circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt signaling pathway in ovarian cancer.

BACKGROUND: CircRNAs are a novel class of evolutionarily conserved noncoding RNA molecules that form covalently closed continuous loop structures without 5' caps and 3' poly(A) tails. Accumulating evidence suggests that circRNAs play important regulatory roles in cancer and are promising biomarkers for cancer diagnosis and prognosis, as well as targets for cancer therapy. In this study, we identify and explore the role of a novel circRNA, circFBXO7, in ovarian cancer. METHODS: rRNA-depleted RNA-sequencing was performed to identify differentially expressed circRNAs between ovarian cancerous and normal tissues. qRT-PCR and single-molecule RNA in-situ hybridization was used to quantify circFBXO7 expression in tumor tissues. The association of circFBXO7 expression with patient prognosis was evaluated by Kaplan-Meier survival analysis. The biological function of circFBXO7 was also investigated using loss-of-function and gain-of-function assays in vivo and in vitro. Luciferase reporter and TOP/FOP-Flash reporter assays were then conducted together with RNA immunoprecipitation and western blot to assess the circFBXO7/miR-96-5p/MTSS1/Wnt/ß-catenin axis. RESULTS: circFBXO7 was downregulated in ovarian cancer which was associated with poor prognosis. Biologically, circFBXO7 overexpression significantly suppressed ovarian cancer cell proliferation, migration, and invasion in vitro, and inhibited tumor growth and metastasis in vivo, whereas its knockdown exerted an opposite role. Mechanistically, circFBXO7 functioned as a competing endogenous RNA for miR-96-5p to regulate the expression of MTSS1. Consequently, downregulation of MTSS1 led to excessive accumulation of ß-catenin and increased phosphorylation of GSK3ß, leading to the translocation of ß-catenin to the nucleus, thereby activating the Wnt/ß-catenin signaling pathway and ultimately promoting ovarian cancer progression. CONCLUSIONS: Our findings indicate that circFBXO7 acts as a bone fide tumor suppressor in ovarian cancer and that the circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt/ß-catenin signaling pathway which may provide a promising target for ovarian cancer therapy.

SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFß/PI3K/AKT/GSK3ß pathway.

OBJECTIVES: We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression. METHODS: The role of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were detected using MTT assay, colony formation assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was inspected by a xenograft tumour model in nude mice. The related mechanisms were further studied. RESULTS: The level of SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and in vivo. Screening of cell cycle-related proteins revealed that CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFß signalling pathway and the PI3K/AKT signalling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFßRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signalling pathway and the phosphorylation of GSK3ß to inhibit its kinase activity. CONCLUSIONS: SCUBE3 promotes HCC development by regulating CCNE1 via TGFß/PI3K/AKT/GSK3ß pathway. In addition, SCUBE3 may be a new molecular target for the clinical diagnosis and treatment of HCC.

Integrated analysis of virus and host transcriptomes in cervical cancer in Asian and Western populations.

Race may influence vulnerability to HPV variants in viral infection and perisistence. Integrated analysis of the virus and host transcriptomes from different populations provides an unprecedented opportunity to understand these racial disparities in the prevalence of HPV and cervical cancers. We performed RNA-Seq analysis of 90 tumors and 39 adjacent normal tissues from cervical cancer patients at Zhejiang University (ZJU) in China, and conducted a comparative analysis with RNA-Seq data of 286 cervical cancers from TCGA. We found a modestly higher rate of HPV positives and HPV integrations in TCGA than in ZJU. In addition to LINC00393 and HSPB3 as new common integration hotspots in both cohorts, we found new hotspots such as SH2D3C and CASC8 in TCGA, and SCGB1A1 and ABCA1 in ZJU. We described the first, to our knowledge, virus-transcriptome-based classification of cervical cancer associated with clinical outcome. Particularly, patients with expressed E5 performed better than those without E5 expression. However, the constituents of these virus-transcriptome-based tumor subtypes differ dramatically between the two cohorts. We further characterized the immune infiltration landscapes between different HPV statuses and revealed significantly elevated levels of regulatory T cells and M0 macrophages in HPV positive tumors, which were associated with poor prognosis. These findings increase our understanding of the racial disparities in the prevalence of HPV and its associated cervical cancers between the two cohorts, and also have important implications in the classification of tumor subtypes, prognosis, and anti-cancer immunotherapy in cervical cancer.

