40 research outputs found

    Retinoic acid-responsive CD8 effector T-cells are selectively increased in IL-23-rich tissue in gastrointestinal GvHD.

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    Gastrointestinal (GI) graft-versus-host disease (GvHD) is a major barrier in allogeneic hematopoietic stem-cell transplantation (AHST). The metabolite retinoic acid (RA) potentiates GI-GvHD in mice via alloreactive T-cells expressing the RA-receptor-alpha (RARα), but the role of RA-responsive cells in human GI-GvHD remains undefined. We therefore used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T-cells in tissues and blood of AHST patients and characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after RA exposure. RARαhi mononuclear cells were increased in GI-GvHD tissue, contained more cellular RA-binding proteins, localized with tissue damage and correlated with GvHD severity and mortality. Using a targeted candidate protein approach we predicted the phenotype of RA-responsive T-cells in the context of increased microenvironmental IL-23. Sequential immunostaining confirmed the presence of a population of RARahi CD8 T-cells with the predicted phenotype, co-expressing the effector T-cell transcription factor T-bet and the IL-23-specific receptor. These cells were increased in GI- but not skin-GvHD tissues and were also selectively expanded in GI-GvHD patient blood. Finally, functional approaches demonstrated RA predominantly increased alloreactive GI-tropic RARahi CD8 effector T-cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing b7 integrin expression on CD8 effector T-cells and reducing CD4 T-cells with a regulatory cell phenotype. In conclusion we have identified a population of RA-responsive effector T-cells with a distinctive phenotype which are selectively expanded in human GI-GvHD and represent a potential new therapeutic target

    Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening.

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    Overexpression of the HER2 protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. We used an inducible breast cancer transformation system that allows investigation of early molecular changes. HER2 overexpression to similar levels as those observed in a subtype of HER2-positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered the transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. HER2 overexpression resulted in opening of many distal regulatory regions and promoted reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype

    Surrogacy tourism: the ethical and legal challenges

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    Although surrogacy seemed to have been practised since ancient times, its resurgence in the contemporary era has been nothing short of phenomenal. With advances made in reproductive technology, it is now possible to fertilise eggs and sperms in laboratories and have the embryo transferred into the womb of a surrogate mother for gestation. Through a combination of push and pull factors, this possibility of gestational surrogacy has led to the meteoric rise of cross-border surrogacy. This paper seeks to highlight the ethical and legal challenges associated with the practice, and calls for better legal oversight at international level

    The use of triangular and pentagonal patches in the numerical representation of surfaces

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    SIGLEAvailable from British Library Document Supply Centre- DSC:D32848/80 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

    Possibilités de culture offertes par la Radiodiffusion Française

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    Charrot Sylvie. Possibilités de culture offertes par la Radiodiffusion Française. In: Femmes Diplômées, n°3, 1952. pp. 1-6

    Quelques notes sur la "Correspondance" de Voltaire ...

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    "Extrait de la Revue d'histoire littéraire de la France, janvier-mars, juillet-septembre 1912, et janvier-mars, juillet-septembre 1913.""C'est une partie de toutes ces fautes [dates fausses, ordre des lettres et des résponses interverti] que je viens signaler ici, en essayant de dresser un Errata général ... de la Correspondance de Voltaire."cover-title,Foot-notes partly bibliographical.Mode of access: Internet.Presentation copy, with author's autograph

    Le neurinome de l'acoustique (du diagnostic au traitement, à propos de 162 cas)

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    ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
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