Identification of Novel GNAS Mutations in Intramuscular Myxoma Using Next- Generation Sequencing with Single-Molecule Tagged Molecular Inversion Probes Elise M
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Germline Mutations Affecting Gα11 in Hypoparathyroidism
T h e new england journal o f medicine of a meta-analysis of studies of the effect of re- terone levels were increased. Although long- duced dietary salt on the incidence of cardiovas- term, modest reductions in salt intake result in cular events and death.1 The authors of the Co- small, physiologic increases in plasma renin ac- chrane report wrote that there was “no strong tivity,3 the preponderance of evidence suggests evidence of benefit.” In a summary statement, we that a reduced salt intake is associated with a wrote that this particular Cochrane analysis con- decreased risk of cardiovascular events and cluded that reducing dietary salt intake did not death. Furthermore, it is worth remembering decrease the risk of death or cardiovascular dis- that diuretics remain one of the most effective ease. Stigler et al. suggest that “indeterminate antihypertensive therapies, and their beneficial results,” rather than no significant effect, would effect on cardiovascular disease is well docu- be a more appropriate interpretation of the analy- mented.4 Nevertheless, as we suggested, in sis. Both interpretations may be correct. Although terms of safety, the lower limit of salt consump- it may not be possible to reject the null hypothe- tion has not been clearly defined. sis with certainty (i.e., no effect of reduced salt), Theodore A. Kotchen, M.D. the analysis should have been powered to detect Allen W. Cowley, Jr., Ph.D. a clinically meaningful difference, and the con- Medical College of Wisconsin clusion of no effect provides more guidance than Milwaukee, WI “indeterminate results” to clinical decision mak- [email protected] ers. -
The Rac Gtpase in Cancer: from Old Concepts to New Paradigms Marcelo G
Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-17-1456 Cancer Review Research The Rac GTPase in Cancer: From Old Concepts to New Paradigms Marcelo G. Kazanietz1 and Maria J. Caloca2 Abstract Rho family GTPases are critical regulators of cellular func- mislocalization of Rac signaling components. The unexpected tions that play important roles in cancer progression. Aberrant pro-oncogenic functions of Rac GTPase-activating proteins also activity of Rho small G-proteins, particularly Rac1 and their challenged the dogma that these negative Rac regulators solely regulators, is a hallmark of cancer and contributes to the act as tumor suppressors. The potential contribution of Rac tumorigenic and metastatic phenotypes of cancer cells. This hyperactivation to resistance to anticancer agents, including review examines the multiple mechanisms leading to Rac1 targeted therapies, as well as to the suppression of antitumor hyperactivation, particularly focusing on emerging paradigms immune response, highlights the critical need to develop ther- that involve gain-of-function mutations in Rac and guanine apeutic strategies to target the Rac pathway in a clinical setting. nucleotide exchange factors, defects in Rac1 degradation, and Cancer Res; 77(20); 5445–51. Ó2017 AACR. Introduction directed toward targeting Rho-regulated pathways for battling cancer. Exactly 25 years ago, two seminal papers by Alan Hall and Nearly all Rho GTPases act as molecular switches that cycle colleagues illuminated us with one of the most influential dis- between GDP-bound (inactive) and GTP-bound (active) forms. coveries in cancer signaling: the association of Ras-related small Activation is promoted by guanine nucleotide exchange factors GTPases of the Rho family with actin cytoskeleton reorganization (GEF) responsible for GDP dissociation, a process that normally (1, 2). -
Molecular Dissection of G-Protein Coupled Receptor Signaling and Oligomerization
