Nashfraser7193

The proviral integration site for Moloney murine leukemia virus (PIM) family of serine/threonine-specific kinases consist of three isoforms, that regulate proliferation, apoptosis, metabolism, invasion and metastasis of cancer cells. Among these, abnormally elevated kinase activity of PIM-1 contributes to the progression of gastric cancer and responsible for poor prognosis and low survival rate in gastric cancer patients. In the present study, we found that resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemical, directly binds to PIM-1 and thereby inhibits its catalytic activity in human gastric cancer SNU-601 gastric cancer cells. This resulted in suppression of phosphorylation of the proapoptotic Bad a known substrate of PIM-1. Resveratrol, by inactivating PIM-1, also inhibited anchorage-dependent growth and proliferation of SNU-601 cells. To understand the molecular interaction between resveratrol and PIM-1, we conducted docking simulation and found that resveratrol directly binds to the PIM-1 at the ATP-binding pocket. In conclusion, the proapototic and anti-proliferative effects of resveratrol in gastric cancer cells are likely to be mediated through suppression of PIM-1 kinase activity, which may represent a novel mechanism underlying its chemopreventive and anticarcinogenic actions.Background The severity and duration of hypoxia is known to determine apoptotic fate in heart, however, its implication during myocardial infarction (MI) remains unaddressed. Therefore the aim of the study was to determine apoptotic regulation in cardiomyocytes under varied hypoxic intensity and duration and to unravel the role of HIF-1α in such modulation. Methods Treatment of cardiomyocytes to varied hypoxic intensity and duration was carried out in vitro, which was mimicked in vivo by dose-dependent Isoproterenol hydrochloride treatment for varied time-points. Myocardium-targeted HIF-1α knockdown in vivo was performed to decipher its role in cardiomyocyte apoptosis under varied stress. Signaling intermediates were analyzed by RT-PCR, immunoblotting and co-immunoprecipitation. DCFDA-based ROS assay, Griess assay for NO release and biochemical assays for estimating caspase activity were performed. Results Severe stress resulted in cardiomyocyte apoptosis in both shorter and longer time-points. Moderate stresate stress. However, silencing of HIF-1α aggravated apoptotic injury during sustained moderate stress. Conclusion ROS-mediated HIF-1α stabilization promotes cardiomyocyte apoptosis on one hand while NO-mediated stabilization of HIF-1α disrupts apoptosis depending upon the severity and duration of hypoxia. Therefore the outcome of modulation of cardiac HIF-1α activity is regulated by both the severity and duration of ischemic stress.Background Patients with locally advanced, non-small cell lung cancer treated with definitive chemoradiotherapy alone often demonstrate persistent or recurrent disease. In the absence of systemic progression, salvage lung resection post-definitive chemoradiotherapy has been utilized as a treatment option. Given the paucity of data, we sought to evaluate the safety and efficacy of salvage pulmonary resections occurring >90 days post-definitive chemoradiotherapy. Methods Retrospective institutional database review identified patients undergoing salvage lung resection at least 90 days after completion of definitive chemoradiotherapy. Primary outcomes evaluated were overall survival and recurrence-free survival. Results 30 patients met inclusion criteria between January 1, 2004 and December 31, 2015. The median time to surgery post-definitive radiotherapy was 279 days (IQR 168- 474 days). Extended resections were performed in 11 patients (37%). Ottawa IIIA or greater complications occurred in 12 patients (40%). 30-day mortality was 6.7% (2 patients). Median overall survival post-salvage resection was 24 months. The median overall survival for an R1 resection was 5.3 months versus 108 months for an R0 resection (p=0.001). Persistent pN1+ salvage resections also did less well compared to pN0, 8.9 vs 28.2 months (p=0.06). For patients who underwent non-extended salvage resection ("simple lobectomy" or "simple pneumonectomy"), the median overall survival was 108.4 months, versus 8.9 months for extended salvage resections (p = 0.02). Conclusions With proper patient selection, salvage lung resections can be performed with acceptable morbidity, mortality, and oncologic outcomes, particularly when a ypN0R0 resection can be achieved by non-extended surgical means.Background Successful surgical treatment of patients with Mycobacterium avium complex pulmonary disease is thought to require complete removal of parenchymal destructive lesions. This study aimed to evaluate the short- and long-term outcomes and the predictors of microbiological recurrence after surgery for Mycobacterium avium complex pulmonary disease. Selleck AG-14361 Methods We conducted a retrospective review of 184 patients undergoing unilateral lung resection for Mycobacterium avium complex pulmonary disease at a single center in Japan between January 2008 and December 2017. Results The median age of the 184 patients was 55.5 years; 133 (72.3%) were females. All but 2 patients had anatomical lung resection. One hundred sixteen (63.0%) patients had limited disease and underwent complete resection; the remaining 68 (37.0%) patients had extensive disease and underwent "debulking" surgery. No operative mortalities occurred. Twenty-one morbidities occurred in 18 of 184 (9.8%) patients, including 3 (1.6%) bronchopleural fistulae. Postoperative sputum-negative status was achieved in 183 (99.5%) patients. Microbiological recurrences occurred in 15 (8.2%) patients. By multivariate analysis, extensive disease was an independent risk factor for recurrence (hazard ratio, 5.432; 95% confidence interval, 1.372-21.50; p = 0.016). Recurrence-free rates were significantly higher in patients with limited disease compared with those with extensive disease (99.0%, 97.4% and 95.0% vs 93.0%, 89.2% and 75.1% at 1, 3, and 5 years, respectively; p less then 0.001). Conclusions Complete resection of parenchymal destructive lesions can achieve excellent microbiological control for patients with limited Mycobacterium avium complex pulmonary disease. The efficacy of "debulking" surgery in patients with extensive disease needs further investigation.