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https://www.readbyqxmd.com/read/30106365/neutropenia-related-to-an-azathioprine-metabolic-disorder-induced-by-an-inosine-triphosphate-pyrophosphohydrolase-itpa-gene-mutation-in-a-patient-with-pr3-anca-positive-microscopic-polyangiitis
#1
Kosuke Honda, Akimitsu Kobayashi, Takahito Niikura, Tsukasa Hasegawa, Zenya Saito, Shuji Ito, Tomoya Sasaki, Kazumasa Komine, Seita Ishizuka, Yutaro Motoi, Takahiro Kubota, Hiroyasu Yamamoto, Takashi Yokoo
A 68-year-old Japanese man was monitored for chronic kidney disease (CKD), with unknown primary disease starting in 2014. His serum creatinine (sCr) was stable at ~ 2.5 mg/dL for ~ 2 years. Two weeks before admission, he had bloody sputum, and sCr increased to 4.63 mg/dL. Soon after admission, the patient developed a high fever with pigment spots on the legs. A kidney biopsy was performed. The kidney specimens showed necrotizing and crescentic glomerulonephritis without granuloma formation. An additional blood-sampling test revealed high titers of PR3-ANCA, and we diagnosed PR3-ANCA-positive microscopic polyangiitis (MPA)...
August 14, 2018: Clinical Nephrology
https://www.readbyqxmd.com/read/30101994/severe-thiopurine-induced-leukocytopenia-and-hair-loss-in-japanese-patients-with-defective-nudt15-variant-retrospective-case-control-study
#2
Mari Kishibe, Hiroyoshi Nozaki, Mizue Fujii, Shin Iinuma, Sawa Ohtsubo, Satomi Igawa, Kyoko Kanno, Masaru Honma, Kan Kishibe, Kensaku Okamoto, Akemi Ishida-Yamamoto
Azathioprine (AZA)-metabolizing enzyme gene polymorphism is strongly related to thiopurine-induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA. Gene polymorphism of thiopurine-metabolizing enzymes NUDT15 R139C, ITPA 94C>A, TPMT*2, TPMT*3B and TPMT*3C was analyzed...
October 2018: Journal of Dermatology
https://www.readbyqxmd.com/read/30048756/diagnostic-accuracy-of-nudt15-gene-variants-for-thiopurine-induced-leukopenia-a-systematic-review-and-meta-analysis
#3
REVIEW
Sarah Cargnin, Armando A Genazzani, Pier Luigi Canonico, Salvatore Terrazzino
We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review...
September 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29967377/diplotype-analysis-of-nudt15-variants-and-6-mercaptopurine-sensitivity-in-pediatric-lymphoid-neoplasms
#4
Shinichi Tsujimoto, Tomoo Osumi, Meri Uchiyama, Ryota Shirai, Takaya Moriyama, Rina Nishii, Yuji Yamada, Ko Kudo, Masahiro Sekiguchi, Yuki Arakawa, Masanori Yoshida, Toru Uchiyama, Kiminori Terui, Shuichi Ito, Katsuyoshi Koh, Junko Takita, Etsuro Ito, Daisuke Tomizawa, Atsushi Manabe, Nobutaka Kiyokawa, Jun J Yang, Motohiro Kato
No abstract text is available yet for this article.
July 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29923122/nudt15-codon-139-is-the-best-pharmacogenetic-marker-for-predicting-thiopurine-induced-severe-adverse-events-in-japanese-patients-with-inflammatory-bowel-disease-a-multicenter-study
#5
Yoichi Kakuta, Yosuke Kawai, Daisuke Okamoto, Tetsuya Takagawa, Kentaro Ikeya, Hirotake Sakuraba, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masaru Shinozaki, Yoh Ishiguro, Shinta Mizuno, Masahiro Takahara, Shunichi Yanai, Ryota Hokari, Tomoo Nakagawa, Hiroshi Araki, Satoshi Motoya, Takeo Naito, Rintaro Moroi, Hisashi Shiga, Katsuya Endo, Taku Kobayashi, Makoto Naganuma, Sakiko Hiraoka, Takayuki Matsumoto, Shiro Nakamura, Hiroshi Nakase, Tadakazu Hisamatsu, Makoto Sasaki, Hiroyuki Hanai, Akira Andoh, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune, Yasuo Suzuki
BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs...
June 19, 2018: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29867468/nudt15-r139c-variants-increase-the-risk-of-azathioprine-induced-leukopenia-in-chinese-autoimmune-patients
#6
Xiang Fei, Qing Shu, Huaijun Zhu, Bingzhu Hua, Shiying Wang, Ling Guo, Yun Fang, Weihong Ge
The aim of this study was to investigate the influence of NUDT15 R139C , thiopurine S-methyltransferase ( TPMT ), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia ( p = 1.86 × 10-7 ; OR: 7.59; 95% CI: 3.16-18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia ( p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia ( p = 0...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29801578/the-pharmacogenetics-of-immune-modulating-therapy
#7
Ingolf Cascorbi
Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29720126/optimal-predictor-for-6-mercaptopurine-intolerance-in-chinese-children-with-acute-lymphoblastic-leukemia-nudt15-tpmt-or-itpa-genetic-variants
#8
Hong Zhou, Lei Li, Peng Yang, Lin Yang, Jin E Zheng, Ying Zhou, Yong Han
BACKGROUND: 6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients...
May 2, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29704867/azathioprine-induced-alopecia-and-leukopenia-associated-with-nudt15-polymorphisms
#9
LETTER
H Nomura, Y Kurihara, M Saito, A Fukushima, Y Shintani, R Shiiyama, S Toshima, A Kamata, J Yamagami, T Funakoshi, K Kameyama, M Amagai, A Kubo, N Umegaki-Arao
No abstract text is available yet for this article.
April 28, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29702976/nudt15-r139c-variation-increases-the-risk-of-azathioprine-induced-toxicity-in-chinese-subjects-case-report-and-literature-review
#10
Xiang Fei, Qing Shu, Bing-Zhu Hua, Shi-Ying Wang, Zhi-Yong Chen, Wei-Hong Ge, Yun Fang
INTRODUCTION: Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics...
April 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29572377/preclinical-evaluation-of-nudt15-guided-thiopurine-therapy-and-its-effects-on-toxicity-and-antileukemic-efficacy
#11
Rina Nishii, Takaya Moriyama, Laura J Janke, Wenjian Yang, Chase C Suiter, Ting-Nien Lin, Lie Li, Kentaro Kihira, Hidemi Toyoda, Ute Hofmann, Matthias Schwab, Masatoshi Takagi, Tomohiro Morio, Atsushi Manabe, Shirley Kham, Nan Jiang, Karen R Rabin, Motohiro Kato, Katsuyoshi Koh, Allen Eng-Juh Yeoh, Hiroki Hori, Jun J Yang
Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15- guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15 -/- mouse model to evaluate the effectiveness of this strategy in vivo...
May 31, 2018: Blood
https://www.readbyqxmd.com/read/29519865/combination-of-common-and-novel-rare-nudt15-variants-improves-predictive-sensitivity-of-thiopurine-induced-leukopenia-in-children-with-acute-lymphoblastic-leukemia
#12
LETTER
Yiping Zhu, Dandan Yin, Yali Su, Xuyang Xia, Takaya Moriyama, Rina Nishii, Fei Liao, Shouyue Zhang, Xia Guo, Qianqian Hou, Yuan Ai, Xueyan Zhou, Shuwen Sun, Duyu Zhang, Yan Zhang, Chao Lin, Yiqi Deng, Xiaoxi Lu, Yuelan Wang, Zhigui Ma, Heyao Wang, Bo Liu, Li Yang, Wei Zhang, Jun J Yang, Yang Shu, Ju Gao, Heng Xu
No abstract text is available yet for this article.
July 2018: Haematologica
https://www.readbyqxmd.com/read/29491687/comparison-of-tpmt-and-nudt15-polymorphisms-in-chinese-patients-with-inflammatory-bowel-disease
#13
COMPARATIVE STUDY
Hong-Hui Wang, Ying He, Hong-Xian Wang, Cheng-Ling Liao, Yu Peng, Li-Jian Tao, Wei Zhang, Hui-Xiang Yang
AIM: To observe gene polymorphisms of TPMT and NUDT15 , and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD). METHODS: This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital...
February 28, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29482072/the-roles-of-human-mth1-mth2-and-mth3-proteins-in-maintaining-genome-stability-under-oxidative-stress
#14
Kazunari Hashiguchi, Michio Hayashi, Mutsuo Sekiguchi, Keiko Umezu
The hydrolysis of nucleotides containing 8-oxo-7,8-dihydroguanine (8-oxoG) is important in the maintenance of genome stability. Human cells possess three types of proteins, MTH1 (NUDT1), MTH2 (NUDT15) and MTH3 (NUDT18), which have the potential to hydrolyze deoxyribonucleoside di- and triphosphates containing 8-oxoG to the monophosphate, the form of which is unusable for DNA synthesis. To elucidate the physiological roles of these enzymes, we constructed single knockout (KO) cell lines for each of the MTH1, MTH2 and MTH3 genes and MTH1 and MTH2-double KO cell lines from the human HeLa S3 line using CRISPR/Cas9...
