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https://www.readbyqxmd.com/read/28525791/determination-of-thiopurine-s-methyltransferase-activity-by-hydrophilic-interaction-liquid-chromatography-hyphenated-with-mass-spectrometry
#1
Daniel Pecher, Svetlana Dokupilová, Zuzana Zelinková, Maikel Peppelenbosch, Veronika Mikušová, Peter Mikuš
Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines used in the therapy of inflammatory bowel diseases (IBD). In this work a new progressive method for the determination of TPMT activity in red blood cells lysates was developed. Analysis was carried out by means of hydrophilic interaction liquid chromatography (HILIC) hyphenated with mass spectrometry (MS). In comparison with reversed-phase high-performance liquid chromatography (RP-HPLC), that has been typically applied in determination of TPMT activity, the HILIC significantly improved the analytical signal provided by MS, shortened analysis time, and improved chromatographic resolution...
May 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28507448/thiopurine-s-methyltransferase-polymorphisms-in-acute-lymphoblastic-leukemia-inflammatory-bowel-disease-and-autoimmune-disorders-influence-on-treatment-response
#2
REVIEW
Rachid Abaji, Maja Krajinovic
The thiopurine S-methyltransferase (TPMT) gene encodes for the TPMT enzyme that plays a crucial role in the metabolism of thiopurine drugs. Genetic polymorphisms in this gene can affect the activity of the TPMT enzyme and have been correlated with variability in response to treatment with thiopurines. Advances in the pharmacogenetics of TPMT allowed the development of dosing recommendations and treatment strategies to optimize and individualize prescribing thiopurine in an attempt to enhance treatment efficacy while minimizing toxicity...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28500740/children-with-low-risk-acute-lymphoblastic-leukemia-are-at-highest-risk-of-second-cancers
#3
Stine N Nielsen, Frank Eriksson, Susanne Rosthoej, Mette K Andersen, Erik Forestier, Henrik Hasle, Lisa L Hjalgrim, Ann Aasberg, Jonas Abrahamsson, Mats Heyman, Ólafur G Jónsson, Kaie Pruunsild, Goda E Vaitkeviciené, Kim Vettenranta, Kjeld Schmiegelow
BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]...
May 13, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28498350/comparison-of-direct-sequencing-real-time-pcr-high-resolution-melt-pcr-hrm-and-pcr-restriction-fragment-length-polymorphism-pcr-rflp-analysis-for-genotyping-of-common-thiopurine-intolerant-variant-alleles-nudt15-c-415c-t-and-tpmt-c-719a-g-tpmt-3c
#4
Wai-Ying Fong, Chi-Chun Ho, Wing-Tat Poon
Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard...
May 12, 2017: Diagnostics
https://www.readbyqxmd.com/read/28476189/analysis-of-thiopurine-s-methyltransferase-deficient-alleles-in-acute-lymphoblastic-leukemia-patients-in-mexican-patients
#5
Silvia Jiménez-Morales, Mireya Ramírez-Florencio, Juan Manuel Mejía-Aranguré, Juan Carlos Núñez-Enríquez, Carolina Bekker-Mendez, José Luis Torres-Escalante, Janet Flores-Lujano, Elva Jiménez-Hernández, María Del Carmen Rodríguez-Zepeda, Yelda A Leal, Pablo Miguel González-Montalvo, Francisco Pantoja-Guillen, José Gabriel Peñaloza-Gonzalez, Erick Israel Gutiérrez-Juárez, Nora Nancy Núñez-Villegas, Maria Luisa Pérez-Saldivar, Francisco Xavier Guerra-Castillo, Luz Victoria Flores-Villegas, María Teresa Ramos-Cervantes, José Manuel Fragoso, María Guadalupe García-Escalante, Doris Del Carmen Pinto-Escalante, Julián Ramírez-Bello, Alfredo Hidalgo-Miranda
BACKGROUND AND AIMS: It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase (TPMT) mutant allele carriers are at high risk to develop severe and potentially fatal hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico...
