2012) Awareness and education of patients receiving bisphosphonates. J Craniomaxillofac Surg, 40: 277-82 Eitner S, Wichmann M, Schlegel KA, Kollmannsberger JE, Nickenig HJ (2012) Oral health-related quality of life and implant therapy: an evaluation of preoperative, intermediate, and post-treatment assessments of patients and physicians. J Craniomaxillofac Surg, 40: 20-3 Krafft T, Winter W, Wichmann M, Karl M (2012) In vitro validation of a novel diagnostic device for intraoperative determination of alveolar bone quality. Int J Oral Maxillo- Total view of a prototypical BoneProbe. fac Implants, 27: 318-28 Matta RE, Schmitt J, Wichmann M, Holst S (2012) Circum- ferential fit assessment of CAD/CAM single crowns - a pilot investigation on a new virtual analytical protocol. Quintes- sence Int, 43: 801-9 Schmitt J, Goellner M, Lohbauer U, Wichmann M, Reich S (2012) Zirconia posterior fixed partial dentures: 5-year clinical results of a prospective clinical trial. Int J Prostho- dont, 25: 585-9

International Cooperations Prof. Dr. M.B. Blatz, University of Pennsylvania, Philadel- phia: USA Prof. Dr. H.P. Weber, Harvard University, Boston: USA Prof. T.D. Taylor, Prof. J.R. Kelley, PhD, University of Con- necticut, Farmington: USA

Histologic section of a dental implant placed following application of the BoneProbe.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 129 UNIVERSITY HOSPITAL

Institute of Clinical and Molecular Virology Chair of Clinical Virology

Address of molecular diagnostics for respiratory patho- replication and the immune defense against Schlossgarten 4 gens and gastroenteritis viruses via multiplex HCMV is another key focus of the Institute. 91054 Erlangen PCR, and on the establishment of protocols for The first research group defines in collabora- Phone: +49 9131 8523563 the quantification of proviral DNA as a supple- tion with Prof. Dr. T. Winkler (Chair of Genet- Fax: +49 9131 8522101 ment to human oncogenic retrovirus diagnos- ics, Faculty of Sciences) the key factors pro- www.virologie.uni-erlangen.de tics. viding protective humoral immunity following HCMV infection. In the murine CMV model, Head of Department Research the protective mechanisms of antibodies in Prof. Dr. med. Bernhard Fleckenstein immunosuppressed host organisms are in- Retroviruses vestigated. For human CMV, antigens which Contact Project managers: Prof. Dr. U. Schubert, Prof. are involved in the induction of neutralizing Dr. rer. nat. Annette Grohmann Dr. T. Gramberg, PD Dr. B. Schmidt, Dr. Dr. H. antibodies are characterized. Their results Phone: +49 9131 8526784 Reil, Dr. A. Kreß clearly disprove the so far commonly-received Fax: +49 9131 8522101 Several HIV research groups and one HTLV re- opinion that antibodies do not play any role [email protected] search group are working at the Institute. The in the protection from CMV infections in risk first research group is studying the interaction of groups. The second research group analyzes Research Focus host and virus proteins on the molecular level in the functional mechanism of viral regulatory •• Retroviruses order to define interface regions of binding part- proteins that exert an essential function for ef- •• Beta-herpesviruses ners that can be used as target structures for an- ficient viral replication and are thus attractive •• DNA Tumor Viruses ti-viral strategies. A major focus of their research novel target molecules for antiviral therapy. encompasses general aspects of HIV-1 biology, The group could recently identify a novel in- Structure of the Department including the role of cellular factors in retrovirus trinsic immune mechanism against herpes vi- assembly. Those studies are focused on the role ruses that could be relevant for the regulation During the past two years, the twelve inde- of the ubiquitine-proteasome-system in late proof herpesviral latency. Furthermore, they are pendent research groups at the Institute of cesses of the HIV replication cycle. The second working together with Prof. Dr. S. Ensminger, Clinical and Molecular Virology focused on research group investigates innate and intrinsic Department of Cardiac Surgery, on a mouse (1) the role of retroviruses in immunodeficien- immunity in retroviral infection. The group fo- xenotransplantation model on the mechanism cy and oncogenesis, (2) the pathogenesis of cuses on antiviral mechanisms of intracellular of CMV induced transplant arteriosclerosis. Beta-herpesviruses, such as the human cyto- restriction factors, such as the proteins of the The third research group investigates the role megalovirus, and (3) DNA tumor virology. The TRIM family or the recently discovered protein of protein kinases which play an important research groups investigated issues of infection SAMHD1 which can inhibit reverse transcription regulatory role in herpesviral replication and biology, tumor virology, vector development, of retroviruses. The immunopathogenesis in pathogenicity. Specific focus is on the cross- therapy research, native and adaptive immu- HIV-1 and HSV-1 infections is addressed by the talk between viral and cellular protein kinases nity, signaling, and epigenetics, thereby apply- third research group. This group could reveal an involved in complex regulatory processes of ing a broad range of virological, biochemical, essential role of the innate immune defense of herpesviral replication cycles. This area of re- molecular, and cell biological as well as immu- plasmacytoid dendritic cells. The fourth research search aims at developing a new generation nological methods. The majority of the staff group is engaged in the interference of flavivirus of antiviral drugs on the basis of protein kinase members are third-party funded PhD students GB Virus C (GBV-C) and immunodeficiency vi- inhibitors. In a translational project, the fourth and post docs of biology, molecular medicine, ruses. The main interest of the research group is research group develops chimeric immunore- biochemistry, and medicine. to elucidate GBV-C specific strategies of HIV rep- ceptors for anti-viral adoptive immunotherapy The National Reference Center for Retrovirus- lication inhibition and to use this knowledge for of CMV infection. es (1996 - 2012) comprised on-topic research the development of new HIV inhibitors. The fifth groups and a large number of services of di- research group focuses on the molecular mech- DNA Tumor Viruses agnostic virology (compare own report). The anisms of the retrovirus HTLV-1 (human T cell Project managers: PD Dr. F. Neipel, PD Dr. Clinical Diagnostic Section offers a broad range lymphotropic virus type 1) and its oncoprotein B. Biesinger, Prof. Dr. A. Ensser, Prof. Dr. W. of state-of-the-art diagnostic tests for all rele- Tax which can lead to the development of ATLL Doerfler vant viral infections, genotyping, and testing of (adult T cell leukemia/lymphoma). In addition, This research focus aims at elucidating the viral tropism as well as antiviral drug resistance cell-cell transmission of HTLV-1 is analyzed. mechanisms of cellular growth transformation testing for immunodeficiency, herpes, and hep- by DNA tumor viruses. The Kaposi’s sarco- atitis viruses. Beta-herpesviruses ma-associated human herpesvirus type 8 (HHV- The Institute created a large number of sub- Project managers: Prof. Dr. M. Mach, Prof. Dr. 8) is associated with certain B-cell lymphomas type panels which are provided nation- and T. Stamminger, Prof. Dr. M. Marschall, Prof. Dr. and Kaposi’s sarcoma. The first group focuses worldwide for both, research institutes and A. Ensser on the identification of genes which are in- diagnosticians. During the last years, major The characterization of molecular mecha- volved in tumor development. They identified activities targeted on the further development nisms of human cytomegalovirus (HCMV) a new receptor for HHV-8, the ephrin receptor

130 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) tyrosine kinase A2 (EphA2). EphA2 is bound to seminar of the Master’s degree program, the Prof. J.U. Jung, Molecular Microbiology & Immunology, the glycoproteins H and L (gH/gL) of HHV-8. students are introduced to original scientific University of Southern California, Los Angeles: USA The binding of these viral glycoproteins not publications. A three-week F2 practical course Prof. J. Chen, Vanderbilt University Medical Center, Nash- ville: USA only mediates entry of the virus into host cells, aims at improving the students’ knowledge of Prof. W. Britt, Department of Microbiology, University of but also induces signal transduction pathways laboratory techniques and at imparting skills Alabama, Birmingham: USA known to be involved in the tumorigenic pro- on how to design scientific projects. In the six- cess by vascularization. Thus, HHV-8 encoun- week F3 practical course, the students work on Meetings and International Training ters and activates cellular genes contributing to their own project under the supervision of a Courses oncogenesis at the earliest stages of infection. group leader. For the Bachelor’s and Master’s 11.-17.05.2011: 13th International CMV/BetaHerpesvirus The second group studies T-cellular signaling degree programs of students of Biology, Inte- Workshop, Nürnberg pathways regulated by the viral oncoproteins grated Life Sciences, and Cell and Molecular 27.03.2012: Cell-based Therapies (Kooperationsforum in StpC and Tip from Herpesvirus saimiri C488 as Biology, the Institute of Clinical and Molecular Zusammenarbeit mit Bayern Innovativ), Erlangen well as Tio from Herpesvirus ateles. Analyzing Virology provides specialization modules. Spe- 14.-16.06.2012: International Symposium Forty Years of Virology at the FAU, Erlangen the cell-differentiating proliferative signaling cial lectures conveying background knowledge pathways that are stimulated by Tip is also a of the research areas of the group leaders are Research Equipment main focus of the third group within the SFB offered to students of all degree programs. ABI, Prism 3100 Genetic Analyzer and data bank 796 (see own report). Furthermore, this group Moreover, the members of the Institute are es- investigates the chromatin structure and repli- sentially involved in the weekly seminars, peri- BD Biosciences, Flow Cytophometer LSR II cation of latent herpesvirus genomes in T and odic workshops, and annual retreats of the GK Leica, confocal microscope TCS SP5 B cells. Novel mechanisms of intrinsic immunity 1071 ”Viruses of the Immune System”. against gamma herpesviruses were revealed in cooperation with Prof. Dr. T. Stamminger. As a Selected Publications visiting professor in the laboratory of Prof. Dr. Hahn S, Setz C, Wild J, Schubert U (2011) The PTAP se- J.U. Jung, University of Southern California, Los quence within the p6 domain of human immunodeficiency virus type 1 Gag regulates its ubiquitination and MHC Angeles, Prof. Dr. A. Ensser continued in 2012 class I antigen presentation. J Immunol, 186: 5706-18 collaborative research projects on autophagy Kress AK, Kalmer M, Rowan AG, Grassmann R, Flecken- and intrinsic immunity involving mutagenesis stein B (2011) The tumor marker Fascin is strongly in- of KSHV bacmids. DNA methylation and/or his- duced by the Tax oncoprotein of HTLV-1 through NF-kB signals. Blood, 117: 3609-12 tone modification have been documented to Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T affect many biomedical processes via the reg- (2011) Evidence for a dual antiviral role of the major nu- ulation of gene expression. The fourth group clear domain 10 component Sp100 during the immedi- characterizes different aspects of DNA-methyl- ate-early and late phases of the human cytomegalovirus replication cycle. J Virol, 85: 9447-58 ation in HIV-1 proviral genomes, in transgenic Full F, Reuter N, Zielke K, Stamminger T, Ensser A (2012) cells, and in the human genome. Herpesvirus saimiri antagonizes nuclear domain 10-insti- tuted intrinsic immunity via an ORF3-mediated selective Teaching degradation of cellular protein Sp100. J Virol, 86: 3541-53 Hahn AS, Kaufmann JK, Wies E, Naschberger E, Pan- teleev-Ivlev J, Schmidt K, Holzer A, Schmidt M, Chen J, In cooperation with the colleagues from the König S, Ensser A, Myoung J, Brockmeyer NH, Stürzl M, Institute of Microbiology, the Institute of Clini- Fleckenstein B, Neipel F (2012) The ephrin receptor tyro- cal and Molecular Virology offers curricular lec- sine kinase A2 is a cellular receptor for Kaposi’s sarcoma- associated herpesvirus. Nat Med, 18: 961-6 tures and practical courses in infectiology and Kropff B, Burkhardt C, Schott J, Nentwich J, Fisch T, Britt immunology to medical students. These gen- W, Mach M (2012) Glycoprotein N of human cytomegalo- eral infectiology courses have been expanded virus protects the virus from neutralizing antibodies. PLoS to dental students, students of Medical Process Pathog, 8: e1002999 Management as well as pharmaceutical stu- International Cooperations dents. Furthermore, our Institute is involved in the Molecular Medicine programs. In the Bach- Prof. W. Rawlinson/Dr. G. Scott, University of New South Wales, Sydney: Australia elor’s degree program, the lectures impart ba- Dr. Y. Couté, Plateforme d’analyses protéomiques, IN- sics of general virology. Viral education is com- SERM U1038/UJF, CEA, Grenoble: France plemented with F1 practical courses offered Prof. B. Ray, University of Burdwan, Bardhaman: India to groups of two or three students including Dr. V. Ciminale, Department of Oncology and Surgical an accompanying methods seminar or offered Sciences, University of Padova, Padova: Italy individually. The students work under the di- Prof. J.A. Levy, University of California, San Francisco: USA rect instruction of the team leaders on current Prof. S. Chou, Oregon Health and Science University, Port- research projects in the lab. In the advanced land: USA

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 131 UNIVERSITY HOSPITAL

Institute of Clinical and Molecular Virology Division of Experimental Therapeutics

Address Teaching Fink KD, Rossignol J, Crane AT, Davis KK, Bavar AM, De- korver NW, Lowrance SA, Reilly MP, Sandstrom MI, von Palmsanlage 5 Hörsten S, Lescaudron L, Dunbar GL (2012) Early cogni- 91054 Erlangen Seminars contribute to the curricula in clini- tive dysfunction in the HD 51 CAG transgenic rat model of Phone: +49 9131 8523504 cal and experimental biomedicine, including Huntington’s disease. Behav Neurosci, 126: 479-87 Fax: +49 9131 8523502 anatomy, pharmacology, reproductive biology, Lescaudron L, Boyer C, Bonnamain V, Fink KD, Lévêque X, Rossignol J, Nerrière-Daguin V, Malouet AC, Lelan F, Dey www.fpz.uni-erlangen.de and laboratory animals sciences. We employ ND, Michel-Monigadon D, Lu M, Neveu I, von Hörsten modern educational technologies in several S, Naveilhan P, Dunbar GL (2012) Assessing the potential Head of Division clinical utility of transplantations of neural and mesenchy- seminars and practical courses which also have mal stem cells for treating neurodegenerative diseases. Prof. Dr. med. Stephan von Hörsten been evaluated repeatedly. The seminars are Methods Mol Biol, 879: 147-64 part of the B.Sc./M.Sc. of Molecular Medicine Vlamings R, Benazzouz A, Chetrit J, Janssen ML, Kozan R, Contact at the FAU and they are integrated in postgrad- Visser-Vandewalle V, Steinbusch HW, von Hörsten S, Temel Dr. Anja Schulze-Krebs Y (2012) Metabolic and electrophysiological changes in uate research programs. the basal ganglia of transgenic Huntington’s disease rats. Phone: +49 9131 8523566 The following seminars are offered to the stu- Neurobiol Dis, 48: 488-94 Fax: +49 9131 8523502 dents of the study course “Molecular Med- Zeef DH, van Goethem NP, Vlamings R, Schaper F, Jahan- [email protected] icine”: “Seminar experimental animals and shahi A, Hescham S, von Hörsten S, Prickaerts J, Temel Y (2012) Memory deficits in the transgenic rat model of knowledge of their reproduction” and „System- Huntington’s disease. Behav Brain Res, 227: 194-8 Research Focus interactions and neuroendocrine-immunology: Antonsen BT, Jiang Y, Veraart J, Qu H, Nguyen HP, Sijbers J, •• Comprehenisve phenotyping and therapy in From anatomy to pathology”. These seminars von Hörsten S, Johnson GA, Leergaard TB (2013) Altered animal models of human neurodegenerative diffusion tensor imaging measurements in aged transgen- impart deep knowledge of the structure and disorders ic Huntington disease rats. Brain Struct Funct, 218: 767-78 function of the nervous-, neuroendocrine- and immune-system. Afterwards the students will Structure of the Department International Cooperations have a comprehensive knowledge about the Prof. A. Petersen, Translational Neuroendocrine Research involved physiological pathways, e.g. the clas- Unit, University of Lund, Lund: Sweden The Division of Experimental Therapy is located sical symptom “fever” as an adaption of the Prof. H.-P. Lipp, Institute of Anatomy, ETH Zurich, Zurich: in the FPZ and contributes to essential responsi- immune-system to pathophysiological process- Switzerland bilities of the FPZ. The FPZ is a interdisciplinary es. These seminars represent a compendium of A.P. Osmand, PhD, Research Center - Graduate School of facility, responsible for fundamental and pre- Medicine, University of Tennessee, Knoxville: USA different medical domains and basic principles clinical animal research here in Erlangen. to allow a broad understanding on the com- In this context, the Division of Experimental Research Equipment plexity of somatic processes. Therapy offers highly standardized methods TSE Systems GmbH, PhenoMaster The seminars “Generation of transgenic mice for the characterization of transgenic animals New Behavior AG, IntelliCage and rats as animal models of human diseases” during preclinical studies in the context of neu- and „Dealing with Experimental animals” (an- Siemens, Advia 120 Hemolytic Analyzer rodegenerative disorders and immunological imal protection law, experimental design, and BD, FACS Canto II research. methods) together with a laboratory training Research are also offered to students of the master study course „Molecular Medicine”. Comprehenisve phenotyping and A further seminar and practical training „Patho- therapy in animal models of human physiological animal models: Pathophysiology neurodegenerative disorders and genetic studies” and „Practical training on The Division of Experimental Therapy deals experimental animals” during the study course with comprehensive phenotyping and trans- „Molecular Medicine” is offered to the students. lational preclinical experimental therapeutic It imparts knowledge on the phenotyping of ex- approaches in primarily transgenic rodent perimental animal models. During the practical models for human neurodegenerative disor- training, the student will take part in ongoing ders. One goal is to provide models with a and routine methods in the context of experi- high predictivity for the human condition. A mental animal phenotyping together with fre- present focus is on neurodegenerative pro- quently used methods. Here, the contents and cesses induced by protein aggregational dis- acquired knowledge depend on the teaching eases (polyglutamine disorders, Parkinson´s and scientific topic of the involved scientists. and Alzheimer´s disease). Various behavioral, neurological, immunological, molecular, and Selected Publications histological techniques are applied to char- Cong WN, Cai H, Wang R, Daimon CM, Maudsley S, Ra- ber K, Canneva F, von Hörsten S, Martin B (2012) Altered acterize the pathophysiology and to develop hypothalamic protein expression in a rat model of Hun- new therapies. tington’s disease. PLoS ONE, 7: e47240

132 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Example of a possible experimental design used for the characterization Cognitive skills of laboratory animal models can be characterized by the of possible beneficial effects of different housing conditions on the be- method of operant learning. It is an automated test system in which havioral phenotype and cognitive skills of transgenic animal models. animals are positively rewarded for the correct application of operant learning software paradigms which can be personalized with regard to the experimental design.

Amyloid plaque deposition and signs of neuroinflammation and neurodegeneration in the McGill-R-Thy1-APP rats. Sections from 13 (a and d) and 20 (b and e) month-old rats were stained for Aß and MHCII (respectively blue and brown reactions). The dense, fibrillar nature of these plaques was confirmed by thioflavine S staining (c and f). From g to i, the presence of neurodegeneration surrounding the sites of plaque deposition (*) was investigated in the same animal (20 month old): Dystrophic cholinergic (VAChT-IR) (g) and glutamatergic (VGluT-IR) (h), but not GABA-ergic (GAD65-IR) (i) neurites were observed, confirming the differential vulnerability of different neurotransmitter systems to amyloid plaques deposition. Scale bar = 500mm in panels a - c and =20mm in panels d - i.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 133 UNIVERSITY HOSPITAL

Institute of Clinical Microbiology, Immunology, and Hygiene Chair of Microbiology and Immunology of Infection

Address hypoxia chambers for in vitro and in vivo anal- Molecular mycology Wasserturmstraße 3-5 yses, fluorescence and confocal laser scanning Project manager: Prof. Dr. S. Krappmann (since 91054 Erlangen microscopes, real-time PCR machines, analyt- 01.05.2012) Phone: +49 9131 8522551/22281 ical fluorescence activated cell sorters (FACS), Omnipresent molds of the genus Aspergillus Fax: +49 9131 851001 sequencing and imaging systems. (e.g. A. fumigatus) represent an increasing www.klimi.med.uni-erlangen.de/ The main clinical work of the Institute is fo- threat for immunocompromised patients. It cused on the diagnostics of bacterial, fungal, is well accepted that pathogenicity of A. fu- Head of Department and parasitic infectious diseases, the hospital migatus is a multi-factorial trait. Major efforts Prof. Dr. med. Christian Bogdan hygiene, and the prevention of infectious dis- in this research group aim at identification of eases by immunization. The Institute runs the virulence determinants (e.g. the nitrogen and Contact university outpatients' clinic for vaccination sulfur metabolism) that support the utilization Dr. rer. nat. Sonja Pötzsch and travel medicine. The diagnostic section of of proteinaceous substrates by A. fumigatus Phone: +49 9131 8522571 the Institute (head: Dr. C. Schoerner) is accred- and allow for its propagation inside the suscep- Fax: +49 9131 851001 ited by the DAKKS and functions as reference tible host. Furthermore, the extant sexual cycle [email protected] center for the nationwide quality control and of A. fumigatus is investigated. These studies proficiency tests in bacteriological, serological, are accompanied by strategies to expand and Research Focus and mycological diagnostic procedures. improve the molecular toolbox of Aspergillus •• Bacterial effector proteins molecular biology. •• Microbial phosphatases Research •• Molecular mycology Innate immunity and therapy of •• Innate immunity and therapy of leishmani- Bacterial effector proteins leishmaniasis asis Project manager: Dr. A. Lührmann Project manager: PD Dr. U. Schleicher •• Innate immunity, macrophages, arginase, The activation of NK cells is part of the early The pathogenic activity of bacteria is based and NO synthase immune response against Leishmania para- on the activity of virulence factors. Many •• Innate immunity, macrophages, and adju- sites. In the mouse models of cutaneous and Gram-negative bacteria have developed so- vants visceral leishmaniasis, the group investigates called secretion systems which directly inject •• Innate immunity, granulocytes, and mast the signals that lead to the stimulation or in- certain bacterial proteins into the host cell. cells hibition of NK cells, the mechanisms by which These effector proteins alter host cells for the •• Tissue milieu and the immune response NK cells contribute to parasite control and the advantage of the microbe. The research group •• Genetic and bacterial factors in chronic in- modulation of the NK cell response for thera- studies the function of such proteins using the flammation peutic purposes. The relevance of the human intracellular bacterium Coxiella burnetii, the NK cell response is studied in humanized mice. causal agent of Q fever, as a model system. A Structure of the Department In another project, the group analyzes the an- major focus is the analysis of the mechanisms ti-parasitic, immunoregulatory and/or wound by which C. burnetii prevents the death of the The Institute of Clinical Microbiology, Im- healing-promoting effects of pharmaceutical host cells, thereby generating an ideal niche for munology, and Hygiene is active in research, sodium chlorite which showed promising ther- its own survival and replication. teaching, and clinical diagnostics. The Institute apeutic effects in cutaneous leishmaniasis in houses the Chair of Microbiology and Im- two clinical trials. munology of Infection and, since November Microbial phosphatases 2008, the independent Division of Infection Project manager: Dr. D. Soulat (since 01.02. Innate immunity, macrophages, Biology (see own report). 85 employees are 2012) arginase, and NO synthase working at the Institute, thereof 24 are paid Human pathogens have developed numer- Project manager: Prof. Dr. C. Bogdan by extramural funding sources. The research is ous strategies to invade their target host or- Nitric oxide which is synthesized from the carried out by eleven scientists with a MD or ganism. One important virulence mechanism amino acid L-arginine in macrophages and PhD degree, 17 PhD students, und ten tech- relies on the secretion of proteins (e.g. phos- other cells by the interferon (IFN)-g indu- nical assistants. phatases) which interfere with cell signaling cible NO synthase (iNOS) is essential for the The different research groups of the Institute events during the host-pathogen interaction. defense against intracellular pathogens and study the innate and adaptive immune re- Pathogen-secreted phosphatases are highly a central regulator of the immune system. In sponse during infectious diseases, investigate specific enzymes which are able to hijack the macrophages, the mechanism underlying the mechanisms of microbial virulence, and analyze cell response and therefore participate in the suppression of iNOS protein synthesis by L-ar- the regulation of basic inflammatory processes, creation of a pathogen friendly environment in- ginine-deficiency which for example occurs using immunological, cell-biological, and mo- side the infected host. The research group cur- after the induction of the arginine-metabo- lecular techniques. Various infectious disease rently studies phosphatases from two human lizing enzyme arginase during an infection models are studied which include infections pathogens: (a) a PIP and tyrosine phosphatase will be studied. Both, the host cell arginase with Coxiella, Listeria, Mycobacteria, Salmo- named LipA from the bacteria Listeria monocy- 1 as well as the arginase of Leishmania par- nella, Leishmania, and Aspergillus. The Institute togenes and (b) a tyrosine phosphatase secret- asites, will be analyzed in this respect. The is fully equipped with laboratories (BSL2, BSL3), ed by the parasite Leishmania major. long-term aim is to unravel whether the host

134 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) cell arginase and/or the parasite arginase are Genetic and bacterial factors in Klingenbeck L, Eckart RA, Berens C, Lührmann A (2013) critical for the lifelong survival of Leishmania chronic inflammation The Coxiella burnetii type IV secretion system substrate CaeB inhibits intrinsic apoptosis at the mitochondrial level. in vivo. Project manager: Prof. Dr. J. Mattner Cell Microbiol, 15: 675-687 Autoimmune responses and inflammatory pro- Innate immunity, macrophages, and cesses of the intestine and the liver reflect the International Cooperations adjuvants result of complex interactions of genetic pre- L.J. Mota, CELLPATH, Instituto de Tecnologia Química e Project manager: Prof. Dr. R. Lang disposition and distinct environmental factors. Biológica, Lisbon: Portugal The group explores which receptors are used Although the autoantigens targeted by the im- H. Haas, Innsbruck Medical University, Innsbruck: Austria by macrophages to detect pathogenic micro- mune system are often ubiquitously expressed, P. Andersen, Statens Serum Institut (SSI), Copenhagen: organisms and their products (e.g. the myco- the inflammatory processes are frequently tis- Denmark bacterial cord-factor trehalose-dimycolate) and sue-specific. In this context, the group investi- P. Murray, St. Jude Children´s Research Hospital, Memphis: how these receptors signal to elicit immune gates the genetic factors that regulate the im- USA responses. The project aims at elucidating the mune responses in the intestine and the liver. O. Mandelboim, The Lautenberg Center for General and mechanisms of action of adjuvants. Another Furthermore, we analyze the role of bacterial Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem: Israel research avenue focuses on the question how antigens in the development of autoimmune the inflammatory response of macrophages is responses by applying targeted gene deletion L. Wicker, University of Cambridge, Cambridge: UK terminated in order to prevent collateral tissue strategies. Prof. Dr. J. Titze, Vanderbilt University, Nashville: USA damage. In this context, one central aspect is the in vitro and in vivo analysis of the ”dual Teaching specificity phosphatases”. These inhibit various kinases that are essential for the production of The employees of the Institute teach students proinflammatory cytokines and chemokines. of human medicine, dental medicine, molecular medicine, biology, and pharmaceutical Innate immunity, granulocytes, sciences in medical microbiology, immunology, and mast cells infectious disease research, and in the field of Project manager: Prof. Dr. H.U. Beuscher clinical infectious disease diagnostics and tropi- The group investigates the survival strategies, cal diseases. The training takes place in form of the immunoregulatory functions, and the pro- seminars, practical courses, lectures, laborato- duction of inflammatory mediators by neutro- ry rotations, as well as bachelor, master, MD, phils from patients with rheumatoid arthritis. and PhD theses. Together with the Institute of The study aims at characterizing an anti-apo- Clinical and Molecular Virology, the Institute ptotic factor and its mechanism of action as organizes an interdisciplinary lecture series on well as possible therapeutic applications. A sec- infectious diseases which serves as a continu- ond project analyzes how mast cells interact ous medical education program for medical with B-lymphocytes, modulate the antibody doctors in the region. synthesis and thereby optimize the specific immune defense of the host organism. Selected Publications Mohammed JP, Fusakio ME, Rainbow DB, Moule C, Fraser Tissue milieu and the immune HI, Clark J, Todd JA, Peterson LB, Savage PB, Wills-Karp M, Figure 1: The 3D-structure and -arrangement of the ho- response Ridgway WM, Wicker LS, Mattner J (2011) Identification motrimer of the phosphatase LmjF.16.0230 from Leish- of Cd101 as a susceptibility gene for Novosphingobium mania major was modeled from its human homologs Project manager: Dr. J. Jantsch aromaticivorans-induced liver autoimmunity. J Immunol, PRL-1. This structural similarity might be an advantage 187: 337-49 It is well established that under physiological for the parasite to hijack the cellular functions controlled conditions (e.g. in certain layers of the skin and Prajeeth Chittappen, Haeberlein Simone, Sebald Heidi, by the human PRL-1. in the gastrointestinal tract) and in inflamed Schleicher Ulrike, Bogdan Christian (2011) Leishmania-In- fected Macrophages Are Targets of NK Cell-Derived Cy- tissues the oxygen levels may be very low tokines but Not of NK Cell Cytotoxicity Infect Immun, 79: (pO2 < 0.5%). Interestingly, under high-salt 2699-2708 diet sodium can accumulate in the skin with- Wenzel J, Held C, Palmisano R, Teufel S, David JP, Wit- out simultaneous water retention resulting in tenberg T, Lang R (2011) Measurement of TLR-Induced interstitial hypertonicity. The group explores Macrophage Spreading by Automated Image Analysis: Differential Role of Myd88 and MAPK in Early and Late the homeostatic role of the immune system in Responses. Front Physiol, 2: 71 orchestrating the peripheral milieu (i.e. oxygen Amich J, Krappmann S (2012) Deciphering metabolic availability and interstitial tonicity) and studies traits of the fungal pathogen Aspergillus fumigatus: redun- how an altered milieu (e.g. hypoxia, intersti- dancy vs. essentiality. Front Microbiol, 3: 414 tial hypertonicity) will regulate the immune Wiese M, Gerlach RG, Popp I, Matuszak J, Mahapatro M, Figure 2: (A) The mould Aspergillus fumigatus. Colonies of mycelia with conidiophores giving rise to the grey- response and defense against infectious path- Castiglione K, Chakravortty D, Willam C, Hensel M, Bog- dan C, Jantsch J (2012) Hypoxia-mediated impairment of green asexual spores that serve as infectious propagules. ogens via the respective transcription factors the mitochondrial respiratory chain inhibits the bacteri- (B) Imaging of cutaneous aspergillosis in an animal mod- (e.g. HIF-1a, TonEBP). cidal activity of macrophages. Infect Immun, 80: 1455-66 el by bioluminescence.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 135 UNIVERSITY HOSPITAL

Institute of Clinical Microbiology, Immunology, and Hygiene Division of Infection Biology

Address infections. Basophils can be efficiently activat- mice immunized with ovalbumin or sheep red Wasserturmstraße 3-5 ed by Fc receptors to which helminths-specific blood cells, but not after infection with lym- 91054 Erlangen antibodies bind. These helminths-specific an- phocytic choriomeningitis virus or mouse cy- Phone: +49 9131 8532735 tibodies are probably generated by long-lived tomegalovirus. This indicates that IL-4/IL-13 is Fax: +49 9131 8532733 plasma cells that were induced by the prima- only required for the germinal center response www.infektionsbiologie.uk-erlangen.de ry infection and constitute the immunological during type 2 immune responses. Further- memory function. It further became apparent more, we could show by deep sequencing in Head of Division that basophils are essential for chronic allergic collaboration with Prof. Dr. O. Pabst from the Prof. Dr. rer. nat. David Vöhringer inflammation of the skin. This pathologic con- Hannover Medical School that the repertoire of dition can be induced by passively sensitizing IgE and IgG1 sequences is largely overlapping. Contact basophils with hapten-specific IgE followed by This indicates that affinity maturation may take Dr. rer. nat. Sonja Pötzsch antigen-mediated IgE crosslinking. As shown place at the level of IgG1-expressing B-cells which then undergo a secondary class switch Phone: +49 9131 8522571 by others before, mast cells are not required recombination event to IgE. In case these re- Fax: +49 9131 851001 for this inflammatory response. The mecha- sults can be confirmed in human allergic indi- [email protected] nisms that regulate protective and pathological viduals, one could think about new therapeutic functions of basophils are subject of our current options that interfere with generation of aller- Research Focus investigations. gen-specific antibodies at the level of IgG1-ex- •• Immune response against helminths and al- pressing B-cells. lergens Plasticity of T-helper cells •• Plasticity of T-helper cells We addressed the question whether CD4 Teaching •• IgE response and germinal center reaction T cells that were already differentiated to Th1, Th17, or regulatory T cells (Treg) could be The Division of Infection Biology is closely asso- reprogrammed to adopt a Th2 phenotype in Structure of the Department ciated to the Institute of Clinical Microbiology, vivo. To address this issue, we used T cell re- Immunology, and Hygiene. Both institutions The Division of Infection Biology was founded ceptor transgenic mice in which most CD4 offer joined lectures, seminars, and practical in 2008 as an independent division at the In- T cells are specific for an epitope derived from courses for students. The teaching activities are stitute of Clinical Microbiology, Immunology, chicken ovalbumin. Furthermore, these mice dedicated to microbiology and immunology and Hygiene. The Division is headed by Prof. had been crossed to IL-4eGFP reporter mice so with a special focus on host-pathogen interac- Dr. D. Vöhringer who was recruited in October that repolarization to Th2 cells could be easily tions. Scientists of the Division also supervise 2010 as W2 professor by the FAU. The Division analyzed by flow cytometry. The T cell recep- students that perform their Bachelor- or Mas- employs three scientists with PhD degree, three tor transgenic cells were first polarized in vitro ter-theses. PhD students, and two technicians. or in vivo to Th1, Th17, or Treg cells and then purified by cytokine capture assay. The purified Selected Publications Research Th1, Th17, and Treg cells were then transferred Dudeck A, Dudeck J, Scholten J, Petzold A, Surianarayanan into naïve recipient mice followed by infection S, Köhler A, Peschke K, Vöhringer D, Waskow C, Krieg T, Immune response against helminths with helminths to study the re-programming Müller W, Waisman A, Hartmann K, Gunzer M, Roers A (2011) Mast cells are key promoters of contact allergy and allergens into Th2 cells. The results indicated that Th1 that mediate the adjuvant effects of haptens. Immunity, Main focus of the research activities is the char- and Th17 cells show remarkable functional 34: 973-84 acterization of type 2 immune responses which plasticity while Treg cells were largely resistant Schwartz C, Voehringer D (2011) Basophils: important are elicited by parasitic worms (helminths) and to repolarization. These findings strengthen the emerging players in allergic and anti-parasite responses. Bioessays, 33: 423-6 allergens. In both situations, the immune sys- hope that pathogenic Th1 or Th17 cells which tem reacts with an increase in Th2 cells, mast often dominate autoimmune responses can be Seidl A, Panzer M, Voehringer D (2011) Protective immunity against the gastrointestinal nematode Nippostrongy- cells, eosinophils, basophils, and production reprogrammed in an antigen-specific manner. lus brasiliensis requires a broad T-cell receptor repertoire. of IgE. Infection of genetically modified mice Immunology, 134: 214-23 with helminths can be used as a model to IgE response and germinal center Voehringer D (2011) Basophils in allergic immune re- study the complex interaction between dif- reaction sponses. Curr Opin Immunol, 23: 789-93 ferent cell types that orchestrate and execute Funded by the ERC starting grant PAS_241506, Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A type 2 immune responses. Work at the Division we studied the regulation of the IgE response (2012) The transcription factor GATA-3 controls cell fate of Infection Biology during the last year could against helminths and allergens. We first com- and maintenance of type 2 innate lymphoid cells. Immu- demonstrate that basophils play an important pared the IgE response in wild-type mice, IL-4/ nity, 37: 634-48 role for protective immunity against differ- IL-13-deficient mice, and mice that lack IL-4/IL- Panzer M, Sitte S, Wirth S, Drexler I, Sparwasser T, ent gastrointestinal helminths. These results 13 expression only in T cells. The results clear- Voehringer D (2012) Rapid in vivo conversion of effector T cells into Th2 cells during helminth infection. J Immunol, are based on studies with basophil-deficient ly showed that the IgE response requires IL-4/ 188: 615-23 mice which had been generated by the work IL-13 from T cells. To our surprise, we further group Vöhringer. We observed that basophils observed that the germinal center response International Cooperations play an important role for protective immunity was dependent on IL-4/IL-13 production from M. Dalod, Center of Immunology of Marseille-Luminy against helminths especially during secondary T cells. This requirement was also observed in (CIML), Marseille: France

136 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) R. Noelle, Dartmouth Medical School, Hanover: USA L. Muzio, Division of Neuroscience, San Raffaele Scientific Institute, Milan: Italy R. Locksley, University of California San Francisco, San Francisco: USA F. Granucci, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan: Italy D. Artis, Department of Microbiology, University of Penn- sylvania, Philadelphia: USA A. Mountford, Department of Biology, University of York, York: UK

Research Equipment MiltenyiBiotec, MACSquant10

The picture shows three germinal centers in the mesenteric lymph node of helminth infected mice on day 12 after infection. Red: anti-CD35 staining to detect follicular dendritic cells. Blue: anti-GL-7 staining to detect germinal center B-cells. Green: anti-IgD to detect resting B-cells.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 137 UNIVERSITY HOSPITAL

Institute of Human Genetics Chair of Human Genetics

Address Another research focus is the clinical and mo- an important factor for ocular outflow, as a Schwabachanlage 10 lecular syndromology. cause of familial open angle glaucoma. Finally, 91054 Erlangen members of the Institute, in collaboration with Phone: +49 9131 8522318 Research the Department of Obstetrics and Gynecology, Fax: +49 9131 8523232 were involved in various studies on genetic fac- www.humangenetik.uk-erlangen.de Developmental genetics tors predisposing to Mayer-Rokitansky-Küster- Project manager: Prof. Dr. A. Winterpacht Hauser (MRKH) Syndrome and ovarian-, Head of Department The group is interested in the molecular basis of breast-, and endometrial cancer. Prof. Dr. med. André Reis developmental processes and their individual variability. This includes epigenetic mechanisms Genetic factors of intellectual disability Contact and regulatory networks of organogenesis and Project managers: PD Dr. R. Abou Jamra, Prof. Prof. Dr. med. André Reis cell differentiation as well as the identification Dr. A. Reis, Dr. C. Zweier Phone: +49 9131 8522318 of variants in specific components of these pro- One of the main scientific topics of the Insti- Fax: +49 9131 8523232 cesses. The projects comprise work on: tute is the elucidation of the molecular basis [email protected] 1. The gene SPOC1 (PHF13) whose expression of intellectual disability. Using homozygosity is associated with survival time in patients with mapping, the first group studied over 100 fam- Research Focus ovarian cancer. The group was able to show ilies with autosomal recessive intellectual disa- •• Developmental genetics that SPOC1 functions as an epigenetic reader bility and identified AP4 deficiency as a novel •• Genetics of complex diseases and writer of histone modifications which plays syndrome caused by mutations in any of the •• Genetic factors of intellectual disability a role in mitosis and in the epigenetic regula- four members of the AP4 complex. The second •• Growth retardation tion of meiosis as well as spermatogonial stem group identified heterozygote loss of function cell maintenance and differentiation; mutations in ARID1B, encoding a subunit of Structure of the Department 2. The nervous system where the group works the SWI/SNF-A chromatin-remodeling com- on the identification of susceptibility genes for plex, as a relatively frequent cause of unspe- Members of the Institute are active in teach- post-operative pain perception. This project is cific intellectual disability. In the framework of ing, research, and health care provision. At the carried out in the context of the Klinische For- a larger collaborative study, the group further end of 2012, a total of 51 persons worked at schergruppe 130 (KFO 130; see own report) performed whole exome sequencing in 51 pa- the Institute: 17 scientists and physicians, ten and in collaboration with the Departments of tients/parent trios. The detection of pathogenic PhD-students, 24 technical and administrative Anesthesiology and Surgery. or most likely pathogenic de novo mutations employees as well as eight graduate students. in 45-55% of cases made a large contribution Ten colleagues were funded through grants. Genetics of complex diseases to the understanding of genetic causes of spo- The Institute runs a genetic clinic for ambula- Project manager: Prof. Dr. A. Reis radic intellectual disability. The third group tory care and genetic counseling of patients Complex or multifactorial diseases are caused identified and characterized a triplication of as well diagnostic laboratories for highly spe- by a combination of mostly unknown environ- the MAPT gene from the microdeletion region cialized cytogenetic and molecular genetic in- mental and genetic factors. The group searches 17q21.31, thus contributing to the character- vestigations. Research activities are organized for genetic susceptibility factors through asso- ization of genotypes and phenotypes in this in research groups. Members of the Institute ciation studies with large patient cohorts. The region. In addition, the group contributed to participate in various collaborative research projects were partially funded by BMBF. In a the delineation of the Nicolaides-Baraitser syn- groups (BMBF and ”Forschergruppen”). The genome wide approach, novel susceptibility drome and to the identification of mutations in head of Institute coordinated a collabora- factors for psoriasis were identified as part of the causative SMARCA2 gene. tive research network on the genetic basis of an international cooperation. Search for rare mental retardation (MRNET) funded by the genetic variants in the previously identified Growth retardation BMBF within the National German Genome psoriatic arthritis susceptibility gene TRAF3IP2 Project manager: PD Dr. C. Thiel Research Network (NGFNplus). He is also the revealed missense variants which, unlike the The velocity of growth as well as growth pat- Chairman of the University Senate and of the frequent variant previously identified, did not terns are fundamentally regulated by genetic IZKF at the Faculty of Medicine. In addition, he affect binding to the interacting molecule factors. The group uses positional strategies served as president of the German Society of TRAF6. Furthermore the initial association of to identify and further characterize the genet- Human Genetics (GfH) in his second term till psoriasis to a copy number variable cluster of ic basis of idiopathic short stature and skeletal June 2012. The Institute runs several core units: b-defensins was replicated in larger cohorts. For dysplasias. This work was partially funded by ”Z3 Genomic Platform” for microarray based PEX and PEX-glaucoma syndrome, the group BMBF (SKELNET network), ELAN-Fond, and genomic analyses and ”Z4 DNA Extraction performed a first genome wide association DFG. This approach leads to the identification Platform (Biobank)” for quality controlled DNA study and identified variants at CNTNAP2 locus of nonsense mutations in NEK1 as the under- extraction of blood samples, both within IZKF, as a novel associated gene. In cooperation with lying cause of short rib-polydactyly syndrome as well as the interfaculty core unit „Ultradeep Prof. M.K. Wirtz (Portland, USA), the group type Majewski. Loss of functional NEK1 protein Sequencing” for massive parallel sequencing. also identified mutations in ASB10, encoding affects formation and morphology of the pri-

138 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) mary cilia (ciliopathy). Moreover, chromosomal International Cooperations breakpoint mapping and functional character- Prof. M. Tartaglia, Superior Health Institute, University of ization outlines the histoneacetyltransferase Rome la Sapienza, Rome: Italy MYST4/KAT6B in a patient with a Noonan-like Dr. A. Barton, arc-Epidemiology Unit, University of Man- syndrome phenotype. chester, Manchester: UK Dr. A. K. Voss, Department of Medical Biology, University Teaching of Melbourne, Parkville: Australia Prof. A. Rauch, Institute of Medical Genetics, University of Zurich, Zurich: Switzerland The Institute is involved in curricular teaching Prof. J. Armour, Institute of Genetics, University of Not- activities in medicine and in the bachelor- and tingham, Nottingham: UK master programs in molecular medicine as well as cellular and molecular biology, respectively. Meetings and International Training During the report period, 21 diploma or mas- Courses ter theses in molecular medicine and cellular 23.-26.06.2012: Tagung der Europäischen Gesellschaft für and molecular biology were finished at the In- Humangenetik (ESHG) gemeinsam mit der Jahrestagung der GfH (Tagungspräsident Prof. Dr. A. Reis), Nürnberg stitute. In addition, doctoral theses in medical and natural sciences were supervised. Prof. Dr. Research Equipment A. Winterpacht received the best lecturer award Applied Biosystems, DNA-Sequencing Automation for Molecular Medicine in summer terms 2011 and 2012. Affymetrix, Genomic-Chip-Platform

Selected Publications Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L (2011) Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet, 88: 788-95 Bördlein A, Scherthan H, Nelkenbrecher C, Molter T, Bösl MR, Dippold C, Birke K, Kinkley S, Staege H, Will H, Win- terpacht A (2011) SPOC1 (PHF13) is required for spermatogonial stem cell differentiation and sustained sper- matogenesis. J Cell Sci, 124: 3137-48 Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, Gordon L, Scott H, Smyth GK, Ahmadian MR, Traut- mann U, Zenker M, Tartaglia M, Ekici A, Reis A, Dörr HG, Rauch A, Thiel CT (2011) Disruption of the histone acet- yltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J Clin Invest, 121: 3479-91 Hoyer J, Ekici AB, Endele S, Popp B, Zweier C, Wiesener A, Wohlleber E, Dufke A, Rossier E, Petsch C, Zweier M, Göhring I, Zink AM, Rappold G, Schröck E, Wieczorek D, Riess O, Engels H, Rauch A, Reis A (2012) Haploinsuffi- ciency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am J Hum Genet, 90: 565-72 Pasutto F, Keller KE, Weisschuh N, Sticht H, Samples JR, Yang YF, Zenkel M, Schlötzer-Schrehardt U, Mardin CY, Frezzotti P, Edmunds B, Kramer PL, Gramer E, Reis A, Acott TS, Wirtz MK (2012) Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet, 21: 1336-49 Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Do- nato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schröck E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (2012) Range of genetic mutations associated with severe non-syndromic sporadic X-Ray presenting features of skeletal dysplasia in patients with autosomal-recessive Short rib-Polydactyly syndrome intellectual disability: an exome sequencing study. Lancet, caused by identified NEK1 mutations. NEK1 is part of the primary cilium (ciliopathy). Immunofluorescence analysis 380: 1674-82 demonstrates characteristic dysmorphic cilia in the patient cells.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 139 UNIVERSITY HOSPITAL

Institute of Neuropathology Chair of Neuropathology

Address this model, we also tested new therapeutic on the treatment of neuroendocrine tumors Schwabachanlage 6 approaches to target DNA methylation. Re- (e.g. pituitary adenomas, craniopharyngeo- 91054 Erlangen search of human epilepsies and histopatho- mas), unique collection of surgical tissue sam- Phone: +49 9131 8526031 logically well-characterized surgical speci- ples is available for a systematic molecular-neu- Fax: +49 9131 8526033 mens obtained from patients with temporal ropathological examination. Our research www.epilepsie-register.de lobe epilepsy opens new avenues to study topics address three major questions: higher brain function in humans, i.e. the (1) Molecular tumorigenesis, Head of Department hippocampus plays a major role in memory (2) Pathogenesis of brain invasion, and Prof. Dr. med. Ingmar Blümcke formation. In addition, our finding of epi- (3) Molecular genetic analysis as a tool for eval- lepsy-induced neurogenesis in the human uating prognosis and therapy. Contact hippocampus offers the possibility to unravel For our biomolecular and genetic analysis, we Prof. Dr. med. Ingmar Blümcke molecular signals for the recruitment, prolifer- have access to a tissue bank comprising more Phone: +49 9131 8526031 ation, and differentiation of adult stem cells in than 500 unique tumors of the pituitary gland Fax: +49 9131 8526033 the human brain. as well as craniopharyngiomas. Major improve- [email protected] ments result from the analysis of b-catenin mu- Molecular myopathology tations in craniopharyngiomas and its impact Research Focus Project manager: Prof. Dr. R. Schröder in the differential diagnosis of cystic tumors •• Focal human epilepsies and animal models The central research topic of our group is of the sellar region. Primary cell cultures of •• Molecular myopathology the pathogenesis of myofibrillar myopathies craniopharyngiomas were used to unravel the •• Neuro-oncology which are morphologically characterized by molecular impact of Wnt signaling and EGFR the presence of pathological protein aggre- Structure of the Department signaling on the pathogenesis and morphol- gation in cross-striated muscle cells. These ogy of this peculiar tumor entity. Future work adult onset and often heritable myopathies Our academic staff and technicians are en- will address the development of novel animal are clinically characterized by a progressive gaged in studies addressing molecular path- models to identify and verify molecular targets, course leading to severe disability and pre- omechanisms of CNS and skeletal muscle dis- needed for therapeutic intervention, e.g. EGFR mature death. To date, no drug treatment is orders. Particular focus is on epilepsy surgery, inhibitor gefitinib. available for these disorders. The main focus neuro-oncology, and myopathies. We have of our current research work is the generation established the neuropathological reference Teaching and characterization of transgenic mouse center for epilepsy surgery and the European models for the IBMPFD disease (Inclusion Epilepsy Brain Bank (supported by EU). Our Institute is enrolled in pathology training Body Myopathy associated with Pagets dis- and lectures. Research ease of bone and Frontotemporal Dementia), the desmin myopathy and cardiomyopathy, Selected Publications Focal human epilepsies and animal and the filamin C-associated myopathy. The Hölsken A, Gebhardt M, Buchfelder M, Fahlbusch R, Blüm- clinical, morphological, biochemical, and cke I, Buslei R (2011) EGFR signaling regulates tumor cell models migration in craniopharyngiomas. Clin Cancer Res, 17: Project manager: Prof. Dr. I. Blümcke molecular analysis of these mouse models 4367-77 This research topic addresses drug-resistant shall provide deeper insights into the molec- Arhzaouy K, Strucksberg KH, Tung SM, Tangavelou K, focal epilepsies in humans. To unravel the ular ”sequence” that leads to pathological Stumpf M, Faix J, Schröder R, Clemen CS, Eichinger L protein aggregation and progressive muscle (2012) Heteromeric p97/p97R155C complexes induce molecular pathogenesis of major entities asso- dominant negative changes in wild-type and autophagy ciated with chronic seizures, e.g. hippocam- damage in these disorders. This work will be 9-deficient Dictyostelium strains. PLoS ONE, 7: e46879 pal sclerosis, glio-neuronal tumors, and focal the basis for novel targeted treatment strate- Blümcke I, Coras R, Miyata H, Ozkara C (2012) Defining cortical dysplasias, we performed systematic gies. Our research is currently funded by the clinico-neuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis. Brain Pathol, analysis using surgically resected brain spec- DFG (research unit FOR 1228, see own re- 22: 402-11 imens and correlated them with clinical his- port), the Else-Kröner-Fresenius Foundation, Clemen CS, Eichinger L, Schroder R (2012) Reply: Hered- tories and postsurgical follow-up data. Our the Johannes und Frieda Marohn-Founda- itary spastic paraplegia caused by a mutation in the VCP work helped to settle new international tion, and the Deutsche Gesellschaft für Mus- gene VCP: A Jack of all trades in neuro- and myodegener- standards for the diagnosis of Focal Cortical kelkranke. ation? Brain, 135: 1-3 Dysplasias. Our group also addresses molec- Kobow K, Blümcke I (2012) The emerging role of DNA methylation in epileptogenesis. Epilepsia, 53 Suppl 9: 11- ular pathomechanisms of epileptogenesis. Neuro-oncology 20 We characterize epigenetic chromatin modi- Project manager: PD Dr. R. Buslei Mühlebner A, Coras R, Kobow K, Feucht M, Czech T, Ste- fications within human surgical specimens as Neuro-oncology plays an important role in our fan H, Weigel D, Buchfelder M, Holthausen H, Pieper T, well as using an experimental animal model clinico-neuropathological surveillance. With Kudernatsch M, Blümcke I (2012) Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE with 24h video-EEG monitoring which helps the international reputation of the Department 2011 classification system and diagnostic implications for to quantitatively examine seizure burden. In of Neurosurgery in Erlangen and its emphasis MRI. Acta Neuropathol (Berl), 123: 259-72

140 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) International Cooperations Prof. J. Engel Jr., Seizure Disorder Center, David Geffen School of Medicine at UCLA, Los Angeles: USA Prof. A. El-Osta, Epigenetics in Human Health and Dis- ease Laboratory, and Preclinical Diabetes Division Baker IDI Heart & Diabetes Institute, Monash University, Mel- bourne: Australia Prof. G. Wiche, Max F. Perutz Laboratories, University of Vienna, Vienna: Austria Prof. F. Cendes, Depatment of Neurology, University of Campinas, Campinas: Brazil Dr. U. Bartels, Department of Paediatrics, SickKids - Hos- pital, Toronto: Canada Axonal reorganization in hippocampus of chronic epilep- Prof. A. Pitkänen, Neurobiology Unit and Vice-Dean of Virtanen Institute, University of Eastern Finland, Kupio: tic rat. Finland Axonal reorganization in the hippocampus of chronic epileptic rats. TIMM staining reveals zinc enriched axons Dr. R. Spreafico, Department of Epilepsy Clinic and Exper- aberrantly invading the supragranular and inner molecu- imental Neurophysiology, IRCCS Foundation Neurological lar layer of the dentate gyrus of chronic epileptic rats, but Institute “Carlo Besta”, Milano: Italy also the infrapyramidal band of CA3 (black arrowheads).

