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Hepatocellular carcinoma (HCC) is the most common liver malignancy that can be developed from hepatitis B and cirrhosis. Many pathophysiological alterations, including hepatitis B virus (HBV) DNA integration, oxidative stress, cytokine release, telomerase homeostasis, mitochondrial damage, epigenetic modification, and tumor microenvironment, are involved in the biological process from hepatitis B to cirrhosis and HCC. N6-methyladenosine (m6A), as an epitranscriptomic modification of RNAs, can regulate the stability, splicing, degradation, transcription, and translation of downstream target RNAs in HBV and liver cancer cells. m6A regulators (writers, erasers, and readers) play an important role in the pathogenesis of HBV-associated HCC by regulating cell proliferation, apoptosis, migration, autophagy, differentiation, inflammation, angiogenesis, and tumor microenvironment. This review summarizes the current progress of m6A methylation in the molecular mechanisms, biological functions, and potential clinical implications of HBV-associated HCC.

Background Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. Methods HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APCmin/+ and APCmin/+ HSF1+/−mice. Results HSF1 expression and activity were reduced after the inhibition of WNT/β-catenin signaling by pyrvinium or β-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or β-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with β-catenin expression in cell lines and primary tissues. After β-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3′-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued β-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APCmin/+ mice when HSF1 was genetically knocked-out or chemically inhibited. Conclusions β-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for β-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of β-catenin-driven cancers.

Objective. To investigate the effect of sevoflurane on the monophasic action potentials (MAPs) in isolated rat hearts after ischemia-reperfusion. Methods. Twenty-four healthy SD male rats, weighing 280–320 g, were randomly divided into three groups after successful preparation of a Langendorff isolated heart perfusion model with a stabilization period perfusion of 15 min with Krebs–Henseleit (K–H) fluid (n = 8): the control group (group A, continuously perfused with K–H fluid for 105 min), the ischemia-reperfusion group (group B, continuously perfused with K–H fluid for 15 min, and then exposed to 60 min of global ischemia induced by Thomas solution followed by 30 min of reperfusion), and the sevoflurane group (group C, K–H fluid contained 1.0 MAC sevoflurane, and other procedures were same as in group B). Heart rate (HR) and MAPs including time course (MAPD50 or MAPD90) of the epicardium (Epi) and endocardium (Endo) were recorded at the time of balance perfusion for 15 min (T0), continuous perfusion for 15 min (T1), reperfusion for 15 min/continuous perfusion for 105 min (T2), and reperfusion for 30 min/continuous perfusion for 120 min (T3), and the transmural dispersion of repolarization (TDR) was calculated. The incidence of arrhythmia, time for restoration of spontaneous heart beat, and duration of arrhythmia were recorded during the period of reperfusion. Results. HR in group B and group C was lower at T2 and T3 than that in group A, while that in group B was significantly lower than that in group A at T2 and T3, and HR in group C was higher than that in group B at T2 and T3 (P<0.05). There was no difference of TDR in each group at T0 and T1 (P>0.05), while TDR in group B was increased at T2 and T3 compared with that in group C and group A (P<0.05). TDR in group C was decreased compared with that in group B at T2 and T3 (P<0.05), while there was no such difference between group C and group A (P>0.05). The time for restoration of spontaneous heart beat and duration of arrhythmia in group C were shorter than those in group B (P<0.05), while cardiac arrhythmia scores in group B were higher than those in group C (P<0.05). There was no difference of MAPD50 in each group (P>0.05). The MAPD90 in group B was much longer than that in other groups at T2 and T3 (P<0.05), while there was no such difference between group C and group A (P>0.05). The prolonged MAPD90 at T2 and T3 in group B strikingly differed from that at T0 and T1 (P<0.05). Nevertheless, there was no such difference in other groups at different time points (P>0.05). Conclusion. Sevoflurane alleviates reperfusion arrhythmia induced by myocardial ischemia-reperfusion through the shortening of MPAD90 in isolated rat hearts.

Background: The association between long-term glycemic variability and diabetic retinopathy (DR) among patients with type 2 diabetes has not been clarified yet. Objective: The aim of this study was to investigate the association of visit-to-visit variability of hemoglobin A1c (HbA1c) and glycated albumin (GA) with the risk of DR in patients with type 2 diabetes. Design: A prospective cohort study of 315 patients (191 males and 124 females) with at least 3 measurements of HbA1c and GA prior to baseline was performed. Different GA and HbA1c variability markers were calculated, including coefficient of variation (CV), variability independent of the mean (VIM), and the average real variability (ARV). Cox proportional hazard regression models were used to explore the association between visit-to-visit HbA1c and GA variability and the risk of DR. Results: During a mean follow-up period of 3.42 years, 81 participants developed incident DR. Multivariate-adjusted hazard ratios (HRs) of DR across tertiles of GA-CV values were 1.00, 1.42, and 2.12 (P for trend=0.027), respectively. When we used GA-VIM and GA-ARV values as exposures, similar positive associations with the risk of DR were found. Multivariable-adjusted HRs of DR associated with each unit increase in GA-CV, GA-VIM, and GA-ARV were 1.05 (95% CI 1.02-1.09), 1.69 (95% CI 1.24-2.32), and 1.13 (95%CI 1.04-1.23), respectively. However, there was no significant association between visit-to-visit variability of HbA1c and the risk of DR after multivariate adjustment. Conclusion: The visit-to-visit variability of GA can predict the risk of incident DR in patients with type 2 diabetes, and the prediction ability is independent of the average HbA1c levels. Disclosure J. Zhou: None. D. Dai: None. Y. Shen: None. J. Lu: None. Y. Wang: None. W. Zhu: None. Y. Bao: None. G. Hu: None. Funding National Key Research and Development Project of China (2018YFC2000802); Shanghai Municipal Education Commission (20161430); Shanghai Municipal Key Clinical Specialty

AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

Background The aim of this study was to investigate the association of visit-to-visit variability of hemoglobin A1c (HbA1c) and glycated albumin (GA) with the risk of lower extremity atherosclerotic disease (LEAD). Method We performed a prospective cohort study of 436 patients with type 2 diabetes (258 men and 178 women) with at least 3 measurements of HbA1c and GA prior to baseline investigation from the Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital. Different HbA1c and GA variability markers were calculated. Multivariable Cox proportional hazard regression models were used to demonstrate the association between visit-to-visit HbA1c and GA variability and the risk of incident or progressive LEAD. Results During a mean follow-up period of 3.77 years, 112 participants developed LEAD. Multivariate-adjusted hazard ratios (HRs) of LEAD across tertiles of GA-CV values were 1.00, 1.06 (95% confidence interval [CI] 0.65–1.75), and 1.71 (95% CI 1.07–2.73) (P for trend = 0.042), respectively. When we used GA-VIM and GA-ARV values as exposures, similar positive associations with the risk of LEAD primary were found. Multivariate-adjusted HRs of LEAD for each 1 unit increase in GA-CV, GA-VIM and GA-ARV were 1.03 (95% CI 1.01–1.06), 1.32 (95% CI 1.03–1.69), and 1.07 (95%CI 1.01–1.15), respectively. However, there was no significant association between visit-to-visit variability of HbA1c and the risk of LEAD. Conclusions Visit-to-visit variability of GA may be an optimal biomarker in relation to LEAD risk among patients with type 2 diabetes.

Supplemental Digital Content is available in the text, The aim of current study was to use Weighted Gene Coexpression Network Analysis (WGCNA) to identify hub genes related to the incidence and prognosis of KRAS mutant (MT) lung adenocarcinoma (LUAD). We involved 184 stage IIB to IV LUAD samples and 59 normal lung tissue samples from The Cancer Genome Atlas (TCGA) database. The R package “limma” was used to identify differentially expressed genes (DEGs). WGCNA and survival analyses were performed by R packages “WGCNA” and “survival,” respectively. The functional analyses were performed by R package “clusterProfiler” and GSEA software. Network construction and MCODE analysis were performed by Cytoscape_v3.6.1. Totally 2590 KRAS MT specific DEGs were found between LUAD and normal lung tissues, and 10 WGCNA modules were identified. Functional analysis of the key module showed the ribosome biogenesis related terms were enriched. We observed the expression of 8 genes were positively correlated to the worse survival of KRAS MT LUAD patients, the 7 of them were validated by Kaplan–Meier plotter database (kmplot.com/) (thymosin Beta 10 [TMSB10], ribosomal Protein S16 [RPS16], mitochondrial ribosomal protein L27 [MRPL27], cytochrome c oxidase subunit 6A1 [COX6A1], HCLS1-associated protein X-1 [HAX1], ribosomal protein L38 [RPL38], and ATP Synthase Membrane Subunit DAPIT [ATP5MD]). The GSEA analysis found mTOR and STK33 pathways were upregulated in KRAS MT LUAD (P