MDEHT: a multivariate approach for detecting differential expression of microRNA isoform data in RNA-sequencing studies.

MOTIVATION: miRNA isoforms (isomiRs) are produced from the same arm as the archetype miRNA with a few nucleotides different at 5 and/or 3 termini. These well-conserved isomiRs are functionally important and have contributed to the evolution of miRNA genes. Accurate detection of differential expression of miRNAs can bring new insights into the cellular function of miRNA and a further improvement in miRNA-based diagnostic and prognostic applications. However, very few methods take isomiR variations into account in the analysis of miRNA differential expression. RESULTS: To overcome this challenge, we developed a novel approach to take advantage of the multidimensional structure of isomiR data from the same miRNAs, termed as a multivariate differential expression by Hotelling's T2 test (MDEHT). The utilization of the information hidden in isomiRs enables MDEHT to increase the power of identifying differentially expressed miRNAs that are not marginally detectable in univariate testing methods. We conducted rigorous and unbiased comparisons of MDEHT with seven commonly used tools in simulated and real datasets from The Cancer Genome Atlas. Our comprehensive evaluations demonstrated that the MDEHT method was robust among various datasets and outperformed other commonly used tools in terms of Type I error rate, true positive rate and reproducibility. AVAILABILITY AND IMPLEMENTATION: The source code for identifying and quantifying isomiRs and performing miRNA differential expression analysis is available at https://github.com/amanzju/MDEHT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Lamivudine therapy for chronic hepatitis B in children: a meta-analysis.

BACKGROUND: Currently, there is no consensus on the effects and safety of lamivudine therapy for chronic hepatitis B (CHB) in children. METHOD: Both English and Chinese databases were searched comprehensively. An odds ratio (OR) and a standard mean difference (SMD) were used to assess the effects and safety of lamivudine therapy for CHB in children. RESULTS: Thirteen eligible studies were included in our analysis. The rates of Hepatitis B virus (HBV) response, biochemical response, hepatitis B e antigen (HBeAg) loss, HBeAg seroconversion, and hepatitis B surface antigen (HBsAg) loss were significantly higher in the lamivudine (LAM) therapy group than in the control group. The changes in children's weight and height were similar between the two groups. CONCLUSIONS: LAM therapy was efficacious for CHB in children. Additionally, it had no side effect on children's height and weight.

Lamivudine plus tenofovir combination therapy versus lamivudine monotherapy for HBV/HIV coinfection: a meta-analysis.

BACKGROUND: Currently, there is no consensus on the efficacy and safety of lamivudine (LAM) plus tenofovir disoproxil fumarate (TDF) combination therapy versus lamivudine monotherapy in HBV/HIV coinfected patients. METHODS: A comprehensive literature search was performed in English and Chinese databases. Both relevant dichotomous and continuous variables were extracted, and the combined outcomes were expressed as a risk ratio (RR) or a standard mean difference (SMD). RESULTS: Eleven eligible studies were included in our analysis. For HBV-relevant outcomes, the proportion of patients with undetectable HBV, the rates of serum alanine aminotransferase (ALT) normalization and hepatitis B e antigen (HBeAg) loss were higher in the combination therapy group than the monotherapy group (RR = 1.42, 95% CI: 1.14-1.76, P = 0.002; RR = 1.36, 95% CI: 1.17-1.58, P < 0.0001; RR = 2.74, 95% CI: 1.20-6.22, P = 0.02). In addition, the rate of HIV RNA-negative conversion was higher in the combination therapy group than the monotherapy group (RR = 1.26, 95% CI: 1.11-1.42, P = 0.0003). CONCLUSION: LAM plus TDF combination therapy was more efficacious than LAM monotherapy in HBV/HIV coinfected patients. As time passes, this difference becomes more pronounced.

LncRNA SFTA1P promotes cervical cancer progression by interaction with PTBP1 to facilitate TPM4 mRNA degradation.

