The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. � 2016 American Association for Cancer Research

Impact of participating to a 330 km long ultra-trail versus a 67 km short ultra-trail on muscular and cardiac genetic regulation by microRNAs

peer reviewedINTRODUCTION: Even though endurance exercise has always shown beneficial action on cardiovascular diseases, the impact of an ultra-endurance experience on the human body has not been studied enough yet. Indeed, the consequences of such effort could represent a major issue to the organism and particularly to the myocardial muscle, could lead to sudden cardiac death when experienced too many times - a phenomenon which is more and more linked to the athletic world. The main objective of this study was to measure the impact of high level physical activity on the expression of different microRNAs such as specific to muscular and cardiac suffering (miR-1, miR 133a and miR 208b), specific to muscular suffering (miR 133b, miR 206, miR 499a and miR 499b) specific to cardiac suffering (miR 208a) and specific to fibrosis (miR 21 and miR 29b). METHODS: The study was conducted on two different trails participants: the “Tor des Géants” (TDG), 330 km long and the “Ultra Tour de Liège” (UTL), 67km long. Blood samples were collected at different timings. Timing of sampling were respectively: 4 days before starting (t0), after completing 148 km (t2), finish line (t3) and 3 days after the end of the race for the TDG (t4) , and for the UTL : just before the starting (t0), at the finish line( t2) : and 3 hours after finishing (t3). There was a number of 12 TDG studied volunteers and 10 from the UTL. MicroRNAs were extracted by using miRneasy® Serum/Plasma kit and qRT-PCR has been employed to measure their expression. RESULTS: Only miR-1, miR-133a, miR-133b, miR-206 and miR-499a showed significant variation in their expression during both races. The variation was found to be linked to the exhaustion during the race. From these data, four out of the five miRNAs showed a higher expression level during the shorter trail (UTL). No correlation was found between miR-208a and frequently used cardiac biomarkers (hs-TnT, sST2 and NT-proBNP). No significant variation was found in fibrosis specific microRNAs (miR-21 and miR-29b). CONCLUSION: From the amount of microRNAs tested, the expression of five of them increased significantly during both the races, which showed myocardial and muscular cellular suffering. Moreover, the levels of miRNA never came back to the baseline during recovery times. However, the fibrotic miRNA did not show any significant increase during in any race, suggesting there was no permanent damage of the heart, but this point needs further investigations

Biochemical markers of musculoskeletal health and aging to be assessed in clinical trials of drugs aiming at the treatment of sarcopenia:consensus paper from an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d’Expérimentation en Santé (CARES SPRL), under the auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging

Abstract In clinical trials, biochemical markers provide useful information on the drug’s mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio — or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations