Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat non-small cell lung carcinoma (NSCLC) patients that have EGFR-activating mutations. EGFR-TKI monotherapy in most NSCLC patients with EGFR mutations who initially respond to EGFR-TKIs results in the development of acquired resistance. We investigated the role of fibroblasts in stromal cell-mediated resistance to gefitinib-induced apoptosis in EGFR-mutant NSCLC cells. While gefitinib induced apoptosis in EGFR-mutant NSCLC cells, apoptosis induction was diminished under stromal co-culture conditions. Protection appeared to be mediated in part by Aurora-A kinase (AURKA) upregulation. The protective effect of stromal cells was significantly reduced by pre-exposure to AURKA-shRNA. We suggest that combinations of AURKA antagonists and EGFR inhibitors may be effective in clinical trials targeting mutant EGFR NSCLCs.
Background and Objectives: Vascular endothelial growth factor (VEGF) has been shown to play an important role in the development and progress of diabetic retinopathy (DR). A number of case-control studies focused on the association between VEGF -2578C/A and risk for DR. But the results were not always consistent, so we performed a meta-analysis to evaluate the precise association between this variant and risk for DR. Methods: All publications on the association between VEGF -2578C/A polymorphism and DR were searched in the following electronic databases: PubMed, Embase, the Cochrane Library and Chinese Biomedical Literature Database, with the last report up to January 2013. This meta-analysis was assessed by Review Manager 5.1. Results: A total of 6 studies were involved in this meta-analysis, including 835 cases and 867 controls. Overall, we found a significant association between this polymorphism and DR (A vs. C: OR = 1.49, 95% CI = 1.26-1.77, p < 0.00001; AA vs. CA + CC: OR = 1.26, 95% CI = 0.94-1.68, p = 0.12; AA + CA vs. CC: OR = 1.56, 95% CI = 1.27-1.91, p < 0.00001; AA vs. CC: OR = 1.67, 95% CI = 1.20-2.32, p = 0.003; CA vs. CC: OR = 1.51, 95% CI = 1.21-1.87, p = 0.0002), but we did not find any significant association in Caucasians in subgroup analysis. The results were not materially altered after the studies which did not fulfill the Hardy-Weinberg equilibrium were excluded. Conclusion: Our meta-analysis supports the association between the VEGF -2578C/A polymorphism and DR, but not in the Caucasian population.
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