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

Practical management of acute gastrointestinal bleeding

x+148hlm.;26c

ZMYM2 restricts 53BP1 at DNA double-strand breaks to favor BRCA1 loading and homologous recombination

An inability to repair DNA double-strand breaks (DSBs) threatens genome integrity and can contribute to human diseases, including cancer. Mammalian cells repair DSBs mainly through homologous recombination (HR) and nonhomologous end-joining (NHEJ). The choice between these pathways is regulated by the interplay between 53BP1 and BRCA1, whereby BRCA1 excludes 53BP1 to promote HR and 53BP1 limits BRCA1 to facilitate NHEJ. Here, we identify the zinc-finger proteins (ZnF), ZMYM2 and ZMYM3, as antagonizers of 53BP1 recruitment that facilitate HR protein recruitment and function at DNA breaks. Mechanistically, we show that ZMYM2 recruitment to DSBs and suppression of break-associated 53BP1 requires the SUMO E3 ligase PIAS4, as well as SUMO binding by ZMYM2. Cells deficient for ZMYM2/3 display genome instability, PARP inhibitor and ionizing radiation sensitivity and reduced HR repair. Importantly, depletion of 53BP1 in ZMYM2/3-deficient cells rescues BRCA1 recruitment to and HR repair of DSBs, suggesting that ZMYM2 and ZMYM3 primarily function to restrict 53BP1 engagement at breaks to favor BRCA1 loading that functions to channel breaks to HR repair. Identification of DNA repair functions for these poorly characterized ZnF proteins may shed light on their unknown contributions to human diseases, where they have been reported to be highly dysregulated, including in several cancers.Genome Instability and Cance

Need assessment on lifestyle modification intervention for colorectal cancer survivors

Conference Theme: Be a Transformer: Your Role in Leading Evidence-based Practice & Health PolicyThe 12th Annual Evidence-Based Practice (EBP) Conference, Phoenix, AZ., 8-10 June 2011

Endoscopic injection of adrenaline for actively bleeding ulcers: a randomised trial

A prospective randomised trial was performed to assess the efficacy of endoscopic injection of adrenaline for actively bleeding ulcers. Emergency endoscopy in 961 patients admitted for upper gastrointestinal haemorrhage identified 68 patients with actively bleeding ulcers. These 68 patients were randomised to receive either endoscopic injection of adrenaline or no endoscopic treatment. After endoscopy both groups were managed in an identical manner, and strict criteria for emergency operation were adhered to in both groups. Bleeding was initially controlled in all 34 patients assigned to the treatment group. Significantly fewer patients in the treatment group than in the control group needed emergency operations (five v 14, respectively). In addition, in the treatment group the median transfusion requirement was significantly less (three v five units of blood) and the median hospital stay shorter (six v eight days). No complications were observed with the injection of adrenaline, and the rate of healing of ulcers in those attending for endoscopy six weeks after discharge was similar in both groups (81% (17 out of 21 patients) in the treatment group v 79% (11 out of 14) in the control group)