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Summary Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to investigate the association of CD14 genotype and plasma levels of soluble (s)CD14 with risk of stable coronary artery disease (CAD), chronic infections and sensitive markers of systemic inflammation.: BackgroundIt has been suggested that genetic variation of the CD14 receptor with increased CD14 gene expression might play a role in atherogenesis. A mechanistic link would consist in its contribution to the inflammatory response seen in this disease.: MethodsWe measured levels of sCD14 (μg/ml; ELISA) in 312 patients with angiographically proven CAD and stable angina pectoris, and in 477 age- and gender-matched healthy blood donors. CD14 genotype was determined by polymerase chain reaction. In addition, seropositivity to Chlamydia pneumoniae and Helicobacter pylori, a complete lipid profile and various sensitive systemic markers of inflammation were measured.: ResultsCD14 C(-260)→T genotype was not independently associated with increased risk of CAD after multivariable adjustments (odds ratio [OR] 1.34; 95% confidence interval [CI] 0.84 to 2.16). However, sCD14 plasma levels were higher in subjects with TT genotype compared with those with CT or CC genotype (p = 0.005). Plasma levels were not different between cases and controls (4.2 ± 1.3 μg/ml vs. 4.3 ± 1.3 μg/ml, p = NS). In multivariable logistic regression, the OR for the presence of CAD was 1.11 (95% CI, 0.65 to 1.91) if the top quintile of the sCD14 distribution was compared with the bottom quintile. There was no consistent association between seropositivity to either C. pneumoniae or H. pylori, or both, and sCD14 levels and between sCD14 levels or CD14 genotype and the various markers of inflammation.: ConclusionsThese results do not confirm an independent relationship between CD14 genotypes or plasma levels of sCD14 and risk of stable CAD in this population. [Copyright &y& Elsevier]