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https://www.readbyqxmd.com/read/29351371/implementation-of-standardized-clinical-processes-for-tpmt-testing-in-a-diverse-multidisciplinary-population-challenges-and-lessons-learned
#1
Kristin W Weitzel, D Max Smith, Amanda R Elsey, Benjamin Q Duong, Benjamin Burkley, Michael Clare-Salzler, Yan Gong, Tara A Higgins, Benjamin Kong, Taimour Langaee, Caitrin W McDonough, Benjamin J Staley, Teresa T Vo, Dyson T Wake, Larisa H Cavallari, Julie A Johnson
Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme)...
January 19, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29350448/clinical-and-genetic-associations-for-carboplatin-related-ototoxicity-in-children-treated-for-retinoblastoma-a-retrospective-noncomparative-single-institute-experience
#2
Sameh E Soliman, Crystal N D'Silva, Helen Dimaras, Irakli Dzneladze, Helen Chan, Brenda L Gallie
BACKGROUND: Children with retinoblastoma treated with carboplatin chemotherapy risk moderate to severe, irreversible hearing loss. Based on published evidence, we hypothesized that ototoxicity risk is associated with clinical parameters and variants in candidate genes in drug metabolism pathways (methyltransferases [thiopurine S-methyltransferase, TPMT] and [catechol-O-methyltransferase, COMT], and drug transporter ABCC3). PROCEDURE: We retrospectively reviewed clinical records of patients with retinoblastoma treated with carboplatin chemotherapy regarding age (at diagnosis and chemotherapy initiation), chemotherapy sessions (cycles number, drug doses, and cumulative carboplatin dose), and hearing loss (defined as ototoxicity ≥grade 2 by at least one classification system)...
January 19, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29349573/mesencephalic-astrocyte-derived-neurotrophic-factor-manf-elevates-stimulus-evoked-release-of-dopamine-in-freely-moving-rats
#3
Juho-Matti Renko, Susanne Bäck, Merja H Voutilainen, T Petteri Piepponen, Ilkka Reenilä, Mart Saarma, Raimo K Tuominen
Neurotrophic factors (NTFs) hold potential as disease-modifying therapies for neurodegenerative disorders like Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown neuroprotective and restorative effects on nigral dopaminergic neurons in various animal models of Parkinson's disease. To date, however, their effects on brain neurochemistry have not been compared using in vivo microdialysis...
January 18, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29348866/protein-methyltransferases-and-demethylases-dictate-cd8-t-cell-exclusion-in-squamous-cell-carcinoma-of-the-head-and-neck
#4
Theodore Vougiouklakis, Riyue Bao, Yusuke Nakamura, Vassiliki Saloura
A subset of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) benefit from pembrolizumab and nivolumab, but the majority of patients do not probably due to lack of activated cytotoxic CD8+ T-cells in their tumor tissues. Herein, we aim to investigate whether specific protein methyltransferases (PMTs) and demethylases (PDMTs) could play any roles in the CD8+ T-cell exclusion process in HPV-negative SCCHN. RNA sequencing data from the TCGA database were interrogated for HPV-negative SCCHN patients using a 10-gene chemokine signature that classifies SCCHN tissues into CD8+ T-cell inflamed and non-CD8+ T-cell inflamed phenotypes...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348610/the-histone-methyltransferase-dot1l-inhibits-osteoclastogenesis-and-protects-against-osteoporosis
#5
Yanpan Gao, Wei Ge
Osteoclasts are absorptive cells that play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role of epigenetic regulation in osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation (H3K79me), during osteoclast formation. Using RANKL-induced RAW264.7 macrophage cells as an osteoclast differentiation model, we found that DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348130/setd1a-protects-hscs-from-activation-induced-functional-decline-in-vivo
#6
Kathrin Arndt, Andrea Kranz, Juliane Fohgrub, Adrien Jolly, Anita S Bledau, Michela Di Virgilio, Mathias Lesche, Andreas Dahl, Thomas Höfer, A Francis Stewart, Claudia Waskow
The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT)-HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation...
January 18, 2018: Blood
https://www.readbyqxmd.com/read/29346752/epitranscriptomic-m6a-regulation-of-axon-regeneration-in-the-adult-mammalian-nervous-system
#7
Yi-Lan Weng, Xu Wang, Ran An, Jessica Cassin, Caroline Vissers, Yuanyuan Liu, Yajing Liu, Tianlei Xu, Xinyuan Wang, Samuel Zheng Hao Wong, Jessica Joseph, Louis C Dore, Qiang Dong, Wei Zheng, Peng Jin, Hao Wu, Bin Shen, Xiaoxi Zhuang, Chuan He, Kai Liu, Hongjun Song, Guo-Li Ming
N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury...
