This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Objective To investigate the action mechanism of long non-coding RNA(lncRNA)-N1LR on blood-brain barrier(BBB)after cerebral ischemia-reperfusion(I/R)injury.Methods Primary rat brain microvascular endothelial cells(BMECs)were cultured and treated with OGD/R to simulate cerebral I/R injury.The experiment was divided into normal control group,ln-cRNA-N1LR OGD group,overexpression group(lncRNA-N1LR overexpression after OGD treat-ment)and silence group(lncRNA-N1LR silence after OGD treatment).The mRNA levels of ln-cRNA-N1LR,claudin-5 and occludin in each group were detected by RT-qPCR.The BBB permea-bility was detected by FITC-dextran infiltration assay.The expression of claudin-5 and occludin were detected by Western blotting.Results The mRNA levels of lncRNA-N1LR,occludin and claudin-5 were significantly decreased(0.31±0.01 vs 1.00±0.10,0.42±0.03 vs 1.01±0.13,0.38±0.03 vs 1.00±0.15,P＜0.05),and the BBB permeability was significantly increased(58.79± 3.04 vs 8.87±0.63,P＜0.05)in the OGD group than the control group.The lncRNA-N1LR over-expression group increased the mRNA expression of lncRNA-N1LR,occludin and claudin-5(0.67±0.07 vs 0.31±0.01,0.92±0.02 vs 0.42±0.03,0.70±0.08 vs 0.38±0.03,P＜0.05),and decreased the BBB permeability(41.57±2.43 vs 58.79±3.04,P＜0.05)than the OGD group.lncRNA-N1LR silence resulted in lower mRNA levels of lncRNA-N1LR,occludin and claudin-5(0.21±0.02 vs 0.31±0.01,0.31±0.03 vs 0.42±0.03,0.22±0.02 vs 0.38±0.03,P＜0.05),and enhanced BBB permeability(72.34±1.43 vs 58.79±3.04,P＜0.05)when compared with the OGD group.Conclusion Up-regulation of lncRNA-N1LR may play a neuroprotective role by reducing BBB permeability.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Objective To investigate the mechanism of metformin on oxygen-glucose deprivation/reoxygenation(OGD/R)injury in U251 cells.Methods Human glioma cell line U251 cells were cultured and divided into 6groups:blank control group,model group,metformin medium dose group,metformin high dose group,agonist group(Wnt3a,Wnt/β-catenin signaling pathway agonist),inhibitor group(metformin+XAV939,Wnt/β-catenin signaling pathway inhibitor).Except for the blank control group,the cells in the other groups were subjected to OGD/R for 2h and then reperfusion for 24h to establish the OGD/R model.The animals were treated with met-formin,Wnt3a and XAV939 24h before modeling.Cell viability and toxicity were detected by CCK-8method and lactate dehydrogenase(LDH)assay.ROS formation was detected by DHE staining.Glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)malond-ialdehyde(MDA),interleukin-6(IL-6),inducible nitric oxide synthase(iNOS)and tumor necrosis factor-α(TNF-α)were de-tected by enzyme-linked immunoadsordent assay(ELISA).The protein expression levels of β-catenin,cyclin D1,p-GSK-3β(Ser9)and GSK-3β were detected by Western blot.Results Compared with blank control group,LDH,ROS,MDA,IL-6,iNOS and TNF-α in model group,metformin group,agonist group and inhibitor group were significantly increase.The relative expression lev-els of SOD,GSH-Px,β-catenin,cyclin D1,p-GSK-3β(Ser9)and cell viability were significantly decreased.Compared with mod-el group,the levels of LDH,ROS,MDA,IL-6,iNOS and TNF-α in metformin group and agonist group were significantly decreased,while the relative expression levels of SOD,GSH-Px,β-catenin,cyclin D1,p-GSK-3β(Ser9)and the cell viability were signifi-cantly increased.Compared with metformin group,LDH,ROS,MDA,IL-6,iNOS and TNF-α in metformin group and inhibitor group were significantly increase,the relative expression levels of SOD,GSH-Px,β-catenin,cyclin D1,p-GSK-3 β(Ser9)and the cell viability were significantly decreased.Conclusion Metformin may play a protective role in OGD/R of U251 cells through Wnt/β-cate-nin signaling pathway.

BACKGROUND: The molecular mechanisms driving tumorigenesis have continually been the focus of researchers. Cuproplasia is defined as copper-dependent cell growth and proliferation, including its primary and secondary roles in tumor formation and proliferation through signaling pathways. In this study, we analyzed the differences in the expression of cuproplasia-associated genes (CAGs) in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication. METHODS: Raw data from 11,057 cancer samples were acquired from multiple databases. Pan-cancer analysis was conducted to analyze the CAG expression, single-nucleotide variants, copy number variants, methylation signatures, and genomic signatures of micro RNA (miRNA)-messenger RNA (mRNA) interactions. The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs. Using single-sample Gene Set Enrichment Analysis (ssGSEA) and Immune Cell Abundance Identifier database, immune cell infiltration was analyzed with the ssGSEA score as the standard. RESULTS: Aberrantly expressed CAGs were found in multiple cancers. The frequency of single-nucleotide variations in CAGs ranged from 1% to 54% among different cancers. Furthermore, the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers. ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma, while the converse was true for MT1A and MT2A . In addition, we established cuproplasia scores and demonstrated their strong correlation with patient prognosis, immunotherapy responsiveness, and disease progression ( P  <0.05). Finally, we identified potential candidate drugs by matching gene targets with existing drugs. CONCLUSIONS This study reports the genomic characterization and clinical features of CAGs in pan-cancers. It helps clarify the relationship between CAGs and tumorigenesis, and may be helpful in the development of biomarkers and new therapeutic agents.
Humans ; Female ; Genomics ; Carcinogenesis ; Carcinoma ; Breast Neoplasms ; Cell Transformation, Neoplastic ; Nucleotides ; Tumor Microenvironment

ObjectiveTo explore the effects of after-school tutoring for school-age children on their emotions and behaviors， and to provide a basis for developing after-school tutoring and psychological support strategies for school-age children. MethodsFour elementary schools in a district of Shanghai were selected by simple random sampling method. Whole group sampling was conducted by class， and parents of students were surveyed by general questionnaire and the scale of strengths and difficulties. Information was collected on the basic conditions of children and families and the results were compared and analyzed. ResultsThis study showed that 88.26% of children attended extracurricular classes， of which 26.16% attended 3 or more classes， 42.5% attended cultural classes， 28.3% attended sports classes， and 59.8% attended art classes. Children who did not attend classes had higher pro-social scores. Children who attended reading class had lower scores for emotional problems that was a protective factor for emotional problems. Children who chose extracurricular programs in sports and reading also had lower overall scores for difficulties. Excessive use of electronic devices by school-age children on weekdays or weekends had a negative effect on emotional and conduct problem scores regardless of whether they chose extracurricular programs. It appeared that the choice of cultural programs， art programs and different levels of exercise intensity had no effect on children's emotions and behaviors. ConclusionFor children with low pro-social level， extracurricular classes should be carefully selected. For extracurricular classes， more reading and sports-related courses can be considered， which have positive effects on school-age children’s emotions and behaviors. Regardless of the choice of extracurricular classes， try to avoid excessive online classes.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins