Interindividual Differences in the Expression of ATP-Binding
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The Pharmacogenomics of Vincristine-Induced Neurotoxicity
THE PHARMACOGENOMICS OF VINCRISTINE-INDUCED NEUROTOXICITY IN PAEDIATRIC CANCER PATIENTS WITH WILMS TUMOR OR RHABDOMYOSARCOMA by Tenneille Loo A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2011 © Tenneille Loo, 2011 Abstract Vincristine is one of the most effective and widely utilized antineoplastic agents. However, the clinical utility of this drug is limited by severely debilitating vincristine- induced neurotoxicities (VIN). Previous studies have associated VIN with genetic polymorphisms in genes involved in the metabolism and transportation of vincristine, including CYP3A4, CYP3A5, and ABCB1. However, the findings of such studies have not been consistently reproduced. This study hypothesizes that there are specific variants in genes involved in general drug absorption, metabolism, distribution, excretion, and toxicity (ADME-Tox) that affect the individual susceptibility to VIN in patients with Wilms tumor and rhabdomyosarcoma. Detailed clinical data was collected from 140 patients with Wilms tumor and rhabdomyosarcoma by retrospective chart review. VIN cases were characterized by type of neurotoxicity, and severity was evaluated using a validated clinical grading system for adverse events (NCI-CTCAE v4.03). A customized Illumina GoldenGate Panel was used to genotype 4,536 single nucleotide polymorphisms (SNPs) in candidate genes involved in the metabolism and transportation pathway of vincristine, as well as in genes broadly involved in ADME-Tox. None of the SNPs that were previously reported to be associated with VIN were found to be significantly associated (p-value < 0.05). With similar effect sizes, six novel genetic variants in five genes (PON1, ABCA4, ABCG1, CY51A1, SLCO1C1) were significantly associated with VIN in both tumor types. -
ABCC12 Monoclonal Antibody, Clone M9II-3
ABCC12 monoclonal antibody, Gene Symbol: ABCC12 clone M9II-3 Gene Alias: MGC27071, MRP9 Catalog Number: MAB6675 Gene Summary: This gene is a member of the superfamily of ATP-binding cassette (ABC) transporters Regulatory Status: For research use only (RUO) and the encoded protein contains two ATP-binding domains and 12 transmembrane regions. ABC proteins Product Description: Rat monoclonal antibody raised transport various molecules across extra- and against partial recombinant ABCC12. intracellular membranes. ABC genes are divided into Clone Name: M9II-3 seven distinct subfamilies: ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White. This gene is a member of Immunogen: Recombinant protein corresponding to the MRP subfamily which is involved in multi-drug amino acids 690-734 of human ABCC12. resistance. This gene and another subfamily member are arranged head-to-tail on chromosome 16q12.1. Host: Rat Increased expression of this gene is associated with breast cancer. [provided by RefSeq] Reactivity: Human References: Applications: ICC, IHC-Fr, WB 1. Multidrug resistance-associated protein 9 (ABCC12) is (See our web site product page for detailed applications present in mouse and boar sperm. Ono N, Van der information) Heijden I, Scheffer GL, Van de Wetering K, Van Deemter E, De Haas M, Boerke A, Gadella BM, De Rooij Protocols: See our web site at DG, Neefjes JJ, Groothuis TA, Oomen L, Brocks L, http://www.abnova.com/support/protocols.asp or product Ishikawa T, Borst P. Ono N, Van der Heijden I, Scheffer page for detailed protocols GL, Van de Wetering K, Van Deemter E, De Haas M, Boerke A, Gadella BM, De Rooij DG, Neefjes JJ, Specificity: M9II-3 reacts with an internal epitope of Groothuis TA, Oomen L, Brocks L, Ishikawa T, Borst P. -
Design and Methods of the Prevalence and Pharmacogenomics of Tenofovir Nephrotoxicity in HIV-Positive Adults in South-Western Nigeria Study Muzamil O
