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. Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation. Am J Physiol Heart Circ Physiol 288: H2512-H2520, 2005. First published January 6, 2005; doi:10.1152/ajpheart.00599.2004.-Ischemic preconditioning (IP) is a cardioprotective mechanism against myocellular death and cardiac dysfunction resulting from reperfusion of the ischemic heart. At present, the precise list of mediators involved in IP and the pathways of their mechanisms of action are not completely known. The aim of the present study was to investigate the role of platelet-activating factor (PAF), a phospholipid mediator that is known to be released by the ischemic-reperfused heart, as a possible endogenous agent involved in IP. Experiments were performed on Langendorff-perfused rat hearts undergoing 30 min of ischemia followed by 2 h of reperfusion. Treatment with a low concentration of PAF (2 ϫ 10 Ϫ11 M) before ischemia reduced the extension of infarct size and improved the recovery of left ventricular developed pressure during reperfusion. The cardioprotective effect of PAF was comparable to that observed in hearts in which IP was induced by three brief (3 min) periods of ischemia separated by 5-min reperfusion intervals. The PAF receptor antagonist WEB-2170 (1 ϫ 10 Ϫ9 M) abrogated the cardioprotective effect induced by both PAF and IP. The protein kinase C (PKC) inhibitor chelerythrine (5 ϫ 10 Ϫ6 M) or the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (5 ϫ 10 Ϫ5 M) also reduced the cardioprotective effect of PAF. Western blot analysis revealed that following IP treatment or PAF infusion, the phosphorylation of PKC-⑀ and Akt (the downstream target of PI3K) was higher than that in control hearts. The present data indicate that exogenous applications of low quantities of PAF induce a cardioprotective effect through PI3K and PKC activation, similar to that afforded by IP. Moreover, the study suggests that endogenous release of PAF, induced by brief periods of ischemia and reperfusion, may participate to the triggering of the IP of the heart. ischemia-reperfusion; WEB-2170; LY-294002 ISCHEMIC PRECONDITIONING (IP) is the phenomenon whereby brief periods of ischemia and reperfusion increase the resistance to myocardial infarction and contractile dysfunction induced by a subsequent sustained episode of ischemia (9, 34 -36). In all species tested, the beneficial effects of IP include protection against necrotic and apoptotic cell death. In some species, it has been shown that IP also induces the prevention of ischemia-reperfusion-induced arrhythmias, a faster recovery from reperfusion-induced myocardial stunning, and a protection of microvasculature function (for reviews, see Refs. 33 and 35

Background Cancer of the larynx in the intermediate/advanced stage still presents a major challenge in terms of controlling the disease and preserving the organ. Among therapeutic options, open partial horizontal laryngectomy is proposed as a function‐sparing surgical technique. Methods We analyzed the clinical outcomes of 555 patients with laryngeal cancer staged pT3 to pT4a who underwent open partial horizontal laryngectomy. Results Five‐year overall survival (OS), disease‐free survival (DFS), locoregional control, local control, laryngectomy‐free survival, and laryngeal function preservation rates were 84.6%, 84.2%, 86.3%, 90.6%, 93.3%, and 91.2%, respectively. DFS, locoregional control, and laryngeal function preservation rates were significantly affected by pT4a staging (68.1%, 71.7%, and 78.0%, respectively), whereas pN+ influenced only DFS (≤72.6%) and locoregional control (≤79.6%). Conclusions Open partial horizontal laryngectomy with a modular approach can be considered effective in terms of prognostic and functional results in intermediate‐stage and selected advanced‐stage laryngeal cancers, even with subglottic extension. © 2015 Wiley Periodicals, Inc. Head Neck 38: E649–E657, 2016

Rastaldo R, Cappello S, Folino A, Berta GN, Sprio AE, Losano G, Samaja M, Pagliaro P. Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol 300: H2308 -H2315, 2011. First published March 4, 2011 doi:10.1152/ajpheart.01177.2010.-We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre-or postconditioning mimetic and whether the improved postischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor (APJ) plays a role in cardioprotection. Langendorffperfused rat hearts underwent 30 min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and lactate dehydrogenase release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 M concentration for 20 min either before ischemia or in early reperfusion, without and with NO synthase inhibition by N G -nitro-L-arginine (L-NNA). In additional experiments, before ischemia also 1 M apelin-13 was tested. APJ protein level was measured before and after ischemia. Whereas before ischemia apelin-13 (0.5 and 1.0 M) was ineffective, after ischemia it reduced infarct size from 54 Ϯ 2% to 26 Ϯ 4% of risk area (P Ͻ 0.001) and limited the postischemic myocardial contracture (P Ͻ 0.001). L-NNA alone increased postischemic myocardial contracture. This increase was attenuated by apelin-13, which, however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min perfusion, i.e., after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level. APJ receptor; ischemia/reperfusion; myocardial protection; preconditioning APELIN IS THE ENDOGENOUS LIGAND for the G protein-coupled APJ receptor. Human, mouse, rat, and cow apelin genes encode a 77-amino acid preprotein with the active sequence in the COOH-terminal region (19,43). Various fragments of apelin have been isolated and classified according to the number of amino acids. Among fragments, apelin-13 and -36 are the most frequently studied, and apelin-13 is considered the most active of them (40). Apelin receptors APJ have been found to be similar to angiotensin II receptor type 1 (25,30,43), but angiotensin II does not bind to APJ receptors (14, 30).Apelin mRNA is expressed in several organs and tissues. In the cardiovascular system, apelin and APJ receptors occur in vascular smooth muscle, endothelial cells, and cardiomyocytes (21,22). Apelin exerts a positive inotropic effect (2, 42) and a nitric oxide (NO)-driven vasodilator activity (14, 15). It protect...