Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Sports, morality and body. The voices of sportswomen under Franco's dictatorship

The aim of this research is to study sportswomen's perceptions and experiences of women's sport in Francoist Spain (1939-1975). The main objective is to analyse the social, moral and aesthetic elements that are present in the experience of these athletes. This study was carried out with an intentional sample of 24 women from Andalusia, Aragon, Asturias, Basque Country, Catalonia and Valencia. They were interviewed by a network of researchers from six universities. Outstanding results show the existence of social limitations to start sports practice (particularly in the post-war period); the importance of sport as a character-building aspect; sport's remarkable influence on their body self-concept; and the incidence on sports of the mainstream moral discourse, which created a female model that even affected sports clothing. The main conclusion is that sportswomen in that period were pioneers and had to fight against most of society in order to develop their facet as athletes, as they would not follow the established model

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

A Genetic Screen for Anchorage-Independent Proliferation in Mammalian Cells Identifies a Membrane-Bound Neuregulin

Anchorage-independent proliferation is a hallmark of oncogenic transformation and is thought to be conducive to proliferation of cancer cells away from their site of origin. We have previously reported that primary Schwann cells expressing the SV40 Large T antigen (LT) are not fully transformed in that they maintain a strict requirement for attachment, requiring a further genetic change, such as oncogenic Ras, to gain anchorage-independence. Using the LT-expressing cells, we performed a genetic screen for anchorage-independent proliferation and identified Sensory and Motor Neuron Derived Factor (SMDF), a transmembrane class III isoform of Neuregulin 1. In contrast to oncogenic Ras, SMDF induced enhanced proliferation in normal primary Schwann cells but did not trigger cellular senescence. In cooperation with LT, SMDF drove anchorage-independent proliferation, loss of contact inhibition and tumourigenicity. This transforming ability was shared with membrane-bound class III but not secreted class I isoforms of Neuregulin, indicating a distinct mechanism of action. Importantly, we show that despite being membrane-bound signalling molecules, class III neuregulins transform via a cell intrinsic mechanism, as a result of constitutive, elevated levels of ErbB signalling at high cell density and in anchorage-free conditions. This novel transforming mechanism may provide new targets for cancer therapy

Potassium and Sodium Transport in Yeast

[EN] As the proper maintenance of intracellular potassium and sodium concentrations is vital for cell growth, all living organisms have developed a cohort of strategies to maintain proper monovalent cation homeostasis. In the model yeast Saccharomyces cerevisiae, potassium is accumulated to relatively high concentrations and is required for many aspects of cellular function, whereas high intracellular sodium/potassium ratios are detrimental to cell growth and survival. The fact that S. cerevisiae cells can grow in the presence of a broad range of concentrations of external potassium (10 M–2.5 M) and sodium (up to 1.5 M) indicates the existence of robust mechanisms that have evolved to maintain intracellular concentrations of these cations within appropriate limits. In this review, current knowledge regarding potassium and sodium transporters and their regulation will be summarized. 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Abstract P3-14-11: Gene-expression analyses identify altered transcription factors and supports the antitumor activity of novel bromodomain inhibitors in triple negative breast cancer

