Impact of peptic ulcer bleeding on the in-hospital outcomes of cirrhotic patients with acute gastrointestinal bleeding: an international multicenter study.

OBJECTIVES: Peptic ulcer is the most common source of non-variceal bleeding. However, it remains controversial whether the outcomes of cirrhotic patients with peptic ulcer bleeding differ from those with variceal bleeding. METHODS: Cirrhotic patients with acute gastrointestinal bleeding (AGIB) who underwent endoscopy and had an identifiable source of bleeding were retrospectively screened from an international multicenter cohort. Logistic regression analyses were performed to explore the impact of peptic ulcer bleeding on in-hospital death and 5-day failure to control bleeding. Propensity score matching (PSM) analysis was performed by matching age, gender, Child-Pugh score, and model for end-stage liver disease score between the peptic ulcer bleeding and variceal bleeding groups. RESULTS: Overall, 1535 patients were included, of whom 73 (4.7%) had peptic ulcer bleeding. Multivariate logistic regression analyses showed that peptic ulcer bleeding was not independently associated with in-hospital death (OR = 2.169, p = 0.126) or 5-day failure to control bleeding (OR = 1.230, p = 0.680). PSM analyses demonstrated that both in-hospital mortality (9.7% vs. 6.3%, p = 0.376) and rate of 5-day failure to control bleeding (6.9% vs. 5.4%, p = 0.787) were not significantly different between the two groups. CONCLUSIONS: The impact of peptic ulcer bleeding on the in-hospital outcomes of cirrhotic patients is similar to that of variceal bleeding.

In this international multicenter study, we included 1535 patients with acute gastrointestinal bleeding (AGIB) and divided them into peptic ulcer bleeding and variceal bleeding groups. We found that only a minority of AGIB episodes in cirrhotic patients was attributed to peptic ulcer. Additionally, after adjusting for the severity of liver dysfunction, the in-hospital mortality and the rate of 5-day failure to control bleeding should be similar between cirrhotic patients with peptic ulcer bleeding and those with variceal bleeding.

cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity.

Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

Identification of the shared molecular mechanisms between major depressive disorder and COVID-19 from postmortem brain transcriptome analysis.

OBJECTIVES: This study aims to investigate the molecular mechanisms underlying the interaction of major depressive disorder (MDD) and COVID-19, and on this basis, diagnostic biomarkers and potential therapeutic drugs are further explored. METHODS: Differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify common key genes involved in the pathogenesis of COVID-19 and MDD. Correlations with clinical features were explored. Detailed mechanisms were further investigated through protein interaction networks, GSEA, and immune cell infiltration analysis. Finally, Enrichr's Drug Signature Database and Coremine Medical were used to predict the potential drugs associated with key genes. RESULTS: The study identified 18 genes involved in both COVID-19 and MDD. Four key genes (MBP, CYP4B1, ERMN, and SLC26A7) were selected based on clinical relevance. A multi-gene prediction model showed good diagnostic efficiency for the two diseases: AUC of 0.852 for COVID-19 and 0.915 for MDD. GO and GSEA analyses identified specific biological functions and pathways associated with key genes in COVID-19 (axon guidance, metabolism, stress response) and MDD (neuron ensheathment, biosynthesis, glutamatergic neuron differentiation). The key genes also affected immune infiltration. Potential therapeutic drugs, including small molecules and traditional Chinese medicines, targeting these genes were identified. CONCLUSION: This study provides insights into the complex biological mechanisms underlying COVID-19 and MDD, develops an effective diagnostic model, and predicts potential therapeutic drugs, which may contribute to the prevention and treatment of these two prevalent diseases.

Retrospective cohort study for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer.

Background: The aim of this article was to establish the clinical prognostic models and identify the predictive radiation dosimetric parameters for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer. Methods: In this retrospective cohort study, patients with rectal adenocarcinoma undergoing concurrent long-term chemoradiotherapy were included. The primary outcome of interest was grade 2 or higher (2+) thrombocytopenia (platelet(PLT) count <75,000/µL). Secondary outcomes included: grade 1 or higher thrombocytopenia (PLT count<100,000/µL) and the PLT count during chemoradiotherapy and its nadir. The risk prediction model was developed by logistic regression to identify clinical predictors of 2+ thrombocytopenia. Univariate linear regression models were used to test correlations between radiation dosimetric parameters and the absolute PLT count at nadirs. Results: This retrospective cohort comprised 238 patients. Fifty-four (22.6%) patients developed thrombocytopenia during concurrent chemoradiotherapy, while 15 (6.3%) patients developed 2+ thrombocytopenia. Four independently associated risk factors, including age, Alb level, PLT count, and chemotherapy regimen, were included in the final model and used to form a 2+ thrombocytopenia probability estimation nomogram. The C-index was 0.87 (95% CI: 0.78-0.96). The calibration plot showed a moderate agreement, and the Brier score was 0.047 (95% CI: 0.025-0.070). The total absolute volume of bone marrow irradiated by 5 Gy, 10 Gy and 15 Gy of radiation (BM-V5ab, BM-V10ab, BM-V15ab), calculated by the volume of bone marrow multiplied by the corresponding Vx, were identified as new predictors. The nadir of PLT was found to be negatively correlated with BM-V5ab (ß = -0.062, P =0.030), BM-V10ab (ß = -0.065, P =0.030) and BM-V15ab (ß = -0.064, P =0.042). Conclusion: The occurrence of 2+ thrombocytopenia during concurrent chemoradiotherapy for rectal cancer can be predicted by the patient's baseline status and chemoradiotherapy regimen, and low dose irradiation of bone marrow can affect the level of platelets during the treatment.