Meetings and International Training Courses 12.-15.09.2012: 57. Jahrestagung der Deutschen Ge- sellschaft für Neuropathologie und Neuroanatomie (DGNN) 2012, Erlangen Activated EGFR in Craniopharyngiomas b-catenin (red) and phosphorylated epithelial growth factor receptor (EGFR-P, green) double immunofluorescence staining of an adamantinomatous craniopharyngioma. Cells with an activated Wnt-signaling pathway representing b-catenin accumulations show also an activation of the EGFR signaling pathway as depicted in Merge (yellow). In- hibition of EGFR signaling could be a new therapeutic treatment option as it interrupts tumor cell migration in vitro.

Intracellular protein aggregates (arrowheads) present a characteristic finding in desmin myopathies. Upper image: Gomori staining. Lower image: Fluorescence microscopic analysis of desmin immunoreactivity.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 141 UNIVERSITY HOSPITAL

Institute of Pathology Chair of General Pathology and Pathological Anatomy

Address The aims of the group which started in Ok- discover molecular prognostic markers and to Krankenhausstraße 8-10 tober 2011 are development and functional identify molecular markers that could be used 91054 Erlangen validation of diagnostic, prognostic, and pre- in the clinical-pathological differential diagno- Phone: +49 9131 8522286 dictive molecular-based markers in soft tissue sis and therapeutic stratification of breast and Fax: +49 9131 8524745 tumors (Sarcomas and GIST), lung cancer, ovarian cancer. www.pathologie.uk-erlangen.de and breast cancer. There is a strong focus The subject of a further research project are on the establishment of next generation se- the molecular changes in tumors of the head Head of Department quencing techniques, such as 454 sequenc- and neck region, in cooperation with the Prof. Dr. med. Arndt Hartmann ing which are more sensitive and allow much Department of Otorhinolaryngology - Head broader analyses as compared to classical and Neck Surgery (Prof. Dr. H. Iro), and the Contact Sanger sequencing. The group is currently Department of Oral and Cranio-Maxillofa- Prof. Dr. med. Arndt Hartmann establishing tumor-type specific gene panels cial Surgery (Prof. Dr. F.W. Neukam, Prof. Dr. Phone: +49 9131 8522286 for simultaneous analysis by 454 sequencing Dr. E. Nkenke). This research project has two Fax: +49 9131 8524745 (e.g. EGFR, KRAS, BRAF, and PI3K mutation objectives: One is to compile a molecular-pa- [email protected] analysis in lung cancer biopsies). Another aim thological and histopathological classifica- is the concurrent analysis of DNA mutations, tion of salivary gland tumors with low and Research Focus DNA methylation patterns, mRNA, and pro- high risk of relapse and progression, the •• Diagnostic Molecular Pathology tein expression profiles in tumor tissues for •• Experimental Tumor Pathology second is to identify early molecular markers a better, multidimensional understanding of to identify dysplastic changes as tumor pre- •• Clinical and Predictive Molecular Pathology the functionally relevant signaling mecha- of Urethelial Carcinoma cursors in the mucosa of the head and neck nisms in cancer. •• Pathology of Immune and Inflammatory Re- region. An additional research project investigates the actions Experimental Tumor Pathology molecular pathology of thymoma. The aim of Project managers: Dr. T. Rau, C. Geppert, Prof. Structure of the Department the research in this project is the detection of Dr. R. Schneider-Stock, Prof. Dr. A. Hartmann, genetic alterations in these rare tumors and the Prof. Dr. A. Agaimy, Dr. D. Wachter, Dr. J. Strehl, The Institute of Pathology includes also the Di- interaction of these tumors with the immune Dr. K. Brunner, Prof. Dr. R. Rieker vision of Nephropathology. A total of 85 mem- system. A major focus is the molecular and biochemical bers of staff work at the Institute of Pathology, characterization of genetic and epigenetic in- 30 are medical professionals or scientists. Of Clinical and Predictive Molecular Pa- duced changes in tumors and preneoplasias of these, 15 are currently financed by third-party thology of Urethelial Carcinoma the gastrointestinal tract. The main focus is on funding. Project managers: Prof. Dr. A. Hartmann, PD research projects for the molecular regulation The Institute of Pathology is responsible for all Dr. R. Stöhr, Dr. C. Stöhr, Dr. J. Giedl, Dr. S. of apoptosis in colorectal carcinomas and ad- pathology diagnostics within the UK Erlangen Bertz eno-carcinomas of the lower oesophagus (Bar- and for more than 30 external hospitals and The research group investigates the basic mo- rett carcinoma). physicians. The pathology diagnoses are car- lecular principles of the development of urethe- Furthermore, we focus on the basic molec- ried out using the latest microscopic, immu- lial carcinoma of the urinary bladder, prostate ular principles of chronic gastritis and Barrett nohistochemical, and molecular methods. In metaplasia and the significance of epigenetic cancer, and renal cell carcinoma. There is a addition to the histopathological evaluations close cooperation with the Department of Urol- of approximately 45,000 samples, more than changes in malignant tumors as well as on the ogy at the FAU at the Waldkrankenhaus St. Ma- 2,500 molecular pathology investigations are functional consequences of early epigenetic rien gGmbH and also with numerous national carried out. changes in the intestinal epithelium in colitis and international cooperation partners. The re- The diagnostics specialties of the Institute are ulcerosa. search group cooperates with several networks urogenital and gynecological pathology as well The molecular characterization of gastrointes- of German urology (German Prostate Cancer as breast pathology. Other focuses are the di- tinal stroma tumors and malignant mucosal Consortium, German Research Consortium Re- agnosis of soft part tumors and gastrointestinal melanomas is to identify new markers for bet- nal Cell Carcinoma, German Research Consor- tumor pathology. The clinical focuses are very ter estimation of the prognosis and therapy closely linked to the research topics of the Insti- response. tium Bladder Cancer). The objective is the iden- tute of Pathology, with associate professorships The second main focus, in cooperation with tification of genomic and epigenetic changes in ”Experimental Tumor Pathology” and ”Diag- the Department of Obstetrics and Gynecology in urothelial carcinomas of the urinary bladder nostic Molecular Pathology”. (Prof. Dr. M. Beckmann, Prof. Dr. P. Fasching), and kidney tumors to identify new markers the West German Study Group (Prof. Dr. U. for early diagnosis and new therapeutic target Research Nitz, Dr. O. Gluz), and the Institute of Pathol- molecules. In prostate cancer, the main focus ogy of the RWTH Aachen (Prof. Dr. E. Dahl), is the identification of epigenetic alterations. Diagnostic Molecular Pathology is on the discovery of genetic and epigenetic In addition, one of the priorities of the work is Project managers: Prof. Dr. F. Haller, Dr. E.A. changes in breast cancer and ovarian carcino- the correlation of clinical-pathological findings Moskalev mas. The objective of the research here is to with the molecular changes.

142 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Pathology of Immune and Tudor CS, Dawson CW, Eckhardt J, Niedobitek G, Büttner Inflammatory Reactions AC, Seliger B, Hartmann A, Buettner M (2012) c-Myc and EBV-LMP1: two opposing regulators of the HLA class I anti- Project manager: PD Dr. M. Büttner-Herold gen presentation machinery in epithelial cells. Br J Cancer, This project examines the interaction between 106: 1980-8 infection and B-cell differentiation in primary and persistent EBV infection and the mecha- International Cooperations nisms and interactions between the immune M. Jasiulionis, Institute of Pharmacology, University Sao system and tumor cells in different tumor Paulo, Sao Paulo: Brazil types (prostate carcinoma, renal cell carcino- S. Jarmalaite, Human Genome Research Centre, Faculty of ma, Hodgkin lymphoma). The objective is the Natural Sciences, Vilnius University, Vilnius: Lithuania identification of mechanisms through which T. Ornthoft, Aarhus University Hospital Skejby, Depart- ment of Molecular Medicine (MOMA), Aarhus: Denmark the tumor cells could escape the immune response of the organism. E. Zwarthoff, Erasmus MC, Rotterdam: The Netherlands Immunohistochemical staining of papillary bladder tumors with anti-MTUS1-antibody; A and B show tumors D. Theodorescu, University of Colorado Cancer Center, Denver: USA with negative staining, C and D show positive, cytoplas- Teaching mic staining (arrows); MTUS1 (microtubule associated P. Real and N. Malats, CNIO, Madrid: Spain tumor suppressor 1) is a tumor suppressor protein which The Institute of Pathology has an essential W. EL-Rifai, Vanderbilt University, Memphis: USA is located in the cytoplasm in small, punctual aggrega- tions. role in the teaching of students of human, dental, and molecular medicine and in de- Meetings and International Training livering the study course ”Medical Process Courses A Management”. In addition to traditional tea- 16.-19.06.2011: 95. Jahrestagung der Deutschen Ge- ching formats (main lectures, block semi- sellschaft für Pathologie e.V., Leipzig nars), the Institute also offers integrated and 31.05.-03.06.2012: 96. Jahrestagung der Deutschen Ge- sellschaft für Pathologie e.V., Berlin interdisciplinary courses. In particular, the teaching course in the autopsy ward and the Research Equipment interdisciplinary course ”Conference of Clini- cal Pathology” have to be mentioned. In the Stratifyer, automated DNA-RNA-extraction system study course ”Molecular Medicine”, we offer BD Biosciences, Flow Cytometer teaching courses such as ”Basic Principles of Roche, GS Junior, 454 Sequencing technology Pathology”, ”Basic Principles of Tumor Biolo- PALM, laser microdissection B gy” (literature seminar), and other subjects of Zeiss, laser scanning microscop molecular pathology. Decon Science Tec GmbH, microscop live-cell-migration unit

Selected Publications Bertz S, Denzinger S, Otto W, Wieland WF, Stoehr R, Hof- staedter F, Hartmann A (2011) Substaging by estimating the size of invasive tumour can improve risk stratification in HDAC inhibitor pT1 urothelial bladder cancer-evaluation of a large hospi- LBH589 tal-based single-centre series. Histopathology, 59: 722-32 induces Fasching PA, Heusinger K, Haeberle L, Niklos M, Hein A, autophagy Renal cell carcinomas carrying TFE3 translocations fre- Bayer CM, Rauh C, Schulz-Wendtland R, Bani MR, Schraud- in tumor cells quently demonstrate TFE3 overexpression. A: Hematoxi- er M, Kahmann L, Lux MP, Strehl JD, Hartmann A, Dimmler (LC3-II lin and eosin staining of a tumor demonstrating typical A, Beckmann MW, Wachter DL (2011) Ki67, chemotherapy punctuates - features of a TFE3 translocation tumor. B: Staining the response, and prognosis in breast cancer patients receiving green, tumor with a TFE3-antibody results in clear nuclear posi- neoadjuvant treatment. BMC Cancer, 11: 486 DAPI - blue). tivity which is caused by TFE3 overexpression. Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, Moskaluk CA, Fradet Y, Lehmann J, Stöckle M, Hartmann A, Lee JK, Theo- dorescu D (2011) A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol, 12: 137-43 Bertz S, Otto W, Denzinger S, Wieland WF, Burger M, Stöhr R, Link S, Hofstädter F, Hartmann A (2012) Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Re- currence, Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer. Eur Urol, http://dx.doi.org/ 10.1016/j.eururo.2012.05.033 Rau TT, Rogler A, Frischauf M, Jung A, Konturek PC, Dimmler A, Faller G, Sehnert B, El-Rifai W, Hartmann A, Voll RE, Schneider-Stock R (2012) Methylation-dependent A) Lung cancer specimen, micropapilly type, with a tumor cell content of <10%. B) 454 sequence analysis reveals a activation of CDX1 through NF-kB: a link from inflamma- therapeutically relevant EGFR exon 19 deletion which is present in 4.3% of all examined alleles, corresponding to 50% tion to intestinal metaplasia in the human stomach. Am J of all tumor cells. C) Due to the high amount of non-neoplastic cells, the mutation is not detectable in the classical Pathol, 181: 487-98 Sanger sequence analysis of the same DNA isolate.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 143 UNIVERSITY HOSPITAL

Institute of Pathology Division of Nephropathology

Address Research - Does stimulation of angiogenesis in CKD by Krankenhausstraße 8-10 hypoxic preconditioning or overexpression of 91054 Erlangen Clinical and experimental Nephro- VEGF lead to improved capillarisation and per- Phone: +49 9131 8522291 pathology fusion after ischemia? Fax: +49 9131 8522601 Project manager: Prof. Dr. K. Amann www.nephropathologie.uk-erlangen.de Clinical and experimental cooperations are well Podocytes as non-hematopoetic antigen- established with clinical partners (Department presenting cells Head of Division of Medicine 4 and Pediatric Nephrology) and This project was performed in collaboration Prof. Dr. med. Kerstin Amann several research groups of the UK Erlangen with Dr. A. Goldwich (Department of Derma- respectively of the FAU working in the field of tology, UK Erlangen). Podocytes are highly dif- Contact nephrology. Main focus of the Division of Ne- ferentiated epithelial cells of the kidney which PD Dr. rer. nat. Christoph Daniel phropathology is to test molecular hypotheses can present antigen and can initiate a specific Phone: +49 9131 8522602 on experimental and human kidney biopsy ma- T cell response in vitro and in vivo. As previous- Fax: +49 9131 8522600 terial. ly shown only for hemopoietic cells, podocytes [email protected] have the capability to activate naive T cells by Proteasome inhibition as a new ther- MHC class I, MHC class II, and crosspresenta- Research Focus apeutic intervention in inflammatory tion. Thus, podocytes may represent novel tar- •• Clinical and experimental nephropathology kidney diseases gets for immunotherapy of inflammatory kid- •• Proteasome inhibition as a new therapeutic In cooperation with Prof. Dr. R. Voll (Depart- ney diseases and potentially also for prevention intervention in inflammatory kidney diseases ment of Immunology, University of Freiburg) of kidney rejection. In this project, we investi- •• Pathomechanisms and modulation of im- and Prof. Dr. M. Wiesner (Department of Med- gate in vitro and in vivo mechanisms of antigen paired angiogenesis and angioadaption in icine 4, UK Erlangen), it is explored whether presentation by podocytes. chronic renal failure proteasome inhibition constitutes a new ther- •• Podocytes as non-hematopoetic antigen- apeutic option in the treatment of Lupus-ne- Regression of cardiovascular changes presenting cells phritis and also other immuno-complex medi- by kidney transplantation •• Regression of cardiovascular changes by kid- ated inflammatory kidney diseases. To test this Patients with CKD represent a disproportion- ney transplantation hypothesis, medical interventions for proteases ately high prevalence and mortality for cardio- inhibition in standard models of systemic Lupus •• Causes and effects of a reduced nephron vascular diseases leading to a significant clinical erythematodes and other inflammatory kidney number problem. diseases are investigated. •• The role of CD26 in the manifestation of Cardiovascular diseases in these patients are ischemia/reperfusion injury and acute rejec- 20 times more common than in age- and Pathomechanisms and modulation of tion in the transplanted kidney gender-matched collective of the general impaired angiogenesis and angioadap- •• The role of PAR-2 in hypertensive kidney and population and up to three times more fre- tion in chronic renal failure heart damage quent than in other risk collectives, such as This project is performed in collaboration with patients with diabetes mellitus. CKD causes Prof. Dr. K.F. Hilgers (Department of Medicine Structure of the Department characteristic myocardial structural changes, 4). Mortality rate is still very high in patients such as left ventricular hypertrophy (LVH), with chronic kidney disease (CKD); it is in fact The Division of Nephropathology together with interstitial myocardial fibrosis, artery as well comparable to that of many cancer patients. the Chair of General Pathology and Pathological as myocardial wall thickening, and an inad- Death from cardiac causes is the leading cause equate low myocardial capillarisation. The Anatomy constitutes the Institute of Pathology. of death in these patients. Cardiac mortality of latter is accompanied by an increase in inter- The Division employs a total of 19 members of young dialysis patients is nearly 1,000-fold great- staff of which seven are financed by third-party er than in the general population. CKD patients capillary distances and a reduced blood and funds. Research is carried out by one postdoc, show characteristical cardiovascular structural oxygen supply contributing to the apparently one PhD student and four technical staff. Since alterations, like left ventricular hypertrophy with reduced ischemia tolerance of the myocar- October 2012, Prof. Dr. F. Engel has filled the reduced myocardial capillary density, increased dium in CKD. So far, it is completely unclear new W2-professorship for "Experimental kidney intercapillary distance, and reduced myocardial whether the cardiovascular changes, caused and circulation research" and has started with ischemia tolerance as well as peripheral artery by a progressive CKD, are reversible. It is com- two staff members to build up his laboratory. disease with higher ischemia susceptibility. Our pletely unclear whether a kidney transplant The Division of Nephropathology is responsible own data as well as data from the literature in- can prevent further progression of cardiovas- for the kidney biopsy diagnosis of the UK Erlan- dicate that impaired angiogenesis in particular cular changes or whether these changes can gen (Department of Medicine 4 and Pediatric in response to hypertrophy or ischemia plays an be regressed. These clinically highly relevant Nephrology of the Department of Pediatrics important pathophysiological role. Using a well issues will be investigated experimentally in and Adolescent Medicine) and of further 90 established animal model of CKD (subtotally rats with subtotale nephrectomy and subse- external biopsy senders. The kidney biopsy dia- nephrectomised rat, SNX), we will address the quent renal transplantation. gnosis is carried out using the latest light-mi- following questions: croscopic, immunohistological, electron micro- - Is ischemia in CKD associated with lower ex- Causes and effects of a reduced scopic, and molecular methods. In this field, pression of proangiogenic factors and/or re- nephron number there are close links with the corresponding duced recruitment of hematopoietic stem cells In cooperation with PD Dr. K. Benz (Depart- structures of the Institute of Pathology. from the bone marrow? ment of Pediatrics and Adolescent Medicine,

144 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) UK Erlangen), we are especially interested in Buettner M, Xu H, Böhme R, Seliger B, Jacobi J, Wiesener learning whether a structural malformation M, Benz K, Amann K (2012) Predominance of TH2 cells and plasma cells in polyoma virus nephropathy: a role for of the kidney - using an animal model of low humoral immunity? Hum Pathol, 43: 1453-62 nephron number - is pre-conditional for the Goldwich A, Steinkasserer A, Gessner A, Amann K (2012) Im- formation of hypertension and kidney dis- pairment of podocyte function by diphtheria toxin - a new reversible proteinuria model in mice. Lab Invest, 92: 1674-85 eases. Hainz N, Thomas S, Neubert K, Meister S, Benz K, Rauh M, Daniel C, Wiesener M, Voll RE, Amann K (2012) The The role of CD26 in the manifestation of proteasome inhibitor bortezomib prevents lupus nephritis ischemia/reperfusion injury and acute in the NZB/W F1 mouse model by preservation of glo- merular and tubulointerstitial architecture. Nephron Exp rejection in the transplanted kidney Nephrol, 120: e47-58 In cooperation with Prof. Dr. S. von Hörsten (Division of Experimental Therapeutics, FAU), we examine whether the lack or inhibition of dipeptidylpeptidase IV (DPP4) reduces ischemia/reperfusion injury and acute rejection. In a rat model for kidney transplantation, changes in DPP4 expression and localization as well as alterations in kidney function were investigated by using DPP4 deficient and wild- type rats. Hereby, we try to identify how DPP4 influences pathological changes in ischemia/ reperfusion injury. After induction of anti-GBM-nephritis, some podocytes The role of PAR-2 in hypertensive (Podocalyxin yellow stain) have direct contact with kidney and heart damage T cells (CD3 red stain) and were not seperated by a base- Protease activated receptor-2 (PAR-2) is a ment membran (Laminin green stain). G-protein coupled receptor that can be activated by numerous serine proteases which were secreted after tissue injury. In this project, we investigate PAR-2 as a potential target for the treatment of inflammatory and fibrotic organ damage. The pathogenetic role of this receptor will be evaluated using PAR-2 deficient mice in an angiotensin II induced hypertensive model.

Teaching

The Division of Nephropathology participates in the teaching of the Institute of Pathology. In addition, nephropathological conferences with the clinical departments of the UK Erlan- gen and external biopsy senders regularily take place. Furthermore, twice a year a kidney pathology course takes place for both, staff of the UK Erlangen and staff of external hospitals.

Selected Publications Amann K, Odoni G, Benz K, Campean V, Jacobi J, Hilgers KF, Hartner A, Veelken R, Orth SR (2011) Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure. Am J Physiol Renal Physiol, 300: F105-12 Benz K, Campean V, Cordasic N, Karpe B, Neuhuber W, Mall G, Hartner A, Hilgers KF, Amann K (2011) Early glo- merular alterations in genetically determined low nephron number. Am J Physiol Renal Physiol, 300: F521-30 Tyralla K, Adamczak M, Benz K, Campean V, Gross ML, Hilgers KF, Ritz E, Amann K (2011) High-dose enalapril treatment reverses myocardial fibrosis in experimental uremic cardiomyopathy. PLoS ONE, 6: e15287

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 145 UNIVERSITY HOSPITAL

Institute of Radiology Chair of Diagnostic Radiology

Address The majority of diagnostic and interventional proved in vitro and in vivo, and there will be Maximiliansplatz 1 imaging procedures in radiology are associ- further investigations on this topic. 91054 Erlangen ated with radiation exposure. CT is the major Phone: +49 9131 8536065 contributor to overall medical x-ray exposition. Functional and metabolic MRI Fax: +49 9131 8536068 Different strategies are followed to reduce dose Project managers: Prof. Dr. M. Uder, PD Dr. R. www.radiologie.uk-erlangen.de while maintaining diagnostic image quality. Janka, Dr. M. Hammon, PD Dr. S. Alibek, Prof. Current projects include high-pitch scanning, Dr. A. Cavallaro Head of Department automated anatomy based tube voltage/tube Diffusion weighted imaging (DWI) visualizes Prof. Dr. med. Michael Uder current adaption, as well as organ based tube the diffusion of free water molecules in tissue. current adaption. Monte-Carlo-simulations pro- The physiological amount of diffusion is dis- Contact vide volume data of dose distribution that al- turbed in tissue with higher cell density par- Dr. med. Ferdinand Kammerer low for risk evaluation and analysis of dose re- ticularly in tumors. The use of DWI develops Phone: +49 9131 8536065 duction techniques. more and more to the third component of MR Fax: +49 9131 8536068 Iterative reconstruction techniques are used imaging beside morphology and contrast en- [email protected] and evaluated to reduce image noise which hancement characteristics. opens the possibility to use less photons for im- In MRI, perfusion measurements without the Research Focus age acquisition and therefore reduce radiation use of contrast material are possible. For that •• Methods of dosage reduction in medical exposure. Metal artifact reduction algorithms purpose, the inflowing (arterial) spins are la- imaging are developed and evaluated to reduce artifacts beled magnetically and their concentration in •• X-ray induced DNA damages in radiology derived from metal hardware (surgical plates, the organ of interest can be measured as signal •• Functional and metabolic MRI prostheses, dental fillings, etc.). intensity. Our focus of interest is on the kidney •• Imaging of the head and neck where the effect of antihypertensive therapy on •• Interventional radiology X-ray induced DNA damages in radiology the kidney perfusion can be visualized directly. •• Cardiovascular imaging Project managers: PD Dr. M. Küfner, Dr. M. Sodium can be used to perform MR imaging in •• Breast imaging Brand, Dr. M. May, PD Dr. S. Schwab, C. En- a similar way as hydrogen. With sodium MRI, gert, Prof. Dr. M. Uder we are able to measure the sodium concentra- Structure of the Department Established dose parameters, as DLP or DAP, tion in tissue non-invasively. Research on this can detect the physical exposure, but give no imaging method is focused on its further tech- The Institute of Radiology of the FAU has four evidence about the individual, biological radia- nical development, its absolute calibration, and subsections (internal medicine, surgery, pedi- tion effects. These effects depend on individual the evaluation of possible clinical applications. atric radiology, and gynecology). There is an factors, like age, body weight, or by the ge- intense cooperation with the Department of netic disposition. Double-strand breaks (DSB) Imaging of the head and neck Neuroradiology. The staff of the Institute con- are among the most significant radiation in- Project managers: Prof. Dr. M. Lell, Dr. M. Kra- sists of 37 medical doctors (thereof four profes- duced DNA damages. DSB can be detected mer, Dr. M. May, Dr. A. Eller, PD Dr. S. Schwab sors and five assistant professors) and 68 radio- by using an immunofluorescence microsco- Methodological and clinical studies evaluat- graphers/assistants (as of end of 2012). pic technique. The sensitive method is based ing the use of CT und MRI in morphological The Institute of Radiology provides the full on the phosphorylation of the histone variant and functional imaging of head and neck tu- range of radiological imaging modalities. Fur- thermore, a variety of interventional proce- H2AX after DSB formation and staining with mors. Cooperation with the Department of dures, like imaging guided biopsies or angio- specific antibodies. Otorhinolaryngology - Head and Neck Sur- graphic therapies, is performed. Recent studies have shown a strong correlation gery (Prof. Dr. H. Iro), Department of Oral and In cooperation with Siemens Healthcare, the between DSB levels and the dose deposed in Cranio-Maxillofacial Surgery (Prof. Dr. Dr. F.W. Imaging Science Institute (ISI) is operated and blood lymphocytes of patients undergoing CT- Neukam), and the Department of Radiation integrates new developments in diagnostic im- scans, cardiac-CT, PET-CT, mammography, or Oncology (Prof. Dr. R. Fietkau). aging and novel IT-solutions into the clinical angiography. Within 24 to 48 hours after ex- Methodological and clinical studies evaluat- routine and into the academic research (see posure, the number of DNA lesions returned ing the use of CT and MRI in the preparation own report). to the baseline levels due to repair. In angio- and planning of reconstructive surgery in co- Different study groups and projects evaluate graphy, DNA damages were also dependent on operation with the Department of Oral and the clinical impact of various imaging proce- the anatomic region exposed and the duration/ Cranio-Maxillofacial Surgery (Prof. Dr. Dr. F.W. dures or go for new developments. Further- fractionation of the exposure. Neukam). more, experimental laboratory studies play a In current studies, the influence of new well-established role in our scientific activities. CT-technologies (e.g. Dual-source CT, Flash- Interventional radiology CT with high-pitch, Flat-panel CT) and of dose Project managers: Prof. Dr. M. Uder, Dr. A. Research reducing approaches (e.g. risk organ based Schmid, PD Dr. M. Küfner, Dr. M. Heinz, Prof. current modulation or lens protection tools) on Dr. M. Lell, PD Dr. R. Janka Methods of dosage reduction in medi- the biological dose is investigated in patients Cooperations with the Department of Surgery cal imaging and in biological phantom models as well. Fur- (Prof. Dr. Dr. h.c. W. Hohenberger), the Depart- Project managers: Prof. Dr. M. Lell, Dr. M. May, Dr. thermore, the potential protective effect of an- ment of Vascular Surgery (Prof. Dr. W. Lang), W. Wüst, Dr. A. Eller, Dr. M. Scharf, Dr. M. Brand tioxidants/radical binding substances could be the Department of Medicine 4 - Nephrolo-

146 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) gy and Hypertension (Prof. Dr. K.U. Eckardt), S. Schwab, Dr. B. Brehm, Dr. M. Meier-Meitin- Eller A, May MS, Scharf M, Schmid A, Kuefner M, Uder the Division of Nephropathology (Prof. Dr. K. ger, PD Dr. B. Adamietz M, Lell MM (2012) Attenuation-based automatic kilovolt selection in abdominal computed tomography: effects on Amann), the Department of Medicine 1 - Gas- Breast imaging (gynecologic radiology) is an radiation exposure and image quality. Invest Radiol, 47: troenterology, Lung Diseases and Endocrinol- important research domain of the Institute 559-65 ogy (Prof. Dr. M.F. Neurath), and the Depart- of Radiology. This research team addresses Kuefner MA, Brand M, Ehrlich J, Braga L, Uder M, Semelka ment of Nuclear Medicine (Prof. Dr. T. Kuwert). questions in the field of new developments RC (2012) Effect of antioxidants on X-ray-induced g-H2AX foci in human blood lymphocytes: preliminary observa- The relevance of the recently established enin digital mammography in cooperation with tions. Radiology, 264: 59-67 dovascular radiofrequency ablation of sympa- different medical systems manufacturers. On thetic nerve fibres in renal arteries is evaluat- Lell MM, Meyer E, Kuefner MA, May MS, Raupach R, Uder the basis of substantial experimental and M, Kachelriess M (2012) Normalized metal artifact reduced in patients with resistant hypertension. In clinical studies, their work includes develop- tion in head and neck computed tomography. Invest Ra- patients with contraindication to the standard ment, implementation, and comparison of diol, 47: 415-21 percutaneous biopsy of kidney transplants, an different digital mammography systems, in- May MS, Deak P, Kuettner A, Lell MM, Wuest W, Scharf alternative transvenous biopsy procedure via a cluding tomosynthesis (hybridsystems). Volu- M, Keller AK, Häberle L, Achenbach S, Seltmann M, Uder transfemoral approach is established. Selective M, Kalender WA (2012) Radiation dose considerations by metric analysis of tumors by mammography intra-individual Monte Carlo simulations in dual source internal radiotherapy and CT-guided irrevers- and (automated) ultrasound and the further spiral coronary computed tomography angiography with ible electroporation are initiated in patients characterization of breast masses by sono- electrocardiogram-triggered tube current modulation and adaptive pitch. Eur Radiol, 22: 569-78 with liver malignancies. New software tools in graphic elastography are under investigation. Anders K, Achenbach S, Petit I, Daniel WG, Uder M, CT-guided interventions are evaluated. Furthermore, a recently introduced MRI-based Pflederer T (2013) Accuracy of automated software-guid- method for diagnosing ductal disease is being ed detection of significant coronary artery stenosis by CT Cardiovascular imaging continuously evaluated. Another main focus in angiography: comparison with invasive catheterisation. Project managers: PD Dr. K. Anders, PD Dr. R. breast MRI lies in the development of new MRI Eur Radiol, 23: 1218-25 Janka, Prof. Dr. M. Lell, Dr. M. Scharf, Dr. M. sequences for better differentiation between May, Dr. A. Schmid, Dr. W. Wüst International Cooperations malignant and benign breast disease. - Pre-clinical and clinical studies in cooperation Prof. L. Defreyne, University Hospital Gent, Gent: Belgium with the Department of Medicine 2 - Cardiolo- Teaching Prof. M. Takahashi, National Cancer Center, Tokyo: Japan gy and Angiology (Prof. Dr. W.G. Daniel, Prof. Prof. D. Enzmann, University of California UCLA, Los An- Dr. S. Achenbach) to evaluate CT and MR for Besides the university standard lectures and geles: USA morphological and functional imaging of ap- practical courses, innovative clinically orientated parent coronary artery disease; courses as interactive discussions of clinical cases Meetings and International Training - Pre-clinical and clinical studies in cooperation are offered regularly. In these courses the stu- Courses with the Department of Medicine 2 - Cardiolo- dents are taught a much more analytic and clin- 25.-27.03.2011: Moderne Mammadiagnostik, Erlangen gy and Angiology (Prof. Dr. W.G. Daniel, Prof. ical than systematic approach towards the in- Dr. S. Achenbach) in line with the ”Excellenz- 30.06.-02.07.2011: MR Compact, Bamberg clusteriniative”, project BD-02, to evaluate the terpretation of radiologic images. A new online 24.-25.09.2011: Mammasonokurs, Erlangen course for students to prepare effectively for the potential of coronary CT-angiography in early 27.-29.04.2012: Moderne Mammadiagnostik, Erlangen state examination was established. Furthermore, diagnosis of coronary artery sclerosis; 14.-16.06.2012: MR Compact, Bamberg - Pre-clinical and clinical trials to standardize read- we always offer the possibility to perform clinical 29.-30.09.2012: Mammasonokurs, Erlangen ing and reporting of coronary CT-angiography; electives or internships at our Institute. Students - Pre-clinical and clinical trials in cooperation wanting a doctor’s degree are supervised when Research Equipment with the Department of Medicine 2 - Cardiol- writing their experimental or clinical thesis. Siemens, Magnetom Verio ogy and Angiology (Prof. Dr. S. Achenbach), the Institute of Medical Physics (PD Dr. W. Selected Publications Siemens, Magnetom Aera Kemmler), and the Division of Trauma Surgery Meier-Meitinger M, Häberle L, Fasching PA, Bani MR, Siemens, Somatom Definiton AS+ (Prof. Dr. F. Hennig) using cardiac MRI (cMRI) Heusinger K, Wachter D, Beckmann MW, Uder M, Siemens, Somatom Definition Flash Schulz-Wendtland R, Adamietz B (2011) Assessment of to assess physiological myocardial adaptation breast cancer tumour size using six different methods. Eur Siemens, Artis floor mounted system in recreational and professional athletes in Radiol, 21: 1180-7 Siemens, Mammomat Inspiration cross-sectional and longitudinal studies; - Pre-clinical and clinical trials in cooperation with the Divisions of Pediatric Cardiology (Prof. Dr. S. Dittrich) and Pediatric Cardiac Surgery (Prof. Dr. R. Cesnejvar) to evaluate cMRI in the diagnosis of congenital heart disease; - Clinical trials to optimize contrast use for 3T-MRA.

Breast imaging Project managers: Prof. Dr. R. Schulz-Wendt- Monte-Carlo-Simulation of dose distribution. land, PD Dr. E. Wenkel, PD Dr. R. Janka, PD Dr. Left: Grayscale image; Middle: Dose distribution; Right: Organ segmentation.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 147 UNIVERSITY HOSPITAL

Institute of Radiology Division of Neuroradiology

Address Research Functional and metabolic MR-Imaging Schwabachanlage 6 There are several ongoing research projects in 91054 Erlangen Clinical and experimental validation of cooperation with different departments and Phone: +49 9131 8539388 flat-panel volume CT facilities (i.e. Department of Psychiatry and Fax: +49 9131 8536179 The project is part of the Leading Edge Cluster Psychotherapy, Division of Child and Adoles- www.neuroradiologie.med.uni-erlangen.de Medical Valley, Network „Imaging”. In cooper- cent Mental Health, Division of Psychosomatics ation with the Department of Medical Physics, and Psychotherapy, Department of Medicine Head of Division Siemens Healthcare, and the Department of 3 - Rheumatology and Immunology, Depart- Prof. Dr. med. Arnd Dörfler Computer Science/Institute of Pattern Recogni- ment of Neurology, Institute of Physiology tion, we evaluate and further develop intrave- and Pathophysiology, Institute of Experimental Contact nous and intraarterial flat-panel volume CT and and Clinical Pharmacology and Toxicology) in- Prof. Dr. med. Arnd Dörfler angiographic techniques and postprocessing volving functional and metabolic MR-Imaging Phone: +49 9131 8539388 algorithms in cerebrovascular disease. Hereby, (e.g. patients with major depressive disorders, Fax: +49 9131 8536179 a focus is set on the optimized visualization of anxiety- and eating disorders, chronic pain syn- [email protected] cerebral microimplants, such as stents, coils dromes, and rheumatoid arthritis). and clips and new perfusion techniques and Research Focus 3D visualizations in stroke patients. Quantitative and qualitative assess- •• Clinical and experimental validation of flat- ment of optical fiber tracts in glau- panel volume CT Multimodal imaging of cerebrovascu- coma patients using diffusion tensor •• Multimodal imaging of cerebrovascular dis- lar diseases imaging eases In cooperation with the Department of In cooperation with the Department of Oph- •• Preoperative comprehensive imaging of ep- Neurology, we participate in several acute thalmology and Computer Science, we evaluate diffusion tensor imaging (DTI) using ilepsy stroke studies. Using multimodal MR imaging algorithms, including perfusion- and dif- 3 Tesla MRI to assess quantitative and qualita- •• Functional and metabolic MR-Imaging fusion-weighted imaging, diffusion tensor tive changes within the optical fiber tracts in •• Quantitative and qualitative assessment of imaging, susceptibility-weighted imaging, glaucoma patients at a very early stage. Dis- optical fiber tracts in glaucoma patients us- arterial spin labeling, and contrast-enhanced orders in optical fiber tracts result in reduced ing diffusion tensor imaging angiographic imaging, we evaluate the indi- fractional anisotropy (FA) and atrophy of the •• Standardization of acquisition and post-pro- vidual indication for acute stroke therapies, tracts which can be used for non-invasive and cessing MRI perfusion techniques (SAPP) such as intravenous thrombolysis, intraarte- fast screening, staging and to evaluate thera- •• Multimodal imaging in glioma and valida- rial thrombectomy, and/or other neuropro- peutical strategies in glaucoma. Moreover, first tion and development of new interventional tective therapies. Hereby, a main focus is the results indicate that DTI can distinguish at an therapies MR-derived patient selection for mechanical early stage between different forms of glauco- •• Simulation of hemodynamics and fluid dy- thrombectomy. Another clinical and scientific ma that require diverse treatment. namics in cerebral aneurysms focus is the evaluation and validation of mechanical devices for revascularization strate- Standardization of acquisition and Structure of the Department gies in acute cerebral stroke. post-processing MRI perfusion techniques (SAPP) In the Division of Neuroradiology, a total of Preoperative comprehensive imaging Broad clinical application of cerebral MR perfu- 39 staff members are employed. Research is of epilepsy sion is limited due to heterogeneous MR pro- performed by twelve medical doctors, five In cooperation with the Epilepsy Center/De- tocols used in the investigations published up postgraduates, and – externally funded – by a partment of Neurology and the Department to date and limited size of study collectives. biologist, two physicists, 16 medical technical of Nuclear Medicine, we evaluate different Therefore an international, prospective, blinded assistents, two study nurses, and a veterinarian, multimodal imaging strategies in the preop- crossover multicenter trial lead by the Depart- respectively. erative work-up of patients with focal seizures ment of Neuroradiology was designed in co- The Division of Neuroradiology performs the refractory to best medical treatment. A major operation with Bayer AG und four international neuroradiological work-up for patients of the focus is put on high-resolution morphologic Centers (Mailand/Italy, Upsala/Sweden, Ontar- UK Erlangen and for many patients referred and functional MR imaging, i.e. MR spectros- io/Canada, and Los Angeles/USA). In a first step, from external hospitals. A special focus is the copy, diffusion tensor imaging, functional MRI, the research team developed a standardized endovascular therapy of neurovascular disea- perfusion- and diffusion-weighted MRI, and MR-perfusion protocol. As next step, a large da- ses, such as acute stroke, aneurysms, stenoses MR volumetry/voxel-based morphometry. Ad- tabase will be generated based on sequence and of neck and brain vessels and arteriovenous ditionally, a dedicated GABA-specific MR spec- contrast media parameters. Collected data will malformations (AVMs), and the minimal-in- troscopy sequence is used to evaluate different be investigated by means of technical and radi- vasive therapy of spinal pain syndromes. antiepileptic therapies. ological parameters and clinical outcome.

