Mendelian Randomization Analyses of Chronic Immune-Mediated Diseases, Circulating Inflammatory Biomarkers, and Cytokines in Relation to Liver Cancer.

Liver cancer is closely linked to chronic inflammation. While observational studies have reported positive associations between extrahepatic immune-mediated diseases and systemic inflammatory biomarkers and liver cancer, the genetic association between these inflammatory traits and liver cancer remains elusive and merits further investigation. We conducted a two-sample Mendelian randomization (MR) analysis, using inflammatory traits as exposures and liver cancer as the outcome. The genetic summary data of both exposures and outcome were retrieved from previous genome-wide association studies (GWAS). Four MR methods, including inverse-variance-weighted (IVW), MR-Egger regression, weighted-median, and weighted-mode methods, were employed to examine the genetic association between inflammatory traits and liver cancer. Nine extrahepatic immune-mediated diseases, seven circulating inflammatory biomarkers, and 187 inflammatory cytokines were analyzed in this study. The IVW method suggested that none of the nine immune-mediated diseases were associated with the risk of liver cancer, with odds ratios of 1.08 (95% CI 0.87-1.35) for asthma, 0.98 (95% CI 0.91-1.06) for rheumatoid arthritis, 1.01 (95% CI 0.96-1.07) for type 1 diabetes, 1.01 (95% CI 0.98-1.03) for psoriasis, 0.98 (95% CI 0.89-1.08) for Crohn's disease, 1.02 (95% CI 0.91-1.13) for ulcerative colitis, 0.91 (95% CI 0.74-1.11) for celiac disease, 0.93 (95% CI 0.84-1.05) for multiple sclerosis, and 1.05 (95% CI 0.97-1.13) for systemic lupus erythematosus. Similarly, no significant association was found between circulating inflammatory biomarkers and cytokines and liver cancer after correcting for multiple testing. The findings were consistent across all four MR methods used in this study. Our findings do not support a genetic association between extrahepatic inflammatory traits and liver cancer. However, larger-scale GWAS summary data and more genetic instruments are needed to confirm these findings.

LncRNA model predicts liver cancer drug resistance and validate in vitro experiments.

Introduction: Hepatocellular carcinoma (HCC) patients may benefit from chemotherapy, but drug resistance is an important obstacle to favorable prognoses. Overcoming drug resistance is an urgent problem to be solved. Methods: Differential expression analysis was used to identify long non-coding RNAs (LncRNAs) that differed in chemotherapy-sensitive and chemotherapy-resistant patients. Machine learning algorithms including random forest (RF), lasso regression (LR), and support vector machines (SVMs) were used to identify important chemotherapy-related LncRNAs. A back propagation (BP) network was then used to validate the predictive capacity of important LncRNAs. The molecular functions of hub LncRNAs were investigated via qRT-PCR and cell proliferation assay. Molecular-docking technique was used to explore candidate drug of targets of hub LncRNA in the model. Results: A total of 125 differentially expressed LncRNAs between sensitive and resistant patients. Seventeen important LncRNAs were identified via RF, and seven factors were identified via LR. With respect to SVM, the top 15 LncRNAs of AvgRank were selected. Five merge chemotherapy-related LncRNAs were used to predict chemotherapy resistance with high accuracy. CAHM was a hub LncRNA of model and expression high in sorafenib resistance cell lines. In addition, the results of CCK8 showed that the sensitivity of HepG2-sorafenib cells to sorafenib was significantly lower than that of HepG2; and the sensitivity of HepG2-sorafenib cells transfected with sh-CAHM was significantly higher than that of Sorafenib. In the non-transfection group, the results of clone formation experiments showed that the number of clones formed by HepG2-sorafenib cells treated with sorafenib was significantly more than that of HepG2; after HepG2-sorafenib cells were transfected with sh-CAHM, the number of clones formed by Sorafenib treatment was significantly higher than that of HepG2 cells. The number was significantly less than that of HepG2-s + sh-NC group. Molecular Docking results indicate that Moschus was candidate drug for target protein of CAHM. Conclusion: Five chemotherapy-related LncRNAs could predict drug resistance in HCC with high accuracy, and the hub LncRNA CAHM has potential as a new biomarker for HCC chemotherapy resistance.

