Survival is not improved by elective repair of abdominal aortic aneurysms smaller than 5.5 cm, even when operative mortality is low.

SUMMARY Translational readthrough, observed primarily in less complex organisms from viruses to Drosophila, expands the proteome by translating select transcripts beyond the canonical stop codon. Here we show that vascular endothelial growth factor-A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed translational readthrough (PTR) generating VEGF-Ax, an isoform containing a unique 22-amino acid C-terminus extension. A cis-acting element in the VEGFA 3′UTR serves a dual function, not only encoding the appended peptide, but also directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough. Remarkably, VEGF-Ax exhibits anti-angiogenic activity in contrast to the pro-angiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is indicated by robust expression in multiple human tissues, but depletion in colon adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as authentic readthrough targets. Overall, our studies reveal a novel protein-regulated PTR event in a vertebrate system.

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This is a repository copy of Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH) : a stepped-wedge cluster-randomised trial. Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH) : a stepped-wedge cluster-randomised trial. The Lancet. ISSN 0140-6736 https://doi.org/10.1016/S0140-6736(18)32521-2 eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ ReuseThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can't change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Implications of all the available evidenceDespite the success of some smaller projects, there was no survival benefit from a national quality improvement programme to implement a care pathway for patients undergoing emergency abdominal surgery. To succeed, large national quality improvement programmes need to allow for differences between hospitals and ensure teams have both the time and resources needed to improve patient care.

Angiogenesis, the formation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endothelial growth factor (VEGF)-A guides and enhances endothelial cell (EC) migration to initiate angiogenesis. Profilin-1 (Pfn-1) is an actin-binding protein that enhances actin filament formation and cell migration, but stimulus-dependent regulation of Pfn-1 has not been observed. Here, we show VEGF-A-inducible phosphorylation of Pfn-1 at Tyr129 is critical for EC migration and angiogenesis. Chemotactic activation of VEGF receptor kinase-2 (VEGFR2) and Src induce Pfn-1 phosphorylation in the cell leading edge, promoting Pfn-1 binding to actin and actin polymerization. Furthermore, Pfn-1 phosphorylation is robustly and preferentially elevated in blood vessels during tissue repair after myocardial infarction in humans. Conditional endothelial knock-in of phosphorylation-deficient Pfn-1Y129F in mice reveals that Pfn-1 phosphorylation is critical for angiogenesis in response to wounding and ischemic injury, but not for developmental angiogenesis. Thus, VEGFR2/Src-mediated phosphorylation of Pfn-1 bypasses canonical, multistep intracellular signaling events to initiate EC migration and angiogenesis, and might serve as a selective therapeutic target for anti-angiogenic therapy.