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JOURNAL ARTICLE
Janakiraman V, Sudhan M, Khalaf F Alsharif, Ibrahim F Halawani, Shiek S S J Ahmed, Shankargouda Patil
BACKGROUND: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened...
August 9, 2023: Journal, Genetic Engineering & Biotechnology
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JOURNAL ARTICLE
Raffaella Franca, Gabriele Stocco, Valentina Kiren, Antimo Tessitore, Franca Fagioli, Paola Quarello, Nicoletta Bertorello, Carmelo Rizzari, Antonella Colombini, Laura Rachele Bettini, Franco Locatelli, Luciana Vinti, Katia Girardi, Daniela Silvestri, Maria Grazia Valsecchi, Giuliana Decorti, Marco Rabusin
In the maintenance phase of Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)- Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m2 /day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2,000-3,000 cells/μL. Pediatric patients with ALL (n = 290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; boys: 56...
August 7, 2023: Clinical Pharmacology and Therapeutics
#23
JOURNAL ARTICLE
Noriaki Yamashita, Masahiro Kawahara, Takayuki Imai, Goichi Tatsumi, Ai Asai-Nishishita, Akira Andoh
Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration...
July 24, 2023: Scientific Reports
#24
JOURNAL ARTICLE
Tyler Shugg, Reynold C Ly, Wilberforce Osei, Elizabeth J Rowe, Caitlin A Granfield, Ty C Lynnes, Elizabeth B Medeiros, Jennelle C Hodge, Amy M Breman, Bryan P Schneider, S Cenk Sahinalp, Ibrahim Numanagić, Benjamin A Salisbury, Steven M Bray, Ryan Ratcliff, Todd C Skaar
BACKGROUND: Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data have the potential to be repurposed to support clinical pharmacogenomics (PGx), current computational approaches have not been widely validated using clinical data. In this study, we assessed the accuracy of the Aldy computational method to extract PGx genotypes from WGS and WES data for 14 and 13 major pharmacogenes, respectively...
2023: Frontiers in Oncology
#25
JOURNAL ARTICLE
Shizuka Suzuki, Kan Uchiyama, Yutaro Motoi, Yuuki Yoshii, Yukari Inoue, Takahiro Kubota, Shunichi Odahara, Yuichiro Ohtaki, Shinichiro Takami, Zensho Ito, Nobuhiro Sato, Toshifumi Ohkusa, Shigeo Koido, Masayuki Saruta
BACKGROUND: Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. METHODS: To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i...
July 15, 2023: BMC Gastroenterology
#26
JOURNAL ARTICLE
Pan Li, Kang Chao, Zhanhua Hu, Lulu Qin, Ting Yang, Jing Mao, Xia Zhu, Pinjin Hu, Xueding Wang, Xiang Gao, Min Huang
INTRODUCTION: Thiopurines, azathiopurine (AZA) and mercaptopurine (6-MP) have been regularly used in the treatment of inflammatory bowel disease (IBD). Despite optimized dosage adjustment based on the NUDT15 genotypes, some patients still discontinue or change treatment regimens due to thiopurine-induced leukopenia. METHODS: We proposed a prospective observational study of lipidomics to reveal the lipids perturbations associated with thiopurine-induced leukopenia...
2023: Frontiers in Nutrition
#27
REVIEW
Anuraag Jena, Chhagan L Birda, Arup Choudhury, Vishal Sharma
BACKGROUND: Pretherapy assessment of specific genetic polymorphism (TPMT, NUDT15, FTO, RUNX1 etc) or enzyme levels (for TPMT) may help personalize the dose of thiopurines and avoid adverse effects. RESEARCH DESIGN AND METHODS: A systematic review of randomized controlled trials (RCTs) comparing personalized versus standard strategy for initial thiopurine dosing was performed. The electronic databases were searched on 27 September 2022. The outcomes were overall adverse effects, myelotoxicity, drug interruptions, and therapeutic efficacy with either strategy...
July 12, 2023: Expert Opinion on Drug Safety
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JOURNAL ARTICLE
Kelsey J Cook, Victoria Grusauskas, Lucy Gloe, Benjamin Q Duong, Renee C Gresh, E Anders Kolb, Manisha Bansal, Allison S Bechtel, Ramamoorthy Nagasubramanian, Susan M Kirwin, Kathryn V Blake, Nathan D Seligson
The risk of severe adverse events related to thiopurine therapy can be reduced by personalizing dosing based on TPMT and NUDT15 genetic polymorphisms. However, the optimal genetic testing platform has not yet been established. In this study, we report on the TPMT and NUDT15 genotypes and phenotypes generated from 320 patients from a multicenter pediatric healthcare system using both Sanger sequencing and polymerase chain reaction genotyping (hereafter: genotyping) methods to determine the appropriateness of genotyping in our patient population...
