DOCSLIB.ORG

The Evolution of Sensory and Neurosecretory Cell Types in Bilaterian Brains

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Evolution of Sensory and Neurosecretory Cell Types in Bilaterian Brains The evolution of sensory and neurosecretory cell types in bilaterian brains DISSERTATION zur Erlangung des Doktorgrades der Naturwissenschaften Doctor rerum naturalium (Dr. rer. nat.) dem Fachbereich Biologie der Philipps-Universität Marburg vorgelegt von Dipl.-Biol. K. G. Kristin Teßmar–Raible aus Görlitz Marburg/ Lahn 2004 Vom Fachbereich Biologie der Philipps-Universität Marburg als Dissertation am angenommen. Erstgutachterin: Prof. Dr. Monika Hassel Zweitgutachterin : Prof. Dr. Renate Renkawitz-Pohl Tag der mündlichen Prüfung: The evolution of sensory and neurosecretory cell types in bilaterian brains To my parents and my husband for their encouragement and patience Acknowledgements I am very thankful to the following persons in Marburg and Heidelberg that made this study possible: Dr. Monika Hassel at Marburg University for the supervision of my PhD thesis and correction of the text; Dr. Detlev Arendt at the EMBL in Heidelberg for giving me the opportunity to spend time in his lab as a guest and for scientific advice; Dr. Monika Hassel, Dr. Renate Renkawitz-Pohl and the other members of my defense committee for reviewing this thesis. I want to acknowledge all members and guests of the Arendt lab, in particular Sebastian Klaus, Heidi Snyman, and Patrick Steinmetz, for for their help, their useful critical comments, and the interesting scientific discussions; in addition, I want to thank Heidi Snyman for very reliable practical help, especially with degenerated PCRs, minipreps, and restriction digests; and Dr. Detlev Arendt for minipreps of the Pdu-barH1 cloning. Moreover, I thank Dr. Florian Raible and Dr. Detlev Arendt for extensive critical feedback on previous versions of this text. There were certainly some difficult times when I was glad to be able to rely on the support and advise of more experienced people. For this, I am especially grateful to Dr. Florian Raible, Dr. Detlev Arendt, Dr. Oliver Hobert, Dr. Jochen Wittbrodt and Dr. Gary Ruvkun. I am thankful to Monika Beutelspacher and Dr. Herrmann Froehlich and the entire Boehringer Ingelheim Foundation not only for the financial support, that enabled me to perform this PhD study, but also for their encouragement and reliability. Much of my plannings and theoretical work depended on literature not easily avaible via the internet. I therefore thank the EMBL Szilárd librarians, especially David Wesley, who got many articles and books for me. I express my thanks for materials to Dr. Nicole Rebscher (anti-rabbit anti- RFamide(s) antibody), Alena Shkumatava and Dr. Carl Neumann (initial aliquots of cyclopamine). My special gratitude belongs to my husband Dr. Florian Raible, who is my truly best partner for both my scientific and personal life. Finally, I feel indebted to my parents and parents in law for their generous advice and help. Table of contents Acknowledgements ..........................................................................................................................i Table of contents ............................................................................................................................ii Index of Figures ...........................................................................................................................vii Index of tables .............................................................................................................................viii 1 INTRODUCTION ..........................................................................................................1 1.1 Defining homology relationships across Bilateria..........................................................2 1.2 Platynereis dumerilii – an ancestral organism for the comparative study of animal development and genome evolution.................................................................................4 1.3 The concept of homologous cell types .............................................................................8 1.4 The bilaterian nervous system........................................................................................12 1.4.1 The apical organ and its cell types...............................................................................................14 1.4.2 Neurosecretory cells.....................................................................................................................16 1.4.3 The vertebrate hypothalamus.......................................................................................................19 1.4.4 Cell types of photosensory structures..........................................................................................21 1.5 Aim of this thesis.............................................................................................................23 2 RESULTS ......................................................................................................................25 2.1 Indications for a conserved molecular organisation of Bilaterian brains ...................26 2.1.1 Pdu-nk2.1 is expressed in the median brain anlage complentary to Pdu-pax6..........................27 2.2 Molecular characterisation of the ciliary and rhabdomeric photoreceptor cell types in Platynereis dumerilii..................................................................................................31 