Long non-coding RNAs (lncRNAs) play key roles in cancer development and progression. However, the biological function and clinical significance of most lncRNAs in cervical cancer remain elusive. In this study, we explore the function and mechanism of lncRNA surfactant associated 1 (SFTA1P) in cervical cancer. We firstly identified SFTA1P by analyzing the RNA sequencing data of cervical cancer from our previous study and from The Cancer Genome Atlas (TCGA). We then verified SFTA1P expression by qRT-PCR. The cell proliferation and migration capacity of SFTA1P was assessed by using CCK-8, colony formation, transwell and wound healing assays. RNA pull-down, RNA immunoprecipitation (RIP), RNA stability and western blot assays were used to reveal potential mechanisms. Athymic nude mice were used to evaluate tumorigenicity and metastasis in vivo. SFTA1P is upregulated in cervical tumor tissues and its high expression is associated with poor prognosis. Biologically, knockdown of SFTA1P inhibited the proliferation, migration, and invasion of cervical cancer cells in vitro, as well as tumorigenesis and metastasis in vivo. Mechanistically, SFTA1P was shown to interact with polypyrimidine tract binding protein 1 (PTBP1) to regulate the stability of tropomyosin 4 (TPM4) mRNA, thereby resulting in malignant cell phenotypes. TPM4 knockdown could attenuate the suppression of cell progression induced by either SFTA1P or PTBP1 knockdown. Our findings demonstrate that SFTA1P can promote tumor progression by mediating the degradation of TPM4 mRNA through its interaction with PTBP1 protein. This provides a potential therapeutic strategy to target the SFTA1P-PTBP1-TPM4 axis in cervical cancer.

Effect of Autologous Bone Marrow Stem Cell Therapy in Patients with Liver Cirrhosis: A Meta-analysis.

Background and Aims: Although autologous bone marrow stem cell (BMSC) transplantation is an effective treatment for liver cirrhosis, there are few reports describing the optimal delivery route and number of injected BMSCs. Methods: A literature search was conducted using PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, and EBSCO. A meta-analysis was performed to assess the effect of BMSCs on liver and coagulation function indices. Subgroup analysis was performed based on number of injected BMSCs, delivery route, and length of follow-up. Results: A total of 15 studies were selected from among 1903 potential studies for analysis. Autologous BMSC transplantation significantly improved aspartate aminotransferase, total bilirubin, albumin, prothrombin time, prothrombin activity, prothrombin concentration, Child-Pugh score, and model for end-stage liver disease. In the subgroup analysis of cell numbers, all four of the indices were significantly improved when the number of BMSCs was >4 × 108. The subgroup analysis referring to the delivery route showed that arterial infusion increased the therapeutic effect over venous infusion. Finally, in the subgroup analysis of follow-up length, the results showed that BMSC therapy significantly improved liver function at 2 weeks after transplantation. In addition, this therapy improved coagulation 4 weeks after the transplant, with a maintenance of efficacy for up to 24 weeks. Conclusions: Autologous BMSC therapy is beneficial for liver improvement and coagulation in patients with liver cirrhosis. The therapeutic effect was generated at 2-4 weeks after transplantation. The effect lasted for 24 weeks but no more than 48 weeks. The greatest benefit to patients was observed with a 4 × 108 autologous BMSC transplant via the hepatic artery.

Efficacy and safety of direct-acting antiviral therapy for chronic hepatitis C genotype 6: A meta-analysis.

BACKGROUND: Because of the heterogeneity of hepatitis C virus (HCV) distribution of different genotypes, large-scale clinical trials on direct-acting antiviral (DAA) mainly included patients with genotype 1 and genotype 3 infection. Data on the efficacy of direct-acting antiviral agents in patients with chronic genotype 6 HCV infection are limited. METHODS: The PubMed, Embase, and the Cochrane Libraries were searched comprehensively. All published clinical trials assessing the efficacy of DAA therapy for patients with chronic genotype 6 HCV infection were included. Sustained virological response (SVR) and rapid virological response (RVR) were pooled. Additional meta-analyses were also performed to compare the efficacy of DAA therapy in HCV-6 versus HCV-1 or HCV-3 patients. RESULTS: Seventeen studies met the inclusion criteria and were included in our meta-analysis. The pooled SVR of all single arms was 95% [95% confidence interval (CI): 0.90-0.97]. The pooled RVR of all single arms was 97% (95% CI: 0.95-0.99). The SVR and RVR were both similar between HCV-6 and HCV-1 or HCV-3. Adverse events were common but rarely caused treatment interruption. CONCLUSION: Based on the available data, our results indicate that DAA treatment is effective and safe for patients with genotype 6 HCV infection, and the efficacy was similar compared to patients with genotype 1 HCV or genotype 3 HCV infection.