148 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) Multimodal imaging in glioma and tional angiography in a new animal model. Eur Radiol, 21: validation and development of new 1779-87 interventional therapies Struffert T, Deuerling-Zheng Y, Kloska S, Engelhorn T, Bo- ese J, Zellerhoff M, Schwab S, Doerfler A (2011) Cerebral In cooperation with the DFG Research Group blood volume imaging by flat detector computed tomog- FOR 661 (see own report), the Department raphy in comparison to conventional multislice perfusion of Neurosurgery, the Institute of Experimen- CT. Eur Radiol, 21: 882-9 tal and Clinical Pharmacology and Toxicology Engelhorn T, Michelson G, Waerntges S, Otto M, El-Rafei A, Struffert T, Doerfler A (2012) Changes of radial diffusiv- (Preclinical Imaging Platform Erlangen, PIPE), ity and fractional anisotopy in the optic nerve and optic and the Department of Nuclear Medicine, we radiation of glaucoma patients. ScientificWorldJournal, evaluate multimodal imaging and new thera- 2012: 849632 py strategies in experimental brain gliomas, Gölitz P, Struffert T, Knossalla F, Saake M, Ott S, Ganslandt O, Doerfler A (2012) Angiographic CT with intravenous using micro-CT, high-field MRI, and micro-PET. contrast injection compared with conventional rotational Additionally, using an elastase-induced and a angiography in the diagnostic work-up of cerebral aneurysms. AJNR Am J Neuroradiol, 33: 982-7 surgical aneurysm model, we evaluate different imaging techniques and new materials and International Cooperations techniques for endovascular treatment and fol- The main focus of the Department of Neuroradiology Prof. C. Strother, Department of Radiology, University of is state-of-the-art imaging of cerebrovascular disease, low-up care. Wisconsin, Madison: USA tumors, and epilepsy and interventional neuroradiology. Dr. A. Bose, Department of Radiology and Neurology, Le- Simulation of hemodynamics and fluid nox Hill Hospital New York, New York: USA dynamics in cerebral aneurysms Prof. Dr. I. Wanke, Prof. Dr. D. Rüfenacht, Institute of Neu- In cooperation with the Department of Com- roradiology, Klinikgruppe Hirslanden, Zurich: Switzerland puter Science/Institute of Pattern Recognition, Prof. Dr. A. El-Rafei, Faculty of Engineering, Ain Shams Uni- Siemens Healthcare, and the Department of versity, Cairo: Egypt Chemical Engeneering/Fluid Mechanics, we Prof. Dr. F.A. Fellner, Dr. J. Trenkler, Institute of Radiology and Neuroradiology, AKH Linz, Linz: Austria evaluate the hemodynamic and fluid dynamics in cerebral aneurysms and malformations. Meetings and International Training A special focus is put on the effects of different Courses endovascular therapies using different endovas- 11.-12.02.2011: Workshop “Advanced Neuro-MRI”, Er- cular microimplants, such as stents and coils. langen Medium-term intention is the development 21.-22.10.2011: Workshop “Advanced Neuro-MRI”, Er- and clinical implementation of a software-plat- langen form used by endovascular radiologists. 02.12.2011: Kursus “Neuroradiologie”, Update Neurolo- gie und Psychiatrie, Düsseldorf Teaching 09.-10.05.2012: Workshop “Innovations in Interventional Neuroradiology”, Erlangen The Department of Neuroradiology is involved 22.-23.06.2012: Workshop “Advanced Neuro-MRI”, Er- in training medical students. We offer a variety langen of lectures and practical courses, partially in co- 11.-12.07.2012: Workshop “Innovations in Interventional Neuroradiology”, Erlangen operation with the Departments of Neurology 24.-25.10.2012: Workshop “Innovations in Interventional and Neurosurgery, Ophthalmology, Computer Neuroradiology”, Erlangen Science, Medical Engineering, Psychiatry and 06.-07.11.2012: Workshop “Zerebrale Aneurysmathera- Psychotherapy, and General Radiology. In addi- pie”, Erlangen tion, we train residents in neuroradiology and 07.12.2012: Kursus “Neuroradiologie”, Update Neurolo- general radiology and radiological technicians. gie und Psychiatrie, Düsseldorf

Selected Publications Research Equipment Engelhorn T, Schwarz MA, Heusch G, Doerfler A, Schulz R Siemens, 3 Tesla Magnetom TimTrio MRT (2011) Reduction of cerebral infarct size by dronedarone. Siemens, 1.5 Tesla Magnetom Aera MRT Cardiovasc Drugs Ther, 25: 523-9 Siemens, Somatom Definition AS+; 128-Zeilen-CT Kloska SP (2011) CT angiographic source images with modern multisection CT scanners: appropriate injection Siemens, Axiom Artis dBA protocol is crucial. AJNR Am J Neuroradiol, 32: E93; au- Siemens, Siemens Axiom Artis zeego thor reply E94 Struffert T, Ott S, Adamek E, Schwarz M, Engelhorn T, Klo- ska S, Deuerling-Zheng Y, Doerfler A (2011) Flat-detector computed tomography in the assessment of intracranial stents: comparison with multi detector CT and conven-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 149 DEGREE PROGRAMS

Human Medicine

Deans of Students decide to take the test can, for the selection by all students during the term. Additionally, Prof. Dr. med. Hans Drexler process in Erlangen, improve their grade of the PERLE offers special courses during the lec- Institute and Outpatient Clinic of Occupational, final secondary school examinations (Abitur). ture free time. In addition, practicing in PERLE Social, and Environmental Medicine within the frameworks of the Introduction into Clinical study section Online-Evaluation Clinical Medicine (EKM) course is a part of the Human Medicine curriculum. Prof. Dr. med. Winfried Neuhuber Each term, all courses are evaluated online by Institute of Anatomy the students with the help of the online evalu- Medical State Examination Pre-clinical study section ation platform EvaSys. The results of the online evaluation are presented and discussed in the In the study year 2011/12, the Human Medi- Address central faculty meeting once per term by the cine students in Erlangen achieved very good Institute and Outpatient Clinic of Occupational, Dean of Student Affairs. A major part of the results in the First Medical State Examination Social, and Environmental Medicine state funds is distributed in the UK Erlangen (1. Abschnitt der Ärztlichen Prüfung). Accord- Schillerstraße 25/29 according to the results of the online evalua- ing to the statistics of the German Institute 91054 Erlangen tion. Each term the students vote for the best for Medical and Pharmaceutical Examination Phone: +49 9131 8522312 lecturers and monetary sums are awarded to Questions (IMPP), the examination results Fax: +49 9131 8522317 the clinic or institute to which the winners be- of the Human Medicine students in Erlangen [email protected] long. It is noteworthy that teaching awards are have been ranking among the top results of www.studiendekanat.med.uni-erlangen.de financed by the achievement-oriented funds al- the medical departments in Germany for many location (LOM). Clinics and institutions whose years. Institute of Anatomy I instructors do best in the online evaluation re- Krankenhausstraße 9 ceive grants for good teaching performance. 91054 Erlangen The best three instructors of the clinical part Phone: +49 9131 8522265 of the degree program (terms 5 – 10) for Hu- Fax: +49 9131 8522863 man Medicine receive grants of 5,000, 3,000, [email protected] and 2,000 Euro, respectively. For the degree erlangen.de programs Dentistry, Molecular Medicine, and Medical Process Management, the best instruc- Aims and Structure tors receive 5,000 Euro each. Instructors in the pre-clinical or theoretical part of the medical In the winter term 2011/2012, 2,116 students degree program (term 1 - 4) receive certificates were enrolled in the study program of Human only; grants cannot be awarded due to cam- Medicine (185 in the 1st term) and in the sum- eralistic accountancy. Additionally, the depart- mer term 2012 this number was 2,170 (175 ments that offer the top ten classes - according in the 1st term). The percentage of women to the student evaluations - are awarded a total studying Human Medicine decreased as com- of 165,000 Euro. A class can, however, only pared to the winter term 2010/2011. In the be taken into account for a grant if it has been winter term 2011/2012 62.8% of the enrolled evaluated by at least 20% of the students in the students were female and in the summer term particular term. 2012, there were 61.4% female students. According to statistics of the FAU, for the winter Skills Lab PERLE term 2011/2012 and the summer term 2012, 6.9% of the students enrolled in the study pro- The Skills Lab PERLE offers students an opportu- gram of Human Medicine were foreigners. nity to practice medical examination skills while Applicants for this degree program are chosen being instructed by well-trained student-tutors according to the criteria of the “Stiftung für and doctors. Students can practice about 30 Hochschulzulassung” (foundation for higher different skills, e.g. auscultation, catheteriza- education admission, the successor of ZVS) tion, taking blood with the help of artificial through the corresponding online platform. arm-models, lumbar puncture, suturing, exam- Applicants are able to improve their chances ination of nervous system as well as of eye and of receiving a place on the degree program ear, preparation for clinical electives (Famula- of Human Medicine in Erlangen by taking the turen) and the practical year (Praktisches Jahr). so-called “Test für medizinische Studiengänge” Skills Lab PERLE, fully funded by student fees, (test for medical degree programs). Taking is a visible enrichment of the medical educa- the test is, however, optional. Applicants who tion in Erlangen. Courses can be attended

150 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) DEGREE PROGRAMS

Dentistry

Speaker or non-academic (the latter also essential to Prof. Dr. med. dent. Anselm Petschelt ensure a good training environment), can be guaranteed on a long-term basis. Teaching Address evaluation is part and parcel of the training Department of Operative Dentistry and program at our dentistry school. The results Periodontology are used in the process of updating and re- Glückstraße 11 structuring our curriculum with a view of 91054 Erlangen achieving steady improvement in the quality Phone: +49 9131 8533602 of teaching. Fax: +49 9131 8533603 Our Dental Department is equipped with high- [email protected] quality technical systems in sufficient numbers so www.studiendekanat.med.uni-erlangen.de/ that we have no trouble satisfying the demands and needs that arise in connection with dentistry Aims and Structure training. National and international quality com- parisons show that our standards are very good. The school of dentistry at the FAU admits ap- All the necessary prerequisites are given for our proximately 110 students per year, despite the students to receive modern, clinically oriented fact that our clinical facilities were originally training in the field of dentistry. designed to accommodate a maximum en- rollment of 100 students. The overall amount of time dedicated to curriculum teaching and examinations at dentistry school is quite considerable, given the extensive role played by practical training, compared to what is the case with students taught at the Faculty of Medi- cine. New licensing regulations for the practice of dentistry have been formulated, but are not likely to go into effect for the foreseeable future. The fact that new licensing regulations for the practice of medicine are already in effect has resulted in a clear separation of the training provided in dentistry from the training provided in medicine. As in the first phase of the Faculty of Medicine, the calculation of admission figures for dentistry school is based on a ratio of students to clinical academic teaching staff. These parameters are considerably less favorable for dentistry students than for medical students (for instance, in terms of the amount of supervision and support provided to students during clinical internships where they are required to treat patients, there is an average ratio of six students per academic staff member in dentistry school as opposed to somewhere between three and Phantom head course within the Department of Opera- six students per academic staff member in the tive Dentistry: Training at simulation models. Faculty of Medicine; academic credit factors for internships are 0.3 for dentistry students as opposed to 0.5 for medical students). The number of students admitted by the university has been constant for the last years, there is no increase resulting from lawsuits. Under the conditions offered by LOM, a performance-based funding scheme, finances for teaching the dentistry school curriculum have improved. Under this scheme the financing of staff positions, whether academic

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 151 DEGREE PROGRAMS

Molecular Medicine

Speaker basic sciences that are taught by the science not have been admitted to Molecular Medicine, Prof. Dr. rer. nat. Michael Wegner faculties (physics, inorganic/physical/organic most students listed medicine, biochemistry, or chemistry). The preclinical aspects are the fo- biotechnology. Coordination cus of the second year, while pathology and Presently, more than 30 applicants compete for Dr. rer. nat. Inga Ebermann experimental therapy conclude the curriculum one admission slot in Molecular Medicine. For in the last year. The B.Sc. program ends with a several years, the admission requirements for Address scientific thesis. the program have been constantly at the highly Institute of Biochemistry The main goal of the consecutive two year selective grade point average of 1.4. Admission Emil-Fischer-Center master program is to convey a deeper under- procedures follow federal and state regulations Fahrstraße 17 standing of science by working with original (Bayerische Hochschulzulassungsverordnung). 91054 Erlangen publications and extended practical training. Accordingly, 90% of admissions are based on Phone: +49 9131 8524620 Whereas the B.Sc. curriculum teaches the basics the Gymnasium grade point average, while an- Fax: +49 9131 8522484 of single disciplines, the M.Sc. program focuses other 10% of admissions are granted based on E-mail: [email protected] on interdisciplinary topics which are taught by a waiting period. www.molmed.med.uni-erlangen.de the Institutes of Biochemistry, Physiology and Following the guide lines from the Bologna Pathophysiology as well as the Departments of declaration, the B.Sc./M.Sc. Molecular Med- Aims and Structure Neurology and Psychiatry and Psychotherapy, icine is characterized by close-meshed and respectively. The Master program ends with a course-related exams which are continuous- The degree program in Molecular Medicine thesis of six month. ly documented in an electronic management combines the subjects of experimental medi- Another focus of the theoretical part of the pro- system. In the master program, the higher cine and the approaches of molecular biology, gram is molecular imaging. This module rep- portion of practical courses allows an individ- biochemistry, and genomics. This program ac- resents another scientific strength of Erlangen, ualized curriculum. The first two months of the knowledges the fact that boundaries which tra- as it puts the program at the interdisciplinary third M.Sc. term are intended as a “mobility ditionally separated biomedical disciplines have junction between basic science and industrial window” to facilitate the integration of inter- long lost their meaning. The Faculty of Medicine application. national internships and industrial placements. offers a future-oriented program for medical sci- The first year students in Molecular Medicine entists interested in research careers in industry, are welcomed by an annual symposium, intro- Perspectives administration, and academics. Nationwide, ducing them to the program and the Faculty this program in Molecular Medicine is met by of Medicine of the FAU. In recent years, these The degree program in Molecular Medicine an extraordinary interest. Each academic year symposia have encountered an extraordinary offers the opportunity to join a high-quality 38 students are admitted from more than 1,000 interest among the new students. Moreover, doctoral program at the FAU. Graduates may applicants. With the winter term 2007/2008, students are offered support by an academic enrol in a doctoral program (Dr. rer. nat.) the diploma program was transformed into a mentoring program. The mentors are recruited offered in collaboration with the Faculty of consecutive B.Sc./M.Sc. program which was among the lecturers involved in the B.Sc. pro- Sciences. The degree program in Molecular established according to the guidelines of the gram, ensuring easy communication between Medicine enables its students to successfully Bologna declaration. The first master students students and faculty. The participation of stu- contribute to scientific and practical work in graduated in the summer of 2012. dent representatives in the study committee medical research, laboratory diagnostics, and ensures the active involvement and participa- medical biotechnology. A variety of occupa- Objectives tion of the students in the further development tional fields in industry, private laboratory, of the degree program. and public institutions are available to the The advances in biomedical research continu- graduates of Molecular Medicine. Industrial ally change our knowledge and understanding Applications, development of employment options include research and de- of basic biological mechanisms and disease-in- student numbers, and imple- velopment as well as production and quality duced alterations, reflected in new and im- mentation of the program control, marketing, or administration. Private proved therapies. The consecutive B.Sc./M.Sc. laboratories, hospitals, and authorities depend program in Molecular Medicine addresses the Potential applicants are introduced to the pro- on university graduates experienced in molec- necessity to teach both, medical and bioscien- gram in Molecular Medicine by the advisory ular diagnostics, DNA and protein diagnostics tific contents. The interdisciplinary curriculum service of the Faculty of Medicine, the central for medical and biotechnological applications. aims at preparing our students for the challeng- advisory service of the FAU, as well as by bro- The degree program in Molecular Medicine es of medical research and enables them to be- chures and the internet homepage. At present, has already proven its concepts through suc- come independent researchers. half of the students enrolled in Molecular Med- cessful professional and academic careers of The B.Sc. program spans six terms in which a icine are in-state students from Bavaria, while its graduates which currently have positions solid education in all basic disciplines of Mo- the other half originate from other German in national and international research institu- lecular Medicine is achieved. The core curric- states or are international students. This situations (e.g. assistant professor at Havard Med- ulum in Molecular Medicine is mainly taught tion demonstrates the nationwide attractiveness ical School) and in industry (e.g. Novartis or by preclinical and theoretical institutes and the of our study program. Having asked students Roche). Graduates of the first generation are NFZ. The first academic year focuses on the for their alternative choices in case they would already holding professorships.

152 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) DEGREE PROGRAMS

Medical Process Management

Speaker of European Credit Transfer and Accumulation able to quickly gain ground on the labor mar- Prof. Dr. med. Dr. h.c. Jürgen Schüttler System (ECTS)-credits, 52% of teaching is done ket, having found very good jobs in the health- by the Faculty of Medicine. The corresponding care sector. Coordination figures are 15% for the Faculty of Business, Prof. Dr. med. Harald Mang, MHBA Economics, and Law, and 4% for the Faculty of Engineering, respectively. About one third of Address the courses are jointly carried out by at least Department of Anesthesiology two faculties. Krankenhausstraße 12 MPM is a “highly application-oriented” degree 91054 Erlangen program. Preparing the students for their fu- Phone: +49 9131 8533676 ture professional life therefore is a pivotal goal. Fax: +49 9131 8539191 By working as interns in medical facilities or [email protected] healthcare-related companies for a minimum www.mpm.med.uni-erlangen.de of twelve weeks, the students get to know the working environment in the healthcare sector. Aims and Structure The degree program starts each October. It is made up of three terms plus the time needed The degree program in Medical Process Man- for writing the master’s thesis. Generally, stu- agement (MPM) is a non-consecutive M.Sc. dents graduate after four terms. A total of 120 program. Lectures are taking place at the FAU. ECTS-credits is necessary to successfully com- In order to be admitted to this full-time study plete the degree program. Students graduate program, candidates require an academic de- as soon as they fulfill the following conditions: gree (e.g. bachelor’s or master’s degree). There Firstly, they must have passed all exams which is a particular interest in receiving applications are written in the course of the first three by graduates of the following subjects: Natural terms. Secondly, they must have completed sciences, computer sciences, engineering, law, their internships. And thirdly, their master’s economics, social sciences, medicine, dentistry, thesis must have been accepted (including a and molecular medicine. thesis defense). The degree program in MPM Participating in this degree program, students has been existing for five years. While it was are able to gain a thorough knowledge of both, taken up by 20 students in 2008, already 30 medical contexts and approaches of treating students enrolled one year later, and in 2012, in an integrated manner. Besides, the curricu- the number amounted to 33 students, respec- lum offers broadly diversified insights into the tively. structures of the German healthcare system MPM is more than just a new master’s degree and into business process management in the program: It is an innovative approach to tackle healthcare sector. Additionally, fundamental the challenges faced by healthcare systems in questions are dealt with concerning quality industrialized countries. So far, no other univer- and risk management, financial management, sity in Germany offers a comparable study pro- medical information technology, and psychol- gram. The degree program is geared towards ogy of communication. the growing demand the healthcare market All in all, the degree program in MPM connects displays for specialists with analytical expertise medicine and healthcare to business process in medical issues. Among other things, gradu- management and information technology. ates are capable to analyze, plan, implement, Strengthening patient-orientation approaches, and evaluate processes which take place in an improving the quality of medical care, and in- interinstitutional and interprofessional realm. creasing efficiency in the healthcare sector are They are thus qualified, for instance, to work the topics that make up the curriculum’s key as process managers in hospitals and surgeries, focus. as case managers for health insurances, and Courses are both highly interconnected and as network managers for healthcare networks. interdisciplinary in order to make sure that Furthermore, graduates are able to work for knowledge and skills are conveyed in a suc- companies belonging to the pharmaceutical cessful manner. Thus, it is not only the Faculty and medical engineering industry. The same of Medicine that is responsible for 30 different applies to consulting companies, IT manufac- courses of the degree program, but also two turers and healthcare management organiza- other faculties. With reference to the number tions. So far, graduates have consistently been

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 153 DEGREE PROGRAMS

Speech Therapy

Speaker therapy which bases on the disciplines medi- Prof. Dr. med. Dr. rer. nat. Ulrich Eysholdt cine, linguistics, psychology, and pedagogics.

Coordination Application Procedure Sabine Degenkolb-Weyers Admission requirement for the degree program Address Speech Therapy is the general qualification for Institut für Logopädie university entrance (allgemeine Hochschulreife) Waldstraße 14 / subject specific qualification for university en- 91054 Erlangen trance in Social Studies (13.Klasse). Application Phone: +49 9131 8532619 procedures follow the regulation “Verordnung Fax: +49 9131 8532615 über die Zulassung zu den öffentlichen Berufs- [email protected] fachschulen für Logopädie” from 19.12.2005. http://www.bfs-logopaedie.uni-erlangen.de/ A preselection of applying students is conducted by drawing lots. Aims and Structure Perspectives With the passage of the “Gesetz zur Einführung einer Modellklausel in die Berufsgesetze der He- Speech therapists diagnose and treat among bammen, Logopäden, Physiotherapeuten und others communication and swallowing disor- Ergotherapeuten”, the B.Sc. degree program ders and counsel patients and their relatives. Speech Therapy was established at FAU in win- Within their domain, speech therapists work ter term 2011/12. The program is met by great independently and assume responsibility for nationwide interest. Out of 500 applicants, 15 their work. students are admitted every year. Potential occupational areas for speech ther- The practical training predominantly takes apists are within the health care sector, e.g. place at the Institute of Speech Therapy. In in hospitals, rehabilitation centers, centers of order to ensure a sound hands-on clinical ed- speech therapy, their own practice, or as free- ucation, the training is supervised by teachers lancers. Furthermore, they may find employ- of speech therapy. The practical training is en- ment within the fields of teaching, science, or hanced by liaison with collaborative partners research. as well as internship blocks which comply with the existing quality standards. External internships deepen the knowledge about the treated speech defects. As the degree program was developed out of a vocational education (Ausbildung) in a full-time vocational school (Berufsfachschule) and is devised as a model degree program, its students are still required to pass the national exam as speech therapists at the end of the sixth term.

Objectives

This degree program aims at conveying the theoretical basis as well as professional expertise in diagnostics, therapy, and counseling in the area of speech therapy. It enables its students to treat their patients independently and with a profound scientific knowledge. It is a full-time degree program that is completed after seven terms with a B.Sc. degree. Hands-on training and science are complementary and can use synergetic effects resulting from the multidisciplinary nature of speech

154 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) CENTRAL FACILITIES OF FACULTY AND UNIVERSITY HOSPITAL

Interdisciplinary Center for Clinical Research (IZKF)

Speaker Core Facilities and Supporting group of Prof. Dr. J. Titze works on „Immune sys- Prof. Dr. med. André Reis Activities tem as regulator of volume and blood pressure“ Modern molecular technologies such as and the group of PD Dr. B. Winner on “Modeling Address genomics, proteomics, and advanced molecu- neurodegenerative diseases using stem cells”. IZKF Office lar imaging require very expensive and sophis- In addition, the IZKF supports six positions for Maximiliansplatz 2 ticated instrumentation and are methodolog- a laboratory rotation and 20 MD-thesis scholar- 91054 Erlangen ically very demanding. Core facilities or units ships. Since 2009 the IZKF in collaboration with Phone: +49 9131 8539223 are centralized platforms that offer access to the ELAN-Fond has offered starting grants to Fax: +49 9131 8535903 these modern methods and technologies to young postdoctoral physicians and scientists up [email protected] a broad user spectrum. Core units also make to 35 years of age without previous significant ex- www.izkf.uk-erlangen.de sure that smaller groups and those with other ternal funding. Candidates should have a visible methodological focus get access to these tech- publication record and projects should be based Aims and Structure nologies. They also ensure that students get di- on an original idea with first tangible results. Pro- rect access to these modern developments. The ject aids include a position for a technician or a The Interdisciplinary Center for Clinical Re- IZKF offers an initial funding of core facilities doctoral student and consumables for two years. search (IZKF) is a central structure of research covering up to five years. After this time it is expected that successful pro- development at the Faculty of Medicine. Its Supporting activities include the “Visiting Pro- jects submit an external grant application. mission is to improve the overall quality of fessor Program” and a biennial international clinical research at the Faculty of Medicine, scientific meeting. to stimulate interdisciplinary research, to ad- Various parameters are used to evaluate the vance the careers of young scientists, and to performance of the IZKF in advancing clinically foster the acquisition of extramural funds. It oriented research at the Faculty of Medicine. was established in 1996 under the major top- Scientific publications and academic success ic “Inflammatory Processes: Etiopathogenesis, of young scientists are the most obvious and Diagnostics, and Therapy”. During the first straightforward parameters. Furthermore, pa- eight years (1996-2004) it received regressive tents, scientific prizes, and offers of professor- funding from the BMBF within the program ships are relevant parameters. In 2012, the “Health related research 2000”. Since 2004 it 40 running projects altogether published 73 has been fully funded by the Faculty of Medi- original articles with a cumulative impact fac- cine within the UK Erlangen and the FAU. The tor (IF) of 432.2. The high quality of many of initial scientific focus on inflammation research these publications is reflected in 55 publica- could be further developed to also accommo- tions with an IF > 3. Given the fact that IZKF date all other focal research areas and interdis- funding starts at an early phase of a project, it ciplinary fields of the Faculty without sacrific- can be considered as a high risk funding pro- ing this distinctive topic. This allows nearly all gram. It is nevertheless reassuring that most institutions of the Faculty of Medicine to file of the projects are successful and thus likely applications with IZKF. IZKF activities can be to be transferred into extramural funding. In subdivided into three major areas: this context it seems noteworthy that nearly half of project leaders raise more extramural Research Grants funds than they receive intramurally by IZKF. The IZKF offers research grants which cover a 30 month period and include one graduate Career Development student, one technician, and consumables. Support and development of young scientists If project leaders apply for external funding has been a central goal of the IZKF since its in- at the end of the project, funding for anoth- ception. Two positions for junior research groups er six months is provided. Project leaders are housed in the NFZ offer an attractive career de- expected to have an active publication record velopment opportunity for outstanding young and own external funding. Preliminary results scientists with a training in medicine or natural should yield the promise of a successful trans- sciences, a strong background, and reputation fer of the project into external funding after in one of the faculties’ main research fields. Over the three years term. Innovative and original a period of up to six years each junior research ideas and concepts are especially valued; the group receives funding for the group leader, one same applies to the clinical relevance and in- postdoctoral and one postgraduate scientist, terdisciplinary approaches. one technical assistant and consumables. The

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 155 CENTRAL FACILITIES OF FACULTY AND UNIVERSITY HOSPITAL

Preclinical Experimental Animal Center (PETZ) of the Franz-Penzoldt-Center (FPZ)

Speaker duction, replacement, or refinement (3R’s) in Prof. Dr. med. Stephan von Hörsten experimental research with animals as well as the responsibility of constant optimization of Contact the housing conditions to the benefit of both, Dr. med. vet. Susanne Schwarz animal welfare and quality of scientific results. Phone: +49 9131 8545580 Central functions of the PETZ are: [email protected] − Providing a responsible and ethical animal treatment in accordance with the local and na- Address tional law authorities, Preclinical Experimental Animal Center (PETZ) − Optimizing and standardizing processes in Palmsanlage 5 animal housing, 91054 Erlangen − Implementing a modern quality assurance, Phone: +49 9131 8523501 − Assuring continuous professional develop- Fax: +49 9131 8523502 ment of the scientific and technical personnel, [email protected] − Providing state-of-the-art research facilities, www.FPZ.uni-erlangen.de − Establishing and providing core units especially in the area of animal phenotyping in Aims and Structure order to assure an effective and standardized application in this highly specialized technical The Preclinical Experimental Animal Center field. (PETZ) belongs to the Faculty of Medicine The PETZ provides statutorily regulated areas of and is a facility of the Franz-Penzoldt-Center operation such as e.g. housing and experimental (FPZ) that serves as a state-of-the-art ex- rooms that meet the safety levels for genetically perimental animal facility for basic and pre- modified organisms S1 and S2, and the biologi- clinical research. The facility resources are cal safety levels (BSL) for infectious agents BSL I primarily meant for users belonging to the and BSL II. We take care that the experimental Faculty of Medicine, but also offer state- work within the facilities is carried out in accord- of-the-art and appropriate animal housing ance with the legal regulations of the German with directly associated experimental facilities Infection Protection Act, Pharmaceuticals Act, for other research groups and associations. Chemicals Act, and Medical Products Acts. The Center is a research-oriented animal fa- Currently, the PETZ is used as a modern ani- cility that provides for customers a modern mal facility by 34 academic chairs and 20 inde- infrastructure and specific-pathogen-free con- pendent units of the FAU. Of these users, 49 are ditions for preclinical animal experiments. The members of the Faculty of Medicine. center offers various research related services, e.g. import of transgenic mouse strains via em- Teaching bryo transfer as well as veterinary advice and supervision for surgical or toxicological studies The CU PTZ organizes qualifying professional de- on large or small animals. Already as early as velopment courses in laboratory animal science the time of project application, the team of the (e.g. FELASA courses), offers the opportunity to PETZ provides competent references in all areas learn animal experimental techniques and func- of the application processes and related questions as a training company (Ausbildungsbe- tions regarding experimental strategy. trieb) for the recognized occupation requiring With its infrastructure, the PETZ supports ef- formal training “laboratory animal technician” fective and optimized science and enables which is certified by the chamber of industry translational medical research in a controlled, and commerce (IHK). The Center is a competent standardized environment most appropriate venue for surgical trainings in students’ educa- for each of the species. Our center represents tion as well as in the professional development a professional and reliable partner on the way of experienced practitioners. It places a priority from the scientific idea and the consecutive on being a family friendly institution and imple- ways ultimately resulting in benefits for the hu- ments the principles of gender equality in its pro- man patients. cesses and management to help its staff achieve a work-life-balance. Research

The superior goal of the PETZ is the continuous implementation of the principles of re-

156 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) CENTRAL FACILITIES OF FACULTY AND UNIVERSITY HOSPITAL

Center for Clinical Studies (CCS)

Speaker and organizational perspective as well as ad- members of the Faculty of Medicine and staff Prof. Dr. med. Dr. h.c. Wolfgang Rascher herence to the relevant legal and regulatory of the UK Erlangen. This comprises obtaining requirements. All counseling services are pro- insurance offers and accompanying the project Managing Director vided free of charge. until its conclusion. Dr. med. Bernd Gebhardt, MBA Study management and clinical Research Address monitoring CCS Erlangen Prior to clinical study start, the CCS Erlangen Clinical studies database of the Östliche Stadtmauerstraße 30a offers various services, ranging from the gen- Faculty of Medicine 91054 Erlangen eration of the study protocol to obtaining The clinical studies database serves to present Phone: +49 9131 8547047 approval from competent authorities and en- the clinical research efforts of the Faculty of Fax: +49 9131 8535120 dorsement of the study protocol by ethics com- Medicine. It contains prospective intervention- [email protected] mittees. This includes multicenter and multina- al clinical studies which may be listed accord- www.ccs.uk-erlangen.de tional clinical research projects. ing to predefined criteria, providing a survey of During the conduct of the clinical study the the clinical research activities. Aims and Structure CCS Erlangen provides clinical monitoring, if requested by the sponsor or the project leader. Education In 2008, the CCS Erlangen was founded as a service shared by the Faculty of Medicine of the Quality management At the request of the Faculty of Medicine, the FAU and the UK Erlangen. From an organiza- Institutions which assume sponsor responsi- CCS Erlangen in collaboration with the Institute tional point of view, it is affiliated with the UK bilities in clinical studies are required to follow of Clinical Pharmacology and Clinical Toxicolo- Erlangen as one of its central facilities. Its tasks standard operating procedures (SOPs). The gy has currently conducted more than 20 ed- comprise: CCS Erlangen Quality Management helps iden- ucational events for investigators, coordinating 1. Provision of counseling and support to tify and develop the SOPs necessary for the ful- investigators, and staff involved in clinical stud- members of the Faculty of Medicine and staff of fillment of sponsor duties. ies. Along with conveying the relevant legal and the UK Erlangen for the conception, planning, If requested by the sponsor or the project lead- regulatory requirements, the sessions focus on conduct, and analysis of clinical studies, taking er, the CCS Erlangen performs audits of study practical aspects and recommendations which into account the relevant legal and regulatory sites or other institutions involved in a clinical may have a major impact on the feasibility and requirements; study to assess their compliance with regulato- timely recruitment of clinical studies. Current- 2. Administration of the insurance for partici- ry requirements. On request, the CCS Erlangen ly more than 400 physicians from the UK Er- pants in clinical studies; provides advice and guidance for inspections langen and the associated academic teaching 3. Administration of the clinical studies data- by the regulatory authorities and audits by the hospitals have attended the courses. base of the Faculty of Medicine; sponsor. 4. Organization of educational events on all aspects of clinical studies. Pharmacovigilance Since its inception, the CCS Erlangen was in- For clinical studies subject to AMG or MPG and volved in more than 250 clinical research pro- sponsored by the UK Erlangen, the CCS Erlan- jects of members of the Faculty of Medicine gen ensures the documentation and timely no- and staff of the UK Erlangen. tification of serious adverse events according to The CCS Erlangen comprises the departments legal and regulatory requirements. For this task of study management and clinical monitoring, the CCS Erlangen uses a dedicated and certi- quality management, pharmacovigilance, and fied database. data management. Data management Counseling and Support In close collaboration with the Medical Center for Clinical Studies for Information and Communication Tech- nology (MIK), the CCS Erlangen develops Counseling study-specific electronic case report forms. On Each year, the CCS Erlangen provides a broad demand, additional services such as the devel- range of counseling services, especially in the opment of the data management plan or data preparatory phase of clinical studies. The main cleaning prior to database lock, are available. focus is on so-called investigator-initiated trials (IITs), planned and conducted by members of Administration of the insurance for the Faculty of Medicine and staff of the UK Er- participants in clinical studies langen. The CCS Erlangen evaluates the feasi- The CCS Erlangen administers the insurance bility of the research project from an economic for participants in clinical studies initiated by

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 157 CENTRAL FACILITIES OF FACULTY AND UNIVERSITY HOSPITAL

Comprehensive Cancer Center Erlangen-EMN

Director chologists are there to assist patients during the This consists mainly of the electronic patient Prof. Dr. med. Matthias W. Beckmann treatment phase. Due to the high level of re- file system SoarianTM and the data warehouse search activity at the CCC, patients have access tool CognosTM. Supplementary to these IT Address to innovative therapeutic approaches. systems there are commercial IT solutions for Östliche Stadtmauerstraße 30 All treatment decisions are taken jointly by the cancer registry, trial management, and bio- 91054 Erlangen experts in each specialty, at meetings known as banking. Data for cancer patients at UK Erlan- Phone: +49 9131 8547029 “tumor conferences.” gen are collected in the clinical cancer registry. Fax: +49 9131 8536393 This enables scientists in the field of cancer Hotline: 0800 8510085 Aims of the CCC ER-EMN research to analyze disease courses and in- [email protected] – Interdisciplinary and inter-organizational op- vestigate and develop improved treatments. www.ccc.uk-erlangen.de timization of care for oncology patients; Research on biomaterials forms the basis for – Interdisciplinary and inter-organizational sup- new discoveries. For this purpose, a biomate- Aims and Structure port for cancer research at the level of clinical rials bank has been set up for both, tumor tis- research, epidemiological research, translation- sue and also body fluids (e.g. pleural effusions, The Comprehensive Cancer Center Erlangen al research, and basic research; urine, etc.), as well as DNA from tumor patients – European Metropolitan Region Nuremberg – Support for regional collaboration in the field and control individuals. These biomaterials are (CCC ER-EMN) is an interdisciplinary center of tumor diagnosis, treatment, and follow-up used with the consent of the patients involved of excellence established to coordinate medi- care together with other hospitals — particularly and enable the development of investigation- cal care, research, and teaching. For patients, university teaching hospitals, specialist oncology al methods at the highest scientific standards physicians, and scientific researchers, the CCC practices, specialist physicians and family doc- to pursue major research goals — speeding up ER-EMN is the central contact for all questions tors, hospices, and rehabilitation facilities; medical progress with new discoveries and the connected to cancer diseases. – Support for interdisciplinary and inter-orga- development of new forms of treatment. The center organizes further education and nizational teaching in oncology; There are currently major research groups for training courses on topics in oncology and – Recruitment of highly talented junior staff for six different tumor entities at the CCC ER- coordinates research projects. In addition, the clinical care and research. EMN: breast cancer, leukemia and lymphoma, CCC ER-EMN runs a free tumor consultancy lung cancer, melanoma, renal cell cancer, and service for patients and their relatives. Research colorectal cancer. Approaches for other tumor Nationwide, there are currently only eleven insti- entities are also being pursued. tutions as leading centers for cancer research and If possible, patients are treated in the frame- treatment, sponsored by German Cancer Aid. work of clinical studies and directly benefit Teaching The CCC ER-EMN was founded in December from clinical progress. This means that they 2007 as the Erlangen University Cancer Center can be treated in accordance with the highest The center offers physicians, private medical by members of staff at the UK Erlangen and safety standards in the context of clinical trials. practices, and hospitals the opportunity to the Faculty of Medicine at the FAU. A cooper- Links with the Center for Clinical Studies (CCS) receive further training in the various fields ination agreement with Bamberg Hospital (So- at UK Erlangen, with the study coordination of- volved in oncology and to consult with experts zialstiftung Bamberg) and Bayreuth Hospital fices at the cooperating hospitals and with the in difficult treatment cases. In addition, the (Krankenhaus Bayreuth, Ltd.) was established Franconia/Southern Thuringia trial network are CCC ER-EMN provides a series of lectures for in January 2013. The respective oncological available for this purpose. physicians and scientists in the field of cancer centers at the Bamberg and Erlangen sites Patient care and clinical research at UK Erlan- research as well as a further training program were certified in accordance with the German gen are supported by a structured IT approach. in oncology for family practitioners. Cancer Society (DKG) criteria in 2011. At the Bayreuth site, DKG certification is planned for spring 2013. Under the aegis of the CCC ER-EMN, there is a total of eleven certified organ cancer centers and 24 interdisciplinary tumor conferences in three oncological centers which are responsible for optimized patient care and multidisciplinary development of clinical pathways according to the most up-to-date standards.

Interdisciplinary treatment based on a clear plan At the CCC’s institutions, all types of cancer are diagnosed and treated as gently and effectively as possible using the most advanced modern technologies. Specially trained nurses and psy-

158 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Emil Fischer Center (EFC)

Speaker tific and technical competence on the analysis Prof. Dr. med. Andreas Ludwig of the proteome, individual proteins, and low molecular agents. The bioanalytical expertise Address further covers a variety of molecular biology Chair of Pharmacology and Toxicology techniques and functional assays. Institute of Experimental and Clinical The intention behind the research center is to Pharmacology and Toxicology bridge chemistry and biomedical sciences lead- Emil Fischer Center ing to new insights in the physiological func- Fahrstr. 17 tion of new bioactive molecules, their interac- 91054 Erlangen tion with target proteins, and the development Phone: +49 9131 8522771 of novel therapeutic strategies. Fax: +49 9131 8522774 Instrumental analysis at the EFC is based on the [email protected] following major equipment: www.efc.uni-erlangen.de – three LC-ion trap-MS, – two LC-triple quadrupol- MS/MS, Aims and Structure – one MALDI-TOF-MS, – one SELDI-TOF-MS, The Emil Fischer Center (EFC) is an association – two NMR 360 and 600 MHz, of faculty members from the Faculty of Science – one CD spectrometer, and the Faculty of Medicine of the FAU. The – one confocal laser microscope (Zeiss LSM 5), center includes full and associate professors – NMR for small animals (4,7 Tesla), from the Chairs of Bioinorganic Chemistry, Bio- – equipment for microinjection and electropo- chemistry and Molecular Medicine, Biochemis- ration, try and Pathobiochemistry, Clinical Pharmacol- – real-time PCR devices, ogy and Clinical Toxicology, Pharmacology and – various electrophysiological setups, and Toxicology, Food Chemistry, Pharmaceutical – a computer cluster. Biology, Pharmaceutical Chemistry, and Phar- maceutical Technology. The objective of the interdisciplinary center is the promotion and conduction of joint research as well as educational projects between pharmaceutical sciences, food chemistry, chemistry, and molecular medicine. The members’ scientific work is interlinked by the EFC which operates a core unit “Bioanalytics“ and several basic technical facilities. The EFC represents the members in respect to external contacts, coordinates interdisciplinary fund-raising activities, and serves as a platform for cooperation with partners from the pharmaceutical and food industry. Research and teaching activities at the EFC are supported by several organizations and research collaborations, such as the SFB 583 and SFB 796, KFO 130, FOR 661, the DFG graduate program 1071, the BMBF, the European Union (EU), and the Elite Network of Bavaria. Interdisciplinary post-graduate training is accomplished by the Emil Fischer Graduate School (EFS; compare own report).

Research and Teaching

Main research topics at the EFC are drugs, drug targets, and bioanalytics. The core unit “Bioanalytics” combines the members’ scien-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 159 INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Erlangen Center for Infection Research (ECI)

Speaker Dr. C. Bogdan, speaker; Prof. Dr. J. Eichler, Prof. “Characterization of the Polyamine Pathway in Leishmania as a Potential Therapeutic Target” Prof. Dr. med. Christian Bogdan Dr. T. Harrer, Prof. Dr. T. Stamminger), a steer- ing committee - consisting of the members of 19.07.2011 Contact the executive board and five additional faculty M. Brigl, MD Brigham and Women‘s Hospital, Department of Pathology Institute of Microbiology – members (Prof. Dr. A. Baur, Prof. Dr. A. Burk- and Division of Rheumatology, Immunology and Allergy, Clinical Microbiology, Immunology ovski, Prof. Dr. B. Fleckenstein, Prof. Dr. I. Iva- Harvard Medical School, USA and Hygiene novic-Burmazovic, and Prof. Dr. R. Lang) - as “Mechanisms that drive NKT cell activation during infections” Wasserturmstraße 3/5 well as the members’ assembly. 91054 Erlangen 21.07.2011 Research Prof. Dr. N. Gow, PhD Phone: +49 9131 8522551 School of Medical Sciences, Institute of Medical Sciences, 8522281 University of Aberdeen, UK Fax: +49 9131 8522573 According to its central tasks and aims, the ECI “The fungal cell wall: Biosynthesis and immune recognition” [email protected] functions as a platform for innovative research ideas to initiate new collaborative applications www.eci.uni-erlangen.de 15.08.2011 for extramural research grants. In summer Dr. M. Kvansakul, PhD 2010, the ECI, along with 24 other German Laboratory Head, Department of Biochemistry, La Trobe Aims and Structure University, Melbourne, Australia universities, participated in a BMBF research “Death is not an option - structural studies of virus medi- The Erlangen Center for Infection Research competition for the foundation of the German ated inhibition of apoptosis” Center for Infection Research (DZI). The ECI’s (ECI) was founded as an interdisciplinary center 15.08.2011 of the FAU on July 28, 2010. The ECI is a con- proposal on “Human Immunodeficiency Virus, J. Tel sortium of more than 30 professors and lec- Herpesviruses and Leishmania: from Mecha- Radboud University Nijmegen Medical Centre nisms of Persistence to Novel Preventive and “The potency of human plasmacytoid dendritic cells to turers and their research groups which belong induce immune responses in melanoma patients: A phase Therapeutic Strategies” which combined pro- to the Faculty of Medicine, the Department I clinical trial” jects from 20 key scientists, received a very of Biology, the Department of Chemistry and positive evaluation by the international re- 13.03.2012 Pharmacy, or the Department of Chemistry PD Dr. J. Clos viewers in terms of its overall scientific quality. and Bioengineering. Infectious disease research Berhard Nocht Institute for Tropical Medicine However, the clinical infectious disease arm of “The Heat Shock Proteins of Leishmania spp. and their is one of the key research areas at the FAU and Roles in Stress Protection, Signal Transduction, and Im- the application as well as the potential contri- the UK Erlangen. mune Evasion” bution of Erlangen to the national center were The ECI focuses on the analysis of the patho- questioned and not ranked high enough which 24.07.2012 genesis of infections in order to improve the Prof. Dr. A. Haas finally resulted in the decision that ECI was not prevention, diagnosis, and therapy of infectious Institute for Cell Biology, University of Bonn selected as one of the seven sites of the DZI. “Reprogramming of host macrophages by Rhodococcus diseases in the long run. Accordingly, the ECI Scientists of the ECI are project leaders within equi” aims at providing a close scientific interaction the recently reapproved SFB 643 and 796, sev- between medical doctors in the clinics (e.g. eral GK (e.g. GK 1071 and GK 1660) as well specialists for infectious diseases, dermatology, as of the Emerging Field Initiative of the FAU. hematology, and oncology) as well as micro- The initiation of new research consortia in the biologists, virologists, infectious disease im- area of infectious diseases and microbial patho- munologists, pathologists, clinical pharmacol- genesis at the FAU remains the primary goal of ogists, pharmaceutical, organic and inorganic the ECI. chemists, and bioengineers. The necessity for an interdisciplinary and interfaculty cooper- Teaching ation and for combining the diverse scientific strength and know-how in the area of infection The researchers of the ECI participate in a num- research becomes particularly apparent when- ber of courses for students and research semi- ever novel anti-infectives, vaccines, or thera- nar series. These include not only the interdis- peutics for the treatment of immunopatholog- ciplinary infectious disease and immunology ical processes during chronic infections are to course for medical students (Q4 series), but be developed. The broad spectrum of expertise also the invitation of national and international of the ECI members in medicine and science infectious disease researchers for guest lectures will serve to open up new fields of research, such as the design and analysis of redox-active Selected lectures metal compounds for the therapy of infections and chronic inflammatory processes. 01.07.2011 S. Roberts, PhD The organizational structure of the ECI compris- Pacific University, School of Pharmacy, Hillsboro, Oregon, es an executive board of four scientists (Prof. USA

160 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Imaging Science Institute (ISI)

Speakers jekt” conducted under the auspices of the Fed- Teaching and advanced training Prof. Dr. med. Alexander Cavallaro eral Ministry of Economics and Technology, are (Institute of Radiology) designed to develop new and intelligent medi- Offering a range of courses and workshops Gerhard Weller (Siemens Healthcare) cal databases. With the aid of such programs it for doctors, technicians, engineers, and radi- will be possible to research and structure med- ographers, the ISI Erlangen enjoys a very high Address ical information in a more intelligent way in national as well as international reputation ISI order to provide fast and reliable assistance via thanks to the professional competence of the Ulmenweg 18 internet searches during diagnostic and thera- course instructors and the excellent training 91054 Erlangen peutic decision-making processes in the future. conditions. Since the founding of the ISI in Phone: +49 9131 8545368 In addition, the ISI plays a pivotal role in the 2005, more than 7,500 people have already Fax: +49 9131 8535699 activities of the leading-edge cluster “Center participated in advanced training courses. [email protected] of Excellence for Medical Technology - Medical [email protected] Valley EMN e.V.”, sponsored by the BMBF. Reference Visits and Public Relations http://www.radiologie.uk-erlangen.de/ Using the four above-mentioned medical de- The ISI Erlangen is also a platform where other imaging-science-institute/ vices, the ISI Erlangen examines many patients medical clinics and the public can bring them- every day for its research programs. Only a selves up to date with the latest developments Aims and Structure sufficiently high number of practice-oriented regarding the research on and application of examinations guarantees the relevance of re- medical imaging systems. Aside from exten- The Imaging Science Institute (ISI) was founded search results. sive information on scientific findings, medical in 2005 as a cooperation project between Sie- The ISI Erlangen optimizes medical devices and professionals and decision-makers working in mens Healthcare and the Institute of Radiology explores their potential further applications. public health all over the world will also learn of the FAU. Its location within the UK Erlangen Ideas for new examination methods and the about quality improvements and about op- allows optimizing in practice modern imaging resultant need for new medical devices are de- portunities to cut costs through the employ- systems to improve quality and efficient diag- veloped in close collaboration between clinical ment of the latest technology. nostic analyses and treatment methods. The users and developers or technicians from the In the eight years since its establishment rough- ISI provides the necessary facilities to transfer medical industry. The result of this collaboration ly 18,000 people from all over the world have new developments regarding the modalities of is that jointly-owned patents are filed on a reg- visited the ISI Erlangen, among them numerous imaging systems and data-processing systems ular basis which attests to the great innovative decision-makers of other clinics as well as rep- into a clinical setting. Aside from conducting strength and extensive expertise of the ISI Er- resentatives of public healthcare systems and scientific evaluation, the ISI is responsible for langen. politicians. training users and technicians in managing new developments.

ISI partners: - Siemens AG Healthcare Sector Industry Sector - Fujitsu Technology - Planar Systems, Inc. - Matrox - Medtron - Medrad, INC. - Barco - Federal Ministry of Economics and Technology - BMBF - Medical Valley EMN e.V.

Research

A wide variety of studies is currently being conducted at the ISI Erlangen. The research areas comprise not only issues such as the optimization of current imaging systems, but also methods for future systems. Large-scale projects, such as the “Medico Pro-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 161 INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Interdisciplinary Center for Aging Research (ICA)

Speaker health situation of older adults receiving home health and a prolonged time of independent Prof. Dr. phil. Frieder R. Lang care in Germany has been studied comprehen- living in old age. For example, positive social sively. relationships substantively contribute to im- Address proved health and longevity as well as to re- Field of Research: Physical Activity ICA duced risks of dementia and frailty. There is also Targeted promotion of physical activity can Kobergerstr. 62 some preliminary evidence suggesting that the improve function, activities, and participation 90408 Nürnberg association of physical activity and nutrition in the course of life and thus help to maintain Phone: +49 911 530296100 partly depends on the quality of social and independence and autonomy. The aim of phys- Fax: +49 911 530296101 family resources. The situation of care giving ical-activity-related interventions is to induce [email protected] relatives with its resulting burdens, challenges, long-term commitment to physical activity. www.ica.fau.de Applied in rehabilitation, such a behavior-ori- and risks is also of great importance. Additional ented exercise therapy (BET) leads to improved projects analyze the situation of family caregiv- Aims and Structure body functions and pain coping competencies ers, particularly with respect to the potentials and less work incapacity days in patients with of psychoeducation of family caregivers. An- Since its foundation in 2003 the Interdisci- chronic back pain (project: PASTOR). Physi- other focus of research is directed on the living plinary Center for Aging Research (formerly cal-activity-related interventions in the elderly conditions and quality of life of seniors living known as Interdisciplinary Center of Geron- lead to positive effects on physical functioning in institutions of residential care concentrating tology - ICG) has been active in the fields of (muscle strength, balance), the risk of falls, the mainly on aspects of social interaction between biological, medical, psychiatric, psychological, risk of dementia, and cognitive performance residents, relatives, and staff. behavioral, humanistic, economic, and tech- (projects: Sturzprävention im Alter, F.i.A.T, GE- Interdisciplinary and comprehensive research nological aging research. The ICA initiates and STALT I and II). An important aspect of long- approaches focus on questions of prevention supports interdisciplinary collaboration on ag- term changes in physical activity behavior is the and interventions strategies with regard to ing research at the FAU. The ICA is also actively affective attitude towards physical activity (pro- dementia and age-related frailty. Additional collaborating with communal institutions of ject: KASPADI). The dissemination of BET can non-clinical research is centered round the pos- medical care and with nursing homes of the successfully be realized in internet-delivered sibilities of assistive technology for supporting region. Currently the ICA has 27 members interventions for various indications (projects: mobility and independent living in later life coming from four different faculties and five Rückenwind (low back pain), ms-intakt, PACE (e.g. EMN-Moves). associated institutions. (multiple sclerosis)). A further area of research lies on motor control, especially after injuries or Teaching Research in persons with neurological conditions and/or movement/gait disorders (e.g. Parkinson´s dis- The majority of the ICA-members is engaged Research of the members of the ICA focuses ease, multiple sclerosis). Besides the individual in the interdisciplinary course offerings of the predominantly on health promoting interven- level, organizational and political aspects play master’s program in gerontology (M.Sc.). Some tion and prevention in the domains of nutri- a central role in physical activity promotion for courses are realized in close cooperation with tion, physical activity, and social environment. the elderly. In order to expand and optimize the associated members of the ICA, especially Each area of research addresses specific social, offers, improving both, internal capacities (e.g. those related to gerontological practice. A se- institutional, technological, and environmental staff training, goal definition, and resource al- ries of lectures (Q7 – medical science of aging) conditions and their effects on physical health, location) as well as cross-organizational and focusing on geriatric and ethical topics are or- autonomy, and personal responsibility. inter-sectoral networks in and between sport, ganized by numerous members of the ICA at Field of Research: Nutrition healthcare, and social care organizations, is es- the medical school of the FAU. Quantity and quality of our daily diet are of sential. Important means to these ends include Furthermore, the ICA operates a collective structured planning processes and networking major importance for health, functionality, and graduate program “gerontology” which pro- between researchers, practitioners, and pol- well-being until very old age. With increasing vides structured lecturing and special PhD- icy-makers (projects: EUNAAPA, PASEO). Of age an adequate nutrition is, however, often workshops for PhD students in gerontology special interest to gerontology are assets and impaired by age related factors and changes as well as in psychology, psychiatry, and sport barriers for the integration of evidence-based, of the health and living situation. Within the sciences. structured interventions for the prevention of framework of the ‘Theo and Friedl Schöller dementia into providers’ routines (project: GE- Foundation Professorship of Clinical Nutrition STALT I). An important focus of this research are in the Elderly’, research is focusing on the rela- difficult-to-reach target groups, such as social- tion between different aspects of nutrition and ly disadvantaged and sedentary older people physical as well as mental functionality in very (project: GESTALT II). old age. In addition, the development of reliable and valid methods for nutritional assess- Field of Research: Social Relations ment in older adults is of interest. Furthermore, Beyond dispute the quality of an efficient so- in a recent multicenter project nutritional and cial network plays a major role in maintaining

162 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Interdisciplinary Center for Public Health (IZPH)

Speaker With its emphasis on Health Technology Assess- Prof. Dr. med. Hans Drexler ment (HTA)/Market Access, Health Promotion/ Speaker and Member of Board of the IZPH Preventive Medicine, and Federal Health Moni- toring, the Center acts as the scientific platform Contact for outcomes research at the FAU and as the Prof. Dr. med. Peter Kolominsky-Rabas, MBA main regional promoter.

