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https://www.readbyqxmd.com/read/29432124/-cdkn2a-b-t2d-gwas-risk-snps-impact-locus-gene-expression-and-proliferation-in-human-islets
#1
Yahui Kong, Rohit B Sharma, Socheata Ly, Rachel E Stamateris, William M Jesdale, Laura C Alonso
Genome-wide association studies link the CDKN2A/B locus with T2D risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14 , p15 , and p16, MTAP, and ANRIL , a lncRNA. The goal of this study was to determine whether CDKN2A/B T2D risk-SNPs impact locus gene expression, insulin secretion, or beta cell proliferation, in human islets. Islets from non-diabetic donors (n=95) were tested for SNP genotype ( rs10811661 , rs2383208 , rs564398 , rs10757283 ), gene expression ( p14 , p15 , p16 , MTAP , ANRIL , PCNA , KI67 , CCND2 ), insulin secretion (n=61) and beta cell proliferation (n=47)...
February 6, 2018: Diabetes
https://www.readbyqxmd.com/read/29398089/tissue-response-and-immunoexpression-of-interleukin-6-promoted-by-tricalcium-silicate-based-repair-materials-after-subcutaneous-implantation-in-rats
#2
Aline S Andrade, Guilherme F Silva, Josette Camilleri, Estela S Cerri, Juliane M Guerreiro-Tanomaru, Paulo S Cerri, Mário Tanomaru-Filho
INTRODUCTION: The aim of the present study was to evaluate the inflammatory response induced by experimental tricalcium silicate cement with 20% zirconium oxide (TSC) and MTA Plus (MTAP; Avalon Biomed Inc, Bradenton, FL) in rat subcutaneous tissues. METHODS: Polyethylene tubes were filled with TSC (n = 20) and MTAP (n = 20) and implanted in the dorsal subcutaneous tissues of 32 rats. Empty tubes were used as the control (control group [CG], n = 20). After 7, 15, 30, and 60 days, the tubes with connective tissue were removed, and the inflammatory cells and immunolabeled cells for interleukin 6 (IL-6) were counted...
February 2, 2018: Journal of Endodontics
https://www.readbyqxmd.com/read/29317335/integrated-case-control-and-somatic-germline-interaction-analyses-of-melanoma-susceptibility-genes
#3
Yao Yu, Hao Hu, Jiun-Sheng Chen, Fulan Hu, Jerry Fowler, Paul Scheet, Hua Zhao, Chad D Huff
While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2...
January 6, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29258562/leishmania-infantum-5-methylthioadenosine-phosphorylase-presents-relevant-structural-divergence-to-constitute-a-potential-drug-target
#4
Hela Abid, Emna Harigua-Souiai, Thouraya Mejri, Mourad Barhoumi, Ikram Guizani
BACKGROUND: The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach...
December 19, 2017: BMC Structural Biology
https://www.readbyqxmd.com/read/29243509/loss-of-mtap-expression-is-a-negative-prognostic-marker-in-ewing-sarcoma-family-of-tumors
#5
Lucas Faria Abrahao-Machado, Bruno Antunes, Renee Zon Filippi, Sahlua Volc, Erica Boldrini, Weder P Menezes, Rui M Reis, Olavo Pires de Camargo
AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival (OS)...
December 15, 2017: Biomarkers in Medicine
https://www.readbyqxmd.com/read/29100284/exosomes-containing-differential-expression-of-microrna-and-mrna-in-osteosarcoma-that-can-predict-response-to-chemotherapy
#6
Ji-Feng Xu, Ya-Ping Wang, Shui-Jun Zhang, Yu Chen, Hai-Feng Gu, Xiao-Fan Dou, Bing Xia, Qing Bi, Shun-Wu Fan
A major challenge in osteosarcoma (OS) is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent. We developed a profiling strategy for serum exosomal microRNAs and mRNAs in OS patients with differential chemotherapeutic responses. Twelve miRNAs were up regulated and 18 miRNAs were under regulated significantly in OS patient with poor chemotherapeutic response when compared with those in good chemotherapeutic response (p<0...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29053210/a-combination-of-mtap-and-bap1-immunohistochemistry-in-pleural-effusion-cytology-for-the-diagnosis-of-mesothelioma
#7
Yoshiaki Kinoshita, Tomoyuki Hida, Makoto Hamasaki, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Kunimitsu Kawahara, Kenzo Hiroshima, Yoshinao Oda, Kazuki Nabeshima
BACKGROUND: Homozygous deletion of 9p21 detected by fluorescence in situ hybridization (FISH) and loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC) are useful for the differentiation between malignant pleural mesothelioma (MPM) and reactive mesothelial hyperplasia. The authors previously described that IHC expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, was correlated with the deletion status of 9p21 FISH in MPM tissues...