Association of epicardial adipose tissue with non-alcoholic fatty liver disease: a meta-analysis.

BACKGROUND: Increased epicardial adipose tissue (EAT) has been proposed as a risk factor for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the association of EAT with NAFLD. METHODS: The PubMed, EMBASE, and Cochrane databases were systematically reviewed by two independent investigators to identify relevant studies assessing the association of EAT thickness (EAT-t) and volume (EAT-v) with NAFLD. Comparisons between NAFLD subjects and controls were performed with meta-analysis and trial sequential analysis (TSA). RESULTS: A total of thirteen case-control studies (n = 2260 patients) were included in the final analysis. The EAT was significantly increased in NAFLD patients compared with the controls (EAT, SMD: 0.73, 95% CI 0.51-0.94, p < 0.001; TSA-adjusted 95% CI 0.07-0.18; p < 0.001). When comparing the subgroups of NAFLD, the EAT-t in the severe-hepatic steatosis subgroup was thicker than that in the moderate subgroup (SMD: 1.43, 95% CI 0.15-2.71, p = 0.029). This study indicated that the EAT-t in the F3-4 fibrosis subgroup was thicker than that in the F0-2 fibrosis subgroup (SMD: 0.72, 95% CI 0.30-1.14, p = 0.001). The proportion of hypertension (OR = 1.64, 95% CI = 1.24-2.18, p = 0.001) and atherosclerotic cardiovascular disease (ASCVD) (OR = 1.66, 95% CI = 1.21-2.28, p = 0.002) was higher in the high-EAT-t group compared with the low-EAT-t group in NAFLD patients. CONCLUSIONS: The EAT was increased in the NAFLD subjects compared to the controls. The increase in the EAT was associated with the severity of steatosis, fibrosis and cardiovascular disease in patients with NAFLD. These findings provide new information regarding the development and progression of NAFLD.

Entecavir-based combination therapies for chronic hepatitis B: A meta-analysis.

BACKGROUND: Currently, there is no consensus on the efficacy and safety of the entecavir (ETV) monotherapy versus the ETV-based combination therapy for chronic hepatitis B. METHODS: A comprehensive literature search was performed on the comparison of ETV-based combination therapy and monotherapy for chronical hepatitis B (CHB) patients in the PubMed, Embase, Web of Science, the Cochrane Libraries, and the Chinese BioMedical Literature Database. Both dichotomous and continuous variables were extracted, and pooled outcomes were expressed as odds ratio (OR) or mean difference (MD). RESULTS: We included randomized clinical trials (RCTs) and cohorts involving Group A: nucleos(t)ide-naive patients (four RCTs, n = 719 patients), Group B: nucleos(t)ide-resistant patients (four cohorts, n = 196 patients), and Group C: entecavir-treated patients with undetectable hepatitis B virus DNA (two RCTs and two cohorts, n = 297). Group A. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar between the two groups [MD, -0.85 (95% CI, -0.173-0.03); OR, 0.92 (95% CI, 0.24-3.56); OR, 1.31 (95% CI, 0.17-9.82)]; Group B. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar; Group C. The ETV-based combination therapy was better for the rate of HBV DNA relapse. CONCLUSION: Based on the current data, ETV-based combination therapy seemed to be no better than ETV monotherapy. Further studies are needed to verify this conclusion.

Recovery of circulating CD56dim NK cells and the balance of Th17/Treg after nucleoside analog therapy in patients with chronic hepatitis B and low levels of HBsAg.