Address Teaching IZPH Schwabachanlage 6 Members of the IZPH are providing interdisci- 91054 Erlangen plinary lectures and courses in the field of Pub- Phone: +49 9131 8535855 lic Health, such as Health Economics, Health Fax: +49 9131 8535854 System Research, Health Promotion, and Pre- [email protected] vention. Special focus is also given to lectures www.public-health.de on Public Health issues for students of the Fac- ulty of Economics and to the master program Aims and Structure “Medical Process Management” (M.Sc.).

“Networking across scientific borders” is the unique selling proposition of the Interdiscipli- nary Center for Public Health (IZPH). The IZPH is a multidisciplinary research center consisting of different faculties of the FAU: The primary objective of the Center is to merge medical, economical, and social sciences and management in order to advance research in public-health and resolve current health care challenges of the aging society. Within the Nürnberg Metropolitan Region the IZPH bundles all relevant stakeholders of the health care management industry, i.e. medical professionals (doctors, hospitals trusts, outpatient sectors), the different statutory health and care insurance providers, health technology providers (global operating companies like Siemens Healthcare and pharmaceutical manufacturers) as well as patients and their family members acting as research platform for the university.

Research

The research focus of the center is driven by its previous interdisciplinary research in the field of public-health and takes special interest with respect to issues of Health Technology Assess- ment (HTA) and Market Access, Health Pro- motion and Preventive Medicine, and Federal Health Monitoring. During the report period the Center performed a number of large-scale studies addressing research topics as need of care and resource use in chronically ill patients (dementia, cancer, and stroke) as well as assessment of health care services funded externally with 2.3 million Euro.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 163 INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Interdisciplinary Center for Ophthalmic Preventive Medicine and Imaging (IZPI)

Speakers (I) Third-party funded projects of the enabling the measurement and training of the Prof. Dr. med. Georg Michelson & Center of Excellence for Medical Tech- stereo vision capacity. We began a tight coop- Prof. Dr.-Ing. Bernhard Schmauss nology “Medical Valley EMN e.V.” eration with the University of Kunming (Prov- IZPI scientists work on two projects of the ince Yunnan, China), leading in 2012 to a Visit- Address “Medical Valley EMN e.V” which deal with tele- ing Professorship. IZPI medical applications in ophthalmology. (2) MR-DTI imaging of the visual tract: A novel Schwabachanlage 6 (1) Telemedical LowCost-Fundus Camera Sys- MRI-method (Diffusion Tensor Imaging, DTI, 91054 Erlangen tem: The goal of this project (A04) is the de- see image) and image pattern analysis allows to quantify the integrity of axons of the cere- Phone: +49 9131 8544494 velopment and clinical validation of a low cost telemedical system for threshold countries for bral part of the optic tract. By this method, it Fax: +49 9131 8536435 early detection of diabetic retinopathy, hyper- becomes possible to detect unknown causes of [email protected] tensive retinopathy, and glaucoma. We suc- vision impairment. In 2012 four peer-reviewed www.izpi.de ceeded in generating high-resolution images articles were published. of the retina by using Superresolution Technol- Aims and Structure ogy. In 2012 four peer-reviewed articles were Teaching published and two patents were accomplished. The “Interdisciplinary Center for Ophthalmic (2) E. Atlas: The goal of the project (A02) is the IZPI researchers give lectures within several Preventive Medicine and Imaging” (IZPI) was development of novel technologies to run an interdisciplinary frameworks of Medical and founded to increase the intensity and the ef- interactive image database, fully accessible by Technical Faculty. At the Faculty of Medicine ficiency of cooperation projects between the mobile communication technology. We suc- the lecture “retinal microangiopathy as early Medical and Technical Faculty of the FAU in the ceeded in platform-independently publishing marker of cardio-vascular diseases” is given field of preventive medicine. The aim is to im- of the data base Atlas of Ophthalmology with as well as lectures for students of the degree prove the conditions of research and the public 6,000 reference images for iOS (Apps iPhone, program “Medical Engineering”. The overall communication of the arising results. iPad) and for Windows 8 (Apps for Tablets with concept of these lectures which are called In the scientific areas medical imaging, pattern Windows 8). In 2012 seven peer-reviewed arti- “Biological and Technical Vision” is to link recognition, and preventive medicine, there cles were published. mechanisms of human vision with the vision was already scientific excellence in the Medical (II) Third-party funded projects of the of machines. For students of „Medical Engi- and Technical Faculty. Embedded in the main School of Advanced Optical Technolo- neering“, we offer the lectures „Biological research focus “Medical Technology” of the gies (SAOT) and Technical Vision” and “Medical Appli- FAU, the IZPI should help to enforce and to im- Several IZPI researchers work on third party cations of photonics”. In addition, a weekly prove the scientific excellence in these topics. funded projects of the SAOT: colloquium “Biological and Technical Vision” (1) 3D-Vision: Within two PhD-projects, a ges- The most important purpose of IZPI is the de- is offered to students of the Technical and Fac- ture-controlled, interactive system is developed, ulty of Medicine. velopment of novel diagnostic methods in the area of preventive medicine. The goal is to develop new technologies for early detection of risk factors or symptoms of diseases. Thus, the areas of interest of IZPI are (1) development of novel technologies and (2) improvement of well-established technologies by optimizing image acquisition, analysis, and medical prediction. The analysis of medical images and data comprises all processes which lead to a medical interpretation or a transformation of the medical image in a symbolic description. To extract relevant risk factors from a given medical image, there is the necessity to develop an effective model of the disease. The model will allow elute relevant information from a given image.

Research

IZPI researchers from the Medical and Techni- cal Faculty cooperate within third-party funded projects of the Center of Excellence for Medi- cal Technology “Medical Valley EMN e.V.” and the School of Advanced Optical Technologies “SAOT”.

164 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Medical Immunology Campus Erlangen

Speaker and personalized methods for the prevention, 31.05.2011 Prof. F. Sallusto, Institute for Research in Bio- Prof. Dr. med. Christian Bogdan diagnostic, and therapy of infectious, autoim- medicine, Bellinzona, Schweiz „Dendritic cells and the demanding task of priming T cell mune, and inflammatory diseases as well as for responses“ Scientific Coordinator neoplasias are developed. 04.07.2011 Prof. Dr. H. Schöler, Max-Planck-Institut für Dr. rer. nat. Sonja Pötzsch During the reporting period the scientists of molekulare Biomedizin, Münster the Medical Immunology Campus Erlangen „Induction of Pluripotency: 20 Years of Research“

Address not only received the approval for a third fund- 25.10.2011 Prof. Dr. A. Diefenbach, Universitätsklinikum Institute of Clinical Microbiology, ing period of the SFB 643 “Strategies of cellular Freiburg Immunology and Hygiene immune intervention” (spokesman: Prof. Dr. G. „Development and Function of Innate Lymphocytes“ Wasserturmstraße 3-5 Schuler), but also succeeded in setting up two 15.11.2011 Prof. Dr. E. Latz, Institute of Innate Immunity, 91054 Erlangen new DFG research consortia (GK 1660 “Adap- Universitätsklinikum Bonn tive Immunity”, spokesman: Prof. Dr. H.-M. „Mechanisms of Inflammasome Activation in Inflammato- Phone: +49 9131 85 22571 ry Diseases“ Fax: +49 9131 85 22573 Jäck; Clinical Research Group 257 “Chronische Darmentzündung”, spokesmen: Prof. Dr. M. 06.12.2011 Prof. M. Sixt, Institute of Science and Technol- [email protected] ogy Austria, Klosterneuburg www.mice.uni-erlangen.de Neurath and Prof. Dr. C. Becker). „Mechanisms of Leukocyte Chemotaxis“

17.01.2012 Prof. O. Mandelboim, Hebrew University Ha- Aims and Structure Teaching dassah Medical School, Jerusalem „Inhibition and activation of immune responses by viral and by cellular miRNA“ The Medical Immunology Campus Erlangen, an The members of the Medical Immunology interdisciplinary center at the Faculty of Medi- Campus Erlangen are involved in teaching 07.02.2012 Prof. F. Granucci, Department of Biotechnolo- gy and Bioscience, University of Milano-Bicocca cine of the FAU, was founded in March 2009 medical students and students of the Bache- „The Multifaceted Roles of CD14 in Innate Immunity“ in order to provide a common organizational lor’s and Master’s degree programs of Molecu- platform to scientists from all areas of immu- lar Medicine at the Faculty of Medicine as well 05.06.2012 Prof. Dr. O. Pabst, Medizinische Hochschule as students of the life science programs at the Hannover nobiology and clinical immunology. Since then, „Generating IgA Repertoire Diversity in the Intestine“ Faculty of Sciences. Furthermore, the Campus several institutes, clinics, clinical divisions, and promotes scientific exchange by hosting na- 19.06.2012 Prof. Dr. T. Hünig, Institut für Virologie und research groups of the UK Erlangen, the Faculty Immunbiologie, Universität Würzburg tional and international speakers of a broad, of Medicine and the Natural Science Faculty of „Oligodendrocytes enforce immune privilege of the interdisciplinary range of topics at the weekly the FAU, the Fraunhofer Institute for Integrat- non-infected brain by deleting the peripheral CD8 T-cell Immunological Colloquium. The annual Joa- repertoire of auto-reactive cells“ ed Circuits IIS, and the Max Planck-Institute for chim Kalden Lecture was initiated by the Me- the Science of Light have been integrated into 10.07.2012 Prof. A. Hayday, Immunology, Infection and dical Immunology Campus Erlangen in order to Inflammatory Disease, King´s College London the Campus. The Medical Immunology Cam- honor outstanding researchers with substantial „Lymphoid stress-surveillance: the benefits and challenges pus Erlangen organizes scientific seminars and of useful autoimmunity“ impact on immunological research, such as the lectures, promotes the research of its members recently deceased Nobel laureate and dendritic 16.10.2012 Dr. A. Lehuen, Institut National de la Santé et by public relation activities, develops teaching de la Recherche Médicale, Université Paris Descartes cell expert, Prof. Dr. R.M. Steinman, in 2011 concepts for immunology in the Bachelor’s and „Regulatory role of NKT cells in viral infection and auto- and the renowned B cell immunologist, Prof. immune diabetes“ Master’s degree programs of Molecular Medi- Dr. K. Rajewsky, in 2012. cine, and coordinates the participation in com- 06.11.2012 G. Eberl, PhD, Lymphoid Tissue Development Unit, Institut Pasteur, Paris petitive federal funding initiatives. By bundling Lectures „Innate lymphoid cells and intestinal homeostasis“ the available scientific resources in the field In 2011 and 2012, the Medical Immunology 27.11.2012 Prof. D. Schendel, Institut für Molekulare Im- of immunology, the Campus is dedicated to Campus Erlangen organized 51 research collo- munologie, Helmholtz Zentrum München strengthen the research focus Immunology and quia with distinguished national and interna- „Selection and use of high-affinity T cell receptors in de- signer lymphocytes for adoptive cell therapy“ Infection Research of the Faculty of Medicine tional guest scientists. The following compila- and, in the long run, to enable the founding of tion is a selection of the complete list, which a Leibniz Institute for Translational Immunolo- can be viewed at the homepage of the interdis- gy and Immunotechnology. Four times a year ciplinary center. the Campus publishes a Newsletter on exciting publications, honors, and awards of the Cam- 11.01.2011 Dr. S. Amigorena, Institut Curie, Paris pus’ nearly 80 members. „Antigen presentation and T cell activation by dendritic cells“

Research 12.04.2011 Prof. M. Karin, University of California, San Diego Medical Immunology Campus Erlangen re- „Control of Tumor Progression and Metastasis by Lympho- cyte-Produced Cytokines“ searchers investigate the basic mechanisms of the development, composition, function, and 03.05.2011 Prof. B. Malissen, Centre d‘Immunologie de Marseille-Luminy deficiencies of the immune system. By trans- „Disentangling the complexity of the dendritic cell net- lating the results into clinical approaches, new works present in the skin and the thymus“

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 165 INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Medical Technology Test and Application Center (METEAN) of the Fraunhofer Institute for Integrated Circuits IIS

Speaker the most appropriate features for cell detec- for both, stationary and home care monitoring. Dipl.-Inf. Christian Weigand, Fraunhofer IIS tion and segmentation that can be applied After optimization towards a micro-system, the for autonomous and robust segmentation of portable vital-sensor system (developed earlier Contact similar image material. within the project SOMATEK) was certified as PD Dr.-Ing. Thomas Wittenberg, Fraunhofer IIS medical class II product. Based on this sensor Decision support systems system, two observer studies were conducted Address The research and development tasks in the in cooperation with the Department of Internal METEAN field of “Computer-Assisted Diagnosis” (CAD) Medicine of the Heidelberg University Hospital Krankenhausstraße 12 are focused on the development of “intelli- and the local Department of Anesthesiology. In 91054 Erlangen gent” systems for computer based detection, Heidelberg, the “KARDIKOM Wireless” system Phone: +49 9131 7767301 analysis, and interpretation of lesions depicted will be tested with respect to clinical use and Fax: +49 9131 7767309 in various medical imaging modalities (endo- its integration into a patient data management www.metean.de scopy, colposcopy, mammography). Improved system, whereas the focus of investigation in early detection of dysplastic tissue within Erlangen will be the user acceptance and suita- Aims and Structure screening programs as well as an objective bility for home care monitoring. differential diagnosis are the main functional Intention and main focus of METEAN is to purposes of the developed CAD-technology. In Teaching combine the research competence in biomed- cooperation with the Institute of Radiology and ical engineering of the Fraunhofer Institute funded by the “International Max-Planck Re- Within METEAN, students of medical and ap- for Integrated Circuits IIS with the clinical ex- search School for Optics and Imaging” and the plied informatics, biomedical technology and pertise of regional partners from industry, re- “Center of Excellence for Medical Technology electronic devices, physics and mathematics of search institutes, and specifically the UK Erlan- – Medical Valley EMN e.V.”, we developed and the FAU as well as of the regional universities of gen in a synergistic way, as to exchange ideas evaluated new methods for computer-assisted applied sciences are educated through assign- for technical solutions with the medical and characterization and analysis of tissue lesions ments and supervision of internships, bachelor- clinical needs and hence provide and open depicted in digital mammography and tomo- and master theses. Additionally, scientists from perspectives for innovative and market-orient- synthesis data. As shown in a preclinical study, METEAN are involved in various lecture units of ed products. The METEAN is not only located the CAD-system may improve the diagnosis of the Medical and Technical Faculty. at the Faculty of Medicine inside facilities of micro-calcifications in mammograms. the the UK Erlangen, it also hosts technical and medical scientists. The involvement of Analysis and wireless transfer of project partners in decision-making processes biosignals of the respiratory and of METEAN extends into the active shaping cardiovascular systems and influencing of strategic, programmatic, In order to detect and extract therapy-relevant and process-related orientation of the scientif- parameters for hemodynamic monitoring, ic research goals. new methods for continuous non-invasive acquisition of biosignals of the respiratory and Research cardiovascular system are investigated in cooperation with the Department of Medicine 4, Computer assisted microscopy the Department of Anesthesiology, and the The analysis of cells by means of fluores- Max-Schaldach Chair for Medical Technology. cent microscopy has been established as A crucial part of this research concentrates on a standard within microbiology, virology, the development of a laboratory prototype and immunology. The research goal of this which can be applied to the human body for subproject as part of the SFB 796 is the con- continuous non-invasive long-term acqui- ception and development of generic image sition of the central arterial blood pressure analysis methods that are capable to provide under daily standard conditions. A further re- solutions for many similar applications in search goal concentrates on the mathemat- analysis of fluorescent micrographs. Central ical modeling of the arterial pulse wave. The problems of automated cell analysis are the information-theoretical characterization of the detection and segmentation of adequate interaction between the respiratory and the cells. Various segmentation methods have cardio-vascular system yields insights about the been developed, implemented, and evaluat- physiological-pathophysiological aspects of the ed for this task which are applicable for fluo- bidirectional influence and regulation of these rescently stained cells with different types of systems. preparations and different applications. Af- Goal of the project “KARDIKOM Wireless”, ter a training phase that is based on some funded by the BMBF, is a continuous monitor- representative images, these methods select ing of patients with cardiac risk constellations

166 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ)

Speaker Prof. Dr. rer. nat. Jürgen Behrens

Address Nikolaus-Fiebiger-Center Glückstraße 6 D-91054 Erlangen Phone: +49 9131 8529110 Fax: +49 9131 8529111 [email protected] www.molmed.uni-erlangen.de

Aims and Structure

The NFZ is a research institution of the Faculty of Medicine. The center harbors the two Chairs of Experimental Medicine I and II (Molecular Pathogenesis Research and Molecular Tumor Research, respectively), a Division of Molecu- lar Immunology as part of the Department of Medicine 3, a division of the Chair of Genetics of the Faculty of Sciences, as well as two junior research groups of the IZKF of the Faculty of Medicine. Additionally, lab space is provided to rotating clinical research groups. The intention of the research center is to strengthen biomedical research in the Faculty of Medicine by stimulating cooperations between basic and clinical researchers and by giving young clinicians the opportunity to carry out our competitive biomedical research projects under the infrastructure of a modern research center.

Research and Teaching

The main research topics at the NFZ comprise different aspects of molecular pathology from tumor biology to connective tissue research including genetic and immunological issues. With the appointment of Prof. Dr. D. Müller as new head of the Chair of Experimental Medi- cine I in 2011, research was extended to cardiovascular diseases. Since Prof. Dr. D. Müller, however, accepted another position in October 2012, the Chair is vacant again.

The NFZ is well equipped with modern research facilities required for cell and molecular biological research and offers a variety of biochemical, immunological, and cell biological seminars, guest lectures, and common graduate student seminars. Central equipment, such as DNA-sequencing, fluorescence activated cell sorting, confocal laser microscopy, surface plas- mon resonance as well as animal facilities, are accessible to all scientists at the center.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 167 INTERDISCIPLINARY CENTERS AND CENTRAL INSTITUTES

Central Institute of Medical Engineering (ZiMT)

Speaker search networks in the field of healthcare engi- At the end of 2012, the bachelor as well as Prof. Dr.-Ing. Joachim Hornegger neering within and around the university. In ad- the master study program have been interna- dition, the institute provides a more transparent tionally certified as an act of quality assurance. Corporate Executive Committee visibility of this highly dynamic scientific topic Compared to other study programs at the FAU, Prof. Dr. Ben Fabry at the FAU. Various chairs of the FAU, especially the healthcare engineering programs were the Prof. Dr.-Ing. Joachim Hornegger the Faculties of Engineering, Sciences and Med- only ones being certified without any specific Prof. Dr. Dr. h.c. Jürgen Schüttler icine as well as the Department of Economics, additional requirements. This confirms the fea- deal with research questions of healthcare en- sibility of the program and its clearly defined Address gineering, such as medical biotechnology, bio- and valid goals which can be realized with the ZiMT materials, medical imaging and processing, existing concept using the organizational and Henkestraße 91 molecular imaging, MR imaging, computation- infrastructural setting at the FAU. 91052 Erlangen al medicine, medical computer science, medical Phone: +49 9131 8526861 process management, bioinformatics, medical 3-D Imaging in Medicine Fax: + 49 9131 8526862 physics, and healthcare management. [email protected] With the goal of internationally promoting the www.zimt.uni-erlangen.de Teaching excellent position in the fields of science, research, and development of our country and Aims and Structure At the FAU, the relevance of “healthcare engi- strengthening the cooperations with recognized neering” as a scientific focus is not only visible centers of excellence in the field of healthcare Medical technology is one of the scientific focus- in research, but also in the educational sector. engineering throughout the world, the BMBF es of the FAU. About 50 professors and university The bachelor program of healthcare engineer- has launched an initiative to advertise Germany lecturers are working in this sector linked togeth- ing was able to show very high numbers of ap- as an excellent research location. Under the moter in the Central Institute of Medical Engineering plications right from the start and is, until today, to “Germany – Land of Ideas”, the campaign will (ZiMT). The coordination of responsibilities of one of the largest study programs at the Faculty highlight the attractiveness of Germany and its numerous cooperation partners as well as inter- of Engineering. The constantly high amount of research environment in important target coun- national visibility are the important core areas students and the goal of having as few students tries in order to initiate new sector-specific coop- of the ZiMT. It is an organizational unit which dropping out as possible were the reasons for erations. Currently, workshops, multiplier events, sharpens the biomedical engineering profile of the introduction of a procedure of determining partnering events, lectures, and presentations the FAU and improves the general conditions for aptitudes for healthcare engineering. Although at conferences and meetings are being orga- interdisciplinary collaboration in the diversified this takes a lot of extra effort, it enables on the nized. BMBF has selected eight participants that research area of healthcare engineering. other hand the offer of a valuable individual highlight its ideals and goals for initial support. Head of the ZiMT is an interdisciplinary joint advisory service before the start of a study pro- Under the auspices of ZiMT and the topic “3-D team consisting of Prof. Dr. J. Hornegger (Fac- gram. In particular, courses such as computer Imaging in Medicine – Cutting Edge Research in ulty of Engineering), Prof. Dr. Dr. h.c. J. Schüt- science, electrical engineering, electronic engi- Germany’s Medical Valley”, the partners conduct tler (Faculty of Medicine), and Prof. Dr. B. Fabry neering, information technology, mechanical workshops abroad with the aim of establishing (Faculty of Sciences). Operatively, the ZiMT is engineering, material engineering as well as international graduate schools and cooperations. managed by an office directed by the executive chemical and biological engineering are embed- Erlangen as a highly innovative location offers manager Dr. K. Höller. ded in the program of healthcare engineering. unique opportunities for young scientists in the Right from the first terms, the basics for math- field of medical 3-D imaging. Research ematics, physics, and medical subjects are set, The expansion of study and research coopera- but also specific references to arts, humanities, tions to internationally attractive and recognized At the FAU, the scientific focus on “healthcare and economics are possible. Another specialty institutions – i.e. the Stanford University and the engineering” is perfectly embedded in an ex- about the healthcare engineering program is Johns Hopkins University, USA – and economical- cellent research environment. Especially, the the high percentage of female students which is ly important partners like Brazil and China have positive decision on the competition “cluster of more than 50%. Until today, no other engineer- already been established. Also, student exchange excellence” of the BMBF for the Center of Ex- ing study program has reached those numbers. programs with the above mentioned partners in cellence for Medical Technology “Medical Valley Since the winter term 2011/2012, the master pro- the USA and Brazil as well as an international ori- EMN e.V.” had a great impact on Erlangen’s program in healthcare engineering is offered at the ented graduate school with the Peking University file. The university organization and all project FAU which implements an interdisciplinary engi- and the FAU have been realized. applications were managed by the ZiMT. The neering education and qualifies students for so- close collaboration with Siemens Healthcare, phisticated multidisciplinary engineering tasks at Fraunhofer IIS, and about 50 medical technology the highest level. Offered specializations are med- enterprises of the metropolitan region complete ical electronics (electrical engineering), medical the excellent research environment at the FAU. imaging and data processing (informatics), and The ZiMT bundles all activities within the uni- medical instrument and production engineering versity together with representatives of the UK and prosthetics (mechanical and material engi- Erlangen. Its mission is the expansion of re- neering).

168 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) DFG COLLABORATIVE RESEARCH CENTERS AND PRIORITY PROGRAMS

Collaborative Research Center 643: Strategies of Cellular Immune Intervention

Speaker Prof. Dr. F. Nimmerjahn focuses on antibod- in murine models. This represents the basis for Prof. Dr. med. univ. Gerold Schuler ies which are essential for defending the body further preclinical and clinical developments. against invading pathogens and show promis- The project of Prof. Dr. J. Siebler and Prof. Dr. M. Address ing results in the therapy of human tumors. In Neurath deals with the transcriptional regulation Hartmannstraße 14 depth knowledge about the cell types involved and pathogenetic relevance of the IL-28/IL-29 91052 Erlangen in phagocytosis and ADCC reactions in vivo is cytokine system in Colitis and Colitis associated Phone: +49 9131 8533819 the basis for the generation of novel therapeutic colon carcinoma. Thereby, the transcriptional Fax: +49 9131 8533701 strategies aiming at modulating these reactions. regulation of the IL-28/IL-29 cytokine gene ex- [email protected] The project of Prof. Dr. M. Herrmann focuses pression will be investigated using murine T cells. www.sfb643.uk-erlangen.de on the immune modulation by apoptotic cells, The functional role of IL-28/IL-29 for the immuno- necrotic cells, and annexins. Apoptotic cells are pathogenesis of colitis and colitis-associated colon Aims and Structure considered to be only weakly immunogenic be- carcinoma will be characterized in vivo using mu- cause of their swift recognition and clearance rine models. The SFB 643 “Strategies of cellular immune in- by phagocytes and can even be tolerogenic. The aim of the project conducted by PD Dr. B. tervention” has been existing since July 2004. The exposure of immature glycoproteins and Schuler-Thurner, PD Dr. N. Schaft, and Prof. Dr. By the end of 2012 the third funding round the phospholipid phosphatidylserine represent G. Schuler is the development of new and in- (2013 – 2016) was approved by the DFG. signals for the phagocytosis of dead (necrotic) novative immunotherapies based on DC espe- The goal of the SFB 643 is the successful im- and dying (apoptotic) cells, respectively. cially for the treatment of patients with cancer plementation of immunological knowledge in The project of Prof. Dr. T. Winkler and Prof. (melanoma as a prime model). Several clinical treatments that are based on a manipulation Dr. M. Mach is concentrating on the adoptive phase I-trials have already been conducted us- of the immune system, i.e. on immune inter- transfer of memory B cells as a new cell based ing peptide-loaded DC and now an additional clinical study was concluded that used DC vention. Immune therapeutic approaches to therapy for infection with Cytomegalovirus af- treat tumors and infectious diseases require the which have been electroporated with defined ter transplantation. Support of the patient’s im- enhancement or stimulation of the immune RNA encoding the tumor associated antigens mune defense against the virus is a major goal response. Conversely, innovative treatments of MAGE-3, MelanA, and Survivin. In addition new in transplantation medicine. Memory B cell inflammatory diseases, including autoimmune and advanced antigen loading strategies have transfer provided long-term protection from diseases, allergic diseases, and transplantation been developed using RNA electroporation. the lethal course of the infection that is invaria- reactions call for novel and improved immu- The project of Prof. Dr. G. Fey and Prof. Dr. bly seen in immunodeficient animals. The data nosuppressive strategies. The SFB 643 is con- W. Hillen dealt with the design and functional provide evidence that a cell based strategy to ceptually structured in three closely intercon- testing of novel antibody-derived agents for the support the humoral immune response can be nected project areas: A) basic immunology, B) treatment of Acute Myeloid Leukemia (AML). effective to combat infectious pathogens in se- immune intervention in animal models, and C) Thereby, chimeric proteins carrying a death-ef- verely immunodeficient hosts. This is the basis therapeutic applications. fector domain for binding to and elimination for the planned clinical trial using adoptively of leukemic cells from AML patients have been transferred CMV-specific memory B cells in Research generated. Human tBid and AIF (apoptosis in- stem cell transplanted patients which will take ducing factor) were used as death-domains. The place during the new funding period. Several representative projects will be de- target antigens were CD33 and CD123 because The project of Prof. Dr. L. Nitschke studies scribed shortly. they are expressed in particularly high density The project of Prof. Dr. U. Schubert investigates the newly developed sialic acid derivatives as on AML leukemia stem cells (LSCs). This project the role of the ubiquitin proteasome system high-affinity ligand analogs for CD22, a B cell has led to the funding of the new start-up bio- (UPS) for antigen presentation via the MHC receptor-associated inhibitory co-receptor, in tech company SpectraMab which will further class I (MHC-I) pathway. order to therapeutically manipulate B cells. develop this approach for the use in humans. The research project of PD Dr. U. Schleicher and CD22 can interact with the CD22 ligands on The ability to adoptively transfer T cells to treat Prof. Dr. C. Bogdan is focused on natural killer bone marrow endothelial cells which might cancer is in the focus of the project of Prof. Dr. (NK) cells and their effector functions in the im- control the homing of circulating mature B A. Mackensen. In recent studies the efficacy of mune response against the intracellular parasite cells and plasma cells into the bone marrow. adoptive T cell transfer therapies for the treat- Leishmania with the aim to elucidate the mech- The therapeutic potential of these modified de- ment of patients with metastatic melanoma has anism leading to the activation of NK cells. rivatives will be explored as a novel therapeutic been shown. Effective cell therapy demands in The project of Prof. Dr. D. Dudziak will trans- tool to treat patients with multiple Myeloma. vivo persistence and/or expansion of the translate the strategy concept of in vivo “antigen The project of Dr. E. Zinser and Prof. Dr. A. ferred TAA-reactive T cells and homing to the targeting“ of Dendritic Cells (DC) into the hu- Steinkasserer concentrates on the immunomod- tumor. Several strategies will be developed to man system. Thereby, the work focuses on the ulatory potential of the soluble CD83 molecule. enhance proliferation, migration, and persis- production of antigen-conjugated antibodies Recombinantly expressed soluble CD83 showed tence of infused tumor-reactive T cells. These to analyze T cell responses in tissue culture and a very interesting therapeutic potential and sup- approaches could improve the efficacy of adop- the characterization of DC in human tissues. pressed paralysis associated with experimental tive T cell therapy for cancer. In the new fund- These data will be important for an eventual autoimmune encephalomyelitis (EAE) which is an ing period the adoptive transfer of CMV/EBV- implementation into the clinic to optimize vac- animal model for human Multiple Sclerosis and in multi-epitope-specific T cells will be tested in a cination. skin-, heart- as well as cornea-transplant studies clinical trial in stem cell transplanted patients.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 169 DFG COLLABORATIVE RESEARCH CENTERS AND PRIORITY PROGRAMS

Collaborative Research Center 796: Reprogramming of Host Cells by Microbial Effectors

Speaker that can be divided into three subgroups that Prof. Dr. rer. nat. Uwe Sonnewald are interconnected: A) Structural basis of molecular interactions, Contact Faculty of Medicine B) Reprogramming of cellular processes, and Prof. Dr. med. Thomas Stamminger C) Replication structures and transport processes.

Address Research Staudtstraße 5 91058 Erlangen Subgroup A: Structural basis of Phone: +49 9131 8528256 molecular interactions Fax: +49 9131 8528254 Structure-function relationships of already [email protected] known effector proteins and their interactions www.sfb796.forschung.uni-erlangen.de with specific cellular targets will be studied in subgroup A. Linear sequence motifs mediating Aims and Structure protein-protein interactions are widely used by pathogenic organisms to reprogram cellular The long-term goal of the SFB 796 “Reprogram- processes. The elucidation of the structural re- ming of host cells by microbial effectors”, which quirements for the promiscuity is the focus of started in January 2009, is the understanding several projects of this sub-area. of the molecular and ultimately structural basis of pathogen-host interactions as well as the Subgroup B: Reprogramming of development of novel strategies for immuniza- cellular processes tion and intervention. In order to achieve this The focus of subgroup B is the elucidation and goal, interactions between known microbial ef- detailed understanding of mechanisms used by fector proteins (e.g. bacterial type III secretion microbial effectors to reprogram cellular pro- machines, viral transport proteins) and host cell cesses, including selected signal transduction structures will be characterized on the molecu- pathways, intrinsic immune responses, targeted lar level. Furthermore, new virulence factors will protein turnover, and the primary metabolism. be identified and their role during pathogenesis will be studied. Subgroup C: Replication structures and The SFB 796 which was initiated by the Fac- transport processes ulty of Science has an interfacultary structure. The focus of subgroup C is the question as to Groups of the Faculty of Medicine and the Fac- how microbial effectors use, and partially con- ulty of Science as well as the Fraunhofer Institute vert, cellular structures for successful microbial for Integrated Circuits (IIS) are involved in the colonization and replication. collaborative research. Although the individual How viral and bacterial proteins modify the cel- research goals of the bio-medical and plant-ori- lular transport is the focus of several projects of ented groups might appear different at first this subgroup. (improved prevention and therapy versus pathogen-resistant and high-yielding crop plants), Central project (Z) the underlying basic concepts in pathogen-host Crucial methods for generating novel insight interactions are expected to be rather similar, are provided by the central project (Z). The rendering a comparative approach highly ap- central project will reach into all research areas pealing. Thus, we expect that the comparative by offering an integrated and state-of-the-art investigation of the reprogramming of central technology platform supporting all groups of cellular processes (e.g. ubiquitin-mediated pro- the SFB 796. tein degradation, vesicular trafficking) in several pathosystems (human and plant pathogenic viruses and bacteria) will enable us to identify general themes that we expect to extend also to pathogens not studied within the SFB 796. To reach the long-term goal, the SFB 796 incorporates closely cooperating scientists with complementary expertise, as well as a core unit to study structure-function relationships. Pres- ently, the SFB 796 harbors 16 different projects

170 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) DFG COLLABORATIVE RESEARCH CENTERS AND PRIORITY PROGRAMS

Priority Program 1468: Osteoimmunology – IMMUNOBONE – A Program to Unravel the Mutual Interactions between the Immune System and Bone

Speaker thermore, the role of bone as “school of im- Prof. Dr. med. Georg Schett mune cells” will be examined. The bone marrow is the home of the hematopoietic Address and immune system. Therefore, it can be Department of Medicine 3 – envisioned that also bone affects the im- Immunology and Rheumatology mune cells. Ultimately, the priority program Ulmenweg 18 will contribute to improve anti-inflammato- 91054 Erlangen ry therapies which inhibit bone resorption. Phone: +49 9131 8539109 Fax: +49 9131 8534770 Teaching [email protected] www.med3.med.uni-erlangen.de The head of the research group is involved in the traditional teaching program (lectures, Aims and Structure seminars, practica) covering all subjects in the field of medicine and molecular medicine as The interdisciplinary project IMMUNOBONE is well as the PhD/MD programs for basic and a priority program (SPP) to unravel the mutual translational research. interactions between the immune system and bone. The priority program is funded by the German Research Foundation (DFG) for the first funding period of three years with a total volume of Euro 7.3 million. At the beginning of 2013, the priority program had a positive evaluation for a second funding period for another three years. The interdisciplinary consortium consists of 20 groups of 15 different research institutions of osteologic orthopedics, rheumatology, and immunology.

Research

Osteoimmunology is a new field of research calling on the hypothesis that the immune system and the bone are in close relation. Scientists suspect a communication between both systems. It is assumed that the interaction between bone and the immune system has an influence on diseases like osteoporosis and arthrosis. The interaction between bone and the immune system was recognized ten years ago by the discovery of a protein termed Receptor Activator of NF-k B Ligand (RANKL). Since then, interest in this field has increased substantically and novel insights into the mutual regulation of bone and the immune system have been achieved. It has been shown that molecules located on the surface of immune cells trigger bone metabolism. Moreover, clinical observations support the thesis that activation of the immune system with subsequent inflammatory disease leads to bone damage. The mechanisms by which the immune system influences bones and vice versa are, however, not completely understood. The IMMUNOBONE consortium investigates which mechanisms and messenger substances trigger overreaching immune reactions. Fur-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 171 JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

BMBF Leading Edge Cluster “Center of Excellence for Medical Technology – Medical Valley EMN e.V.“

Speaker is generating innovative excellence in its core Ophthalmology Prof. Dr.-Ing. Erich R. Reinhardt research areas of diagnostic imaging, intelli- Among diseases of the eye, defective vision gent sensors, treatment systems, and ophthal- such as presbyopia, cataracts, glaucoma, and Deputy Speaker and mology, as well as horizontal innovations for age-related macular degeneration are by far Contact Faculty of Medicine product and process optimization, a subject the most prevalent and economically signifi- Prof. Dr. med. Dr. h.c. Jürgen Schüttler with broad application. cant diseases. Together with the Department of Ophthalmology, leading technological com- Address Diagnostic imaging panies who operate on a global basis within Medical Valley EMN Association The use of innovative diagnostic imaging tech- the Medical Valley EMN cluster are developing Henkestraße 91 nologies results in earlier detection of disease laser applications for refractive surgery, artificial 91052 Erlangen and therefore less invasive, more cost-effec- lenses, and diagnostic systems in a number of Phone: +49 9131 5302863 tive treatment. Diagnostic imaging is equally Leading Edge Cluster projects. Fax: +49 9131 9704921 important for optimizing minimally invasive [email protected] interventions and determining the effective- Horizontal innovations for product www.medical-valley-emn.de ness of treatment. The diagnostic imaging core and process optimization research area includes projects many of which In addition to the core technology research Aims and Structure were performed in cooperation with the De- areas, horizontal innovations for product and partment of Obstetrics and Gynecology, the process optimization are also being generated Following its application as a “Center of Excel- Institute of Radiology, the Department of in the Leading Edge Cluster. With the partici- lence for Medical Engineering”, the Medical Val- Otorhinolaryngology and the Department of pation of the Interdisciplinary Center for Public ley EMN was announced on 26 January 2010 as Medicine 1. Health, the “ProHTA” project is creating mod- one of five winners in the Leading Edge Cluster els to simulate the effect of new technologies Competition sponsored by the BMBF. The deci- Intelligent sensors on the quality of care as well as on direct and sive, unique selling feature of the Medical Valley indirect costs. At the same time it is supporting In conjunction with communication and infor- EMN Leading Edge Cluster is the common ob- the search for potential efficiency levers for new mation technologies, intelligent sensors can jective among all industrial and academic cluster technologies and products. partners: Interdisciplinary, research-based further contribute significantly to reducing costs in the development of products, services, and solutions health system. Within the projects in this core that help to verifiably improve the effectiveness research area, miniaturized sensor modules are and efficiency of healthcare. being developed that can reliably measure vital In July 2012, the substantial progress in imple- care-related data such as breathing and circu- menting the strategy was confirmed through lation parameters in mobile situations outside the independent Leading Edge Cluster jury. hospitals. The modules help optimize the treat- Central evaluation criteria for the development ment of different illnesses with rapidly growing of the cluster were the progress made in imple- patient numbers, such as heart insufficiency. menting the cluster strategy and the progress The following project of the Department of in achieving the stated objectives. The Leading Medicine 2 associated with this core research Edge Cluster projects accounted for these sig- area: nificant contributions. Within the projects, the “Home monitoring of patients with cardiac respective contribution to increase the efficien- insufficiency to avoid decompensation and re- cy of health care was estimated. For Germany duce hospitalization rates”. alone a total potential reduction in health ex- penses of more than 7.5 billion Euro per year Treatment systems is estimated for at the same time unchanged Most of the research projects in this area are quality of health care. The products and services being carried out in cooperation with the De- developed in these projects are very competitive partment of Anesthesiology, the Institute of due to their level of innovation and thus likely to gain market share. The estimated sales po- Experimental and Clinical Pharmacology and tential of some of the products and services is Toxicology, the Department of Psychiatry and almost 500 million Euro annually. The project Psychotherapy, the Institute of Medical Infor- ideas have already led to more than 50 patents matics, Biometry, and Epidemiology, the Chair and the results were published in over 100 pub- for Technical Thermodynamics, and the De- lications. partment of Medicine 1. The projects are designed to increase personalization and safety in Research drug therapy, prove treatment with anti-infec- tive drugs to be more efficient and economic, To further consolidate its leading position in the and develop innovative procedures for early global market, the Medical Valley EMN cluster diagnosis and safe treatment.

172 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

BMBF-Network “Clinics and Pathophysiology of Osteophytes and Ankylosis (ANCYLOSS)”

Speaker also facilitates the translation of results from lab- Prof. Dr. med. Georg Schett oratory into clinical research. This implementation is achieved by different strategies: Genetic Address and biomarkers studies will optimize prediction Department of Medicine 3 – of osteophyte formation and high-resolution Rheumatology and Immunology imaging will improve the detection of osteo- Ulmenweg 18 phyte formation. The ANCYLOSS consortium 91054 Erlangen focuses the mechanistic and clinical aspects of Phone: +49 9131 8539109 musculoskeletal diseases and specifically the Fax: +49 9131 8534770 mechanisms relevant to the crosstalk between [email protected] inflammation, bone, and the adipose tissue. www.ancyloss.com One of the exciting findings of the ANCYLOSS Aims and Structure project was the observation that diabetes constitutes an independent risk predictor for severe The ANCYLOSS consortium is funded with- joint diseases. By using a well-documented in the BMBF framework “scientific networks prospective epidemiological cohort of healthy of musculoskeletal diseases”. The project was individuals (Bruneck cohort), we could show designed to investigate the molecular mecha- that diabetes is associated with later develop- nisms and clinical impact of osteophytes (new ment of severe osteoarthrosis resulting in joint bone formations) in joint diseases, such as os- replacement surgery. Importantly, this associa- teoarthritis (OA), psoriasis arthritis (PsA), and tion was independent from the two other ma- ankylosis spondylitis (AS). The project has been jor risk factors for osteoarthrosis, i.e. age and weight. Since its foundation, the consortium funded with a total amount of 1.5 million Euro has published 34 scientific publications and by the Deutsches Zentrum für Luft- und Raum- contributed to improve know-how about mus- fahrt (DLR; national aeronautics and space re- culoskeletal diseases. search center) for the first period of three years in 2010. Within the six different work packages Teaching the expertise were bundled from different scientific fields, such as bone biology, lipid me- The interdisciplinary research is particularly tabolism, molecular biology, genetics, animal suitable for the education of young scientists. models, imaging, and clinical research. Three The research group leaders supervise basic as of these projects (WP 1 - 3) concentrate on the well as clinically oriented theses in medicine pathophysiology of osteophyte formation and and biology. The results of the interdisciplinary joint ankylosis, the other three projects (WP 4 - research will be rapidly implemented in lec- 6) are more clinically orientated and determine tures and advance training courses (medicine/ biomarkers as well as imaging tools to better molecular medicine/medical physics) in order visualize osteophytes. to raise interest among young scientists to join this project. Research

Primary goals of this collaborative project are to understand the mechanisms of osteophyte formation in degenerative and inflammatory rheumatic disease as well as to build concepts and strategies to therapeutically interfere with the onset and progression of such lesions. ANCYLOSS is the first consortium which pursues research on osteophytes by using an interdisciplinary approach. Hitherto the scientific concepts in rheumatic diseases focused on disease aspects such as inflammation, pain, and functional impairment, but did not sufficiently target the structural aspects of rheumatic diseases. The interdisciplinary structure of the project

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 173 JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

BMBF Core Program “Molecular Diagnostics”

Speakers in Erlangen, Frankfurt, and Bochum in cooper- Prof. Dr. rer. nat. Dr. rer. biol. hum. ation with clinics of Cologne and Schwabach Michael Stürzl together with Siemens Healthcare Diagnostic Prof. Dr. med. Roland Croner Products GmbH are cooperating. It is a specific clue of this study that all investigations are Address exclusively carried out on routinely acquired Molecular and Experimental Surgery paraffin-embedded and formalin-fixed materi- Department of Surgery al. This will foster the spread and commercial Schwabachanlage 10 exploitation of the potential test in the future. 91054 Erlangen The major innovative components for the pro- Phone: +49 9131 8533109 ject were established in previous studies by Fax: +49 9131 8532077 members of the consortium. Polyprobe-test for determination of the tumor [email protected] (1) Predictive and prognostic relevant marker stage (primary endpoint) and the prediction www.polyprobe-bmbf.de/ signatures were identified through performing of response to standard therapy (secondary extensive transcriptome analysis on fresh tis- endpoint) will be evaluated. In the course of Aims and Structure sues of colorectal carcinomas. Different marker a follow-up period (36 months after the end signatures were detected which highly signif- of patient recruitment), it will be investigated Molecular medicine has gained a significant icantly identify metastatic tumor stages (Prof. whether the established biomarker signatures increase in scientific and technological knowl- Dr. R.S. Croner, UK Erlangen) and predict an- can also predict disease free survival or total edge in the past years. The present challenge giogenesis-related survival (Prof. Dr. M. Stürzl, cancer-related survival in the recruited patients. is to transfer available knowledge of basic re- UK Erlangen), as well as responses to chemo- The study is carried out in a non-randomized search into clinical application. In this frame- therapy (Prof. Dr. W. Brückl, UK Erlangen) and prospective manner. It is aimed at recruiting work, the development of reliable diagnostic radio-chemotherapy (Prof. Dr. C. Rödel, PD Dr. 650 patients. Accordingly, this study will be and prognostic markers for a powerful molecu- F. Rödel, Clinical Center Frankfurt). one of the largest studies on this subject world- lar diagnostics is still at the very beginning for (2) The industrial partner of the consortium has wide. many diseases. One of the major bottlenecks is established a technology for the isolation of RNA the validation of potential biomarkers. There- from formalin-fixed, paraffin-embedded tissues fore, an improved connection of the results which are acquired from routine pathological of basic research with clinical findings from procedures. In this process, the RNA is isolated well characterized patient cohorts is expected by silicate-coated magnetic beads which bind to significantly foster the development and nucleic acids with high affinity. Based on this validation of novel markers for individualized simple, but efficient purification principle, the treatment in the future. The BMBF has estab- extraction of RNA from tissue sections could lished the core program Molecular Diagnostics be fully automated. The process has been opti- to address this point. The primary goal of this mized so that one thin section of a tumor tissue program is to support molecular diagnostic reis sufficient to extract RNA amounts sufficiently search in Germany and to transfer results from high enough for quantitative RT-PCR analyses basic research to clinically available and eco- of the expression of more than 1,000 different nomically exploitable products or processes. genes (Polyprobe-test). Siemens Healthcare Diagnostic Products GmbH has established this Research key technology at the UK Erlangen and in addition has provided the required equipment for The central research topic of the research the procedure in the course of the cooperation. group headed by Erlangen is colorectal carci- In the project, 61 different molecular markers noma. World-wide more than 945,000 colorec- which have been identified in previous stud- tal carcinomas are newly diagnosed per year, ies will be validated in an independent patient and 492,000 patients die of them. The goal of cohort. Currently, three markers have been the study is the validation and diagnostic ap- identified from previous analysis (n = 80) which plication of RNA expression profiles in order to correlate significantly with metastasis in inde- predict the tumor stages and the responses to pendent retrospective (n = 82) and prospective standard therapies of colorectal carcinoma. The (n = 203) patient cohorts. During further anal- project is sponsored by the BMBF and an in- ysis of 177 cases, these three markers showed dustrial partner with a total of two million Euro. a significant correlation with survival during a Within the frame of this project, different in- five year follow-up period. Up to the end of the stitutes and departments of the clinical centers funding period, the predictive power of the

174 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

BMBF-Network “Eating Disorders Diagnostic and Treatment Network (EDNET)”

Speaker weak and there are virtually no evidence-sup- gy. The Department of Child and Adolescent Prof. Dr. med. Martina de Zwaan ported treatment interventions. Therefore, Psychiatry in Essen is part of an international three of the five randomized controlled psycho- consortium planning the first genome-wide as- Address therapy trials in this network focus specifically sociation study in AN including 4,000 patients. Klinik für Psychosomatik und Psychotherapie on the treatment of AN. The network includes The German group has collected one of the Medizinische Hochschule Hannover an outpatient treatment trial for AN comparing largest AN cohorts world-wide including the Carl-Neuberg-Straße 1 focal psychodynamic psychotherapy, cogni- DNA samples from the patients of EDNET. To 30625 Hannover tive-behavioral therapy and treatment as usual determine moderators and mediators of treat- Phone: +49 511 5326570 (ANTOP), a trial comparing in- and day-patient ment outcome in psychotherapy trials, a sepa- Fax: +49 511 5323190 treatment in adolescents with AN (ANDI), and rate proposal using a novel statistical approach [email protected] two internet-based relapse prevention trials has been included. Conceptually, treatment www.ednet-essstoerungen.de for patients with AN (VIA) and BN (IN@) after moderators specify for whom and under which discharge from inpatient treatment. A further conditions the treatment is effected. Treatment Aims and Structure study compares an internet-based guided mediators identify why and how treatments self-help intervention with a face-to-face cog- have effects and identify possible mechanisms The BMBF issued a request for application for nitive-behavioral therapy for overweight and (causal links between treatment and outcome) „Networks in Research on Psychotherapy“. This obese patients with Binge-eating disorder (IN- through which a treatment might achieve its funding instrument enables for the first time to TERBED). In total, more than 1,000 patients effects. Finally, members of the network to- conduct adequately powered, high-quality, have been included into the five psychotherapy gether with other experts in the field of eating multi-center, randomized, controlled psycho- trials. The long-term success will be investigated disorders have developed level 3 diagnostic therapy trials in Germany meeting international in follow-up assessments conducted six months and treatment guidelines for eating disorders. quality standards. Of the 38 nationwide, multi- to 1.5 years after the end of the acute treat- These evidence-based guidelines were pub- disciplinary, and disease-specific applications, ment phase. Additional funding will enable us lished on the webpage of the Association of the five networks were selected by international to conduct long-term follow-up examinations Scientific Medical Societies in Germany. The reviewers, including the Eating Disorders Diag- of up to five years. Overall 35 clinical centers studies in EDNET are highly innovative and will nostic and Treatment Network (EDNET). The are recruiting and treating patients within the generate unique results justifying the extraordi- funding period runs from 2007 to 2013. In this five psychotherapy trials. The treatment phase nary effort. These milestone studies will clearly network, the leading eating disorder researchers has already been completed in all studies. The increase our international visibility and com- in Germany collaborate and coordinate their last follow-up examinations are currently ongo- petitiveness in this research field and will con- research efforts. The network comprises nine ing. Associated studies are grouped around the tribute to our knowledge on the efficacy and centers which are all university based depart- core treatment studies covering neuropsychol- mechanisms of change of treatment in patients ments of psychosomatic medicine, child and ogy, structural as well as functional neuroim- with eating disorders. The network members adolescent psychiatry and clinical psychology, aging, genetics, epigenetics, and endocrinolo- have already published numerous papers. located all over Germany (Aachen, Bochum, Dresden, Essen, Erlangen, Heidelberg, Leipzig, München, Tübingen). The central coordination was located in Erlangen until September 2011 and moved to Hannover Medical School as of October 2011. The Coordination Center for Clinical Trials in Marburg is responsible for randomization and data management of the whole network. This ensures uniformly high quality standards as all studies have to meet GCP criteria. The data monitoring was originally coordinated in Erlangen and has been located in Hannover since October 2011.

