Pancreatic cancer (PC) is a common and highly malignant tumor. Basement membrane (BM) is formed by the crosslinking of extracellular matrix macromolecules and acts as a barrier against tumor cell metastasis. However, the role of BM in PC prognosis, immune infiltration, and treatment remains unclear. This study collected transcriptome and clinical survival data of PC via TCGA, GEO, and ICGC databases. PC patients (PCs) from the First Affiliated Hospital of Dalian Medical University were obtained as the clinical validation cohort. BM-related genes (BMRGs) were acquired from GeneCards and basement membraneBASE databases. A total of 46 differential-expressed BMRGs were identified. Then the BM-related prognostic model (including DSG3, MET, and PLAU) was built and validated. PCs with a low BM-related score had a better outcome and were more likely to benefit from oxaliplatin, irinotecan, and KRAS(G12C) inhibitor-12, and immunotherapy. Immune analysis revealed that BM-related score was positively correlated with neutrophils, cancer-associated fibroblasts, and macrophages infiltration, but negatively correlated with CD8+ T cells, NK cells, and B cells infiltration. PCs from the clinical cohort further verified that BM-related model could accurately predict PCs' outcomes. DSG3, MET, and PLAU were notably up-regulated within PC tissues and linked to a poor prognosis. In vitro experiments showed that DSG3 knockdown markedly suppressed the proliferation, migration, and invasion of PC cells. Molecular docking indicated that epigallocatechin gallate had a strong binding activity with DSG3, MET, and PLAU and may be used as a potential therapeutic agent for PC. In conclusion, this study developed a BM-related model associated with PC prognosis, immune infiltration, and treatment, which provided new insights into PC stratification and drug intervention.
Abstract Background Acute pancreatitis (AP) is an unpredictable and potentially fatal disorder. A derailed or unbalanced immune response may be the root of the disease’s severe course. Disorders of lipid metabolism are highly correlated with the occurrence and severity of AP. We aimed to characterize the contribution and immunological characteristics of lipid metabolism-related genes (LMRGs) in non-mild acute pancreatitis (NMAP) and identify a robust subtype and biomarker for NMAP. Methods The expression mode of LMRGs and immune characteristics in NMAP were examined. Then LMRG-derived subtypes were identified using consensus clustering. The weighted gene co-expression network analysis (WGCNA) was utilized to determine hub genes and perform functional enrichment analyses. Multiple machine learning methods were used to build the diagnostic model for NMAP patients. To validate the predictive effectiveness, nomograms, receiver operating characteristic (ROC), calibration, and decision curve analysis (DCA) were used. Using gene set variation analysis (GSVA) and single-cell analysis to study the biological roles of model genes. Results Dysregulated LMRGs and immunological responses were identified between NMAP and normal individuals. NMAP individuals were divided into two LMRG-related subtypes with significant differences in biological function. The cluster-specific genes are primarily engaged in the regulation of defense response, T cell activation, and positive regulation of cytokine production. Moreover, we constructed a two-gene prediction model with good performance. The expression of CARD16 and MSGT1 was significantly increased in NMAP samples and positively correlated with neutrophil and mast cell infiltration. GSVA results showed that they are mainly upregulated in the T cell receptor complex, immunoglobulin complex circulating, and some immune-related routes. Single-cell analysis indicated that CARD16 was mainly distributed in mixed immune cells and macrophages, and MGST1 was mainly distributed in exocrine glandular cells. Conclusions This study presents a novel approach to categorizing NMAP into different clusters based on LMRGs and developing a reliable two-gene biomarker for NMAP.
Abstract Objectives To assess the safety and efficacy of anlotinib (a multi‐targeted tyrosine kinase inhibitor) combined with toripalimab (a PD‐1 monoclonal antibody) in the treatment of unresectable biliary tract cancer (BTC). Methods In this prospective, single‐arm, single‐centre exploratory clinical study, patients with locally progressed or metastatic BTC were included. Patients were treated with anlotinib (12 mg, PO, QD, for 2 weeks and then stopped for a week, 21 days for a cycle) and toripalimab (240 mg, IV, Q3W). The primary endpoint of the study was the objective response rate (ORR), as defined in RECIST version 1.1 criteria. Results In this study, 15 BTC patients who met the criteria were enrolled. The ORR was 26.7%, the median progression‐free survival (mPFS) was 8.6 months (95% CI: 2.1–15.2), the median overall survival (mOS) was 14.53 months (95% CI: 0.8–28.2) and the disease control rate (DCR) was 87.6%. A patient with hilar cholangiocarcinoma was successfully converted after three cycles of treatment and underwent surgical resection. Furthermore, patient gene sequencing revealed that STK11 was mutated more frequently in patients with poor outcomes. In addition, patients with a CD8/Foxp3 ratio > 3 had a longer survival than those with a CD8/Foxp3 ratio ≤ 3 ( P = 0.0397). Conclusions In patients with advanced BTC, the combination of anlotinib and toripalimab demonstrated remarkable anti‐tumor potential, with increased objective response rates (ORR), longer overall survival (OS) and progression‐free survival (PFS). Moreover, STK11 and CD8/Foxp3 may be as biomarkers that can predict the effectiveness of targeted therapy in combination with immunotherapy.
