Role and Mechanism of miR-181a-5p in Mice with Chronic Obstructive Pulmonary Disease by Regulating HMGB1 and the NF-κB Pathway.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. This study explored the mechanism of miR-181a-5p in the inflammatory response in COPD mice. COPD mouse models were established by cigarette smoke (CS) exposure following pretreatment with recombinant adeno-associated virus (rAAv)-miR-181a-5p, si-HMGB1 (high mobility group box 1), and NF-κB pathway inhibitor PDTC, respectively. Pathological changes of lung tissues were determined by HE staining. Bronchoalveolar lavage fluid was collected to count total cells, neutrophils, and lymphocytes using a Countess II automatic cell counter. Expressions of neutrophil elastase (NE) and inflammatory factors (TNF-α, IL-6, IL-8, and IFN-γ) were detected by ELISA. Binding relationship between miR-181a-5p and HMGB1 was predicted on starBase and validated by dual-luciferase assay. miR-181a-5p expression was detected by RT-qPCR, and expressions of HMGB1, IκBα, and p-IκBα were detected by western blot. The expression level of miR-181a-5p was lower in lung tissues. miR-181a-5p overexpression alleviated inflammatory response and pathological changes of lung tissues in COPD mice, with decreased pulmonary inflammation scores, total cells, neutrophils, and lymphocytes and expressions of NE and inflammatory factors. HMGB1 expression level was increased in COPD mice. miR-181a-5p targeted HMGB1. si-HMGB1 relieved inflammatory responses in COPD mice. NF-κB was activated in COPD mice, evidenced by degraded IκBα and increased p-IκBα levels. si-HMGB1 significantly restrained the activation of NF-κB pathway. Briefly, miR-181a-5p targets HMGB1 to inhibit the NF-κB pathway, thus alleviating the inflammatory response in COPD mice.

Immune checkpoint inhibitors as first-line therapy for non-small cell lung cancer: A systematic evaluation and meta-analysis.

Recently, immune checkpoint inhibitors (ICIs) present promising application prospects in treating non-small cell lung cancer (NSCLC). This study aimed to investigate optimal treatment strategy by comparing the first-line treatment strategies with ICIs in NSCLC. We retrieved relevant studies on first-line therapy of NSCLC with ICIs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were treatment-related serious adverse events (tr-SAEs) with grade 3 or higher and objective response rate (ORR). We also conducted a Bayesian network meta-analysis. We included 14 studies involving 7,823 patients and compared seven different interventions. In PD-L1 nonselective NSCLC, nivolumab+ipilimumab had good PFS and ORR, pembrolizumab significantly prolonged OS, and nivolumab had the fewest adverse events (AEs). For PD-L1-positive patients, nivolumab remarkably prolonged OS. For those with negative PD-L1, nivolumab+ipilimumab also showed an advantage. In addition, nivolumab+ipilimumab significantly prolonged the PFS in both PD-L1-negative and -positive patients. For patients with PD-L1 tumor proportion score (TPS) within 1-49%, atezolizumab+chemotherapy remarkably prolonged PFS and OS. For those with PD-L1 TPS ≥50%, pembrolizumab prolonged OS and atezolizumab+chemotherapy significantly prolonged PFS. Nivolumab combined with ipilimumab showed advantages in OS, PFS and ORR in most patients. Nivolumab+ipilimumab may be the optimal first-line therapy for NSCLC.

Adiponectin and the risk of gastrointestinal cancers in East Asians: Mendelian randomization analysis.

BACKGROUND: Adiponectin is an important adipocytokine and has been associated with the risks of gastrointestinal cancers (GICs). Mendelian randomization (MR) analysis is needed to assess the causal relationships between adiponectin and GICs. METHODS: We retrieved the summary data of genome-wide association studies for adiponectin and six types of GICs in East Asians. A series of quality control steps were performed to select the eligible genetic instrumental tools. Horizontal pleiotropy and between-SNP heterogeneity were tested to choose the primary MR method. We also conducted sensitivity analyses to test the robustness of the main findings. RESULTS: We detected neither heterogeneity nor horizontal pleiotropy for the eligible SNPs in all of the MR analyses. Inverse variance weighted (IVW) was therefore used as the primary method, and suggested that per 10% increase in log-transformed adiponectin level was significantly associated with a decreased risk of gastric cancer (odds ratio [OR] = 0.88, 95% CI 0.81, 0.96), whereas with an increased risk of hepatocellular carcinoma (OR = 1.26, 95% CI 1.09, 1.44) and of biliary tract cancer (OR = 1.54, 95% CI 1.12, 2.12). However, only the association between adiponectin and HCC risk was statistically significant after correction for multiple testing. No statistically significant association was detected between adiponectin and esophageal (OR = 1.05, 95% CI 0.89, 1.23), pancreatic (OR = 1.04, 95% CI 0.78, 1.37), and colorectal cancers (OR = 1.00, 95% CI 0.93, 1.07). Sensitivity analyses did not find contradictory results. CONCLUSION: High level of adiponectin may have a causal effect on and can serve as a biomarker for the carcinogenesis of gastric cancer, hepatocellular carcinoma, and biliary tract cancer.