Refining the Accuracy of Validated Target Identification Through Coding Variant Fine- Mapping in Type 2 Diabetes
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Small Cell Ovarian Carcinoma: Genomic Stability and Responsiveness to Therapeutics
Gamwell et al. Orphanet Journal of Rare Diseases 2013, 8:33 http://www.ojrd.com/content/8/1/33 RESEARCH Open Access Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics Lisa F Gamwell1,2, Karen Gambaro3, Maria Merziotis2, Colleen Crane2, Suzanna L Arcand4, Valerie Bourada1,2, Christopher Davis2, Jeremy A Squire6, David G Huntsman7,8, Patricia N Tonin3,4,5 and Barbara C Vanderhyden1,2* Abstract Background: The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. Method: The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. Results: BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Transcriptional Control of Tissue-Resident Memory T Cell Generation
Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells. -
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 Characterization and Role of RREB1 in Human Bladder Cancer
The Characterization and Role of RREB1 in Human Bladder Cancer Matthew David Nitz Sebring, Fl B.S. Wheaton College, 2003 M.S ., University of Virginia, 2009 A Dissertation presented to the Graduate Faculty of the University of Virginia in Cand idacy for the Degree of Doctor of Philosophy Department of Molecular Physiology and Biological Physics University of Virginia August, 2011 I Abstract RREB1 is a C2H2 zinc-finger protein that has previously been associated with malignancy but little is known about its expression, composition of splice variants, or role in cancer phenotypes. Total RREB1 expression decreased in human bladder cancer tumors compared to paired normal tissue. Rigorous comparison of commercial RREB1 antibodies allowed for the identification of RREB1 splice variants in the cytoplasm and nucleus on western blot. Five RREB1 splice variants were identified and designated: RREB1α, RREB1β, RREB1γ, RREB1δ, RREB1ε. Immunohistochemistry of RREB1 in a bladder cancer tissue microarray demonstrated that RREB1 expression positively correlates with the squamous cell histology. Transient depletion of RREB1 in bladder cancer cell lines (UMUC3 and KU7) decreased cell growth in vitro and similar results were seen in prostate cancer cell lines (LNCAP and PC3). siRNA duplexes that target RREB1 isoforms showed RREB1α and RREB1β, but not RREB1β alone, were necessary for in vitro UMUC3 cell growth and in vivo subcutaneous tumor growth. RREB1 depletion was found to decrease the expression of tumor associated protein CD24. Cloning of the CD24 promoter revealed a hypoxia response element, which led to the discovery of hypoxia induced CD24 RNA expression and promoter activity. RREB1 depletion decreased the expression of two additional hypoxia responsive genes (VEGFA and IGFBP3) without affecting the mRNA stability. -
The Middle Temporal Gyrus Is Transcriptionally Altered in Patients with Alzheimer’S Disease
1 The middle temporal gyrus is transcriptionally altered in patients with Alzheimer’s Disease. 2 1 3 Shahan Mamoor 1Thomas Jefferson School of Law 4 East Islip, NY 11730 [email protected] 5 6 We sought to understand, at the systems level and in an unbiased fashion, how gene 7 expression was most different in the brains of patients with Alzheimer’s Disease (AD) by mining published microarray datasets (1, 2). Comparing global gene expression profiles between 8 patient and control revealed that a set of 84 genes were expressed at significantly different levels in the middle temporal gyrus (MTG) of patients with Alzheimer’s Disease (1, 2). We used 9 computational analyses to classify these genes into known pathways and existing gene sets, 10 and to describe the major differences in the epigenetic marks at the genomic loci of these genes. While a portion of these genes is computationally cognizable as part of a set of genes 11 up-regulated in the brains of patients with AD (3), many other genes in the gene set identified here have not previously been studied in association with AD. Transcriptional repression, both 12 pre- and post-transcription appears to be affected; nearly 40% of these genes are transcriptional 13 targets of MicroRNA-19A/B (miR-19A/B), the zinc finger protein 10 (ZNF10), or of the AP-1 repressor jun dimerization protein 2 (JDP2). 14 15 16 17 18 19 20 21 22 23 24 25 26 Keywords: Alzheimer’s Disease, systems biology of Alzheimer’s Disease, differential gene 27 expression, middle temporal gyrus. -
Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells
Published OnlineFirst May 6, 2011; DOI: 10.1158/1535-7163.MCT-10-1028 Molecular Cancer Therapeutic Discovery Therapeutics Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells Chunyu Zhang1, Abdel G. Elkahloun2, Hongling Liao3, Shannon Delaney1, Barbara Saber1, Betsy Morrow1, George C. Prendergast4, M. Christine Hollander1, Joell J. Gills1, and Phillip A. Dennis1 Abstract Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non–small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogen- esis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity. -