2.2.1 Ciliary photoreceptor cell types...................................................................................................31 2.2.2 The opsin active in Platynereis ciliary PRCs closer relates to vertebrate rod and cone opsins than to canonical invertebrate opsins.................................................................................32 2.2.3 The Platynereis ciliary photoreceptor cells express rx, a transcription factor specific for the differentiating vertebrate rods and cones...........................................................................34 2.2.4 Rhabdomeric photoreceptor cell types ........................................................................................37 2.2.5 Platynereis atonal homolog/Pdu-ath is transiently expressed in the larval eye precursors .......38 2.2.6 Pdu-brn3 demarcates the larval eye region..................................................................................40 2.2.7 Cloning of Pdu-barH1 as additional rhabdomeric PRC marker gene ........................................42 2.2.8 Larval, but not adult eye regions are histaminergic ....................................................................44 2.3 Molecular characterisation of neuroendocrine regions and cell types in Platynereis .........................................................................................................................................44 TABLE OF CONTENTS iii 2.3.1 The Platynereis median episphere expresses homologs of transcription factors that are highly specific for the median/ventral forebrain in vertebrates ...................................................45 2.3.2 Orthologs of sim, pou3 and gsx transcription factors, essential for the formation of hypothalamic neuropeptidergic neurons, are also present in the apical organ region of Platynereis larvae................................................................................................................54 2.3.3 Analysis of markers that indicate specific differentiated cell types and exist in the median/ventral forebrain of vertebrates.............................................................................60 2.3.4 The lipophilic dye DiI stains a distinct set of cells in Platynereis larvae, including cells of the apical organ.........................................................................................................................76 2.4 A whole mount in situ hybridization screen uncovers additional genes involved in bilaterian brain development .........................................................................................78 2.5 The Hedgehog (Hh) pathway is involved in the development of the episphere in the Platynereis dumerilii trochophora.................................................................................81 2.5.1 Cloning and expression of members of the Hh-pathway in Platynereis dumerilii ....................83 2.5.2 Interfering with the hh-pathway using the drug cyclopamine ....................................................86 3 DISCUSSION................................................................................................................98 3.1 Equivalence between bilaterian photosensory and neurosecretory systems on different levels.................................................................................................................99 3.2 Common ancestry/homology is the most likely cause for the occurence of equivalent cell types across Bilateria ............................................................................................102 3.2.1 The master control gene concept: a valid alternative explanation?..........................................103 3.2.2 The molecular fingerprint is a useful criterium for cross-species comparisons.......................105 3.3 Is there conservation on the level of brain areas across Bilateria?...........................105 3.3.1 Robustness in molecular specification of regions within phyla as prerequisite for interphyletic comparison..................................................................................................107 3.3.2 No conservation of otx, bf-1, emx regions? ..............................................................................108
Load more

Recommended publications
  • Cyclopamine Inhibition of Sonic Hedgehog Signal Transduction Is
    Developmental Biology 224, 440–452 (2000) doi:10.1006/dbio.2000.9775, available online at http://www.idealibrary.com on View metadata, citation and similar papers at core.ac.uk brought to you by CORE Cyclopamine Inhibition of Sonic Hedgehog Signalprovided by Elsevier - Publisher Connector Transduction Is Not Mediated through Effects on Cholesterol Transport John P. Incardona,* William Gaffield,† Yvonne Lange,‡ Adele Cooney,§ Peter G. Pentchev,§ Sharon Liu,¶ John A. Watson,¶ Raj P. Kapur,ሻ and Henk Roelink*,1 *Department of Biological Structure and Center for Developmental Biology and ࿣Department of Pathology, University of Washington, Seattle, Washington 98195; †Western Regional Research Center, ARS, United States Department of Agriculture, Albany, California 94710; ‡Department of Pathology, Rush–Presbyterian–St. Luke’s Medical Center, Chicago, Illinois 60612; §Developmental and Metabolic Neurobiology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892; and ¶Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143 Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport.
