Tensiomyographic Characteristics of Rectus Femoris after a Single Bout of Intense Exercise

It is not well known how local fatigue can impair the contractile properties of skeletal muscle, so the aim of this study was to determine the Tensiomyographic (TMG) characteristics of Rectus Femoris (RF) after a single bout of intense exercise. Approach: Twelve healthy male volunteers (mean±SEM; age, 24.16±0.62 years, height 172.02±1.21 cm, body mass 71.84±2.19 kg, BMI 24.42±0.70 kg m-1) were recruited. Results: In session 1, a graded exercise test on cycle ergometer was performed in order to determine subject’s maximal oxygen uptake (VO2max) and power at this key point (pVO2max). In a second testing session, TMG rest values were assessed and then all subjects carried out 2 min of cycling at pVO2max after which TMG analysis was applied again. The results showed subject’s VO2max values of 53.44±2.67 ml kg-1 min-1, reaching a mean pVO2max of 270.83±8.61 W. Maximal radial displacement (Dm) and time from the onset of electrical stimulus to 10% of Dm (Td) were significantly lower at post-test (from 7.577.57±0.92-4.37±0.67 mm; p = 0.01, for Dm and from 25.25±0.57-22.44±0.89 ms; p≤0.05, for Td). Conclusion/Recommendations: It can be concluded that a brief and intense exercise consisting in 2 min of cycling at PVO2max provokes a reduction in contractile properties of RF considering TMG parameters such as Dm and Td. More studies are needed to clarify the role of muscle fatigue on temporal TMG parameters

Cardiovascular risk factors, caloric intake and practice of physical activity in college students. A preliminary study.

The aim of this investigation were to determine the level of physical activity practice and to define the presence of cardiovascular risk factors associated with body composition and caloric intake in college students. A total of 81 college students (38 and 41 females and males, respectively) were submitted to a complete evaluation that consisted of an analysis of food-intake behavior, measures of several body composition variables (height, weight, body mass index, fat and muscle mass, waist and hip circumferences, waist-hip ratio, and sum of 6 skinfolds), blood pressure assessment, and physical activity level calculation. The results show sex differences in blood pressure and body composition variables; although an optimal food-intake patterns, a high level of physical activity practice and the absence of cardiovascular risk factors seem to generate healthy profiles in this population. Key words:cardiovascular risk factors, food-intake patterns, physical activity, college students

A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

Acute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy

Structure–Activity Relationship in a Purine-Scaffold Compound Series with Selectivity for the Endoplasmic Reticulum Hsp90 Paralog Grp94

Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design <b>18c</b>, a derivative with good potency for Grp94 (IC₅₀ = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of <b>18c</b> was confirmed in cells through several functional readouts. Compound <b>18c</b> was also inert when tested against a large panel of kinases. We show that <b>18c</b> has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor