ABSTRACT
The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim(-/-) primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17â¼92 cluster. Bim mRNA levels were also elevated in miR-17â¼92(+/-) endothelial cells cultured under steady-state conditions, suggesting that miR-17â¼92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis/physiology , Endothelial Cells/metabolism , Forkhead Transcription Factors/metabolism , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Bcl-2-Like Protein 11 , Forkhead Box Protein O3 , Forkhead Transcription Factors/genetics , Membrane Proteins/genetics , Mice , MicroRNAs/metabolism , Proto-Oncogene Proteins/genetics , RNA, Messenger/metabolism , Transcriptional ActivationABSTRACT
A middle aged woman referred for an abdominal mass was found to have large amounts of dopa (3-4-dihydroxyphenylalanine) metabolites in her urine. At operation a tumour affecting almost the entire left lobe of the liver was removed. Histologically the tumour was a metastatic carcinoid. After operation the excretion of dopa metabolites fell substantially, confirming that the tumour was the source. Apparently, owing to an enzyme defect the tumour had been unable to decarboxylate dopa. These findings are further evidence of a neural origin for the endocrine system of the gut.
Subject(s)
Carcinoid Tumor/metabolism , Dihydroxyphenylalanine/metabolism , Liver Neoplasms/metabolism , Carcinoid Tumor/secondary , Female , Humans , Liver Neoplasms/secondary , Middle AgedABSTRACT
This report gives an account of the work during six months of a community nurse team attached to the doctors working from a new health centre. The team consisted of two community nurses, who had both health visiting and Queen's nursing qualifications, and a State-enrolled nurse. The community nurses, in addition to undertaking all the health visiting for the population at risk, assessed the social and nursing needs of patients at the request of the general practitioners and ensured that these needs were met. When necessary they undertook practical nursing tasks in the home and in the health centre, but most of the bedside nursing in the home was done by the State-enrolled nurse.The needs of the population at risk were such that only one State-enrolled nurse could usefully be employed, and this proved to be a considerable disadvantage. Despite this, the experimental work pattern held advantages to patients, doctors, and nurses, and is potentially capable of providing a satisfying and economic division of responsibilities, with different tasks being carried out by the individual most appropriately qualified.