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A Novel Approach to Identify Driver Genes Involved in Androgen-Independent Prostate Cancer
Schinke et al. Molecular Cancer 2014, 13:120 http://www.molecular-cancer.com/content/13/1/120 RESEARCH Open Access A novel approach to identify driver genes involved in androgen-independent prostate cancer Ellyn N Schinke1, Victor Bii1, Arun Nalla1, Dustin T Rae1, Laura Tedrick1, Gary G Meadows1 and Grant D Trobridge1,2* Abstract Background: Insertional mutagenesis screens have been used with great success to identify oncogenes and tumor suppressor genes. Typically, these screens use gammaretroviruses (γRV) or transposons as insertional mutagens. However, insertional mutations from replication-competent γRVs or transposons that occur later during oncogenesis can produce passenger mutations that do not drive cancer progression. Here, we utilized a replication-incompetent lentiviral vector (LV) to perform an insertional mutagenesis screen to identify genes in the progression to androgen-independent prostate cancer (AIPC). Methods: Prostate cancer cells were mutagenized with a LV to enrich for clones with a selective advantage in an androgen-deficient environment provided by a dysregulated gene(s) near the vector integration site. We performed our screen using an in vitro AIPC model and also an in vivo xenotransplant model for AIPC. Our approach identified proviral integration sites utilizing a shuttle vector that allows for rapid rescue of plasmids in E. coli that contain LV long terminal repeat (LTR)-chromosome junctions. This shuttle vector approach does not require PCR amplification and has several advantages over PCR-based techniques. Results: Proviral integrations were enriched near prostate cancer susceptibility loci in cells grown in androgen- deficient medium (p < 0.001), and five candidate genes that influence AIPC were identified; ATPAF1, GCOM1, MEX3D, PTRF, and TRPM4. -
Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. -
The Complex SNP and CNV Genetic Architecture of the Increased Risk of Congenital Heart Defects in Down Syndrome
Downloaded from genome.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Research The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome M. Reza Sailani,1,2 Periklis Makrythanasis,1 Armand Valsesia,3,4,5 Federico A. Santoni,1 Samuel Deutsch,1 Konstantin Popadin,1 Christelle Borel,1 Eugenia Migliavacca,1 Andrew J. Sharp,1,20 Genevieve Duriaux Sail,1 Emilie Falconnet,1 Kelly Rabionet,6,7,8 Clara Serra-Juhe´,7,9 Stefano Vicari,10 Daniela Laux,11 Yann Grattau,12 Guy Dembour,13 Andre Megarbane,12,14 Renaud Touraine,15 Samantha Stora,12 Sofia Kitsiou,16 Helena Fryssira,16 Chariklia Chatzisevastou-Loukidou,16 Emmanouel Kanavakis,16 Giuseppe Merla,17 Damien Bonnet,11 Luis A. Pe´rez-Jurado,7,9 Xavier Estivill,6,7,8 Jean M. Delabar,18 and Stylianos E. Antonarakis1,2,19,21 1–19[Author affiliations appear at the end of the paper.] Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21–specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Chicken Linkage Disequilibrium Is Much More Complex Over Much Longer Distance Than Previously Appreciated
Look Over the Horizon - Chicken Linkage Disequilibrium is Much More Complex Over Much Longer Distance than Previously Appreciated Ehud Lipkin ( [email protected] ) Hebrew University of Jerusalem Janet E. Fulton Hy-Line (United States) Jacqueline Smith University of Edinburgh David W. Burt University of Edinburgh Morris Soller Hebrew University of Jerusalem Research Article Keywords: Chicken, long-range linkage disequilibrium, QTL, F6, LD blocks Posted Date: June 17th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-598396/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/23 Abstract Background Appreciable Linkage Disequilibrium (LD) is commonly found between pairs of loci close to one another, decreasing rapidly with distance between the loci. This provides the basis studies to map Quantitative Trait Loci Regions (QTLRs), where it is custom to assume that the closest sites to a signicant markers are the prime candidate to be the causative mutation. Nevertheless, Long-Range LD (LRLD) can also be found among well-separated sites. LD blocks are runs of genomic sites all having appreciable LD with one another. High LD and LRLD are often separated by genomic sites with which they have practically no LD. Thus, not only can LD be found among distant loci, but also its pattern may be complex, comprised of fragmented blocks. Here, chicken LRLD and LD blocks, and their relationship with previously described Marek’s Disease (MD) QTLRs, were studied in an F6 population from a full-sib advanced intercross line, and in eight commercial pure layer lines. -