July 6, 2023: Clinical and Translational Science
#29
REVIEW
Devendra Desai, Anuraag Jena, Vishal Sharma, Toshifumi Hibi
INTRODUCTION: Thiopurine toxicity is related to genetic polymorphism. Thiopurine methyltransferase (TPMT) variants do not explain thiopurine toxicity in more than half of patients. Asians, despite the low prevalence of TPMT variants, are more susceptible to thiopurine toxicity. Since 2014, studies from many Asian countries have shown a strong association between nucleoside diphosphate-linked moiety X-type motif (NUDT) 15 polymorphism and thiopurine-induced myelotoxicity. AREAS COVERED: An English language literature search was performed for TPMT and NUDT15 genetic variants in inflammatory bowel disease and other diseases...
2023: Expert Review of Clinical Pharmacology
#30
REVIEW
Tracy Sandritter, Rachel Chevalier, Rebecca Abt, Valentina Shakhnovich
Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase ( TPMT ) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic testing has become more readily available for other genes relevant to drug dose individualization. Common medications prescribed by gastroenterologists for conditions other than inflammatory bowel disease now have actionable guidelines, which can improve medication efficacy and safety; however, a clear understanding of how to interpret the results remains a challenge for many clinicians, precluding wide implementation of genotype-guided dosing for drugs other than 6-mercaptopurine and azathioprine...
June 16, 2023: Pharmaceuticals
#31
JOURNAL ARTICLE
Natalie Yu, Danujan Sriranganathan, Gareth J Walker, Aleksejs Sazonovs, Helen Wilding, Christopher Roberts, Nicholas A Kennedy, Tariq Ahmad, Ray K Boyapati, Nik S Ding, Jonathan P Segal
BACKGROUND AND AIMS: Nudix hydrolase 15 (NUDT15) genetic variants confer an increased risk of thiopurine-induced leukopenia (TIL), however their global prevalence in Inflammatory Bowel Disease (IBD) patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants, were included...
June 22, 2023: Journal of Crohn's & Colitis
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JOURNAL ARTICLE
Yoichi Kakuta, Yoshitaka Kinouchi, Atsushi Masamune
Genetic analysis of inflammatory bowel disease has identified many disease susceptibility genes in a large number of cases, mainly in Europe and North America. However, because of the ethnic differences in genetic background, analysis in various ethnic groups is needed. Although genetic analysis in East Asia began at the same time as in the West, the total number of patients analyzed has remained limited in Asia. To address these issues, meta-analyses across East Asian countries are underway, and the genetic analysis of inflammatory bowel disease in East Asians is entering a new phase...
June 6, 2023: Journal of Gastroenterology and Hepatology
#33
JOURNAL ARTICLE
Awol Mekonnen Ali, Haileyesus Adam, Daniel Hailu, Ephrem Engidawork, Rawleigh Howe, Teferra Abula, Marieke J H Coenen
Introduction: Genetic variation in the thiopurine S-methyltransferase ( TPMT ) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA , TPMT , NUDT15 , XDH , and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia...
2023: Frontiers in Pharmacology
#34
JOURNAL ARTICLE
Aimeé Salas-Hernández, Macarena Galleguillos, Matías Carrasco, Andrés López-Cortés, María Ana Redal, Dora Fonseca-Mendoza, Patricia Esperón, Farith González-Martínez, Ismael Lares-Asseff, Alberto Lazarowski, Verónica Loera-Castañeda, Diadelis Remírez, Matías F Martínez, Rodrigo Vargas, Fabricio Rios-Santos, Antonio Macho, Juan P Cayún, Germán R Perez, Carolina Gutierrez, Leslie C Cerpa, Tamara Leiva, Susan Calfunao, Lesly Xajil, Christopher Sandoval, Marcelo Suárez, Ariana Gonzalez, Gabriela Echeverría-Garcés, Luis Sullón-Dextre, Eugenia Cordero-García, Alexis R Morales, Andrea Avendaño, Enrique Sánchez, Laura C Bastone, Cesar Lara, Patricia Zuluaga-Arias, Ana María Soler, Julio Da Luz, Gabriela Burgueño-Rodríguez, Marcelo Vital, Elizabeth Reyes-Reyes, Alexander Huaccha, Yeimy V Ariza, Naomi Tzul, Ana L Rendón, Roberto Serrano, Larissa Acosta, Angelo Motta-Pardo, Leonardo Beltrán-Angarita, Erika Brand, Miguel A Jiménez, Gladys Maribel Hidalgo-Lozada, Marina M J Romero-Prado, Karla Escobar-Castro, Mariel Umaña-Rivas, Juan D Vivas, Paola Lagos, Yineth Ballén Martínez, Sharleth Quesada, Camila Calfio, Maria L Arias, María A Lavanderos, Dante D Cáceres, Alberto Salazar-Granara, Nelson M Varela, Luis A Quiñones
Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC...
