BackgroundDifferences in prognosis and baseline clinical presentation have been documented among patient with acute coronary syndrome and coronary artery disease with obstructive (ObCAD) or nonobstructive arteries (NObCAD), but the rates of events largely varied across single studies. We carried out a meta‐analysis to compare the clinical presentation and prognosis of NObCAD versus ObCAD acute coronary syndrome patients, as well as of the subjects with zero versus mild occlusion.Methods and ResultsSearches were made in MedLine, EMBASE, Cochrane databases, and proceedings of international meetings up to June 30, 2015. We compared the risk of events of NObCAD versus ObCAD patients using random‐effect meta‐analyses. We also performed meta‐analyses to estimate the yearly or monthly outcome rates in each single group. In NObCAD and ObCAD patients, respectively, the combined yearly rates were as follows: 2.4% versus 10.1% (all‐cause mortality); 1.2% versus 6.0% (myocardial infarction), 4.0% versus 12.8% (all‐cause mortality plus myocardial infarction), 1.4% versus 5.9% (cardiac death), and 9.2% versus 16.8% (major cardiovascular events). In the studies directly comparing NObCAD versus ObCAD, all of the above outcomes were significantly less frequent in NObCAD subjects (with risk ratios ranging from 0.33 to 0.66). No differences in any outcome rate were observed between mild occlusion (1–49% stenosis) and zero occlusion patients.Conclusions NObCAD in patients with acute coronary syndrome has a significantly lower cardiovascular risk at baseline and a subsequent lower likelihood of death or main cardiovascular events. However, these subjects are still at high risk for cardiovascular mortality and morbidity, suggesting potential undertreatment and calling for specific management.

Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple‐negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three‐dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6‐depleted, triple‐negative MDA‐MB‐231 cells rearranged the actin cytoskeleton and restored epidermal growth factor‐mediated invasion. In patients with localized, lymph node‐negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse‐free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

We recently identified an endomembrane-based signalling cascade that is activated by the KDEL receptor (KDELR) on the Golgi complex. At the Golgi, the KDELR acts as a traffic sensor (presumably via binding to chaperones that leave the ER) and triggers signalling pathways that balance membrane fluxes between ER and Golgi. One such pathway relies on Gq and Src. Here, we examine if KDELR might control other cellular modules through this pathway. Given the central role of Src in extracellular matrix (ECM) degradation, we investigated the impact of the KDELR-Src pathway on the ability of cancer cells to degrade the ECM. We find that activation of the KDELR controls ECM degradation by increasing the number of the degradative structures known as invadopodia. The KDELR induces Src activation at the invadopodia and leads to phosphorylation of the Src substrates cortactin and ASAP1, which are required for basal and KDELR-stimulated ECM degradation. This study furthers our understanding of the regulatory circuitry underlying invadopodia-dependent ECM degradation, a key phase in metastases formation and invasive growth.

A novel fluorescently labeled folate conjugate in which four folic acid units are covalently conjugated with a 7-nitro-benzofurazan fluorophore by means of a calix[4]arene platform was synthesized by using a Cu-catalyzed azide-alkyne cycloaddition reaction (click chemistry). The synthesized construct (FA-C4-NBD) was characterized by mass spectrometry, NMR and fluorescence spectroscopy. Confocal fluorescence microscopy experiments were carried out to evaluate the cell penetration ability of FA-C4-NBD on normal and cancer cells. The cellular uptake of FA-C4-NBD proceeds via folate receptor-mediated endocytosis. FA-C4-NBD is internalized into HeLa cancer cells which express high levels of folate receptors, whereas the uptake into fibroblast NIH3T3 cells which have very low expression levels of folate receptors is negligible. The involvement of the folate receptor was corroborated by competition tests with free folic acid. Co-localization analysis with different organelle markers indicated that FA-C4-NBD is not eliminated by recycling towards the outside of the cell, but accumulates intracellularly in the endo-lysosomal system.