Genetic effect of metformin use on risk of cancers: evidence from Mendelian randomization analysis.

BACKGROUND: Increasing number of studies reported the positive effect of metformin on the prevention and treatment of cancers. However, the genetic causal effect of metformin utilization on the risk of common cancers was not completely demonstrated. METHODS: Two-sample Mendelian Randomization (two-sample MR) analysis was conducted to uncover the genetically predicted causal association between metformin use and 26 kinds of cancers. Besides, two-step Mendelian Randomization (two-step MR) assessment was applied to clarify the mediators which mediated the causal effect of metformin on certain cancer. We utilized five robust analytical methods, in which the inverse variance weighting (IVW) method served as the major one. Sensitivity, pleiotropy, and heterogeneity were assessed. The genetic statistics of exposure, outcomes, and mediators were downloaded from publicly available datasets, including the Open Genome-Wide Association Study (GWAS), FinnGen consortium (FinnGen), and UK Biobank (UKB). RESULTS: Among 26 kinds of common cancers, HER-positive breast cancer was presented with a significant causal relationship with metformin use [Beta: - 4.0982; OR: 0.0166 (95% CI: 0.0008, 0.3376); P value: 0.0077], which indicated metformin could prevent people from HER-positive breast cancer. Other cancers only showed modest associations with metformin use. Potential mediators were included in two-step MR, among which total testosterone levels (mediating effect: 24.52%) displayed significant mediating roles. Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent outcomes. CONCLUSION: Metformin use exhibited a genetically protective effect on HER-positive breast cancer, which was partially mediated by total testosterone levels.

Oncolytic Vaccinia Virus Carrying Aphrocallistes vastus Lectin (oncoVV-AVL) Enhances Inflammatory Response in Hepatocellular Carcinoma Cells.

Aphrocallistes vastus lectin (AVL) is a C-type marine lectin derived from sponges. Our previous study demonstrated that oncolytic vaccinia virus carrying AVL (oncoVV-AVL) significantly enhanced the cytotoxicity of oncoVV in cervical cancer, colorectal cancer and hepatocellular carcinoma through the activation of Ras/ERK, MAPK/ERK and PI3K/Akt signaling pathways. In this study, the inflammatory response induced by oncoVV-AVL in a hepatocellular carcinoma cell (HCC) model was investigated. The results showed that oncoVV-AVL increased the levels of inflammatory cytokines including IL-6, IL-8 and TNF-α through activating the AP-1 signaling pathway in HCC. This study provides novel insights into the utilization of lectin AVL in the field of cancer therapy.

The benefit of anti-angiogenic therapy in EGFR exon 21 L858R mutant non-small cell lung cancer patients: a retrospective study.

Patients with epidermal growth factor receptor (EGFR) exon 21 L858R substitution benefit less from standard EGFR tyrosine kinase inhibitor (TKI) treatment, and whether anti-angiogenic therapy was beneficial to the EGFR L858R subpopulation was inconclusive. A retrospective study was conducted to investigate the survival benefit and the target characteristics of the anti-angiogenic agent in the EGFR L858R patients in our center, comparing those treated with or without anti-angiogenic therapy (cohort A and cohort B). At the median follow-up time of 31.0 months vs 32.7 months (cohort A vs. B) respectively, Cohort A (n = 58) had a significantly prolonged median OS compared to Cohort B (n = 101) (60.0 months vs.37.0 months, HR 0.51, p = 0.016). Anti-angiogenic therapy significantly prolonged the OS in patients with liver metastases (NA vs.26.0 months, HR 0.17, p = 0.023) comparing to patients without liver metastases (60.0 months vs.37.0 months, HR 0.63, p = 0.129). For brain metastatic patients, anti-angiogenic treatment tended to improve median OS with (65.0 months vs.35.0 months, HR 0.29, p = 0.068) or without brain radiotherapy (73.0 months vs.29.0 months, HR 0.24, p = 0.171). The grade 3 or more adverse events were manageable and consistent with previous studies. Patients with EGFR L858R mutation treated with anti-angiogenic therapy in their course of treatment had a significantly prolonged OS compared to those who had never received an anti-angiogenic agent. Patients with liver metastases might benefit more from anti-angiogenic therapy than those without.

Arctigenin prevents the progression of osteoarthritis by targeting PI3K/Akt/NF-κB axis: In vitro and in vivo studies.

Osteoarthritis (OA), which is principally featured by progressive joint metabolic imbalance and subsequent degeneration of articular cartilage, is a common chronic joint disease. Arctigenin (ATG), a dietary phyto-oestrogen, has been described to have potent anti-inflammatory effects. Nevertheless, its protective effects on OA have not been clearly established. The target of our following study is to evaluate the protective effects of ATG on IL-1ß-induced human OA chondrocytes and mouse OA model. Our results revealed that the ATG pre-treatment effectively decreases the level of pro-inflammatory mediators, such as prostaglandin E2 (PGE2), nitrous oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-6 and tumour necrosis factor alpha (TNF-α) in IL-1ß-induced human chondrocytes. In addition, ATG protects against the degradation of extracellular matrix (ECM) under the stimulation of IL-1ß and the possible mechanism might be connected with the inactivation of phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor-kappa B (NF-κB) axis. Furthermore, a powerful binding capacity between ATG and PI3K was also uncovered in our molecular docking research. Meanwhile, ATG may act as a protector on the mouse OA model. Collectively, all these findings suggest that ATG could be utilized as a promising therapeutic agent for the treatment of OA.