Sun, Chenyu

851 Background: Diffuse idiopathic skeletal hyperostosis (DISH) has been associated with increased risk of vertebral fractures in elderly men with prostate cancer. However, its potential role in the development of malignancies is poorly defined. In particular, the relationship between DISH and gastrointestinal (GI) cancers—including esophageal, gastric, colorectal, liver, biliary system, and pancreatic cancers—has not been examined. This study aimed to explore the risk of GI cancers among patients with DISH compared to those without DISH. We also assessed survival and incidence of vertebral fractures in these groups. Methods: Using the Mayo Clinic Platform (Full AMC1 dataset), we identified patients with and without a documented history of DISH. Outcomes included (1) prevalence and risk of GI cancers, (2) survival among GI cancer patients, and (3) vertebral fracture incidence. Relative risks (RRs) and hazard ratios (HRs) were calculated using SPSS20.0 and platform-based statistical tools, respectively. Kaplan–Meier survival analyses were performed to evaluate cancer survival outcomes. Results: A total of 6,189,860 patients were included, of whom 2,802 (0.05%) had DISH and 6,187,058 (99.95%) did not. Patients with DISH had a significantly higher prevalence of GI cancers compared with those without (RR = 1.63, 95% CI: 1.377–1.930). Survival analysis suggested worse outcomes among GI cancer patients without DISH (HR = 1.72, 95% CI: 1.25–2.35). Vertebral fracture incidence appeared lower among DISH patients, although low event numbers limit the reliability of this observation. Conclusions: DISH is associated with increased risk of GI cancers, while GI cancer patients without DISH may experience poorer survival. The observed trend toward lower vertebral fracture incidence among DISH patients should be interpreted cautiously due to limited event numbers. These findings highlight the importance of integrating musculoskeletal and oncologic perspectives in patient management and warrant further mechanistic and interventional studies. Survival analysis. Statistic Without DISH With DISH Patient Count 214,180 109 1 Month Survival 95.3% 98.2% 5 Month Survival 82.2% 87.9% 10 Month Survival 72.4% 85.1% 30 Month Survival 54.3% 74.1% 60 Month Survival 44.9% 60.6% Log-Rank 11.90 P-Value 0.00056 Hazard Ratio 1.72 (95% CI: 1.25 - 2.35)

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.

AbstractBackgroundParticipation in colonoscopies is an essential aspect of endoscopic training. The purpose of this study was to explore the impact of fellow/trainee participation on colonoscopy outcomes.MethodsThis meta‐analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO). From database inception to July 2022, studies investigating fellow involvement and colonoscopy outcomes were searched across Cochrane library, PubMed, and other databases. The random‐effects model was applied to generate more conservative estimates. Sensitive analysis was conducted to explore whether the result would depend on a particular study. Egger's test and Begg's test were used to estimate the potential for publication bias.ResultsSeventeen studies including 30,062 participants were included. We found that fellow/trainee involvement enhanced the overall rates of adenoma detection and polyp detection (OR = 1.26, 95% CI = 1.14–1.40, p < 0.001; OR = 1.29, 95% CI = 1.02–1.63, p = 0.020, respectively). The mean number of adenoma/polyps per colonoscopy was also higher with fellow/trainee participation (MD = 0.12, 95% CI = 0.08–0.17, p < 0.001; MD = 0.15, 95% CI = 0.02–0.28, p = 0.020, respectively).ConclusionIn addition to its educational purpose, fellow or trainee involvement is associated with beneficial effects on colonoscopy outcomes.

AbstractBackground and AimWe aim to systematically investigate gastrointestinal (GI) hospitalizations in the United States during the early phase of the COVID‐19 pandemic on a national level and the consequence that may inform practice and policies.MethodsA retrospective cross‐sectional analysis of adult hospitalizations with GI‐related diagnoses or procedures in the United States in 2020 was used, with hospitalizations from 2016 to 2019 used for contextual information.ResultsHospitalizations with principal and secondary GI diagnoses decreased by 13.3% and 8.2% from 2019 to 2020, respectively. Most GI diagnoses decreased in 2020, with a few exceptions including alcoholic liver disease (increased by 7.8% as a principal diagnosis) and acute liver failure (increased by 11.6% as a secondary diagnosis). The mortality rate of hospitalizations with GI disease increased in 2020 compared with 2019 (for principal diagnosis: adjusted odds ratio 1.08, 95% confidence interval 1.03–1.13, P = 0.001; for secondary diagnosis: adjusted odds ratio 1.10, 95% confidence interval 1.07–1.13, P < 0.001). Most GI procedures decreased except for a notable 8.3% increase in gastrostomy. The per‐GI‐hospitalization rate of procedures increased for hospitalizations with a principal GI diagnosis (56.4% vs 55.6%, P = 0.003) or unchanged for hospitalizations with secondary GI diagnoses (18.3% vs 18.2%, P = 0.512).ConclusionThe COVID‐19 pandemic resulted in a decrease in the volume of GI hospitalizations and procedures in 2020, but there was an increase in the mortality rate and some specific diagnoses including alcoholic liver disease and acute liver failure. These findings will likely enlighten future research and healthcare resource allocation for GI diseases.

Abstract Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.

Abstract Although costimulatory molecules have been shown to boost antitumor immune responses, their significance in stomach adenocarcinoma (STAD) is unknown. The purpose of this study was to examine the gene expression patterns of costimulatory molecule genes in STAD and to develop a predictive signature to aid in therapy selection and outcome prediction. We used 60 costimulatory family genes from prior research to conduct the first complete costimulatory molecule analysis in STAD patients. For the two groups discovered, consensus clustering analysis based on these 60 genes indicated unique distribution patterns and prognostic differences. Then, using Lasso and Cox regression analysis, 9 costimulatory molecular gene pairs (CMGPs) of prognostic value were discovered. With these 9 CMGPs, we were able to develop a costimulatory molecule-related prognostic signature, which performed well in an external dataset. For STAD patients, the signature was proved to be a risk factor independent of clinical characteristics, indicating that this may be employed in conjunction with clinical considerations. An further connection between the signature and immunotherapy response was discovered. People who had high mutation rates, an abundance of infiltrating immune cells, and an immunosuppressive milieu were classed as high-risk. It is possible that patients classed as high-risk have a better prognosis for immunotherapy since these patients have greater cytolytic activity scores and immunophenoscores of CTLA4 and PD-L1/PD-L2 blocker As a consequence, clinicians might use our signature to better assess patient prognosis and develop treatment plans.

AbstractObjectivesStudies on the association between metformin use and the risk of oesophageal cancer (OC) have generated controversial findings. This updated meta-analysis was conducted to reassess the effects of metformin on OC.MethodsA comprehensive search strategy was conducted to select relevant studies from origination to February 2021. Heterogeneity was evaluated through the Q test and I2 statistics. HRs and 95% CIs were pooled through either random-effect or fixed-effect models. Meta-regression, subgroup analyses, sensitivity analysis and publication bias diagnosis were also performed.ResultsSeven studies with 5 426 343 subjects were included. Metformin use was associated with reduced risk of OC (HR=0.69, 95% CI 0.54 to 0.87, p&lt;0.001). Sensitivity analysis suggested that the results were relatively stable.ConclusionMetformin is associated with a reduced risk of OC. More well-designed studies are still needed to further elaborate on these associations.PROSPERO registration numberCRD42021237127.

Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.