OBJECTIVES:To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis. METHODS:A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites. RESULTS:A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD. CONCLUSIONS:From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.
OBJECTIVES:To investigate outcomes of pregnancy termination in women with pulmonary hypertension (PH) and the correlations of anesthetic management strategies and intraoperative blood pressure variability with postoperative adverse events. METHODS:Sixty-two women underwent termination of pregnancy complicated by PH from June, 2019 to December, 2024 in Guangdong Provincial People's Hospital, including 24 women with mild-to-moderate PH and 38 with severe PH. Perioperative parameters and clinical outcomes of the patients were compared between the two groups. RESULTS:The most common subtype of PH in these women was pulmonary arterial hypertension (82.3%), caused primarily by congenital heart diseases (most frequently atrial or ventricular septal defects). The majority of the women underwent pregnancy termination by dilation and curettage (P=0.02) under general anesthesia (P=0.002). A total of 5 postoperative adverse events were recorded, including PH crisis (3 cases), arrhythmia requiring intervention (1 case), and pulmonary embolism (1 case). After multivariate adjustment, the severity of PH was significantly correlated with both postoperative ICU admission and prolonged postoperative length of stay (P<0.05). Among the patients undergoing dilation and curettage, the incidence of postoperative adverse events was significantly higher in patients receiving intrathecal anesthesia (P=0.014). A high blood pressure variability during surgery was correlated with a high rate of postoperative adverse events (P<0.05), which was significantly lower in patients with a blood pressure variability below the third tertile (OR=10.25, 95% CI=1.06-98.84, P=0.034). CONCLUSIONS:Postoperative recovery following pregnancy termination is associated with the severity of PH. Anesthetic methods for pregnancy termination should be individualized. Patients with a high intraoperative blood pressure variability have an increased risk of postoperative adverse events, and inhaled nitric oxide therapy is effective for reducing pulmonary arterial pressure during surgery.
Neoadjuvant immunotherapy is reshaping the treatment landscape of locally advanced gastric cancer (GC). The central clinical challenge has expanded from whether immunotherapy can enhance treatment efficacy to accurate identification of patients who are most likely to benefit and optimization of the subsequent surgical intervention. Accumulating evidence indicates that perioperative immunotherapy-based regimens can improve pathological complete response (pCR) rates and event-free survival (EFS) of the patients, promoting a shift from conventional chemotherapy plus radical surgery toward biomarker-guided, integrated precision treatment. For therapeutic stratification, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) expression, and refined human epidermal growth factor receptor 2 (HER2) classification have emerged as key indicators for predicting treatment response and selecting eligible patients. Meanwhile, treatment response assessment has evolved beyond conventional radiological evaluation to a multimodal framework incorporating pathological assessment, liquid biopsy, endoscopy, functional imaging, and artificial intelligence (AI)-assisted analysis, thereby providing more comprehensive support for individualized therapeutic decision-making. However, improved treatment efficacy has also raised new questions for surgical management. In particular, discordant responses between primary tumors and regional lymph nodes have challenged whether D2 radical gastrectomy planned according to pretreatment clinical staging remains the optimal surgical strategy. This review systematically summarizes the evolution of neoadjuvant treatment strategies for locally advanced GC, comprehensive response assessment, and redefinition of gastrectomy extent and lymphadenectomy strategy. Looking forward, with the clinical translation of emerging therapeutic targets such as Claudin 18.2 (CLDN18.2) and fibroblast growth factor receptor 2 (FGFR2), together with the maturation of AI-driven multimodal assessment systems, GC surgery may move beyond traditional anatomical boundaries. This transition potentially enables "maximally tolerated radical resection" to "function-preserving surgery guided by biological radicality", ultimately providing truly individualized precision surgical treatment for patients with locally advanced GC.
OBJECTIVES:To investigate the protective effect of lipocalin-2 (LCN2) gene knockout against sepsis-induced acute lung injury (ALI) and vascular endothelial dysfunction in mice and the mediating role of the nuclear factor-κB (NF-κB) signaling pathway. METHODS:Wild-type (WT) C57BL/6 mice receiving sham operation or cecal ligation and puncture (CLP) to induce sepsis were randomized into 3 subgroups for intraperitoneal injections of saline, PDTC, or Bay 11-7082 (n=10). Twenty LCN2 knockout (LCN2KO) mice were randomized for sham operation or CLP modeling. Pulmonary histopathological changes, lung wet-to-dry (W/D) ratio, lung index, Evans blue extravasation, and serum TNF-α and IL-6 levels in the mice were assessed. The colocalization of NF-κB, ICAM-1, and VCAM-1 with CD31 were analyzed using immunofluorescence staining, and endothelial cell apoptosis was examined with TUNEL/CD31 double staining. Western blotting and co-immunoprecipitation assay were performed to analyze the protein expressions of LCN2, p-P65/P65, ICAM-1, VCAM-1 and VE-cadherin and the interaction between LCN2 and P65. RESULTS:The WT mice receiving CLP showed severe lung structural damage with obvious edema and inflammation. In contrast, both the LCN2KO mouse and PDTC-treated WT mouse models of CLP showed milder lung injury with lower W/D ratio, lung index, Evans blue leakage, serum TNF‑α and IL-6 levels and markedly reduced colocalization signals of NF-κB, ICAM-1, and VCAM-1 with CD31. CLP resulted in significantly increased expression levels of LCN2, p-P65/P65, ICAM-1, and VCAM-1, lowered VE-cadherin levels, and enhanced endothelial cell apoptosis, and all these changes were significantly ameliorated in LCN2KO mice and WT mice with NF‑κB inhibitor treatment. Co-immunoprecipitation results suggested the interaction between lung LCN2 and P65. Bay 11-7082 significantly reduced inflammatory cytokine production, downregulated p-P65 expression and its downstream adhesion molecules, and restored VE-cadherin expression. CONCLUSIONS:LCN2 knockout alleviates sepsis-induced ALI and vascular endothelial dysfunction in mice by inhibiting NF-κB signaling.
OBJECTIVES:To investigate the therapeutic mechanism of Chaihu Shugan San (CSS) for treatment of menopausal syndrome (MPS) with liver qi stagnation. METHODS:Fifty-six female C57BL/6 mice were randomized into sham-operated group (n=13) and bilateral ovariectomy (OVX) groups (n=43), and the latter group was further randomized equally into menopausal group, menopausal liver qi stagnation (MPS+CUMS) group subjected to chronic unpredictable mild stress (CUMS), and CSS treatment group (with CSS gavage at daily dose of 6.47 g/kg for 28 days). MPS model establishment was validated by vaginal smears and behavior tests. The levels of sex hormones, neurotransmitters, and inflammatory cytokines in the serum and hippocampus were measured by ELISA. Hippocampal morphology was observed using HE and Golgi staining, and immunofluorescence staining and Western blotting were used to detect the expressions of microglial markers, synaptic plasticity proteins and C3/C3aR pathway proteins in the hippocampal CA1 region. RESULTS:The OVX mice showed disrupted estrous cycles. The MPS+CUMS mice exhibited obvious depression-like behaviors, abnormal sex hormones and neurotransmitters, elevated inflammatory factors, hippocampal CA1 neuronal loss with disordered arrangement and pyknosis, reduced dendritic spines, increased microglial markers, decreased synaptic plasticity proteins, and upregulated C3/C3aR pathway. All these changes were significantly improved or corrected after CSS treatment in MPS+CUMS mice. CONCLUSIONS:CSS alleviates MPS with liver qi stagnation possibly by inhibiting C3/C3aR-mediated M1 microglial polarization and improving synaptic plasticity.
