Genetic Parameters and Associated Genomic Regions for Global
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A Cell Line P53 Mutation Type UM
A Cell line p53 mutation Type UM-SCC 1 wt UM-SCC5 Exon 5, 157 GTC --> TTC Missense mutation by transversion (Valine --> Phenylalanine UM-SCC6 wt UM-SCC9 wt UM-SCC11A wt UM-SCC11B Exon 7, 242 TGC --> TCC Missense mutation by transversion (Cysteine --> Serine) UM-SCC22A Exon 6, 220 TAT --> TGT Missense mutation by transition (Tyrosine --> Cysteine) UM-SCC22B Exon 6, 220 TAT --> TGT Missense mutation by transition (Tyrosine --> Cysteine) UM-SCC38 Exon 5, 132 AAG --> AAT Missense mutation by transversion (Lysine --> Asparagine) UM-SCC46 Exon 8, 278 CCT --> CGT Missense mutation by transversion (Proline --> Alanine) B 1 Supplementary Methods Cell Lines and Cell Culture A panel of ten established HNSCC cell lines from the University of Michigan series (UM-SCC) was obtained from Dr. T. E. Carey at the University of Michigan, Ann Arbor, MI. The UM-SCC cell lines were derived from eight patients with SCC of the upper aerodigestive tract (supplemental Table 1). Patient age at tumor diagnosis ranged from 37 to 72 years. The cell lines selected were obtained from patients with stage I-IV tumors, distributed among oral, pharyngeal and laryngeal sites. All the patients had aggressive disease, with early recurrence and death within two years of therapy. Cell lines established from single isolates of a patient specimen are designated by a numeric designation, and where isolates from two time points or anatomical sites were obtained, the designation includes an alphabetical suffix (i.e., "A" or "B"). The cell lines were maintained in Eagle's minimal essential media supplemented with 10% fetal bovine serum and penicillin/streptomycin. -
Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies
International Journal of Molecular Sciences Review Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies 1, 1, 1,2, Quynh Nguyen y , Kenji Rowel Q. Lim y and Toshifumi Yokota * 1 Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, Canada; [email protected] (Q.N.); [email protected] (K.R.Q.L.) 2 The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, AB T6G2H7, Canada * Correspondence: [email protected]; Tel.: +1-780-492-1102 These authors contributed equally to the work. y Received: 28 December 2019; Accepted: 19 January 2020; Published: 22 January 2020 Abstract: Cardiomyopathies are diseases of heart muscle, a significant percentage of which are genetic in origin. Cardiomyopathies can be classified as dilated, hypertrophic, restrictive, arrhythmogenic right ventricular or left ventricular non-compaction, although mixed morphologies are possible. A subset of neuromuscular disorders, notably Duchenne and Becker muscular dystrophies, are also characterized by cardiomyopathy aside from skeletal myopathy. The global burden of cardiomyopathies is certainly high, necessitating further research and novel therapies. Genome editing tools, which include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) systems have emerged as increasingly important technologies in studying -
Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. -
Genome-Wide Copy Number Variant Analysis For
An et al. BMC Medical Genomics (2016) 9:2 DOI 10.1186/s12920-015-0163-4 RESEARCH ARTICLE Open Access Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population Yu An1,2,4, Wenyuan Duan3, Guoying Huang4, Xiaoli Chen5,LiLi5, Chenxia Nie6, Jia Hou4, Yonghao Gui4, Yiming Wu1, Feng Zhang2, Yiping Shen7, Bailin Wu1,4,7* and Hongyan Wang8* Abstract Background: Ventricular septal defects (VSDs) constitute the most prevalent congenital heart disease (CHD), occurs either in isolation (isolated VSD) or in combination with other cardiac defects (complex VSD). Copy number variation (CNV) has been highlighted as a possible contributing factor to the etiology of many congenital diseases. However, little is known concerning the involvement of CNVs in either isolated or complex VSDs. Methods: We analyzed 154 unrelated Chinese individuals with VSD by chromosomal microarray analysis. The subjects were recruited from four hospitals across China. Each case underwent clinical assessment to define the type of VSD, either isolated or complex VSD. CNVs detected were categorized into syndrom related CNVs, recurrent CNVs and rare CNVs. Genes encompassed by the CNVs were analyzed using enrichment and pathway analysis. Results: Among 154 probands, we identified 29 rare CNVs in 26 VSD patients (16.9 %, 26/154) and 8 syndrome-related CNVs in 8 VSD patients (5.2 %, 8/154). 12 of the detected 29 rare CNVs (41.3 %) were recurrently reported in DECIPHER or ISCA database as associated with either VSD or general heart disease. Fifteen genes (5 %, 15/285) within CNVs were associated with a broad spectrum of complicated CHD. -
