Control of P-Glycoprotein Activity by Membrane Cholesterol Amounts and Their Relation to Multidrug Resistance in Human CEM Leukemia Cells †

International audienceP-glycoprotein (P-gp) is the most well-known ATP-binding cassette (ABC) transporter involved in unidirectional substrate translocation across the membrane lipid bilayer, thereby causing the typical multidrug resistance (MDR) phenotype expressed in many cancers. We observed that in human CEM acute lymphoblastic leukemia cells expressing various degrees of chemoresistance and where P-gp was the sole MDR-related ABC transporter detected, the amount of esterified cholesterol increased linearly with the level of resistance to vinblastine while the amounts of total and free cholesterol increased in a nonlinear way. Membrane cholesterol controlled the ATPase activity of P-gp in a linear manner, whereas the P-gp-induced daunomycin efflux decreased nonlinearly with the depletion of membrane cholesterol. All these elements suggest that cholesterol controls both the ATPase and the drug efflux activities of P-gp. In addition, in CEM cell lines that expressed increasing levels of elevated chemoresistance, the amount of P-gp increases to a plateau value of 40% of the total membrane proteins and remained unvaried while the amount of membrane cholesterol increased with the elevation of the MDR level, strongly suggesting that cholesterol may be directly involved in the typical MDR phenotype. Finally, we showed that the decreased daunomycin efflux by P-gp due to the partial depletion of membrane cholesterol was responsible for the efficient chemosensitization of resistant CEM cells, which could be totally reversed after cholesterol repletion

How metabolomics can contribute to bio-processes: a proof of concept study for biomarkers discovery in the context of nitrogen-starved microalgae grown in photobioreactors

International audienc

Données complémentaires sur la géométrie du plissement et sur les variations de forme et d'orientation de l'ellipsoïde de deformation dans l'arc ibéro-armoricain

Note déposée le 14 novembre 1975, présentée à la séance du 27 novembre 1975, manuscrit définitif reçu le 23 janvier 1976.National audiencepas de résum

Different Genetic Signatures of Small‐Cell Lung Cancer Characterize <scp>Anti‐GABA_BR</scp> and <scp>Anti‐Hu</scp> Paraneoplastic Neurological Syndromes

International audienceObjective: Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABA B R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABA B R or anti-Hu PNS compared with SCLC without PNS. Methods: A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABA B R, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes

L’exil chilien en France

À partir de 1973, des milliers d'exilés chiliens fuient la dictature de Pinochet et sont accueillis en France où ils suscitent un ample mouvement de sympathie. Ce dossier retrace les étapes et les caractéristiques de cette migration chilienne en France en analysant les profils sociologiques des exilés et les conditions d'accueil qui leur ont été proposées à leur arrivée par les pouvoirs publics et les associations. Des articles explorent différentes facettes de leur installation dans une situation d'exil qui se prolonge, se transmet à leurs enfants et incite certains à un retour au Chili à la fin des années 1980. La région grenobloise est retenue comme territoire d'observation. Cet exil chilien donne lieu également à un formidable développement culturel et artistique, dans lequel la littérature occupe une place essentielle. As of 1973, thousands of Chilean exiles fled the Pinochet dictatorship and were welcomed in France where they arose a strong movement of sympathy. This issue recounts the stages and the characteristics of this Chilean migration in France by analyzing the sociological profiles of the exiles and the conditions of their reception by public authorities and associations upon their arrival. Various articles investigate the different aspects of their settlement in a lasting situation of exile which they pass on to their children and prompt some to return to Chile in the late 1980s. The Grenoble region is examined as a study area. This Chilean exile results in tremendous cultural and artistic growth, in which literature is an integrated part

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

International audiencePrimary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung