Optimal torque control of a synchronous machine

International audienc

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5

International audienceLysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa.Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839).Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab.Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine

Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5 alpha-dihydrotestosterone regulation

Purpose Resistance to androgen-deprivation therapies and progression to so-called castrate-resistant prostate cancer (CRPC) remain challenges in prostate cancer (PCa) management and treatment. Among other alterations, CRPC has been associated with metabolic reprogramming driven by androgens. Here, we investigated the role of androgens in regulating glutaminolysis in PCa cells and determined the relevance of this metabolic route in controlling the survival and growth of androgen-sensitive (LNCaP) and CRPC (DU145 and PC3) cells. Methods PCa cells (LNCaP, DU145 and PC3) and 3-month old rats were treated with 5 alpha-dihydrotestosterone (DHT). Alternatively, LNCaP cells were exposed to the glutaminase inhibitor BPTES, alone or in combination with the anti-androgen bicalutamide. Biochemical, Western blot and extracellular flux assays were used to evaluate the viability, proliferation, migration and metabolism of PCa cells in response to DHT treatment or glutaminase inhibition. Results We found that DHT up-regulated the expression of the glutamine transporter ASCT2 and glutaminase, both in vitro in LNCaP cells and in vivo in rat prostate cells. BPTES diminished the viability and migration of PCa cells, while increasing caspase-3 activity. CRPC cells were found to be more dependent on glutamine and more sensitive to glutaminase inhibition. BPTES and bicalutamide co-treatment had an additive effect on suppressing LNCaP cell viability. Finally, we found that inhibition of glutaminolysis differentially affected glycolysis and lipid metabolism in both androgen-sensitive and CRPC cells. Conclusion Our data reveal glutaminolysis as a central metabolic route controlling PCa cell fate and highlight the relevance of targeting glutaminase for CRPC treatment.FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalization in Axis I -Strengthening research, technological development and innovation [007491, 029114]; National Funds by the FCT-Foundation for Science and Technology [UID/Multi/00709/2013]; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [SFRH/BD/111351/2015, SFRH/BD/104671/2014, IF/00614/2014/CP12340006]; FCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal [IF/00614/2014]; FCT Research Center gran

Design et Transmédia : le croisement des disciplines de SHS

Cette dixième livraison de la revue RFSIC propose un dossier Design et Transmédia. Ce dossier est important car il s’inscrit délibérément dans le croisement de notre discipline avec un autre secteur : le Design. Il est vrai que tous les objets communiquent, particulièrement les objets construits, comme ceux de l’architecture, parfois au sens le plus trivial du terme. Que l’on pense, par exemple, à la tour Burj Khalifa à Dubaï. Comme à l’hôtel Bellagio à Las Vegas, la société WET Design a installé un système de fontaines qui s’animent lors des spectacles façon son et lumière. Toutes les demi-heures à partir de 18 h, ces fontaines se mettent à danser, sur une longueur de 275 mètres et sur une hauteur pouvant atteindre 150 mètres. Le spectacle est différent à chaque fois par ses mouvements, ses couleurs et ses musiques : un air d’opéra interprété par Andrea Bocelli, un chant oriental ou une chanson swahili… [en savoir +