Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma

Two Years of Experience in the Implantation of Heartmate III.

Left ventricular assist devices as long-term mechanical circulatory support are increasingly used as an option for medically refractory advanced heart failure. Heartmate III is one of the alternative devices for circulatory support in those patients. Analyze a two years Heartmate III implantation Program. From November 2015 to August 2017, Heartmate III was implanted in 16 patients with chronic end-stage heart failure, in 81% (n = 13) as a bridge to transplant and 19% (n = 3) as destination therapy. We did a review off demographic, clinical and surgical data, and we analyzed the overall survival using the Kaplan-Meier method, excluding patients who were transplanted. Heartmate III was implanted in 16 male patients (100%) with age 55.8 ± 11.1 years (limits 38-74 years) and body surface area 2.0 ± 0.19 m2. The baseline hemodynamic data revealed a cardiac index 2.1 ± 0.4 l / min / m2 and a left ventricular ejection fraction of 20.7 ± 7.3%. Ischemic cardiomyopathy was the most common etiology in this chronic heart failure population (n = 9; 56%). Seven patients (44%) were classified INTERMACS 4; five (31%) in profile 2; three (19%) in profile 3 and one (6%) in profile 1. The implantation of the devices was performed under Cardiopulmonary Bypass (78.6 ± 25.7 min), and 25% of the patients (n = 4) had right ventricular dysfunction, requiring postoperative temporary right ventricle support. As complications, 6 patients (38%) manifested bleeding requiring surgery and 2 (12%) reported gastrointestinal bleeding, 4 (25%) developed driveline infection, 3 of them were treated (18%) with conservative therapy and in 1 patient (6%) with driveline transposition. During the total follow-up time (19 months), three patients (18%) were transplanted; two deaths occured due to pulmonary embolism and ischemic stroke respectively; verified by the Kaplan Meier method, an overall survival rate of 92.9 ± 6.9%, stable from 6 months after implantation. The 6 months survival rate of 92.9% proves the efficacy of this therapy for our patients and all of them were INTERMACS profils lower than 4. Despite the small number of patients enrolled and the follow-up duration limiting our study, we demonstrated the first experience of our center in the treatment of high-risk population. In conclusion, we show that the Heartmate III was consistent in low INTERMACS profile patients