Tianjin Medical University General Hospital

Poor-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as World Federation of Neurosurgical Societies (WFNS) grades IV-V on admission, is associated with high mortality and disability. Although treatment initiation within 72 h is commonly recommended, the differential efficacy of specific subintervals during this therapeutic window (e.g., < 12 h, 12-24 h, and 24-72 h) has not been established. This study aims to determine the optimal timing of treatment of poor-grade aSAH using a large multicenter cohort. This cohort study included 990 cases of poor-grade (defined as WFNS grades IV-V on admission) aSAH identified retrospectively across 12 centers. Patients were classified into three different treatment time windows: < 12 h (n = 320), 12-23 h (n = 220), and ≥ 24 h (n = 450) after symptom onset. Outcomes included mortality, unfavorable outcome (modified Rankin scale [mRS] scores 3-6), and dependency (mRS scores 3-5) at follow-up. Cox proportional hazards regression models and competing risk analyses were used to assess the association between treatment delay and outcomes. During a median follow-up of 34.3 months, mortality rates were 46.6% for < 12 h, 38.2% for 12-23 h, and 32.4% for ≥ 24 h. Cox regression analysis revealed that treatment delays of 12-23 h (adjusted hazard ratio 0.73, 95% confidence interval 0.55-0.95) and ≥ 24 h (adjusted hazard ratio 0.64, 95% confidence interval 0.51-0.81) were associated with lower all-cause mortality compared to treatment within 12 h. Additionally, treatment delay of ≥ 24 h was associated with lower aSAH-related mortality (adjusted hazard ratio 0.62, 95% confidence interval 0.47-0.81). No significant association was found for aSAH-unrelated mortality. These findings were consistent across various patient characteristics in subgroup analyses. Our findings indicate that treatment delay of less than 12 h after symptom onset was associated with increased mortality risk and exacerbated long-term clinical outcomes in patients with poor-grade aSAH in contemporary practice. However, the lack of control groups limits the generalizability of these data to clinical practice. Future prospective studies are warranted to confirm these results.

Cyclin L1 (CCNL1) is highly expressed in multiple cancer types and has been linked to poor prognosis. However, the expression pattern of CCNL1 in breast cancer and its specific role in regulating breast cancer progression remain largely unknown. This study used cell and molecular biology techniques to examine how CCNL1 regulates the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of breast cancer cells. The applied methods encompassed plasmid transfection, Transwell assay, wound-healing assay, Western blot analysis, co-immunoprecipitation (Co-IP), and rescue assay. For the analysis of CCNL1-related factors and pathways, bioinformatics platforms including Metascape and HURI were also employed. CCNL1 is highly expressed in breast cancer cells and is associated with a poor prognosis. CCNL1 overexpression increased breast cancer cell invasion and migration and accelerated proliferation. Overexpression of CCNL1 was found to upregulate the mesenchymal marker Vimentin and downregulate the epithelial marker E-cadherin expression. There is close relationship between CCNL1, the NF-κB and PI3K/AKT signaling pathways. The direct interaction is verified between CCNL1 and DVL3 by Co-IP, indicating a negative correlation between the two proteins. CCNL1 overexpression affects breast cancer cells' paclitaxel sensitivity through the PI3K/AKT pathway. CCNL1 activates the NF-κB signaling pathway through its interaction with DVL3; additionally, it promotes the PI3K/AKT pathway. Together, these two mechanisms enable CCNL1 to exert a regulatory role in the progression of breast cancer.

Falls threaten the physical and mental health of older persons. Studies of the relationship between oral health and falls were fragmented in their selection of oral health indicators. We aimed to analyze whether and to what extent self-reported oral health was associated with falls among community-dwelling older adults in China. A cross-sectional study was conducted using data from physical examination and questionnaire survey for older adults in Tianjin, China. 2150 community-dwelling individuals aged 60 and older were included. Self-reported history of falls during the past year and oral health were collected using questionnaires. In the oral health index, fewer missing teeth, wearing dentures, no toothache, no bleeding gums, and brushing teeth at least twice a day were assigned as a score of 1, respectively. Oral health index was calculated by summing the scores of each item and ranged from 0 to 5, with higher scores indicating better oral health status. Logistic regression controlled for potential confounders was employed to analyze the association between oral health and falls. The prevalence of fall within the previous year was 12.6%. Logistic regression model showed that participants with higher oral health index (≥ 4) had a 26% lower fall rate than those with lower scores (OR = 0.71; 95% CI: 0.52 to 0.97) after adjusting for age, sex, health status and behaviors, and muscle status. Specifically, older adults who had lost 3–5 teeth (OR = 1.72; 95% CI: 1.01 to 2.69) and gingival bleeding (OR = 1.95; 95% CI: 1.20 to 3.17) had a higher fall prevalence rate compared with those losing 2 or fewer teeth and no gingival bleeding, respectively. Older adults with worse oral health, particularly more missing teeth and gingival bleeding, might be more vulnerable to falls. More attention paid to oral health may be helpful for fall prevention.