Background To use competing analyses to estimate the prognostic value of KRAS mutation status in colorectal cancer (CRC) patients and to build nomogram for CRC patients who had KRAS testing. Method The cohort was selected from the Surveillance, Epidemiology, and End Results database. Cumulative incidence function model and multivariate Fine-Gray regression for proportional hazards modeling of the subdistribution hazard (SH) model were used to estimate the prognosis. An SH model based nomogram was built after a variable selection process. The validation of the nomogram was conducted by discrimination and calibration with 1,000 bootstraps. Results We included 8,983 CRC patients who had KRAS testing. SH model found that KRAS mutant patients had worse CSS than KRAS wild type patients in overall cohort (HR = 1.10 (95% CI [1.04–1.17]), p < 0.05), and in subgroups that comprised stage III CRC (HR = 1.28 (95% CI [1.09–1.49]), p < 0.05) and stage IV CRC (HR = 1.14 (95% CI [1.06–1.23]), p < 0.05), left side colon cancer (HR = 1.28 (95% CI [1.15–1.42]), p < 0.05) and rectal cancer (HR = 1.23 (95% CI [1.07–1.43]), p < 0.05). We built the SH model based nomogram, which showed good accuracy by internal validation of discrimination and calibration. Calibration curves represented good agreement between the nomogram predicted CRC caused death and actual observed CRC caused death. The time dependent area under the curve of receiver operating characteristic curves (AUC) was over 0.75 for the nomogram. Conclusion This is the first population based competing risk study on the association between KRAS mutation status and the CRC prognosis. The mutation of KRAS indicated a poor prognosis of CRC patients. The current competing risk nomogram would help physicians to predict cancer specific death of CRC patients who had KRAS testing.

Background We aimed to use competing risk model to assess whether very early onset pancreatic cancer (VEOPC ) ( Methods We selected pancreatic adenocarcinoma (PDAC) patients as our cohort from the Surveillance, Epidemiology, and End Results (SEER) database. The impact of cancer specific death was estimated by competing risk analysis. Multivariate Fine-Gray regression for proportional hazards modeling of the subdistribution hazard (SH) model based nomogram was constructed, which was internally validated by discrimination and calibration with 1,000 bootstraps. Results Our cohort included 1,386 VEOPC patients and 53,940 older patients. We observed that in unresectablePDAC patients, VEOPC had better cancer specific survival (CSS) than each older group (45–59 years, 60–69 years, 70–79 years and >79 years). There was no significant prognostic difference between VEOPC and each older group in resectablePDAC. Our competing nomogram showed well discrimination and calibration by internal validation. Conclusion For unresectable PDAC patients, VEOPC had better CSS than older patients. Our competing risk nomogram might be an easy-to-use tool for the specific death prediction of VEOPC patients with PDAC.

The aim of current study was to use competing risk model to assess whether medullary carcinoma of the breast (MCB) has a better prognosis than invasive ductal carcinomas of breast cancer (IDC), and to build a competing risk nomogram for predicting the risk of death of MCB. We involved 3,580 MCB patients and 319,566 IDC patients from Surveillance, Epidemiology, and End Results (SEER) database. IDC was found to have a worse BCSS than MCB (Hazard ratio (HR) > 1, p 1, p 0.05). After a penalized variable selection process, the SH model-based nomogram showed moderate accuracy of prediction by internal validation of discrimination and calibration with 1,000 bootstraps. In summary, MCB patients had a better prognosis than IDC patients. Interestingly, unmarried status in addition to expected risk factors such as larger tumor size and increasing number of positive lymph nodes were found to worsen the BCSS of MCB. We also established a competing risk nomogram as an easy-to-use tool for prognostic estimation of MCB patients.

Additional file 2: Supplemnetary Figures 1-6. Fig. S1. WNT/β-catenin signaling activates HSF1. Fig. S2. β-catenin has no effects on the RNA and protein half-life of HSF1. Fig. S3. The effect of microRNAs on HSF1 expression in CRC. Fig. S4. m6A modification of HSF1 mRNA. Fig. S5. The effects of miR455-3p and m6A modification on HSF1. Fig. S6. Volcano plot displays differentially regulated genes upon LiCl treatment.

Aim There is a paucity of studies regarding the association between long-term glycemic variability with the risk of diabetic retinopathy (DR) in patients with type 2 diabetes. Therefore, the purpose of this study is to explore the association of glycated albumin (GA) variability and HbA1c variability with the risk of DR in patients with type 2 diabetes. Methods This prospective cohort study included 315 inpatients with type 2 diabetes (191 males and 124 females) with at least 3 measurements of GA and HbA1c within 2 years prior to the baseline investigation. Different GA and HbA1c variability markers were calculated, including CV, variability independent of the mean (VIM), and the average real variability (ARV). Cox proportional hazard regression models were used to explore the association between visit-to-visit variability of GA and HbA1c and the risk of DR. Results After an average follow-up of 3.42 years, 81 patients developed incident DR. Multivariable-adjusted (diabetes duration, smoking status, systolic blood pressure, albumin to creatinine ratio, triglycerides, using fibrates, and mean HbA1c) hazard ratios of DR associated with each unit increase in GA-CV, GA-VIM, and GA-ARV were 1.05 (95% CI 1.02–1.09), 1.69 (95% CI 1.24–2.32), and 1.13 (95%CI 1.04–1.23), respectively. However, there was no significant association between visit-to-visit HbA1c variability and the risk of DR. Conclusions The present study indicated that visit-to-visit variability of GA can predict the risk of incident DR in patients with type 2 diabetes, and the prediction ability is independent of the average HbA1c levels.