133A Cluster Enhances Cancer Cell Migration and Invasion in Lung-Squamous Cell Carcinoma Via Regulation of Coronin1c
Journal of Human Genetics (2015) 60, 53–61 & 2015 The Japan Society of Human Genetics All rights reserved 1434-5161/15 www.nature.com/jhg ORIGINAL ARTICLE Downregulation of the microRNA-1/133a cluster enhances cancer cell migration and invasion in lung-squamous cell carcinoma via regulation of Coronin1C Hiroko Mataki1, Hideki Enokida2, Takeshi Chiyomaru2, Keiko Mizuno1, Ryosuke Matsushita2, Yusuke Goto3, Rika Nishikawa3, Ikkou Higashimoto1, Takuya Samukawa1, Masayuki Nakagawa2, Hiromasa Inoue1 and Naohiko Seki3 Lung cancer is clearly the primary cause of cancer-related deaths worldwide. Recent molecular-targeted strategy has contributed to improvement of the curative effect of adenocarcinoma of the lung. However, such current treatment has not been developed for squamous cell carcinoma (SCC) of the disease. The new genome-wide RNA analysis of lung-SCC may provide new avenues for research and the development of the disease. Our recent microRNA (miRNA) expression signatures of lung-SCC revealed that clustered miRNAs miR-1/133a were significantly reduced in cancer tissues. Here, we found that restoration of both mature miR-1 and miR-133a significantly inhibited cancer cell proliferation, migration and invasion. Coronin-1C (CORO1C) was a common target gene of the miR-1/133a cluster, as shown by the genome-wide gene expression analysis and the luciferase reporter assay. Silencing of CORO1C gene expression inhibited cancer cell proliferation, migration and invasion. Furthermore, CORO1C-regulated molecular pathways were categorized by using si-CORO1C transfectants. Further analysis of novel cancer signaling pathways modulated by the tumor-suppressive cluster miR-1/133a will provide insights into the molecular mechanisms of lung-SCC oncogenesis and metastasis. -
The Transition from Primary Colorectal Cancer to Isolated Peritoneal Malignancy
medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with a hypermutant, hypermethylated state Sally Hallam1, Joanne Stockton1, Claire Bryer1, Celina Whalley1, Valerie Pestinger1, Haney Youssef1, Andrew D Beggs1 1 = Surgical Research Laboratory, Institute of Cancer & Genomic Science, University of Birmingham, B15 2TT. Correspondence to: Andrew Beggs, [email protected] KEYWORDS: Colorectal cancer, peritoneal metastasis ABBREVIATIONS: Colorectal cancer (CRC), Colorectal peritoneal metastasis (CPM), Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS & HIPEC), Disease free survival (DFS), Differentially methylated regions (DMR), Overall survival (OS), TableFormalin fixed paraffin embedded (FFPE), Hepatocellular carcinoma (HCC) ARTICLE CATEGORY: Research article NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.02.24.20027318; this version posted February 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . NOVELTY AND IMPACT: Colorectal peritoneal metastasis (CPM) are associated with limited and variable survival despite patient selection using known prognostic factors and optimal currently available treatments. -
Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from in Vitro Model Systems
International Journal of Molecular Sciences Review Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from In Vitro Model Systems Ritu Nayak, Idan Rosh, Irina Kustanovich and Shani Stern * Sagol Department of Neurobiology, University of Haifa, Haifa 3498838, Israel; [email protected] (R.N.); [email protected] (I.R.); [email protected] (I.K.) * Correspondence: [email protected] Abstract: Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite Citation: Nayak, R.; Rosh, I.; number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant Kustanovich, I.; Stern, S. Mood advances using these novel models, much more work remains to fully understand the mechanisms Stabilizers in Psychiatric Disorders by which these disorders affect the patients’ brains. -
Signature Redacted Thesis Supervisor Certified By