January 17, 2018: Neuron
https://www.readbyqxmd.com/read/29346429/the-farnesoid-x-receptor-agonist-obeticholic-acid-upregulates-biliary-excretion-of-asymmetric-dimethylarginine-via-mate-1-during-hepatic-ischemia-reperfusion-injury
#8
Andrea Ferrigno, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Luciano Adorini, Plinio Richelmi, Mariapia Vairetti
BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated...
2018: PloS One
https://www.readbyqxmd.com/read/29345285/the-epitranscriptome-m6a-writer-mettl3-promotes-chemo-and-radioresistance-in-pancreatic-cancer-cells
#9
Kosuke Taketo, Masamitsu Konno, Ayumu Asai, Jun Koseki, Masayasu Toratani, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii, Kazuhiko Ogawa
N6-methyladenosine (m6A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m6A epitranscriptomics, indicating its crucial roles in the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m6A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m6A is significant for each of the numerous genes remain unclear...
February 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29345269/tributyltin-induces-epigenetic-changes-and-decreases-the-expression-of-nuclear-respiratory-factor-1
#10
Saki Hanaoka, Keishi Ishida, Saki Tanaka, Shuichiro Sakamoto, Katsuhiro Okuda, Seigo Sanoh, Shigeru Ohta, Yaichiro Kotake
Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells. First, we found that exposure to 300 nM TBT decreases NRF-1 expression...
January 18, 2018: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/29344904/mgmt-assessment-in-pituitary-adenomas-comparison-of-different-immunohistochemistry-fixation-chemicals
#11
Alexander S G Micko, Romana Höftberger, Adelheid Wöhrer, Matthias Millesi, Engelbert Knosp, Stefan Wolfsberger
PURPOSE: Despite the established role of O6-methyl-guanine-DNA methyltransferase (MGMT) as a marker for temozolomide response, consensus of the most reliable method to assess MGMT expression in pituitary adenomas is still missing. Currently, immunohistochemistry (IHC) assessment of formaldehyde fixed tissue samples is most widely used in a semiquantitative description. As formaldehyde fails to completely preserve nucleic acids, RCL2, an alcohol-based formaldehyde-free fixative, has been proposed as a more reliable alternative in terms of cell stability...
January 17, 2018: Pituitary
https://www.readbyqxmd.com/read/29344279/positive-expression-of-smyd2-is-associated-with-poor-prognosis-in-patients-with-primary-hepatocellular-carcinoma
#12
Shan-Ru Zuo, Xiao-Cong Zuo, Yang He, Wei-Jin Fang, Chun-Jiang Wang, Heng Zou, Pan Chen, Ling-Fei Huang, Li-Hua Huang, Hong Xiang, Shi-Kun Liu
Purpose: SET and MYND domain-containing protein2 (SMYD2), a histone lysine methyltransferases, is a candidate human oncogene in multiple tumors. However, the expression dynamics of SMYD2 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. Methods: The SMYD2 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) in HCC tissues and matched adjacent non-tumorous tissues. SMYD2 was silenced in HCC cell lines to determine its role in tumor proliferation and cell cycle progression, and the possible mechanism...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29344166/identification-and-functional-analysis-of-risk-related-micrornas-for-the-prognosis-of-patients-with-bladder-urothelial-carcinoma
#13
Ji Gao, Hongyan Li, Lei Liu, Lide Song, Yanting Lv, Yuping Han
The aim of the present study was to investigate risk-related microRNAs (miRs) for bladder urothelial carcinoma (BUC) prognosis. Clinical and microRNA expression data downloaded from the Cancer Genome Atlas were utilized for survival analysis. Risk factor estimation was performed using Cox's proportional regression analysis. A microRNA-regulated target gene network was constructed and presented using Cytoscape. In addition, the Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, followed by protein-protein interaction (PPI) network analysis...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29343972/targeting-histone-methyltransferase-and-demethylase-in-acute-myeloid-leukemia-therapy
#14
REVIEW
Germana Castelli, Elvira Pelosi, Ugo Testa
