Nerve Growth Factor (NGF)-Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma.

Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral mucosa and in HNSCC. HNSCC cell lines were treated with mitomycin C (MMC) and cell survival was investigated. Normal and malignant epithelial cells expressed NGF mRNA. NTRK1 was upregulated in 80% of HNSCC tissue, and 50% of HNSCC samples were p75NTR positive. Interestingly, in HNSCC tissue: NTRK1 and p75NTR immunohistochemical reactions were mutually exclusive. Detroit 562 cell line contained only p75NTR, UPCI-SCC090 cells synthesized NTRK1 but not p75NTR and SCC-25 culture had p75NTR and NTRK1 in different cells. NGF (100 ng/mL) significantly improved (1.4-fold) the survival of cultured UPCI-SCC090 cells after MMC-induced cell cycle arrest, while Detroit 562 cells with high levels of p75NTR did not even get arrested by single short MMC treatment. p75NTR in HNSCC might be related with NGF-independent therapy resistance, while NTRK1 might transduce a survival signal of NGF and contribute in this way to improved tumor cell survival after cell cycle arrest.

Reduction ascending aortoplasty: A retrospective analysis of outcomes and risk factors.

Objectives: Indication for Reduction of Ascending Aortoplasty (RAA) and long-term outcomes remain unclear. This study analyzed the outcomes after nonreinforced RAA in two Austrian centers. Methods: Patients with RAA at two Austrian centers between 6/2,009 and 6/2,017 were retrospectively analyzed. Aortic diameters were measured by CT pre- and post-operatively. Patients were assigned according to valve morphology and imaging modality. Results: Overall, 253 patients underwent RAA [women: 30.8%; median age 74 (63-79) years] with a mean preoperative ascending diameter of 44.7 (±3.5) mm. RAA-related postoperative adverse events occurred in 1.2% (n = 3) over a follow-up of a median of 3.8 (2.4-5.5) years: One type A aortic dissection, one lethal aortic rupture at the suture line, and one suture line bleeding with cardiac tamponade and need of surgical revision. The overall survival rate was 89.7%. Aortic valve morphology itself was no risk factor for mortality (Log-Rank: 0.942). One hundred and forty patients had a tricuspid [TAV: (55.3%)] aortic valve and 113 patients had a bicuspid aortic valve [BAV: (44.7%)]. Redilatation to a diameter >50 mm according to CT follow-up occurred in 5.7% (n = 5 of 87). One patient needed reoperation with RAA and aortic valve replacement due to a prosthesis-patient mismatch after aortic valve replacement and aortic redilatation. Conclusion: Non-reinforced RAA is a safe, feasible, and reproducible procedure with low rates of perioperative complications in selected patients primarily undergoing aortic valve repair with a dilated ascending aorta. Aortic valve morphology has no impact on mortality after RAA.

The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts.

Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti-angiogenic mediators in the heart are scarce. Here we study the expression of the anti-angiogenic factor pigment epithelium-derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2'dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor-alpha decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF-induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down-regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease.

Bbeta(15-42) protects against acid-induced acute lung injury and secondary pseudomonas pneumonia in vivo.

RATIONALE: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far. OBJECTIVES: To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. METHODS: The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated. MEASUREMENTS AND MAIN RESULTS: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. CONCLUSIONS: The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Short-term clinical outcomes for intermittent cold versus intermittent warm blood cardioplegia in 2200 adult cardiac surgery patients.

BACKGROUND: Aim of the present study was to compare clinical outcome of intermittent cold (ICC) versus intermittent warm (IWC) blood cardioplegia in different cardiosurgical procedures. METHODS: Two thousand one hundred and eighty-eight patients were retrospectively divided into 5 groups: isolated coronary artery bypass surgery (CABG; N.=1203), isolated aortic valve surgery (AVR; N.=374), isolated mitral valve surgery (MVR; N.=151), combined AVR+CABG (N.=390), and combined MVR+CABG (N.=70). Myocardial protection was performed by ICC (N.=1578) or IWC (N.=610) blood cardioplegia. In logistic regression models the effect of cardioplegia on 30-day mortality, IABP/ECLS (intraaortic balloon-pump/extracorporal life support) implantation, transient neurological deficit, stroke, renal failure, new-onset atrial fibrillation, and troponin T release was estimated. Potential modifications of the effect of cardioplegia by logistic EuroSCORE, cross-clamping time, ejection fraction, and op-status elective versus urgent/emergent were investigated. RESULTS: There were no statistically significant differences between ICC and IWC regarding 30-day mortality (odds ratio [OR]=0.70; 95% CI: 0.39-1.23; P=0.219), IABP/ECLS support (OR=0.60; 95% CI: 0.23-1.55; P=0.294), transient neurological deficit (OR=0.90; 95% CI: 0.65-1.24; P=0.541), stroke (OR=0.79; 95% CI: 0.40-1.54; P=0.495), renal failure (OR=1.07; 95% CI: 0.57-1.99; P=0.825), and atrial fibrillation (OR=0.96; 95% CI: 0.77-1.18; P=0.713) across all 5 groups. Troponin t release was significantly higher in ICC compared to IWC (by 0.029±0.015 ng/mL; P=0.046) in univariate analysis; this effect was lowered by risk-factor adjustment and lost statistical significance. The effect of cardioplegia was not significantly different between groups. In urgent/emergent surgery ICC resulted in a significantly higher 30-day mortality (OR=3.03; P=0.024) compared to IWC. CONCLUSIONS: The comparison of IWC and ICC blood cardioplegia in different cardiosurgical procedures showed no statistical significant difference in myocardial protection. The use of ICC, however, appeared overall associated with a slightly better clinical outcome except in patients undergoing urgent/emergent CABG where IWC led to a reduction in 30-day-mortality.

