A novel Nodal enhancer dependent on pluripotency factors and Smad2/3 signaling conditions a regulatory switch during epiblast maturation

During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the binding of pluripotency factors at the Nodal locus and called this sequence “highly bound element” (HBE). Luciferase-based assays, the analysis of fluorescent HBE reporter transgenes, and a conditional mutation of HBE allowed us to establish that HBE behaves as an enhancer, is activated ahead of other Nodal enhancers in the epiblast, and is essential to Nodal expression in embryonic stem cells (ESCs) and in the mouse embryo. We also showed that HBE enhancer activity is critically dependent on its interaction with the pluripotency factor Oct4 and on Activin/Nodal signaling. Use of an in vitro model of epiblast maturation, relying on the differentiation of ESCs into epiblast stem cells (EpiSCs), revealed that this process entails a shift in the regulation of Nodal expression from an HBE-driven phase to an ASE-driven phase, ASE being another autoregulatory Nodal enhancer. Deletion of HBE in ESCs or in EpiSCs allowed us to show that HBE, although not necessary for Nodal expression in EpiSCs, is required in differentiating ESCs to activate the differentiation-promoting ASE and therefore controls this regulatory shift. Our findings clarify how early Nodal expression is regulated and suggest how this regulation can promote the specification of extra-embryonic precusors without inducing premature differentiation of epiblast cells. More generally, they open new perspectives on how pluripotency factors achieve their function

Observance des patients sous antivitamines K (connaissance des patients et gestion de leur traitement)

Un pour cent de la population bénéficie d'un traitement anticoagulant. Les anticoagulants sont responsables de 18000 hospitalisations par an, les accidents hémorragiques étant les motifs les plus fréquents. il s'agit là d'un véritable problème de santé publique, étant donné le caractère indispensable de ces médicaments dans certaines pathologies et la fréquence de sa prescription. Une bonne observance médicamenteuse est indispensable pour réduire le nombre d'accidents iatrogènes. La connaissance et la compréhension du traitement par le patient et sa capacité à le gérer sont des facteurs indispensables à une bonne observance. C'est à l'aide d'un questionnaire simple et adapté aux patients, relatif aux connaissances et à la gestion de leur traitement, que j ai tenté d'évaluer les facteurs favorisant la mauvaise observance thérapeutique. Ce questionnaire a été distribué dans des cabinets de médecine de ville ou à l hôpital, sur la Guadeloupe. Il était distribué aux patients sous AVK qui le remplissaient seul et le remettaient par la suite de manière anonyme dans une urne. Soixante-deux patients ont répondu à cette étude, permettant de souligner des lacunes dans la connaissance et la gestion du traitement et d'évoquer des causes à celles-ci. Des recommandations officielles récentes existent pour accompagner les patients et les aider à gérer leur traitement, montrant bien que ce problème est loin d'être résolu, mais que des solutions se présentent pour réduire le risque iatrogène des anticoagulants oraux : outils d'aide à l'observance, éducation thérapeutique, recherche sur de nouveaux médicaments.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib.

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. METHODS: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. RESULTS: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. CONCLUSIONS: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.British Journal of Cancer advance online publication 14 February 2017; doi:10.1038/bjc.2017.23 www.bjcancer.com

Exploring the neural basis of phonological representations from sounds and vision

Speech is a multisensory signal that we can decipher from the voice and/or the lips. If the successive computational steps necessary to transform the auditory signal into meaningful language representations have been extensively explored, little is known on how the visual input of speech is processed in the brain; and how auditory and visual speech information are combined to converge onto a unified linguistic percept. In this study, we aim to identify brain regions that are involved in auditory (phonemes) and visual (visemes) phonology and explore whether some brain regions can be considered as multisensory abstract phonological regions supporting both auditory and visual phonological representations. We rely on functional magnetic resonance imaging (fMRI) in healthy adults to classify brain activity patterns evoked by phonemes and visemes. Preliminary results suggest that a network of visual, motor, auditory and frontal regions are involved in viseme recognition. Interestingly, auditorily defined phonological regions (in superior temporal gyrus - STG) seem to be involved in visual phonological representations as well. Moreover, overlap between auditory and visual decoding in mid- and posterior STG and in motor cortex indicate that these regions could be involved in the integration of auditory and visual speech phonology