// Xia Chen 1, * , Rui Wu 1, * , Yiwei Kong 1, * , Yuting Yang 1, * , Yu Gao 1 , Dandan Sun 1 , Qizhen Liu 1 , Dongjun Dai 1 , Zeyuan Lu 1 , Niansong Wang 1 , Sheng Ge 3 , Feng Wang 1, 2 1 Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China 2 Department of Nephrology, Shanghai Eighth People’s Hospital, Shanghai 200233, China 3 Department of Clinical Nutrition, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China * These authors contributed equally to this work Correspondence to: Sheng Ge, email: gesheng607@126.com Feng Wang, email: zyzwq1030@163.com Keywords: tanshinone, kidney, diabetes Received: January 25, 2017 Accepted: March 02, 2017 Published: March 29, 2017 ABSTRACT Oxidative stress and inflammation have been demonstrated to be involved in the onset and promotion of diabetic nephropathy (DN).Tanshinone IIA (Tan) possesses both antioxidant and anti-inflammatory properties. Here, the aim of the present study was to explore whether Tan could attenuate renal damage in the rats with streptozotocin (STZ)-induced diabetes and its potential mechanisms. Tan was gavaged to STZ-induced diabetic rats at the dose of 10mg/kg once a day for 12 weeks. Tan treatment significantly attenuated albuminuria and renal histopathology in diabetic rats. Besides, Tan treatment also effectively inhibited oxidative stress and inflammatory reaction in the kidneys of diabetic rats. Our study provided evidence that the protective effect of Tan on diabetes-induced renal injury is associated with inhibition of oxidative stress and inflammation. Tan may be a potential candidate for the treatment of DN.

// Cheng Zhang 1 , Jinyun Li 2 , Tao Huang 2 , Shiwei Duan 2 , Dongjun Dai 2 , Danjie Jiang 2 , Xinbing Sui 3 , Da Li 3 , Yidan Chen 1 , Fei Ding 1 , Changxin Huang 1 , Gongying Chen 1 , Kaifeng Wang 1 1 Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China 2 Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China 3 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China Correspondence to: Kaifeng Wang, email: wangkf2000@163.com Gongying Chen, email: chengongying@hotmail.com Keywords: meta-analysis, DNA methylation, biomarker, hepatocellular carcinoma Received: May 03, 2016 Accepted: November 01, 2016 Published: November 08, 2016 ABSTRACT DNA methylation is an epigenetic mechanism in the pathogenesis of hepatocellular carcinoma (HCC). Here, we conducted a systematic meta-analysis to evaluate the contribution of DNA methylation to the risk of HCC. A total of 2109 publications were initially retrieved from PubMed, Web of Science, Cochrane Library, Embase, CNKI and Wanfang literature database. After a four-step filtration, we harvested 144 case-control articles in the meta-analysis. Our results revealed that 24 genes (carcinoma tissues vs adjacent tissues), 17 genes (carcinoma tissues vs normal tissues) and six genes (carcinoma serums vs normal serums) were significantly hypermethylated in HCC. Subgroup meta-analysis by geographical populations showed that six genes (carcinoma tissues vs adjacent tissues) and four genes (carcinoma tissues vs normal tissues) were significantly hypermethylated in HCC. Our meta-analysis identified the correlations between a number of aberrant methylated genes ( p16 , RASSF1A , GSTP1 , p14 , CDH1 , APC , RUNX3 , SOCS1 , p15 , MGMT , SFRP1 , WIF1 , PRDM2 , DAPK1 , RARβ , hMLH1 , p73 , DLC1 , p53 , SPINT2 , OPCML and WT1 ) and HCC. Aberrant DNA methylation might become useful biomarkers for the prediction and diagnosis of HCC.

Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m6A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m6A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.

