Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma

About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins

Effects of two pre-workout supplements on concentric and eccentric force production during lower body resistance exercise in males and females: a counterbalanced, double-blind, placebo-controlled trial

Abstract Background Pre-workout supplements purportedly enhance feelings of energy, reduce fatigue and improve exercise performance. The purpose of this study was to examine the performance effects of caffeinated and non-caffeinated multi-ingredient pre-workout supplements. Methods In a counterbalanced, double-blind, placebo-controlled design, eccentric and concentric force production during lower body resistance exercise on a mechanized squat device were assessed after supplement ingestion. Repetitions-in-reserve/RPE and subjective feelings of energy, focus and fatigue were also examined. Twenty-one resistance-trained adults (12 F, 9 M) completed three conditions in random order: caffeinated supplement, non-caffeinated supplement and placebo. Subjects were not informed of the presence of a placebo condition. Thirty minutes after supplement ingestion, a 3-repetition maximum test and 5 sets of 6 repetitions were completed using the squat device. Each repetition involved 4-s eccentric and concentric phases, and the force signal throughout each repetition was sampled from a load cell contained within the squat device. The scaled and filtered force signals were analyzed using customized software. Repeated measures analysis of variance and appropriate follow-up analyses were utilized to compare dependent variables, and relevant effect sizes (d) were calculated. Results Supplement or placebo ingestion led to similar subjective responses (p > 0.05). Energy (+8 to 44%; d = 0.3 to 0.8) and focus (+8 to 25%; d = 0.3 to 0.5) were acutely increased by supplement or placebo ingestion and decreased as the exercise session progressed. Fatigue was acutely decreased by supplement or placebo ingestion (−7 to 38%; d = −0.1 to −0.6) and increased as the exercise session progressed. Eccentric and concentric forces were unimproved by supplementation during the exercise sets for both sexes. In the non-caffeinated supplement condition only, maximal eccentric force production was lower during sets 3 to 5, as compared to set 1 (p < 0.05). Effect size data indicated that both the caffeinated and non-caffeinated supplements may contribute to small increases in concentric force production in males (+5 to 20%, d = 0.2 to 0.4 relative to placebo), but not females. Conclusions As compared to placebo, caffeinated and non-caffeinated multi-ingredient pre-workout supplements failed to improve concentric and eccentric force production. In males, effect size data indicate a possible small benefit of supplementation on concentric force production, although this was not statistically significant. When resistance-trained subjects were unaware of the presence of a placebo, resistance exercise performance was similar regardless of whether a placebo or multi-ingredient supplement was ingested