UNIVERSITY of CALIFORNIA RIVERSIDE Investigations Into The
UNIVERSITY OF CALIFORNIA RIVERSIDE Investigations into the Role of TAF1-mediated Phosphorylation in Gene Regulation A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Cell, Molecular and Developmental Biology by Brian James Gadd December 2012 Dissertation Committee: Dr. Xuan Liu, Chairperson Dr. Frank Sauer Dr. Frances M. Sladek Copyright by Brian James Gadd 2012 The Dissertation of Brian James Gadd is approved Committee Chairperson University of California, Riverside Acknowledgments I am thankful to Dr. Liu for her patience and support over the last eight years. I am deeply indebted to my committee members, Dr. Frank Sauer and Dr. Frances Sladek for the insightful comments on my research and this dissertation. Thanks goes out to CMDB, especially Dr. Bachant, Dr. Springer and Kathy Redd for their support. Thanks to all the members of the Liu lab both past and present. A very special thanks to the members of the Sauer lab, including Silvia, Stephane, David, Matt, Stephen, Ninuo, Toby, Josh, Alice, Alex and Flora. You have made all the years here fly by and made them so enjoyable. From the Sladek lab I want to thank Eugene, John, Linh and Karthi. Special thanks go out to all the friends I’ve made over the years here. Chris, Amber, Stephane and David, thank you so much for feeding me, encouraging me and keeping me sane. Thanks to the brothers for all your encouragement and prayers. To any I haven’t mentioned by name, I promise I haven’t forgotten all you’ve done for me during my graduate years. -
Role of Tafazzin in Hematopoiesis and Leukemogenesis
Role of Tafazzin in Hematopoiesis and Leukemogenesis by Ayesh Seneviratne A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Ayesh Seneviratne 2020 Role of Tafazzin in Hematopoiesis and Leukemogenesis Ayesh Seneviratne Doctor of Philosophy Institute of Medical Science University of Toronto 2020 Abstract Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling (Seneviratne et al., 2019). ii Acknowledgments Firstly, I would like to thank Dr. Aaron Schimmer for his guidance and support during my PhD studies. I really enjoyed our early morning meetings where he provided much needed perspective to navigate the road blocks of my project, whilst continuing to push me. It was a privilege to be mentored by such an excellent clinician scientist. I hope to continue to build on the skills I learned in Dr. Schimmer’s lab as I progress on my path to become a clinician scientist. Working in the Schimmer lab was a wonderful learning environment. I would like to especially thank Dr. -
Anti-VPS4A Antibody (ARG43067)
Product datasheet [email protected] ARG43067 Package: 50 μg anti-VPS4A antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes VPS4A Tested Reactivity Hu, Ms, Rat Tested Application FACS, IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name VPS4A Antigen Species Human Immunogen Recombinant protein corresponding to M1-K71 of Human VPS4A. Conjugation Un-conjugated Alternate Names SKD2; SKD1; hVPS4; Protein SKD2; SKD1A; Vacuolar protein sorting-associated protein 4A; VPS4-1; EC 3.6.4.6; VPS4 Application Instructions Application table Application Dilution FACS 1:150 - 1:500 IHC-P 1:200 - 1:1000 WB 1:500 - 1:2000 Application Note IHC-P: Antigen Retrieval: Heat mediation was performed in EDTA buffer (pH 8.0). * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Calculated Mw 49 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer 0.2% Na2HPO4, 0.9% NaCl, 0.05% Sodium azide and 4% Trehalose. Preservative 0.05% Sodium azide Stabilizer 4% Trehalose Concentration 0.5 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed www.arigobio.com 1/3 before use. Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Gene Symbol VPS4A Gene Full Name vacuolar protein sorting 4 homolog A (S. -