Sorafenib prevents the proliferation and induces the apoptosis of liver cancer cells by regulating autophagy and hypoxia-inducible factor-1.

Sorafenib has been approved as a systemic drug for advanced liver cancer; however, the underlying mechanisms remain unclear. The present study aimed to investigate the effects of sorafenib on the proliferation, autophagy and apoptosis of HepG2 cells under hypoxia. Briefly, reverse transcription-quantitative PCR and western blotting was performed to quantify HIF-1, LC3II/I, mTOR and p70s6K expression levels. Cell proliferation was determined using the Cell Counting Kit-8 assay and the cell apoptosis rate was evaluated using flow cytometry. The results demonstrated that autophagy and apoptosis were induced by hypoxia, and that sorafenib further enhanced hypoxia-induced autophagy and apoptosis in HepG2 cells in a dose-dependent manner. Furthermore, the mechanism of sorafenib-mediated autophagy in liver cancer cell were investigated by using chloroquine (CQ). The results showed that CQ significantly inhibited autophagy by decreasing LC3II/LC3I ratio in HepG2 cells treated with sorafenib and/or hypoxia. By contrast, sorafenib could increase the expression of hypoxia-inducible factor-1 (HIF-1) and of the autophagy marker (LC3II/I) and decrease the expression of mammalian target of rapamycin and p70 ribosomal S6 kinase in HepG2 cells under normoxia and hypoxia conditions, suggesting that sorafenib could induce hypoxia and autophagy in liver cancer cells. In addition, sorafenib was demonstrated to prevent proliferation and induce apoptosis of HepG2 cells under normoxia and hypoxia. Sorafenib could also prevent the malignant behavior of HepG2 by inducing hypoxia and autophagy. In summary, the findings from the present study suggested that sorafenib may inhibit liver cancer progression by activating autophagy and HIF-1 signaling pathway.

Evaluation of efficacy and safety of endovascular coiling for patients with aneurysmal subarachnoid hemorrhage: A protocol for systematic review and meta-analysis.

BACKGROUND: There is an elevated risk of rebleeding when the aneurysm is left untreated in patients diagnosed with aneurysmal subarachnoid hemorrhage (SAH). Occlusion of the lumen of the aneurysm using endovascular coiling is a common method to prevent rebleeding by occluding the aneurysm. This study aims to evaluate the efficacy and safety of endovascular coiling in patients with aneurysmal SAH. METHODS: A systematic search for relevant articles will be performed in 4 English electronic databases, including MEDLINE (from 1966 to October 2020), EMBASE (from 1980 to October 2020), the Cochrane Library (from 2020, issue 10), Scopus (from 1823 to October 2020), and 3 Chinese electronic databases, including Chinese Biomedical Literature Database (from 1995 to October 2020), WanFang (last searched October 2020), and China National Knowledge Infrastructure (last searched October 2020). This study will comprise randomized controlled trials (RCTs) that evaluate the effectiveness and safety of using endovascular coiling in the treatment of aneurysmal SAH. The articles in the databases will be independently screened by 2 authors to select potential studies, extract data, and evaluate the bias risk in the selected studies. This study will use suitable statistical methods to merge result data. RESULTS: The results of this study will be useful in determining the efficacy and safety of endovascular coiling for treating patients with aneurysmal SAH. CONCLUSION: The findings of this study will summarize the most recent evidence on the effectiveness and safety of using endovascular coiling to treat aneurysmal SAH. ETHICS AND DISSEMINATION: The present work does not involve any humans or animals; therefore, ethical approval is not needed. SYSTEMATIC REVIEW REGISTRATION: December 2, 2020.osf.io/yj4gq (https://osf.io/yj4gq/).