MOLECULAR DISSECTION OF G-PROTEIN COUPLED RECEPTOR SIGNALING AND OLIGOMERIZATION BY MICHAEL RIZZO A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Biology December, 2019 Winston-Salem, North Carolina Approved By: Erik C. Johnson, Ph.D. Advisor Wayne E. Pratt, Ph.D. Chair Pat C. Lord, Ph.D. Gloria K. Muday, Ph.D. Ke Zhang, Ph.D. ACKNOWLEDGEMENTS I would first like to thank my advisor, Dr. Erik Johnson, for his support, expertise, and leadership during my time in his lab. Without him, the work herein would not be possible. I would also like to thank the members of my committee, Dr. Gloria Muday, Dr. Ke Zhang, Dr. Wayne Pratt, and Dr. Pat Lord, for their guidance and advice that helped improve the quality of the research presented here. I would also like to thank members of the Johnson lab, both past and present, for being valuable colleagues and friends. I would especially like to thank Dr. Jason Braco, Dr. Jon Fisher, Dr. Jake Saunders, and Becky Perry, all of whom spent a great deal of time offering me advice, proofreading grants and manuscripts, and overall supporting me through the ups and downs of the research process. Finally, I would like to thank my family, both for instilling in me a passion for knowledge and education, and for their continued support. In particular, I would like to thank my wife Emerald – I am forever indebted to you for your support throughout this process, and I will never forget the sacrifices you made to help me get to where I am today. -
A GTP-State Specific Cyclic Peptide Inhibitor of the Gtpase Gαs
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.25.054080; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs Shizhong A. Dai1,2†, Qi Hu1,2†, Rong Gao3†, Andre Lazar1,4†, Ziyang Zhang1,2, Mark von Zastrow1,4, Hiroaki Suga3*, Kevan M. Shokat1,2* 5 1Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA 2Howard Hughes Medical Institute 3Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 10 4Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94158, USA *Correspondence to: [email protected], [email protected] †These authors contributed equally. 15 20 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.25.054080; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract: The G protein-coupled receptor (GPCR) cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable receptors and enzymes with the exception of the stimulatory G protein α subunit, Gαs. -
Ubiquitylome Profiling of Parkin-Null Brain Reveals Dysregulation Of
Neurobiology of Disease 127 (2019) 114–130 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium T homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons Key J.a,1, Mueller A.K.b,1, Gispert S.a, Matschke L.b, Wittig I.c, Corti O.d,e,f,g, Münch C.h, ⁎ ⁎ Decher N.b, , Auburger G.a, a Exp. Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany b Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB; Clinic for Neurology, Philipps-University Marburg, 35037 Marburg, Germany c Functional Proteomics, SFB 815 Core Unit, Goethe University Medical School, 60590 Frankfurt am Main, Germany d Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France e Inserm, U1127, Paris, F-75013, France f CNRS, UMR 7225, Paris, F-75013, France g Sorbonne Universités, Paris, F-75013, France h Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt am Main, Germany ARTICLE INFO ABSTRACT Keywords: Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among Parkinson's disease its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin Mitochondria triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear howse- Parkin lective neural circuits become vulnerable and finally undergo atrophy. Ubiquitin We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein Calcium targets of Parkin activity, an ubiquitin E3 ligase. -
Hras Intracellular Trafficking and Signal Transduction Jodi Ho-Jung Mckay Iowa State University
Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 2007 HRas intracellular trafficking and signal transduction Jodi Ho-Jung McKay Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Biological Phenomena, Cell Phenomena, and Immunity Commons, Cancer Biology Commons, Cell Biology Commons, Genetics and Genomics Commons, and the Medical Cell Biology Commons Recommended Citation McKay, Jodi Ho-Jung, "HRas intracellular trafficking and signal transduction" (2007). Retrospective Theses and Dissertations. 13946. https://lib.dr.iastate.edu/rtd/13946 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. HRas intracellular trafficking and signal transduction by Jodi Ho-Jung McKay A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Genetics Program of Study Committee: Janice E. Buss, Co-major Professor Linda Ambrosio, Co-major Professor Diane Bassham Drena Dobbs Ted Huiatt Iowa State University Ames, Iowa 2007 Copyright © Jodi Ho-Jung McKay, 2007. All rights reserved. UMI Number: 3274881 Copyright 2007 by McKay, Jodi Ho-Jung All rights reserved. UMI Microform 3274881 Copyright 2008 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. -