Abstract Introduction: Identification of novel therapeutic targets in triple negative breast cancer (TNBC) is a main goal. In silico evaluation of human tumors by gene expression analyses can identify functions that could be pharmacologically inhibited. BET bromodomain inhibitors are a new family of compounds that reduce activity of oncogenic transcription factors through the inhibition of bromodomains. Material and methods: We performed gene expression and functional analyses comparing triple negative tumors with normal breast samples. RT-PCR was used to evaluate genes down-regulated by treatment with the BET bromodomain inhibitors JQ1 and OTOX15 at different time points in MDA-MB231 cells. Cell proliferation and colony growth was measured by MTT uptake and 3D growth in matrigel in a panel of cell lines including HS578T, BT549, MDA-MB231 and HCC3153 treated with JQ1 and OTOX15. Evaluation of apoptosis and cell cycle was performed by flow cytometry using Annexin V and propidium iodide, respectively. Western-blot was used for evaluation of protein expression. Xenografted animals were used for the assessment of the in vivo activity of JQ1. Results: Gene expression analyses identified upregulated genes including a number of transcription factors. These genes were more expressed in MDA-MB231 compared with MCF-10A. Treatment with JQ1 reduced the expression of some transcription factors at different time points. JQ1 and OTX015 reduced proliferation and cell growth in a panel of triple negative cell lines. They also led to arrest at the G0/G1 phase in HS578T and MDA-MB231 at 12 and 24 hours; that was confirmed by the biochemical evaluation of cell cycle mediators. An induction of apoptosis was observed at 48 hours in HS578T. JQ1 at 50 mg/kg daily reduced tumor growth in MDA-MB231 xenografted in nude mice. Conclusion: Gene-expression profiling identified upregulated transcription factors in triple negative tumors compared with normal breast human samples. BET bromodomain inhibitors reduced the expression of some of these genes in cellular models. JQ1 shows clear antitumor activity in vitro and in vivo. Citation Format: Ocana A, Perez-Peña J, Serrano-Heras G, Corrales-Sanchez V, Montero JC, Gascón-Escribano MJ, Picazo MG, García-Olmo DC, Martin M, Pandiella A. Gene-expression analyses identify altered transcription factors and supports the antitumor activity of novel bromodomain inhibitors in triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-11.</jats:p

Abstract P6-13-18: Triple-negative kinase profile guides in the selection of the multi-kinase inhibitor EC70124 as an active antitumor agent

Abstract Introduction: Identification of the kinase profile of triple negative tumors can guide in the selection of active multi-kinase inhibitors. We describe the preclinical selection of a novel kinase inhibitor based on the kinase profile identified in human samples. Methods: phosphokinase profiles of human samples were performed using two kinase arrays: human phospho-RTK array kit (# ARY001, R&amp;D Systems, Abingdon, UK) and the PathScan RTK Signaling Antibody Array Kit (# 7982,Cell Signaling Technology). Based on the kinase profile, inhibitors against activated proteins were evaluated in a panel of triple negative cell lines. Proliferation and growth was measured by MTT uptake. Evaluations of apoptosis and cell cycle were performed by flow cytometry using Annexin V and propidium iodide, respectively. Gene-set enrichment analyses were performed to identify relevant functions mediated by the drug and the identified genes were confirmed by RT-PCR. The in vivo antitumoral effect was evaluated using xenografted animals. Results: Several kinases were constitutive activated in human tumors, including AKT and pS6, among others . Pharmacological screening identified PI3K/mTOR inhibitors as the most active agents. The novel multi-kinase inhibitor, EC-70124 showed clear antitumor activity. Doses of EC70124 in the nanoMolar ranged reduced proliferation and cell growth in a panel of triple negative cell lines including HS578T, BT549, MDA-MB231 and HCC3153. Treatment with EC70124 inhibited the PI3K/mTOR pathway and induced DNA damage. Gene set enrichment analyses showed different cellular functions induced by the compound. EC70124 showed activity in xenografted animals. Pharmacodynamic analyses supported the inhibition of the PI3K/mTOR pathway in vivo. Conclusion: the kinase profile of human triple negative tumors identified major activated pathways including the PI3K/mTOR route. The novel kinase inhibitor EC70124 inhibited the PI3K/mTOR pathway showing clear antitumor activity. Evaluation of the kinase profile followed by functional studies is an attractive approach to rationally select active antitumoral agents. Citation Format: Perez-Peña J, Serrano-Heras G, Corrales-Sánchez V, Nieto-Jimenez C, Gascón-Escribano MJ, Montero JC, Moris F, Martin M, Pandiella A, Ocana A. Triple-negative kinase profile guides in the selection of the multi-kinase inhibitor EC70124 as an active antitumor agent. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-18.</jats:p