Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas

Sixty Years of Modern Human Origins in the American Anthropological Association

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65197/1/aa.2003.105.1.89.pd

COUP-TFII Controls Mouse Pancreatic β-Cell Mass through GLP-1-β-Catenin Signaling Pathways

Background: The control of the functional pancreatic beta-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how beta-cell mass is determined

Neandertal-Modern Human Contact in Western Eurasia: Issues of Dating, Taxonomy, and Cultural Associations

Supporting Assimilation views of Neandertal/modern human interaction, chronostratigraphic reasoning indicates that the “transitional” industries of Europe predate modern human immigration, in agreement with their association with Neandertals in the Châtelperronian at the Grotte du Renne and St.-Césaire. Supporting the Neandertals' species separateness and less developed cognition, those industries are alternatively claimed to relate to pioneer groups of modern humans; the latter would have been the true makers of the precocious instances of symbolic material culture that, under Assimilation, are assigned to the Neandertals. However, the taxonomy of the Kent's Cavern and Grotta del Cavallo dental remains is uncertain, and their poor stratigraphic context precludes dating by association. The opposite happens at the Grotte du Renne, whose stratigraphic integrity is corroborated by both taphonomy and dating. Not questioning that the Early Ahmarian is a cultural proxy for modern humans and a source for the Protoaurignacian of Europe, its claimed emergence ~46–49 ka ago at Kebara refl ects the dating of Middle Paleolithic charcoal—to be expected, because the Early Ahmarian units at the back of the cave are made up of reworked Middle Paleolithic sediments derived from the entrance. The dating of inherited material also explains the old results for the Aurignacian of Willendorf II and Geissenklösterle. At the latter, the dates on anthropically modified samples of the hunted taxa (reindeer and horse) place its Aurignacian occupations in the same time range as elsewhere in Europe, after ~40 ka ago. The hypothesis that Neandertal/modern human contact in Europe resulted in a process of assimilation in connection with the spread of the Protoaurignacian ~41.5 ka ago remains unfalsified.info:eu-repo/semantics/publishedVersio

Analyse de facteurs génétiques impliqués dans le développement du diabète de type 1 chez la souris NOD

Le diabète de type 1 (DT1) est une maladie multifactorielle pour laquelle des facteurs environnementaux associés à un terrain génétique de prédisposition sont responsables de la destruction auto-immune des cellules |3 insulino-sécrétrices par des lymphocytes T. Au locus Iddô du chromosome 6 murin, les allèles NOD confèrent à la lignée témoin NOD (CO) une susceptibilité au DT1 alors que les allèles C3H/HeJ confèrent une protection contre la maladie à la lignée congénique NOD.C3H 6.VHI (lignée 6.YIII). Mes résultats suggèrent que plusieurs facteurs concourent à une meilleure régulation de la réaction auto-immune chez la lignée 6. VTH : (i) une activité suppressive in vivo accrue des cellules T régulatrices, (ii) une diminution de la voie de signalisation TLR1 conduisant à l'altération des signaux de costimulation au niveau des cellules T et à la diminution de l'expression de cytokines pro-inflammatoires par les macrophages, (iii) une altération du développement des cellules iNKT CD4+.Type 1 diabetes (T1D) is a multifactotial disease: some environmental factors in association with susceptible genetic background lead to the destruction of insuline-producing {J cells by autoreactive T cells. NOD alleles at the Idd6 locus (murine chromosome 6) confer susceptibility to T1D whereas C3H/HeJ alleles in NOD genetic background confer resistance to the disease. Our studies of the congenic mouse strain NOD.C3H 6.VTH (strain 6.VHI) showed that some factors are responsible of its diabetes resistance : (i) a higher suppressive function of regulatory T cells, (ii) the downregulation of Tlrl gene expression leads to reduced costimulatory signals on T cells and to the downregulation of pro-inflammatory cytokines genes expression by macrophages. Genetic(s) factor(s) involved in this phenotype localize at the Idd6.3 locus (iii) a two fold reduction of iNKT CD4+ cells subset, restricted to the Idd6.2 locus.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Bulletin archéologique

Charbonneaux Jean, Vallois René, Picard Charles, Dugas Charles, David Le Suffleur A. Bulletin archéologique. In: Revue des Études Grecques, tome 42, fascicule 194, Janvier-mars 1929. pp. 39-102

Bulletin archéologique

Charbonneaux Jean, Vallois René, Picard Charles, Dugas Charles, David Le Suffleur A. Bulletin archéologique. In: Revue des Études Grecques, tome 44, fascicule 204, Janvier-mars 1931. pp. 34-111

Bulletin archéologique

Charbonneaux Jean, Vallois René, Dugas Charles, Picard Charles, David Le Suffleur A. Bulletin archéologique. In: Revue des Études Grecques, tome 39, fascicule 179, Janvier-mars 1926. pp. 97-192

Bulletin archéologique

Charbonneaux Jean, Vallois René, Picard Charles, Dugas Charles, David Le Suffleur A. Bulletin archéologique. In: Revue des Études Grecques, tome 45, fascicule 209, Janvier-mars 1932. pp. 32-110