Soluble CD83 inhibits acute rejection by up regulating TGF-ß and IDO secretion in rat liver transplantation.

BACKGROUND: Allogeneic transplantation immune tolerance is currently a hot research issue and soluble CD83(sCD83) is a novel immunomodulator with great potential in inducing transplantation tolerance. OBJECTIVE: To investigate the mechanism of the immune tolerance effect of sCD83 on rat liver transplantation. METHOD: A rat liver transplantation model was established to study the effects of sCD83 on the expression levels of IL-2, IL-10, and TGF-ß in peripheral blood and the mRNA expressions of foxp3, TGF-ß, and Indoleamine 2,3-dioxygenase (IDO) in liver. The expression changes of costimulatory molecules CD80, CD86, and MHC-II on the surface of DC cells and the expressions of IDO + DC cell, TGF-ß + CD4 + T cell, and CD4 + CD25 + Foxp3 + T cell were analyzed and compared. RESULTS: sCD83 alleviated the rejection activity index (RAI) of rat liver transplantation in the early stage, increased the expressions of TGF-ß, IL-10 in peripheral blood and the mRNAs of IDO, TGF-ß and foxp3 in the transplanted liver, and down-regulated the expressions of MHC-II, CD86, and CD80 in DC cells, resulting in significant increased numbers of tolerogenic TGF-ß + CD4 + T cells, Treg cells, and IDO + DC cells with low expression. CONCLUSION: sCD83 inhibited acute rejection after liver transplantation in an allogeneic rat, and the mechanism was associated with the effect that sCD83 increased the expression of TGF-ß, activated IDO immunosuppressive pathway, and increased tolerogenic DC cells and Treg cells.

Expression of tripartite motif-containing 44 and its prognostic and clinicopathological value in human malignancies:a meta-analysis.

BACKGROUND: Previous researches have reported that tripartite motif-containing 44 (TRIM44) is related to the prognosis of multiple human tumors. This study was designed to systematically assess the prognostic value of TRIM44 in human malignancies and summarize its possible tumor-related mechanisms. METHODS: The available databases were searched for eligible studies that evaluated the clinicopathological and prognostic roles of TRIM44 in patients with malignancies. The hazard ratios (HR) and odds ratios (OR) were combined to assess the predictive role of TRIM44 using Stata/SE 14.1 software. RESULTS: A total of 1740 patients from thirteen original studies were finally included in this study. The results of the combined analysis showed that over-expression of TRIM44 protein was significantly correlated with shorter overall survival (OS) (HR = 1.94, 95% CI: 1.60-2.35) and worse disease-free survival (DFS) (HR = 2.13, 95% CI: 1.24-3.65) in cancer patients. Additionally, the combined ORs indicated that elevated expression level of TRIM44 protein was significantly associated with lymph node metastasis (OR = 2.69, 95% CI: 1.71-4.24), distant metastasis (OR = 10.35, 95% CI: 1.01-106.24), poor tumor differentiation (OR = 1.78, 95% CI: 1.03-3.09), increased depth of tumor invasion (OR = 2.72, 95% CI: 1.73-4.30), advanced clinical stage (OR = 2.75, 95% CI: 2.04-3.71), and recurrence (OR = 2.30, 95% CI: 1.34-3.95). Furthermore, analysis results using Gene Expression Profiling Interactive Analysis (GEPIA) showed that the expression level of TRIM44 mRNA was higher in most tumor tissues than in the corresponding normal tissues, and the relationship between TRIM44 mRNA level and prognosis in various malignant tumors also explored in GEPIA and OS analysis webservers. CONCLUSIONS: TRIM44 may serve as a valuable prognostic biomarker and a potential therapeutic target for patients with malignancies.

Prognostic and Clinicopathological Significance of lncRNA MVIH in Cancer Patients.

