Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAF mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis.

Background: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAF mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety.

Methods: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas 4800 BRAF V600 Mutation Test).

Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms.

Alterations in the circadian blood pressure pattern are frequently observed in hypertension and lead to increased cardiovascular morbidity. However, there are no studies that have investigated a possible implication of the Period2 gene, a key component of the molecular circadian clock, on the circadian rhythms of blood pressure and heart rate. To address this question, we monitored blood pressure, heart rate, and locomotor activity 24 h a day by telemetry in mice carrying a mutation in the Period2 gene and in wild-type control mice.

Hemodynamic consequences of chronic parasympathetic blockade with a peripheral muscarinic antagonist.

Whereas the sympathetic nervous system has a well-established role in blood pressure (BP) regulation, it is not clear whether long-term levels of BP are affected by parasympathetic function or dysfunction. We tested the hypothesis that chronic blockade of the parasympathetic nervous system has sustained effects on BP, heart rate (HR), and BP variability (BPV). Sprague-Dawley rats were instrumented for monitoring of BP 22-h per day by telemetry and housed in metabolic cages.

Mutation of the circadian clock gene Per2 alters vascular endothelial function.

Background: The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (Per2) in endothelial function in a mouse model.

Methods And Results: Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endothelium-dependent relaxations to acetylcholine in aortic rings suspended in organ chambers.

Multiple mechanisms involved in obesity-induced hypertension.

Obesity and hypertension are two major cardiovascular risk factors gaining epidemic proportions in our modern world. The interplay between hypertension, obesity and their major detrimental outcome, cardiovascular disease, is multifaceted and can be represented as the three corners of a triangle. Obesity and hypertension both lead to cardiovascular complications.

A role for suppressed thermogenesis favoring catch-up fat in the pathophysiology of catch-up growth.

Catch-up growth is a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases. We show here that after growth arrest by semistarvation, rats refed the same amount of a low-fat diet as controls show 1) lower energy expenditure due to diminished thermogenesis that favors accelerated fat deposition or catch-up fat and 2) normal glucose tolerance but higher plasma insulin after a glucose load at a time point when their body fat and plasma free fatty acids (FFAs) have not exceeded those of controls. Isocaloric refeeding on a high-fat diet resulted in even lower energy expenditure and thermogenesis and increased fat deposition and led to even higher plasma insulin and elevated plasma glucose after a glucose load.

Short-term (5-day) changes in food intake alter daily hemodynamics in rabbits.

Background: In humans, particularly among individuals trying to lose weight, cycles of hypophagia followed by cycles of hyperphagia are quite common and may lead to an increased cardiovascular morbidity. The aim of the present study was to evaluate the alterations in daily mean arterial pressure (MAP) and heart rate (HR) during short-term (5-day) changes in food intake.

Methods: Adult male rabbits instrumented for continuous (24 h/day) telemetric recording of blood pressure (BP) and HR were subjected to five 14-day periods of altered food intake.