Research

Anorexia nervosa (AN) is a severe mental disorder with the highest standardized mortality ratio among all psychiatric disorders. The long- term outcome unfortunately has not improved over the last decades. In regard to treatment efficacy, the evidence to date is judged to be

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 175 JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

German Chronic Kidney Disease (GCKD-Study): National Cohort Study on Chronic Kidney Disease

Speaker Research Prof. Dr. med. Kai-Uwe Eckardt More than 5,200 patients with impaired kidney Contact function have been included and will be ob- Dr. med. Stephanie Titze served over a period of ten years. Observations on the course of the disease, symptoms, and Address complications will be correlated with genetic Department of Medicine 4 - Nephrology and information and findings from bioanalytical ap- Hypertension proaches in blood and urine samples applying UK Erlangen modern biostatistical methods of data analysis. The study aims at establishing valid associa- Phone: +49 9131 8543068 tions between biomarkers affecting the disease Fax: +49 9131 8533388 progression and opening insights to the ques- [email protected] tion why patients with kidney disease have a www.gckd.de tremendously increased risk and disposition of cardiovascular diseases, including elevat- Aims and Structure ed blood pressure, myocardial infarction, and stroke. Another research focus is placed on the Chronic kidney disease is an increasing health implications and consequences of kidney im- problem, affecting approximately 10% of the pairment on general health and quality of life. population. The burden of morbidity and These findings on disease course and associat- mortality associated with chronic kidney dis- ed complications will open ways for a more de- ease derives from progression to end stage liberate and focused application of diagnostic renal disease with requirement of dialysis. Pa- and therapeutic procedures, improve the over- tients suffering from chronic kidney disease all prognosis, and help to postpone or avoid have a disproportionate risk of cardiovascular onset of dialysis. diseases including myocardial infarction and stroke. However, the course of progression of kidney and cardiovascular disease in the setting of renal disease is highly variable and factors determining progression and complication rates are to a large extend unknown.

The number of randomized controlled trials in nephrology lags behind all other medical disciplines. To address these questions, the FAU is coordinating a large prospective observational cohort study in Germany including the cooperation with the universities of Aachen, Berlin, Frei- burg, Hannover, Heidelberg, Innsbruck, Jena, München, Regensburg, and Würzburg and a network of approximately 200 nephrologists from different regions all over Germany. The study aims at gaining important insights on the heterogeneity of disease courses in observing a large number of patients over a long period of time, opening ways for a more deliberate and focussed application of existing diagnostic and therapeutic procedures and development of novel and more effective therapies. The GCKD Study is funded by the KfH Foun- dation of Preventive Medicine and the BMBF.

176 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

National Genome Research Network – Mental Retardation Network (MRNET)

Speaker nally, candidate genes and their respective sig- in which a comprehensive analysis using next Prof. Dr. med. André Reis naling pathways were functionally investigated generation sequencing of the genetic architec- using cellular assays and animal models. ture of severe ID was reported. Address Overall, the coordinated research and collabo- In summary, the MRNET results substantially Institute of Human Genetics ration between the MRNET members allowed extended the diagnostic options in affected pa- Schwabachanlage 10 the identification of some 80 genes for intel- tients and contributed to a better understand- 91054 Erlangen lectual disability. A total of 49 publications in ing of disease etiology as well as the underlying Phone: +49 9131 8522318 international peer reviewed journals were pub- pathomechanisms. It is now already possible Fax: +49 9131 8523232 lished, of which 15 were in highly regarded to determine the genetic cause in over 60% of [email protected] journals with an impact factor >10. Two pub- patients with ID. A further important finding www.german-mrnet.de lications can be highlighted, one in the journal was that the majority of mutations found in the Nature in which 50 novel genes for autosomal patients represent new (de novo) mutations. Aims and Structure recessive ID were described and another paper Therefore, these parents have only a slightly in the prestigious medical journal The Lancet increased recurrence risk. Intellectual disability (ID) or mental retardation has a prevalence of about 2% in the general population and is a major unresolved problem in health care. During the last years it became evident that genetic factors play an important role in the etiology of ID. The German Mental Retardation Network (MRNET) is a national network dedicated to the systematic investigation of genetic causes of ID. MRNET was funded from 2008 - 2011 within the medical genome research program (National Genome Research Network, NGFNplus) of the BMBF with a total budget of 6.3 million Euro. The central coordination located in Erlangen brought together the efforts of ten centers distributed throughout Germany and one each in Switzerland and The Netherlands.

Research

The project combines a medical genetic approach with systematic genome analysis. To date more than 2,600 patients were recruited and received a standardized clinical evaluation based on international phenotype ontology. Patient’s data were collected in a specially developed, pseudonymized database. Sporadic as well as familial cases were included and several strategies for gene identification were applied. Disease causing submicroscopic aberrations (copy number variants, CNVs) were detected using state of the art micro-array based technologies in about 15% of cases. Patients with similar phenotype to those with the CNV were screened for point mutations in candidate genes from the respective genomic region (figure). In familial cases we studied cosegregation of genetic markers with the disease (linkage analysis) to likewise reveal candidate genes from linked regions. Furthermore, some patients ARID1B, a frequently mutated gene in intellectual disability. a) Detection of a 2.5 Mb sumicroscopic genomic deletion in the index patient, chromosomes of both parents are normal. were subject to comprehensive sequencing b) Gene content of the deletion interval. of the entire coding sequence (exome) with c) Genomic structure of ARID1B gene with point mutations of different patients with similar phenotype (according to next-generation sequencing technologies. Fi- Hoyer et al. Am J Hum Genet 2012).

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 177 JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

Bavarian Immunotherapy Network (BayImmuNet): Adoptive Immunotherapy

Speaker this approach may find a place as a targeted Teaching Prof. Dr. med. Andreas Mackensen therapy for some human cancers. Furthermore, it is well established that the curative poten- The heads of the clinical research group are in- Contact tial of allogeneic bone marrow transplantation volved in the traditional teaching program (lec- Prof. Dr. med. Armin Gerbitz (BMT) is due to immunocompetent donor tures, seminars, practica) covering all subjects T cells inducing potent antineoplastic effects in the field of medicine and molecular medicine Address against host tumor cells, the “graft versus tu- and the PhD and MD program for basic and Department of Medicine 5 – mor” (GvT) reaction. translational research. Hematology and Oncology However, GvT reactions are mostly associat- Ulmenweg 18 ed with the graft-versus-host disease (GvHD) 91054 Erlangen which is the major cause of morbidity and mor- Phone: +49 9131 8535954 tality after allogeneic BMT. Fax: +49 9131 8535958 This project aims at developing new strategies [email protected] for the priming, selection, and expansion of an- www.bayimmunet.de tigen-specific effector T cells (CTL) under the guidelines of good manufacturing procedures Aims and Structure (GMP) that will be used for adoptive T cell therapy in patients with solid and hemato- Immunotherapy – the therapeutic interference logic malignancies. CTLs generated with pep- with the human immune system – is one of tide-pulsed antigen presenting cells are often the most important cornerstones of modern peptide reactive, but not reactive with tumors medical research. One of the current chal- that express the gene of interest due to low lenges is the translation of innovative therapy level expression or impaired antigen processing approaches from the laboratory into clinical by the tumor cells. application. In the area of immunotherapy To circumvent this, we will focus on an ap- – particularly antibody therapy and cellular proach of full-length proteins or overlapping therapy – Bavaria has excellent scientific teams peptides to generate T cell lines with a broader and, consequently, a high degree of scientific antigenic repertoire. The focus of another clin- potential. Many of the projects carried out by ical study will be on the comparative analysis those teams are already at a stage in which of different chemotherapeutic strategies for rapid translation into clinical application can the induction of lymphopenia before adoptive be expected. However, on the part of the uni- T cell transfer. versity hospitals there is an investment bot- Changing the equilibrium of various immune tleneck that is preventing rapid and efficient cell populations may result in a selective ad- translation into clinical application. BayIm- vantage being given to adoptively transferred muNet, a unique network established by the T cells. Successful accomplishment of the aims Bavarian state government in 2008 with a could yield a new treatment option for patients start-up financing of ten million Euro, has set with certain types of cancer, particularly malig- itself the goal of achieving faster translation of nant melanoma and hematologic diseases after new approaches in immunotherapy into clin- allogeneic BMT. ical application. Five clinical research groups The new building housing the Center for Inter- were established at the Universities of Erlan- nal Medicine (INZ) provides clean-rooms with- gen, Regensburg, Würzburg, and München in the hematology department for the cGMP (LMU and TU München). complyant production of cellular products. Currently, a quality management handbook Research for the manufacturing of T cells is generated in order to prepare a clinical study for adoptive Realization that cellular immune reactions, me- T cell therapy of CMV and EBV specific –cells diated primarily by activated T-lymphocytes after allogeneic stem cell transplantation. The recognizing defined antigens, are responsible generation of virus specific T cells is now pos- for the rejection of tumors in experimental sible under cGMP conditions and the Depart- models has led to multiple attempts to develop ment of Medicine 5 has applied for a manu- effective immunotherapies for the treatment of facturing license with the local authorities. In cancer patients based on stimulating T cell re- addition, BayImmunNet is financing a phase I activity against cancer antigens. study after approval by the federal authorities, Recent success using adoptive transfer of tu- the “Paul-Ehrlich Institute”, which will suppos- mor-specific T cells has fueled optimism that edly start in 2013.

178 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

Bavarian Research Cooperation for Adult Neuronal Stem Cells (ForNeuroCell II)

Speaker Prof. Dr. med. Jürgen Winkler

Deputy Speakers Prof. Dr. med. Ulrich Bogdahn Department of Neurology University of Regensburg

Prof. Dr. rer. nat. Magdalena Götz Department of Physiological Genomics Ludwig-Maximilian-University München

Address Division of Molecular Neurology Schwabachanlage 6 91054 Erlangen Phone: +49 9131 8539324 Fax: +49 9131 8536597 [email protected]

Aims and structure I. Blümcke’s project deals with the functional Cell also made strong efforts to interact with characterization of adult human hippocampal national and international stem cell networks. The research network ForNeuroCell focuses on stem cells and their directed differentiation The goal of ForNeuroCell is to form a “Bavarian adult neural stem cells based regenerative strat- into dopaminergic neurons. The central aim nucleus” for stem cell-based technologies and egies for acute and chronic neurodegenerative of this project is the characterization of hu- translational approaches. diseases in order to explore its future potential man hippocampal stem cells in patients with for clinical implementation. ForNeuroCell links pharmaco-resistant temporal lobe epilepsy. In Teaching modern neuroscience together with innovative this project, the group succeeded in showing imaging technologies and translational neurobi- that a close relationship exists between hip- The administrative core of ForNeuroCell, head- ology. The network is funded for its second pe- pocampal plasticity and cognitive performance ed by Dr. R. Lederer together with J. Burczyk, riod (2009 - 2012). It consists of ten projects lo- of epilepsy patients. In addition, adult human made large efforts to support activities for cated at the Universities of Erlangen, München, hippocampal stem cells are made available to young undergraduate and graduate students. Regensburg, Würzburg, and the Helmholtz the entire network. PD Dr. J. Klucken’s and Prof. Travel grants for graduate students and young Center München. The research network covers Dr. J. Winkler’s project characterizes adult neu- researchers as well as doctoral seminars with the following major topics: Molecular and cellu- ral progenitor cells in Parkinson‘s disease mod- the topics „Biostatistic“ and „Grant Writing lar biology of stem cells, stem cell production, els. The aim of this project is to redirect adult for Scientists“ were organized. In November stem cell imaging, and preclinical testing of stem and progenitor cells from the ventricular 2012, an outstanding symposium was held stem cells. This combined approach opens the wall, not only towards the adjacent striatum, at the Carl-Friedrich-von-Siemens-Foundation possibility to implement adult neural stem cell but also locally to differentiate these precursors (München) with numerous international speak- based regenerative approaches for the clinic. into dopaminergic neurons. Studies of neural ers from the USA and Switzerland. progenitor cells from transgenic mouse models Research of Parkinson‘s disease illustrate that these cells already show synuclein aggregates interfering The projects from Erlangen are headed by Prof. with the survival and differentiation of these Dr. M. Wegner (Institute of Biochemistry), Prof. cells. By analyzing protein aggregation pro- Dr. I. Blümcke (Institute of Neuropathology), cesses together with activation of dopaminer- and PD Dr. J. Klucken/Prof. Dr. J. Winkler (Di- gic transcription factors, it remains to be seen vision of Molecular Neurology). The project whether recruited endogenous progenitors of Prof. Dr. M. Wegner focuses on the role of have the potential to obtain a neuronal phe- distinct Sox proteins during adult oligoden- notype. In addition to the projects in Erlangen, drogenesis. The family of Sox proteins plays a basic molecular and cellular research projects critical role in oligodendrocyte development at the LMU München and the Helmholtz-Cen- and myelination. The goal of this project is ter in München and imaging projects at the to investigate the role of these proteins dur- University of Regensburg and the Technical ing oligodendrogenesis in preclinical mod- University of München are performed within els of neurodegenerative disorders. Prof. Dr. this network. The research network ForNeuro-

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 179 JOINT RESEARCH PROJECTS OF THE BMBF AND OTHER NETWORKS

National Reference Center for Retroviruses

Speaker tocol for the quantification of proviral DNA Research Prof. Dr. med. Bernhard Fleckenstein was established which is used as a parameter of progression of HTLV associated diseases. In addition to epidemiological analysis and Address Additionally, among serology and sequence evaluation of HIV-1 resistance (which have Institute of Clinical and Molecular Virology analyses, this protocol is inevitable for the been performed in close cooperation with the Schlossgarten 4 clarification of infections with unusual clinical RKI), the detailed analysis of different virus pop- 91054 Erlangen manifestations of HTLV infections. Finally, in the ulations has become another important aspect Phone: +49 9131 8523563 beginning of 2012, we successfully performed of clinical research. For the detection of resist- Fax: +49 9131 8522101 again a quality control trial for HTLV serology ant viruses which might be present only as a [email protected] with participants from Germany, Austria, and minority in the patient, ultra-deep sequencing www.viro.med.uni-erlangen.de Switzerland. has been introduced in order to replace the In the field of HIV-2 diagnostics, a real-time PCR classical methods (such as allele-specific PCR). Aims and Structure protocol for the determination of the plasma vi- In cooperation with the Institute of Patholo- ral load was established and used for diagnosis gy, two different platforms have been estab- Human immunodeficiency viruses (HIV-1, HIV- and surveillance of antiretroviral HIV-2 therapy. lished. These methods for genotype HIV drug 2) and human T cell leukemia virus (HTLV) be- Moreover, in addition to the existing HIV-1 sub- resistance and coreceptor tropism analysis are long to the retrovirus family. type panel, a HIV-2 subtype panel was created, closely investigated at the moment and are ex- From its foundation in 1996 by the Robert consisting of eight different isolates. As there pected to become a routine part of diagnostics. Koch Institute (RKI) until the retirement of are no commercial tests available for HIV-2 viral Finally, the efforts of the NRC are broadened the head of the Institute, Prof. Dr. B. Flecken- load quantification, this panel (which is meas- by a large number of projects focused on basic stein, in October 2012, the National Reference ured by three in-house-methods) is one of the and clinical research and addressed by the sci- Center (NRC) for Retroviruses was located at best characterized HIV-2 reagents in the world. entific groups localized at the Institute. These the Institute of Clinical and Molecular Virolo- At the same time, the existing HIV-1 subtype projects are supported by grants from the DFG, gy, FAU. In generally, the main tasks of a NRC panel was complemented with seven further BMBF, European Union, and by several industry partners. are the development, standardization, and HIV-1 isolates, including the very rare HIV-1 improvement of diagnostic and therapeutic group N. The HIV-1 and HIV-2 subtype panels Teaching procedures, distribution of reference materials, can still be provided. epidemiological surveillance, support in cases For many years, the identification and charac- Due to its task as the NRC for Retroviruses over of ambiguous laboratory results, and other di- terization of HIV-1 drug resistance associated many years, the Institute offers a broad range agnostic issues as well as advisory service and mutations has been a further topic of the NRC. of HIV-related seminars to medical students public relations. In addition to the continuous updates of the and students of molecular medicine and bio- bioinformatically supported resistance interpre- sciences. There are lectures about HIV-1 rep- Diagnostic tation system geno2pheno, the NRC continued lication, pathogenesis and therapy, and a lec- to coordinate a team of clinical virologists gen- ture on tropical medicine, focusing HIV in high In the function of a NRC for Retroviruses, our erating the German HIV-1 resistance interpre- prevalence countries. In addition, the HIV sem- Institute has offered a broad range of methods tation system HIV-GRADE. Both interpretation inar addresses recent scientific results of HIV in all diagnostic fields relating to retroviruses. tools are freely available online. In 2012, the and HTLV research performed by members of This service continues even after Prof. Dr. B. NRC additionally introduced the SmartGene the Institute. An experimental training course Fleckenstein’s retirement and will be steadi- program for the evaluation of HIV sequence for retrovirology offers the possibility to learn ly expanded. It comprises serological antigen data in routine diagnosis. This program facil- important methods in the laboratories of the and antibody tests and nucleic acid analyses itates the comparison of HIV sequence data, Institute. for the detection of retroviral infections as well e.g. in order to evaluate the development of as methods for the characterization of viruses resistance in different samples of the same per- with respect to subtype, drug susceptibility, son or to rule out contaminations in samples of and coreceptor tropism. The Institute has vast different persons. experience in validating the efficacy of antiret- Since 1998, the Retrovirus-Bulletin has been roviral drugs. The range of methods in test- an essential part of public relations. The NRC ing antiretroviral drug susceptibility covers all quarterly published this bulletin to provide sci- currently approved antiretroviral drug classes, entific and clinical information on HIV, AIDS, including integrase inhibitors and CCR5-core- and other retroviral infections like HTLV-1/2 (in ceptor antagonists. German). The Bulletin was freely distributed by In 2011 and 2012, major activities of the NRC mail to a broad readership, like specialized clini- targeted on the further development of meth- cians and members of the public health system ods for HTLV diagnostics. A real-time PCR pro- and of the HIV community.

180 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH UNITS

Clinical Research Unit 130: Determinants and Modulators of Postoperative Pain

Speaker proach, modern methods of molecular and cell • Medial prefrontal cortex activity is predictive Prof. Dr. med. Dr. h.c. Jürgen Schüttler biology as well as experimental pathophysiolo- for hyperalgesia and pharmacological antihy- gy and clinical studies were applied to identify peralgesia. Address neurobiological, pharmacological, genetic, and • Noxious electrical stimulation may represent Department of Anesthesiology psycho-social factors of postoperative pain and a neurostimulatory paradigm with antihyperal- Krankenhausstraße 12 to characterize clinical and pathophysiological gesic properties. 91054 Erlangen settings that may facilitate the development of • fMRI analysis of central pain processing re- Phone: +49 9131 8533677 persistent pain. vealed an increased degree of connectivity, Fax: +49 9131 8539191 Many projects also applied functional magnetic clustering, and modularity in the thalamus, [email protected] resonance imaging (fMRI) in rodents and men. periaqueductal gray, and the amygdala of www.anaesthesie.uk-erlangen.de/e169/e2368 Test subjects and patients were enrolled by the chronic pain (TNFtg) mice. acute pain service as well as by the interdiscipli- • Patients with Crohn’s disease (CD) require Aims and Structure nary pain center of the Department of Anesthe- significantly higher postoperative opioid doses siology. The acute pain service was in charge than patients undergoing comparable severe The clinical research unit (KFO) 130 was estab- of all patients that received postoperative pain abdominal surgery. However, CD patients do lished at the Department of Anesthesiology in therapy by means of patient-controlled-analge- not display increased pain sensitivity in terms August 2005. It was funded by the DFG until sia (PCA) techniques. The Department of Anes- of lowered thresholds to thermal and mechan- the end of the year 2012. Contributing De- ical stimuli. Furthermore, common variants thesiology also provided physicians and study partments and Institutes were: Anesthesiology, in OPRM1 and specific ‘high pain sensitivity’ nurses in charge of enrolling patients and coor- Experimental and Clinical Pharmacology and COMT haplotypes are not accounting for high dinating informed consent. Toxicology, Physiology and Pathophysiology, opioid needs. These are the most important scientific findings Neurology, Human Genetics (all Erlangen), • Hypervigilance and attentional avoiding of achieved by the KFO: Physiological Psychology (University Bamberg), negative experiences in patients are predictors • Anesthetics and analgesic drugs exhibit Pharmacology (University Zurich). The clinical of postoperative pain ratings and consumption pro-nociceptive effects by activating the noci- research unit was directed scientifically by Prof. of analgesics. ceptive membrane proteins TRPV1 and TRPA1. Dr. C. Nau. • HCN2 ion channels play a central role in in- Teaching Research flammatory and neuropathic pain. • Inhibition of a specific glycine receptor sub- The KFO provided young scientists and princi- The focus of the interdisciplinary research team type (GlyR a3) by PGE2-induced receptor pal investigators with research rotations, thus was postoperative pain that persists beyond phosphorylation underlies central inflammato- enabling scientific activity within the projects. the expected healing period. Persistent pain ry pain sensitization, but not pain after periph- The annually hosted “Pain Days” offered in- has an incidence of up to 50%, depending on eral nerve injury. spiration for a more effective translation of the type and extent of surgery, and is linked to • Endocannabinoids, produced upon strong preclinical knowledge into clinical practice. In an increased risk for the development of chron- nociceptive stimulation, activate type 1 can- April 2012, the KFO hosted an international ic pain. Continuous inflammatory processes or nabinoid (CB1) receptors on inhibitory dorsal symposium which attracted renowned national inadvertent intraoperative nerve injuries con- horn neurons to reduce the synaptic release of and international experts in pain research (see tribute to the pathobiology of persistent pain. GABA and glycine and thus render nociceptive pictures). Risk factors for persistent pain are pre-existing neurons excitable to nonpainful stimuli. pain, repeated surgery, and severe postopera- • Targeting spinal GABA(A) receptors con- tive pain. Largely unknown was the influence taining the a2 and/or a3 subunits leads to of intra- and postoperative applied anesthetics pronounced analgesia. The selective activation and analgesic drugs, genetic factors, and psy- by an a1-sparing benzodiazepine site ligand is chological susceptibility on persistent pain. effective against inflammatory and neuropathic In an interdisciplinary and translational ap- pain.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 181 RESEARCH UNITS

Clinical Research Unit 257: Molecular pathogenesis and optimized therapy of chronic inflammatory bowel disease (CEDER)

Speaker ly active IBD specialists and experienced basic • Project 5: Analysis of the molecular mech- Prof. Dr. med. Markus F. Neurath scientists in Erlangen. On the basis of clinical anism of action of cyclosporin A in ulcerative Department of Medicine 1 – Gastroenterology, specimens and preclinical models, the re- colitis. Project managers: Dr. B. Weigmann/ Lung Diseases, and Endocrinology search group will develop new strategies and Prof. Dr. R. Atreya (Department of Medicine 1 Ulmenweg 18 approaches for a more specific molecular or – Gastroenterology, Lung Diseases, and Endo- 91054 Erlangen immunologically based therapy of IBD which is crinology) Phone: +49 9131 8535204 already aligned at this time to the development • Project 6: Characterization and expansion of Fax: +49 9131 8535209 of clinical applications. For example, innovative regulatory T cells to establish a cell-based thera- [email protected] approaches to influence angiogenesis, mucosal py of IBD. Project managers: Prof. Dr. M.F. Neur- healing, and aberrant immune responses are ath/Prof. Dr. G. Schuler (Department of Medi- developed and evaluated experimentally. In ad- Contact cine 1 – Gastroenterology, Lung Diseases, and dition, methods are established to improve indi- Prof. Dr. rer. nat. Christoph Becker Endocrinology/ Department of Dermatology) vidualized diagnosis and therapy of IBD and the Department of Medicine 1 – Gastroenterology, • Central project: Project to coordinate the molecular mechanisms of action of established Lung Diseases, and Endocrinology scientific program of the KFO 257. Project therapies are being researched. Should the KFO Kussmaul Campus for Medical Research managers: Prof. Dr. C. Becker/PD Dr. J. Mudter 257 succeed in developing preclinical therapy Hartmannstraße 14 concepts, testing in clinical trials will be sought. (Department of Medicine 1 – Gastroenterolo- 91052 Erlangen The KFO 257 has two positions to allow rota- gy, Lung Diseases, and Endocrinology) Phone: +49 9131 8535886 tion of clinicians into laboratories. Fax: +49 9131 8535209 Teaching [email protected] Research http://www.medizin1.uk-erlangen.de/e110677/ Seminars on IBD: The KFO 257 is structured into seven • Immune pathogenesis and treatment of in- Aims and structure projects: flammatory bowel disease (Dr. C. Neufert/Prof. • Project 1: Mechanisms of cytokine-mediated Dr. C. Becker) Ulcerative colitis and Crohn’s disease are pro- immune pathogenesis of inflammatory bowel • Molecular Medicine (Prof. M.F. Neurath/ totypes of recurrent chronic inflammation of disease. Project managers: Prof. Dr. C. Becker/ Prof. Dr. C. Becker/Dr. I. Atreya) the intestine. In addition to the inflammatory PD Dr. J. Mudter (Department of Medicine 1 • Molecular mechanisms of tumor develop- processes in the gut, patients often suffer from – Gastroenterology, Lung Diseases, and Endo- ment in the intestine (Dr. C. Neufert/Prof. Dr. extraintestinal manifestations (e.g. arthritis, er- crinology) C. Becker) ythema nodosum, pyoderma gangrenosum, • Project 2: Functional analysis of the immu- • Physiology and pathophysiology of the gut primary sclerosing cholangitis). Research in re- nomodulator sCD83 in the pathogenesis and (Prof. Dr. C. Becker) cent years has led to the realization that both, therapy of inflammatory bowel disease. Pro- Current scientific literature (Topic: Research environmental and genetic factors and a misdi- ject managers: Prof. Dr. A. Steinkasserer/Dr. M. publications on IBD) rected activation of the intestinal immune sys- Lechmann (Division of Immune Modulation, Research progress seminar (Topic: Current re- tem to the intestinal flora, are key pathogenetic Department of Dermatology) search findings of the KFO 257) factors for the development of these diseases. • Project 3: Role of the Wnt/-catenin sig- The aim of the Clinical Research Unit (KFO) is to naling pathway in IBD. Project manager: Prof. Meetings and International Training develop and evaluate concepts for the patho- Dr. J. Behrens (Chair of Experimental Medicine Courses genesis of chronic inflammatory bowel disease II (Molecular Oncology)) 21.05.2011 Doctor-Patient-Seminar IBD (IBD) in order to develop new diagnostic and • Project 4: Immune regulation of angiogene- 30.11.2011 ERIC Erlanger Interdisciplinary IBD therapeutic approaches for the clinical man- sis in IBD. Project managers: Prof. Dr. M. Stürzl/ Symposium agement of these diseases. This translational Dr. M. Waldner (Department of Surgery/De- 03.03.2012 Doctor-Patient-Seminar IBD research approach will be conducted in a close partment of Medicine 1 – Gastroenterology, 28.03.2012 ERIC Erlanger Interdisciplinary IBD interaction between clinically and scientifical- Lung Diseases, and Endocrinology) Symposium

182 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH UNITS

Research Unit 661: Multimodal Imaging in Pre-Clinical Research

Speaker TP5: Development and evaluation of ultra- At the Institute of Medical Physics, the pro- Prof. Dr. Dr. med. h.c. mult. Willi A. Kalender, sound imaging modalities for small animal im- jected CT developments, in particular for mi- PhD aging (Prof. Dr.-Ing. H. Ermert, Research group cro-CT, focused on optimization of image for High Frequency Engineering, Ruhr-Univer- quality at minimal dose, the implementation of Address sity Bochum; Prof. Dr.-Ing. R. Lerch, Chair of dual-energy methods, and the development of Institute of Medical Physics Sensor Technology, FAU) tools for dynamic micro-CT. New approaches Henkestraße 91 TP6: Combination of optical fluorescence im- to CT image reconstruction aimed at maximal 91052 Erlangen aging with Micro CT procedures for fusion im- low-contrast detectability for a given dose or, Phone: +49 9131 8522310 aging on small animals (Prof. Dr. A. Langenbu- as an alternative, at minimal dose for a given Fax: +49 9131 8522824 cher, Institute of Medical Physics). Prolongation level of image quality. [email protected] for phase 2 was not granted. The research group for High Frequency Engi- www.imp.uni-erlangen.de TP7: Interaction between Tumor-Nekrosis-Fac- neering at the Ruhr University Bochum and tor (TNF) and Interleukin-1 (IL-1) in the struc- the researchers of Sensor Technology at the Aims and Structure tural lesion of joints in the context of inflamed FAU worked on the application of various ul- joint diseases (Prof. Dr. G. Schett, Department trasound imaging modalities in small animal A team of scientists from different faculties and of Medicine 3 – Rheumatology and Immunol- imaging, the comparison of these modalities research areas was supported by the DFG from ogy; Prof. Dr. K. Engelke, Institute of Medical to MRT, micro-CT, and PET. Another research topic was the technical combination of ultra- October 2006 to September 2009 with about Physics) sound and micro-CT in a multi-modal system to 3.5 million Euro in the area “Multimodal Im- TP8: Molecular imaging with small animal posi- make use of the spatial resolution of micro-CT aging in Pre-clinical Research”, with emphasis tron emission tomography (μPET) and new PET and the contrast resolution of ultrasound. on computed tomography and small animal tracers for arthritis and tumor models (Prof. Dr. In the Department of Neuroradiology at the imaging. In the final assessment of the DFG, O. Prante, Prof. Dr. T. Kuwert, Department of UK Erlangen, the work focus was on the field the results of phase 1 were rated as very good. Nuclear Medicine) A prolongation for another three years from of medical biological basic research and clin- October 2009 to September 2012 with a fund- Research ical application. One topic was to scrutinize the sensitivity of micro CT in correlation to a ing of about three million Euro was therefore 64 slice CT and a small animal MRT during the approved by the DFG. In total, six subprojects Using the field of small animal imaging, a mul- acute phase of cerebral ischemia. The intention were prolonged directly from phase 1; another ti-disciplinary team endeavored to improve was to deploy CT to encircle ischemic tissue subproject with the topic small animal posi- the assessment of anatomical and functional that is not yet irreversibly damaged and still tron emission tomography was added and in- relationships in the same animal under com- treatable. tegrated into phase 2. The results of phase 2 parable conditions and in repetitive sequences At the Institute of Experimental and Clinical were presented at the conference “Molekulare using Computed Tomography (CT), Magnetic Pharmacology and Toxicology, the researchers Bildgebung (MoBi) 2012” in September 2012 Resonance Tomography (MR), Positron Emis- focused on the improvement of functional MRI in Erlangen. sion Tomography (PET), and Ultrasound (US), (fMRI) respectively angioplasty by recording both organ- and pathology-oriented. The and merging data of vascular trees of rodents Subprojects: combination of biochemical, functional, and and optimizing modeling. This work enhanced TP1: Contrast, dose, spatial, and temporal morphologic information should improve the not only the resolution, but also the under- resolution in computed tomography focusing possibilities for early non-invasive diagnosis and standing of the translation of neuronal activities on micro CT and small animal imaging (Prof. could finally lead to improved and often more into signals that are detected in MR. Dr. Dr. h.c. W.A. Kalender, Institute of Medical cost-efficient patient care. The Department of Medicine 3 - Rheumatolo- Physics) It was the central goal of the Research Unit gy and Immunology was working on the high TP2: 3D and 4D statistical CT image recon- (FOR) 661 to enhance and transfer the recent resolution imaging of bone damages due to ar- struction (Prof. Dr. M. Kachelrieß, Institute of developments in the field of X-ray CT and to thritis with micro-CT and micro MR in small an- Medical Physics) augment them with further efforts in basic CT imals. The research focus was to be expanded TP3: Multimodal imaging in the acute phase of research and the combination of micro-CT with on the quantification of angiogenesis in arthrit- cerebral ischemia: Micro CT and Micro MR ex- other slice imaging modalities, such as MR, ic inflamed joints in correlation to architecture aminations with the focal ischemia model (Prof. PET, and US, in order to improve the visualiza- and extent of the vessel net. Dr. A. Dörfler, Prof. Dr. T. Engelhorn, Depart- tion and evaluation of new therapy methods in With the subproject of the Department of Nu- ment of Neuroradiology) chronic pain, stroke, or malignant tumors. The clear Medicine, the imaging modality PET was TP4: Optimized multimodal imaging of the ce- cooperation of the participating institutes and also available for functional imaging of arthritis rebral vessel to improve functional imaging of departments offered considerable synergistic and tumor models on small animals by using pain induced activity (PD Dr. A. Hess, Prof. Dr. effects by the alliance of basic research (TP1, new peptide-based PET tracer. Dr. h.c. K. Brune, Institute of Experimental and TP2, TP5, and TP8) and clinical application Clinical Pharmacology and Toxicology) (TP3, TP4, and TP7).

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 183 RESEARCH UNITS

Research Unit 832: Regulators of Humoral Immunity

Speakers On the one hand, congenital disorders of the also establishing “genetically tailored“ mouse Prof. Dr. rer. nat. Thomas Winkler complex differentiation schema can lead to im- models here in Erlangen will be employed by Faculty of Natural Sciences mune deficiencies – which means to a special sus- the research unit (compare figure 2), for better Prof. Dr. rer. nat. Hans-Martin Jäck ceptibility to conditions ranging from infectious understanding molecular and cellular processes Faculty of Medicine diseases to life-threatening immune defects. How- during the humoral immune response that can- ever, excessive and misdirected immune respon- not be specifically investigated in either the cell Address ses, such as those of allergies and autoimmune cultures or the human being. Nikolaus-Fiebiger-Center diseases, are caused by disorders in the regula- Glückstraße 6 tion of the immune response. In autoimmune Teaching 91054 Erlangen patients, the immune system frequently develops Phone: +49 9131 8535913 antibodies that react to structures of their own All project leaders are actively integrated into Fax: +49 9131 85 39343 body instead of pathogens. The research unit di- the supervision of the respective doctoral stu- [email protected] rects the focus of its work towards the clarification dents as members of the doctoral supervisory www.for832.uni-erlangen.de of such undesirable developments. The approach commissions. All members of the research unit of the research unit is initially focused on funda- are also actively involved in public relation (such Aims and Structure mental research because it will only be possible as the Long Night of the Sciences and supervi- to develop new types of therapy through a better sion of seminar theses for high school students). Since 2008, the DFG has sponsored a new inter- understanding of the molecular circuits and com- departmental research unit (FOR) with the main plex cell-cell interactions in the immune defense topic of “Regulators of the Humoral Immune that is imparted by the antibody. Response” and granted a total volume of two At the present time, an efficient humoral im- million Euro for it. Seven scientists from the Insti- mune response cannot be adequately recon- tute for Biology of the Faculty of Natural Science structed “in the test tube”. The high degree of (three projects) and the UK Erlangen (four pro- complexity and the multitude of cellular and jects) are participating in the research unit. Five molecular interactions between B-cells and oth- of the eight participating project leaders which er cells of the immune system require studies on include both, biologists and clinicians, are resid- the living organism, on both tissue sections and ing at the NFZ. In close cooperation, the seven cells that have been isolated from the suitable projects research the molecular circuits that are animal models through appropriate cell-sort- involved in the control and regulation of anti- ing methods. Consequently, one experimental body-producing B-lymphocytes. Cell-culture focus of FOR 832 is the use of the mouse as and mouse models are employed. Meetings on an animal model for the humoral immune re- a regular basis (such as at the monthly B-Cell sponse. The research of the previous years has Club), a mutual concept for the education of clearly demonstrated that the processes of anti- doctoral students analogous to the program of body formation occur in a very similar manner in the expired GK 592, the participation in supervi- mice and humans. The possibility of using and Figure 1: Histology of a B-cell follicle in the spleen sory commissions for doctoral students, as well as scientific colloquia (B-cell retreat), additionally promote the mutual scientific objective.

Research

The B-cell is at the center of attention of FOR 832. During its maturation in the bone marrow, the genes for the antibody molecules are assembled by rearranging the corresponding DNA segments. This process creates millions of B-cells, all of which produce a different type of antibody. This molecule is either directed at a specific pathogen or at a molecular structure that generally signals an attack. The mature B-cell initially carries its antibody to the cell surface, thus allowing to detect an appropriate signal. In this case, the B-cell is activated in the peripheral lymphatic organs and releases large amounts of soluble protective antibodies into the blood. FOR 832 concentrates on these complex regulatory processes during the maturation and activation of B-cells. Figure 2: Gene Deletion by the Cre/Lox System

184 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH UNITS

Research Unit 894: Fluid Mechanical Basis of the Human Voice

Speaker allow a review and verification of the results To investigate predefined clinical observed ir- Prof. Dr. rer. nat. Dr. med. Ulrich Eysholdt and assumptions. In the international fluid dy- regularities and their impact on voice quality, namics and voice research community, differ- a water driven model was developed by the Address ent approaches are still applied and discussed group from Freiberg. Here, the fluid dynamics Division of Phoniatrics and Pediatric Audiology on their own. Hence, FOR 894 is performing are easier to observe due to the increased time Department of Otorhinolaryngology - Head pioneer research. To coordinate and lead the scale. This model is especially appropriate for and Neck Surgery interdisciplinary group, the DFG established a observing eddy induced acoustics. Bohlenplatz 21 W2-professorship on Computational Medicine. The experimental work is supplemented by a 91054 Erlangen Prof. Dr.-Ing. Michael Döllinger is the scientific numerical 2d-finite element method model Phone: +49 9131 8532782 manager of FOR 894. (figure) and a 3d-finite volume model. Thus, Fax: +49 9131 8532687 fluid volume as well as mechanical induced [email protected] Research acoustics can be analyzed directly. However, http://for894.forschung.uni-erlangen.de/ due to the complexity, these models cause high for894_2/index.php?lang=en The strategy of FOR 894 is the application of computational costs. different experimental and numerical models, By these approaches the different acoustic Aims and Structure yielding a comprehensive description of voice sources can be investigated and analyzed. In production. The bases for the models are endo- the future, conclusions for medical conserva- Participating Institutions: Division of Phoniat- scopic high speed digital video recordings from tive as well as surgical treatments will be driven, rics and Pediatric Audiology, Chair of Applied both, healthy and pathological subjects. At the based on the cause-and-effect chain. Mathematics II, Chair of Sensor Technology, Division of Phoniatrics and Pediatric Audiology, Institute for Process Technology and Machin- biomechanical models are fitted to the record- Teaching ery, Institute of Fluid Mechanics; Institute of ed dynamics for receiving quantitative informa- Mechanics and Fluid Dynamics (TU Bergaka- tion on the severity of diseases. The participating groups in FOR 894 supervise demie Freiberg); Institute of Mechanics and For analyzing fluid mechanical causalities, an mathematical, technical, and medical theses Mechatronics (Vienna University of Technolo- air driven physical model has been developed as well as interdisciplinary master theses and gy). Funded since 2008. representing a realistic model of human voice student research projects. The principal inves- Voice production within the larynx is still not production. Vocal folds consisting of a silicon tigators of the different projects are involved entirely understood, neither in normal nor in mixture are set into vibration and allow to in lectures in three different faculties: medical, pathological voice. The goal of the interdiscipli- experimentally analyze the entire chain of flu- engineering, and natural sciences. nary research unit (FOR) 894 is to substantiate id-structure-acoustic interaction. The materi- knowledge of normal and pathological vocal al parameters of the synthetic vocal folds are fold dynamics and of the resulting acoustic adapted to human laryngeal tissue by numer- signal. Human voice is the result of a complex ical optimization algorithms (Institute of Ap- process comprising fluid dynamics coupled plied Mathematics II). The model enables the with moving elastic tissue. Analyzing such variation of pressure, air flow, and elongation complexities necessitates different modeling of the synthetic vocal folds (Chair of Sensor approaches. Therefore, departments from dif- Technology). Hence, impacts on dynamics and ferent research fields are working together to acoustics can be observed and analyzed. How- derive a better picture of the entire voice origi- ever, irregularities cannot be separated regard- nation process. The different suggested models ing their cause and resulting effect.

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 185 RESEARCH UNITS

Research Unit 1228: Molecular Pathogenesis of Myofibrillar Myopathies

Speaker dress molecular pathways contributing to the Prof. Dr. med. Rolf Schröder pathogenesis of MFM. In the second funding period, FOR 1228 will focus on the following Address major goals: Institute of Neuropathology 1) Characterization of individual and shared Schwabachanlage 6 disease mechanisms in myofibrillar myopathies 91054 Erlangen due to pathogenic desmin-, plectin-, filamin C-, Phone: +49 9131 8544579 and VCP-mutations. Fax: +49 9131 8526033 2) Systematic analyses of disease-specific cell [email protected] and animal models. www.myofibrillar-myopathies.com 3) Validation of cell and animal models for pharmacological treatment strategies. Aims and Structure 4) Proteomic characterization of the composition of pathological protein aggregates in skel- The multilocation research unit (FOR) 1228 etal muscle biopsies from patients with geneti- has been funded by the DFG since November cally proven MFM-causing gene mutations and 2009. This research unit aims at clarifying the mouse models. molecular processes that lead to progressive 5) Identification of novel candidate genes skeletal muscle and cardiac damage in myofi- that cause human myofibrillar myopathies brillar myopathies. FOR 1228 combines the by laser dissection microscopy followed by scientific expertise of physicians, biologists, proteomic analysis and genomic DNA se- and biochemists and is composed of 13 distin- quencing. guished groups from the Universities of Erlan- 6) A multi-scale approach addressing biome- gen, Bonn, Bochum, Köln, Heidelberg, Ulm, chanical properties of MFM in myoblasts, myo- and Vienna. After a positive evaluation in July fibers, and whole muscles. 2012, FOR 1228 was granted a second fund- FOR 1228 offers the unique opportunity to ing period until November 2015. The finan- unravel the molecular “MFM sequence” that cial support of the DFG sums up to 3.6 million leads to pathological protein aggregation Euro for a six year term of funding. and progressive muscle damage. Currently Illustration of pathological protein aggregates in a no causative or ameliorating therapy is avail- skeletal muscle biopsy from a patient with myofibillar Research able for MFM. The joint work of FOR 1228 myopathy by indirect double immunofluorescence and will therefore not only provide deeper mech- electron microscopy. A: Labeling of pathological protein aggregates by doublestains with antibodies against Myofibrillar myopathies (MFM) are progres- anistic and preclinical insight into the patho- Desmin and B-Crystallin. B: Ultrastructural visualization sive and devastating diseases of human skel- genesis of MFM, but also aims at paving the of pathological protein aggregates (*) in direct vicinity to etal and cardiac muscles that often lead to way to novel targeted treatment concepts. a myonucleus (N) and to myofribrills (M). premature death. MFM are histopathologi- As translational approach we will therefore cally characterized by desmin-positive protein study the therapeutic effect of drugs and aggregates and myofibrillar degeneration. compounds that directly target pathological While about half of all MFM are caused by protein aggregation processes. In addition, mutations in genes encoding sarcomeric and gene replacement strategies by AAV-mediat- extra-sarcomeric proteins (desmin, filamin ed gene transfer will be evaluated. C, plectin, VCP, FHL1, ZASP, myotilin, and B-crystallin, BAG3, DNAJB6), the other half of Teaching these diseases is due to still unresolved gene defects. During the first funding period, FOR The participating groups of FOR 1228 are 1228 has made substantial contributions to supervising PhD and/or medical theses. The our current understanding of the molecu- principal investigators of individual projects lar pathogenesis of desminopathies, plecti- are also actively participating in the teaching nopathies, filamin C-, FHL1- and VCP-related of students in the field of medicine, molecular MFM. Major joint achievements have been medicine, biology, and biochemistry. the establishment and validation of MFM-related animal and cell models, the adaptation and refinement of laser microdissection and proteomic analysis of pathological protein aggregates and biochemical approaches to ad-

186 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH UNITS

Project Group of the Academy of Science and Literature, Mainz

Speaker Section B: Oncogenesis induced by total of five patients suffering from an immune Prof. Dr. med. Bernhard Fleckenstein the Kaposi sarcoma associated human reconstitution inflammatory syndrome (IRIS). herpesvirus 8 In these patients, a strong increase in CD4+ T Address Project leader: PD Dr. F. Neipel cells upon initiation of antiretroviral therapy is Institute of Clinical and Molecular Virology This research group is analyzing the early steps accompanied by the occurrence of opportun- Schlossgarten 4 of the infection of a cell by human herpesvi- istic infections. In one patient with a hyper- 91054 Erlangen rus-8 (HHV-8), also termed Kaposi sarcoma as- proliferative genital lesion caused by infections Phone: +49 9131 8523563 sociated human herpesvirus (KSHV). Infection with HSV-1 and human papillomavirus type 54, Fax: +49 9131 8522101 of a cell by a herpesvirus is a complex, mul- significantly increased levels of CD40 ligand [email protected] ti-step process. It involves the interaction of at were detected in the plasma for more than a www.adwmainz.de/index least three viral glycoproteins with one or more year. The PDC of the patient showed signs of cellular receptors. The highly conserved viral immune activation. These results suggest that Aims and Structure envelope-protein complex formed by glyco- the impaired PDC innate immune response proteins H and L (gH/gL) is essential for this contributes to the persistence and reactivation Persistence and chronic infections of viral path- process. Using molecular biological methods, of herpes- and papillomavirus infections. Alto- ogens are essential requirements for the devel- the group identified the ephrin receptor tyros- gether, the data of the group support impor- opment of AIDS and virus induced tumors. The ine-kinase A2 (EphA2) as a cellular receptor for tant functions of PDC in the immune defense. Academy of Sciences and Literature in Mainz KSHV gH/gL. Using a multitude of approaches supports a project group at the Institute of they could unequivocally show that EphA2 is of Section D: Transformation mediated Clinical and Molecular Virology together with crucial importance for the infection of endothe- by human T cell lymphotropic virus the State of Bavaria which is devoted to inves- lial cells by KSHV. Notably, the observed effects type 1 (HTLV-1) tigate persistent and oncogenic viruses of the were highly specific for EphA2 and could not Project leader: Dr. A. Kreß hematopoetic system. be observed with closely related ephrin-recep- This research group analyses host cell factors tors. In particular, knock-out of EphA2 on mu- which are deregulated after transformation by Research rine cells resulted in complete block of KSHV Human T cell lymphotropic virus type 1 (HTLV- infection. In summary, the data from the group 1) and which contribute to pathogenesis. Section A: Mechanism of the viral inter- clearly show that EphA2 - a receptor tyros- HTLV-1 is an oncogenic retrovirus which trans- ference between GB Virus C and HIV-1 ine-kinase that is known to play important roles forms CD4+ T cells via the viral transactivator Project leader: Dr. Dr. H. Reil in neovascularization and oncogenesis - is an protein Tax to permanent growth. Moreover, This research group is studying the pheno- essential factor for the infection of endothelial HTLV-1 is the causative agent of adult T cell menon of viral interference. In HIV patients, cells by KSHV. leukemia/lymphoma (ATLL). After the research persistence of a human non-pathogenic virus, group found out that the tumor marker Fascin the GB virus C (GBV-C), can result in a delayed Section C: Plasmacytoid dentritic cells, is a novel, NF-κB-dependent Tax target gene, AIDS progression. The focus of this project is the innate immune defense against the studies could be extended to the tumor- the clarification of the underlying mechanisms. Human Immunodeficiency virus Type 1 virus Epstein-Barr virus and its oncoprotein Here, it could be shown that the GBV-C surface (HIV-1) and Herpes simplex virus Type latent membrane protein 1 (LMP1). Use of protein E2 is significantly involved. The respon- 1 (HSV-1) infections several methods revealed that NF-κB signal- sible region could be identified to range from Project leader: Prof. Dr. B. Schmidt ing is important for LMP1-mediated induction the E2 amino acid 29 to 72. Peptides from this This research group focuses on the role of plas- of Fascin in overexpression systems as well as region are able to inhibit HIV entry efficiently macytoid dendritic cells (PDC) in virus infec- in EBV-transformed lymphocytes. Therefore, (IC50 von 0,1 und 2 μM). The E2 peptides bind tions. PDC were identified as main producers NF-κB-dependent induction of Fascin is a com- directly the HIV transmembrane protein gp41 of type I interferons in the blood in 1999. The mon feature of viral oncoproteins encoded by and suppress entry steps that follow after the group could show a reduced number and func- the lymphotropic tumor viruses HTLV-1 and HIV receptor binding. The exact E2 binding re- tion of PDC in HIV-1 infected patients which EBV. Thus, induction of Fascin seems to reveal a gion could be identified as the disulfide loop of results in an impaired immune response to new quality of virus-induced oncogenesis. gp41. Cysteine residues within the loop region viral and bacterial stimuli. It characterized the and the E2 N-terminus turned out to be essen- chronic immune activation in HIV-1 infection as tial. Bioinformatic analysis revealed a sequence one of the reasons for the reduced interferon similarity between the N-termini of HIV gp120 production. On many immune cells, CD40 li- and GBV-C E2. Since gp120 interacts with the gand, a molecule of the TNF family, was found disulfide loop of gp41 to form functional HIV to be upregulated. In parallel, the receptor surface spikes, it is assumed that this structural CD40 was upregulated on the PDC. The en- gp120 mimicry enables E2 to bind the disulfide hanced interaction of ligand and receptor leads loop. By this mechanism, the gp120-gp41 in- to a reduced production of type I interferons at terface may be disturbed and the membrane physiological levels. To verify the clinical rele- fusion between virus and cell is inhibited. vance of this model, the group investigated a

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Integrated Research Training Group within Collaborative Research Center 643: Strategies of Cellular Immune Intervention

Speaker Project area B: different industrial occupational fields and the Prof. Dr. rer. nat. Dr. med. habil. Immune intervention in animal models improvement of the students’ presentation Martin Herrmann Project area C: and scientific writing skills. The SFB emphasiz- Therapeutic applications. es on translating experimental data into clinical Address practice. Therefore, courses will be offered that Department of Medicine 3 Teaching deal with the GMP-production of cell based Ulmenweg 18 medicine and medical auxiliary material, qual- 91058 Erlangen We believe that our structured mentoring ity management, certification, and accredita- Phone: +49 9131 8536990 and education program will not only result in tion. Project-related courses, optional visits in Fax: +49 9131 8535776 better trained doctoral students, but will also external laboratories over the course of sever- [email protected] make them independent scientists early in al months within the trainee program, and a www. Grk643.de their career. Our goal is based upon the fol- guest speaker program teach the candidates lowing mentoring and educational units: Every how to take personal responsibility, establish in- Aims and Structure graduate student will be accompanied by a ternational networks, and discuss their research support-commission. It consists of the direct projects with international scientist. The Research Training Group (GK) is integrated supervisor and two part-project-leaders of the We have experienced that especially the inten- in the SFB 643 “Strategies of Cellular Immune SFB 643. In a bi-weekly regular meeting the sive scientific exchange does not only educate Intervention”. It will train the doctoral can- candidates discuss literature, methodical prob- the candidates to the better, but also helps didates to become highly qualified scientists. lems, and their own research-data. Internal them to become independent scientists very With a structured educational and support pro- Report-Symposia and Network-Meetings with early in their career. By including the support gram, it will prepare purposefully for the job. other topically relevant and external GK will commission and an intense exchange between train the candidates to present their research in Our offer to the students includes a bi-weekly the candidates and their mentors, “wrong di- front of a larger council. Workshops imparting rections” are detected and the education of the regular meeting, workshops on communication the following skills are held: Knowledge of the candidates is streamlined. and GMP-production, project-related workshops that allow students to spend time in labs outside of Erlangen. Additionally, each student gets the chance to gain organizational skills, build up scientific networks, and discuss their research with internationally recognized scientists. Final- ly, the close supervision of the students by three faculty members streamlines and focuses each research project and thus facilitates the completion of the thesis in a timely manner.