    [Show full text]
  • Endocrinology
    Endocrinology INTRODUCTION Endocrinology 1. Endocrinology is the study of the endocrine system secretions and their role at target cells within the body and nervous system are the major contributors to the flow of information between different cells and tissues. 2. Two systems maintain Homeostasis a. b 3. Maintain a complicated relationship 4. Hormones 1. The endocrine system uses hormones (chemical messengers/neurotransmitters) to convey information between different tissues. 2. Transport via the bloodstream to target cells within the body. It is here they bind to receptors on the cell surface. 3. Non-nutritive Endocrine System- Consists of a variety of glands working together. 1. Paracrine Effect (CHEMICAL) Endocrinology Spring 2013 Page 1 a. Autocrine Effect i. Hormones released by cells that act on the membrane receptor ii. When a hormone is released by a cell and acts on the receptors located WITHIN the same cell. Endocrine Secretions: 1. Secretions secreted Exocrine Secretion: 1. Secretion which come from a gland 2. The secretion will be released into a specific location Nervous System vs tHe Endocrine System 1. Nervous System a. Neurons b. Homeostatic control of the body achieved in conjunction with the endocrine system c. Maintain d. This system will have direct contact with the cells to be affected e. Composed of both the somatic and autonomic systems (sympathetic and parasympathetic) Endocrinology Spring 2013 Page 2 2. Endocrine System a. b. c. 3. Neuroendocrine: a. These are specialized neurons that release chemicals that travel through the vascular system and interact with target tissue. b. Hypothalamus à posterior pituitary gland History of tHe Endocrine System Bertold (1849)-FATHER OF ENDOCRINOLOGY 1.
    [Show full text]
  • Atrazine and Cell Death Symbol Synonym(S)
    Supplementary Table S1: Atrazine and Cell Death Symbol Synonym(s) Entrez Gene Name Location Family AR AIS, Andr, androgen receptor androgen receptor Nucleus ligand- dependent nuclear receptor atrazine 1,3,5-triazine-2,4-diamine Other chemical toxicant beta-estradiol (8R,9S,13S,14S,17S)-13-methyl- Other chemical - 6,7,8,9,11,12,14,15,16,17- endogenous decahydrocyclopenta[a]phenanthrene- mammalian 3,17-diol CGB (includes beta HCG5, CGB3, CGB5, CGB7, chorionic gonadotropin, beta Extracellular other others) CGB8, chorionic gonadotropin polypeptide Space CLEC11A AW457320, C-type lectin domain C-type lectin domain family 11, Extracellular growth factor family 11, member A, STEM CELL member A Space GROWTH FACTOR CYP11A1 CHOLESTEROL SIDE-CHAIN cytochrome P450, family 11, Cytoplasm enzyme CLEAVAGE ENZYME subfamily A, polypeptide 1 CYP19A1 Ar, ArKO, ARO, ARO1, Aromatase cytochrome P450, family 19, Cytoplasm enzyme subfamily A, polypeptide 1 ESR1 AA420328, Alpha estrogen receptor,(α) estrogen receptor 1 Nucleus ligand- dependent nuclear receptor estrogen C18 steroids, oestrogen Other chemical drug estrogen receptor ER, ESR, ESR1/2, esr1/esr2 Nucleus group estrone (8R,9S,13S,14S)-3-hydroxy-13-methyl- Other chemical - 7,8,9,11,12,14,15,16-octahydro-6H- endogenous cyclopenta[a]phenanthren-17-one mammalian G6PD BOS 25472, G28A, G6PD1, G6PDX, glucose-6-phosphate Cytoplasm enzyme Glucose-6-P Dehydrogenase dehydrogenase GATA4 ASD2, GATA binding protein 4, GATA binding protein 4 Nucleus transcription TACHD, TOF, VSD1 regulator GHRHR growth hormone releasing
    [Show full text]
  • Diversity of Central Oxytocinergic Projections
