SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity

Unusual cause of exercise-induced ventricular fibrillation in a well-trained adult endurance athlete: a case report

<p>Abstract</p> <p>Introduction</p> <p>The diseases responsible for sudden deaths in athletes differ considerably with regard to age. In young athletes, congenital malformations of the heart and/or vascular system cause the majority of deaths and can only be detected noninvasively by complex diagnostics. In contrast, in older athletes who die suddenly, atherosclerotic disease of the coronary arteries is mostly found. Reports of congenital coronary anomalies as a cause of sudden death in older athletes are rare.</p> <p>Case presentation</p> <p>A 48-year-old man who was a well-trained, long-distance runner collapsed at the finish of a half marathon because of a myocardial infarction with ventricular fibrillation. Coronary angiography showed an anomalous origin of the right coronary artery from the left sinus of Valsalva with minimal wall alterations. Multislice computed tomography of the coronary arteries confirmed these findings. Cardiomagnetic resonance imaging demonstrated a mild hypokinesia of the basal right- and left-ventricular posterior wall. An electrophysiological study showed an inducible temporary polymorphic ventricular tachycardia and an inducible ventricular fibrillation. The athlete was subsequently treated by acetylsalicylic acid 100 mg (0-1-0), bisoprolol 2.5 mg (1-0-0) and atorvastatin 10 mg (0-0-1) and was instructed to keep his training intensity under the 'individual anaerobic threshold'. Intense and long-lasting exercise under extreme environmental conditions, particularly heat, should also be avoided.</p> <p>Conclusion</p> <p>This case report presents a coronary anomaly as the most likely reason for an exercise-induced myocardial infarction with ventricular fibrillation in a well-trained 48-year-old endurance athlete. Therefore, coronary anomalies have also to be considered as a possible cause of cardiac problems in older athletes.</p

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Background: Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. Methods: We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0–8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC 0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. Discussion: Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PD characteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. Trial registration: EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776)