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Histone deacetylase

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https://www.readbyqxmd.com/read/28440559/a-phase-2-study-of-mocetinostat-a-histone-deacetylase-inhibitor-in-relapsed-or-refractory-lymphoma
#1
Connie L Batlevi, Michael Crump, Charalambos Andreadis, David Rizzieri, Sarit E Assouline, Susan Fox, Richard H C van der Jagt, Amanda Copeland, Diane Potvin, Richard Chao, Anas Younes
Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31)...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28440397/hypermethylation-of-mirna-589-promoter-leads-to-upregulation-of-hdac5-which-promotes-malignancy-in-non-small-cell-lung-cancer
#2
Changhong Liu, Desheng Lv, Mo Li, Xuefei Zhang, Ge Sun, Yu Bai, Dongmin Chang
Histone deacetylases (HDACs) are crucial for regulating chromatin activity, which plays a critical role in cell proliferation, differentiation, and apoptosis of various cancers. Therefore, HDAC inhibitors have been applied as effective therapeutic agents for cancer treatment. However, the expression profiles and regulatory mechanisms of histone deacetylases in lung cancer are not well understood. In the present study, aberrant high levels of HDAC5 were observed in non-small cell lung cancer (NSCLC) and further analysis indicated a negative relationship between HDAC5 and a tumor suppressor, miR‑589‑5p, in NSCLC specimens...
April 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28439875/epigenetic-repression-of-mir-375-is-the-dominant-mechanism-for-constitutive-activation-of-the-pdpk1-rps6ka3-signalling-axis-in-multiple-myeloma
#3
Shotaro Tatekawa, Yoshiaki Chinen, Masaki Ri, Tomoko Narita, Yuji Shimura, Yayoi Matsumura-Kimoto, Taku Tsukamoto, Tsutomu Kobayashi, Eri Kawata, Nobuhiko Uoshima, Tomohiko Taki, Masafumi Taniwaki, Hiroshi Handa, Shinsuke Iida, Junya Kuroda
Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28439316/epigenetic-assays-for-chemical-biology-and-drug-discovery
#4
REVIEW
Sheraz Gul
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28438776/the-immunoproteasome-is-induced-by-cytokines-and-regulates-apoptosis-in-human-islets
#5
Morten Lundh, Marco Bugliani, Tina Dahlby, Danny Hung-Chieh Chou, Bridget Wagner, Seyed Mojtaba Ghiasi, Vincenzo De Tata, Zhifei Chen, Marianne Nissen Lund, Michael J Davies, Piero Marchetti, Thomas Mandrup-Poulsen
In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. INS-1, INS-1E and human islets were exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules. Gene expression was assessed by microarray or quantitative PCR. Proteasome activities were analyzed using luminescent assays. Protein oxidation, Western blotting and electron microscopy were used to examine mechanisms underlying cytokine-induced apoptosis...
April 24, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28437180/a-novel-drug-induced-hybrid-electrospun-pcl-cell-derived-ecm-scaffold-for-liver-tissue-engineering
#6
Rhiannon Grant, David Hay, Anthony Callanan
Liver transplant is the only treatment option for patients with end-stage liver failure, however there are too few donor livers available for transplant. Whole organ tissue engineering presents a potential solution to the problem of rapidly escalating donor liver shortages world-wide. A major challenge for liver tissue engineers is the creation of a hepatocyte micro-environment; a niche in which liver cells can survive and function optimally. While polymers and decellularized tissues pose an attractive option for scaffold manufacturing, neither alone has thus far proved sufficient...
February 24, 2017: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/28436940/disruption-of-spatiotemporal-hypoxic-signaling-causes-congenital-heart-disease-in-mice
#7
Xuejun Yuan, Hui Qi, Xiang Li, Fan Wu, Jian Fang, Eva Bober, Gergana Dobreva, Yonggang Zhou, Thomas Braun
Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases are attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. Here, we have demonstrated that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing islet 1 (ISL1) in the secondary heart field (SHF) are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating NK2 homeobox 5 (Nkx2...