    Cell and Tissue Research (2019) 375:41–48 https://doi.org/10.1007/s00441-018-2960-5 REVIEW Diversity of central oxytocinergic projections Gustav F. Jirikowski1 Received: 21 September 2018 /Accepted: 6 November 2018 /Published online: 29 November 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Localization and distribution of hypothalamic neurons expressing the nonapeptide oxytocin has been extensively studied. Their projections to the neurohypophyseal system release oxytocin into the systemic circulation thus controlling endocrine events associated with reproduction in males and females. Oxytocinergic neurons seem to be confined to the ventral hypothalamus in all mammals. Groups of such cells located outside the supraoptic and the paraventricular nuclei are summarized as Baccessory neurons.^ Although evolutionary probably associated with the classical magocellular nuclei, accessory oxytocin neurons seem to consist of rather heterogenous groups: Periventricular oxytocin neurons may gain contact to the third ventricle to secrete the peptide into the cerebrospinal fluid. Perivascular neurons may be involved in control of cerebral blood flow. They may also gain access to the portal circulation of the anterior pituitary lobe. Central projections of oxytocinergic neurons extend to portions of the limbic system, to the mesencephalon and to the brain stem. Such projections have been associated with control of behaviors, central stress response as well as motor and vegetative functions. Activity of the different oxytocinergic systems seems to be malleable to functional status, strongly influenced by systemic levels of steroid hormones. Keywords Hypothalamo neurohypophyseal system . Circumventricular organs . Liquor contacting neurons . Perivascular system . Limbic system Introduction been shown to occur in prostate, gonads, or skin, OTexpression in the brain seems to be confined to the hypothalamus.
    [Show full text]
  • Oxytocin-Functions: an Overview
    MOJ Anatomy & Physiology Review Article Open Access Oxytocin-functions: an overview Abstract Volume 6 Issue 4 - 2019 Oxytocin is a neuropeptide containing nine amino acids produced by paraventricular and supraoptic nuclei of hypothalamus. Oxytocin is derived from a Greek word ‘oxutokia’ Roopasree B, Jophy Joseph, Mukkadan JK meaning sudden delivery and it is well known for its role in parturition and lactation. In Department of Physiology, Little Flower Institute of Medical addition oxytocin performs a wide spectrum of functions. Oxytocin is a hormone with great Sciences and Research, India potential and it is a great facilitator of life. The purpose of this review is to cover almost all the functions of oxytocin - reproductive functions, social functions, role in human Correspondence: Mukkadan JK, Research Director, Department of Physiology, Little Flower Medical Research behaviour and other biologically significant functions.. Centre LFMRC, Angamaly, Kerala, India, Tel 91 9387518037, Fax Keywords: oxytocin, functions, neurophysin I, magnocellular neurons 0484 2452646, Email Received: July 24, 2019 | Published: August 16, 2019 Introduction (GPCR) family. It is coupled to phospholipase C through Gαq11.20,21 Once Oxytocin binds to its receptor, it gives rise to a cascade of Oxytocin is a non a-peptide hormone containing nine amino acids, reactions that finally activates the enzyme Phospholipase-C. This with one disulphide linkage between the 1st and 6th cysteine residue. enzyme produces ITP (inositol triphosphate) and DAG (1, 2-diacyl It is also called as α-Hypophamine. Half-life is found to be minutes. It glycerol) and also activates intracellular Ca++ release, which in turn is known to be the 1st polypeptide hormone that has been sequenced set off various cellular events.9 and synthesized biochemically.
