Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and esophageal adenocarcinoma risk

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis in esophageal adenocarcinoma (EA). Polymorphisms in the VEGF gene have been associated with altered VEGF expression and plasma VEGF levels. We hypothesized that polymorphisms of VEGF may contribute to EA risk. Functional polymorphisms in the VEGF gene (−460C/T, +405C/G and +936C/T) were determined in 308 patients with EA and 546 healthy controls. Logistic regression analysis was employed to assess the associations between genotypes, haplotypes of VEGF and EA risk, adjusting for multiple confounding factors. Compared with the +936CC genotype, the combined +936CT+TT genotypes were significantly associated with increased risk of developing EA, with adjusted odds ratio (OR) = 1.49 [95% confidence interval (CI), 1.05–2.12; P = 0.027]. The −460CT+CC were associated with increased risk of EA in smokers (adjusted OR = 1.57; 95% CI, 1.07–2.30; P = 0.021), whereas the −460CT/CC were associated with decreased risk of EA (adjusted OR = 0.47; 95% CI, 0.25–0.91; P = 0.025) in non-smokers. Compared with non-smokers with the +460TT, smokers with the +460CT+CC had significantly higher risk of EA (adjusted OR = 3.32; 95% CI, 1.56–7.10; P = 0.002). No overall or interacting association with EA risk was found for the +405C/G polymorphism. Haplotype CGT (−460C/+405G/+936T) was significantly associated with higher risk of EA (adjusted OR = 1.70; 95% CI, 1.04–2.73; P = 0.034). These results suggested that cigarette smoking modifies the association between VEGF polymorphisms and EA risk among Caucasians

Cells release prions in association with exosomes

Prion diseases are infectious neurodegenerative disorders linked to the accumulation in the central nervous system of the abnormally folded prion protein (PrP) scrapie (PrPsc), which is thought to be the infectious agent. Once present, PrPsc catalyzes the conversion of naturally occurring cellular PrP (PrPc) to PrPsc. Prion infection is usually initiated in peripheral organs, but the mechanisms involved in infectious spread to the brain are unclear. We found that both PrPc and PrPsc were actively released into the extracellular environment by PrP-expressing cells before and after infection with sheep prions, respectively. Based on Western blot with specific markers, MS, and morphological analysis, our data revealed that PrPc and PrPsc in the medium are associated with exosomes, membranous vesicles that are secreted upon fusion of multivesicular endosomes with the plasma membrane. Furthermore, we found that exosomes bearing PrPsc are infectious. Our data suggest that exosomes may contribute to intercellular membrane exchange and the spread of prions throughout the organism