Neural Basis of Reward Anticipation and Its Genetic Determinants
Neural basis of reward anticipation and its genetic determinants Tianye Jiaa,b, Christine Macarea,b, Sylvane Desrivièresa,b, Dante A. Gonzalezc, Chenyang Taod, Xiaoxi Jid, Barbara Ruggeria,b, Frauke Neese,f, Tobias Banaschewskie, Gareth J. Barkera, Arun L. W. Bokdeg, Uli Brombergh, Christian Büchelh, Patricia J. Conroda,i, Rachel Dovec, Vincent Frouinj, Jürgen Gallinatk, Hugh Garavanl,m, Penny A. Gowlandn, Andreas Heinzk, Bernd Ittermanno, Mark Lathropp, Hervé Lemaitreq, Jean-Luc Martinotq, Tomáš Pausr,s,t, Zdenka Pausovau, Jean-Baptiste Polinej,v, Marcella Rietschele,w, Trevor Robbinsx, Michael N. Smolkay, Christian P. Müllerz, Jianfeng Fengd,aa, Adrian Rothenfluhc,1, Herta Flore,f,1, Gunter Schumanna,b,1,2, and the IMAGEN Consortium3 aInstitute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, United Kingdom; bMedical Research Council Social, Genetic and Developmental Psychiatry Centre, London SE5 8AF, United Kingdom; cDepartment of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390; dCenter for Computational Systems Biology, Fudan University, Shanghai 200433, People’s Republic of China; eDepartment of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Heidelberg, Germany; fDepartment of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Heidelberg, Germany; gTrinity College Institute of Neuroscience and Discipline of Psychiatry, -
Genetic and Bioinformatic Analyses of the Expression and Function of PI3K
Zhou et al. BMC Medical Genomics 2012, 5:34 http://www.biomedcentral.com/1755-8794/5/34 RESEARCH ARTICLE Open Access Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library Jin Zhou1, Geng Bo Chen3, Yew Chung Tang4, Rohit Anthony Sinha1, Yonghui Wu8, Chui Sun Yap1, Guihua Wang5, Junbo Hu5, Xianmin Xia5, Patrick Tan2,8,9,10, Liang Kee Goh3,6,7 and Paul Michael Yen1* Abstract Background: While there is strong evidence for phosphatidylinositol 3-kinase (PI3K) involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene that encodes the PI3K regulatory subunit p55γ, is over-expressed in glioblastoma and ovarian cancers, but its expression in gastric cancer (GC) is not known. We thus used genetic and bioinformatic approaches to examine PIK3R3 expression and function in GC, the second leading cause of cancer mortality world-wide and highly prevalent among Asians. Methods: Primary GC and matched non-neoplastic mucosa tissue specimens from a unique Asian patient gastric cancer library were comprehensively profiled with platforms that measured genome-wide mRNA expression, DNA copy number variation, and DNA methylation status. Function of PIK3R3 was predicted by IPA pathway analysis of co-regulated genes with PIK3R3, and further investigated by siRNA knockdown studies. Cell proliferation was estimated by crystal violet dye elution and BrdU incorporation assay. Cell cycle distribution was analysed by FACS. Results: PIK3R3 was significantly up-regulated in GC specimens (n = 126, p < 0.05), and 9.5 to 15% tumors showed more than 2 fold increase compare to the paired mucosa tissues. -
B Inhibition in a Mouse Model of Chronic Colitis1
The Journal of Immunology Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-B Inhibition in a Mouse Model of Chronic Colitis1 Feng Wu and Shukti Chakravarti2 Fibrosis is a major complication of chronic inflammation, as seen in Crohn’s disease and ulcerative colitis, two forms of inflam- matory bowel diseases. To elucidate inflammatory signals that regulate fibrosis, we investigated gene expression changes under- lying chronic inflammation and fibrosis in trinitrobenzene sulfonic acid-induced murine colitis. Six weekly 2,4,6-trinitrobenzene sulfonic acid enemas were given to establish colitis and temporal gene expression patterns were obtained at 6-, 8-, 10-, and 12-wk time points. The 6-wk point, TNBS-w6, was the active, chronic inflammatory stage of the model marked by macrophage, neu- trophil, and CD3؉ and CD4؉ T cell infiltrates in the colon, consistent with the idea that this model is T cell immune response driven. Proinflammatory genes Cxcl1, Ccl2, Il1b, Lcn2, Pla2g2a, Saa3, S100a9, Nos2, Reg2, and Reg3g, and profibrogenic extra- cellular matrix genes Col1a1, Col1a2, Col3a1, and Lum (lumican), encoding a collagen-associated proteoglycan, were up-regulated at the active/chronic inflammatory stages. Rectal administration of the NF-B p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-B by 60% and down- regulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not down- regulated. Among extracellular matrix gene expressions Lum was suppressed while Col1a1 and Col3a1 were not. Thus, effective treatment of fibrosis in inflammatory bowel disease may require early and complete blockade of NF-B with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-B. -