The aim of the present study was to use a competing risk model to analyze the prognostic value of mucinous adenocarcinoma (MAC) in patients with colorectal cancer (CRC). An additional aim was to construct nomograms for estimating the 3- and 5-year overall survival (OS) and cancer specific survival (CSS) rates of patients with primary CRC with MAC. The data were extracted from the Surveillance, Epidemiology, and End Results database, and a Multivariate Cox model and competing risk model were applied to assess the OS and CSS. Cox-based and competing risk-based nomograms were constructed and internally validated by discrimination and calibration, using the bootstrapping method with 1,000 times replicates. A total of 13,035 MAC and 61,958 non-mucinous adenocarcinoma (NMAC) CRC patients were enrolled in the present study. Compared with NMAC, MAC patients had a poorer OS and CSS time in the overall population, and in subgroups that comprised metastatic, non-metastatic, male, site of sigmoid colon, rectosigmoid junction and rectal CRC cases (HR>1; P

Glycated albumin (GA) and the variation of consecutive GA measurements are demonstrated to be associated with chronic diabetic complications. Compared to hemoglobin A1c, GA can provide more accurate glycemic information in patients with specific clinical conditions such as hemoglobin diseases, end-stage renal diseases on dialysis, or in patients who experience drastic changes in glucose level. Meanwhile, the use of GA is limited in several clinical situations such as obesity, autoimmune diseases, and predicting adverse pregnancy outcomes and arterial stiffness. This review summarized the clinical significance and research progress of GA and its variability.

Aberrant promoter methylation of multiple genes is associated with various diseases, including Alzheimer's disease (AD). The goal of the present study was to determine whether dopamine receptor D4 (DRD4) promoter methylation is associated with AD. In the current study, the methylation levels of the DRD4 promoter were measured in 46 AD patients and 61 controls using bisulfite pyrosequencing technology. The results of the present study demonstrated that DRD4 promoter methylation was significantly higher in AD patients than in controls. A further breakdown analysis by gender revealed that there was a significant association of DRD4 promoter methylation with AD in males (23 patients and 45 controls). In conclusion, the results of the present study demonstrated that elevated DRD4 promoter methylation was associated with AD risk in males.

Previous studies have suggested that increased opioid receptor κ1 (OPRK1) and opioid receptor δ1 (OPRD1) methylation levels are involved in Alzheimer's disease (AD). In the present study, the methylation levels of two opioid receptor genes, opioid receptor µ1 (OPRM1) and opioid related nociceptin receptor 1 (OPRL1), were analyzed for their association with AD. Gene methylation levels were measured using bisulfite pyrosequencing in DNA samples derived from blood samples of 51 AD patients and 63 controls. The results indicated that there were significantly elevated promoter methylation levels of OPRM1 and OPRL1 in AD (OPRM1: P=0.007; OPRL1: P=2.987x10‑6). Dual‑luciferase reporter gene assays demonstrated that the promoter fragments of these two genes were able to promote gene expression (OPRM1: Fold‑change=2.616, P=0.003; OPRL1: Fold change=11.395, P=0.007). In addition, receiver operating characteristic analyses further indicated that a methylation panel of four opioid receptor genes (area under the curve=0.848, sensitivity=0.723, and specificity=0.879) performed well in the prediction of AD. These results suggested that opioid receptor genes may be used as potential methylation biomarkers for the diagnosis of AD.

Androgen deprivation therapy (ADT) was an important management for metastatic prostate cancer. However, patients would finally progress to the metastatic castration-resistant prostate cancer (mCRPC) and lose sensitivity to ADT. In addition to lower testosterone level, ADT could cause anemia, which might impair the chemotherapy efficiency and worsen the outcomes of cancer patients. However, inconsistent results were found between anemia and mCRPC prognosis. Our study was the first systematic review to evaluate the influence of anemia in mCRPC prognosis. Thirteen studies with 6,484 samples were involved in this meta-analysis. We found anemia would worsen the Overall survival (OS) of mCRPC patients in both prognostic designed studies (HR = 1.55, 95% CI = 1.24-1.94) and retrospective designed studies (HR = 1.82, 95% CI = 1.52-2.18). Prognostic analyses also demonstrated that anemia associated with poor Progression free survival (PFS) (HR = 1.47, 95% CI = 1.22-1.75). In conclusion, we found that anemia was significantly associated with poor OS and PFS of mCRPC patients. Larger RCTs are needed for future study, especially for the evaluation of treatment value for anti-anemia in mCRPC.