April 24, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28436938/geminin-facilitates-foxo3-deacetylation-to-promote-breast-cancer-cell-metastasis
#8
Lei Zhang, Meizhen Cai, Zhicheng Gong, Bingchang Zhang, Yuanpei Li, Li Guan, Xiaonan Hou, Qing Li, Gang Liu, Zengfu Xue, Muh-Hua Yang, Jing Ye, Y Eugene Chin, Han You
Geminin expression is essential for embryonic development and the maintenance of chromosomal integrity. In spite of this protective role, geminin is also frequently overexpressed in human cancers and the molecular mechanisms underlying its role in tumor progression remain unclear. The histone deacetylase HDAC3 modulates transcription factors to activate or suppress transcription. Little is known about how HDAC3 specifies substrates for modulation among highly homologous transcription factor family members. Here, we have demonstrated that geminin selectively couples the transcription factor forkhead box O3 (FoxO3) to HDAC3, thereby specifically facilitating FoxO3 deacetylation...
April 24, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28433417/mechanistic-insights-into-epigenetic-modulation-of-ethanol-consumption
#9
Igor Ponomarev, Claire E Stelly, Hitoshi Morikawa, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking...
March 12, 2017: Alcohol
https://www.readbyqxmd.com/read/28432707/suberoylanilide-hydroxamic-acid-a-novel-histone-deacetylase-inhibitor-improves-the-development-and-acetylation-level-of-miniature-porcine-handmade-cloning-embryos
#10
J M Sun, K Q Cui, Z P Li, X R Lu, Z F Xu, Q Y Liu, B Huang, D S Shi
Histone deacetylase inhibitors (HDACis) can change the histone acetylation and significantly enhance the developmental competence of the pre-implantation SCNT embryo. To select a proper histone deacetylase inhibitor to improve the success rate and potentially developmental ability of handmade cloning (HMC) embryos of miniature porcine, we compared the effect of two histone deacetylase inhibitors (SAHA vs. VPA) on HMC embryo development, their histone acetylation level and the expression level of relevant genes...
April 22, 2017: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/28432429/enhanced-production-of-recombinant-proteins-by-a-small-molecule-protein-synthesis-enhancer-in-combination-with-an-antioxidant-in-recombinant-chinese-hamster-ovary-cells
#11
Joseph Camire, Dongjoo Kim, Soonjo Kwon
The improvement in the production of recombinant proteins has been linked in a number of small molecules such as carboxylic acids to the inhibition of histone deacetylase, leading to increased transcription of genes. However, carboxylic acids such as pentanoic acid and butanoic acid have been shown to promote an apoptotic response in Chinese hamster ovary (CHO) cell culture. Supplementation of cultures with antioxidants has shown the ability to reduce the apoptotic response of carboxylic acid supplementation, leading to increased therapeutic protein production...
April 21, 2017: Bioprocess and Biosystems Engineering
https://www.readbyqxmd.com/read/28432333/metabolomic-and-proteomic-analysis-of-maize-embryonic-callus-induced-from-immature-embryo
#12
Fei Ge, Hongmei Hu, Xing Huang, Yanling Zhang, Yanli Wang, Zhaoling Li, Chaoying Zou, Huanwei Peng, Lujiang Li, Shibin Gao, Guangtang Pan, Yaou Shen
The low ratio of embryonic callus (EC) induction has inhibited the rapid development of maize genetic engineering. Still, little is known to explain the genotype-dependence of EC induction. Here, we performed a large-scale, quantitative analysis of the maize EC metabolome and proteome at three typical induction stages in two inbred lines with a range of EC induction capabilities. Comparison of the metabolomes and proteomes suggests that the differential molecular responses begin at an early stage of development and continue throughout the process of EC formation...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431263/epigenetic-therapy-and-chemosensitization-in-solid-malignancy
#13
REVIEW
Sean M Ronnekleiv-Kelly, Anup Sharma, Nita Ahuja
Epigenetic modifications result in dynamic shifts between transcriptionally active and suppressed states. The potentially reversible nature of epigenetic changes underlies the concept of epigenetic therapy, which serves to reprogram cancer cells as opposed to inducing cytotoxicity that occurs with standard chemotherapeutics. There are numerous enzymes involved in epigenetic changes and each can be potentially targetable. Although many investigations have evaluated the clinical potential of the various epigenetic therapies, currently only histone deacetylase inhibitors and DNA methyltransferase inhibitors are approved for use in specific hematologic malignancies...
