Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Producción CientíficaBackground: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13

The contribution of wildlife to sustainable natural resource utilization in Namibia: A Review

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Sensory acceptability and chemical characteristics of healthy rib-eye steaks from forage‐finished steers

Consumer interest in health benefits of forage-finished beef has led to increased product demand. To date, little information on sensory characteristics of cooked forage-finished beef is available. We evaluated sensory acceptability and chemical characteristics of rib-eye steaks from forage-finished steers. Rib-eye steaks from 3 forage-finished steers [S1 (bermudagrass+ryegrass, etc.); S2 (bermudagrass+ryegrass+berseem, etc.); S3 (bermudagrass+berseem+forage soybean+brown midrib sorghum, etc.)], and one C [commercial steak], cooked by grilling and/or 2-sided grilling, were evaluated for chemical composition and microbial safety. Sensory liking [overall-appearance (OAR) and fat-appearance (FA) for raw steaks; overall-appearance (OAC), overall-flavor (OF), juiciness, tenderness, and overall-liking (OL) for cooked steaks] were evaluated by 112 Hispanic consumers. Data were analyzed (PROC MIXED, a=0.05). C (raw) had higher fat (50.2% compared to 23.0-24.9%) and lower protein (49.4% compared to 73.5-74.4%, dry weight basis) contents compared with S1 and S2. S1 and S3 had higher omega-3 (0.49-0.55 compared to 0.09%), lower omega-6/omega-3 ratio (2.51-2.81 compared to 10.07), and lower PUFA (4.31-4.77 vs. 8.4%) contents than C, thus exhibiting a healthier fatty acid profile. Concerning raw steaks, S3 had higher OAR (6.9 compared to 5.4-5.9) and FA (5.9 compared to 4.9-5.1) liking scores than other samples. Purchase intent based on visual appearance was highest for S3 (85.7%). Concerning cooked steaks, the 2 cooking methods did not cause significant differences in liking scores. Juiciness and OL scores of C steaks (both cooking methods) and S3 (2-sided grilling) were not significantly different. Purchase intent (after health benefits of forage-finished steaks was informed) increased from 62.0-73.8 to 69.8-85.7%. The mean drop of liking scores was -1.00 to -2.50 and -0.50 to -2.50 on the 9-point OL scale, respectively, when cooked steaks were not-juicy-enough and not-tender-enough. Cooked and raw rib-eye steaks were free of E. coli . This study demonstrated that forage-finished steaks are healthier than grain-fed commercial steaks and have market potential toward Hispanic population