Research

The SFB 643 “Strategies of Cellular Immune In- tervention” has been existing since July 2004 and is currently in its third funding round. The goal of the research center is the successful implementation of immunological knowledge in treatments that are based on a manipulation of the immune system, i.e. on immune intervention. Immune therapeutic approaches to treat tumors and infectious diseases require the enhancement or stimulation of the immune response. Conversely, innovative treatments of inflammatory diseases, including autoimmune diseases, allergic diseases, and transplantation reactions call for novel and improved immunosuppressive strategies. The research program is conceptually structured in three closely interconnected project areas: Project area A: Basic immunology

188 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH TRAINING GROUPS AND PROGRAMS

Integrated Research Training Group within Collaborative Research Center 796: Erlangen School of Molecular Communication

Speaker Project area A: Structural basis of for one session within the first international Prof. Dr. rer. nat. Andreas Burkovski molecular interactions conference of the SFB in October 2011. Acqui- Research in project area A centers on structure/ sition of soft skills is an important part of the Address function relationships of previously identified individual development of the students and will Chair of Microbiology effector proteins and their interactions with support their scientific work and future career. Staudtstraße 5 specific cellular targets. Major topics include With this in mind, a number of tailor-made 91058 Erlangen investigation of the HIV regulatory Vpr protein, workshops are organized to improve pres- Phone: +49 9131 8528086 of HIV mimetic molecules, structural analyses entation and communication skills and writing Fax: +49 9131 8528082 of the potyvirus with plant chaperones and the techniques. In addition to these courses, fur- [email protected] development of bioinformatic tools for the pre- ther training in specific techniques or methods, www.sfb796-gk.forschung.uni-erlangen.de diction of protein-protein interactions. such as statistics or fluorescence microscopy, are also provided on student request. Aims and Structure Project area B: Reprogramming cellular processes The Research Training Group (GK) “Erlangen The focus of project area B is the detailed eluci- School of Molecular Communication” forms dation of mechanisms used by microbial effec- part of the Collaborative Research Center “Re- tors to reprogram cellular processes, including programming of Host Cells by Microbial Effec- selected signal transductions pathways, intrin- tors” (SFB 796), an interdisciplinary cooper- sic immune responses, targeted protein turn- ation of groups from the Faculty of Medicine over, and the primary metabolism. Research and the Faculty of Natural Sciences of the FAU objects range from viral pathogens (herpesvi- as well as the UK Erlangen and the Fraunhofer rus saimiri, herpes-simplex virus 1, human cy- Institute of Integrated Circuits. The GK offers tomegalovirus) to bacterial pathogens of plant an attractive doctoral program, primarily for and human cells (Xanthomonas campestris, students of the natural sciences, but also for Corynebacterium diphtheriae). medical students. There is a strong emphasis on lively scientific exchange and interdisci- Project area C: Replication structures plinary work and this is promoted by annual and transport processes retreats, an engaging series of seminars and a Project area C focuses on the question of how mentoring program. As a special feature, the microbial effectors use and partially convert GK offers now a fast track program. Outstand- cellular structures for successful colonization ing students will be given the opportunity to and replication. A number of different types replace the two-year master degree by a one- year curricular phase, thus starting their doctor- of host/pathogen interactions are also investi- al studies more quickly. gated in this area, namely the role of molec- First funding period: 2009 - 2012 ular chaperones during virus replication and Prolongation: 2012 - 2016 spreading in plants, the structure, and function of the nuclear egress complex of the human Research cytomegalovirus, the influence of the vesicles transport in plants by type III effectors from X. The strong focus on interdisciplinary research campestris as well as the development of new at the GK “Erlangen School of Molecular Com- methods for the expression analysis of Salmo- munication” is both, attractive and challeng- nella-virulence proteins. ing. The research within the SFB 796 aims at investigating the dynamic interplay between Teaching microbial effectors (viruses and bacteria) and their host cells. This is achieved by examining The GK offers structured research training in in- both, the intrinsic response of plant and mam- ternationally renowned laboratories. Each doc- malian cells and the microbial host cell manip- toral student is supervised by two experienced ulation at the molecular and cellular level. This scientists: The principal investigator of the rel- research raises the question whether similar evant SFB project and another SFB member. structures and mechanisms have developed The training program is complimented by sci- in the heterogenic host/pathogen interactions entific and method lectures. Graduate students during evolution. These general themes may are given the opportunity to choose the topics be extended to other pathogens not investi- for the GK seminars according to their own re- gated within the SFB initiative. quirements and were also given responsibility

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 189 RESEARCH TRAINING GROUPS AND PROGRAMS

Research Training Group 1071: Viruses of the Immune System

Speaker Prof. Dr. med. Bernhard Fleckenstein

Address Institute of Clinical and Molecular Virology Schlossgarten 4 91054 Erlangen Phone: +49 9131 8523563 Fax: +49 9131 8522101 [email protected] www.grk1071.uni-erlangen.de

Aims and Structure Figure 1: Graduate studies in the GK 1071

The GK 1071 “Viruses of the Immune Sys- Section A: Viral immunodeficiency larly, the International GK Symposium in Er- tem” provides an internationally oriented, Projects in this field investigate the interactions langen is realized together with students of structured training mainly for PhD, but also of Human Immunodeficiency Virus (HIV) with other research training groups and the Long for MD students. It is based on an estab- its host cells as well as with other viruses. They Night of the Sciences is presented at the Insti- lished interdisciplinary cooperation among aim at the definition of mechanisms relevant to tute of Virology by the members of GK 1071. scientists of the Faculty of Medicine and the pathogenesis and at potential targets for thera- Faculty of Natural Sciences at the FAU. The peutic intervention. special feature of the GK 1071 is an integrated exchange program with Harvard Medical Section B: School (HMS). Students holding a diploma Basis of Prevention and Therapy Humoral, cellular, and innate immune respons- or master degree in life sciences or molecular es to viruses are the main topic of projects in medicine from Erlangen join the laboratory of this section. Understanding immunological a participating Harvard faculty member and, processes controlling infection may lead to upon completion of their thesis, graduate as novel strategies for specific prevention and Dr. rer. nat. from FAU. Joint retreats provide therapy. an intense exchange between students and faculty members from Erlangen and Boston. Section C: Lymphotropic tumor viruses Figure 2: Logo for the Long Night of the Sciences at the This direct interaction enforces the mentor- Institute of Virology (drawing/copyright Kristin Katsch This research field covers various aspects of viral ing program and enables the students to gain 2009) oncogenesis. The viruses investigated induce insight into the everyday life at one of the various forms of lymphoma which are relevant leading research institutions. The resulting as human diseases or as model systems for lym- internationalization should promote the PhD phocyte growth transformation. projects and the professional perspectives of the students. Teaching Second funding period: 2009 – 2013. Our program strives for a comprehensive, in- Research ternationally oriented graduate training that fosters both, scientific and personal skills of The scientific focus of the GK 1071 is on the the PhD students. To this end, their research interface of virology and immunology. Current projects are accompanied by a mentoring pro- projects mainly concentrate on two groups of gram. An early independence is supported by persisting lymphotropic viruses, herpesviruses mandatory research reports at the retreats and and retroviruses. They are clinically relevant by student travel funds that allow for participa- as causative agents of human tumors and tion in scientific conferences. Personal develop- AIDS. Research topics include the basis of AIDS ment is further boosted by activities mediating pathogenesis and viral oncology as well as ther- complementary skills for a career in science or apy and prophylaxis of viral infections. Thus, industry. Among these are an autonomous stu- this network contributes to the research focus dent seminar, workshops on presentation, and on infectiology/immunology at the Faculty of writing techniques as well as the organization Medicine. of scientific and public-oriented events. Particu-

190 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH TRAINING GROUPS AND PROGRAMS

Research Training Group 1660: Key Signals of Adaptive Immune Response

Speaker To achieve this goal, we have recruited 20 re- (3) research symposia and network meetings Prof. Dr. rer. nat. Hans-Martin Jäck search groups headed by internationally rec- with members of other external training grants, ognized experts in the field of the biology of (4) external laboratory visits, Address dendritic cells, B cells, and T cells from nine (5) and the guest speaker seminar series. Division of Molecular Immunology institutes and clinical departments at the FAU. The students will also organize seminars and work- Nikolaus-Fiebiger-Center All supervisors have external funding and are shops for the public and high school students and Glückstraße 6 experienced in graduate training. supervise small research projects for undergradu- 91054 Erlangen ates. The doctoral students will be mentored by a Phone: +49 9131 8535913 Teaching three-member thesis advisory committee. To in- Fax: +49 9131 8539343 ternationally position our doctoral students, they [email protected] During their theses, the doctoral graduate and will organize the 4th International GK Symposi- www.lymphozyten.de medical students will participate in the success- um on “Regulators of Adaptive Immunity”. Our fully tested core events and activities of the ex- research and innovative training concept will not Aims and Structure pired GK 592: only lead to a reduction in the time required to (1) A bi-weekly doctoral regular meeting or- finish a doctoral program, but it will also provide Since October 2010, the DFG and Bavaria have ganized by the students, a high-quality training environment for young been supporting the first doctoral Fast-Track (2) subject-specific as well as interdisciplinary scientists at an internationally competitive level. program that was established at a German uni- and softskills workshops, versity. To increase the attractiveness of our program and to recruit the best students, we have developed an innovative doctoral pilot program for under- graduates with a bachelor‘s degree which will lead to the Dr. rer. nat. in 4.5 years. The program will also accept nine doctoral students with a master‘s or diploma degree (associated graduates). In addition, we have developed a doctoral training program for six talented medical students that runs parallel to the medical school program (figure 1). The doctoral students with a bachelor’s degree will first pass through a 1.5-year training program where they will receive extensive training in immunology and related disciplines, participate in three research-oriented laboratory rotations (including one at an external laboratory), and attend communication and softskills workshops. After the training period, they will start their thesis with one of the participating mentors. The main objective of this new training program is to teach and foster young scientists in Figure 1: Structure of the training program of the GK 1660 the field of adaptive immunity.

Research

Our research program focuses on the molecular analysis of three cell populations (dendritic cells, B cells, and T cells) which will contribute to our fundamental understanding of how the adaptive immune response works under physiologic as well as pathophysiologic conditions (figure 2). The main research interest is on the intra- and extracellular signaling factors which control the activation as well as the interaction of these cell types. Beyond the molecular analysis of these three cell types in mouse model systems, the physiological activation and regulation of the essential key signals shall be identified. Moreover, the role of these signals in autoimmunity and inflammatory disease will be investigated. Figure 2: Research focus of the GK 1660

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 191 RESEARCH TRAINING GROUPS AND PROGRAMS

Emil Fischer Graduate Program of Pharmaceutical Sciences and Molecular Medicine (EFS)

Speaker out the Graduate Program, all PhD students Prof. Dr. rer. nat. Markus Heinrich are independently counseled by a mentor and a co-mentor. Interdisciplinary seminars provide Address insights into the research topics and methods Professor of Pharmaceutical Chemistry of the other groups of the Emil Fischer Center. Department of Chemistry und Pharmacy The PhD students are actively involved in the Emil Fischer Center selection of seminar topics. Additional lectures Schuhstraße 19 by high profile speakers from other institutions 91052 Erlangen are provided on a regular basis. The scientific Phone: +49 9131 8524115 training is complemented by training in soft Fax: +49 9131 8522585 skills required in the academic environment as [email protected] well as in the industry. Regular “research days” www.efs.uni-erlangen.de are held to provide an opportunity for the PhD students to present and discuss their methods Aims and Structure and data in an interdisciplinary framework. Since the start of the program in December It is the aim of the Emil Fischer Graduate Pro- 2008, over 70 PhD students have enrolled in gramme to supply young researchers pursuing the program. Already 25 candidates successful- their doctoral thesis with an interdisciplinary ly completed the program with a PhD and a environment with key qualifications required EFS-certificate. for a successful career in drug target research and drug development. Main areas of interest are the identification and characterization of target proteins, signal cascades, drugs and mechanisms of action, and related bioanalytical techniques. The program is supported by members of the following chairs of the Faculties of Natural Sci- ence and Medicine: • Chair of Bioinorganic Chemistry • Chair of Biochemistry and Molecular Medicine • Chair of Biochemistry and Pathobiochemis- try • Chair of Clinical Pharmacology and Clinical Toxicology • Chair of Pharmacology and Toxicology • Chair of Food Chemistry • Chair of Physiology • Chair of Clinical Nuclear Medicine • Chair of Pharmaceutical Biology • Chair of Pharmaceutical Chemistry • Chair of Pharmaceutical Technology. In 2011, the Chairs of Organic and Pharmaceu- tical Chemistry at Regensburg University were integrated in the Graduate Programme.

Research and Teaching

The Graduate Program provides a framework of activities including seminars and counseling in order to allow the PhD students to acquire interdisciplinary skills that reach far beyond the particular topic of their PhD thesis. Through-

192 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH TRAINING GROUPS AND PROGRAMS

BioMedTec International Graduate School of Science (BIGSS): Lead Structures of Cell Function

Speaker (ENB), which in turn was founded in Bavaria Prof. Dr. rer. nat. Paul Rösch in 2004. The fundamental idea of the ENB was to provide the best possible framework for the Address scientific careers of students with excellent Chair of Biopolymers background. For that, primarily a best possible University of Bayreuth supervision of the projects was necessary. Con- 95440 Bayreuth sequently, the PhD students were supported by Phone: +49 921 553540 theses advisory committees consisting of three 553541 supervisors. The privileges of the PhD students Fax: +49 921 553544 included numerous offers to acquire soft skills [email protected] and a generous travel budget that ensured the www.bigss.de possibility to participate at international scientific congresses and workshops. There were, Aims and Structure however, also several obligatory yearly events, like written yearly progress report, summer Involved universities were Bayreuth, Erlan- school, seminars, and evaluation by indepen- gen-Nürnberg, and Würzburg. dent international reviewers. Participants from the Faculty of Medicine were: The annual summer school was a highlight • Prof. Dr. C.M. Becker, Chair of Biochemistry with varying topics every year. In 2009, it was and Molecular Medicine held in Erlangen and for the first time organized entirely by the PhD students themselves. • Prof. Dr. B. Fleckenstein, Institute of Clinical The annual Bayreuther Strukturtage, organized and Molecular Virology in cooperation with the research center for • Prof. Dr. C. Korbmacher, Institute of Cellular Bio-Macromolecules of the University of Bay- and Molecular Physiology reuth, became the main annual meeting of the • Prof. Dr. U. Schubert, Institute of Clinical and graduate school. Molecular Virology Taken together, these mechanisms and a first- • Prof. Dr. T. Stamminger, Institute of Clinical rate selection of students guaranteed a high and Molecular Virology degree of interdisciplinarity, a vivid scientific exchange, and high quality dissertations. • Prof. Dr. H. Sticht, Professorship of Bioinfor- The success of the graduate school was reflect- matics ed by many publications in important journals • Prof. Dr. M. Wegner, Chair of Biochemistry within the funding period of BIGSS. and Pathobiochemistry. Funding period: 2004 - 2012.

Research

The International Graduate School BIGSS (BioMedTec International Graduate School of Science) was themed “Lead Structures of Cell Function”, indicating that the focus of interest was in the area of biological macromolecular structures. The graduate school applied molecular biology, molecular modeling, bioinformatics, X-ray crystallography, and spectroscopic methods such as nuclear magnetic resonance (NMR) to understand the structure and function of biomolecules. The duration of the individual grants was limited to three years and offered optimal conditions for 19 PhD students. The graduate school resulted from an initiative of the BioMedTec Franken e.V. which forms a network of the Universities of Bayreuth, Erlan- gen-Nürnberg, and Würzburg. It constituted one out of the ten graduate schools which are embedded into the “Elite Network of Bavaria”

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 193 RESEARCH TRAINING GROUPS AND PROGRAMS

Erlangen Graduate School in Advanced Optical Technologies (SAOT)

Speaker techniques. Moreover, technical specifica- speakers of leading international research in- Prof. Dr.-Ing. Dr. h.c. Alfred Leipertz tions are defined which will serve as the basis stitutions contributing with a talk to a major for future development and engineering of subject usually last up to three days, e.g. the Address bio-optical sensors and apparatuses for med- past workshops on “Retina image processing“ Paul Gordan Straße 6 ical applications. To realize these objectives, and “Advanced Optical Methods for Diagnos- 91052 Erlangen the Clinical Photonics Laboratory (CPL) was tics, Assessment, and Monitoring of Clinical Phone: +49 9131 8525858 established inside SAOT. The CPL is equipped Therapy and Surgery“. During the weeklong Fax: +49 9131 8525851 with a worldwide unique apparatus pool for academies which take place outside Erlangen [email protected] the comprehensive characterization of optical twice a year, the doctoral candidates are in www.aot.uni-erlangen.de properties of biological tissues. CPL runs sev- charge of contributing to the success of the www.exzellenz-initiative.de/erlangen- eral collaborations with international institutes formed group work on a specific focus or have optical-technologies and with several medical and clinical research to give short presentations on the activities institutes of the FAU. To intensify the interdisci- in their own field. Additionally the successful Aims and Structure plinary and international collaborations, SAOT participation in the entrance academy, which organizes international workshops routinely. is organized once a year, is mandatory for all In November 2006, the SAOT was established The “Postdoctoral Medical Research Center”, SAOT doctoral candidates. At the end of this in cooperation with the Faculty of Medicine at which will be established in 2013 and will be academy they have to pass the entrance exam- the FAU within the framework of the excellence supported by SAOT with personnel, allows ination which comprises problems covering all initiative of the German federal and state gov- doctoral candidates from SAOT and Postdocs scientific topics of SAOT. ernments to promote science and research at from the Faculty of Medicine to work together German universities and has been continued for on joint interdisciplinary research projects. another five years in November 2012. SAOT offers a structured, internationally oriented (work- Teaching ing language English) and interdisciplinary education program to doctoral candidates. It is During the terms, SAOT offers standard lec- hosted by the Faculties of Engineering, Natural tures which are related to the application Science, and Medicine and is embedded into an of optical technologies in medicine. Special international network of distinguished experts SAOT activities related to the educational in their respective fields of optical technologies. program comprise seminars, workshops, and The scientific topics SAOT focuses on are opti- academies. Outstanding scientists from in- cal metrology, optical material processing, op- ternational leading institutions are invited to tics in medicine, optics in communication and give an one hour talk on specialized themes information technologies, optical materials, and at the SAOT seminar. Workshops with several systems and computational optics.

Research

Intensive research work is carried out in each of the different SAOT topics which are in their activities and topics partly overlapping. This in particular is true for the topic “Optics in Medicine” which can be considered to form an application field of the other topics. Thus it is inherently interdisciplinary, covering e.g. optical diagnostics as well as optical therapy and surgery. Thus, the further development of optical techniques in medicine demands an intensive and comprehensive exchange and collaboration between the different schools involved. The topic “Optics in Medicine” deals with the fundamental functioning principles of the human body, its organs and tissues under the exposure of optical radiation covering a broad field of frequencies and light strength. These detailed investigations of the interaction of light and tissue promote the development of improved diagnostics, therapy, and surgery

194 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH SUPPORT AND FOUNDATIONS

Advancement of Women and Gender Research Promotion

Speaker It started first in 2008 at the Faculty of Medi- the path to make the decision for a scientific Prof. Dr. med. Kerstin Amann cine. The core of the program constitutes on university career. Each term three to five guest individual mentoring/coaching of young fe- speakers from the medical sector are invited. Deputies male scientists by experienced female and male The 30-40 minutes lasting Gender Lectures en- Prof. Dr. (TR) Yesim Erim professors on all strategic questions regarding joy an increasingly good reputation. Prof. Dr. rer. nat. Ursula Schlötzer-Schrehardt career development and the implementation of those in concrete steps. The mentoring is com- Address bined with a top-class seminar program on ca- Women‘s Representative Office of the reer relevant topics, such as Funding, Work-Life- Faculty of Medicine Balance, Bibliometry, and “Appeal”-Coaching. Institute of Pathology 18 Mentees participate in the current round Division of Nephropathology which started in March 2012 (nine physicians, Krankenhausstraße 8-10 seven natural scientists and two psychologists). 91054 Erlangen The mentees are supervised by 18 female/male Germany mentors (17 of FAU, one of TU Munich). The Phone: +49 9131 8524729 mentoring program ends after 18 months in Fax: +49 9131 8524724 October 2013. [email protected] www.frauenbeauftragte.uni-erlangen.de Gender Mainstreaming

Aims and Structure Additionally Ariadne mentees are involved in the appeal committee in a subject oriented con- The women’s representative of the Faculty of Me- sulting manner. To make appeal process more dicine was placed at the disposal of academic staff transparent, it is looked after that in addition to of the FAU and UK Erlangen. In October 2007, the woman’s representative one further female the Executive Board of the FAU and the Faculty of expert is elected in the appeal committee, so Medicine concluded a target agreement to sup- that a minimum of two women are part of the port women in science. The targets for 2012 are: appeal committee. Furthermore, a member of • Increase in the number of habilitated women the Senate of the University takes care of the from 17% (2004/2006) to 25% (2012); commission in order to achieve a consequent, • Increase in the number of female professors systematic, and consistent integration of gen- from 7% (2006) to 10% (2012). der aspects during appeal process. The actual numbers of academic females within the Faculty of Medicine are shown in the ad- Headhunting joining table. The target was achieved and the aimed increase Headhunting was first started in 2008. We try reached. The new target agreement (2013 - to raise the number of applicants for professor 2017) was signed on 12th June 2013. calls. In 2012 two vacancies for professorships ______were occupied by headhunted women. ______Status as of winter term 2012 ______Female students 1st term 66% (193/291) Travel grants and scholarships ______Female students in total 63% (2027/3218) Talented postdoctoral students can apply for Females graduated 57% (368/650) ______financial support to attend scientific confer- ______Females habilitated 2012 32% (16/50) ences. The so called travel grant can be ap- ______Female professors in total: 7% (10/136) plied for once a year and for a maximum of three times in a row. Prerequisite is an active ______W1 16% (1/6) participation at the particular conference, e. g. W2 10% (8/80) ______a poster contribution. In 2012, 14 out 15 ap- ______W3 2% (1/50) plications were supported which amounts to a total funding of € 8,923. Mentoring program – ARIADNEmed Gender Lectures

Project coordinator: Dr. phil. M. Zirngibl The woman’s representative introduced the Part of the target agreement is the installation Gender Lectures in order to invite female sci- of a mentoring program called ARIADNEmed. entists who can serve as role models and ease

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 195 RESEARCH SUPPORT AND FOUNDATIONS

ELAN Program for Supporting Clinical Research and Teaching

Speaker numbers of grant proposals from the respective completed, representing a total funding of Prof. Dr. rer. nat. Michael Wegner departments reflects both, their sizes and re- 13.5 million Euro. From these projects, 298 pa- search activities, although to a different extent. pers (22 in 2011, 18 in 2012) were published Contact The average funding was about 37,000 Euro mostly in high ranking or well respected jour- Research Office of the Faculty of Medicine in 2011 and increased in 2012 to 38,000 Euro nals. Additionally, 101 (9 in 2011, 3 in 2012) Prof. Dr. rer. nat. Katrin Schiebel in standard program and about 105,000 Euro grants were acquired from external funding Östliche Stadtmauerstraße 30a in the “first-application-program”. The total sources (2.25 million Euro in 2011, 0.6 million 91054 Erlangen amount of funding requested was 1.6 million Euro in 2012) amounting since 1998 to a total Phone: +49 9131 8524604 Euro in 2011 and increased in 2012 up to 2.1 of about 18.1 million Euro. Fax: +49 9131 8522224 million Euro. The total amount of granted mon- In conclusion, the ELAN program has success- [email protected] ey in standard program oscillated around 1.3 fully stimulated a surge in high quality research www.elan.med.uni-erlangen.de million Euro annually reflecting the total availa- projects from all clinical departments. This em- ble resources. External peer review of grant pro- phasizes the value of this program as a tool to Aims and Structure posals is required for funding requests above dynamically improve clinical research within 20,000 Euro. Besides scientific excellence of the Faculty of Medicine. The ELAN program has been designed accord- the project, the committee also considers in its Since summer 2012 applications, peer review, ing to the guidelines of the National Science funding decisions compliance with other prime decisions, part of the financial administration, Council and the Conference of Ministers of goals of the ELAN program, e.g. start or young and final evaluation have been handled by a Cultural Affairs to support clinical research and investigator support. Since 1998, a total of web-based system to increase efficiency and teaching. A total of 1.3 million Euro annually 565 out of 614 granted projects have been transparency (compare screenshot). is devoted to fund projects for limited periods of time, taking also into account the previous work done by the respective researchers. Deci- sions on the distribution of funding are made by a committee of faculty members consisting of seven professors from various clinical and preclinical departments, the Dean of the Fac- ulty, the clinical director, and the chairman of the research advisory board. Main purposes of the program are to financially support research projects, promote innovative didactic models, and internationalize clinical teaching as well as its evaluation.

Funding

First and foremost, funding is provided for projects of highly qualified young investigators and newly established groups. Besides this, pilot projects are supported and financial gaps in ongoing investigations are bridged. The best young investigators are additionaly supported by a co-initiated and co-financed “first-application-program” together with the IZKF. It is intended to enable as many qualified investigators as possible to raise further funding from external grant providers. A short term support for personnel and running costs for six to twelve months appears best suited for this purpose in the standard program, whereas an extension of up to 24 month for the “first-application-program” is possible. From mid-1998 until the end of 2012, a total of 826 grant applications has been received (2011: 50, 2012: 52), coming from virtually all clinical departments. The

196 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH SUPPORT AND FOUNDATIONS

Jakob-Herz-Prize

Speaker all professors of the Faculty. The committee of his death. It was only in 1983 that the citizens Dean of the Faculty of Medicine the Jakob-Herz-Prize consists of the professors of Erlangen regretted the destructions dating Prof. Dr. med. Dr. h.c. Jürgen Schüttler of the commission for research and young aca- from the Third Reich and installed a new me- demics of the Faculty of Medicine who evaluate morial at the corner Universitätsstraße/Kran- Address the proposed candidates. The final decision is kenhausstraße. This memorial can be regarded Dean’s Office of the Faculty of Medicine made by the faculty council. The prize compris- as a compensation for the destroyed one and Östliche Stadtmauerstraße 30a es the amount of 10,000 Euro, a certificate, and shows the following sentence: “We remem- 91054 Erlangen a medal with the portrait of Jakob Herz. ber Jakob Herz to whom citizens of Erlangen Phone: +49 9131 8529334 erected and destroyed a memorial”. In 2000, Fax: +49 9131 8522224 History and Funding the principal at that time of the FAU, Prof. Dr. [email protected] G. Jasper, disclosed a bronze memorial plaque www.forschungsreferat.med.uni-erlangen.de/ This Prize has been designed in honor of the in honor of Jakob Herz at the Hugenottenplatz. e2960/index_ger.html prominent physician and researcher from Erlan- In 2011, the well-known scientist Prof. Gar- gen, Prof. Dr. Jakob Herz (1819-1871). Prof. Dr. ret A. FitzGerald, Institute for Translational Aims and Structure J. Herz was in due course the leading instruc- Medicine and Therapeutics, Philadelphia, tor of pathological anatomy and surgery and USA, was the Jakob-Herz-laureate elected by Since 2009, the Faculty of Medicine of the FAU is considered as the founder of surgical anat- the Faculty of Medicine for his achievements together with the Research Foundation of Medi- omy. In 1869, Prof. Dr. J. Herz was nominated within the field of cardiovascular diseases cine has been awarding the Jakob-Herz-Prize for as the first Jewish professor in the kingdom of (figure). His contributions regarding the com- medical research. This prize is named after Prof. Bavaria. At this time he has already been hon- prehension of the role of cyclooxygenase-2 Dr. Jakob Herz, the famous physician from Erlan- orary citizen of Erlangen for two years. Prof. inhibitors for the development of arterioscle- gen and the first Bavarian Jewish professor. The Dr. J. Herz died in 1871 as a consequence of rosis, of the significance of the circadian clock award is granted for outstanding scientific suc- his tireless commitment to his patients and to for pharmacotherapy and his development cess in the whole field of theoretical and clinical science. His larger than life memorial at the Er- of the low-dose aspirin therapy reflect only medicine. Individual achievements in research langer Hugenottenplatz was destroyed by the one part of his scientific achievement which can be honored as well as lifetime achievements. Nazis. During the National Socialism, his native is focused on translational medicine (trans- The prize is awarded biennial in the course of a town Bayreuth removed a memorial plaque ferring findings from basic science to clinical ceremony arranged by the Faculty of Medicine. at his birthplace and renamed streets which practice). Besides many awards, Prof. G.A. This ceremony includes a talk given by the lau- were named after Jakob Herz. Therefore, the FitzGerald was bestowed honorary doctor- reate. religious persecution did not end for the Jew- ates by the universities of Edinburgh, Dublin, Adequate candidates can be recommended by ish physician, scientist, and philanthropist with and Frankfurt (Main).

Prof. Dr. Dr. h.c. J. Schüttler (left), Dean of the Faculty of Medicine, and President Prof. Dr. K.-D. Grüske (right) congratulate Prof. Dr. G.A. FitzGerald. (Photographer: B. Böhner)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 197 RESEARCH SUPPORT AND FOUNDATIONS

Johannes and Frieda Marohn-Foundation

Speaker Accepted projects (Time of funding 2011 – 2012) Prof. Dr. med. Dr. med. dent. Dr. h.c. Friedrich W. Neukam Financial year Budget Number of accepted applications Contact € € Helga Zosig 2011 305.472,20 9 = 208.344,00 Johannes and Frieda Marohn-Foundation 2012 304.389,49 € 8 = 246.563,00 € Universitätsstraße 19 91054 Erlangen Phone: +49 9131 8526955 Finalized projects (Time of funding 2010 - 2012) Fax: +49 9131 8526928 [email protected] Number of projects Number of publications Continued funding by other foundations * Aims and Structure 15 12 (from 9 projects) 4 projects According to the founders’ will, the purpose of * DFG = 2 projects; other foundations = 2 projects the Johannes and Frieda Marohn-Foundation is the promotion of new innovative projects 11 projects could not obtain further financial support of the Faculty of Medicine of the FAU, serving diagnosis, prevention, and therapy of diseases in general. Projects dealing with diseases in the field of gastroenterology, including all liver and pancreatic diseases inclusive diabetes, cancer, and medical data bases shall be supported preferentially. On the other hand, the founders explicitly have stated that the purpose of the Foundation can be adapted to other modern developments and needs of medical research taking place at the Faculty of Medicine of the FAU. According to the rules of the Foundation, five members of the Faculty have to be elected for a three years period as members of the scientific board of the Foundation. Five additional members of the Faculty have to be elected to replace members of the scientific board in case of time conflicts or conflicts of interest. Only clearly defined, relevant scientific projects will be granted. Grants can be used for personnel, equipment, consumables as well as for cooperation costs between scientific and Johannes Marohn Frieda Marohn clinical departments. Grant applications should be sent to the president of the scientific committee. The rules of the Foundation can be provided by the secretary of the Johannes and Frieda Marohn-Foundation.

198 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) RESEARCH SUPPORT AND FOUNDATIONS

Research Foundation of Medicine

Speaker Euro or more are listed on a special table of for the best dissertation study (thesis) in the Prof. Dr. med. Werner G. Daniel honor placed in the main entrance hall of the field of clinical and basic research, respective- UK Erlangen, with a fostering sum of 100,000 ly. In 2012, Dr. B. Hohberger (Department of Address Euro it becomes possible to establish an own Ophthalmology) and Dr. S. Uderhardt (De- Research Foundation of Medicine self-named foundation within the Research partment of Medicine 3 – Rheumatology and at the UK Erlangen Foundation, and in certain cases a lecture hall Immunology) were awarded this prize for their Ulmenweg 18 may become named after a particularly gener- outstanding theses in the fields of clinical re- 91054 Erlangen ous sponsor (e.g. the “Rudolf-Wöhrl-Hörsaal” search respectively biomedical basic science. Phone: +49 9131 8535301 named in 2009 after the late Rudolf Wöhrl, the Fax: +49 9131 8535303 founder of the well-known fashion boutiques [email protected] who donated a sum of 250,000 Euro for re- www.forschungsstiftung.uk-erlangen.de search projects). Account details: Account number 62 000, Due to the innovative model of the Foun- Sparkasse Erlangen dation, many generous sponsors could be IBAN: DE69763500000000062000 found during the last five years. In addition, BIC: BYLADEM1ERH an appeal to donate not yet changed Deut- schemark to the Foundation (and receive the Aims and Structure donation receipt on the calculated Euro sum) contributed to the successful development. (left to right): The laureates for outstanding doctoral The Research Foundation of Medicine at the UK Thus, in 2012 the Foundation was able to theses in 2012, Dr. S. Uderhardt and Dr. B. Hohberger, together with Prof. Dr. W.L. Neuhuber Erlangen was founded in December 2007 by an distribute already more than 700.000 Euro initiative of professors of the UK Erlangen and for the various projects. This high amount of the Faculty of Medicine of the FAU. The initial money became possible also by a “Match- capital stock of almost 150,000 Euro was giving-Funds” concept, established by the UK en by 36 founder members - mainly directors Erlangen in 2011. It increases all financial of departments and institutes, but also other supports given by the Research Foundation persons, like the mayor of the city of Erlan- by the same amount out of the clinic income gen - out of their personal assets. The Research that is subject to income tax. The “Match- Foundation is intended to be a permanent and ing-Funds” program has also stimulated the stable means of financing in particular medical willingness of donators for funding immense- research, independent from public funding and ly. The “Matching-Funds” concept is success- (left to right): Press appeal to donate D-Mark with the support. Thus, former patients, alumni, and fully practiced in countries as USA, Great Brit- Bavarian Interior Minister, J. Herrmann, Prof. Dr. B. Fleck- other patrons can support with their donations ain, and others, and the Foundation hopes enstein, Mayor Dr. S. Balleis, Prof. Dr. Dr. h.c. J. Schüttler, individual projects as well as certain medical dis- that the Bavarian State Government may and Prof. Dr. W.G. Daniel. ciplines or clinics, and also medical research at take over the concept in a modified version the UK Erlangen in general. Model for our ini- for a general use in other foundations at Ba- tiative was the long-lasting successful culture of varian universities. foundations at the universities in the USA. The Research Foundation of Medicine at the UK Erlangen has meanwhile supported nu- Goals merous projects. This is true for many clinical and basic research projects as well as for the The Research Foundation of Medicine at the UK “Erlanger Medizinische Bürgervorlesung”, a Erlangen pursues four main goals: series of 12 - 14 lectures on up-to-date med- • Advancement of research in all fields of basic ical topics, initiated in 2007 and addressed and clinical sciences in medicine, each term to interested citizens. During the • Advancement of training and further educa- last 13 terms, the “Erlanger Medizinische tion of students, physician, and scientists, Bürgervorlesung” has reached an audience of • Promotion of the public health care system, 35,000 to 40,000 persons, and it was awarded especially in the fields of prevention and early with the Erlanger Medizinpreis 2012. For the diagnosis of disease, and third time, the Research Foundation - together • Benevolence within the medical care of pa- with the Faculty of Medicine - has given the tients in need. Jakob-Herz-Prize to an outstanding researcher in the field of medicine: In 2011 the prize Development was given to Prof. Garret A. FitzGerald, Phil- adelphia, USA, and in 2013 to Prof. Peter J. The Foundation provides attractive honors and Ratcliffe, Oxford, England. Furthermore, the Poster appealing to donate D-Mark (the appeal is still stimulations for sponsors: donators of 10,000 Foundation also awards every year a prize up to date)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 199 RESEARCH SUPPORT AND FOUNDATIONS

Further Foundations for Research Support

In addition to the ELAN program, the Research Diseases and Endocrinology, UK Erlangen, was Staedtler-Foundation. In 2011, Dr. I. Göhring Foundation of Medicine, and the Johannes and given the prize for his outstanding contribu- of the Institute of Human Genetics was award- Frieda Marohn Foundation, more than 20 dif- tions concerning „Molecular fate mapping of ed with this prize of the Staedtler foundation, ferent foundations and endowments are estab- cross presenting dendritic cells via Batf3 report- and in 2012, Dr. S. Zenk of the Institute of Clin- lished at the Faculty of Medicine and support er mice”. ical Microbiology, Immunology, and Hygiene research projects at different levels. Further- The Sofie Wallner Foundation (contact: S. Pen- was rewarded for his outstanding graduation. more, there are donations to the Faculty of schuck) also supports cancer research; especial- The Novartis foundation supports especially Medicine (e.g. Dr. Jahn Donation, Elise Pittroff ly travel grants are given to highly gifted young young investigators at our Faculty of Medicine. Donation). Science supporting foundations are researchers interested in oncology to enable a In 2011, Dr. F. Full (Institute of Clinical and Mo- of particular relevance for the research pro- research project at a guest laboratory in a for- lecular Virology) was given the grant, in 2012, gress. eign country. In 2011, S. Lehnert, T. Siller, and Dr. K. Mandery (Institute of Experimental and The most important foundations that are ad- J. Wild were awarded, in 2012 L. Wolf, D. Wer- Clinical Pharmacology and Toxicology) was ministrated by the FAU and closely connected ner, and T. Middendorf were given the Sofie awarded with this research support. to the Faculty of Medicine are mentioned in Wallner Prize. The Foundation for Teaching was founded to detail below. Research projects in environmental medicine support and improve the education of young The Dr. Fritz Erler Award for a reputed physi- can be supported by the Adolf Rohrschneider clinicians (contact: S. Penschuck). In 2011, Dr. cian engaged in meritorious surgical medicine Foundation (contact: J. Hubert). P. Burger (Department of Psychiatry and Psy- is donated every three years by the Dr. Fritz Er- The Wilhelm and Helene Dörfler Foundation chotherapy) and Dr. K. Singler (Chair of Inter- ler Fund. In 2012 the prize was given to Prof. (contact: Prof. Dr. G. Schett, Department of nal Medicine V) were supported by the Foun- (em.) Dr. W. Steiner, former director of the Medicine 3 – Rheumatology and Immunology, dation for their postgraduate studies “Master Department of Otolaryngology in Göttingen, UK Erlangen) offers support for projects in clini- of Medical Education” (MME). for his outstanding contributions in the field of cal immunology (especially rheumatology). More detailed information can be obtained “Transoral laser surgery in malignant tumors in The Johanna Prey Foundation supports research from the central university administration of otolaryngology”. The Dr. Fritz Erler junior prize in the field of Alzheimer’s disease, especially by the FAU, Division F3 – Körperschaft und Stiftun- was given to PD Dr. K. Gelse, Division of Trau- giving grants for doctoral theses (contact: S. gen. ma Surgery of the FAU, to appreciate his results Penschuck). In 2011, M. Schindler (Chair of in “Cellular and molecular therapy approaches Psychogerontology) was supported. in cartilage defects and arthritis”. The Dr. Ernst and Anita Bauer Foundation is an The Gottfried and Lieselotte Naumann Fund unaffiliated donation with base in Nürnberg. supports ophthalmology, especially clinical oph- Its aim is to support gifted young physicians thalmo-pathology and contribution to micro- originating from the Middle Franconian area. surgery of the eye (contact: S. Penschuck). In Awards for outstanding research results, bene- a four-year rhythm the prize is given to an ex- fits for doctoral theses, postdoctoral qualifica- traordinary researcher. The next award ceremo- tions, and research projects as well as grants ny will take place in 2014. to stay in a foreign laboratory are given by this The Dr. Norbert Henning Foundation (contact: foundation. E. Hoffmann) gives a prize for research in the The Luise Prell foundation as well as the Fritz field of gastroenterology every two years. In and Maria Hofmann foundation decorate out- 2012, PD Dr. J. Wehkamp, Robert Bosch Hos- standing master and diploma theses (contact: pital Stuttgart, was awarded for his scientific J. Hubert). The Fritz and Maria Hofmann Prize achievements in the field of „Association of was given to A.K. Wiegers in 2011 and to F. a Functional Variant in the Wnt Co-Receptor Fröb in 2012 for their excellent diploma the- LRP6 with Early Onset Ileal Crohn´s Disease“. ses. F. Winter (2011) and J. Stump (2012) were The Dr. Kurt and Margarete Groß Donation awarded for their outstanding diploma theses supports specific achievements in the field of in the reporting period. cardiology, cardiac-physiology, or cardiac sur- The best and most concise postdoctoral qual- gery. The next award ceremony will take place ification (Habilitation) is awarded annually by in 2014. the Thiersch Prize. PD Dr. K. Zimmermann of The Ria Freifrau von Fritsch Foundation (con- the Institute of Physiology and Pathophysiol- tact: S. Penschuck) was established to support ogy was the laureate in 2011, and PD Dr. C. cancer research and to finance the Ria Freifrau Thiel of the Institute of Human Genetics was von Fritsch Prize for an outstanding research awarded in 2012. achievement. In 2012, Dr. K. Hildner, Depart- The most outstanding doctoral theses are ment of Medicine 1 – Gastroenterology, Lung awarded by the Staedtler Prize, provided by the

200 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) ACADEMIC SOCIETY

Physico-Medical Society Erlangen

Corporate Management disciplinary research approaches and achieve- 11.07.2012 Prof. Dr. med. Christian Bogdan (President) ments. Prof. Dr. Dr. h.c. mult. W.A. Kalender, PhD Prof. Dr. Dr. med. h.c. Willi A. Kalender, PhD From 1984 to 2012, eleven volumes of reports Institut für Medizinische Physik, FAU „CTDI and Patient Dose: A European Perspec- (Vice-President) were published, each of them consisting of tive“ Prof. Dr.-Ing. Dr. rer. med. Ulrich Hoppe (Sec- four single issues. Beside scientific papers, the retary) reports contain recent outstanding academic Prof. Dr. med. Thomas Pasch (Treasurer) 11.12.2012 speeches, for example inaugural or farewell Prof. Dr. med. Dr. h.c. Karl-Heinz Plattig (Past Prof. I. Batinic-Haberle speeches, addresses on the occasion of honor- Treasurer) Duke University, Durham, USA ary promotions and the annual graduation cer- „The therapeutic effects of Manganese-con- Contact emony of the Faculty of Medicine of the FAU. taining porphyrins in radiation, cancer and central nervous system injuries“ Prof. Dr. med. Christian Bogdan Institute of Microbiology – Clinical Microbiolo- Lectures gy, Immunology, and Hygiene 02.02.2011 Wasserturmstraße 3-5 Prof. Dr. med. Dr. sci. nat. C. Klein 91054 Erlangen Klinik für Pädiatrische Hämatologie/Onkologie, Phone: +49 9131 85 22551 (office) Medizinische Hochschule Hannover 22281 (secretary) „Novel monogenic disorders of the human Fax: +49 9131 85 22573 immune system: from genetic defects to gene [email protected] therapy“ www.physicomedica-erlangen.de

