Global, regional, and national burden of gallbladder and biliary diseases from 1990 to 2019.

BACKGROUND: Gallbladder and biliary diseases (GABDs) are a major public health issue. AIM: To analysis the cause-specific incidence, prevalence, and years lived with disability (YLDs) and its temporal trends of GABDs at the global, regional, and national level. Data on GABD were available from the Global Burden of Disease study 2019. METHODS: The estimated annual percentage change (EAPC) was used to quantify temporal trend in GABD age-standardized incidence rates (ASIRs), age-standardized prevalence rate (ASPR), and age-standardized YLD rate (ASYR) by region, sex. We analyzed the relationship between the GABD burden and country development level using the human development index (HDI). RESULTS: In 2019, the incident cases of GABD were 52003772, with an ASIR of 63432/100000 population. Globally, the number of incident cases and ASIR of GABD increased 97% and 58.9% between 1990 and 2019. Although, the ASPR and ASYR decreased from 1990 to 2019, the number of prevalent and YLDs cases increased. The highest ASIR was observed in Italy, and the highest ASPR and ASYR was observed in United Kingdom. The highest burden of GABD was found in low-SDI region, and the burden in female was significantly higher than males. A generally negative correlation (ρ = -0.24, P < 0.05) of GABD with the EAPC and human development index (HDI) (in 2021) were observed for ASIR. What's more, no correlation in ASPR (ρ = -0.06, P = 0.39) and ASYR (ρ = -0.07, P = 0.36) of GABD with the EAPC and HDI (in 2021) were observed, respectively. CONCLUSION: GABD remain a major global public health challenge; however, the burden of GABD varies geographically. Globally, the number of incident cases and ASIR of GABD increased between 1990 and 2019. The results of our study provide insight into the global disease burden of GABD and may assist policymakers in formulating effective policies to mitigate modifiable risk factors.

Overexpression of CENPL mRNA potentially regulated by miR-340-3p predicts the prognosis of pancreatic cancer patients.

BACKGROUND: In our previous study it was found that CENPL was overexpressed in hepatocellular carcinoma and significantly predicted patient's prognosis. However, the expression and prognostic value of CENPL in other gastrointestinal tumors remain unknown. Therefore, we investigated the expression and prognostic value of CENPL in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). METHODS: In this study, Oncomine, GEPIA, OncoLnc, TIMER, cBioPortal, miRWalk and ENCORI databases were used to analyze the level of CENPL mRNA, prognostic value and potential regulatory mechanism of CENPL mRNA in tumors. The CENPL expression and clinicopathological data regarding PAAD were from the UCSC Xena database and univariate and multivariate Cox regression analyses were performed using R (Version 3.6.3). Immunohistochemical staining was used to verify the expression of CENPL protein in clinical specimens. Cytoscape (Version: 3.7.2) was used to visualize microRNA (miRNA) that potentially regulates CENPL. RESULTS: Gene differential expression analysis showed that CENPL mRNA was significantly overexpressed in ESCA, STAD, PAAD, COAD and READ (p < 0.01). The overexpression of CENPL mRNA was significantly correlated with the poor prognosis of PAAD patients (p < 0.05). However, there was no significant correlation between the level of CENPL mRNA and the prognosis of ESCA, STAD, COAD and READ patients (p > 0.05). Univariate and multivariate Cox regression analyses suggested that CENPL was a prognostic risk factor for PAAD. The mutation rate of CENPL in PAAD was 2.2% (17/850). There was no significant correlation between the CENPL expression and the infiltration levels of immune cells in PAAD (|Cor|< 0.5). Immunohistochemical staining showed that CENPL was overexpressed in 42% (11/26) of PAAD specimens, which was significantly higher compared with that in the normal tissues. The expression of miR-340-3p and miR-484 in PAAD were significantly lower than in the normal tissues (p < 0.05) and PAAD patients with lower expression of miR-340-3p had poorer prognosis (p < 0.05). CONCLUSION: CENPL potentially regulated by miR-340-3p, is overexpressed in PAAD and predicts patient's prognosis, suggestive of a diagnostic and prognostic value in PAAD patients.

