Exocytosis of Weibel-Palade bodies: how to unpack a vascular emergency kit.

The blood vessel wall has a number of self-healing properties, enabling it to minimize blood loss and prevent or overcome infections in the event of vascular trauma. Endothelial cells prepackage a cocktail of hemostatic, inflammatory and angiogenic mediators in their unique secretory organelles, the Weibel-Palade bodies (WPBs), which can be immediately released on demand. Secretion of their contents into the vascular lumen through a process called exocytosis enables the endothelium to actively participate in the arrest of bleeding and to slow down and direct leukocytes to areas of inflammation. Owing to their remarkable elongated morphology and their secretory contents, which span the entire size spectrum of small chemokines all the way up to ultralarge von Willebrand factor multimers, WPBs constitute an ideal model system for studying the molecular mechanisms of secretory organelle biogenesis, exocytosis, and content expulsion. Recent studies have now shown that, during exocytosis, WPBs can undergo several distinct modes of fusion, and can utilize fundamentally different mechanisms to expel their contents. In this article, we discuss recent advances in our understanding of the composition of the WPB exocytotic machinery and how, because of its configuration, it is able to support WPB release in its various forms.

Circulating DNA in solid organ cancers-analysis and clinical application.

Circulating tumour DNA (ctDNA) is that fraction of circulating DNA that is derived from a patient's cancer. For a number of years, patients with haematological malignancies have had their disease diagnosed or monitored using tests based on detecting specific cytological or molecular biomarkers in blood. It has long been appreciated that the more common epithelial malignancies also shed DNA into the blood and that this tumour-derived DNA generally contributes a minor percentage of the overall cell-free DNA burden in peripheral blood. The biotech revolution has transformed our ability to detect, quantify and interpret genetic events. This has led to a renewed interest in the potential of using a simple blood test to both diagnose cancer and longitudinally monitor the response to medical interventions in patients with solid organ malignancies.In this review we provide a summary of the literature to date and describe the main attributes of the current analytical approaches to ctDNA. We then focus on the potential clinical applications. There is increasing evidence to support the routine analysis of ctDNA in clinical decision-making for certain subgroups of patients with so-called hotspot mutations, particularly in lung and colorectal cancer. With continued refinement and technological progress, non-invasive molecular biomarkers including of ctDNA may be clinically useful at all stages of cancer management from diagnosis to disease progression.