Heat shock factor 1 (HSF1) generally exhibits its properties under stress conditions. In tumors, HSF1 has a pleiotropic feature in regulating growth, survival, and aggressiveness of cancer cells. In this study, we found HSF1 was increased in colorectal cancer (CRC) and had a positive correlation with shorter disease-free survival (DFS). Knockdown of HSF1 in CRC cells attenuated their growth while inhibiting mTOR activation and glutamine metabolism. HSF1 inhibited the expression of microRNA137 (MIR137), which targeted GLS1 (glutaminase 1), thus stimulating GLS1 protein expression to promote glutaminolysis and mTOR activation. HSF1 bound DNA methyltransferase DNMT3a and recruited it to the promoter of lncRNA MIR137 host gene (MIR137HG), suppressing the generation of primary MIR137. The chemical inhibitor of HSF1 also reduced cell growth, increased apoptosis, and impaired glutamine metabolism in vitro. Moreover, both chemical inhibition and genetic knockout of HSF1 succeeded in increasing MIR137 expression, reducing GLS1 expression, and alleviating colorectal tumorigenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice. In conclusion, HSF1 expression was increased and associated with poor prognosis in CRC. By recruiting DNMT3a to suppress the expression of MIR137 that targets GLS1 mRNA, HSF1 stimulated GLS1-dependent mTOR activation to promote colorectal carcinogenesis. Therefore, targeting HSF1 to attenuate glutaminolysis and mTOR activation could be a promising approach for CRC treatment.

N6-methyladenosine (m6A) is the most abundant mRNA modification. With the development of antibody-based sequencing technologies and the findings of m6A-related “writers”, “erasers”, and “readers”, the relationships between m6A and mRNA metabolism are emerging. The m6A modification influences almost every step of RNA metabolism that comprises mRNA processing, mRNA exporting from nucleus to cytoplasm, mRNA translation, mRNA decay, and the biogenesis of long-non-coding RNA (lncRNA) and microRNA (miRNA). Recently, more and more studies have found m6A is associated with cancer, contributing to the self-renewal of cancer stem cell, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy. Inhibitors of m6A-related factors have been explored, and some of them were identified to inhibit cancer progression, indicating that m6A could be a target for cancer therapy. In this review, we are trying to summarize the regulation and function of m6A in human carcinogenesis.

Schizophrenia (SCZ) is one of the most complex mental illnesses affecting ~1% of the population worldwide. SCZ pathogenesis is considered to be a result of genetic as well as epigenetic alterations. Previous studies have aimed to identify the causative genes of SCZ. However, DNA methylation of long non-coding RNAs (lncRNAs) involved in SCZ has not been fully elucidated. In the present study, a comprehensive genome-wide analysis of DNA methylation was conducted using samples from two male patients with paranoid and undifferentiated SCZ, respectively. Methyl-CpG binding domain protein-enriched genome sequencing was used. In the two patients with paranoid and undifferentiated SCZ, 1,397 and 1,437 peaks were identified, respectively. Bioinformatic analysis demonstrated that peaks were enriched in protein-coding genes, which exhibited nervous system and brain functions. A number of these peaks in gene promoter regions may affect gene expression and, therefore, influence SCZ-associated pathways. Furthermore, 7 and 20 lncRNAs, respectively, in the Refseq database were hypermethylated. According to the lncRNA dataset in the NONCODE database, ~30% of intergenic peaks overlapped with novel lncRNA loci. The results of the present study demonstrated that aberrant hypermethylation of lncRNA genes may be an important epigenetic factor associated with SCZ. However, further studies using larger sample sizes are required.

Alzheimer's disease (AD) is a common neurodegenerative disorder that can destroy the memory of sufferers and lead to distress for the individual and society. Brain-derived neurotrophic factor (BDNF) and butyrylcholinesterase (BCHE) are two genes associated with β-amyloid plaques and neurofibrillary tangles that are two key factors in the pathophysiology of AD. The aim of the current meta-analysis was to evaluate the association between BDNF Val66Met (rs6265), BDNF C270T (rs2030324) and BCHE-K (rs1803274) polymorphisms and AD. A comprehensive meta-analysis was performed using the online database PubMed without a time limitation. A total of 56 articles evaluating 12,563 cases and 12,622 controls were selected for the current meta-analysis. The results showed a moderate association of the BDNF C270T polymorphism with the risk of AD in Asians under a dominant model (P=0.03; odds ratio, 1.88; 95% confidence interval, 1.08–3.27). No other significant association was found during the meta-analysis for the other two polymorphisms (P>0.05). The current meta-analysis suggests that BDNF C270T is a risk factor for AD in Asians. This meta-analysis has been, to the best of our knowledge, the most comprehensive meta-analysis of BDNF Val66Met, BDNF C270T and BCHE-K to date.