Exploration of the relationship between tumor mutation burden and immune infiltrates in colon adenocarcinoma.

Background: Tumor mutation burden (TMB) was correlated with the immunotherapeutic response in various malignancies. We aimed to evaluate the TMB immune signature in colon adenocarcinoma (COAD). Methods: Gene expression profile, mutation and clinical data of COAD patients were obtained from The Cancer Genome Atlas (TCGA) database. The samples were divided into high and low TMB level groups to identify differentially expressed genes (DEGs). Functional enrichments analyzes were performed to identify the biological functions of the DEGs. Then, immune cell infiltration signatures were calculated by the CIBERSORT algorithm. Finally, Cox proportional hazard model was constructed to estimate the prognostic value of the identified immune-related genes. Results: Gene set enrichment analysis in the high-TMB level group showed that DEGS were enriched in immune-related pathways, such as antigen processing and presentation, Toll-like receptor signaling and natural killer cell-mediated cytotoxicity. A higher infiltration level of CD8+ T cells, CD4+ T cells, activated NK cells , M1 Macrophages and T follicular helper cells was observed in the high-TMB level group. Furthermore, a Cox regression model combined with survival analysis based on the expression level of four identified prognostic genes was constructed, validated anf revealed that higher risk-score levels conferred poor survival outcomes in COAD patients. Conclusions: Our data demonstrate that the high TMB levels are associated with an immune signature in COAD and deepen the molecular understanding of TMB function in tumor immunotherapy.

The Cancer Genome Atlas (TCGA) based m6A methylation-related genes predict prognosis in hepatocellular carcinoma.

The current study aims to investigate the significance of N6-methyladenosine (m6A) methylation-related genes in the clinical prognosis of hepatocellular carcinoma (HCC) using bioinformatics analyses based on The Cancer Genome Atlas (TCGA) database. Transcriptome data and corresponding clinical data on m6A methylation-related genes (including 15 genes) were obtained from TCGA database. Differential expression of 15 genes was identified. Survival curves of subgroups based on m6A methylation-related gene expression levels were plotted. We selected potential predictive genes and analyzed their prognostic values using bioinformatics methods. Eleven genes (METTL3, YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2, FTO, KIAA1429, HNRNPC, HNRNPA2B1, and RBM15) were found to be overexpressed in HCC. Of these, five genes had worse survival (P < 0.05). There was a significant difference in the survival rate between subgroups with different expression levels of m6A. We selected five potential predictors (METTL3, KIAA1429, ZC3H13, YTHDF1, and YTHDF2) that met the independent predictive value. ZC3H13 was upregulated in patients with high cancer risk, whereas METTL3, KIAA1429, YTHDF1, and YTHDF2 were downregulated. In summary, we found that the expression levels of m6A methylation-related genes were different in patients with HCC and correlated with survival and prognosis. This implies that m6A methylation-related genes may be promising prognostic indicators or therapeutic targets for HCC.

Efficacy and Safety of Peripherally Acting Mu-Opioid Receptor Antagonists for the Treatment of Opioid-Induced Constipation: A Bayesian Network Meta-analysis.

OBJECTIVE: To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC). METHODS: Randomized controlled trials (RCTs) were searched for OIC therapy comparing PAMORAs with placebo. Both a pairwise and network meta-analysis were performed. The surface under the cumulative ranking area (SUCRA) was used to determine the efficacy and safety of OIC treatment using different PAMORAs. RESULTS: The primary target outcome was a response that achieves an average of three or more bowel movements (BMs) per week. In the network meta-analysis, four PAMORAs (naldemedine, naloxone, methylnaltrexone, and alvimopan) showed a better BM response than the placebo. Naldemedine was ranked first (odds ratio [OR] = 2.8, 95% credible interval [CrI] = 2-4.5, SUCRA = 89.42%), followed by naloxone (OR = 2.9, 95% CrI = 1.6-5.3, SUCRA = 87.44%), alvimopan (OR = 2.2, 95% CrI = 1.3-3.5, SUCRA = 68.02%), and methylnaltrexone (OR = 1.7, 95% CrI = 1.0-2.8, SUCRA = 46.09%). There were no significant differences in safety found between the PAMORAs and the placebo. CONCLUSIONS: We found that PAMORAs are effective and can be safely used for the treatment of OIC. In network meta-analysis, naldemedine and naloxone appear to be the most effective PAMORAs for the treatment of OIC.