Targeted Polymerase Chain Reaction-Based Enrichment and Next Generation Sequencing for Diagnostic Testing of Congenital Disorders of Glycosylation Melanie A
ARTICLE Targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation Melanie A. Jones, PhD1, Shruti Bhide, MS1, Ephrem Chin, MB(ASCP), QLC1, Bobby G. Ng, BS2, Devin Rhodenizer, BS1, Victor W. Zhang, MD, PhD1, Jessica J. Sun, MS1, Alice Tanner, PhD, MS1, Hudson H. Freeze, PhD2, and Madhuri R. Hegde, PhD, FACMG1 2 Purpose: Congenital disorders of glycosylation are a heterogeneous stability and in the immune response ; hence, the proper devel- group of disorders caused by deficient glycosylation, primarily affecting opment and functioning of many organ systems depend on the N-linked pathway. It is estimated that more than 40% of congenital normal N-glycosylation. Deficient N-glycosylation results in 3 disorders of glycosylation patients lack a confirmatory molecular multiple organ dysfunction that can be life threatening. Con- diagnosis. The purpose of this study was to improve molecular genital disorders of glycosylation (CDG) are a group of more diagnosis for congenital disorders of glycosylation by developing than 30 autosomal recessive disorders caused by deficient gly- 4 and validating a next generation sequencing panel for comprehensive cosylation, primarily affecting the N-linked pathway. Symp- mutation detection in 24 genes known to cause congenital disorders toms of CDG can include severe developmental delay, ataxia, of glycosylation. Methods: Next generation sequencing validation seizures, liver fibrosis, retinopathy, cardiac dysfunction, and 3,5 was performed on 12 positive control congenital disorders of gly- coagulopathies. CDG occurs worldwide, with an estimated 6 cosylation patients. These samples were blinded as to the disease- prevalence as high as 1 in 20,000. -
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Research Article The Majority of Viral-Cellular Fusion Transcripts in Cervical Carcinomas Cotranscribe Cellular Sequences of Known or Predicted Genes Irene Kraus,1,3,4 Corina Driesch,4 Svetlana Vinokurova,5 Eivind Hovig,2 AchimSchneider, 6 Magnus von Knebel Doeberitz,5 and Matthias Du¨rst4 1Institute of Pathology, Rikshospitalet University Hospital; 2Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway; 3NorChip AS, Klokkarstua, Norway; 4Gyna¨kologischeMolekularbiologie, Frauenklinik der Friedrich-Schiller-Universita¨t,Jena, Germany; 5Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; and 6Frauenklinik mit Hochschulambulanz der Charite´, Campus Benjamin Franklin und Campus Mitte, Berlin, Germany Abstract virus lies in its oncogenes E6 and E7, underlined by their con- Integration of human papillomavirus (HPV) DNA into the host stitutive expression in HPV-induced cervical carcinomas (4, 5). The genome is a frequent event in cervical carcinogenesis and is E6 and E7 oncoproteins mediate mitogenic and antiapoptotic reported to occur at randomly selected chromosomal sites. stimuli by interacting with numerous regulatory proteins of the host cell that control the cell cycle (6, 7). Moreover, the viral However,as the databases are being up-dated continuously, the knowledge based on sequenced viral integration sites also oncoproteins induce mitotic defects and genomic instability by expands. In this study,viral-cellular fusion transcripts of a uncoupling centrosome duplication from the cell division cycle preselected group of 74 cervical carcinoma or cervical (8, 9). During malignant progression, viral DNA is frequently intraepithelial neoplasia grade 3 (CIN3) biopsies harboring integrated into the host genome (10, 11).