Background: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling (ABPP). From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry (MS). Among these proteins, chromate reductase/nicotinamide adenine dinucleotide (NADH) phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource (UniProt) database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Immune checkpoint blockade therapy has demonstrated remarkable efficacy in treating various malignancies; however, its clinical application remains challenged by low response rates and immune-related adverse events. Immunoglobulin superfamily member 11 (IGSF11), an inhibitory immune checkpoint molecule, serves as a specific ligand for the V-domain immunoglobulin suppressor of T cell activation (VISTA). Through the IGSF11/VISTA axis, it suppresses T cell function and represents a promising novel target for cancer immunotherapy. IGSF11 is widely expressed across multiple tumor types, though its regulatory mechanisms vary depending on the malignancy. Studies have confirmed that blocking the IGSF11-VISTA interaction or specifically inhibiting IGSF11 exerts antitumor effects. While IGSF11 is closely associated with patient prognosis, its prognostic significance differs among cancer types. This review systematically summarizes the structural characteristics of IGSF11, its regulatory mechanisms, interaction with VISTA, and functional role within the tumor microenvironment.
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Humans ; Immunotherapy ; Neoplasms/metabolism* ; B7 Antigens/chemistry* ; Animals ; Molecular Targeted Therapy ; Tumor Microenvironment

Sini Decoction (SNT) is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold. However, elucidating the mechanism of action of SNT remains challenging due to its complex multiple components. This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE)-based drug affinity responsive target stability (DARTS) with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction. The analysis identified 590 proteins, with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group. Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments, the findings indicate that protein disulfide-isomerase A3 (PDIA3) may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.
Myocardial Infarction/genetics* ; Proteomics/methods* ; Drugs, Chinese Herbal/chemistry* ; Animals ; Protein Disulfide-Isomerases/genetics* ; Male ; Two-Dimensional Difference Gel Electrophoresis/methods* ; Humans ; Rats ; Rats, Sprague-Dawley ; Electrophoresis, Gel, Two-Dimensional

Sennoside A(SA),a typical prodrug,exerts its laxative effect only after its transformation into rhei-nanthrone catalyzed by gut microbial hydrolases and reductases.Hydrolases have been identified,but reductases remain unknown.By linking a photoreactive group to the SA scaffold,we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling(ABPP).From lysates of an active strain,Bifidobacterium pseudocatenulatum(B.pseu-docatenulatum),397 proteins were enriched and subsequently identified using mass spectrometry(MS).Among these proteins,chromate reductase/nicotinamide adenine dinucleotide(NADH)phosphate(NADPH)-dependent flavin mononucleotide(FMN)reductase/oxygen-insensitive NADPH nitroreductase(nfrA)was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource(UniProt)database screening.We also determined that recombinant nfrA could reduce SA.Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Medication reconciliation plays a key role in improving patient medication safety,reducing inappropriate polypharmacy,and promoting the high-quality development of pharmaceutical services.Compared to advanced international guidelines,China's medication reconciliation service standards have deficiencies in areas such as definition and process design,and multidisciplinary team building.There is a need to establish a comprehensive medication reconciliation effect evaluation index system,develop pharmacist-led multidisciplinary teams,promote the advancement of artificial intelligence and big data technologies,and strengthen outpatient and community medication reconciliation coverage,thereby contributing to the high-quality development of pharmaceutical services in China.

Objective: This study aimed to compare outcomes and adverse events of patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT) with cisplatin single-agent chemotherapy vs. CCRT with cisplatin combined with paclitaxel dualagent therapy. The primary outcomes are overall survival (OS), progression-free survival (PFS), local recurrence (LR), distant metastasis (DM) and the occurrence of adverse events. Methods: This retrospective cohort study included patients with FIGO 2009 stage IB1-IVA cervical squamous cell carcinoma undergoing radical CCRT. Patients were divided into groups A and B, treatment outcomes were compared between the two groups after 1:1 proportional propensity score matching. Results: Medical records of 1,203 patients were reviewed and 572 patients were finally included for propensity score matching. After propensity score matching, 121 pairs of patients were selected for analysis. The OS, PFS, LR and DM rates were 78.5% and 83.5% (p=0.417), 73.3% and 78.5% (p=0.312), 6.6% and 2.5% (p=0.123), 19% and 15.7% (p=0.497) for groups A and B, respectively. Further subgroup analysis according to stage and lymph node metastatic status showed no difference in survival between the two groups. The incidence of grade 3–4 acute haematological toxicities was different between the two groups (p<0.05). Conclusion Cisplatin combined with paclitaxel CCRT couldn’t improve the survival rates of patients with LACC. However, the hematological toxicity of combination chemotherapy is more severe but controllable. Cisplatin single-agent therapy remains the first choice for CCRT. Further prospective studies are indicated to provide evidence for the efficacy of cisplatin plus paclitaxel in dual-agent concurrent therapy.

Objective: This study aimed to compare outcomes and adverse events of patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT) with cisplatin single-agent chemotherapy vs. CCRT with cisplatin combined with paclitaxel dualagent therapy. The primary outcomes are overall survival (OS), progression-free survival (PFS), local recurrence (LR), distant metastasis (DM) and the occurrence of adverse events. Methods: This retrospective cohort study included patients with FIGO 2009 stage IB1-IVA cervical squamous cell carcinoma undergoing radical CCRT. Patients were divided into groups A and B, treatment outcomes were compared between the two groups after 1:1 proportional propensity score matching. Results: Medical records of 1,203 patients were reviewed and 572 patients were finally included for propensity score matching. After propensity score matching, 121 pairs of patients were selected for analysis. The OS, PFS, LR and DM rates were 78.5% and 83.5% (p=0.417), 73.3% and 78.5% (p=0.312), 6.6% and 2.5% (p=0.123), 19% and 15.7% (p=0.497) for groups A and B, respectively. Further subgroup analysis according to stage and lymph node metastatic status showed no difference in survival between the two groups. The incidence of grade 3–4 acute haematological toxicities was different between the two groups (p<0.05). Conclusion Cisplatin combined with paclitaxel CCRT couldn’t improve the survival rates of patients with LACC. However, the hematological toxicity of combination chemotherapy is more severe but controllable. Cisplatin single-agent therapy remains the first choice for CCRT. Further prospective studies are indicated to provide evidence for the efficacy of cisplatin plus paclitaxel in dual-agent concurrent therapy.

BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged