Read by QxMD icon Read


Jing He, Ling Liu
As an important drug during maintenance treatment of acute lymphoblastic leukemia (ALL), 6-mercaptopurine (6-MP) has several side effects, including hepatotoxicity and bone marrow suppression. Since its tolerability varies from person to person, 6-MP treatment should be individualized. The deficiency of thiopurine methyltransferase (TPMT) enzyme activity is associated with 6-MP intolerance. There is a lower frequency of mutation in TPMT alleles among Asian patients. Recent studies have shown that in ALL patients with NUDT15 gene mutation, the maximum tolerated dose of 6-MP is lower than the conventional dose...
January 2019: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Petr Man, Milan Fábry, Irena Sieglová, Daniel Kavan, Petr Novák, Aleš Hnízda
Germline mutations in NUDT15 cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V18I mutants using thermolysin-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature...
January 9, 2019: Biochimica et biophysica acta. Proteins and proteomics
K Saida, K Kamei, M Ogura, S Matsumura, Y Kano, M Sato, A Andoh, K Ishikura
BACKGROUND: Azathioprine (AZA) is the drug recommended for the continuation of immunosuppressive treatment after renal transplant in women during pregnancy. CASE REPORT: A 37-year-old Japanese female developed agranulocytosis and severe alopecia after initiation of AZA (50 mg), used as an alternative to mycophenolate mofetil (MMF, 1000 mg) therapy in anticipation of a planned pregnancy. Within 4 days of the initiation of AZA therapy, the patient developed a high fever, leucopenia, and cranial alopecia...
December 2018: Transplantation Proceedings
Yulan Liu, Yang Meng, Lu Wang, Zhou Liu, Jiao Li, Weiguo Dong
Background and aim: Despite several studies being conducted to examine the associations between the NUDT15 R139C polymorphism and thiopurine-induced leukopenia in the Asian population, the results remain inconsistent. This meta-analysis determined the risk of thiopurine-induced leukopenia conferred by the NUDT15 R139C polymorphism. Materials and methods: All eligible studies published in English up to May 2018 were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library...
2018: OncoTargets and Therapy
Jun J Yang, Michelle Whirl-Carrillo, Stuart A Scott, Amy J Turner, Matthias Schwab, Yoichi Tanaka, Guilherme Suarez-Kurtz, Elke Schaeffeler, Teri E Klein, Neil A Miller, Andrea Gaedigk
No abstract text is available yet for this article.
December 4, 2018: Clinical Pharmacology and Therapeutics
Sanjeev Khera, Amita Trehan, Prateek Bhatia, Minu Singh, Deepak Bansal, Neelam Varma
PURPOSE: Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population. METHOD: In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing...
November 24, 2018: Cancer Chemotherapy and Pharmacology
Yan-Ting Lin, Wei Liu, Yun He, Yun-Li Wu, Wan-Nan Chen, Xin-Jian Lin, Xu Lin
BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis...
2018: Cellular Physiology and Biochemistry
Mary V Relling, Matthias Schwab, Michelle Whirl-Carrillo, Guilherme Suarez-Kurtz, Ching-Hon Pui, Charles M Stein, Ann M Moyer, William E Evans, Teri E Klein, Federico Guillermo Antillon-Klussmann, Kelly E Caudle, Motohiro Kato, Allen E J Yeoh, Kjeld Schmiegelow, Jun J Yang
TPMT activity exhibits a monogenic co-dominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmalogic effecs of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduces the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting dosesof azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes...
November 17, 2018: Clinical Pharmacology and Therapeutics
Sheng Zhang Lim, Eng Wee Chua
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds , are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear...
2018: Frontiers in Pharmacology
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
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
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
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
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
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
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
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
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
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)
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
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"