// Mengjiao Han 1 , Dongjun Dai 1 , Neelum Aziz Yousafzai 1 , Faliang Wang 2 , Hanying Wang 1 , Qiying Zhou 1 , Haiqi Lu 1 , Wenxia Xu 2 , Lifeng Feng 2 , Hongchuan Jin 2 and Xian Wang 1 1 Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China 2 Labortaory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China Correspondence to: Xian Wang, email: wangx118@zju.edu.cn Keywords: CXXC4, GDF15, apoptosis, gastric cancer Received: June 30, 2017 Accepted: September 05, 2017 Published: October 06, 2017 ABSTRACT Worldwide, gastric cancer is one of the most fatal cancers. Epigenetic alterations in gastric cancer play important roles in silencing of tumor suppressor genes. We previously found that CXXC finger protein 4 (CXXC4) was a novel tumor suppressor in gastric cancer. In this report, we demonstrated that CXXC4 inhibited growth of gastric cancer cells as a pro-apoptotic factor. This inhibition could be reversed by the pan-caspase inhibitor called Z-VAD-FMK. However, CXXC4 with mutations in its DNA binding domain failed to induce apoptosis. Growth differentiation factor 15 (GDF15) was identified as one of potential targets responsible for CXXC4-induced apoptosis. CXXC4 activated GDF15 transcription through enhancing the interaction of transcription factor Sp1 with GDF15 promoter. In summary, the nuclear protein CXXC4 activated apoptosis in gastric cancer through up-regulating its novel potential downstream target GDF15. GDF15 might be a promising target for clinical treatment of gastric cancer with CXXC4 deficiency.

Coronary artery disease (CAD) has become the main cause of mortality worldwide. Lectin galactoside-binding soluble-2 (LGALS2) is involved in the cytokine lymphotoxin-α (LTA) cascade that may influence the progress of CAD. The aim of the present study was to assess the association between the LGALS2 3279C>T (rs7291467) polymorphism and CAD. A total of 562 cases and 572 controls were recruited to examine the association. A systematic meta-analysis was performed to evaluate the contribution of LGALS2 3279C>T polymorphism to the risk of CAD among 12,093 cases and 11,020 controls. There was no significant association found in the present case-control study. However, the meta-analysis showed that LGALS2 3279C>T played a protective role in CAD (P=0.008, odds ratio (OR), 0.90; 95% confidence interval (95% CI), 0.82-0.97) and particularly in the Asian population (P=0.006; OR, 0.82; 95% CI, 0.71-0.94). The present case‑control study did not find a significant associa - tion between LGALS2 3279C>T and CAD in the Eastern Han Chinese population. However, the meta-analysis indicated that LGALS2 3279C>T played a protective role in CAD, suggesting an ethnic difference in the association of the locus with CAD.

Promoter DNA methylation may reflect the interaction between genetic backgrounds and environmental factors in the development of metabolic disorders, including type 2 diabetes (T2D). Calcium/calmodulin-dependent protein kinase 1D (CAMK1D), cryptochrome 2 (CRY2) and calmodulin 2 (CALM2) genes have been identified to be associated with a risk of T2D. Therefore, the aim of the present study was to investigate the contribution of promoter DNA methylation of these genes to the risk of T2D. Using bisulfite pyrosequencing technology, the DNA methylation levels of the CpG dinucleotides within the CAMK1D, CRY2 and CALM2 gene promoters were measured in 48 patients with T2D and 48 age- and gender-matched healthy controls. The results demonstrated that the promoters of these three genes were hypomethylated in the peripheral blood of all the subjects, and DNA methylation of these three genes did not contribute to the risk of T2D.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder that affects ~2% of the population aged ≥65 years. The degeneration of dopamine neurons in the substantia nigra contributes to the pathogenesis of PD. Dopamine receptor D2 (DRD2) and dopamine receptor D3 (DRD3) are two key subtypes of dopamine receptors. The aim of our study was to evaluate the association between the polymorphisms of DRD2 and DRD3 genes and PD. Meta-analyses were conducted from 16 studies (46 stages) among 4,279 cases and 5,661 controls between PD and 9 polymorphisms (DRD2: rs1800497, rs1079597, rs6278, rs6279, rs273482, rs1799732 and rs1076563; DRD3: rs6280 and rs2134655). A significant association was observed between DRD3 rs2134655 polymorphism and PD [P=0.01, odds ratio (OR)=1.17, 95% confidence interval (CI): 1.03–1.32] and a borderline association was observed between DRD2 rs1800497 polymorphism and PD in Europeans (P=0.05, OR=1.13, 95% CI: 1.00–1.27). Findings of the current meta-analysis suggested that DRD3 rs2134655 polymorphism was associated with a 17% increased risk of PD and that DRD2 rs1800497 polymorphism had a potential to increase the risk of PD by 13% in Europeans. Future large-scale studies are required to confirm the ethnic difference of DRD2 rs1800497 polymorphism and to determine whether there were significant associations of PD with other polymorphisms in DRD2 and DRD3 genes.

