Pathway-Based Analysis of Genome-Wide Association Data
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Thiopurine Drug Therapy
Thiopurine Drug Therapy Thiopurine drug therapy is used for autoimmune diseases, inflammatory bowel disease, acute lymphoblastic leukemia, and to prevent rejection after solid organ transplant. The inactivation of thiopurine drugs is catalyzed in part by thiopurine Tests to Consider methyltrasferase (TPMT) and nudix hydrolase 15 (NUDT15). Variants in the TPMT and/or NUDT15 genes are associated with an accumulation of cytotoxic metabolites Thiopurine Methyltransferase, RBC leading to increased risk of drug-related toxicity with standard doses of thiopurine 0092066 drugs, and the effects on thiopurine catabolism can be additive. Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry The enzyme activity phenotype of TPMT can also be measured directly when Phenotype test to assess risk for severe performed prior to drug administration. Complementary to pretherapeutic tests, myelosuppression with standard dosing of concentrations of thiopurines and metabolites can be measured after initiation of thiopurine drugs therapy to optimize dose. Use for individuals being considered for thiopurine therapy Must be performed before thiopurine therapy is initiated Disease Overview Can also detect rapid metabolizer phenotype Prevalence TPMT and NUDT15 3001535 Method: Polymerase Chain Very low/absent TPMT activity: ~3/1,000 individuals Reaction/Fluorescence Monitoring Intermediate TPMT activity: ~10% of Caucasian individuals Normal TPMT activity: ~90% of individuals Genotyping test to assess genetic risk for severe myelosuppression -
Identification and Analysis of Single-Nucleotide Polymorphisms in the Gemcitabine Pharmacologic Pathway
The Pharmacogenomics Journal (2004) 4, 307–314 & 2004 Nature Publishing Group All rights reserved 1470-269X/04 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway AK Fukunaga1 ABSTRACT 2 Significant variability in the antitumor efficacy and systemic toxicity of S Marsh gemcitabine has been observed in cancer patients. However, there are 1 DJ Murry currently no tools for prospective identification of patients at risk for TD Hurley3 untoward events. This study has identified and validated single-nucleotide HL McLeod2 polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes 1Department of Clinical Pharmacy and Pharmacy involved in gemcitabine metabolism. Pyrosequencing was utilized to Practice, Purdue University, W. Lafayette, IN, determine the SNP allele frequencies in genomic DNA from European and 2 USA; Departments of Medicine, Genetics, and African populations (n ¼ 190). A total of 14 genetic variants (including 12 Molecular Biology and Pharmacology, Washington University School of Medicine and SNPs) were identified in eight of the gemcitabine metabolic pathway genes. the Siteman Cancer Center, St Louis, MO, USA; The majority of the database variants were observed in population samples. 3Department of Biochemistry and Molecular Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that Biology, Indiana University School of Medicine, were found to be significantly different between the European and African Indianapolis, IN, USA populations (Po0.05). This study provides the first step to identify markers Correspondence: for predicting variability in gemcitabine response and toxicity. Dr HL McLeod, Washington University The Pharmacogenomics Journal (2004) 4, 307–314. -
Is TPMT Testing a Predictor of Duration of Use Or Long-Term Benefit of Thiopurine Agents? Shatoya R
Grand Valley State University ScholarWorks@GVSU Masters Theses Graduate Research and Creative Practice 12-2018 Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya R. Wilson Grand Valley State University Follow this and additional works at: https://scholarworks.gvsu.edu/theses Part of the Chemical and Pharmacologic Phenomena Commons Recommended Citation Wilson, Shatoya R., "Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents?" (2018). Masters Theses. 914. https://scholarworks.gvsu.edu/theses/914 This Thesis is brought to you for free and open access by the Graduate Research and Creative Practice at ScholarWorks@GVSU. It has been accepted for inclusion in Masters Theses by an authorized administrator of ScholarWorks@GVSU. For more information, please contact [email protected]. Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya Renee Wilson A Thesis Submitted to the Graduate Faculty of GRAND VALLEY STATE UNIVERSITY In Partial Fulfillment of the Requirements For the Degree of Master of Health Science Biomedical Science December 2018 Dedication This is dedicated to my sister and father, for their support and love. I thank you for listening to me when I needed to practice with or vent to someone. I would also like to dedicate this to my thesis committee, who helped me grow as a student and researcher. For your guidance, I am grateful. 3 Acknowledgements I would like to thank my thesis committee, Dr. Debra Burg, David Chesla, and Dr. John Capodilupo for their mentorship and guidance. -
Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 May 2019 doi:10.20944/preprints201905.0358.v1 Peer-reviewed version available at Int. J. Mol. Sci. 2019, 20, 3210; doi:10.3390/ijms20133210 1 of 39 1 Review 2 Recent topics on the mechanisms of 3 immunosuppressive therapy-related neurotoxicities 4 Wei Zhang 1, Nobuaki Egashira 1,2,* and Satohiro Masuda 1,2 5 1 Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 6 Kyushu University, Fukuoka 812-8582, Japan 7 2 Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan 8 * Correspondence: [email protected], Tel.: 81-92-642-5920 9 Abstract: Although transplantation procedures have been developed for patients with end-stagec 10 hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. 11 Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin 12 inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly 13 increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is 14 commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. 15 The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability 16 or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in 17 electrophysiological state. Other immunosuppressants can also induce neuropsychiatric 18 complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces 19 depression and headache; methotrexate affects the central nervous system; mouse monoclonal 20 immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and 21 patients using corticosteroids usually experience cognitive alteration. -
Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A
Case Report DOI: 10.4274/tjh.2013.0082 Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy Pediatrik Bir Lösemi Olgusunda Tiyopurin S-Metiltransferaz *3A/*3C Polimorfizmi ile İlişkili Ağır Miyelotoksisite-Steroid Tedavisinin Etkisi Burcu Fatma Belen1, Türkiz Gürsel1, Nalan Akyürek2, Meryem Albayrak3, Zühre Kaya1, Ülker Koçak1 1Gazi University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey 2Gazi University Faculty of Medicine, Department of Pathology, Ankara, Turkey 3Kırıkkale University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey Abstract: Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C. Key Words: Myelosuppression, Thiopurine S-methyl transferase, Acute leukemia Özet: Miyelosupresyon, -
Clinical Pharmacology of Antiмcancer Agents
A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved. -
Risk-Adapted Therapy for Young Children with Embryonal Brain Tumors, High-Grade Glioma, Choroid Plexus Carcinoma Or Ependymoma (Sjyc07)
SJCRH SJYC07 CTG# - NCT00602667 Initial version, dated: 7/25/2007, Resubmitted to CPSRMC 9/24/2007 and 10/6/2007 (IRB Approved: 11/09/2007) Activation Date: 11/27/2007 Amendment 1.0 dated January 23, 2008, submitted to CPSRMC: January 23, 2008, IRB Approval: March 10, 2008 Amendment 2.0 dated April 16, 2008, submitted to CPSRMC: April 16, 2008, (IRB Approval: May 13, 2008) Revision 2.1 dated April 29, 2009 (IRB Approved: April 30, 2009 ) Amendment 3.0 dated June 22, 2009, submitted to CPSRMC: June 22, 2009 (IRB Approved: July 14, 2009) Activated: August 11, 2009 Amendment 4.0 dated March 01, 2010 (IRB Approved: April 20, 2010) Activated: May 3, 2010 Amendment 5.0 dated July 19, 2010 (IRB Approved: Sept 17, 2010) Activated: September 24, 2010 Amendment 6.0 dated August 27, 2012 (IRB approved: September 24, 2012) Activated: October 18, 2012 Amendment 7.0 dated February 22, 2013 (IRB approved: March 13, 2013) Activated: April 4, 2013 Amendment 8.0 dated March 20, 2014. Resubmitted to IRB May 20, 2014 (IRB approved: May 22, 2014) Activated: May 30, 2014 Amendment 9.0 dated August 26, 2014. (IRB approved: October 14, 2014) Activated: November 4, 2014 Un-numbered revision dated March 22, 2018. (IRB approved: March 27, 2018) Un-numbered revision dated October 22, 2018 (IRB approved: 10-24-2018) RISK-ADAPTED THERAPY FOR YOUNG CHILDREN WITH EMBRYONAL BRAIN TUMORS, HIGH-GRADE GLIOMA, CHOROID PLEXUS CARCINOMA OR EPENDYMOMA (SJYC07) Principal Investigator Amar Gajjar, M.D. Division of Neuro-Oncology Department of Oncology Section Coordinators David Ellison, M.D., Ph.D. -
COVID-19: Viral–Host Interactome Analyzed by Network Based