BACKGROUND AND AIMS: Much evidence indicates that the soluble antigens secreted by hepatitis B virus (HBV) inhibit the function of the immune system. The aim of this study is to investigate, after treatment with nucleoside (acid) analogs (NAs) and the inhibition of viral replication, whether the immune systems of patients with a peripheral blood HBV-DNA level <1000 IU/mL, hepatitis B e antigen (HBeAg) disappearance, and a decrease in hepatitis B surface antigen (HBsAg) levels could be reconstructed. METHODS: The frequency and phenotype of circulating natural killer (NK) cells, dendritic cells (DCs), T-helper (Th) cells, regulatory T (Treg) cells, CD4+, CD8+ T cells, T follicular helper (Tfh) cells and B cells subtypes were tested by flow cytometry in chronic hepatitis B (CHB) patients and healthy controls (HCs). The levels of HBV-related serum HBsAg, HBeAg, HBV-DNA load, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. RESULTS: Regarding the innate immune system, an increased frequency of CD56dim NK cells was found in the therapeutic response (TR) group compared with that in the immune-active phase (IA) group. Additionally, regarding the adaptive immune system, the Th17/CD4+CD25+CD127dimTreg ratio was reduced in the TR group. Additionally, the frequency of CD40L+CXCR5+CD4+T cells and CD40+CD19+CD27+CD38+B cells was significantly higher than that of HCs, while that of PDL1+CD19+ B cells was lower. Furthermore, the frequencies of CTLA4+CD4+T cells and CTLA4+CD8+T cells in patients with CHB were significantly higher than those in HCs. CONCLUSION: After NA treatment and the inhibition of viral replication, circulating CD56dim NK cells and the balance of Th17/Treg can be recovered. Restoring circulating CD56dim NK cells and the Th17/Treg balance may help reduce HBsAg levels in patients.

Tfh cell-mediated humoral immune response and HBsAg level can predict HBeAg seroconversion in chronic hepatitis B patients receiving peginterferon-α therapy.

UNLABELLED: Hepatitis B e antigen (HBeAg) seroconversion constitutes a significant milestone in the treatment of HBeAg-positive patients with chronic hepatitis B (CHB), but studies have yet to identify the specific humoral immune mechanisms behind the process or any accurate markers that can determine the virus-host immune status and, thereby, predict the degree of HBeAg seroconversion achievable. In the present longitudinal study, higher frequencies of circulating CXCR5(+)CD4(+) T cells and CD19(+)CD38(+) B cells were found in peginterferon-α treated HBeAg-positive CHB patients in whom HBeAg seroconversion had been achieved. What's more, both cell types peaked at 24 weeks for the HBeAg seroconversion group, while showing only a slight variation in the HBeAg non-seroconversion group. In addition, circulating CXCR5(+)CD4(+) T cells and hepatitis B surface antigens (HBsAg) were assessed at 24 weeks and 12 weeks, respectively, and the use of their ratio was explored in terms of its ability to predict HBeAg seroconversion. CONCLUSION: Dysfunction of the humoral immune response mediated by CXCR5(+)CD4(+) T cells is associated with the failure of HBeAg seroconversion. The CXCR5(+)CD4(+) T cells/HBsAg ratio is an ideal marker for predicting HBeAg seroconversion in CHB patients.

Circulating T follicular helper cells are associated with rapid virological response in chronic hepatitis C patients undergoing peginterferon therapy.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with abnormal T cell and B cell immune responses. T follicular helper (TFH) cells are a subset of CD4(+) T-helper cells and can activate B cells. This study aimed to investigate the role of circulating CXCR5(+)CD4(+) TFH cells, CD19(+) B cells and the associated cytokines in patients with chronic HCV infection. METHODS: The frequencies and phenotypes of circulating TFH cells and B cell subtypes were characterized using flow cytometry in chronic hepatitis C (CHC) patients and in healthy controls (HCs). The expression of IFN-γ, IL-12p70, IL-5, IL-13, IL-17F, IL-22, IL-23, TGF-ß1, IL-10 and IL-21 associated with Th1, Th2, Th17, regulatory T cells (Treg) and TFH cells were analyzed using a Quantibody array. The patients' clinical parameters were detected, and the effect of pegylated interferon plus ribavirin treatment on these immune indicators in CHC patients was determined. RESULTS: The frequency of CXCR5(+)CD4(+) T cells was significantly higher in CHC patients compared to HCs. There were no significant differences in CD19(+) B cells, CD19(+)CD27(+) B cells, or CD19(+)CD38(+) B cells between CHC patients and HCs. The expressions of cytokines associated with the CD4(+) Th lineage were higher in CHC patients than in HCs, except for IL-21. Patients with rapid virological response (RVR) showed an increased CXCR5(+)CD4(+) T cell count and decreased PD-1(+) CXCR5(+)CD4(+) T cell count compared to non-RVR patients after PEG-IFN/ribavirin treatment. CONCLUSIONS: These data demonstrate that circulating TFH cells and CD4(+) Th lineage-associated cytokines may play a role in HCV-related immune responses.