Rheumatoid arthritis (RA) is an immune-mediated chronic inflammatory disease that causes huge destruction to human body. IL1B encodes key mediator IL-1β protein, which plays an important role in the pathogenesis of inflammatory syndromes. The aim of this study was to evaluate the association between IL1B polymorphisms and RA. A meta-analysis was performed on the association between three IL1B polymorphisms (IL1B-31: rs1143627; IL1B-511: rs16944; IL1B + 3954: rs1143634) and RA. A trend of significant association was observed between IL1B + 3954 and RA (p = 0.06, odd ratio (OR) = 1.19, 95% confidential interval (CI) = 1.00-1.42). A significant association was found in Europeans under the dominant model between IL1B-511T and RA (p = 0.03, OR = 0.89, 95% CI = 0.81-0.99). Our meta-analysis indicated that IL1B ? 511-T played a protective role against RA in Europeans, and that IL1B + 3954-T had the potential to increase the risk of RA. Future large-scale studies should be considered to confirm the association between IL1B polymorphisms and RA.

Parkinson disease (PD) is a neurological disorder with huge destruction to human body, which affects approximately 2% of the population aged 65 years or older. As antioxidants in the stress defence systems, glutathione S-transferases (GSTs) are dimeric cytosolic enzymes with an important role in the pathogenesis of PD. The aim of this study was to evaluate the association between the polymorphisms of GST genes and PD. Meta-analyses were conducted from 17 studies (38 stages) among 3419 cases and 5686 controls between four polymorphisms (GSTT1 deletion polymorphism; GSTM1 deletion polymorphism; GSTP1-104: rs1695; GSTP1-114: rs1799811) and PD. There is no significant association between the four GST gene variants and PD. A further subgroup study by ethnicity observed a risky role of GSTM1 deletion polymorphism with PD in Europeans (p = 0.013, OR = 1.126, 95% CI = 1.025-1.236), and a protective role of GSTM1 deletion polymorphism with PD in Latin Americans (p = 0.032, OR = 0.750, 95% CI = 0.577-0.975). Our meta-analysis suggested that GSTM1 deletion polymorphism increased the risk of PD in Europeans, but reduced the risk of PD in Latin Americans. Future large-scale studies might be needed to confirm the ethnic difference of GSTM1 deletion polymorphism, and to check whether there was significant association of PD for other GST genetic polymorphisms.

AIM The aim of this study was to assess whether rs1333049 was associated with coronary heart disease (CHD) in Han Chinese. METHODS This case-control study was involved with 599 CHD patients and 591 non-CHD controls. Meanwhile, a comprehensive meta-analysis was also conducted to establish the contribution of rs1333049 to CHD. RESULTS Our results showed that rs1333049 increased the risk of CHD by 38% (OR=1.38, 95% CI=1.18-1.62). A breakdown analysis by gender further indicated that rs1333049 increased the risk of CHD in men by 29% (OR=1.29, 95% CI=1.05-1.58) and in women by 64% (OR=1.64, 95% CI=1.25-2.16). A follow-up subgroup analysis by age showed there was a significant association between rs1333049 and CHD in women younger than 65 (≤55 years: p=0.001, 55-65 years: p=0.008) and in men aged between 55 and 65 years (p=0.005). Our meta-analysis was involved with 21 studies (25 stages) among 20969 cases and 34114 controls. Our results showed that rs1333049 led to a significantly increased risk of CHD (OR=1.30, 95% CI=1.21-1.39). Further subgroup analyses by ethnicity showed rs1333049 increased the CHD risk by 30% in Europeans (OR=1.30, 95% CI=1.16-1.47) and 27% in Asians (OR=1.27, 95% CI=1.22-1.33). CONCLUSIONS Our case-control study and meta-analysis suggest that rs1333049 is a useful risk marker of CHD.

MiRNAs are potent regulators of gene expression, and most miRNAs have from several to several thousands of gene targets. Validating the numerous gene targets of a given miRNA remains challenging despite the existence of various tools and databases that predict candidate gene-miRNA pairs. In the present study, we present a high-throughput but flexible method that applies a PCR-based application to simulate the binding of miRNAs to their gene targets. Using hsa-miR-377 as an illustrative example, our method was able to identify 13 potential targets of hsa-miR-377. Moreover, our results include 2 genes (SOD2 and PPM1A) that have already been verified as targets of hsa-miR-377. Our method may provide an alternative way of identifying the gene targets of miRNAs for future research.