Observational epidemiological studies indicate a higher fracture incidence in rheumatoid arthritis (RA) patients compared to the general population. However, the causal relationship between RA and fracture risk, particularly traumatic and osteoporotic fractures, is not well established. We performed Mendelian randomization (MR) analysis to evaluate the causal relationship between RA and fracture risk. We performed a MR analysis using summary statistics from genome-wide association studies to investigate the causal association between RA and the risk of traumatic fractures at 9 sites and 3 types of osteoporotic fractures. The primary analysis used inverse-variance weighting, supplemented by MR-Egger regression and other methods to assess causal relationships and sensitivity analyses, including heterogeneity and pleiotropy assessments, using R software with appropriate packages. The inverse-variance weighting results demonstrated a causal relationship between genetically predicted RA and an elevated risk of fractures, particularly traumatic fractures of the long bones and osteoporotic fractures, including fractures of shoulder and upper arm (odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.020–1.062, P = 9.06e-05), fractures of forearm (OR = 1.026, 95% CI: 1.007–1.044, P = .006), fracture of femur (OR = 1.036, 95% CI: 1.009–1.064, P = .009), fractures of lower leg, including joint (OR = 1.031, 95% CI: 1.016–1.047, P = 6.38e-05), fractures of rib(s), sternum, and thoracic vertebrae (OR = 1.041, 95% CI: 1.018–1.064, P = 4.08e-04), osteoporotic with pathological features (OR = 1.128, 95% CI: 1.071–1.188, P = 5.54e-06), postmenopausal osteoporotic with pathological features (OR = 1.060, 95% CI: 1.002–1.123, P = .044), and drug-induced osteoporotic with pathological features (OR = 1.255, 95% CI: 1.124–1.400, P = 5.02e-05). This study highlights the genetic causal link between RA and an increased risk of traumatic and osteoporotic fractures, presenting a new direction for future exploration of the mechanisms underlying RA-related fractures.
Objectives To assess the safety and efficacy of the combination of brachial artery (BA) cutdown with purse-string suture (PSS) for BA preclosure during fenestrated thoracic endovascular aortic repair (f-TEVAR). Methods We reviewed the consecutive data in our center from January 2022 to May 2023. Clinical data were analyzed retrospectively, including the baseline characteristics, procedural details, complications, and outcomes. Dichotomous data were summarized as absolute values and percentages. Continuous variables were presented as median values and interquartile ranges (IQRs). All patients underwent arterial cutdown with the PSS technique for BA preclosure. The technique was considered successful when complete hemostasis was achieved and confirmed by ultrasonography 24 h postoperatively. The patients were followed up 30 days postoperatively for access-related complications. Results Forty-eight patients who underwent f-TEVAR with 48 BA access sites were included [36 males and 12 females; median age: 62 (IQR: 30-78) years]. The median body mass index was 27.3 (IQR: 21.2-32.7) kg/m 2 . The median access establishing and closing times were 7.8 (IQR: 6-9.3) min and 3.7 (IQR: 2.5-5) min, respectively. The median operative time and length of stay were 75 (IQR: 63-87) min and 7 (IQR: 5-9) days, respectively. Although the success rate was 100%, partial numbness in the median nerve distribution was noted in 1 patient in the forearm. This resolved spontaneously and no permanent neurological problem was seen. No other access-related complications were noted, and the total complication rate was 2.1% (1/48). Conclusions BA preclosure with the PSS technique is safe and effective for left subclavian artery revascularization in Stanford B aortic dissection and can be another option for access closure during f-TEVAR.
Acidic leucine rich nuclear phosphoprotein-32A (ANP32A) protein has a variety of functions, such as regulating cell differentiation, influencing cell apoptosis and cell cycle progression. Our previous study demonstrated that high expression of ANP32A was found in the tumor tissues of colorectal cancer (CRC) patients and was positively associated with tumor grading. However, the function and underlying mechanisms of ANP32A in CRC metastasis have not been fully explored. In this study, we found that ANP32A knockdown significantly attenuated the migration and invasion, and epithelial-mesenchymal transition (EMT) in cells. Further mechanistic studies revealed that ANP32A knockdown inhibited the expression of β-catenin and phosphorylated-ERK. The immunofluorescent staining experiment has revealed that ANP32A was expressed in the cell membrane, cytosol and nucleus, and its expression was positively associated with β-catenin expression levels. Moreover, the ability of cell migration and invasion was inhibited, the expression of E-cadherin was enhanced following ANP32A knockdown, and these affects were abolished by an ERK activator PMA, enhanced by an ERK inhibitor PD98059. Moreover, our animal experiment also demonstrated that silenced ANP32A inhibited CRC cell growth, multi-organ metastasis, ERK activation and EMT progression in vivo. Collectively, these findings demonstrated that ANP32A promotes CRC progression and that may be a promising target for the anti-metastasis treatment of CRC.
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