Hassan et al. BMC Nephrology (2020) 21:436 https://doi.org/10.1186/s12882-020-02082-3 STUDY PROTOCOL Open Access Design and methods of the prevalence and pharmacogenomics of tenofovir nephrotoxicity in HIV-positive adults in south-western Nigeria study Muzamil O. Hassan1,2* , Raquel Duarte3, Victor O. Mabayoje4, Caroline Dickens3, Akeem O. Lasisi5 and Saraladevi Naicker6 Abstract Background: Individuals of African descent are at higher risk of developing kidney disease than their European counterparts, and HIV infection is associated with increased risk of nephropathy. Despite a safe renal profile in the clinical trials, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy although the underlying mechanisms remain undetermined. We aim to establish the prevalence of and risk factors for TDF-induced kidney tubular dysfunction (KTD) among HIV-I and II individuals treated with TDF in south-west Nigeria. Association between TDF-induced KTD and genetic polymorphisms in renal drug transporter genes and the APOL1 (Apolipoprotein L1) gene will be examined. Methods: This study has two phases. An initial cross-sectional study will screen 3000 individuals attending the HIV clinics in south-west Nigeria for KTD to determine the prevalence and risk factors. This will be followed by a case- control study of 400 KTD cases and 400 matched controls to evaluate single nucleotide polymorphism (SNP) associations. Data on socio-demographics, risk factors for kidney dysfunction and HIV history will be collected by questionnaire. Blood and urine samples for measurements of severity of HIV disease (CD4 count, viral load) and renal function (creatinine, eGFR, phosphate, uric acid, glucose) will also be collected. -
ABCG1 (ABC8), the Human Homolog of the Drosophila White Gene, Is a Regulator of Macrophage Cholesterol and Phospholipid Transport
ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport Jochen Klucken*, Christa Bu¨ chler*, Evelyn Orso´ *, Wolfgang E. Kaminski*, Mustafa Porsch-Ozcu¨ ¨ ru¨ mez*, Gerhard Liebisch*, Michael Kapinsky*, Wendy Diederich*, Wolfgang Drobnik*, Michael Dean†, Rando Allikmets‡, and Gerd Schmitz*§ *Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, 93042 Regensburg, Germany; †National Cancer Institute, Laboratory of Genomic Diversity, Frederick, MD 21702-1201; and ‡Departments of Ophthalmology and Pathology, Columbia University, Eye Research Addition, New York, NY 10032 Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved November 3, 1999 (received for review June 14, 1999) Excessive uptake of atherogenic lipoproteins such as modified low- lesterol transport. Although several effector molecules have been density lipoprotein complexes by vascular macrophages leads to proposed to participate in macrophage cholesterol efflux (6, 9), foam cell formation, a critical step in atherogenesis. Cholesterol efflux including endogenous apolipoprotein E (10) and the cholesteryl mediated by high-density lipoproteins (HDL) constitutes a protective ester transfer protein (11), the detailed molecular mechanisms mechanism against macrophage lipid overloading. The molecular underlying cholesterol export in these cells have not yet been mechanisms underlying this reverse cholesterol transport process are characterized. currently not fully understood. To identify effector proteins that are Recently, mutations of the ATP-binding cassette (ABC) trans- involved in macrophage lipid uptake and release, we searched for porter ABCA1 gene have been causatively linked to familial HDL genes that are regulated during lipid influx and efflux in human deficiency and Tangier disease (12–14). -
Alternating Hypoglycemia and Hyperglycemia in a Toddler with a Homozygous P.R1419H ABCC8 Mutation: an Unusual Clinical Picture