Functional alterations in NO, PGI2 and EDHF pathways in the aortic endothelium after myocardial infarction in rats.

BACKGROUND: Previous work on endothelial dysfunction in post-MI heart failure has shown conflicting results. AIM: To analyze gender related alterations in NO-, PGI(2)- and EDHF-dependent endothelial function in the thoracic aorta 7 and 42 days after myocardial infarction (MI). METHODS AND RESULTS: MI was induced by coronary artery ligation in female and male Sprague-Dawley rats. There was no gender related difference in infarct-size or in the impairment of fractional shortening of the left ventricle 42 days after coronary ligation. Neither acetylcholine-induced (Ach) vasodilation nor basal PGI(2) production in the aorta was modified by coronary ligation. Interestingly, 7 days after MI, basal NO production was impaired and the EDHF component of Ach-induced vasodilation was up-regulated, in both male and female rats. However, 42 days post-MI, basal NO was only impaired in male rats, while EDHF was only up-regulated in female rats. CONCLUSION: MI induced impairment of functional activity of basal NO production and adaptive up-regulation of the EDHF component of Ach-induced relaxation. The above alterations in endothelial function in the aorta were gender-specific at 42 days but not 7 days after MI. Some of the previously reported discrepancies in the development of endothelial dysfunction in the post-MI period may be gender related differences.

Nitric oxide in cardiac transplantation.

The endothelium of coronary arteries has been identified as an important organ locally regulating coronary perfusion and cardiac function by paracrine secretion of nitric oxide (NO) and other vasoactive mediators. Therefore, the established organ procurement in cardiac transplantation using hypothermic storage solutions designed to preserve myocytes but not endothelial cells has to be critically discussed. Heart transplantation is a prestigious high-end treatment for end-stage heart failure patients with promising survival rates: 84% one-year and 65% five-year survival. However, these survival rates are still far from being satisfying requiring further research in organ preservation and perioperative management. This review will focus on possible strategies to improve donor and recipient management in regard to a functional endothelium and NO. The following topics will be addressed: (1) NO and ischemia/reperfusion, to understand the mechanisms that lead to NO depletion and its consequences. (2) NO and hypothermia, to understand the effects of hypothermia on the endothelium. (3) Current status of donor and recipient management, to describe the strategies used today. (4) Possible new approaches: NO-scavenging and NO-substitution, to describe the recent research that is performed in this area including some of our own results. (5) Outlook in donor and recipient management, to give possible new directions, deducted from our current knowledge.

Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade.

OBJECTIVE: Ischemia/reperfusion injury caused by cardioplegic arrest is still a major challenge in patients with reduced left ventricular function. We investigated the effect of chronic versus acute administration of the selective endothelin-A receptor antagonist (ERA) TBC-3214Na during ischemia/reperfusion in failing hearts. METHODS: Male Sprague-Dawley rats underwent coronary ligation. Three days after myocardial infarction (MI), 19 randomly assigned animals (ERA chronic) were administered TBC-3214Na continuously with their drinking water, 29 MI rats received placebo, and 3 rats died during the observation period. Six weeks after infarction, hearts were evaluated in a blood-perfused working heart model during 60 minutes of ischemia and 30 minutes of reperfusion. In 14 MI rats, TBC-3214Na (ERA acute) was added to the cardioplegic solution during ischemia. Thirteen MI rats served as control. RESULTS: At a similar infarct size, postischemic recovery of cardiac output (ERA chronic: 91% +/- 10%, ERA acute: 86% +/- 11% vs control: 52% +/- 15%; P < .05) and external heart work (ERA chronic: 90% +/- 10%, ERA acute: 85% +/- 13% vs control: 51% +/- 17%; P < .05) was significantly enhanced in both TBC-3214Na-treated groups whereas recovery of coronary flow was only improved in ERA acute rats (ERA acute: 121% +/- 23% vs ERA chronic: 75% +/- 13%; control: 64% +/- 15%; P < .05). Blood gas measurements showed enhanced myocardial oxygen delivery and consumption with acute TBC-3214Na therapy. Additionally, high-energy phosphates (phosphocreatine) were significantly higher and transmission electron microscopy revealed less ultrastructural damage under acute TBC-3214Na administration. CONCLUSION: Acute endothelin-A receptor blockade is superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts. Therefore, acute endothelin-A receptor blockade might be an interesting option for patients with heart failure undergoing cardiac surgery.