Single-Cell Transcriptomics of the Mouse Thalamic Reticular Nucleus by Taibo Li S.B., Massachusetts Institute of Technology (2015) Submitted to the Department of Electrical Engineering and Computer Science in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2017 @ Massachusetts Institute of Technology 2017. All rights reserved. A uthor ... ..................... Department of Electrical Engineering and Computer Science May 25, 2017 Certified by. 3ignature redacted Guoping Feng Poitras Professor of Neuroscience, MIT Signature redacted Thesis Supervisor Certified by... Kasper Lage Assistant Professor, Harvard Medical School Thesis Supervisor Accepted by . Signature redacted Christopher Terman Chairman, Masters of Engineering Thesis Committee MASSACHUSETTS INSTITUTE 0) OF TECHNOLOGY w AUG 14 2017 LIBRARIES 2 Single-Cell Transcriptomics of the Mouse Thalamic Reticular Nucleus by Taibo Li Submitted to the Department of Electrical Engineering and Computer Science on May 25, 2017, in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science Abstract The thalamic reticular nucleus (TRN) is strategically located at the interface between the cortex and the thalamus, and plays a key role in regulating thalamo-cortical in- teractions. Current understanding of TRN neurobiology has been limited due to the lack of a comprehensive survey of TRN heterogeneity. In this thesis, I developed an integrative computational framework to analyze the single-nucleus RNA sequencing data of mouse TRN in a data-driven manner. By combining transcriptomic, genetic, and functional proteomic data, I discovered novel insights into the molecular mecha- nisms through which TRN regulates sensory gating, and suggested targeted follow-up experiments to validate these findings. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
A Master Autoantigen-Ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases
bioRxiv preprint doi: https://doi.org/10.1101/2021.07.30.454526; this version posted August 4, 2021. 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 4.0 International license. A Master Autoantigen-ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases Julia Y. Wang1*, Michael W. Roehrl1, Victor B. Roehrl1, and Michael H. Roehrl2* 1 Curandis, New York, USA 2 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA * Correspondence: [email protected] or [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.30.454526; this version posted August 4, 2021. 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 4.0 International license. Abstract Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. -
Embryonic Transcriptome and Proteome Analyses on Hepatic Lipid
Na et al. BMC Genomics (2018) 19:384 https://doi.org/10.1186/s12864-018-4776-9 RESEARCH ARTICLE Open Access Embryonic transcriptome and proteome analyses on hepatic lipid metabolism in chickens divergently selected for abdominal fat content Wei Na, Yuan-Yuan Wu, Peng-Fei Gong, Chun-Yan Wu, Bo-Han Cheng, Yu-Xiang Wang, Ning Wang, Zhi-Qiang Du* and Hui Li* Abstract Background: In avian species, liver is the main site of de novo lipogenesis, and hepatic lipid metabolism relates closely to adipose fat deposition. Using our fat and lean chicken lines of striking differences in abdominal fat content, post-hatch lipid metabolism in both liver and adipose tissues has been studied extensively. However, whether molecular discrepancy for hepatic lipid metabolism exists in chicken embryos remains obscure. Results: We performed transcriptome and proteome profiling on chicken livers at five embryonic stages (E7, E12, E14, E17 and E21) between the fat and lean chicken lines. At each stage, 521, 141, 882, 979 and 169 differentially expressed genes were found by the digital gene expression, respectively, which were significantly enriched in the metabolic, PPAR signaling and fatty acid metabolism pathways. Quantitative proteomics analysis found 20 differentially expressed proteins related to lipid metabolism, PPAR signaling, fat digestion and absorption, and oxidative phosphorylation pathways. Combined analysis showed that genes and proteins related to lipid transport (intestinal fatty acid-binding protein, nucleoside diphosphate kinase, and apolipoprotein A-I), lipid clearance (heat shock protein beta-1) and energy metabolism (NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit10andsuccinatedehydrogenase flavoprotein subunit) were significantly differentially expressed between the two lines.