sPLA2-V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove

The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A(2) (sPLA(2)-V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (lysoPCh) and platelet activating factor (PAF). Remarkably, lysoPCh and PAF impaired the protein C binding ability of sEPCR. Inhibition of sPLA(2)-V, responsible for lysoPCh and PAF generation, improved APC binding to endothelial cells. EPCR-dependent protein C activation and APC antiapoptotic effect were thus significantly enhanced. In contrast, endothelial cell supplementation with sPLA(2)-V inhibited both APC generation and its antiapoptotic effects. We conclude that APC generation and function can be modulated by changes in phospholipid occupancy of its endothelial cell receptor.     

Combined lung and liver procurement in controlled donation after circulatory death using normothermic abdominal perfusion. Initial experience in two Spanish centers

Combining simultaneously lung and liver procurement in controlled donation after circulatory death (cDCD) using normothermic abdominal perfusion (NRP) for abdominal grafts and cooling and rapid recovery technique (RR) for the lungs increases the complexity of the procurement procedure and might injure the grafts. A total of 19 cDCDs from two centers using this combined procedure were evaluated, and 16 liver and 21 lung transplantations were performed. As controls, 34 donors after brain death (DBDs) were included (29 liver and 41 lung transplantations were performed). Two cDCD liver recipients developed primary nonfunction (12.5%). No cases of ischemic cholangiopathy were observed among cDCD recipients. The 1‐year and 2‐year liver recipients survival was 87.5% and 87.5% for the cDCD group, and 96% and 84.5% for the DBD group, respectively (P = .496). The 1‐year and 2‐year lung recipients survival was 84% and 84% for the cDCD group and 90% and 90% for the DBD group, respectively (P = .577). This is the largest experience ever reported in cDCD with the use of NRP combined with RR of the lungs. This combined method offers an outstanding recovery rate and liver and lung recipients survival comparable with those transplanted with DBDs. Further studies are needed to confirm our findings.     

The prognostic value of peripheral retinal nonperfusion in diabetic retinopathy using ultra-widefield fluorescein angiography

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate the prognostic value of peripheral retinal nonperfusion in patients with diabetic retinopathy using ultra-widefield...     

The presence of extracapsular extension is associated with an increased risk of death from prostate cancer after radical prostatectomy for patients with seminal vesicle invasion and negative lymph nodes

ObjectivesDetermining clinicopathologic features that stratify the risk of disease progression in patients with seminal vesicle invasion at radical prostatectomy remains critical for patient counseling, clinical trial enrollment, and the judicious application of secondary therapies. Then, we evaluated the prognostic significance of concomitant extracapsular extension (ECE) in patients with seminal vesicle invasion and negative lymph nodes at radical prostatectomy.MethodsWe identified 1,132 patients who underwent prostatectomy between 1987 and 2009 and were found to have pT3bN0 disease. Median postoperative follow-up was 10.6 years (interquartile range, 5.9–15.3). Survival was estimated using the Kaplan-Meier method and compared for patients with and without ECE with the log-rank test. The association of ECE with outcome was evaluated using Cox proportional hazards regression models.ResultsA total of 693 (61%) patients were noted to have ECE. Compared with pT3bN0 patients without ECE, patients with pT3bN0 tumors and ECE had a significantly worse 15-year biochemical recurrence-free survival (29% vs. 39%; P<0.001), systemic progression-free survival (71% vs. 81%; P<0.001), cancer-specific survival (80% vs. 89%; P<0.001), and overall survival (50% vs. 63%; P<0.001). On multivariate analysis, the presence of ECE was associated with significantly increased risks of systemic progression (hazard ratio [HR], 1.56; P=0.006), death from prostate cancer (HR, 1.71; P=0.01), and all-cause mortality (HR, 1.35; P=0.007). Meanwhile, adjuvant hormonal therapy, which was received by 334 patients (29.5%), was associated with significantly decreased risks of systemic progression (HR, 0.50; P=0.0004) and cancer death (HR, 0.57; P=0.03), but not all-cause mortality (HR, 0.81; P=0.09). Limitations included retrospective design and nonstandardized application of secondary treatments.ConclusionsThe presence of ECE in patients with pT3bN0 prostate cancer is associated with increased risks of systemic progression and cancer death. Pending validation, ECE may be incorporated into risk stratification or staging classification or both. Meanwhile, these patients continue to represent ideal candidates for adjuvant therapy trials.     

Does a Non-Circular Chainring Improve Performance in the Bicycle Motocross Cycling Start Sprint?

Maximising power output during the initial acceleration phase of a bicycle motocross (BMX) race increases the chance to lead the group for the rest of the race. The purpose of this study was to investigate the effect of non-circular chainrings (Q-ring) on performance during the initial acceleration phase of a BMX race. Sixteen male cyclists (Spanish National BMX team) performed two counterbalanced and randomized initial sprints (3.95s), using Q- ring vs. circular chainring, on a BMX track. The sample was divided into two different groups according to their performance (Elite; n = 8 vs. Cadet; n = 8). Elite group covered a greater distance using Q-ring (+0.26 m, p = 0.02; D = 0.23), whilst the improvement for the Cadet (+0.04 m) was not significant (p = 0.87; D = -0.02). Also, there was no significant difference in power output for the Elite group, while the Cadet group revealed larger peak power with the circular chainring. Neither lactate level, nor heart rate showed significant differences due to the different chainring used. The non-circular chainring improved the initial acceleration capacity only in the Elite riders.

Key Points

• This work provides novel results demonstrating very significant improvements in the sprint performance of BMX cycling discipline using a non-circular chainring system.
• This study seeks a practical application from scientific analysis
• All data are obtained in a real context of high competition using a sample comprised by the National Spanish Team.
• Some variables influencing performance as subjects’ physical fitness are discussed.
• Technical equipment approved by International Cycling Union is studied to check its potentially beneficial influence on performance.

Key words: Power, efficiency, pedalling, biomechanics, lactate     

Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

(2R,3R,4S,5R)‐2‐(6‐Amino‐9H‐purin‐9‐yl)‐5‐((((1r,3S)‐3‐(2‐(5‐(tert‐butyl)‐1H‐benzo[d]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ‐5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ‐5676 had moderate to high clearance, low oral bioavailability with a steady‐state volume of distribution 2–3 fold higher than total body water. EPZ‐5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half‐life (t_1/2) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro–in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to f_u‐corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ‐5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N‐dealkylated product (M4) as well as an N‐oxide (M6). Copyright © 2014 John Wiley & Sons, Ltd.     

EPZ011989, A Potent,Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

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