November 2016: Archives of Medical Research
https://www.readbyqxmd.com/read/28462921/one-amino-acid-makes-a-difference-characterization-of-a-new-tpmt-allele-and-the-influence-of-sam-on-tpmt-stability
#6
Yan Ping Heidi Iu, Sara Helander, Anna Zimdahl Kahlin, Chun Wah Cheng, Chi Chung Shek, Moon Ho Leung, Björn Wallner, Lars-Göran Mårtensson, Malin Lindqvist Appell
Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A > C, named TPMT*41, together with the more common variant *3C c.719A > G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively...
May 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28445188/tpmt-comt-and-acyp2-genetic-variants-in-paediatric-cancer-patients-with-cisplatin-induced-ototoxicity
#7
Signe Thiesen, Peng Yin, Andrea L Jorgensen, Jieying E Zhang, Valentina Manzo, Laurence McEvoy, Christopher Barton, Susan Picton, Simon Bailey, Penelope Brock, Harish Vyas, David Walker, Guy Makin, Srinivas Bandi, Barry Pizer, Daniel B Hawcutt, Munir Pirmohamed
OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design...
June 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28406961/pharmacogenetic-variants-in-tpmt-alter-cellular-responses-to-cisplatin-in-inner-ear-cell-lines
#8
Amit P Bhavsar, Erandika P Gunaretnam, Yuling Li, Jafar S Hasbullah, Bruce C Carleton, Colin J D Ross
Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant...
2017: PloS One
https://www.readbyqxmd.com/read/28391009/the-promise-of-pharmacogenomics-in-reducing-toxicity-during-acute-lymphoblastic-leukemia-maintenance-treatment
#9
REVIEW
Shoshana Rudin, Marcus Marable, R Stephanie Huang
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity...
April 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/28346068/institutional-profile-university-of-florida-health-personalized-medicine-program
#10
Larisa H Cavallari, Kristin W Weitzel, Amanda R Elsey, Xinyue Liu, Scott A Mosley, Donald M Smith, Benjamin J Staley, Almut G Winterstein, Carol A Mathews, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo, Petr Starostik, Michael J Clare-Salzler, David R Nelson, Julie A Johnson
The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations...
April 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28321040/whole-exome-sequencing-detects-variants-of-genes-that-mediate-response-to-anticancer-drugs
#11
Sumiko Ohnami, Takeshi Nagashima, Kenichi Urakami, Yuji Shimoda, Fukumi Kamada, Junko Saito, Akane Naruoka, Masakuni Serizawa, Yoko Masuda, Shumpei Ohnami, Masatoshi Kusuhara, Ken Yamaguchi
Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023)...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28317081/pharmacogenetic-predictors-of-treatment-related-toxicity-among-children-with-acute-lymphoblastic-leukemia
#12
REVIEW
Rochelle R Maxwell, Peter D Cole
PURPOSE OF REVIEW: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). RECENT FINDINGS: Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities...
March 20, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28295989/pharmacokinetics-of-two-6-mercaptopurine-liquid-formulations-in-children-with-acute-lymphoblastic-leukemia
#13
Jaszianne A Tolbert, Shasha Bai, Susan M Abdel-Rahman, Keith J August, Scott J Weir, Gregory L Kearns, Kathleen A Neville
BACKGROUND: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. METHODS: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts...
March 10, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28277331/nudt15-genotype-distributions-in-the-korean-population
#14
Hyoung-Tae Kim, Rihwa Choi, Hong-Hee Won, Yon Ho Choe, Ben Kang, Kiwuk Lee, Hong Hoe Koo, Keon Hee Yoo, Young-Ho Kim, Soo-Youn Lee
Thiopurines have a narrow therapeutic range because of frequent toxicity (i.e. marrow suppression), which is only partly explained by TPMT genetic polymorphisms, especially within Asian populations. Recent studies have identified NUDT15 variation as another important factor affecting thiopurine metabolism. In this study, a total of four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal) were genotyped in 920 Korean individuals using direct sequencing of NUDT15 for the first time in a Korean population...