Messina et al. J Transl Med (2020) 18:233 https://doi.org/10.1186/s12967-020-02405-w Journal of Translational Medicine RESEARCH Open Access COVID-19: viral–host interactome analyzed by network based-approach model to study pathogenesis of SARS-CoV-2 infection Francesco Messina1†, Emanuela Giombini1†, Chiara Agrati1, Francesco Vairo1, Tommaso Ascoli Bartoli1, Samir Al Moghazi1, Mauro Piacentini1,2, Franco Locatelli3, Gary Kobinger4, Markus Maeurer5,6, Alimuddin Zumla7,8, Maria R. Capobianchi1* , Francesco Nicola Lauria1†, Giuseppe Ippolito1† and COVID 19 INMI Network Medicine for IDs Study Group Abstract Background: Epidemiological, virological and pathogenetic characteristics of SARS-CoV-2 infection are under evaluation. A better understanding of the pathophysiology associated with COVID-19 is crucial to improve treatment modalities and to develop efective prevention strategies. Transcriptomic and proteomic data on the host response against SARS-CoV-2 still have anecdotic character; currently available data from other coronavirus infections are there- fore a key source of information. Methods: We investigated selected molecular aspects of three human coronavirus (HCoV) infections, namely SARS- CoV, MERS-CoV and HCoV-229E, through a network based-approach. A functional analysis of HCoV–host interactome was carried out in order to provide a theoretic host–pathogen interaction model for HCoV infections and in order to translate the results in prediction for SARS-CoV-2 pathogenesis. The 3D model of S-glycoprotein of SARS-CoV-2 was compared to the structure of the corresponding SARS-CoV, HCoV-229E and MERS-CoV S-glycoprotein. SARS-CoV, MERS-CoV, HCoV-229E and the host interactome were inferred through published protein–protein interactions (PPI) as well as gene co-expression, triggered by HCoV S-glycoprotein in host cells. -
Ingenuity Pathway Analysis of Human Facet Joint Tissues: Insight Into Facet Joint Osteoarthritis
EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 2997-3008, 2020 Ingenuity pathway analysis of human facet joint tissues: Insight into facet joint osteoarthritis CHU CHEN*, SHENGYU CUI*, WEIDONG LI, HURICHA JIN, JIANBO FAN, YUYU SUN and ZHIMING CUI Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China Received August 17, 2019; Accepted January 30, 2020 DOI: 10.3892/etm.2020.8555 Abstract. Facet joint osteoarthritis (FJOA) is a common the top 5 IPA networks (with a score >30). The present study degenerative joint disorder with high prevalence in the elderly. provides insight into the pathological processes of FJOA from FJOA causes lower back pain and lower extremity pain, and a genetic perspective and may thus benefit the clinical treat- thus severely impacts the quality of life of affected patients. ment of FJOA. Emerging studies have focused on the histomorphological and histomorphometric changes in FJOA. However, the dynamic Introduction genetic changes in FJOA have remained to be clearly deter- mined. In the present study, previously obtained RNA deep Facet joint osteoarthritis (FJOA) is a common degenerative sequencing data were subjected to an ingenuity pathway joint disorder that causes the degeneration and breakdown analysis (IPA) and canonical signaling pathways of differ- of cartilage and restricts the movement of joints (1). It has entially expressed genes (DEGs) in FJOA were studied. The been reported that lumbar FJOA occurs at high prevalence top 25 enriched canonical signaling pathways were identified and the presence of FJOA is highly associated with age (2,3). and canonical signaling pathways with high absolute values A community-based cross-sectional study indicated that of z-scores, specifically leukocyte extravasation signaling, in populations aged <50 years, the prevalence of FJOA was Tec kinase signaling and osteoarthritis pathway, were inves- <45%, while it was ~75% in populations aged >50 years (4). -
Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries Into Optimized Therapies Thai Hoa Tran1,2, Avanthi Tayi Shah3,4, and Mignon L