Clinical Utility of Recently Identified Diagnostic, Prognostic, And
Modern Pathology (2017) 30, 1338–1366 1338 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms Arantza Onaindia1, L Jeffrey Medeiros2 and Keyur P Patel2 1Instituto de Investigacion Marques de Valdecilla (IDIVAL)/Hospital Universitario Marques de Valdecilla, Santander, Spain and 2Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA Genomic profiling studies have provided new insights into the pathogenesis of mature B-cell neoplasms and have identified markers with prognostic impact. Recurrent mutations in tumor-suppressor genes (TP53, BIRC3, ATM), and common signaling pathways, such as the B-cell receptor (CD79A, CD79B, CARD11, TCF3, ID3), Toll- like receptor (MYD88), NOTCH (NOTCH1/2), nuclear factor-κB, and mitogen activated kinase signaling, have been identified in B-cell neoplasms. Chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and marginal zone lymphomas of splenic, nodal, and extranodal types represent examples of B-cell neoplasms in which novel molecular biomarkers have been discovered in recent years. In addition, ongoing retrospective correlative and prospective outcome studies have resulted in an enhanced understanding of the clinical utility of novel biomarkers. This progress is reflected in the 2016 update of the World Health Organization classification of lymphoid neoplasms, which lists as many as 41 mature B-cell neoplasms (including provisional categories). Consequently, molecular genetic studies are increasingly being applied for the clinical workup of many of these neoplasms. In this review, we focus on the diagnostic, prognostic, and/or therapeutic utility of molecular biomarkers in mature B-cell neoplasms. -
RGS22 Antibody (Pab)
21.10.2014RGS22 antibody (pAb) Rabbit Anti-Human/Mouse/Rat Regulator of G-protein signaling 22 (PRTD -NY2) Instruction Manual Catalog Number PK-AB718-7001 Synonyms RGS22 Antibody: Regulator of G-protein signaling 22, PRTD-NY2 Description Regulator of G-protein signaling (RGS) proteins contain an 120 amino acid conserved domain, termed the RGS domain, that acts as a GTPase-activating protein that acts to reduce the signal transmitted by the receptor-activated G-alpha subunit. RGS22 is a recently identified member of this family that localizes to the testis and can interact with guanine nucleotide binding proteins alpha 11, 12, and 13 (GNA11, GNA12, and GNA13). While RGS22 has been postulated to play a role in spermiogenesis in the testis, it is also expressed in several cancer cell lines with an epithelial origin and associated with cancer metastasis. Its overexpression in a highly metastatic cancer causes a decrease in cell migration and a reduction of the invasive potential of the cells, suggesting that RGS22 may be a potential prognostic biomarker for metastasis. Quantity 100 µg Source / Host Rabbit Immunogen RGS22 antibody was raised against a 19 amino acid synthetic peptide near the amino terminus of human RGS22. Purification Method Affinity chromatography purified via peptide column. Clone / IgG Subtype Polyclonal antibody Species Reactivity Human, Mouse, Rat Specificity At least four isoforms of RGS22 are known to exist; this antibody will detect the three longest isoforms. RGS22 antibody is predicted to not cross-react with other RGS proteins Formulation Antibody is supplied in PBS containing 0.02% sodium azide. Reconstitution During shipment, small volumes of antibody will occasionally become entrapped in the seal of the product vial. -
Myopia Genetics Report