May 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28262261/pharmacogenetics-of-anti-cancer-drugs-state-of-the-art-and-implementation%C3%A2-%C3%A2-recommendations-of-the-french-national-network-of-pharmacogenetics
#15
Sylvie Quaranta, Fabienne Thomas
Individualized treatment is of special importance in oncology because the drugs used for chemotherapy have a very narrow therapeutic index. Pharmacogenetics may contribute substantially to clinical routine for optimizing cancer treatment to limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for some key applications: dihydropyrimidine dehydrogenase (DPYD) genotyping for fluoropyrimidine (5-fluorouracil, capecitabine), UDP glucuronosylstransferase (UGT1A1) for irinotecan and thiopurine S-methyltransferase (TPMT) for thiopurine drugs...
January 30, 2017: Thérapie
https://www.readbyqxmd.com/read/28212467/comparison-of-6-mercaptopurine-with-6-thioguanine-for-the-analysis-of-thiopurine-s-methyltransferase-activity-in-human-erythrocyte-by-lc-ms-ms
#16
Shenghui Mei, Xindi Li, Xiaoqing Gong, Xiaoyi Zhang, Xingang Li, Li Yang, Leting Zhu, Heng Zhou, Yonghong Liu, Anna Zhou, Xinghu Zhang, Zhigang Zhao
Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established...
February 17, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28172435/p154-complete-sequence-based-nudt15-and-tpmt-variants-for-predicting-thiopurine-induced-leukopenia-in-patients-with-crohn-s-disease
#17
T J Kim, E R Kim, S N Hong, D K Chang, Y-H Kim
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28153823/comparison-of-self-report-and-electronic-monitoring-of-6mp-intake-in-childhood-all-a-children-s-oncology-group-study
#18
Wendy Landier, Yanjun Chen, Lindsey Hageman, Heeyoung Kim, Bruce C Bostrom, Jacqueline N Casillas, David S Dickens, William E Evans, Kelly W Maloney, Leo Mascarenhas, A Kim Ritchey, Amanda M Termuhlen, William L Carroll, Mary V Relling, F Lennie Wong, Smita Bhatia
Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy...
April 6, 2017: Blood
https://www.readbyqxmd.com/read/28140508/identifying-unknown-enzyme-substrate-pairs-from-the-cellular-milieu-with-native-mass-spectrometry
#19
Kalli C Catcott, Jing Yan, Wanlu Qu, Vicki H Wysocki, Zhaohui Sunny Zhou
The enzyme-substrate complex is inherently transient, rendering its detection difficult. In our framework designed for bisubstrate systems-isotope-labeled, activity-based identification and tracking (IsoLAIT)-the common substrate, such as S-adenosyl-l-methionine (AdoMet) for methyltransferases, is replaced by an analogue (e.g., S-adenosyl-l-vinthionine) that, as a probe, creates a tightly bound [enzyme⋅substrate⋅probe] complex upon catalysis by thiopurine-S-methyltransferase (TPMT, EC 2.1.1.67). This persistent complex is then identified by native mass spectrometry from the cellular milieu without separation...
January 31, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28110955/determination-of-inosine-5-monophosphate-dehydrogenase-activity-in-red-blood-cells-of-thiopurine-treated-patients-using-hplc
#20
Audrey Beringer, Antony Citterio-Quentin, Rebeca Obenza Otero, Clémence Gustin, Rebecca Clarke, Jean-Paul Salvi, Roselyne Boulieu
Thiopurine drugs are commonly used in immune diseases and to a lesser extent, in transplant rejection prophylaxis: however interindividual variability in drug response and in the occurrence of adverse events is observed. Genetic variation in thiopurine S-methyltransferase (TPMT) doesn't completely explain the occurrence of all adverse events and drug response variability. The potential implication of other enzymes involved in thiopurine metabolism, such as ITPA, has been investigated over the last decade but little data is available on inosine 5'-monophosphate dehydrogenase (IMPDH) in patients treated with thiopurine drugs...
February 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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