04.05.2011 Aims and Structure Prof. Dr. med. F. Alves Universitätsmedizin Göttingen, Max-Planck-In- The Physico-Medical Society Erlangen (PMSE), also known as Societas physico-medica Erlan- stitut für Experimentelle Medizin, Abteilung gensis, was founded on March 20th, 1808 in Hämatologie und Onkologie, Göttingen order to exchange “ideas, observations, and „Preclinic evaluation of novel concepts for tu- experiences between all the areas of natural mor therapy by near infrared fluorescence im- sciences and medicine”. These first statutes aging and flat-panel computed tomography“ and articles, defined in the year 1808, are still valid; by amendment of the statutes in 1990, 16.11.2011 the technical disciplines have also been admit- Prof. Dr.-Ing. Dr. rer. med. U. Hoppe ted. On June 18th, 2008, the PMSE celebrated UK Erlangen, Hals-Nasen-Ohren-Klinik, Audiol- its 200th birthday in a ceremony at the castle ogische Abteilung of the FAU. In the year of the 200th birthday of „Elektronische Innenohrprothesen zur Thera- the PMSE, the Medical Society, which had sep- pie der Schwerhörigkeit und Taubheit: Coch- arated from the PMSE in 1958 after the 150th lea-Implantate“ birthday celebration of the Societas physico-medica Erlangensis, merged again with the 02.05.2012 PMSE. Prof. P. Ponka, MD PhD As of December 31st, 2012, the Society has Lady Davis Institute, Department of Physiolo- 384 members inside and outside Germany, gy and Medicine, McGill University, Quebec, with four of them being honorary and 36 be- Canada ing corresponding members. Once per year „The role of iron in health and disease“ the Society holds a members´ assembly upon invitation by the council. Every term the Society holds three to four reg- 06.06.2012 ular meetings with scientific lectures. These Prof. Dr. rer. nat. P.H. Seeberger are primarily given by invited national and in- Max Planck Institute of Colloids and Interfaces, ternational scientists, but also by members of Department of Biomolecular Systems, Potsdam the PMSE. According to its primary goal, i.e. to „Using chemical glycomics to understand in- promote the scientific exchange between dif- fectious diseases and to create vaccines against ferent fields of research, the PMSE preferentially bacteria and parasites: malaria and meningo- invites guest speakers with outstanding inter- cocci as examples“

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 201 APPENDIX

Selection of Honors and Prizes

2011

Honorary doctorate of the University of Zurich, 1st Award of Clinical Research, Janssen Prize Switzerland Dermatology/Immunology Prof. Dr. med. Willi A. Kalender Dr. Ulrike Hüffmeier Institute of Human Genetics Honorary doctorate of the Grodno State Medical University, Belarus Langener Science Award Prof. Dr. med. Stefan Schwab Prof. Dr. David Vöhringer Head of the Division of Infection Biology Member of the German National Academy of Sciences Leopoldina Young Investigator Award, 18th Conference of Prof. Dr. Karl-Heinz Leven Retroviruses and Opportunistic Infections (CROI), Director of the Institute of the History of Medicine and Medical Ethics Boston, USA Dr. Susan Jung Member of the AcademiaNet Department of Pediatrics and Adolescent Medicine Prof. Dr. Diana Dudziak Department of Dermatology

Honorary Member of the German Primate Center Prof. Dr. Bernhard Fleckenstein Director of the Institute of Clinical and Molecular Virology

Federal Cross of Merit on the Bond (Bundesverdienstkreuz am Bande) Prof. Dr. Eberhard Paul, FRCP (Glasg.) a.D., Apl. Prof. at the FAU Private practice for Dermatology, Nürnberg

Alfred Hauptmann Award Prof. Dr. Ingmar Blümcke Head of the Division of Nephropathology

Anton von Tröltsch Award Prof. Dr. Christoph Alexiou Department of Otorhinolaryngology – Head and Neck Surgery

Sponsorship Award of the German Cancer Aid Prof. Dr. Dr. Michael Stürzl, Dr. Elisabeth Naschberger Department of Surgery

Erlanger Award for Medicine, Technique, and Health Prof. Dr. Elmar Gräßel und Sabine Pickel Department of Psychiatry and Psychotherapy

Award for Excellence in Clinical Research 2011 Prof. Dr. Georg Schett Director of the Department of Medicine 3 – Rheumatology and Immunology

Garabed Eknoyan Award Prof. Dr. Kai-Uwe Eckardt Director of the Department of Medicine 4 - Nephrology and Hypertension

Award for brain research in geriatrics, Witten Prof. Dr. Piotr Lewczuk Department of Psychiatry and Psychotherapy

202 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

2012

Honorary Member of the Chinese Society for Science Award of the German Society of Plastic, Anesthesiology Reconstructive, and Aesthetical Surgery Prof. Dr. Dr. h.c. Jürgen Schüttler PD Dr. Andreas Arkudas Director of the Department of Anesthesiology Department of Plastic and Hand Surgery

Honorary Member of the Academia Eurasiana 2nd Place Early Researcher Award Neurochirurgica Dr. Stephanie Stiel Prof. Dr. Rudolf Fahlbusch Division of Palliative Medicine Former director of the Department of Neurosurgery Young Investigator Award and participation at Honorary Member of the Science Council of 19th Conference of Retroviruses and Opportunis- Jan-Evangelista-Purkyne University in Ùsti nad tic Infections (CROI), Seattle, USA Labem Sebastian Müller, B.Sc. Prof. Dr. Dr. h.c. Karl-Heinz Plattig Institute of Clinical and Molecular Virology Institute of Physiology and Pathophysiology 17. André Schroeder Research Award Safe-Anesthesia-Award of the Foundation Dr. Dr. Cornelius von Wilmowsky German Anesthesiology Department of Oral and Cranio-Maxillofacial Surgery Dr. Michael St. Pierre Department of Anesthesiology Thieme Teaching Award Dr. Georg Breuer Brocher Award Department of Anesthesiology Prof. Dr. Andreas Frewer Institute of the History of Medicine and Medical Ethics William D. Wagner Award Dipl.-Ing. Karl-Heinz Schaller Award of the „Alliance of Democracy and Institute and Outpatient Clinic of Occupational, Social, and Tolerance“ Environmental Medicine Work Group Medicine and Human Rights Professorship for Medical Ethics

Award of the German Society of the History of Medicine, Science, and Technology Dr. Nadine Metzger Institute of the History of Medicine and Medical Ethics

Rolf Hansen Award Markus Ries Institute of Medical Informatics, Biometry, and Epidemiology

Research Fellow 2012 of the Alexander von Humboldt Foundation Prof. I. Muiznieks, Riga, Lithuania Institute of Clinical and Molecular Virology

Loeffler-Frosch-Medal of the German Society for Virology Prof. Dr. Walter Doerfler Institute of Clinical and Molecular Virology

Fellowship Award of European College of Neuropsychopharmacology (ECNP) Dr. Davide Amato, M.Sc., PhD Department of Psychiatry and Psychotherapy

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 203 APPENDIX

Doctorate Theses, Board Qualifications, Additional Qualifications, Habilitations

Institute of Anatomy Löhmann, Christian, Dr. med.: Develop- Institute of Physiology and Chair of Anatomy I mental profiling by mass spectrometry of Pathophysiology phosphocholine containing phospholipids in Chair of Physiology the rat nervous system reveals temporo-spatial Doctorate Theses 2011 gradients Kustermann, Andreas, Dr. med.: Calretinin Doctorate Theses 2011 und Somatostatin als Marker für verschiedene Doctorate Theses 2012 Tröltzsch, Markus, Dr. med.: Prevalence and Nervenzellpopulationen in der Submukosa des association of headaches, temporomandibular menschlichen Darms Lall, Deepti, Dr. rer. nat.: Transgenic overex- joint disorders, and occlusal interferences pression of glycine transporter 1 and develop- Doctorate Theses 2012 mental changes in activity of glycine transpor- Doctorate Theses 2012 ters in mouse central nervous system Beck, Martin, Dr. med.: ChAT und NOS in Huth, Tobias, Dr. med.: Einfluss vonb -site-APP- myenterischen Neuronen des Menschen: Ko- cleaving enzyme 1 (BACE1) auf neuronale Na- Existenz und Ko-Absenz triumströme Kosteletzky, Frauke, Dr. med.: Der Einfluss von König, Sergej, Dr. med.: Lokalisation und Ver- Institute of Biochemistry – teilung von GluR2/3-Rezeptorimmunreaktivität Kratzen auf Jucken und die Sympathischen Re- im Ösophagus der Maus Emil-Fischer-Center flexe induziert durch Cowhage und Histamin Kühn, Mathias, Dr. med. dent.: Typisierung Chair of Biochemistry and Pathobiochemistry Rückel, Michael, Dr. med. dent.: Mikroneuro- der quergestreiften Muskulatur im Mäuseöso- graphische Untersuchung von C-Nervenfasern an Patienten mit Chemotherapie-induzierter phagus Doctorate Theses 2011 Schuy, Julia, Dr. med.: Quantitative Analyse Neuropathie Weller, Konrad, Dr. med.: Neuropeptidfreiset- und chemische Kodierung der ‚spiny Typ I Neu- Bremer, Magdalena, Dr. rer. nat.: Impact of zung aus Axonen des Vagusnerven: Untersu- ronen‘ im menschlichen Darm the transcription factor Sox10 on Schwann cell homeostasis chungen zur Stimulation und Interaktion axonal Wahlbuhl-Becker, Mandy, Dr. rer. nat.: Anal- exprimierter Ionenkanäle und Rezeptoren ysis of a neural crest-specific Sox10 enhancer Institute of Anatomy in the mouse Habilitation 2011 Chair of Anatomy II Lampert, Angelika, PD Dr. med.: Spannungs- gesteuerte Na+-Kanäle und ihre Bedeutung in Doctorate Theses 2012 der Schmerzentstehung Doctorate Theses 2011 Küspert, Melanie, Dr. rer. nat.: Analysis of reg- Peters, Johannes, Dr. med.: Vergleichender ulation and molecular function of the transcrip- Nachweis der Wachstumsfaktoren NGF und tion factor Sox10 in mouse glial cells Institute and Outpatient Clinic of Oc- ProNGF an der Augenoberfläche und im Trä- cupational, Social, and Environmental nenapparat Medicine Institute of Cellular and Chair of Occupational and Social Medicine Doctorate Theses 2012 Molecular Physiology Garreis, Fabian, Dr. rer. nat.: Expression und Doctorate Theses 2011 Regulation antimikrobieller Peptide an der Au- Chair of Physiology (Vegetative Physiology) genoberfläche und im Tränenapparat des Men- Bär, Barbara, Dr. med.: Influence of carbon disulfide, lifestyle factors, and constitution on schen Doctorate Theses 2011 Pfütze, Daniel, Dr. med.: Morphologisch-funk- blood pressure and serum lipid levels of male Moritz, Andreas, Dr. med.: Zur Interaktion von tionelle Untersuchungen von pro-NGF, NGF employees Sexualhormonen mit Corticosteroiden bei der Eckert, Elisabeth, Dr. rer. nat.: Development und TNF-a an gesunden Zellen und Geweben Regulation des L-Typ Ca2+ Stroms in isolierten and application of analytical methods for the de- der Augenoberfläche sowie dem Pterygium termination of mercapturic acids in human urine oculi linksventrikulären Kardiomyozyten der Ratte as metabolites of important alkylating agents Reiss, Beate, Dr. med.: Nachweis und Funk- Schütz, Vera, Dr.: Charakterisierung des L-Typ + Rochlitzer, Ellen, Dr. med.: Analysis made on tion der Surfactant - Proteine A, B, C und D in Ca2 -Stroms im linken Ventrikel des Herzens von Ga11-defizienten Mäusen ECG abnormalities of employees exposed to gesundem und degenerativ verändertem Ge- carbon disulfide referring to the Minnesota code lenkknorpel Schicht, Martin, Dr. rer. nat.: Humane Surfac- Doctorate Theses 2012 tant Proteine - Detektion und Charakterisierung Doctorate Theses 2012 Frank, Magdalena, Dr. med.: Zur Lokalisation Hopf, Hans-Georg Michael, Dr. med.: Blood + von K Kanaluntereinheiten in Lipid Rafts und lead levels during corrosion protection work Board Qualification 2012 dem Einfluss des Cholesterolgehaltes der Zell- on power poles – influential factors and time Paulsen, Friedrich, Prof. Dr. med. membran auf K+ Ströme in linksventrikulären course Kardiomyozyten der Ratte Lüersen, Lars, Dr. rer. biol. hum.: Study on percutaneous ex vivo penetration of aromatic Board Qualification 2011 amines through excised human skin and the in- Institute of Biochemistry – fluence of skin creams Korbmacher, Christoph, Prof. Dr. med. Emil-Fischer-Center Penkert, Sabine, Dr. med.: Aromatic amines in Wagner, Michael, Dr. med. habil. the rubber industry – dermal uptake, internal Chair of Biochemistry and Molecular Medicine exposure, and strain Habilitation 2012 Doctorate Theses 2011 Board Qualification 2011 Wagner, Michael, PD Dr. med.: Pathophysiolo- Hupfer, Stephan Werner, Dr. rer. nat.: Verän- gie der Regulation kardialer K+ und Ca2+ Ströme Baumeister, Thomas derte Genexpression im ZNS der Calciumka- Jüngert, Barbara nal-mausmutante Cacna 2d2 entla Straube, Sabine

204 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Board Qualification 2012 Institute of Medical Informatics, Sawall, Stefan, Dr. rer. biol. hum.: Preclinical Korinth, Gintautas Biometry, and Epidemiology In-Vivo Micro-CT of the Heart Wilhelmy, Jochen, Dr. rer. biol. hum.: Lossless Chair of Medical Informatics and Lossy Raw Data Compression in CT Imaging

Institute of Experimental and Clinical Doctorate Theses 2011 Pharmacology and Toxicology Ramming, Thomas, Dr. med.: Elektronische Institute of the History of Medicine Untersuchungsanforderungen für Labor und Chair of Pharmacology and Toxicology and Medical Ethics Radiologie: Eine Usability-Studie zur Bewertung klinischer Anwendungen Chair of the History of Medicine Doctorate Theses 2011 Tech, Hendryk, Dr. med.: Longitudinale Eva- Hofmann, Florian, Dr. rer. nat.: Untersuchungen luation der Einführung eines Patientendaten- Doctorate Theses 2011 management-Systems auf der Interdiszipli- zur Rolle von If im hypertrophen Herz der Maus Heinzelmann, Ruth, Dr. med.: Johann Baltha- Milbradt, Anita, Dr. rer. nat.: Konditionelle nären Operativen Intensivstation des Klinikums der Universität Erlangen sar Erhart (1700-1756) und seine Korrespon- Gendeletion des Ryanodinrezeptors RyR2 im denz mit Christoph Jacob Trew (1695-1769) Herzen der Maus Holinski, Cornelia, Dr. med.: Friedrich Heinrich Doctorate Theses 2012 Loschge (1755-1840) Leben und Werk Doctorate Theses 2011 Mühlenweg, Martin, Dr. med.: Optimierung Matentzoglu, Silvia, Dr. med.: Zur Psychopa- des klinischen Prozesses Mintsioglou, Dimitrios, Dr. rer. nat.: Untersu- thologie in den hippokratischen Schriften chung der prädisponierenden Faktoren für die Mitzel-Kaoukhov, Heidrun, Dr. med.: Die Brie- Schmerzverarbeitung bei gesunden Probanden Habilitation 2012 fe Johann Heinrich Schulzes (1687-1744) an anhand eines experimentellen Schmerzmodells Schmid, Matthias, Dr. rer. nat.: Erweiterung Christoph Jacob Trew von Boosting-Verfahren auf neue Modellsitua- Board Qualification 2012 tionen hochdimensionaler Daten Institute of the History of Medicine Renner, Bertold, Dr. med. and Medical Ethics Institute of Medical Physics Professorship for Medical Ethics Chair of Medical Physics Institute of Experimental and Clinical Doctorate Theses 2012 Pharmacology and Toxicology Doctorate Theses 2011 Graf, Janna, Dr. med.: Weibliche Genitalver- Chair of Clinical Pharmacology and Beister, Marcel, Dr. rer. biol. hum.: GPU-ba- stümmelung und die Praxis in Deutschland. Clinical Toxicology sierte Iterative Bildrekonstruktion und Arte- Hintergründe-Positionen-Erfahrungen in der fakt-Korrekturen in der Computertomographie Frauenheilkunde Kolb, Stephan, Dr. med.: Der Ethikkreis der Doctorate Theses 2011 Brauweiler, Robert, Dr. rer. biol. hum.: Design und Erprobung von Perfusions-Modellen in der Medizinischen Klinik 4 im Klinikum Nürnberg. Kindla, Jürgen, Dr. rer. nat.: Organic anion dynamischen Computertomographie Evaluation der Beratungsfälle von 1999-2011 transporting polypeptides (OATPs): Expression Chen, Wei, Dr. rer. biol. hum.: Anwendungen von im Kontext der historischen Entwicklung einer und Lokalisation beim Mammakarzinom und Grafikkarten in der Computertomographie: Mon- patientenzentrierten Medizin ihre Bedeutung für Arzneimittelinteraktionen te Carlo Simulationen und Korrekturverfahren Weisenseel, Nicole, Dr. med.: Behandlungs- Kraft, Michaela, Dr. med.: Expression der Eisa, Fabian, Dr. rer. biol. hum.: Dynamische zentren für Folteropfer. Geschichte, Ethik und Transportproteine OATP2A1 und OATP2B1 im kontrastmittelverstärkte Computertomographie internationale Kooperation menschlichen Auge und deren funktionelle Be- im klinischen und präklinischen Einsatz deutung für die Pharmakokinetik des Antiglau- Jin, Yannan, Dr. rer. biol. hum.: Implementa- kommittels Latanoprost tion and optimization of Dual Energy Compu- Nikolaus-Fiebiger-Center of Poguntke, Maren, Dr. med.: Transport von ted Tomography Arzneistoffen durch das Breast Cancer Resist- Weigel, Michaela, Dr. rer. biol. hum.: Untersu- Molecular Medicine ance Protein: eine Metaanalyse chungen zu dedizierter Brust-Computertomo- Chair of Experimental Medicine I graphie (Molecular Pathogenesis Research) Doctorate Theses 2012 Yohannes, Indra, Dr. rer. biol. hum.: Develop- ment of Tissue- and Water-equivalent Materials Fahrmayr, Christina, Dr. rer. nat.: Aufnahme, Doctorate Theses 2011 Metabolismus und Export von Arzneimitteln for Calibration and Quality Assurance in CT and in der Leber: tripel- und quadrupeltransfizierte Radiotherapy Eitzinger, Nicole, Dr. rer. nat.: Etablierung Zelllinien zur Analyse funktioneller Interaktionen und Phänotypanalyse einer Ucma-defizienten Mauslinie Paulus, Barbara, Dr. med.: ATP-Binding Cas- Doctorate Theses 2012 sette (ABC)-Transporter im humanen Myokard: Baer, Matthias, Dr. rer. biol. hum.: CT Scatter Expressionsänderung bei Herzinsuffizienz Simulation and CT Scatter Reduction Methods Nikolaus-Fiebiger-Center of Hupfer, Martin, Dr. rer. biol. hum.: Dosisre- duktion in der Mikro-Computertomographie Molecular Medicine Institute of Medical Informatics, Meyer, Esther, Dr. rer. biol. hum.: Metal Artifact Chair of Experimental Medicine II Biometry, and Epidemiology Reduction in Clinical Computed Tomography (Molecular Oncology) Chair of Medical Biometry and Epidemiology Nowak, Tristan, Dr. rer. biol. hum.: Untersu- chungen zur Auflösungsverbesserung und Do- sisreduktion in der Computertomographie Doctorate Theses 2011 Doctorate Theses 2012 Ritschl, Ludwig, Dr. rer. biol. hum.: Artefakt- Tanneberger, Kristina, Dr. rer. nat.: Duale po- Braisch, Ulrike, Dr. rer. biol. hum.: Tobacco- korrekturen in der mobilen Flachdetektor-ba- sitive und negative Regulation des Wnt-Signal- associated risk of multiple malignomas sierten Kegelstrahl-CT wegs durch Amer1/WTX

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 205 APPENDIX

Doctorate Theses 2012 Habilitation 2012 Board Qualification 2011 Pfister, Astrid, Dr. rer. nat.: Funktionelle Cha- Heppner, Hans-Jürgen, PD Dr. med.: Dia- Dexl, Sylvia, Dr. med. rakterisierung von Amer2, ein neuer negativer gnostik und Therapie schwerer Infektionen Meyer, Verena, Dr. med. Regulator des Wnt/b-catenin Signalwegs und beim alten Menschen Plettke, Regina, Dr. med. ein neuer EB1-Interaktionspartner Wirth, Rainer, PD Dr. med.: Decision criteria for Günther, Susanne, Dr. med. Enteral Nutrition in Old Age Board Qualification 2012 Department of Orthopedics in the Kränzlein, Diana, Dr. med. Waldkrankenhaus St. Marien gGmbH Department of Anesthesiology Kühn, Monika, Dr. med. Chair of Anesthesiology Leuthold, Christian, Dr. med. Chair of Orthopedics and Orthopedic Surgery Mell, Jan, Dr. med. Pohle, Rebecca, Dr. med. Doctorate Theses 2011 Doctorate Theses 2011 Reinhardt, Melanie, Dr. med. Fischer, Jonas, Dr. med.: Evaluation des Köckeritz, Steffen, Dr. med.: Anwendung von Saalfrank-Schardt, Christina, Dr. med. postoperativen Verlaufs der Peptide Procalcito- Botulinumtoxin A in der Behandlung der spas- Tröster, Andreas, Dr. med. nin, midregionales proAdrenomedullin, C-ter- tischen infantilen Cerebralparese Wagner, Sören, Dr. med. minales proEndothelin-1, midregionales pro Schramm, Anja, Dr. med.: Orthopädische The- Wehrfritz, Andreas, Dr. med. atriales natriuretisches Peptid und C-terminales Wilken, Verena, Dr. med. rapie der Poliomyelitis acuta anterior proArgininvasopressin bei herzchirurgischen Patienten unter besonderer Berücksichtigung Doctorate Theses 2012 systemisch-inflammatorischer und infektiöser Additional Qualification 2011 Nowak, Melanie, Dr. med.: Klinische und postoperativer Komplikationen Alt, Christina, Dr. med.: Emergency Medicine radiologische Nachuntersuchung einer Kurz- Hausmann, Christine, Dr. med.: Einfluss einer Eisenried, Andreas, Dr. med.: Emergency zusätzlichen Ketaminmedikation auf Entzün- schaft-Hüftgelenksendoprothese-Untersuchung Medicine dungsreaktion und Katabolierate bei Patienten 6 Jahre postoperativ Engelen, Wolf-Christian, Dr. med.: Emergency mit schwerer Sepsis. Eine vergleichende Unter- Zingler, Katharina, Dr. med.: Vergleich der Medicine suchung zweier Analgosedierungsverfahren kortikalen und spongiösen Knochenreaktion Frank, Paul, Dr. med.: Emergency Medicine Niedermirtl, Florian, Dr. med.: Das intravenö- des Beckens nach Implantation einer zement- Münster, Tino, PD Dr. med.: Special Pain se Anästhetikum Propofol aktiviert nozizeptive Therapy freien Hüftendoprothese in Abhängigkeit von Neurone über TRPA1-, TRPV1- und GABA A-Re- patienten- und prothesenspezifischen Charak- Nau, Carla, Prof. Dr. med.: Intensive Care zeptoren Medicine teristika- eine CT- gestützte Knochendichteun- Petterich, Nico, Dr. med.: Einfluss verschiede- tersuchung in vivo Schneider, Thomas-Michael, Dr. med.: Emer- ner Primingdosierungen auf die Anschlagszeit gency Medicine von Cisatracurium an der Kehlkopfmuskulatur Eisenried, Andreas, Dr. med.: Emergency und am Musculus adductor pollicis Medicine Department of Orthopedics in the Pircher, Rebecca, Dr. med.: Vergleich der analgetischen Potenz von Isofluran, Sevofluran und Waldkrankenhaus St. Marien gGmbH Desfluran im cross-over Design bei der Ratte Additional Qualification 2012 Division of Orthopedic Rheumatology Rehner, Dietlinde, Dr. med.: Lokalanästhetika Nau, Carla, Prof. Dr. med.: Special Pain Therapy aktivieren und sensibilisieren den Capsaicin-Re- zeptor TRPV1 Board Qualification 2011 Habilitation 2012 Walz, Florian, Dr. med.: Pharmakodynamische Pauser, Johannes, Dr. med. Modellbildung anästhesieassoziierter Verände- Birkholz, Torsten, PD Dr. med.: Patientenmo- rungen quantitativer EEG-Variablen und phy- nitoring in Risikosituationen siologischer Parameter während Desfluranap- Institute for Biomedicine of Aging plikation bei der Ratte Chair of Internal Medicine (Geriatrics) Department of Cardiac Surgery Doctorate Theses 2012 Chair of Cardiac Surgery Doctorate Theses 2011 Lieret, Elke, Dr. med.: Identifikation geeigneter Doctorate Theses 2011 Kieslich, Barbara, Dr. med.: Nursing home – EEG-Parameter für das Narkosemonitoring durch no return home? Approximation ihres Rausch-Signal-Verhältnisses Gebhardt, Julia, Dr. med.: Noninvasive Mag- Leikauf, Ruth, Dr. med.: Influence of exercise anhand eines lokalen Polynom-Schätzers netic Resonance Imaging of Vessels affected by and food restriction on laboratory parameters Saßmann, Volker, Dr. med.: Anwendungsbe- Transplant Arteriosclerosis in an Experimental of the aging rat obachtung zum Nachweis einer analgetischen Mouse Allograft Model Wirkung von Dexamethason bei endoprotheti- Heim, Christian, Dr. med.: Die Infektion mit mu- schem Hüftgelenkersatz: Vermindert eine Gabe rinem Cytomegalie-Virus verstärkt die Ausbildung Doctorate Theses 2012 von 8 mg Dexamethason i.v. zur Narkoseeinlei- von Transplantat-Arteriosklerose im experimentel- Wehr, Helmut, Dr. med.: Practicality and Rele- tung den postoperativen Schmerzmittelbedarf? len Mausaortentransplantationsmodell vance of the Frailty Criteria by Fried in a Gener- Tiebel, Nils, Dr. med.: Quantitativ-sensorische al Practitioner’s Office in a Rural Area Testung bei Patienten mit M. Crohn: Unter- Board Qualification 2011 schiede zwischen Patienten mit hohem und Rörick, Olaf, Dr. med. niedrigen postoperativen Opioid-Bedarf Rubio-Lopez, Alvaro, Dr. med. Habilitation 2011 Vogel, Sascha, Dr. med.: Einflussfaktoren einer Bauer, Jürgen, PD Dr. med.: Body Composi- postoperativ messbaren Skelett- und Herzmus- tion and Functionality in Old Age – Approaches kelschädigung bei mittels Herz-Lungen-Ma- Additional Qualification 2011 for Therapeutical Interventions schine operierten Patienten Rörick, Olaf, Dr. med.: Emergency Medicine

206 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Habilitation 2011 Department of Medicine 1 – Gastro- basierten Entscheidungsunterstützung für die Harig, Frank, PD Dr. med.: Selektive Retroper- enterology, Lung Diseases, and Endo- kalkulierte Antibiotikatherapie fusion crinology Chair of Internal Medicine I Doctorate Theses 2012 Günther, Claudia, Dr. rer. nat.: Regulation of programmed cell death in the intestinal epithe- Department of Dermatology Doctorate Theses 2011 Chair of Skin and Veneral Diseases lium and its role in intestinal homeostasis Baum, Svenja, Dr. med.: Untersuchungen zur Hagel, Wolfgang, Dr. med.: Evaluation der Mortalität bei Blutungen am unteren Gastroin- Doppelballon-Enteroskopie bei der Diagnostik Doctorate Theses 2011 testinaltrakt. und Therapie von Patienten mit Blutungen im Hoffmann, Christian, Dr. rer. nat.: Analyse der Begemann, Margit, Dr. med.: Spektrum und mittleren Gastrointestinaltrakt. TCR Biologie und Entwicklung neuer therapeu- Komplikationen sonographisch gesteuerter In- Hauck, Tabea, Dr. med.: Einflüsse einer tischer Strategien bei der HIV-1 Infektion terventionen an der Medizinischen Klinik 1 Er- adäquaten Continuous-Positive-Airway-Pressure langen in den Jahren 2005-2006. Therapie auf die Plasmaspiegel der Peptidhor- Ertl, Franz, Dr. med.: Spektrum und Komp- mone Apelin, Obestatin und Leptin bei Patien- Doctorate Theses 2012 likationen sonographisch gesteuerter Interven- ten mit neu diagnostiziertem Schlafapnoe-Syn- Böhm, Stefanie, Dr. rer. nat.: Adoptive T-cell- tionen an der Medizinischen Klinik 1 Erlangen drom. receptor transfer to examine human T-cell im- in den Jahren 2007-2008 Klein, Matthias, Dr. med.: Doppelballon-En- munology in vitro Gilsbach, Stefanie, Dr. med.: Medikamentöse teroskopie basierte endoskopisch retrograde Bosch-Voskens, Caroline, Dr. med. (MD, PhD): Kombinationstherapie bei kolorektalem Kar- Cholangiopankreatikographie mit bilio-pankrea- Immunotherapeutic strategies in patients with zinom im Metastasenmodell der Ratte. tischen Interventionen an Patienten mit Zustand solid malignancies - Crossing the line between Grensemann, Sven, Dr. med.: Effekte eines nach komplexen Bauchoperationen. scientific possibility and clinical reality additiven Trainings der Atemmuskulatur bei Pa- Kraupa, Werner, Dr. med.: Behandlung von Epp, Raphael, Dr. med. dent.: Altersentwicklung tienten mit mittelschwerer COPD. okkludierten Gallengangsendoprothesen mit von Typ IV-Sensibilisierungen auf p-Phenylendia- Jakubaß, Volker, Dr. med.: Einführung eines Stoßwellenlithotripsie. Eine experimentelle in- min und deren klinische Relevanz im Patienten- Behandlungspfades für ambulant erworbene vitro Analyse kollektiv der Hautklinik des Universitätsklinikums Pneumonie. Bedeutung für Liegedauer und Neumann, Florian, Dr. med.: Früherkennung Erlangen im Vergleich zum Informationsverbund Prognose. von dysplastischen Kolonläsionen mit Fluo- Dermatologischer Kliniken (IVDK) Jugl, Veronika, Dr. med.: ARFI - ein neuer sono- reszenz-Videoendoskopie in Kombination mit Hack, Carolin, Dr. med.: CD4+CD25+ regu- graphischer Surrogatparameter der Leberfibro- Hexaminolavulinat als Photosensibilisator, eine latorische T-Zellen unter perennialer versus prä- sierung. Dosisfindungs- und Machbarkeitsstudie. saisonaler spezifischer Immuntherapie bei Typ Kellermann, Carla, Dr. med.: Beeinflussung Wittkopf, Nadine, Dr. rer. nat.: Regulation of I-Allergie auf Inhalationsallergene der TNBS-induzierten Colitis im Tiermodell Paneth cell biology in gastrointestinal inflam- Maronna, Andreas, Dr. med.: Ex vivo Isolation durch Modulation des Cannabinoidsystems. mation und Charakterisierung von CD4+CD25+ regu- Kleye, Christin, Dr. med.: Evaluation einer latorischen T-Zellen unter perennialer versus öffentlich angebotenen Spirometrie als Maß- präsaisonaler spezifischer Immuntherapie bei Board Qualification 2011 nahme zur Primärprävention von Folgeerkran- Typ I-Allergie auf Inhalationsallergene kungen des Rauchens. Albrecht, Heinz, Dr. med. Koucky, Kathrin, Dr. med.: Palliative Erstli- Ende, Anke, Dr. med. Additional Qualification 2012 nientherapie mit einer wöchentlichen Hoch- Janson, Christopher, Dr. med. Heinzerling, Lucie, Dr. med. (MD, PhD): Drug- dosisbehandlung aus 5-Fluorouracil und Natri- based Tumor Therapy umfolinat als 24h-Infusion (AIO Regime) plus Board Qualification 2012 Irinotecan bei Patienten mit metastasierten Hildner, Kai, Prof. Dr. med. Adenokarzinomen des Magens und des gas- Neufert, Clemens, Dr. med. Habilitation 2011 troösophagealen Übergangs gefolgt von se- kundärer Metastasenresektion nach Down- Schaft, Niels, PD Dr. rer. nat.: Functional ma- Additional Qualification 2011 nipulation of T-cells by RNA transfection sizing. Resheq, Yazid, Dr. med.: Neue immunologi- Heide, Roland, Dr. med.: Intensive Care sche Therapieansätze für den Diabetes mellitus Medicine Typ 1 am Non-Obese-Diabetic-Mausmodell Department of Dermatology unter besonderer Berücksichtigung antigen Additional Qualification 2012 Division of Immune Modulation präsentierender Zellen. Janson, Christopher, Dr. med.: Emergency Röhrig, Sandra, Dr. med.: Palliative systemische Medicine Doctorate Theses 2012 Kombinationschemotherapie mit Gemcitabin und 5-Fluorouracil als 24h-Infusion bei Patienten Seitz, Christine: Production of Recombinant Habilitation 2011 Human Soluble CD83 in an Eukaryotic System mit metastasiertem Pankreaskarzinom and Generation of Tissue-Specific CD83 Knock- Rus, Crina, Dr. med.: Funktionelle Charakte- Boxberger, Frank, PD Dr. med.: Multimodale out Mice risierung von Mutationen des Calcium-Sen- Therapie gastrointestinaler Tumore Stein, Marcello, Dr. rer. nat.: Characterization sing-Rezeptors bei Patienten mit familiärer hy- Frieser, Markus, PD Dr. med.: Radiofrequenz- of the CD83 promoter/enhancer complex pokalziurischer Hyperkalzämie: Wirkung des ablation als interventionelles Ultraschallver- Theodoridis, Alexandros: Modulation of den- Kalzimimetikum NPS R-568 fahren in Lebertumoren dritic cell migration by herpes simplex virus Walter, Victoria, Dr. med.: Stellenwert der En- Mudter, Jonas, PD Dr. med.: Bedeutung des In- type 1 dosonographie in der präoperativen Diagnostik terleukin-6/Interleukin-17 Signaltransduktions- des Pankreaskarzinoms. weges bei chronisch entzündlichen Darmer- Zenker, Corinna, Dr. med.: Endoskopische krankungen und experimenteller Colitis Interventionen bei Patienten mit chronisch Zopf, Yurdagül, PD Dr. med.: Indikationen und entzüdlichen Darmerkrankungen. Komplikationsrisiken bei interventionell-en- Zwickel, Philipp, Dr. med.: Entwicklung, Im- doskopisch angelegten Sonden bei Patienten plementierung und Evaluation einer wissens- mit Mangelernährung

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Department of Medicine 2 – Department of Medicine 3 – Doctorate Theses 2012 Cardiology and Angiology Rheumatology and Immunology Brachs, Sebastian, Dr. rer. nat.: Analysis of Chair of Internal Medicine II Chair of Internal Medicine III the function of the murine protein EFhd2/Swi- prosin-1 in B cell development and immune response in vivo Doctorate Theses 2011 Doctorate Theses 2011 Baum, Christina, Dr. med.: Pathophysiologi- Balzer, Michael, Dr. med.: Peroxisome Pro- Habilitation 2012 sche Relevanz von systemischen Zytokinen für liferator-Activated Receptor g Coactivator-1 a die Entwicklung von Koronarkalk (PGC-1a) in der Pathogenese der Sklerodermie Mielenz, Dirk, PD Dr. rer. nat. Dr. habil. med.: Böhmer, Kerstin, Dr. med.: Einfluss der Rekon- Huhn, Konstantin, Dr. med.: Auswirkungen Functional analysis of novel adaptor proteins struktionsparameter auf die Dichte koronarer eines Einzelnukleotid-Polymorphismus im Adi- during selection and activation of B cells atherosklerotischer Plaques in der Dual Source ponectin-Gen auf Pathogenese und klinische CT. Manifestation der Systemischen Sklerose Frick, Maike Veronika, Dr. med.: Is it possible Kireva, Trayana, Dr. rer. nat.: Rolle des Trans- Department of Medicine 4 – to quantify angles and angle changes at coro- kriptionsfaktors Fra-1 Nephrology and Hypertension nary artery bifurcations online? Lang, Veronika, Dr. med.: Resistenz der von Chair of Internal Medicine IV Geier, Barbara, Dr. med.: Segmentale Syn- Marginalzonen B-Zellen initiierten T-Zell un- chronität und Volumenänderung des linken abhängigen Immunantwort Typ 2 gegenüber Ventrikels während ventrikulärer Schrittmacher- dem Proteasomeninhibitor Bortezomib Doctorate Theses 2011 stimulation - Ultraschallbasierte Analyse durch Müller, Ralf, Dr. rer. nat.: Die Rolle der p38MAP- Gimm, Tina, Dr. rer. nat.: Functional role of the Real Time 3D Echokardiographie. Ka und MAPKAPK-2 in einem murinen Modell hypoxia-inducible protein 2 Hagel, Alexander F., Dr. med.: Detektion des der anti-Basalmembran Glomerulonephritis Heersink, Claudia, Dr. med.: Acid-induced cur- rechtsventrikulären Infarktes mittels kardio- Munoz Becerra, Luis Enrique, Dr. rer. nat.: rents in chemically stimulated renal afferents vaskulärer Magnetresonanztomographie Dual Role of Clearance Deficiency in the Etiolo- Knier, Benjamin, Dr. med.: Effect of the plas- Regler, Melanie, Dr. med.: Antiathero-sklero- gy and in the Pathogenesis of SLE minogen-plasmin system on hypertensive renal tische Eigenschaften von Resveratrol: Moleku- Schäfer, Valentin, Dr. med.: Risiken von Infek- and cardiac damage lare und funktionale Effekte auf humane En- tionen und malignen Erkrankungen bei Riesen- Leis, Bastian, Dr. med.: The pressure inde- dothelzellen und Monozyten zellarteriitis pendent effect of salt on end organ damage in Turan, Nesrin, Dr. med.: Randomisierter Ver- Uderhardt, Stefan, Dr. med.: Molekulare resistant hypertension gleich von transradialer und transfemoraler Regulation des Knochenremodeling bei ent- Koronarangiographie und -intervention bei zündlicher Arthritis Doctorate Theses 2012 Patienten über 75 Jahre: Erfolgsrate und proze- durale Daten Rodionova, Kristina, Dr. med.: Meaning of dif- Doctorate Theses 2012 ferent populations of dorsal root ganglion neu- Bergmann, Christina, Dr. med.: Inhibition of rons in sensory peptidergic renal innervation Doctorate Theses 2012 glycogen synthase kinase 3b induces dermal fi- Striepe, Kristina, Dr. med.: Comparison of dif- Bertogg, Kaja, Dr. med.: Der Einfluss der Herz- brosis by activation of the canonical Wnt path- ferent calcium channel blockers regarding their phase auf die Prävalenz von Bewegungsartefak- way effect on intrarenal hemodynamics in patients ten beim Koronarkalknachweis mittels Com- Funke, Robin, Dr. med.: Epigenetisches Silenc- with arterial hypertension putertomographie ing von endogenen Inhibitoren des WNT-Sig- Wiese, Melanie, Dr. rer. nat.: Impact of hy- Bietau, Christian, Dr. med.: Sicherheit und Ef- nalweges durch Promoter Methylierung in der poxia and the influence of the hypoxia-indu- fektivität eines Bare-Metal-Stents der zweiten Systemischen Sklerose cible factor HIF-1α on the antibacterial capacity Generation. Ergebnisse des Coroflex® Blue- Janko, Christina, Dr. rer. nat.: Impact of CRP of dendritic cells and macrophages Registers der Medizinischen Klinik 2 - Kardio- on dying and dead cells logie und Angiologie des Universitätsklinikums Schroeder, Kristin, Dr. rer. nat.: Tolerance Board Qualification 2011 Erlangen. mechanisms for anit-DNA autoantibodies in Dahlmann, Anke, Dr. med. Roth, Simon-Petrus, Dr. med.: Inflammation the germinal center Friedrich, Stefanie, Dr. med. und Myokardinfarkt - Die Rolle von FcgRIIa als Strapatsas, Tobias, Dr. med.: Ungleichgewicht Matheis, Edi, Dr. med. unabhängiger Risikofaktor für das Auftreten von angiogenen und angiostatischen Faktoren Ott, Christian, Dr. med. von Komplikationen der Atherosklerose bei Patienten mit Mischkollagenose Raff, Ulrike, Dr. med. Schönegger, Carolin, Dr. med.: Kontrastver- Röseler, Tilmann, Dr. med. stärkte kardiale Magnetresonanztomographie Board Qualification 2012 Türk, Tobias, Dr. med. zur Risikostratifizierung nach reperfundiertem Krönke, Gerhard, Dr. med. Weidemann, Alexander, Dr. med. Myokardinfarkt Reisch, Annja, Dr. med. Ronneberger, Monika, Dr. med. Board Qualification 2012 Board Qualification 2012 Lehmann, Marina, Dr. med. Marwan, Mohamed, Dr. med. Ritt, Martin, Dr. med. Pflederer, Tobias, PD Dr. med. Department of Medicine 3 – Rheumatology and Immunology Habilitation 2011 Habilitation 2011 Division of Molecular Immunology Warnecke, Christina, PD Dr. med. vet.: Iden- Pflederer, Tobias, PD Dr. med.: Diagnostik der tification and functional characterization of koronaren Herzerkrankung mittels Computer- Doctorate Theses 2011 novel target genes of the hypoxia-inducible tomographie transcription factors (HIF) Kroczek, Carmen, Dr. rer. nat.: Functional analysis of Swiprosin-1 in proximal B cell recep- Habilitation 2012 tor signaling Habilitation 2012 Rittger, Harald, PD Dr. med.: Interventionelle Porstner, Martina, Dr. rer. nat.: A role for mi- Bernhard, Wanja, PD Dr. med.: Renal effects of Therapieverfahren bei akutem Myokardinfarkt croRNAs during plasma cell differentiation and pharmacological induction of hypoxia-induci- und stabiler KHK im höheren Lebensalter. in multiple myeloma ble transcription factors

208 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Ditting, Tilmann Johannes, PD Dr. med.: The Schwarz, Marc, Dr. rer. nat.: Interaction of mi- Rübner, Mattias, Dr. rer. nat.: Epigenetic DNA- autonomic renal innervation – afferent regula- croglia with malignant gliomas methylation of the HERV-W promoter in abnor- tory mechanisms mal human placentogenesis and tumorigenesis. Scheffler, Miriam, Dr. med.: Doppler der Uterinarterien in Kombination mit maternal Department of Nuclear Medicine Department of Medicine 5 – anamnestischen und biochemischen Faktoren Chair of Clinical Nuclear Medicine als Screening-Test für Präeklampsie und intra- Hematology and Oncology uterine Wachstumsrestriktion am Ende des er- Chair of Hematology and Oncology Doctorate Theses 2011 sten Trimesters. Schmid, Monika Stefanie, Dr. med.: Assozi- Doctorate Theses 2011 Sonntag, Christina, Dr. med.: Erfolg der Ra- ation von anamnestischen und epidemiolo- dioiodablation nach totaler Thyreoidektomie gischen Faktoren mit der Endometriose - eine Gary, Regina, Dr. rer. nat.: Characterization and bei differenzierten Schilddrüsenkarzinomen krankenhausbasierte Fall-Kontroll-Studie. functional analysis of the transfer of cell compo- Stellwag, Stefanie, Dr. med.: Untersuchung nents from human antigen-presenting cells onto der Bedeutung der genetischen Variation T cells via antigen-specific trogocytosis Doctorate Theses 2012 D1853N des ataxia telangiectasia-mutated Kammerer, Sara, Dr. med.: Evaluierung der gene (ATM-Gen) für das Risiko und die Prog- Doctorate Theses 2012 Aussagekraft und Relevanz nuklearmedizini- nose einer Mammakarzinomerkrankung. scher Bildgebung bei Patienten mit Verdacht Goldmann, Katja, Dr. rer. nat.: Immunmodu- Stratmann, Alexandra, Dr. med.: Zufriedenheit auf primären Knochentumor lation durch orale Applikation von Antigen von Schwangeren mit der Patient-Controlled- Reinfelder, Julia, Dr. med.: Effects of recom- kodierenden Chitosan-DNA Nanopartikeln Epidural-Analgesia (PCEA) unter der Geburt am binant human thyroid-stimulating hormone Meinhardt, Kathrin, Dr. rer. nat.: Isolierung und Erlanger Kollektiv in den Jahren 2005-2008. superagonists on thyroidal uptake of 18F-fluo- Charakterisierung muriner NK-Zell-Subpopula- Tappert, Verena, Dr. med.: Genetische Poly- rodeoxyglucose and radiodide tionen zur Untersuchung ihrer Rolle während der morphismen im methyl-CpG binding domain Wrubel, Scarlett Margot Annelies, Dr. med.: Graft-versus-Host-Erkrankung Protein 4 (MBD4)-Gen beim Mammakarzinom. Biodistribution und Analyse von 68Ga-mark- Ünlühan, Nesrin, Dr. med.: Neurokinin 1 Re- ierten RGD-Multimeren an tumortragenden Board Qualification 2012 ceptor Gene Polymorphism might be correlat- Nacktmäusen mit Hilfe der Kleintier-Positro- ed with recurrence rates in endometriosis. Erney, Birgit, Dr. med. nen-Emissions-Tomographie Haibach, Martina, Dr. med. Walther, Annette, Dr. med.: Expression von Müller, Andrea, Dr. med. Gonadotropin-Releasing-Hormon und Gona- dotropin-Releasing-Hormon-Rezeptor in Endo- metriose-Gewebe. Habilitation 2012 Department of Obstetrics and Weihbrecht, Sebastian, Dr. med.: Assozia- Ullrich, Evelyn, Prof. Dr. med.: Dendritische Gynecology tionen zwischen Polymorphismen im Topo- Zellen und natürliche Killerzellen in der anti- Chair of Obstetrics and Gynecology isomerase Iia Gen mit der Länge des HER2-Am- tumoralen Therapie und Immunregulation plikons auf Chromosom-17-Implikationen für Doctorate Theses 2011 Mechanismen der Genamplifkation und die Brandt, Ina, Dr. med.: Untersuchung der Pro- Prognose bei Mammkarzinompatientinnen. Department of Neurology liferationshemmung von Brustkrebszellen durch Wiesinger, Erika, Dr. med.: Clinical examination and laparoscopy cannot be replaced Chair of Neurology das Bioflavonoid Quercetin in Kombination mit dem mTOR-Inhibitor Everolimus (RAD001). by imaging techniques when diagnosing the Cupisti, Dita, Dr. med.: Neuzeitlicher Schwanger- MRKH-syndrome. Doctorate Theses 2012 schaftsabruch: Vitamin K-Antagonist? Weiss, Silvia, Dr. med.: Evidence for a progeni- Dilling, Sabine, Dr. med.: Nabelschnurblutent- Doctorate Theses 2012 tor cell population in the human pituitary nahmen in der Frauenklinik des Universitäts- Bahnmüller, Bea, Dr. med.: Comparison of klinikums Erlangen: Einfluss von maternalen, laparascopic surgery with open surgery in fetalen und geburtshilflichen Parametern auf women with endometrial cancer. das gewonnene Nabelschnurblut und dessen Fru, Chi-Ira, Dr. med.: Investigation of correla- Department of Neurology Eignung zur Einlagerung als autologes oder tion between antioxidant property of seminal Division of Molecular Neurology allogenes Stammzellpräparat. plasma and sperm quality. Groh, Nicole, Dr. med.: Untersuchung der Geisler, Klaudija, Dr. med.: The perfused swine Proliferationshemmung von Brustkrebszellen Board Qualification 2012 uterus model: long-term perfusion. durch Chloroquin in Kombination mit dem Hochreuther, Christina, Dr. med.: Einfluss der Schlachetzki, Johannes, Dr. med. mTOR-Inhibitor Everolimus (RAD001). mütterlichen Bindung auf die Entwicklung einer Henglein, Kathrin, Dr. med.: Vergleich von fünf postpartalen Depression. Die MATER-Studie. verschiedenen Hysterektomieverfahren. Horn, Jasmin, Dr. med.: Marked Improvements Department of Neurosurgery Henning, Jens, Dr. med.: In vitro studies on in Training for Students in their Pratical Year. Chair of Neurosurgery the influence of human seminal plasma on the Developments in German Gynecology Teaching contractility of the extracorporeally perfused from 2006 to 2010 and the Prospects. non-pregnant porcine uterus. Doctorate Theses 2011 Schibel, Annika, Dr. med.: Influence of Ma- Klingsiek, Peter Andreas, Dr. med.: Lifestyle ternal Smoking during Pregnancy on Oxidant Heckel, Alexandra, Dr. med.: The role of xCT und Endometriose - Ergebnisse aus einer Fall- Status in Amniotic Fluid. in the progression of malignant gliomas Kontroll-Studie. Segl, Petra, Dr. med.: Differences in success Merk, Sabine, Dr. med.: Lebensqualität und Zu- rates between patients with ectopic pregnan- friedenheit nach Hysterektomie - Ein Vergleich cy treated with 30mg methotrexate and those Doctorate Theses 2012 von fünf verschiedenen Operationsverfahren. treated by salingotomy. Schlaffer, Sven-Martin, Dr. med.: Einfluss Rix, Nadine, Dr. med.: Teilnahmerate an einer präoperativer medikamentöser Therapien auf chemopräventiven Behandlung in der IBIS-II die Proliferationsaktivität von Hypophysenade- Studie - eine prospektive Kohortenstudie im Board Qualification 2011 nomen bei Akromegalie Rahmen des Mammographiescreenings. Engel, Julia, Dr. med.