    [Show full text]
  • Review Article Mouse Homologues of Human Hereditary Disease
    I Med Genet 1994;31:1-19 I Review article J Med Genet: first published as 10.1136/jmg.31.1.1 on 1 January 1994. Downloaded from Mouse homologues of human hereditary disease A G Searle, J H Edwards, J G Hall Abstract involve homologous loci. In this respect our Details are given of 214 loci known to be genetic knowledge of the laboratory mouse associated with human hereditary dis- outstrips that for all other non-human mam- ease, which have been mapped on both mals. The 829 loci recently assigned to both human and mouse chromosomes. Forty human and mouse chromosomes3 has now two of these have pathological variants in risen to 900, well above comparable figures for both species; in general the mouse vari- other laboratory or farm animals. In a previous ants are similar in their effects to the publication,4 102 loci were listed which were corresponding human ones, but excep- associated with specific human disease, had tions include the Dmd/DMD and Hprt/ mouse homologues, and had been located in HPRT mutations which cause little, if both species. The number has now more than any, harm in mice. Possible reasons for doubled (table 1A). Of particular interest are phenotypic differences are discussed. In those which have pathological variants in both most pathological variants the gene pro- the mouse and humans: these are listed in table duct seems to be absent or greatly 2. Many other pathological mutations have reduced in both species. The extensive been detected and located in the mouse; about data on conserved segments between half these appear to lie in conserved chromo- human and mouse chromosomes are somal segments.
    [Show full text]
  • Sonidegib for the Treatment of Advanced Basal Cell Carcinoma
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2016 Sonidegib for the treatment of advanced basal cell carcinoma Ramelyte, Egle ; Amann, Valerie C ; Dummer, Reinhard DOI: https://doi.org/10.1080/14656566.2016.1225725 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125862 Journal Article Accepted Version Originally published at: Ramelyte, Egle; Amann, Valerie C; Dummer, Reinhard (2016). Sonidegib for the treatment of advanced basal cell carcinoma. Expert Opinion on Pharmacotherapy, 17(14):1963-1968. DOI: https://doi.org/10.1080/14656566.2016.1225725 Sonidegib for the treatment of advanced basal cell carcinoma Egle Ramelyte1,2,MD, Valerie C. Amann1, MD, Reinhard Dummer 1, MD, 1 - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland 2 - Vilnius University, Centre of Dermatovenereology, Vilnius, Lithuania Corresponding author: Reinhard Dummer, MD University Hospital of Zurich Department of Dermatology Gloriastrasse 31 CH-8091, Zürich, Switzerland Phone: 41-44-255-2507 Fax: 41-44-255-8988 E-mail: [email protected] 1 Abstract Introduction. Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and it’s role in pathogenesis of BCCs, Smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor – vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression.
    [Show full text]
  • Assessment Report
    25 June 2015 EMA/472165/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Odomzo International non-proprietary name: sonidegib Procedure No. EMEA/H/C/002839/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion .............................................................................. 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11
    [Show full text]
  • Structural and Functional Evolution of the Vasopressin/Oxytocin Superfamily
    The Journal of Neuroscience, September 1995, 15(g): 5989-5998 Structural and Functional Evolution of the Vasopressin/Oxytocin Superfamily: Vasopressin-Related Conopressin Is the Only Member Present in Lymnaea, and Is Involved in the Control of Sexual Behavior R. E. Van Kesteren,’ A. B. Smit,’ R. P. J. De Lange,’ K. S. Kits,’ F. A. Van Golen,’ R. C. Van Der Schors,’ N. D. De With,’ J. F. Burke,* and W. P. M. Geraertsl ‘Graduate School Neurosciences Amsterdam, Institute of Neurosciences, Faculty of Biology, Department of Experimental Zoology, Vrije Universiteit, Amsterdam, The Netherlands and *Sussex Centre for Neuroscience, School of Biological Sciences, University of Sussex, Brighton, United Kingdom It has been suggested that the gene duplication that led to Vasopressin and oxytocin are nonapeptides that are present in the formation of the vasopressin/oxytocin two-gene family all placental mammals. Although similar in structure, they serve occurred early during vertebrate evolution. However, the different functions (Ramsay, 1983). Vasopressin has anti-diuretic existence of both vasopressin- and oxytocin-related pep- activities and is involved in hydromineral regulation, whereas tides in invertebrates suggests that this duplication may oxytocin has uterotonic and milk-ejection activities and regulates have occurred much earlier, although there is no evidence aspects of reproductive behavior. Peptides related to both vaso- for the co-occurrence of vasopressin- and oxytocin-related pressin and oxytocin are present in all vertebrate classes, except peptides in the same invertebrate species. We report here the cyclostomes, which have only the vasopressin-related pep- that in Lymnaea only the vasopressin-related peptide Lys- tide vasotocin (reviewed by Acher, 1993).