Effects of probucol on hepatic tumor necrosis factor-alpha, interleukin-6 and adiponectin receptor-2 expression in diabetic rats.

BACKGROUND AND AIMS: Probucol is a lipid-lowering agent with anti-oxidant effects. Oxidative stress and inflammation are important in the pathophysiology of insulin resistance. We aimed to evaluate the effects of probucol on liver histological changes, serum and hepatic levels of adipokines in rats with high fat-induced type 2 diabetes (T2D). METHODS: Thirty-six rats were divided into a normal control group, a high fat-induced T2D group and a probucol treatment group. After six weeks of treatment with probucol, we evaluated liver histological changes and measured homeostasis model assessment index (HOMA-IR), serum superoxide dismutase (SOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, adiponectin and hepatic TNF-alpha, IL-6 and adiponectin receptor-2 (adipoR2) mRNA. RESULTS: The degree of hepatic steatosis and inflammation, HOMA-IR, serum ALT, TNF-alpha and IL-6 concentrations, and hepatic TNF-alpha and IL-6 mRNA expression in diabetic rats were significantly higher compared with normal controls. Serum SOD and adiponectin concentrations and hepatic adipoR2 mRNA expression in diabetic rats were significantly lower compared with normal controls. Probucol significantly reduced the degree of hepatic steatosis, HOMA-IR, serum ALT, TNF-alpha and IL-6 concentrations, and hepatic TNF-alpha and IL-6 mRNA expression. Probucol significantly raised serum SOD and adiponectin concentrations and hepatic adipoR2 mRNA expression. CONCLUSIONS: In rats with high fat-induced T2D, treatment with probucol improved insulin sensitivity, hepatic steatosis by raising circulating adiponectin and hepatic adipoR2 levels, in addition to reducing pro-inflammatory cytokines in the circulation and liver.

Angiotensin-converting enzyme inhibitors improve hepatic steatosis by modulating expression of tumour necrosis factor-alpha, interleukin-6 and adiponectin receptor-2 in rats with type 2 diabetes.

1. Angiotensin-converting enzyme inhibitors (ACEI) are hypotensive drugs that have been shown to prevent Type 2 diabetes mellitus (T2DM) in high-risk individuals. However, in T2DM, the effects of ACEI on hepatic steatosis are not known. The aim of the present study was to examine the effects of ACEI on changes in liver histology and hepatic mRNA expression of adipokines in rats with T2DM. 2. Thirty-six rats were divided into a normal control group, a T2DM group and a fosinopril-treated group. After six weeks of treatment with 5 mg/kg per day fosinopril, an ACEI, changes in liver histology, serum fasting glucose (FG), insulin, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, adiponectin were evaluated, as was hepatic TNF-alpha, IL-6 and adiponectin receptor-2 (adipoR2) mRNA expression. 3. The degree of hepatic steatosis and inflammation, serum FG, insulin, TG, TC, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression were significantly higher in rats with T2DM than in normal controls. Serum adiponectin concentrations and hepatic adipoR2 mRNA expression in rats with T2DM were significantly lower than in normal controls. Fosinopril significantly reduced the degree of hepatic steatosis, serum FG, insulin, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression. Fosinopril significantly increased serum adiponectin concentrations and hepatic adipoR2 mRNA expression. 4. In conclusion, the ACEI improved insulin sensitivity and hepatic steatosis in rats with T2DM by increasing circulating adiponectin and hepatic adipoR2 levels, in addition to reducing pro-inflammatory cytokine levels in the circulation and liver.