October 20, 2017: Cancer
https://www.readbyqxmd.com/read/29022512/schistosoma-mansoni-purine-and-pyrimidine-biosynthesis-structures-and-kinetic-experiments-in-the-search-for-the-best-therapeutic-target
#8
Vitor Hugo Balasco Serrão, Humberto D'Muniz Pereira, Juliana Roberta Torini de Souza, Larissa Romanello
BACKGROUND: Schistosoma mansoni is the etiological agent of schistosomiasis, a debilitating treatment neglected tropical disease that affects approximately 218 million people worldwide. Despite its importance, the treatment of schistosomiasis relies on a single drug, praziquantel. Some reports on the resistance of S. mansoni to this drug have stimulated efforts to develop new drugs to treat this disease. S. mansoni possesses all the same pyrimidine pathways (de novo, salvage and thymidylate cycles) as those of its host...
October 11, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28988007/chromosome-copy-number-variation-in-telomerized-human-bone-marrow-stromal-cells-insights-for-monitoring-safe-ex-vivo-expansion-of-adult-stem-cells
#9
Jorge S Burns, Linda Harkness, Abdullah Aldahmash, Laurent Gautier, Moustapha Kassem
Adult human bone marrow stromal cells (hBMSC) cultured for cell therapy require evaluation of potency and stability for safe use. Chromosomal aberrations upsetting genomic integrity in such cells have been contrastingly described as "Limited" or "Significant". Previously reported stepwise acquisition of a spontaneous neoplastic phenotype during three-year continuous culture of telomerized cells (hBMSC-TERT20) didn't alter a diploid karyotype measured by spectral karyotype analysis (SKY). Such screening may not adequately monitor abnormal and potentially tumorigenic hBMSC in clinical scenarios...
September 25, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28880543/the-transition-state-structure-for-human-mat2a-from-isotope-effects
#10
Ross S Firestone, Vern L Schramm
Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S-adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anticancer target in tumor cells lacking expression of 5'-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP(-/-). The remainder can be rendered MTAP(-) through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A...
October 4, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28720843/clinical-study-of-genomic-drivers-in-pancreatic-ductal-adenocarcinoma
#11
Michael T Barrett, Ray Deiotte, Elizabeth Lenkiewicz, Smriti Malasi, Tara Holley, Lisa Evers, Richard G Posner, Timothy Jones, Haiyong Han, Mark Sausen, Victor E Velculescu, Jeffrey Drebin, Peter O'Dwyer, Gayle Jameson, Ramesh K Ramanathan, Daniel D Von Hoff
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples...
August 8, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28620131/exosomes-containing-differential-expression-of-microrna-and-mrna-in-osteosarcoma-that-can-predict-response-to-chemotherapy
#12
Ji-Feng Xu, Ya-Ping Wang, Shui-Jun Zhang, Yu Chen, Hai-Feng Gu, Xiao-Fan Dou, Bing Xia, Qing Bi, Shun-Wu Fan
A major challenge in osteosarcoma (OS) is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent. We developed a profiling strategy for serum exosomal microRNAs and mRNAs in OS patients with differential chemotherapeutic responses. Twelve miRNAs were up regulated and 18 miRNAs were under regulated significantly in OS patient with poor chemotherapeutic response when compared with those in good chemotherapeutic response (p<0...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28213009/immunohistochemical-detection-of-mtap-and-bap1-protein-loss-for-mesothelioma-diagnosis-comparison-with-9p21-fish-and-bap1-immunohistochemistry
#13
COMPARATIVE STUDY
Tomoyuki Hida, Makoto Hamasaki, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Kunimitsu Kawahara, Akinori Iwasaki, Tatsuro Okamoto, Yoshinao Oda, Hiroshi Honda, Kazuki Nabeshima
OBJECTIVES: Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16(INK4A) (p16) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique...
February 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28026167/heat-capacity-changes-for-transition-state-analogue-binding-and-catalysis-with-human-5-methylthioadenosine-phosphorylase
#14
Ross S Firestone, Scott A Cameron, Jerome M Karp, Vickery L Arcus, Vern L Schramm
Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of 5'-methylthioadenosine (MTA). Its action regulates cellular MTA and links polyamine synthesis to S-adenosylmethionine (AdoMet) salvage. Transition state analogues with picomolar dissociation constants bind to MTAP in an entropically driven process at physiological temperatures, suggesting increased hydrophobic character or dynamic structure for the complexes. Inhibitor binding exhibits a negative heat capacity change (-ΔCp), and thus the changes in enthalpy and entropy upon binding are strongly temperature-dependent...