Published OnlineFirst June 9, 2017; DOI: 10.1158/1078-0432.CCR-16-0115 Review Clinical Cancer Research Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies Thai Hoa Tran1,2, Avanthi Tayi Shah3,4, and Mignon L. Loh3,4 Abstract Survival of children with cancers has dramatically improved aberrant activation of signaling pathways, and epigenetic modi- over the past several decades. This success has been achieved fiers that can be targeted by novel agents. Thus, the recently through improvement of combined modalities in treatment described genomic and epigenetic landscapes of many child- approaches, intensification of cytotoxic chemotherapy for hood cancers have expanded the paradigm of precision med- those with high-risk disease, and refinement of risk stratifica- icine in the hopes of improving outcomes while minimizing tion incorporating novel biologic markers in addition to tra- toxicities. In this review, we will discuss the biologic rationale ditional clinical and histologic features. Advances in cancer for molecularly targeted therapies in genomically defined sub- genomics have shed important mechanistic insights on disease sets of pediatric leukemias, solid tumors, and brain tumors. biology and have identified "driver" genomic alterations, Clin Cancer Res; 23(18); 5329–38. Ó2017 AACR. Introduction which may represent actionable therapeutic targets. In this review, we will discuss how genomic discoveries are being translated from Survival rates for children diagnosed with cancer have the bench into the clinic, resulting in the development of precision improved substantially over the past five decades. Today, long- medicine trials for specific subtypes of pediatric hematologic term survival is expected for approximately 80% of children malignancies, solid tumors, and brain tumors. -
Immunosuppressive Therapy DR
OCTOBER 2017 Immunosuppressive Therapy DR. ANDREW MACKIN BVSc BVMS MVS DVSc FANZCVSc DipACVIM Professor of Small Animal Internal Medicine Mississippi State University College of Veterinary Medicine, Starkville, MS A number of established immunosuppressive agents have been used in small animal medicine for many decades. Some have justifiably fallen out of favor whereas, for others, new and promising uses have been described in the recent veterinary literature. Established “old favorites” have included cyclophosphamide, chlorambucil, azathioprine, danazol and vincristine, although cyclophosphamide and danazol are rarely used as immunosuppressive agents these days. Several potent immunosuppressive drugs developed over the past few decades in human medicine have recently made the leap to our small animal patients, and our use of drugs such as cyclosporine, leflunomide and mycophenolate is growing. Cyclophosphamide Cyclophosphamide, a cell-cycle nonspecific nitrogen mustard derivative alkylating agent, was one of the first major chemotherapeutic agents approved by the FDA over 50 years ago, and has since become very well-established in human medicine as both an antineoplastic drug and as an immunosuppressive agent. Within a few years of FDA approval in the late 1950s, the use of cyclophosphamide for the prevention of transplant rejection in experimental models and for the treatment of both neoplasia and immune-mediated diseases was described in both dogs and cats. Cyclophosphamide has persisted to this day as one of the core drugs used in many small animal cancer chemotherapeutic protocols. In contrast, after many years as one of the most commonly immunosuppressive drugs utilized to treat immune-mediated diseases in cats and dogs, the use of cyclophosphamide as an immunosuppressive agent in small animal patients has in the past two decades essentially faded away. -
Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models Wendy L
Cancer Therapy: Clinical Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models Wendy L. Allen,1 Vicky M. Coyle,1Puthen V. Jithesh,1Irina Proutski,1Leanne Stevenson,1Cathy Fenning,1 Daniel B. Longley,1Richard H. Wilson,1Michael Gordon,2 Heinz-Josef Lenz,2 and Patrick G. Johnston1 Abstract Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time. Experimental Design: Data analysis identified a list of genes that were acutely altered in the parental cells following SN38 treatment as well as constitutively altered in the SN38-resistant cells. Results: Independent validation of 20% of these genes by quantitative reverse transcription- PCR revealed a strong correlation with the microarray results: Pearson’s correlation was 0.781 (r2 =0.61,P < 0.000001) for those genes that were acutely altered in the parental setting following SN38 treatment and 0.795 (r2 =0.63,P < 0.000002) for those genes that were constitutively altered in the SN38-resistant cells. We then assessed the ability of our in vitro- derived gene list to predict clinical response to 5-fluorouracil/irinotecan using pretreatment metastatic biopsies from responding and nonresponding colorectal cancer patients using both unsupervised and supervised approaches. When principal components analysis was used with our in vitro classifier gene list, a good separation between responding and nonresponding patients was obtained, with only one nonresponding and two responding patients separating with the incorrect groups.