Objectives: LncRNA associated with microvascular invasion in hepatocellular carcinoma (lncRNA MVIH) is a newly discovered long non-coding RNA that aberrantly up-regulates and holds prognostic value in various tumors. The aim of the review and meta-analysis is to assess its prognostic potential and functions in malignant tumors. Materials and methods: PubMed, PMC, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Database were carefully searched for articles published as of Jan. 1, 2018. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to demonstrate prognostic value of lncRNA MVIH using Stata 12.0 software. Results: Six original studies including 830 cancer patients were ultimately enrolled in this meta-analysis. The pooled results showed that elevated lncRNA MVIH expression was significantly correlated with unfavorable OS (HR=2.17, 95% CI: 1.58-2.76, p < 0.001) and RFS/DFS/PFS (HR=2.21, 95% CI: 1.54-2.87, p < 0.001) in cancer patients. Additionally, high expression of lncRNA MVIH was related to positive lymph node metastasis (OR = 3.04, 95% CI: 1.37-6.75, p = 0.006) and advanced clinical stage (OR = 2.52, 95% CI: 1.68-3.79, p < 0.001). Conclusions: LncRNA MVIH over-expression was associated with poor clinical outcomes in multiple cancer types. More studies are warranted to verify and strengthen the clinical value of lncRNA MVIH in human cancers.

Prognostic value of pretreatment systemic immune-inflammation index in patients with gastrointestinal cancers.

BACKGROUND: Numerous studies have reported the relationship between systemic immune-inflammation index (SII) and prognosis in gastrointestinal (GI) cancers, but no consensus has been reached. We aimed to systematically evaluate the prognostic value of SII in patients with GI cancers. METHODS: Relevant published papers regarding the prognostic value of SII in patients with GI cancers were obtained from a number of electronic databases. The overall hazard ratios and the corresponding 95% confidence intervals (95% CIs) were calculated using a fixed or random effects model to assess the relationship between SII and prognosis through Stata SE 12.0. RESULTS: A total of 24 eligible published articles with 9,626 patients were included. From the pooled results, we found that high SII indicated worse overall survival (OS) in patients with GI cancers (HR = 1.52, 95%CI: 1.29-1.74). And patients with high SII had poorer disease-free survival (HR: 2.28, 95% CI: 1.46-3.10), time to recurrence (HR: 1.70, 95% CI: 1.11-2.30), and recurrence-free survival (HR: 1.60, 95% CI: 1.19-2.00) when compared with those with low SII values. CONCLUSIONS: SII might serve as a noninvasive and powerful tool for predicting survival outcome in patients with GI cancers.

Preoperative albumin-to-globulin ratio as a significant prognostic indicator in urologic cancers: a meta-analysis.

BACKGROUND: Emerging studies reported that preoperative albumin-to-globulin ratio (AGR) correlated with tumor progression and prognosis in several types of cancer. The aim of this study was to systematically explore the association between preoperative AGR and clinical outcomes in cancers of the urinary system. METHODS: Relevant articles were searched in PubMed, Embase and Web of Science by two independent investigators from inception to June 1, 2018. Eligible studies were selected based on predetermined selection criteria. Summarized HRs or ORs and 95% CIs were calculated for prognosis and clinicopathologic features with the fixed-effects or random-effects models. RESULTS: Eight cohort studies comprising 2,668 patients were included for analysis. The pooled results showed that a low AGR significantly correlated with poor OS (HR: 0.38, 95% CI: 0.27-0.48, P<0.001), worse cancer-specific survival (CSS) (HR: 0.36, 95% CI: 0.22-0.50, P<0.001) and inferior event-free survival (EFS) (HR: 0.36, 95% CI: 0.25-0.48, P<0.001) in urologic cancers. In addition, patients in low and high AGR groups showed significant differences in lymphovascular invasion (P<0.001), pT status (P<0.001) and pN status (P<0.001). CONCLUSION: Preoperative AGR might be a valuable, cheap and reproducible prognostic bio-marker in urologic cancers following surgical resection.