J Pediatr Endocr Met 2015; 28(3-4): 345–351 Patient report Open Access Shira Harel, Ana S.A. Cohen, Khalid Hussain, Sarah E. Flanagan, Kamilla Schlade-Bartusiak, Millan Patel, Jaques Courtade, Jenny B.W. Li, Clara Van Karnebeek, Harley Kurata, Sian Ellard, Jean-Pierre Chanoine and William T. Gibson* Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture Abstract Results: A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of Background: Inheritance of two pathogenic ABCC8 alleles insulin secretion, with postprandial hyperglycemia fol- typically causes severe congenital hyperinsulinism. We lowed by hypoglycemia. Microarray revealed homozygo- describe a girl and her father, both homozygous for the sity for the regions encompassing KCNJ11 and ABCC8. Her same ABCC8 mutation, who presented with unusual father had developed diabetes at 28 years of age. Sequenc- phenotypes. ing of ABCC8 identified a homozygous missense mutation, Methods: Single nucleotide polymorphism microarray p.R1419H, in both individuals. Functional studies showed and Sanger sequencing were performed. Western blot, absence of working KATP channels. rubidium efflux, and patch clamp recordings interrogated Conclusion: This is the first description of a homozygous the expression and activity of the mutant protein. p.R1419H mutation. Our findings highlight that homozy- gous loss-of-function mutations of ABCC8 do not neces- sarily translate into early-onset severe hyperinsulinemia. *Corresponding author: William T. Gibson, Child and Family Research Institute, Department of Medical Genetics, British Keywords: ABCC8; diabetes; hyperglycemia; hyperinsu- Columbia Children’s Hospital, 950 West 28th Avenue, Vancouver, linism; hypoglycemia. BC, V5Z 4H4, Canada, Phone: +1-604-875-2000 ext. -
A Single-Cell Transcriptomic Landscape of Primate Arterial Aging
ARTICLE https://doi.org/10.1038/s41467-020-15997-0 OPEN A single-cell transcriptomic landscape of primate arterial aging Weiqi Zhang 1,2,3,4,5,13, Shu Zhang6,7,13, Pengze Yan3,8,13, Jie Ren7,9,13, Moshi Song3,5,8, Jingyi Li2,3,8, Jinghui Lei4, Huize Pan2,3, Si Wang3,5,8, Xibo Ma3,10, Shuai Ma2,3,8, Hongyu Li2,3, Fei Sun2,3, Haifeng Wan3,5,11, ✉ ✉ ✉ Wei Li 3,5,11, Piu Chan4, Qi Zhou3,5,11, Guang-Hui Liu 2,3,4,5,8 , Fuchou Tang 6,7,9,12 & Jing Qu 3,5,11 Our understanding of how aging affects the cellular and molecular components of the vas- 1234567890():,; culature and contributes to cardiovascular diseases is still limited. Here we report a single-cell transcriptomic survey of aortas and coronary arteries in young and old cynomolgus monkeys. Our data define the molecular signatures of specialized arteries and identify eight markers discriminating aortic and coronary vasculatures. Gene network analyses characterize tran- scriptional landmarks that regulate vascular senility and position FOXO3A, a longevity- associated transcription factor, as a master regulator gene that is downregulated in six subtypes of monkey vascular cells during aging. Targeted inactivation of FOXO3A in human vascular endothelial cells recapitulates the major phenotypic defects observed in aged monkey arteries, verifying FOXO3A loss as a key driver for arterial endothelial aging. Our study provides a critical resource for understanding the principles underlying primate arterial aging and contributes important clues to future treatment of age-associated vascular disorders. 1 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. -
5' Untranslated Region Elements Show High Abundance and Great
International Journal of Molecular Sciences Article 0 5 Untranslated Region Elements Show High Abundance and Great Variability in Homologous ABCA Subfamily Genes Pavel Dvorak 1,2,* , Viktor Hlavac 2,3 and Pavel Soucek 2,3 1 Department of Biology, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic 2 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic; [email protected] (V.H.); [email protected] (P.S.) 3 Toxicogenomics Unit, National Institute of Public Health, 100 42 Prague, Czech Republic * Correspondence: [email protected]; Tel.: +420-377593263 Received: 7 October 2020; Accepted: 20 November 2020; Published: 23 November 2020 Abstract: The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is studied intensively. The regulation of translation initiation is implicated as the major mechanism in the processes of post-transcriptional modifications determining final protein levels. In the current bioinformatics study, we mapped the features of the 50 untranslated regions (50UTR) known to have the potential to regulate translation, such as the length of 50UTRs, upstream ATG codons, upstream open-reading frames, introns, RNA G-quadruplex-forming sequences, stem loops, and Kozak consensus motifs, in the DNA sequences of all members of the subfamily. Subsequently, the conservation of the features, correlations among them, ribosome profiling data as well as protein levels in normal human tissues were examined. The 50UTRs of ABCA genes contain above-average numbers of upstream ATGs, open-reading frames and introns, as well as conserved ones, and these elements probably play important biological roles in this subfamily, unlike RG4s. -