Special Issue IMI – Myopia Genetics Report Milly S. Tedja,1,2 Annechien E. G. Haarman,1,2 Magda A. Meester-Smoor,1,2 Jaakko Kaprio,3,4 David A. Mackey,5–7 Jeremy A. Guggenheim,8 Christopher J. Hammond,9 Virginie J. M. Verhoeven,1,2,10 and Caroline C. W. Klaver1,2,11; for the CREAM Consortium 1Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands 3Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland 4Department of Public Health, University of Helsinki, Helsinki, Finland 5Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia 6Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania, Australia 7Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia 8School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom 9Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, United Kingdom 10Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands 11Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands Correspondence: Caroline C. W. The knowledge on the genetic background of refractive error and myopia has expanded Klaver, Erasmus Medical Center, dramatically in the past few years. This white paper aims to provide a concise summary of Room Na-2808, P.O. Box 2040, 3000 current genetic findings and defines the direction where development is needed. CA, Rotterdam, the Netherlands; [email protected]. We performed an extensive literature search and conducted informal discussions with key MST and AEGH contributed equally to stakeholders. -
Tumor Markers
Tumor Markers Alan H.B. Wu, Ph.D. Professor, Laboratory Medicine, UCSF Section Chief, Clinical Chemistry, Toxicology, Pharmacogenomics Laboratory, SFGH Learning objectives • Know the ideal characteristics of a tumor marker • Understand the role of tumor markers for diagnosis and management of patients with cancer. • Know the emerging technologies for tumor markers • Understand the role of tumor markers for therapeutic selection How do we diagnose cancer today? Physical Examination Blood tests CT scans Biopsy Human Prostate Cancer Normal Blood Smear Chronic Myeloid Leukemia Death rates for cancer vs. heart disease New cancer cases per year Cancer Site or Type New Cases Prostate 218,000 Lung 222,500 Breast 207,500 Colorectal 149,000 Urinary system 131,500 Skin 68,770 Pancreas 43,100 Ovarian 22,000 Myeloma 20,200 Thyroid 44,700 Germ Cell 9,000 Types of Tumor Markers • Hormones (hCG; calcitonin; gastrin; prolactin;) • Enzymes (acid phosphatase; alkaline phosphatase; PSA) • Cancer antigen proteins & glycoproteins (CA125; CA 15.3; CA19.9) • Metabolites (norepinephrine, epinephrine) • Normal proteins (thyroglobulin) • Oncofetal antigens (CEA, AFP) • Receptors (ER, PR, EGFR) • Genetic changes (mutations/translocations, etc.) Characteristics of an ideal tumor marker • Specificity for a single type of cancer • High sensitivity and specificity for cancerous growth • Correlation of marker level with tumor size • Homogeneous (i.e., minimal post-translational modifications) • Short half-life in circulation Roles for tumor markers • Determine risk (PSA) -
140503 IPF Signatures Supplement Withfigs Thorax
Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network. -
Identification of HRAS Mutations and Absence of GNAQ Or GNA11
Modern Pathology (2013) 26, 1320–1328 1320 & 2013 USCAP, Inc All rights reserved 0893-3952/13 $32.00 Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi Ryan P Bender1, Matthew J McGinniss2, Paula Esmay1, Elsa F Velazquez3,4 and Julie DR Reimann3,4 1Caris Life Sciences, Phoenix, AZ, USA; 2Genoptix Medical Laboratory, Carlsbad, CA, USA; 3Dermatopathology Division, Miraca Life Sciences Research Institute, Newton, MA, USA and 4Department of Dermatology, Tufts Medical Center, Boston, MA, USA HRAS is mutated in B15% of Spitz nevi, and GNAQ or GNA11 is mutated in blue nevi (46–83% and B7% respectively). Epithelioid blue nevi and deep penetrating nevi show features of both blue nevi (intradermal location, pigmentation) and Spitz nevi (epithelioid morphology). Epithelioid blue nevi and deep penetrating nevi can also show overlapping features with melanoma, posing a diagnostic challenge. Although epithelioid blue nevi are considered blue nevic variants, no GNAQ or GNA11 mutations have been reported. Classification of deep penetrating nevi as blue nevic variants has also been proposed, however, no GNAQ or GNA11 mutations have been reported and none have been tested for HRAS mutations. To better characterize these tumors, we performed mutational analysis for GNAQ, GNA11, and HRAS, with blue nevi and Spitz nevi as controls. Within deep penetrating nevi, none demonstrated GNAQ or GNA11 mutations (0/38). However, 6% revealed HRAS mutation (2/32). Twenty percent of epithelioid blue nevi contained a GNAQ mutation (2/10), while none displayed GNA11 or HRAS mutation. Eighty-seven percent of blue nevi contained a GNAQ mutation (26/30), 4% a GNA11 mutation (1/28), and none an HRAS mutation.