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Board Qualification 2012 optischer Kohärenztomographie im Methoden- und Sox9 bei der terminalen Differenzierung Faschingbauer, Florian, Dr. med. vergleich von Osteoblasten unter Bisphosphonatgabe - Jud, Sebastian, Dr. med. Schrems-Hös, Laura, Dr. med.: Einfluss von eine experimentelle Untersuchung Lermann, Johannes, Dr. med. Papillengröße und Glaukomstadium auf die Fitz-Kretschmar, Michaela, Dr. med. dent.: Rauh, Claudia, Dr. med. Glaukomdiagnostik mit dem Heidelberg Retina Einfluss von Bisphosphonaten auf die terminale Ünlühan, Nesrin, Dr. med. Tomograph Differenzierung von Osteoblasten: Eine Immun- Stuhlfelder, Konstanze, Dr. med.: Betreuung histochemische, experimentelle Analyse von Kindern mit septo-optischer Dysplasie Göthel, Wolfgang, Dr. med. dent.: Polysac- Habilitation 2012 (SOD) - Erfahrungen der Augenklinik und der charid-Template-strukturierte bioaktive Kera- Goecke, Tamme, PD Dr. med.: Untersuchungen Kinder- und Jugendklinik miken mit modulierter Oberfläche - eine tierex- zur prä-, peri- und postpartalen Depression. Susilo-Sigit, Tina Maria, Dr. med.: Regulation perimentelle Analyse Löhberg, Christian, PD Dr. med.: Prognos- der Expression von LOXL1 und elastischen Hirschinger, Andreas, Dr. med. dent.: Verglei- tische Relevanz von epidemiologischen und Mikrofibrillen: Ein in vitro-Modell für das Pseu- chende tierexperimentelle Studie zur Anwen- molekularen Risikofaktoren bei Patientinnen doexfoliationssyndrom. dung und Osseointegration eines neuartigen bo- mit Mammakarzinom. Tourtas, Theofilos, Dr. med.: Endotheliale vinen Knochenersatzmaterials im Schweinekiefer Oppelt, Patricia Gerlinde, PD Dr. med.: Hor- Keratoplastik: Vergleich zwischen Descemet Kassler, Stefan, Dr. med. dent.: Osseo-Inte- monelle und anatomische Veränderungen in membrane endothelial keratoplasty und gration elektronenstrahlgesinterter Titanim- der Entwicklung und Funktion des weiblichen Descemet stripping plantate mit und ohne LbL-Pamidronat- Genitals. Zeller, Caterina, Dr. med.: Klinisch-pathologi- Beschichtung - eine tierexperimentelle Studie Thiel, Clemens Falk, PD Dr. med.: Versorgungs- sche Korrelationen bei Patienten mit lympho- Knipfer, Christian, Dr. med. dent.: Speech Intelli- aspekte und Gesundheitsökonomie in der gy- proliferativen Erkrankungen der okuären Adnexe gibility Enhancement Through Maxillary Dental näkologischen Onkologie. Rehabilitation with Telescopic Prostheses and Complete Dentures - a Prospective Study Using Board Qualification 2011 Automatic, Computer-based Speech Analysis Heindl, Ludwig, Dr. med. Lutz, Rainer, Dr. med.: Biofunctionalization Department of Ophthalmology Huchzermeyer, Cord, Dr. med. of titanium implants with a biomimetic active Chair of Ophthalmology Raum, Christoph, Dr. med. peptide (P-15) promotes early osseointegration Rössler, Katrin, Dr. med. Möst, Tobias, Dr. med. dent.: Tierexperimen- telle Studie zur Knocheneinheilung chemisch Doctorate Theses 2011 Board Qualification 2012 oberflächenmodifizierter Implantate im Typ-2 Bellios, Nikolaos, Dr. med.: Überschwellige diabetischen Schwein periphere Stimulation bei präperimetrischen Bellios, Nikolaus, Dr. med. Rieder, Julia, Dr. med. dent.: Tierexperimen- Glaukomen Brückner-Schmutterer, Kerstin, Dr. med. telle Studie zum Osseointegrationsverhalten Hirschmann, Tobias, Dr. med.: Ergebnisse König, Yanyan, Dr. med. biofunktionalisierter dentaler Implantate später Therapie von exzentrischer Fixation bei Rusche, Philipp, Dr. med. dent.: Der Einfluss verschiedenen Amblyopieformen. Habilitation 2011 einer biomimetischen Implantatbeschichtung Hohberger, Bettina, Dr. med.: Frequency de- mit integriertem BMP-2 und VEGF auf die Os- Bachmann, Björn, PD Dr. med.: Chirurgische pendency of temporal contrast adaptation in seointegration und konservative Therapieansätze zur funk- normal subjects. Stüber, Christopher, Dr. med. dent.: Biofunk- tionellen und morphologischen Verbesserung Kleinschmidt, Martin, Dr. med.: Ergebnisse der tionalisierung von Implantatoberflächen mit ein- von Hornhauttransplantationen. perforierenden Re-Keratoplastik bei visuslimi- er festgelegten Konzentration (200µg/ML) eines tierendem Astigmatismus nach Kornea-Trans- synthetisch hergestellten Peptids (P-15) bei di- plantation Habilitation 2012 abetischen gegenüber gesunden Versuchstieren Raster, Markus, Dr. med.: Der Einfluss der Jacobi, Christina, PD Dr. med.: Vaskuläre Er- Tima, Dominik, Dr. med. dent.: Biofunktiona- Chloroquineinnahme auf die multifokale Elek- krankungen der Netzhaut lisierung von Implantatoberflächen mit unter- troretinographie an einer brasilianischen Popu- Lämmer, Robert, PD Dr. med.: Glaukom-De- schiedlichen Konzentrationen der syntheti- schen Kollagenteilsequenz P-15 lation. tektion und morphometrische Verfahren zur Tran-Vinh, Han, Dr. med. dent.: Die Etabli- Progressionsanalyse im Langzeitverlauf erung eines Streptozotocin-induzierten dia- Doctorate Theses 2012 betischen Schweines und die Beurteilung der Atorf, Jenny, Dr. rer. nat.: Funktionsanalyse der pathologischen Veränderungen des Knochens Mausretina mittels Ganzfeld-Elektroretinogra- Vogel, Melanie, Dr. med. dent.: In-vitro-Unter- phie. Department of Oral and suchungen zur differentiellen Expression von Calabrese, Stefano, Dr. med.: Histopathologi- Cranio-Maxillofacial Surgery RANK(L) - Relevanz für die Exklusivität der Bisphos- sche Untersuchung von retrocornealen Membra- Chair of Dental, Oral, and Maxillofacial Medi- phonat-assoziierten Nekrose im Kieferknochen nen bei irreversiblem Transplantatversagen cine – especially Oral and Maxillofacial Surgery Wiesheu, Reinhard, Dr. med. dent.: Verglei- Herold, Elvira, Dr. med.: Therapie der Kera- chende tierexperimentelle Studie zur Anwend- tokonjunktivitis sicca mit Augentropfen aus au- Doctorate Theses 2011 ung eines bovinen Knochenersatzmaterials tologem Serum Pangeni, Gobinda, Dr. rer. biol. hum.: Inter- Adam, Nikola, Dr. med. dent.: Ossäre Regenera- pretation von Elektroretinogrammen bei sinus- tion eines experimentellen critical size-Defektes Doctorate Theses 2012 förmig modulierten Stimuli verschiedener Fre- der Schweinekalotte mit einem biphasischen Döring, Hendrik, Dr. med. dent.: Klinisch quenzen und Kontraste. Knochenersatzmaterial (HA/TCP)- Einfluss einer vergleichende Studie zur Zufriedenheit von Riss, Stephan, Dr. med.: Pentacam-based biodegradierbaren Zellulose-Membran auf Ossi- Patienten mit implantatgetragener Unterkief- Big-Bubble Deep Anterior Lamellar Keratoplas- fikation und Mineralisation er-Totalprothese im Vergleich zur totalprothe- ty (DALK) in Patients with Keratoconus Berner, Alexandra Katharina, Dr. med. dent.: tischen Versorgung im zahnlosen Unterkiefer Schrell, Constanze, Dr. med.: Ciclosporin A Relevanz von TGF-ß, Smad 2/3, Smad 7 und Gorecki, Patricia, Dr. med. dent.: Beurteilung 0,05% Augentropfen zur Therapie der Kera- Galektin-3 für die Bisphosphonat-assoziierte der Bedeutung der Expression melanomassozi- tokonjunktivitis sicca Kiefernekrose ierter Antigene A (MAGE-A) in Leukoplakien der Schrems, Wolfgang, Dr. med.: Glaukomdia- Draschowski, Cornelia, Dr. med. dent.: Im- Mundhöhle für das maligne Entartungsrisiko gnostik mit Scanning Laser Polarimetrie und munhistochemische Analyse von Msx1, Rankl dieser Läsionen

210 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Lagarie, Sebastian, Dr. med. dent.: Knöcherne Kräck, Angelina, Dr. med.: Objective Classifica- endokrine Regulationsmechanismen in der Verankerung und Primärstabilität von dentalen tion of Organic Voice Disorders using Endoscopic pädiatrischen Intensivmedizin Implantaten im Oberkiefer des Menschen. Eine High-Speed Imaging Mückstein-Hupfer, Sieglinde, Dr. med.: experimentelle Untersuchung Tiemann, Melanie, Dr. med.: Static tensile Wirkung eines selektiven Interleukin-8-Rezep- Schlittenbauer, Tilo, Dr. med.: Identifikation tests using the hemilarynx model: Measuring torantagonisten auf die pulmonale Hyper- genetischer Risikofaktoren bei Patienten mit bis- the local deformation and relaxation behavior tonie und die im Rahmen der Inflammation auftretenden Interleukine -8 und -1ß bei Sur- phosphonat-assoziierten Kieferknochennekro- of porcine vocal folds factant-depletierten Ferkeln mit akutem Atem- sen am Beispiel von HLA-DRB1 und HLA-DQB1 Weigel, Stephanie, Dr. med.: The hemilarynx- model: Reproducibility of the deformation of notsyndrom vocal folds and analysis of the material proper- Münzel, Kathrin, Dr. med.: Gefäßveränderun- Additional Qualification 2012 ties of the vocal folds gen nach intrauteriner Wachstumsretardierung Neukam, Valentin, Dr. med. dent.: Untersu- Bumiller, Lars, Dr. med.: Plastic Surgery chung des Risikos einer belastungsinduzierten Stockmann, Philipp, Dr. med. Dr. med. dent.: Habilitation 2012 Hyperthermie bei Kindern und Jugendlichen Plastic Surgery Haderlein, Tino, PD Dr.-Ing.: Automatische mit hypohidrotischer ektodermaler Dysplasie Messung der Stimmqualität bei laryngealer Oehme, Ann-Kathrin, Dr. med.: Unerwün- Habilitation 2011 Heiserkeit schte Arzneimittelwirkungen bei Kindern - ein Vergleich zweier Studien Stelzle, Florian, PD Dr. med. Dr. med. dent.: Offergeld, Ramona, Dr. med.: Bedeutung von Methoden der Hart- und Weichgewebebear- Department of Pediatric and Corticotropin-releasing-Hormon für die Leptin- beitung in der Mund-, Kiefer- und Gesichts- Adolescent Medicine expression und die Synzytialisierung von chirurgie primären humanen Trophoblasten Chair of Pediatrics Schäfer, Michaela, Dr. med.: Knochendichte bei jungen Frauen mit Ullrich-Turner-Syndrom Doctorate Theses 2011 nach Therapie mit Wachstumshormon Department of Otorhinolaryngology – Scheu, Svenja, Dr. med.: Visuell evozierte Po- Bani Hashemi-Begerow, Souzan, Dr. med.: Ex- Head and Neck Surgery tentiale bei Früh- und Reifgeborenen: Reifung pression Hypoxie-induzierbarer vasoaktiver und prognostische Bedeutung Chair of Otorhinolaryngology Faktoren im Gehirn der adulten Ratte unter Straßer, Katja, Dr. med.: Expression von HIF-re- Einfluss von Hypoxie und chemischen HIF-Sta- gulierten Genen in der Plazenta und im Gehirn bilisatoren Doctorate Theses 2011 der neonatalen Maus unter systemischer Hypoxie Geißler, Bettina, Dr. med.: Effekt von Adre- Sinzenich, Katharina, Dr. med.: Bluttransfu- nomedullin auf den Verlauf der mesangioproli- sionen bei Hals-Nasen-Ohren-Patienten ferativen Glomerulonephritis bei der Ratte Habilitation 2011 Hermann, Kathrin, Dr. med.: Anti-apoptoti- Benz, Kerstin, PD Dr. med.: Nierenstruktur Doctorate Theses 2012 scher Einfluss von Syncytin-1 in Staurosporin- und -funktion bei genetisch bedingter er- behandelten CHO-Zellen niedrigter Nephronenzahl im Tiermodell der Lang, Anne, Dr. med.: Atypisches Fibroxanthom Lukas, Kristin, Dr. med.: Analyse der Arznei- GDNF-heterozygoten Knockout-Maus - Tumorentität und Therapiekonzepte mitteltherapie auf einer neonatologischen In- Paulides, Marios, PD Dr. med.: Late effects af- Velegrakis, Stylianos, Dr. med.: Langzeit- tensivstation ter oncologic treatment of Ewing‘s-, osteo- or ergebnisse der endonasalen Chirurgie bei May, Julia, Dr. med.: Suppression von Inter- soft tissue sarcomas in children Choanalatresie leukin 8, Cyclooxygenase 2, Prostaglandin E3-Rezeptor und Prostaglandinen durch Pare- Habilitation 2012 Board Qualification 2011 coxib und Indometacin im Tiermodell der neo- Hinkes, Bernward, PD Dr. med.: Hereditäre natalen B-Streptokokkensepsis Brase, Christoph, Dr. med. Formen des nephrotischen Syndromes im Mölkner, Vera, Dr. med.: Das Anti-Müller Hor- frühen Kindesalter - molekulare Grundlagen Scherl, Claudia, Dr. med. mon bei Kindern mit kongenitalem adrenogen- und ihre klinische Relevanz italen Syndrom und 21-Hydroxylase-Defekt Lehner, Manfred, PD Dr. rer. nat.: Dendritische Board Qualification 2012 Plattner, Erika, Dr. med.: Entwicklungsneuro- Zellen und genetisch modifizierte T-Zellen für logischer Verlauf bei Hochrisiko-Frühgeborenen Birk, Stephanie, Dr. med. die zelluläre Immuntherapie von Tumoren der Geburtsjahrgänge 2000-2004 Neubert, Antje, PD Dr. rer. nat.: The role of Göderer, Lisa, Dr. med. Schulz-Harder, Karoline, Dr. med.: Wirkung adverse drug reactions in paediatric medication Kapsreiter, Markus, Dr. med. von Interleukin-1ß und Transforming Growth safety Mantsopoulos, Konstantinos, Dr. med. Factor ß1 auf den villösen Zytotrophoblasten Völkl, Thomas Michael Karl, PD Dr. med.: Traxdorf, Maximilian, Dr. med. in vitro Neue Therapieziele bei Kindern und Jugend- Vehorn, Mareike, Dr. med.: AGS-Risiko- lichen mit adrenogenitalem Syndrom (AGS) schwangerschaften Additional Qualification 2012 durch 21-Hydroxylase-Defekt Kirsche, Hanspeter, Dr. med.: Allergology Doctorate Theses 2012 Albrecht, Andrea, Dr. med.: Entwicklungsneu- rologischer Langzeitverlauf von Neugeborenen Department of Pediatric and Department of Otorhinolaryngology – mit perinataler Asphyxie Adolescent Medicine Bauer, Penelope, Dr. med.: Kardiologische Rei- Division of Pediatric Cardiology Head and Neck Surgery henuntersuchung jugendlicher Sportler Division of Phoniatrics and Pediatric Audiology Berk, Susanne, Dr. med.: Etablierung eines Fluoreszenz-Fusionsassays an verschiedenen Board Qualification 2011 trophoblastären und Syncytin-überexprimier- Doctorate Theses 2012 Webinger, Jasmin, Dr. med. enden Zellreihen Bocklet, Tobias, Dr. rer. biol. hum.: Diagnose- Kartheuser, Yvonne, Dr. med.: Hyperton-hy- unabhängige Analyse der Sprachverständlich- peronkotische Kochsalzlösungen und der Ein- Additional Qualification 2012 keit am Beispiel maligner Kehlkopferkrankungen fluss auf die akute Blutdruckregulation durch Schmidt, Thomas: Emergency Medicine

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 211 APPENDIX

Department of Plastic and Department of Psychiatry and Öckl, Karin, Dr. med.: Prognose des Kolonkar- Hand Surgery Psychotherapy zinoms erhoben am Krankengut der Chirurgi- Division of Child and Adolescent Mental Health schen Klinik am Universitätsklinikum Erlangen im Zeitraum 1978-2004 Doctorate Theses 2011 Schuhmann, Sabine, Dr. med.: Therapiemög- Hammon, Matthias, Dr. med.: GBP-1 trans- Doctorate Theses 2012 lichkeiten der Hepatitis C-Reinfektion nach Le- genic EPC in the AV Loop Model Wangler, Susanne, Dr. med.: Neurofeedback bertransplantation mit pegylierten Interferonen Schnürer, Stefan, Dr. med.: Perfusion Quantifi- in children with ADHD: Specific event-related und Ribavirin cation in Pig Muscle potential findings of a randomized controlled Tonak, Julia, Dr. med.: Die Evalutation von Hu- trial manem Guanylat-Bindungsprotein-1 als Mark- Doctorate Theses 2012 er im Blutserum für Entzündung und Sepsis Wunder, Thomas, Dr. med.: Die gastrale De- Klumpp, Dorothee, Dr. med.: Muscle Tissue Board Qualification 2012 kompression nach Anlage einer großlumigen Engineering and Nanomatrices Kupfer, Stefanie, Dr. med. PEG-Sonde Yuan, Quan, Dr. med.: HIF 1 α and hypoxia in Wangler, Susanne, Dr. med. the AV Loop Model Wichmann, Christa, Dr. med. Doctorate Theses 2012 Board Qualification 2011 Kuhn, Elisabeth, Dr. rer. nat.: Ein neues Additional Qualification 2011 Chip-basiertes paralleles Transfektionsverfahren Arkudas, Andreas, Dr. med. Vogel, Simone: Child and Adolescent Psycho- für die Analyse parakriner Zellinteraktionen therapy Löbbert, Marko: Die Etablierung der lapa- Board Qualification 2012 roskopisch assistierten linksseitigen Hemicolek- Merz, Katrin, Dr. med. tomie bei Divertikulitis Additional Qualification 2012 Saalabian, Ali, Dr. med. Raabe, Eva, Dr. med.: Gallenwegskomplika- Bleiziffer, Oliver, Dr. med. Busch, Katrin: Child and Adolescent Psycho- tionen nach orthotopen Lebertransplanta- therapy tionen - Inzidenz, Risikofaktoren und Thera- pieverfahren Habilitation 2012 Villanueva, Marie-Therese: Langzeitlebensqua- Habilitation 2011 Arkudas, Andreas, PD Dr. med.: Replantations lität bei Patienten nach multimodaler Therapie of the Upper Extremity Heinrich, Hartmut, PD Dr. sc. hum.: Clinical eines Rektumkarzinoms Dragu, Adrian, PD Dr. med.: Postbariatric Plas- effects and neurophysiological mechanisms of tic Surgery neurofeedback in children with attention-defi- Polykandriotis, Elias, PD Dr. med.: Models of cit/hyperactivity disorder Board Qualification 2011 autonomous vascularization in regenerative Schildberg, Claus, Dr. med. medicine: studies on early and late angiogenic phenomena Department of Surgery Board Qualification 2012 Chair of Surgery Lux, Philipp, Dr. med. Zhang, Wei, Dr. med. Department of Psychiatry and Doctorate Theses 2011 Psychotherapy Habilitation 2011 Chair of Psychiatry and Psychotherapy Beron, Katja, Dr. med.: Neuentwicklung eines elektronischen Antriebes für ein Koloskop - Er- Knorr, Christian, PD Dr. med.: Regionale Hy- mittlung grundlegender Anforderungen und perthermieverfahren als multimodales Thera- Doctorate Theses 2011 Messung von Vorschubkräften für eine Sicher- piekonzept in der chirurgischen Behandlung Welzel, Oliver, Dr. rer. biol. hum.: Untersu- heitsabschaltung von lokoregional-metastasierten Malignomen chung heterogener Eigenschaften hippocam- Hammon, Matthias, Dr. med.: Untersuchung am Beispiel des Malignen Melanoms - Aktueller paler Synapsen mittels Fluoreszenzmikroskopie der angiogenen Eigenschaften von murinen, Stand und Perspektiven embryonalen, endothelialen Vorläuferzellen in Naschberger, Elisabeth, PD Dr. rer. nat.: Mole- vitro und in vivo. kulare Mechanismen und klinische Bedeutung Doctorate Theses 2012 Hohnheiser, Annika, Dr. med.: Malignant der entzündlichen Gefäßaktivierung Kleinow, Martina, Dr. rer. biol. hum.: Balanced melanoma of the skin: Long-term follow-up and time to first recurrence Scorecard einer psychiatrischen Universitätskli- Habilitation 2012 nik: Die Entwicklung und deren Auswirkungen Hörske, Carolin, Dr. med.: Long-term out- auf die Klinikstrukturen unter Betrachtung der comes and quality of life after rectal carcinoma Demir, Resit, PD Dr. med.: Hypoxie und ma- Promotoren Führung, Kommunikation und surgery ligne Progression von Tumorzellen Qualitätsmanagement Hunger, Kordula, Dr. med.: Das Risiko maligner Pleuraergüsse und Thoraxwandmetastasen von intrapulmonalen Malignomen nach per- Department of Surgery Habilitation 2011 thorakaler Feinnadelpunktion - eine retrospek- Donath, Carolin, PD Dr. rer. nat.: Versorgungs- tive Fall-Kontroll-Studie und eine prospektive Division of Thoracic Surgery forschung bei Demenz: diagnostische und histologische Untersuchung therapeutische Versorgung von Patienten und Knoch, Miriam, Dr. med.: Langzeitergebnisse Board Qualification 2011 Versorgung von pflegenden Angehörigen mit der Behandlung der morbiden Adipositas mit- Oster, Oliver, Dr. med. Unterstützungsangeboten tels weitenregulierbaren Magenbands Meyer, Anne, Dr. med.: Kolorektales Karzinom Aktion Habilitation 2012 Meyer, Jörg, Dr. med.: Sicherheit und Effekti- Lenz, Bernd, PD Dr. med.: Aktivierende und or- vität der präemtiven Strategie zur Behandlung ganisierende Sexualhormoneffekte bei Alkoholab- der Zytomegalievirus (CMV) Infektion nach or- hängigkeit: Genetik und Neuroendokrinologie thotoper Lebertransplantation

212 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Department of Surgery Department of Surgery Department of Operative Dentistry Division of Transfusion Medicine and Division of Trauma Surgery and Peridontology Hemostaseology Chair of Dental, Oral, and Maxillofacial Medi- Doctorate Theses 2011 cine – especially Operative Dentistry, Periodon- Doctorate Theses 2011 Krinner, Sebastian, Dr. med.: Vergleich des tology, and Pediatric Dentistry Verlaufs der neuromuskulären Blockade nach Hollein, Lucie, Dr. med.: Kryokonservierung Applikation von Mivacurium bei Schulkindern von Plazentarestblut: Eine vergleichende Studie unterschiedlicher Altersgruppen im Rahmen Doctorate Theses 2011 zwischen unmanipuliertem Vollblut und volu- einer total intravenösen Anästhesie Adam, Milan, Dr. med. dent.: Über die Eig- menreduziertem Leukozytenkonzentrat. Pachowsky, Milena, Dr. med.: Diagnostik der Meininghaus, Barbara, Dr. med.: Evaluation nung von Phantommodellen zur Testung der linksventrikulären ‚non-compaction‘ Kardiomyo- des neuen Thrombozytenfunktionsanalysers Rigidität von Zahntraumaschienen pathie mittels der Magnetresonanztherapie DiaMed Impact® im Vergleich zur Impedanz- Auer, Friedrich, Dr. med. dent.: Konstruktion aggregometrie mittels Multiplate® bei Patien- und Evaluation zweier neuer artifizieller Mo- ten unter Therapie mit Acetylsalicylsäure und/ Board Qualification 2011 delle für die Rigiditätsbestimmung von Trau- oder Clopidogrel Kolvenbach, Carl, Dr. med. maschienen Oremek, Damian, Dr. med.: In-vitro-Qualitäts- Schulz-Drost, Stefan, Dr. med. Grasser, Andrea, Dr. med. dent.: Polymeri- kontrollen bestrahlter und leukozytendeple- sationsspannung und -schrumpf dentaler Fül- lungskomposite tierter Erythrozytenkonzentrate in der additiven Board Qualification 2012 Lösung PAGGS-M Kirsten, Maria, Dr. med. dent.: „Gesunde Zäh- Rießner, Katrin, Dr. med.: Die Bedeutung der Dobre, Andra, Dr. med. ne für Schüler“ Kariesvorsorge an Hauptschu- Eigen- und Familienanamnese in der Thrombo- len Ergebnisse nach 2 Jahren philiediagnostik Additional Qualification 2011 Kohlhase, Friedrich, Dr. med. dent.: Mundhy- Schmieger, Tobias, Dr. med.: Von-Willebrand Mauerer, Andreas, Dr. med.: Special Accident giene und Patientenzufriedenheit von Klinikpa- Faktor, Faktor VIII sowie frei und zellulär in Surgery tienten einer Universitätszahnklinik Thrombozyten zirkulierende Wachstumsfak- Lauterbach, Madeleine, Dr. med. dent.: toren der Angiogenese vor und nach Resektion Additional Qualification 2012 Physikalische Eigenschaften eines dentalen eines kolorektalen Karzinoms Komposits in Abhängigkeit von Verarbeitungs- Gelse, Kolja, PD Dr. med.: Special Accident temperatur und Lagerungsdauer Surgery Mackert, Tobias, Dr. med. dent.: Über die Doctorate Theses 2012 Haftkraft von adhäsiv befestigten Faserstiften Braun, Sabine, Dr. med.: Gepaarte Studie zur Department of Urology nach künstlicher Alterung Validierung des neuen Thrombozytenaggregot- Chair of Urology Meyer, Florian, Dr. med. dent.: Über die meters PAP-8® und zur Untersuchung des Ein- Dimensionsstabilität von Wurzelkanalfüllmate- flusses der Einstellung der Thrombozytenkonz- rialien auf Guttapercha-Basis entration des plättchenreichen Plasmas auf die Doctorate Theses 2012 Nagler, Tonia, Dr. med. dent.: Zeitabhängige Ergebnisse der Thrombozytenaggregations- Huppert, Verena, Dr. med.: Tet-regulierte in- Putzeffektivität einer neuen Handzahnbürste testung mit PAP-8® und PAP-4® duzierbare Expression von Kandidatengenen in im Vergleich mit einer ADA-Referenzzahnbürste Dlimi, Afif, Dr. med.: Einfluss der Konzentration serotonergen Neuronen von transgenen Mäu- Wießner, Jessica, Dr. med. dent.: Über die Ent- unterschiedlicher Zellpopulationen auf die Vita- sen fernung von Kalziumhydroxid aus dem Wurzel- lität kryokonservierter Stammzellkonzentrate. kanal (Einfluss des Spülvolumens) Eiche, Christian, Dr. med.: Von-Willebrand- Nolte, Elke, Dr. rer. nat.: The role of micro- Wießner, Thomas, Dr. med. dent.: Effektivität Faktor-Aktivität und von-Willebrand-Faktor- RNAs in prostate carcinoma verschiedener Spültechniken bei der Entfernung Multimerenverteilung bei Patienten mit von Kalziumhydroxid aus dem Wurzelkanal kolorektalem Karzinom. Board Qualification 2012 Frisch, Andreas, Dr. med.: Bestrahlung leuko- Wimmer, Stefan, Dr. med. dent.: Zum Ver- Keck, Bastian, Dr. med. zytendepletierter Erythrozytenkonzentrate in gleich verschiedener Methoden der Haftkraft- der additiven Lösung SAG-M aus dem Blut- messung von Dentaladhäsiven nach künstlicher spendedienst Suhl zu verschiedenen Zeitpunk- Additional Qualification 2012 Alterung ten. Harlander-Weikert, Eva: Fellow of the Europe- Klein, Caroline, Dr. hum. biol.: Ex vivo Expan- an Board of Urology; FEBU: Andrology Doctorate Theses 2012 sion hämatopoetischer Stamm- und Vorläufer- Keck, Bastian, Dr. med.: Drug-based Tumor Franz, Florian, Dr. med. dent.: Einfluss der Kle- zellen aus Nabelschnurblut in Kokultur mit Therapy bepunktausdehnung und des Schienentyps auf mesenchymalen Stromazellen aus Amnion, Keck, Bastian: Fellow European College of Chorion, Whartonscher Sulze, Fruchtwasser, die Schienenrigidität - Untersuchung mittels Sexual Medicine; FECSM: Andrology Nabelschnurblut und Knochenmark. der dynamischen Periotestmethode Luther, Romy, Dr. med.: Veränderungen des Dr. Rogenhofer, Michael: Fellow of the Euro- Henkel, Mario, Dr. med. dent.: Untersuchung pH-Wertes in Thrombozytenkonzentraten in pean Board of Urology; FEBU: Andrology des Aushärteverhaltens lichthärtender Füllungs- Abhängigkeit von Temperatur und dem Ver- Engehausen, Dirk, Prof. Dr. med.: Medical komposite mittels dielektrischer Analyse (DEA) hältnis aus humanem Plasma und additiven Quality Management Khursan, Tamer, Dr. med. dent.: Physikalische Lösungen zur Thrombozytenkonservierung. Wullich, Bernd, Prof. Dr. med.: Fellow Euro- Enddaten eines neu entwickelten Kompositma- Schiffer, Katharina, Dr. med.: Bestrahlung von pean College of Sexual Medicine; FECSM: An- terials Babybeuteln aus leukozytendepletierten Ery- drology Knöllinger, Melissa, Dr. med. dent.: Einfluss throzytenkonzentraten in der additiven Lösung eines nanogefüllten Schutzlackes auf das Ermü- SAG-M zu verschiedenen Zeitpunkten dungsverhalten eines Glasionomerzementes in Schoetz, Anna Maria, Dr. med.: In-vitro-Qua- destillierten Wasser und künstlichen Speichel litätskontrollen von leukozytendepletierten Lücking, Julia, Dr. med. dent.: Einfluss von Ze- Erythrozytenkonzentraten in SAG-M nach Be- mentprovisorien und Adhäsivprocedere auf die strahlung mit 30 Gray an Tag +14, +28 oder marginale Adaptation von Kompositrestaura- +35. tionen

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 213 APPENDIX

Wimmer, Romana, Dr. med. dent.: Effizienz Institute of Clinical and Pritschet, Kathrin, Dr. rer. nat.: Internalization dreier Prophylaxepulver zur Belagentfernung - Molecular Virology of human immunodefi ciency virus type 1 in eine In-vitro-Untersuchung plasmacytoid dendritic cells Chair of Clinical Virology Ries, Moritz, Dr. rer. nat.: Endogenous immune Habilitation 2012 activation by cellular DNA in HIV-1 infection Doctorate Theses 2011 Sommermann, Thomas, Dr. rer. nat.: The role Berthold, Christine, PD Dr. med. dent. habil.: Adler, Martina, Dr. rer. nat.: Intrinsic immunity of NFκB in glucose import and the survival of Conservative Dentistry after Dento-Alveolar against the human cytomegalovirus-characteri- B-cell lymphomas Trauma zation of cellular restriction factors and analysis Sörgel, Stefan, Dr. rer. nat.: Functional and of viral antagonistic mechanisms molecular characterization of the HIV-1 acces- Department of Orthodontics and De Jong, Sarah Jill, Dr. rer. nat.: Dissecting the sory protein Vpr with focus on virus – host in- Tio- NF-κB signalosome in human T cells Orofacial Orthopedics teraction Giede-Jeppe, Antje, Dr. med.: Generation Zielke, Barbara, Dr. rer. nat.: The HCMV en- Chair of Dental, Oral, and Maxillofacial Medicine and characterization of recombinant human coded mRNA-export factor pUL69 – functional – especially Orofacial Orthopedics cytomegaloviruses harboring mutations of the conservation within the Betaherpesvirinae and UAP56- and/or RNA interaction domains of the identifi cation of mRNA-targets during infection RNA export factor pUL69 Doctorate Theses 2011 Zielke, Katrin, Dr. rer. nat.: The insulator pro- Hahn, Sabine, Dr. rer. nat.: Targeting the hu- tein CTCF and cohesins are critical for Herpesvi- Detterbeck, Andreas Markus Wilhelm, Dr. man immunodeficiency virus type-1 Gag protein rus saimiri genome maintenance med. dent.: Von der Kieferabformung zum virt- into the defective ribosomal product pathway uellen ModOf the jaw impression to the virtual enhances its MHC class I antigen presentation model: A pilot study on accuracy of industrial Kirmaier, Andrea, Dr. rer. nat.: Replication and CT-based measurements of impression materi- Persistence of Primate Lentiviruses Institute of Clinical Microbiology, als Ködel, Yvonne, Dr. rer. nat.: Impact of N-terminal peptides derived from glycoprotein E2 of Immunology, and Hygiene GB virus C on HIV replication Chair of Microbiology and Immunology of Doctorate Theses 2012 Kreß, Andrea K., Dr. rer. nat.: The Tax pro- Infection Hanke, Sebastian, Dr. med. dent.: Three-di- tein of Human T cell lymphotropic virus type 1 mensional computed tomography based rating (HTLV-1) as a multifunctional oncoprotein Doctorate Theses 2011 of unilateral impacted canines Lohmaier, Jens, Dr. med.: Functional analysis Prinz, Patrick, Dr. med. dent.: Burnout, de- of the HIV-1 rev-protein with heterologous ex- Häberlein, Simone, Dr. rer. nat.: Mechanisms pression and depersonalization – Psychological port signals of Transmission and Innate Immune Control of factors and coping strategies among students Mahmoudian, Shohreh, Dr. rer. nat.: Effect Leishmania Parasites of dentistry and medicine of cytomegaloviruses on the development of Wagner, Caroline, Dr. rer. nat.: Characteri- Schiller, Peter Johannes, Dr. med. dent.: A transplant arteriosclerosis and characterization zation of the Salmonella Pathogenicity Island new coordinate system based on the Frankfort of potentially associated viral G-protein cou- 4-encoded proteins SiiE, SiiA and SiiB: a new horizontal and Christa galli for computed to- pled receptors mechanism of bacterial adhesion mography analysis of mandibular asymmetry Neumann, Liane, Dr. rer. nat.: Structure and Wiese, Melanie, Dr. rer. nat.: Impact of hy- - a comparative study function of the HIV-1 gag-protein p6 poxia and the influence of the hypoxia-indu- Wille, Alexander, Dr. med. dent.: Comparison Ruhland, Wolfgang Christian, Dr. med.: The cible factor HIF-1α on the antibacterial capacity of two-dimensional measurements on the basis impact of polymorphisms in the HIV-1 protease of dendritic cells and macrophages of conventional reference points in the respec- on the development of resistance tive FRS and mediansagittal projected coordi- Schmidt, Katharina Anna, Dr. rer. nat.: Mech- Doctorate Theses 2012 anisms and consequences of interferon- inhibi- nates in the volume-based CT γ Jebran, Fahwad, Dr. med.: In vitro und in vivo tion by the viral interferon regulatory factor 3 Wirkung von pharmazeutischem Natriumchlor- (vIRF-3) of Kaposi s sarcoma associated herpes- id bei der kutanen Leishmaniose Board Qualification 2011 virus (KSHV) Heckhoff, Uta, Dr. med. dent. Habilitation 2011 Doctorate Theses 2012 Schleicher, Ulrike, PD Dr. rer. nat.: Mechanis- Board Qualification 2012 Dietz, Monika, Dr. rer. nat.: Effector functions men der angeborenen Immunität bei intrazel- of the protective humoral immune response Hofmann, Elisabeth, Dr. med. dent. lulären Erregern Kunz, Katharina, Dr. med. dent. against cytomegalovirus Medelnik, Jürgen, Dr. med. dent. Heilmann, Andreas, Dr. rer. nat.: Epstein-Barr Strobel, Karin, Dr. med. dent. virus Rta activation of lytic gene promoters and its regulation by the viral LF2 protein Institute of Human Genetics Karbach, Astrid, Dr. rer. nat.: The humoral im- Chair of Human Genetics mune response against glycoprotein B, a major Department of Prosthodontics determinant of cytomegalovirus Chair of Dental, Oral, and Maxillofacial Medicine Katsch, Kristin, Dr. rer. nat.: Modulation of cel- Doctorate Theses 2011 – especially Prosthetic Dentistry lular signaling pathways by the oncoproteins of Uebe, Steffen, Dr. rer. nat.: Identifikation und T-lymphotropic herpesviruses Charakterisierung neuer genetischer Risikofak- Mazumder, Eman Dey, Dr. rer. nat.: Tyrosine toren für komplexe Erkrankungen Habilitation 2012 residues Y114 and Y127 of rhadinoviral onco- Schmitt, Johannes, PD Dr. med. dent.: The long protein Tip are central to STAT activation term outcome of full ceramic dental restorations Naumann, Anja, Dr. rer. nat.: Epigenetic and Doctorate Theses 2012 from the material and biological point of view functional characterization of the 5’-upstream Bezold, Viola, Dr. med.: Identifizierung von region of the human FMR1 gene Genen für autosomal-rezessiv vererbte men- Postler, Thomas, Dr. rer. nat.: The Cytoplasmic tale Retardierung: Mutationsscreening im Domain of the HIV-1 and SIV Envelope Glyco- TUSC3-Gen und Homozygotiekartierung zur protein: Functional Properties and Topology Identifizierung neuer Genloci

214 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Grosch, Melanie, Dr. rer. nat.: Identifizierung Rogler, Anja, Dr. rer. nat.: Role of chromosome Institute of Radiology und Charakterisierung von Genen mit spezieller 8p-deletions and loss of SFRP1-expression in Division of Neuroradiology Funktion in der Skelettentwicklung urothelial carcinoma of the urinary bladder Krumbiegel, Mandy, Dr. rer. nat.: Genetische Röhring, David, Dr. med.: Effekte einer oralen Faktoren in der Ätiologie und Pathogenese des Therapie mit Atorvastatin auf Atherosklerose Additional Qualification 2011 Pseudoexfoliationssyndroms und Entzündungsmediatoren bei experimen- Dölken, Marc, PD Dr. med.: Neuroradiology Schöb, Dominik, Dr. med.: Homozygotiekar- teller Niereninsuffizienz im Tiermodell der ApoE-/-Knock out Maus. tierung bei Kindern mit primärem nephro- Habilitation 2011 tischen Syndrom Dölken, Marc, PD Dr. med.: High-resolution Board Qualification 2011 magnetic resonance imaging and magnetic Facharztausbildung 2012 Söder, Stephan, Dr. med. resonance spectroscopy for diagnosis and ther- Hoyer, Juliane, Dr. med. apy of epileptic seizures Zweier, Christiane, Dr. med. Board Qualification 2012 Wachter, David, Dr. med. Habilitation 2011 Hüffmeier, Ulrike, PD Dr. med.: Genetische Habilitation 2011 Risikofaktoren für Psoriasis vulgaris und Psori- Büttner-Herold, Maike, PD Dr. med.: EBV-as- asis arthritis soziierte Tumoren in Interaktion mit dem Im- Thiel, Christian Thomas, PD Dr. med.: Iden- munsystem tifizierung und Charakterisierung genetischer Schwarz-Furlan, Stephan, PD Dr. med.: His- Ursachen von Wachstumsstörungen topathologische Prognosefaktoren von Kar- zinomen des oberen Aerodigestivtraktes Stöhr, Robert, PD Dr. med.: Initiating and pro- Institute of Pathology gression related alterations in human bladder Chair of General Pathology and Pathological cancer Anatomy

Doctorate Theses 2011 Institute of Radiology Benicke, Julia, Dr. med.: Gut differenzierte Bar- Chair of Diagnostic Radiology rett-Adenocarcinome werden häufig als „hoch- gradige intrarepitheliale Neoplasie“ unterdia- gnostiziert Board Qualification 2011 Gores, Heinz, Dr. med.: Einfluss unterschiedli- Heinrich, Marc, Dr. med. cher Wurfgrößen auf Glomerulusanzahl und Heinz, Marco, Dr. med. glomerulärem Volumen in einem Modell der Köhler, Julia, Dr. med. intrauterinen Wachstumsrestriktion der Ratte. Knauth, Solweig, Dr. med.: Kardiale Ver- Board Qualification 2012 änderungen, Atherosklerose und Arterioskle- rose in verschiedenen Gefäßprovinzen von Pa- Meier-Meitinger, Martina, Dr. med. tienten mit chronischer Niereninsuffizienz im Schlechtweg, Philipp, Dr. med. Vergleich zu nierengesunden Patienten. Schwantzer, Anja, Dr. med.: Effekte einer Habilitation 2011 salzreichen Diät auf die Progession der diabe- Adamus, Ralf, PD Dr. med.: Development and tischen Nephropathie im tierexperimentellen evaluation of new techniques in the endovas- Modell der ZDF-Ratte. cular system Thomas, Susanne, Dr. med.: Effekte der Pro- Alibek, Sedat, PD Dr. med.: Improvement in teasomeninhibition auf Nierenveränderungen cross sectional imaging in children and adoles- im Mausmodell einer experimentellen Lupus- cents nephritis. Anders, Katharina, PD Dr. med.: Computerto- Varga, Ildiko, Dr. med.: Morphologische und mographie der Koronarien - Optimierung von immunhistologische Charakterisierung der Ge- Untersuchungstechnik und Patientenselektion fäßveränderungen bei Patienten mit gering- Schwab, Siegfried, PD Dr. med. univ.: Com- gradig eingeschränkter Nierenfunktion und plementary imaging modalities in breast can- fortgeschrittener Niereninsuffizienz. cer diagnostics Zemler, Barbara, Dr. med.: Der Grad der Dif- ferenzierung, die Häufigkeit der Lymphgefäß- und der Veneneinbrüche von Barrett- Frühcarci- Habilitation 2012 nomen sind abhängig von der Tiefeninfiltration Adamietz, Boris, PD Dr. med.: Elastography of breast tumors Doctorate Theses 2012 Roemer, Frank, PD Dr. med.: Role of magnetic resonance imaging in cross-sectional and longi- Bott, Simone, Dr. med.: Effekte einer oralen The- tudinal evaluation of knee osteoarthritis rapie mit S 18886, einem TP-Rezeptor-Antagonis- ten, auf kardiovaskuläre Strukturveränderungen im Hypertonie-Modell der doppelt transgenen „human renin-angiotensinogen rats“ (dTGR)

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 215 APPENDIX

216 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

In Memorian

2011

Prof. Dr. med. Wolf-Dieter Keidel Professor emeritus of the Chair of Physiology

Prof. Dr. med. Walter Kersten Professor emeritus of the Chair of Biochemistry

Prof. Dr. med. Eberhard Lungershausen Professor emeritus of the Chair of Psychiatry

Ralph M. Steinman, MD, Henry G. Kunkel Professor and Senior Physician at the Rockefeller University New York Honorary doctorate of the Faculty of Medicine

Prof. Dr. med. Gerhard Kittel Former head of the Division of Phoniatrics and Pediatric Audiology at the Department of Otorhinolaryngology

2012

Prof. Dr. med. Dietrich Hohmann Former head of the Department of Orthopedics at the Waldkrankenhaus

Prof. Dr. med. Dieter Platt Former director of the Institute for Biomedicine of Aging

Prof. Dr. Dr. h.c. Rudolf Artur Pfeiffer Professor emeritus of the Chair of Human Genetics and Anthropology Honorary doctorate at the University of Rennes

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 217 218 Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) APPENDIX

Personnel Index Directors, Heads, and Speakers

A H R Achenbach, Stephan, 70 Hartmann, Arndt, 142 Rascher, Wolfgang, 98, 157 Alzheimer, Christian, 22 Heinrich, Markus, 192 Reinhardt, Erich R., 172 Amann, Kerstin, 144, 195 Hennig, Friedrich, 120 Reis, André, 138, 155, 177 Herrmann, Martin, 188 Rösch, Paul, 193 B Hirschfelder, Ursula, 126 S Beckmann, Matthias W., 88, 158 Hohenberger, Werner, 112 Schett, Georg, 72, 171, 173 Behrens, Jürgen, 44, 46, 167 Horch, Raymund E., 102 Schmauss, Bernhard, 164 Betz, Peter, 32 Hornegger, Joachim, 168 Blümcke, Ingmar, 140 Schröder, Rolf, 186 Schüttler, Jürgen, 54, 153, 181, 197 Bogdan, Christian, 134, 160, 165, 201 I Schuler, Gerold, 64, 169 Brune, Kay, 30 Iro, Heinrich, 94 Schwab, Stefan, 80 Buchfelder, Michael, 84 J Sieber, Cornel C., 52 Burkovski, Andreas, 189 Jäck, Hans-Martin, 74, 184, 191 Sirbu, Horia, 116 C Sonnewald, Uwe, 170 K Carbon, Roman T., 114 Steinkasserer, Alexander, 66 Kalender, Willi A., 38, 183 Sticht, Heinrich, 18 Cavallaro, Alexander, 161 Korbmacher, Christoph, 20 Stürzl, Michael, 174 Cesnjevar, Robert, 62 Kornhuber, Johannes, 104 Swoboda, Bernd, 50 Croner, Roland, 174 Kruse, Friedrich E., 90 U D Kuwert, Torsten, 86 Uder, Michael, 146 Daniel, Werner G., 199 L de Zwaan, Martina, 175 Lang, Frieder R., 162 V Dittrich, Sven, 100 Leipertz, Alfred, 194 Vöhringer, David, 136 Dörfler, Arnd, 148 Leven, Karl-Heinz, 40 von Hörsten, Stephan, 132, 156 Drexler, Hans, 24, 150, 163 Ludwig, Andreas, 26, 159 W E Wegner, Michael, 14, 16, 152, 196 M Eckardt, Kai-Uwe, 76, 176 Weigand, Christian, 166 Mackensen, Andreas, 78, 178 Eckstein, Reinhold, 118 Weller, Gerhard, 161 Michelson, Georg, 164 Erim, Yesim, 108 Weyand, Michael, 60 Moll, Gunther H., 106 Eysholdt, Ulrich, 96, 154, 185 Wichmann, Manfred, 128 N Winkler, Jürgen, 82, 179 F Neuhuber, Winfried, 10, 150 Winkler, Thomas, 184 Fietkau, Rainer, 110 Neukam, Friedrich W., 92, 198 Wullich, Bernd, 122 Finotto, Susetta, 56 Neurath, Markus F., 68, 182 Fleckenstein, Bernhard, 130, 180, 187, 190 O Frewer, Andreas, 42 Ostgathe, Christoph, 58 Forst, Raimund, 48 Fromm, Martin F., 28 P Paulsen, Friedrich, 12 G Petschelt, Anselm, 124, 151 Gefeller, Olaf, 34 Prokosch, Hans-Ulrich, 36

Research Report of the Faculty of Medicine of the FAU (Reporting Period 2011 – 2012) 219 Publisher Faculty of Medicine of the Friedrich-Alexander-Universität Erlangen-Nürnberg Östliche Stadtmauerstraße 30a 91054 Erlangen

Editor Ursula Niederweis, M.A. Tel.: 09131-8523708, Fax: 09131-8522224 [email protected]

Setting/Processing/Printing Druckhaus Haspel Willi-Grasser-Str. 13a 91056 Erlangen Tel.: 09131-9200770, Fax: 09131-9200760 [email protected]

Cover The cover shows the new medical lecture building (© UK Erlangen) as well as figures of research projects within the Faculty of Medicine.

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