2023: Frontiers in Pharmacology
#35
JOURNAL ARTICLE
Pageneck Chikondowa, Derick Munkombwe, Zedias Chikwambi, Patience Kuona, Collen Masimirembwa
Background: 6-mercaptopurine usage is associated with myelotoxicity and increased risk in patients carrying metabolism-related genetic variations. This study aimed to determine the frequency of candidate gene polymorphisms and their association with 6-mercaptopurine intolerance. Methods: A total of 41 patients on acute lymphoblastic leukaemia treatment were genotyped for TPMT and NUDT15 (rs116855232) alleles, and their association with dose intensity was analyzed. Results: The defective TPMT*3C allele frequency was 9...
May 30, 2023: Pharmacogenomics
#36
Juan Gu, Yupei Lin, Yuhe Wang
Azathioprine is clinically used as an immunosuppressant for treating autoimmune diseases. However it has narrow therapeutic indices due to frequent myelosuppression. Polymorphic variants of genes coding for thiopurine S-methyltransferase ( TPMT ) and nucleoside diphosphate-linked moiety X motif 15 ( NUDT15 ) are critical determinants of AZA intolerance, and the differences in frequencies of the two genetic variants exist among people of different ethnicities. Most reports regarding NUDT15 variant, AZA-induced myelosuppression occurred in patients with inflammatory bowel disease and acute lymphoblastic leukemia...
2023: Frontiers in Pharmacology
#37
JOURNAL ARTICLE
Makoto Yamaguchi, Ken-Ichi Iwata, Yuto Fukuda, Kazunori Haruta, Takako Suzuki, Yuka Torii, Yoshinori Ito, Jun-Ichi Kawada
No abstract text is available yet for this article.
March 10, 2023: Pediatric Infectious Disease Journal
#38
JOURNAL ARTICLE
Elena Gómez-Rubio, Javier Garcia-Marin
NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to a poor prognosis in neoplastic and immunologic diseases treated with thioguanine drugs. Despite this, the role of NUDT15 in physiology and molecular biology is quite unclear, as is the mechanism of action of this enzyme...
March 12, 2023: Journal of Biomolecular Structure & Dynamics
#39
JOURNAL ARTICLE
Mai-Lan Nguyen, Anh Vu Hoang, Bich Tram Duong, Nguyen The Nguyen Phung
6-Mercaptopurine (6-MP) serves as the backbone of maintenance therapy in acute lymphoblastic leukemia. The nucleoside diphosphate-linked moiety X-type motif 15 genes ( NUDT15 ) affects the metabolism of 6-MP and thiopurine-related neutropenia in the Asian population. This study reports the influence of these variants on 6MP-induced neutropenia in children with acute lymphoblastic leukemia (ALL). A total of 102 children were enrolled in this retrospective cohort study. NUDT15 variants on exon 1 and exon 3 were identified by Sanger sequencing...
April 13, 2023: HGG advances
#40
JOURNAL ARTICLE
Tetsuichiro Isono, Daiki Hira, Yoshito Ikeda, Masahiro Kawahara, Satoshi Noda, Atsushi Nishida, Osamu Inatomi, Noriki Fujimoto, Akira Andoh, Tomohiro Terada, Shin-Ya Morita
While nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphism Arg139Cys (rs116855232) is known to be a risk factor for thiopurine-induced severe leukopenia, association with the NUDT15 gene polymorphism Arg139His (rs147390019) has not yet been clarified. In addition, the accuracy of TaqMan PCR to assess these two polymorphisms has not been investigated. In this study, we evaluated TaqMan PCR for detection of the NUDT15 single-nucleotide polymorphisms (SNPs) and examined the clinical impact of Arg139His on thiopurine-induced leukopenia...
2023: Biological & Pharmaceutical Bulletin
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