March 2018: Mutation Research
https://www.readbyqxmd.com/read/29470173/preemptive-nudt15-genotyping-redefining-the-management-of-patients-with-thiopurine-induced-toxicity
#15
Swarup A V Shah, Minal U Paradkar, Devendra C Desai, Tester F Ashavaid
BACKGROUND: Thiopurine methyltransferase (TPMT) gene variants have achieved limited success in predicting the outcome of thiopurine therapy, which shows wide inter-individual variations. The literature indicates a strong association between the NUDT15 gene variant and thiopurine-induced toxicity in Asian patients. The present study intends to explore the role of the NUDT15 variant (C415T) in Indian patients on thiopurine therapy. METHODS: NUDT15 and TPMT genotyping were performed using amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) and the restriction fragment length polymorphism (RFLP) technique...
March 28, 2018: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29398872/influence-of-nudt15-variants-on-hematological-pictures-of-patients-with-inflammatory-bowel-disease-treated-with-thiopurines
#16
Yuichiro Kojima, Yosuke Hirotsu, Wataru Omata, Makoto Sugimori, Shinya Takaoka, Hiroshi Ashizawa, Keiko Nakagomi, Dai Yoshimura, Kenji Hosoda, Yoji Suzuki, Hitoshi Mochizuki, Masao Omata
AIM: The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines. METHODS: Ninety-six Japanese patients with IBD were enrolled...
January 28, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29210335/predictive-role-of-nudt15-variants-on-thiopurine-induced-myelotoxicity-in-asian-inflammatory-bowel-disease-patients
#17
Natalia Sutiman, Sylvia Chen, Khoon Lin Ling, Sai Wei Chuah, Wai Fook Leong, Vinayak Nadiger, Madeline Tjai, Chris San Choon Kong, Brian John Schwender, Webber Chan, Hang Hock Shim, Wee Chian Lim, Chiea Chuen Khor, Yin Bun Cheung, Balram Chowbay
BACKGROUND: Genetic variants of TPMT and NUDT15 have been reported to predict the inter-patient variability in response and toxicity profiles of patients receiving thiopurine therapy. However, the clinical utility of TPMT genotyping in guiding thiopurine doses has been questionable, in part due to underlying differences in the prevalence of TPMT variants in both Caucasian and Asian populations. Several NUDT15 variants have been associated with thiopurine-induced leukopenia, particularly in Asian cohorts...
January 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29206869/measurements-of-6-thioguanine-nucleotide-levels-with-tpmt-and-nudt15-genotyping-in-patients-with-crohn-s-disease
#18
Ji Hyeon Lee, Tae Jun Kim, Eun Ran Kim, Sung Noh Hong, Dong Kyung Chang, Li-Hwa Choi, Hye In Woo, Soo-Youn Lee, Young-Ho Kim
The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn's disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD...
2017: PloS One
https://www.readbyqxmd.com/read/29192347/pharmacogenetics-of-thiopurines-for-inflammatory-bowel-disease-in-east-asia-prospects-for-clinical-application-of-nudt15-genotyping
#19
REVIEW
Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations...
February 2018: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29071720/antituberculosis-drug-induced-adverse-events-in-the-liver-kidneys-and-blood-clinical-profiles-and-pharmacogenetic-predictors
#20
Xuejiao Hu, Mei Zhang, Hao Bai, Lijuan Wu, Yanqing Chen, Liu Ding, Zhenzhen Zhao, Wu Peng, Tangyuheng Liu, Jiajia Song, Yinyu Li, Xiaojun Lu, Xuerong Chen, Yanhong Zhou, Binwu Ying
Antituberculosis drug-induced adverse drug reactions (ATD-ADRs) are increasing globally, and it is key to identify candidate ATD-ADRs loci for clinical management. We prospectively enrolled 1,235 highly suspicious tuberculosis (TB) inpatients to investigate the profiles and genetic risk factors of ATD-ADRs in the liver, kidneys, and blood. Overall, 644 subjects were eligible and genotyped for seven polymorphisms in drug-metabolizing enzymes and transporter genes. Clinical follow-up and blood analysis were performed regularly...
August 2018: Clinical Pharmacology and Therapeutics
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