Multidrug Transporter MRP4/ABCC4 As a Key Determinant of Pancreatic
www.nature.com/scientificreports OPEN Multidrug transporter MRP4/ ABCC4 as a key determinant of pancreatic cancer aggressiveness A. Sahores1, A. Carozzo1, M. May1, N. Gómez1, N. Di Siervi1, M. De Sousa Serro1, A. Yanef1, A. Rodríguez‑González2, M. Abba3, C. Shayo2 & C. Davio1* Recent fndings show that MRP4 is critical for pancreatic ductal adenocarcinoma (PDAC) cell proliferation. Nevertheless, the signifcance of MRP4 protein levels and function in PDAC progression is still unclear. The aim of this study was to determine the role of MRP4 in PDAC tumor aggressiveness. Bioinformatic studies revealed that PDAC samples show higher MRP4 transcript levels compared to normal adjacent pancreatic tissue and circulating tumor cells express higher levels of MRP4 than primary tumors. Also, high levels of MRP4 are typical of high-grade PDAC cell lines and associate with an epithelial-mesenchymal phenotype. Moreover, PDAC patients with high levels of MRP4 depict dysregulation of pathways associated with migration, chemotaxis and cell adhesion. Silencing MRP4 in PANC1 cells reduced tumorigenicity and tumor growth and impaired cell migration. Transcriptomic analysis revealed that MRP4 silencing alters PANC1 gene expression, mainly dysregulating pathways related to cell-to-cell interactions and focal adhesion. Contrarily, MRP4 overexpression signifcantly increased BxPC-3 growth rate, produced a switch in the expression of EMT markers, and enhanced experimental metastatic incidence. Altogether, our results indicate that MRP4 is associated with a more aggressive phenotype in PDAC, boosting pancreatic tumorigenesis and metastatic capacity, which could fnally determine a fast tumor progression in PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, due to its late diag- nosis, inherent resistance to treatment and early dissemination 1. -
Molecular Structure of a Novel Cholesterol-Responsive a Subclass ABC Transporter, ABCA9
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Regensburg Publication Server BBRC Biochemical and Biophysical Research Communications 295 (2002) 408–416 www.academicpress.com Molecular structure of a novel cholesterol-responsive A subclass ABC transporter, ABCA9 Armin Piehler,1 Wolfgang E. Kaminski,1 Juurgen€ J. Wenzel, Thomas Langmann, and Gerd Schmitz* Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauß-Allee 11, D-93042, Regensburg, Germany Received 25 May 2002 Abstract We recently identified a novel ABC A subclass transporter, ABCA6, in human macrophages. Here, we report the molecular cloning of an additional ABC A subfamily transporter from macrophages denoted ABCA9. The identified coding sequence is 4.9 kb in size and codes for a 1624 amino acid protein product. In accordance with the proposed nomenclature, the novel transporter was designated ABCA9. The putative full-length ABC transporter polypeptide consists of two transmembrane domains and two nu- cleotide binding folds and thus conforms to the group of full-size ABC transporters. We identified alternative ABCA9 mRNA variants in human macrophages that predict the existence of three truncated forms of the novel transporter. Among the human ABC A subfamily transporters, ABCA9 exhibits the highest amino acid sequence homology with ABCA8 (72%) and ABCA6 (60%), respectively. The striking amino acid sequence similarity between these transporter molecules supports the notion that they represent an evolutionary more recently emerged subgroup within the family of ABC A transporters, which we refer to as ‘‘ABCA6-like transporters.’’ ABCA9 mRNA is ubiquitously expressed with the highest mRNA levels in heart, brain, and fetal tissues. -
ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center
University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Medical Sciences Commons Recommended Citation Fukuda, Yu , "ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters" (2008). Theses and Dissertations (ETD). Paper 345. http://dx.doi.org/10.21007/etd.cghs.2008.0100. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Interdisciplinary Program Research Advisor John D. Schuetz, Ph.D. Committee Linda Hendershot, Ph.D. James I. Morgan, Ph.D. Anjaparavanda P. Naren, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0100 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/345 ABCB6 IS A PORPHYRIN TRANSPORTER WITH A NOVEL TRAFFICKING SIGNAL THAT -
WO 2013/043130 Al 28 March 2013 (28.03.2013) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/043130 Al 28 March 2013 (28.03.2013) P O P C T (51) International Patent Classification: Building Level 5, Singapore 16875 1 (SG). KHOR, Chiea- C12Q 1/68 (2006.01) Chuen; Genome Institute of Singapore, 60 Biopolis Street, Genome, Singapore 138672 (SG). (21) International Application Number: PCT/SG2012/00035 1 (74) Agent: CHUNG, Jing Yeng; Marks & Clerk Singapore LLP, Tanjong Pagar, P.O Box 636, Singapore 9108 16 (22) International Filing Date: (SG). 24 September 2012 (24.09.2012) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/537,904 22 September 201 1 (22.09.201 1) US HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (71) Applicants: SINGAPORE HEALTH SERVICES PTE KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, LTD [SG/SG]; 31 Third Hospital Avenue, #03-03 Bowyer ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Block C, Singapore 168753 (SG). AGENCY FOR SCI¬ NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, ENCE, TECHNOLOGY AND RESEARCH [SG/SG]; 1 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, Fusionopolis Way, #20-10 Connexis, Singapore 138632 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (SG). -
Genome-Wide Identification, Characterization and Phylogenetic Analysis of ATP-Binding Cassette (ABC) Transporter Genes in Common Carp (Cyprinus Carpio)
RESEARCH ARTICLE Genome-Wide Identification, Characterization and Phylogenetic Analysis of ATP-Binding Cassette (ABC) Transporter Genes in Common Carp (Cyprinus carpio) Xiang Liu1,2☯, Shangqi Li1☯, Wenzhu Peng1, Shuaisheng Feng1, Jianxin Feng3, Shahid Mahboob4,5, Khalid A. Al-Ghanim4, Peng Xu1,6* 1 CAFS Key Laboratory of Aquatic Genomics and Beijing Key Laboratory of Fishery Biotechnology, Centre for Applied Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China, 2 Department of Aquaculture, College of Animal Sciences, Shanxi Agriculture University, Taigu, Shanxi, China, 3 Henan Academy of Fishery Sciences, Zhengzhou, China, 4 Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia, 5 Department of Zoology, GC University, Faisalabad, Pakistan, 6 College of Ocean & Earth Science, Xiamen University, Xiamen, China ☯ These authors contributed equally to this work. * [email protected] OPEN ACCESS Citation: Liu X, Li S, Peng W, Feng S, Feng J, Mahboob S, et al. (2016) Genome-Wide Identification, Characterization and Phylogenetic Abstract Analysis of ATP-Binding Cassette (ABC) Transporter Genes in Common Carp (Cyprinus carpio). PLoS The ATP-binding cassette (ABC) gene family is considered to be one of the largest gene ONE 11(4): e0153246. doi:10.1371/journal. families in all forms of prokaryotic and eukaryotic life. Although the ABC transporter genes pone.0153246 have been annotated in some species, detailed information about the ABC superfamily and Editor: Anthony M. George, University of Technology the evolutionary characterization of ABC genes in common carp (Cyprinus carpio) are still Sydney, AUSTRALIA unclear. In this research, we identified 61 ABC transporter genes in the common carp Received: January 12, 2016 genome.