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29343685/the-protective-role-of-dot1l-in-uv-induced-melanomagenesis
#15
Bo Zhu, Shuyang Chen, Hongshen Wang, Chengqian Yin, Changpeng Han, Cong Peng, Zhaoqian Liu, Lixin Wan, Xiaoyang Zhang, Jie Zhang, Christine G Lian, Peilin Ma, Zhi-Xiang Xu, Sharon Prince, Tao Wang, Xiumei Gao, Yujiang Shi, Dali Liu, Min Liu, Wenyi Wei, Zhi Wei, Jingxuan Pan, Yongjun Wang, Zhenyu Xuan, Jay Hess, Nicholas K Hayward, Colin R Goding, Xiang Chen, Jun Zhou, Rutao Cui
The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29343074/understanding-the-influence-of-antipsychotic-drugs-on-global-methylation-events-and-its-relevance-in-treatment-response
#16
Babu Swathy, Koramannil R Saradalekshmi, Indu V Nair, Chandrasekharan Nair, Moinak Banerjee
AIM: The present study intends to evaluate whether antipsychotic drugs can modulate the host epigenome and if so whether drug-induced epigenetic modulation can explain the heterogeneity in drug response. METHODS: Present study was conducted in in vitro cells and significance of these in vitro observations was further evaluated in a clinical setting, between drug responsive and nonresponsive schizophrenia patients. A number of DNA modifications were assessed at global level using 5-methylcytosine, 5-hydroxymethylcytosine and 5-formylcytosine followed by evaluating the expression of epigenetic modifier genes and their crosstalk with miRNAs...
January 18, 2018: Epigenomics
https://www.readbyqxmd.com/read/29342140/atomic-structure-of-the-eukaryotic-intramembrane-ras-methyltransferase-icmt
#17
Melinda M Diver, Leanne Pedi, Akiko Koide, Shohei Koide, Stephen B Long
The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29341603/pokmt1-from-the-polyketomycin-biosynthetic-machinery-of-streptomyces-diastatochromogenes-t%C3%A3-6028-belongs-to-the-emerging-family-of-c-methyltransferases-that-act-on-coa-activated-aromatic-substrates
#18
Xun Guo, Ivana Crnovcic, Chin-Yuan Chang, Jun Luo, Jeremy R Lohman, Monica Papinski, Andreas Bechthold, Geoffrey P Horsman, Ben Shen
Recent biochemical characterizations of the MdpB2 CoA ligase and MdpB1 C-methyltransferase (C-MT) from the maduropeptin (MDP, 2) biosynthetic machinery revealed unusual pathway logic involving C-methylation occurring on a CoA-activated aromatic substrate. Here we confirmed this pathway logic for the biosynthesis of polyketomycin (POK, 3). Biochemical characterization unambiguously established that PokM3 and PokMT1 catalyze the sequential conversion of 6-methylsalicylic acid (6-MSA, 4) to form 3,6-dimethylsalicylyl-CoA (3,6-DMSA-CoA, 6), which serves as the direct precursor for the 3,6-dimethylsalicylic acid (3,6-DMSA) moiety in the biosynthesis of 3...
January 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29340103/anti-neoplastic-drugs-increase-caveolin-1-dependent-migration-invasion-and-metastasis-of-cancer-cells
#19
Natalia I Díaz-Valdivia, Claudia C Calderón, Jorge E Díaz, Lorena Lobos-González, Hugo Sepulveda, Rina J Ortíz, Samuel Martinez, Veronica Silva, Horacio J Maldonado, Patricio Silva, Sergio Wehinger, Verónica A Burzio, Vicente A Torres, Martín Montecino, Lisette Leyton, Andrew F G Quest
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339748/dot1-regulates-nucleosome-dynamics-by-its-inherent-histone-chaperone-activity-in-yeast
#20
Soyun Lee, Seunghee Oh, Kwiwan Jeong, Hyelim Jo, Yoonjung Choi, Hogyu David Seo, Minhoo Kim, Joonho Choe, Chang Seob Kwon, Daeyoup Lee
Dot1 (disruptor of telomeric silencing-1, DOT1L in humans) is the only known enzyme responsible for histone H3 lysine 79 methylation (H3K79me) and is evolutionarily conserved in most eukaryotes. Yeast Dot1p lacks a SET domain and does not methylate free histones and thus may have different actions with respect to other histone methyltransferases. Here we show that Dot1p displays histone chaperone activity and regulates nucleosome dynamics via histone exchange in yeast. We show that a methylation-independent function of Dot1p is required for the cryptic transcription within transcribed regions seen following disruption of the Set2-Rpd3S pathway...
January 16, 2018: Nature Communications
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