Deepm5C: A deep-learning-based hybrid framework for identifying human RNA N5-methylcytosine sites using a stacking strategy

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Therapeutic effectiveness of a single exercise session combined with Walk Aide functional electrical stimulation in post-stroke patients:a crossover design study

A growing body of evidence has suggested that the imbalance of epigenetic markers and oxidative stress appears to be involved in the pathophysiology and progression of stroke. Thus, strategies that modulate these biomarkers might be considered targets for neuroprotection and novel therapeutic opportunities for these patients. Physical exercise has been reported to induce changes in these epigenetic markers and improve clinical outcomes in different populations. However, little is reported on this in post-stroke patients. The purpose of this study was to investigate the effect of a single exercise session with Walk Aide functional electrical stimulation(FES) on cognitive performance, clinical functional parameters, oxidative stress and epigenetic modulation in post-stroke individuals. In this crossover design study, 12 post-stroke individuals aged 54–72 years of either sexes were included and subjected to a single session of exercise(45 minutes) without Walk Aide functional electrical stimulation(EXE alone group), followed by another single session of exercise(45 minutes) with Walk Aide functional electrical stimulation(EXE + FES group). The clinical functional outcome measures, cognitive performance and blood collections for biomarker measurements were assessed pre-and post-intervention. After intervention, higher Berg Balance Scale scores were obtained in the EXE + FES group than in the EXE alone group. There was no significant difference in the Timed Up and Go test results post-intervention between EXE alone and EXE + FES groups. After intervention, a better cognitive performance was found in both groups compared with before the intervention. After intervention, the Timed Up and Go test scores were higher in the EXE + FES group than in the EXE alone group. In addition, the intervention induced lower levels of lipid peroxidation. After intervention, carbonyl level was lower, superoxide dismutase activity and superoxide dismutase/catalase activity ratio were higher in the EXE + FES group, compared with the EXE group alone. In each group, both histone deacetylase(HDAC2) and histone acetyltransferase activities were increased after intervention compared with before the intervention. These findings suggest that a single exercise session with Walk Aide FES is more effective on balance ability and cognitive performance compared with conventional exercise alone in post-stroke patients. This is likely to be related to the regulation of oxidative stress markers. The present study was approved by the Research Ethics Committee of the Methodist University Center-IPA(approval No. 2.423.376) on December 7, 2017 and registered in the Brazilian Registry of Clinical Trials—Re BEC(RBR-9 phj2 q) on February 11, 2019.     

Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma

The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.     

No clear survival benefit of azacitidine for lower‐risk myelodysplastic syndromes: A retrospective study of Nagasaki

The efficacy of azacitidine (AZA) on survival of lower risk (LR) ‐ myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long‐term survival benefit of AZA for patients with LR‐MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR‐MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis‐stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection‐related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients.     

TET1-CD对乳腺癌细胞MDA-MB-231 增殖和迁移的影响及其作用机制

[摘要] 目的：探讨TET1 催化结构域（TET1-CD）基因高表达对乳腺癌细胞MDA-MB-231 增殖、迁移的影响及其可能的作用机制。方法：慢病毒感染建立高表达TET1-CD的MDA-MB-231 细胞系，用qPCR检测细胞中TET1-CD mRNA的表达，Transwell实验和细胞划痕实验检测细胞的迁移能力，MTT 法和克隆形成实验检测细胞的增殖能力，WB实验检测MDA-MB-231 细胞上皮间质转化（EMT）途径相关蛋白E-cadherin、Vimentin、MMP2 以及Wnt、Hedgehog(HH)通路相关蛋白的表达水平。结果：过表达TET1-CD提高乳腺癌MDA-MB-231 细胞TET1-CD的表达水平（P<0.01），明显抑制MDA-MB-231 细胞的增殖和迁移能力（均P<0.01）。过表达TET1-CD 可使乳腺癌MDA-MB-231 细胞E-cadherin 表达上升，Vimentin、MMP2 表达下调（均P<0.05）；可使β-catenin、C-myc、CyclinD1、Gli1 蛋白表达水平降低（均P<0.05）。结论：过表达TET1-CD可能通过Wnt、HH信号通路抑制EMT途径进而抑制乳腺癌细胞MDA-MB-231 的增殖和迁移。     

Long noncoding RNA ANRIL promotes the malignant progression of cholangiocarcinoma by epigenetically repressing ERRFI1 expression

Long noncoding RNAs (lncRNAs) have recently been verified to have significant regulatory functions in many types of human cancers. The lncRNA ANRIL is transcribed from the INK4b‐ARF‐INK4a gene cluster in the opposite direction. Whether ANRIL can act as an oncogenic molecule in cholangiocarcinoma (CCA) remains unknown. Our data show that ANRIL knockdown greatly inhibited CCA cell proliferation and migration in vitro and in vivo. According to the results of RNA sequencing analysis, ANRIL knockdown dramatically altered target genes associated with the cell cycle, cell proliferation, and apoptosis. By binding to a component of the epigenetic modification complex enhancer of zeste homolog 2 (EZH2), ANRIL could maintain lysine residue 27 of histone 3 (H3K27me3) levels in the promoter of ERBB receptor feedback inhibitor 1 (ERRFI1), which is a tumor suppressor gene in CCA. In this way, ERRFI1 expression was suppressed in CCA cells. These data verified the key role of the epigenetic regulation of ANRIL in CCA oncogenesis and indicate its potential as a target for CCA intervention.     

The influence of epigenetics in relation to oral health

The immune response is influenced by genetic and epigenetic factors, as well as disease and environmental factors. The term ‘epigenetics’ describes changes in the genome that influence the gene expression without altering the DNA sequence. In contrast to genetic changes in the DNA, epigenetic changes are reversible and are influenced by environmental factors. The aim of this study is to review the literature on epigenetic modifications with respect to oral health and inflammatory conditions in the oral cavity and to discuss the potential use of this new research field for the dental hygienists' and/or dentists' clinical work. Relevant publications were identified using the PubMed database without limits. The searches were conducted during January to March 2012 and resulted in articles published between 1912 and 2012. Key factors such as environment, diet, smoking, bacteria and inflammation were identified to be relevant to oral health. The result of this review article shows that there is a void in the research on epigenetics in relation to oral health. Identification of epigenetic modifications correlating with oral health may not only present a link between the influence of genetics and that of the environment on oral diseases but also provide new treatment models and tools for the dental professionals.