April 8, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28429797/sirtuins-in-the-phylum-basidiomycota-a-role-in-virulence-in-cryptococcus-neoformans
#14
Samantha D M Arras, Jessica L Chitty, Maha S I Wizrah, Paige E Erpf, Benjamin L Schulz, Milos Tanurdzic, James A Fraser
Virulence of Cryptococcus neoformans is regulated by a range of transcription factors, and is also influenced by the acquisition of adaptive mutations during infection. Beyond the temporal regulation of virulence factor production by transcription factors and these permanent microevolutionary changes, heritable epigenetic modifications such as histone deacetylation may also play a role during infection. Here we describe the first comprehensive analysis of the sirtuin class of NAD+ dependent histone deacetylases in the phylum Basidiomycota, identifying five sirtuins encoded in the C...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429280/synergistic-anti-cancer-effects-of-epigenetic-drugs-on-medulloblastoma-cells
#15
Juan Yuan, Núria Llamas Luceño, Bjoern Sander, Monika M Golas
PURPOSE: Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastoma patients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastoma patients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain...
April 20, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28425856/apicidin-inhibited-proliferation-and-invasion-and-induced-apoptosis-via-mitochondrial-pathway-in-non-small-cell-lung-cancer-glc-82-cells
#16
Jianye Zhang, Zhenzhu Lai, Wenjing Huang, Huiping Ling, Minting Lin, Sili Tang, Yun Liu, Yiwen Tao
Apicidin, an inhibitor of histone deacetylase obtained from the mangrove endophytic fungi Fusarium sp., showed a wide range of antiproliferative activity against various cancer cell lines. Apicidin has also been reported to induce apotosis via Fas/Fas ligand. Yet few studies have focused on mitochondrial pathway for its anti-tumor activity. Here, we evaluated its involved mitochondrial mechanism against lung cancer GLC-82 cells. Its structure was elucidated by MS and NMR spectroscopic data, and comparison of those data with published data...
April 19, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28425177/design-and-synthesis-of-c3-substituted-%C3%AE-carboline-based-histone-deacetylase-inhibitors-with-potent-antitumor-activities
#17
Yong Ling, Jiao Feng, Lin Luo, Jing Guo, Yanfu Peng, Tingting Wang, Xiang Ge, Qibing Xu, Xinyang Wang, Hong Dai, Yanan Zhang
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low-micromolar range. In particular, the HDAC inhibition IC50 value of N-(2-(dimethylamino)ethyl)-N-(4-(hydroxylcarbamoyl)benzyl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (9 h) is five-fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat)...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28424407/the-expression-of-histone-deacetylase-hdac1-correlates-with-the-progression-and-prognosis-of-gastrointestinal-malignancy
#18
Lin-Lin Cao, Zhihong Yue, Lianhua Liu, Lin Pei, Yue Yin, Li Qin, Jie Zhao, Huixin Liu, Hui Wang, Mei Jia
Gastrointestinal malignancy is a severe public health threat worldwide, and survival for most types of gastrointestinal cancer is very poor. Therefore, finding better cancer biomarkers to diagnose gastrointestinal malignancy and predict patient survival is essential. HDAC1 has been reported to be closely associated with several types of cancer, but the precise role of HDAC1 in gastrointestinal cancer is not clear. Recently, quite a few studies have investigated the correlation between HDAC1 expression and clinical features or prognosis in multiple types of gastrointestinal malignancies, but the results were inconsistent...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424323/dosing-three-drug-combinations-that-include-targeted-anti-cancer-agents-analysis-of-37-763-patients
#19
Mina Nikanjam, Sariah Liu, Jincheng Yang, Razelle Kurzrock
BACKGROUND: Combining targeted and cytotoxic agents has the potential to improve efficacy and attenuate resistance for metastatic cancer. Information regarding safe starting doses for clinical trials of novel three-drug combinations is lacking. MATERIALS AND METHODS: Published phase I-III adult oncology clinical trials of three-drug combinations involving a targeted agent were identified by PubMed search (January 1, 2010 to December 31, 2013). A dose percentage was calculated to compare the dose used in combination to the single agent recommended dose: (U...
April 19, 2017: Oncologist
https://www.readbyqxmd.com/read/28421257/histone-deacetylase-inhibitors-reverse-age-related-increases-in-side-effects-of-haloperidol-in-mice
#20
Janitza L Montalvo-Ortiz, Daniel W Fisher, Guadalupe Rodríguez, Deyu Fang, John G Csernansky, Hongxin Dong
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects...
April 18, 2017: Psychopharmacology
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