    [Show full text]
  • Australian Public Assessment Report for Odomzo
    Australian Public Assessment Report for Odomzo Proprietary Product Name: Sonidegib Sponsor: Novartis Pharmaceuticals Australia Pty Ltd November 2019 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]
  • Hedgehog Targeting by Cyclopamine Suppresses Head and Neck Squamous Cell Carcinoma and Enhances Chemotherapeutic Effects
    ANTICANCER RESEARCH 33: 2415-2424 (2013) Hedgehog Targeting by Cyclopamine Suppresses Head and Neck Squamous Cell Carcinoma and Enhances Chemotherapeutic Effects CHRISTIAN MOZET*, MATTHAEUS STOEHR*, KAMELIA DIMITROVA, ANDREAS DIETZ and GUNNAR WICHMANN Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, Leipzig, Germany Abstract. Background: The hedgehog signaling pathway prognosis is worse for those with metastatic disease (2). (HH) is involved in tumorigenesis in a variety of human Besides known risk factors (e.g. alcohol and smoking) and malignancies. In head and neck squamous cell carcinomas occupational exposure to other poorly understood factors, the (HNSCC), Hh overexpression was associated with poor entirety of the relevant tumor biology is still unclear. prognosis. Therefore, we analyzed the effect of Hh signaling Mortality rates of HNSCC have remained almost unchanged blockade with cyclopamine on colony formation of cells from for decades, even though the detection of tumor-specific HNSCC samples. Patients and Methods: HNSCC biopsies pathways has developed rapidly and offers a number of new were cultured alone for reference or with serial dilutions of targets in tumor therapy regimes (e.g. the epidermal growth cyclopamine (5-5,000 nM), docetaxel (137.5-550 nM), or factor-receptor, EGFR, and its tyrosine kinases). Proven cisplatin (1,667-6,667 nM) and their binary combinations. standardized concepts of tumor therapy in first- or second- Cytokeratin-positive colonies were counted after fluorescent line protocols are combinations of well-established cytostatic staining. Results: Cyclopamine concentration-dependently drugs such as platinum-derivates like cisplatin, taxanes like inhibited HNSCC ex vivo [(IC50) at about 500 nM]. In binary docetaxel or others (e.g.
    [Show full text]
  • Content Outline
    ® THE AMERICAN BOARD OF PEDIATRICS CONTENT OUTLINE Pediatric Endocrinology Subspecialty In-training, Certification, and Maintenance of Certification Examinations i INTRODUCTION This document was prepared by the American Board of Pediatrics Subboard of Pediatric Endocrinology for the purpose of developing in-training, certification, and maintenance of certification examinations. The outline defines the body of knowledge from which the Subboard samples to prepare its examinations. The content specification statements located under each category of the outline are used by item writers to develop questions for the examinations; they broadly address the specific elements of knowledge within each section of the outline. ii EXAMINATION PERCENTAGE LIST Approximate Percent in Examination Page I. Carbohydrate Metabolism..................................................16.0...................1 II. Bone and Mineral Metabolism ..........................................10.0.................13 III. Thyroid Hormones (Thyroxine [T4] and Triiodothyronine [T3]) ............14.0.................30 IV. Adrenal Disorders..............................................................12.0.................43 V. Pituitary/Hypothalamus .....................................................10.0.................58 VI. Growth...............................................................................10.0.................73 VII. Reproductive Endocrine System........................................12.0.................85 VIII. Other Hormones...................................................................2.0...............105
    [Show full text]