ZHX2 Promotes Hif1α Oncogenic Signaling in Triple-Negative Breast
bioRxiv preprint doi: https://doi.org/10.1101/2021.05.27.445959; this version posted May 28, 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. 1 ZHX2 Promotes HIF1 Oncogenic Signaling in Triple-Negative Breast Cancer 2 Wentong Fang,1,2* Chengheng Liao, 3* Rachel Shi, 3 Jeremy M. Simon, 2,4,5 Travis S. 3 Ptacek, 2,5 Giada Zurlo, 3 Youqiong Ye, 6,7 Leng Han, 7 Cheng Fan, 2 Christopher Llynard 4 Ortiz, 8,9,10 Hong-Rui Lin, 8 Ujjawal Manocha, 2 Weibo Luo, 3 William Y. Kim, 2 Lee-Wei Yang, 5 8,9,11 and Qing Zhang3* 6 7 1 Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, 8 Nanjing, Jiangsu 210029, China 9 2 Lineberger Comprehensive Cancer Center, University of North Carolina School of 10 Medicine, Chapel Hill, NC 27599, USA 11 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 12 75390, USA 13 4 Department of Genetics, Neuroscience Center, University of North Carolina, Chapel Hill, 14 NC 27599, USA 15 5 UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of 16 North Carolina, Chapel Hill, NC 27599, USA 17 6 Shanghai Institute of Immunology, Faculty of Basic Medicine, Shanghai Jiao Tong 18 University School of Medicine, Shanghai, 200025, China 19 7 Department of Biochemistry and Molecular Biology, The University of Texas Health 20 Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA 21 8 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 22 300, Taiwan bioRxiv preprint doi: https://doi.org/10.1101/2021.05.27.445959; this version posted May 28, 2021. -
Knowledge Management Enviroments for High Throughput Biology
Knowledge Management Enviroments for High Throughput Biology Abhey Shah A Thesis submitted for the degree of MPhil Biology Department University of York September 2007 Abstract With the growing complexity and scale of data sets in computational biology and chemoin- formatics, there is a need for novel knowledge processing tools and platforms. This thesis describes a newly developed knowledge processing platform that is different in its emphasis on architecture, flexibility, builtin facilities for datamining and easy cross platform usage. There exist thousands of bioinformatics and chemoinformatics databases, that are stored in many different forms with different access methods, this is a reflection of the range of data structures that make up complex biological and chemical data. Starting from a theoretical ba- sis, FCA (Formal Concept Analysis) an applied branch of lattice theory, is used in this thesis to develop a file system that automatically structures itself by it’s contents. The procedure of extracting concepts from data sets is examined. The system also finds appropriate labels for the discovered concepts by extracting data from ontological databases. A novel method for scaling non-binary data for use with the system is developed. Finally the future of integrative systems biology is discussed in the context of efficiently closed causal systems. Contents 1 Motivations and goals of the thesis 11 1.1 Conceptual frameworks . 11 1.2 Biological foundations . 12 1.2.1 Gene expression data . 13 1.2.2 Ontology . 14 1.3 Knowledge based computational environments . 15 1.3.1 Interfaces . 16 1.3.2 Databases and the character of biological data . -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. -
Study of Human Regulatory Mutations Associated with Pancreatic Diseases
Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa Mestrado em Biologia Celular e Molecular Departamento de Biologia da Faculdade de Ciências da Universidade do Porto (FCUP) Orientador José Bessa, PhD, Instituto de Investigação e Inovação em Saúde (i3S) Coorientador Chiara Perrod, PhD, Instituto de Investigação e Inovação em Saúde (i3S) 2018/19 This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Todas as correções agreement No 680156 – ZPR). determinadas pelo júri, e só essas, foram efetuadas. O Presidente do Júri, Porto, ______/______/_________ Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa Mestrado em Biologia Celular e Molecular Departamento de Biologia da Faculdade de Ciências da Universidade do Porto (FCUP) Orientador José Bessa, PhD, Instituto de Investigação e Inovação em Saúde (i3S) Coorientador Chiara Perrod, PhD, Instituto de Investigação e Inovação em Saúde (i3S) 2018/19 FCUP i Study of human regulatory mutations associated with pancreatic diseases by humanizing the zebrafish genome. Inês Maria Batista da Costa, BSc Mestrado em Biologia Celular e Molecular Departamento de Biologia Faculdade de Ciências da Universidade do Porto (FCUP) Rua do Campo Alegre s/n 4169-007 Porto, Portugal [email protected] / [email protected] Tel.: +351 917457361 Supervisor