February 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27994653/association-of-common-variants-in-mtap-with-susceptibility-and-overall-survival-of-osteosarcoma-a-two-stage-population-based-study-in-han-chinese
#15
Liqiang Zhi, Dan Liu, Stephen G Wu, Tianqing Li, Guanghui Zhao, Bo Zhao, Meng Li
Osteosarcoma (OS) is a common malignant tumor, which exists widely in the bone of children and adolescents, and genetic factors may influence its susceptibility. Recently, the gene MTAP has been reported to be associated with OS in a Caucasian population. To investigate the association of common variants in MTAP with OS risk in Han Chinese individuals, we designed a two-stage case-control study with 392 OS patients and 1,578 unrelated healthy controls of Han Chinese individuals. A total of 17 tagging single nucleotide polymorphisms (SNPs) were firstly genotyped in the discovery stage, and single-SNP association and haplotypic association analyses have been performed...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27960044/genetic-variants-at-9p21-3-are-associated-with-risk-of-esophageal-squamous-cell-carcinoma-in-a-chinese-population
#16
Xiaoming Lin, Caiwang Yan, Yong Gao, Jiangbo Du, Xun Zhu, Fei Yu, Tongtong Huang, Juncheng Dai, Hongxia Ma, Yue Jiang, Rong Yin, Zhibin Hu, Guangfu Jin, Lin Xu, Hongbing Shen
Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues...
February 2017: Cancer Science
https://www.readbyqxmd.com/read/27935959/crystal-structure-of-schistosoma-mansoni-adenosine-phosphorylase-5-methylthioadenosine-phosphorylase-and-its-importance-on-adenosine-salvage-pathway
#17
Juliana Roberta Torini, José Brandão-Neto, Ricardo DeMarco, Humberto D'Muniz Pereira
Schistosoma mansoni do not have de novo purine pathways and rely on purine salvage for their purine supply. It has been demonstrated that, unlike humans, the S. mansoni is able to produce adenine directly from adenosine, although the enzyme responsible for this activity was unknown. In the present work we show that S. mansoni 5´-deoxy-5´-methylthioadenosine phosphorylase (MTAP, E.C. 2.4.2.28) is capable of use adenosine as a substrate to the production of adenine. Through kinetics assays, we show that the Schistosoma mansoni MTAP (SmMTAP), unlike the mammalian MTAP, uses adenosine substrate with the same efficiency as MTA phosphorolysis, which suggests that this enzyme is part of the purine pathway salvage in S...
December 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/27929028/concordance-between-somatic-copy-number-loss-and-down-regulated-expression-a-pan-cancer-study-of-cancer-predisposition-genes
#18
Ran Wei, Ming Zhao, Chun-Hou Zheng, Min Zhao, Junfeng Xia
Cancer predisposition genes (CPGs) are a class of cancer genes in which germline variants lead to increased risk of cancer. Research has revealed that copy number variation (CNV) may be linked to cancer susceptibility in CPGs. In this pan-cancer analysis, we explored the relationship between somatic CNV and gene expression changes in CPGs. Based on curated 827 human CPGs from literature, we firstly identified 729 CPGs with precise CNV information from 5067 tumor samples using TCGA CNV data. Among them, 128 CPGs tended to have more frequent copy number losses (CNLs) compared with copy number gains (CNGs)...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27851804/experimentally-assessed-reactive-aggression-in-borderline-personality-disorder
#19
Olga Kogan-Goloborodko, Elisabeth Brügmann, Jonathan Repple, Ute Habel, Benjamin Clemens
Approximately 73% of patients suffering from Borderline personality disorder (BPD) exhibit aggressive behaviour, which severely hinders therapeutic work and clinical improvement. Because the underlying mechanisms of aggression in BPD are not yet completely understood, additional research in this domain has a high clinical and scientific relevance. We employed a modified version of the Taylor Aggression Paradigm (mTAP), in order to examine for the first time whether this task can be used to differentiate between BPD patients and healthy controls with regard to reactive aggression...
2016: PloS One
https://www.readbyqxmd.com/read/27779859/continuous-fluorescence-assays-for-reactions-involving-adenine
#20
Ross S Firestone, Scott A Cameron, Peter C Tyler, Rodrigo G Ducati, Adam Z Spitz, Vern L Schramm
5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5'-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5'-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product...
December 6, 2016: Analytical Chemistry
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