Lung adenocarcinoma (LUAD) is a major subtype of lung cancer that frequently develops brain metastases. Tumor heterogeneity substantially complicates disease management, and reliable biomarkers for metastatic progression remain lacking. LIM domain kinase 1 (LIMK1), a key regulator of cytoskeletal dynamics, has been implicated in tumor progression; however, its role in regulating brain metastasis in LUAD remains unclear. Single-cell RNA sequencing data from 11 primary LUAD tumors and 10 brain metastases were analyzed to identify malignant epithelial subclusters associated with metastatic dissemination. Tumor evolutionary trajectories and gene regulatory networks were explored using pseudotime trajectory analysis and weighted gene co-expression network analysis. LIMK1 expression was validated using The Cancer Genome Atlas dataset, as well as RT–qPCR and Western blotting in LUAD tissues and cell lines. Functional assays, including cell proliferation, colony formation, migration, and invasion, were performed following LIMK1 knockdown in LUAD cell lines. Six malignant epithelial subclusters were identified, among which clusters 0 and 4 were significantly enriched in brain metastases and associated with poor survival outcomes. LIMK1 was identified as a hub gene within these metastasis-associated clusters. LIMK1 expression was markedly upregulated in LUAD tissues and cell lines, and elevated LIMK1 levels predicted an unfavorable prognosis. Functional experiments demonstrated that LIMK1 depletion significantly inhibited tumor cell proliferation, migration, and invasion, while partially reversing epithelial–mesenchymal transition (EMT). Mechanistically, LIMK1 was found to promote LUAD progression through activation of the PI3K/AKT/mTOR signaling pathway. LIMK1 represents a novel prognostic biomarker and metastasis-associated regulator in LUAD. By driving EMT and activating PI3K/AKT/mTOR signaling, LIMK1 facilitates malignant progression, highlighting its potential as a therapeutic target for LUAD patients with brain metastases.

Aspirin (Asp) therapy reduces the risk of arterial thrombotic events. However, aspirin-related adverse effects, particularly cerebral hemorrhage with its high mortality and disability rates, remain a significant concern. Interestingly, long-term antiplatelet therapy does not appear to exacerbate bleeding severity in patients with hemorrhagic cerebrovascular disease, suggesting potential compensatory mechanisms inducing platelet activation post-hemorrhage. Brain-derived microvesicles (BDMVs) have been implicated in platelet activation, although the underlying molecular mechanisms are unclear. This study employed flow cytometry (FCM), ELISA, and hopping probe ion conductance microscopy (HPICM) to demonstrate that BDMVs significantly activate and induce morphological changes in aspirin-treated platelets. We discovered the presence of cyclooxygenase-1 (COX-1) on BDMVs. Then, the phosphorylated proteomics was used to analyze the effect of BDMVs on aspirin-treated platelet quantitatively and validate the involvement of several signaling molecules. Biological validation showed that BDMVs increased phospholipase C (PLC), protein kinase C (PKC) and Akt phosphorylation. We also used PLC inhibitor U73122 to treat BDMV-intervened platelet and found reduced phosphorylation of the downstream signaling molecule PKC. These findings suggest that COX-1 within BDMVs may partially counteract the inhibitory effect of aspirin on platelets. Furthermore, BDMVs, combined with arachidonic acid (AA), activate aspirin-treated platelets and suggest the involvement of the PLC/PKC pathway. This study provides a theoretical basis for the early treatment of patients with clinical aspirin-related cerebral hemorrhage.