Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) — the most common chromosomal translocation observed in childhood ALL — which leads to an ETV6–RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, PCMH=8.94 × 10−9, OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10−11, OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10−9, OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10−7, OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6–RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis

Epstein-Barr Virus Evades CD4+ T Cell Responses in Lytic Cycle through BZLF1-mediated Downregulation of CD74 and the Cooperation of vBcl-2

Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II αβ dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function

CD74 is a survival receptor on colon epithelial cells

AIM: To investigate the expression and function of CD74 in normal murine colon epithelial cells (CEC) and colon carcinoma cells

Key Sectors: A New Proposal from Network Theory

Garcia Muniz A. S., Morillas Raya A. and Ramos Carvajal C. Key sectors: a new proposal from network theory, Regional Studies. There is a long tradition of studies in the input-output field for determining key sectors. Their analysis allows the identification of those sectors that affect the demand and supply system greatly, therefore constituting the basis for the growth and development of a territory. In order to pinpoint those sectors whose position is more relevant in the economy, a definition of centrality measures is proposed from network theory that is considered to be new in the input-output field. The definition is based on the consideration of three complementary characteristics: total effects, mediative effects and immediate effects. The term used for these measures is 'multilevel indicators' and these indicators have the enormous advantage of allowing different sized structures to be compared and the key sector concept to be approached from a relational and global viewpoint. [image omitted] Garcia Muniz A. S., Morillas Raya A. et Ramos Carvajal C. Secteurs cles: une nouvelle proposition de la theorie des reseaux, Regional Studies. Il existe une longue tradition d'etudes dans le domaine des entrees-sorties pour determiner les secteurs-cles. Ces analyses permettent d'identifier les secteurs qui ont un fort impact sur le systeme de l'offre et de la demande et constituent donc la base de la croissance et du developpement des territoires. Afin de localiser les secteurs dont la position concerne davantage l'economie, nous proposons, en nous appuyant sur la theorie des reseaux, une definition de mesures de la centralite que nous estimons etre nouvelle dans le domaine des entrees-sorties. Cette definition repose sur l'examen de trois caracteristiques complementaires: effets totaux, effets mediatiques et effet immediat. Ces mesures, que nous appelons indicateurs multi-niveaux, presentent le tres grand avantage de permettre la comparaison de structures de tailles differentes et d'aborder le concept de secteur-cle d'un point de vue relationnel et global. Theorie des reseaux Analyse des entrees-sorties Secteurs-cles Garcia Muniz A. S., Morillas Raya A. und Ramos Carvajal C. Schlusselsektoren - ein neuer Vorschlag von der Netzwerktheorie, Regional Studies. Zur Ermittlung von Schlusselsektoren gibt es eine lange Tradition an Studien im Bereich Input-Output. Diese Analysen ermoglichen die Identifizierung von Sektoren mit einer hohen Auswirkung auf das Angebots- und Nachfragesystem, weshalb sie die Grundlage fur das Wachstum und die Entwicklung eines Gebiets darstellen. Um die Sektoren herauszuarbeiten, deren Position in der Wirtschaft relevanter ist, schlagen wir von der Netzwerktheorie ausgehend eine Definition von Messgrossen fur Zentralitat vor, die wir im Bereich Input-Output fur neu erachten. Die Definition beruht auf der Berucksichtigung von drei einander erganzenden Merkmalen: Gesamteffekte, mediative Effekte und unmittelbare Effekte. Diese Messgrossen, die wir mehrschichtige Indikatoren nennen, bieten den enormen Vorteil, dass sie es ermoglichen, Strukturen verschiedener Grosse zu vergleichen und das Konzept der Schlusselsektoren aus einer relationalen und globalen Perspektive zu behandeln. Netzwerktheorie Input-Output-Analyse Schlusselsektoren Garcia Muniz A. S., Morillas Raya A. y Ramos Carvajal C. Sectores clave: una nueva propuesta a partir de la teoria de redes, Regional Studies. La determinacion de los denominados sectores clave ha suscitado una larga tradicion en el analisis input-output. Su analisis permite identificar aquellas ramas que poseen un alto efecto multiplicador en la demanda y la oferta del sistema y que, por tanto, suponen los pilares del crecimiento y desarrollo de una region o nacion. Para detectar aquellos sectores con una posicion mas relevante dentro de la economia proponemos a partir de la Teoria de Redes la definicion de medidas de centralidad que consideramos nuevas en el ambito input-output. Su definicion esta basada en la consideracion de tres caracteristicas complementarias: efectos totales, efectos inmediatos y efectos de intermediacion. Estas medidas, que denominaremos de forma generica indicadores multinivel, poseen la ventaja de permitir la comparacion entre estructuras de distinto tamano y ofrecer una aproximacion desde un punto de vista relacional y global al concepto de sector clave. Teoria de redes Analisis input-output Sectores claveNetwork theory, Input-output analysis, Key sectors,

A Fuzzy clustering approach to the key sectors of the Spanish economy

The search for key sectors in an economy has been and still is one of the more recurrent themes in input-output analysis. When using clustering techniques, sectors can only belong to a group, having a particular performance. But, actually, the same sector could be important from different perspectives at the same time, to a different degree. So, a fuzzy clustering approach is needed. In this work we propose a multidimensional approach to classify the productive sectors of the Spanish input-output table for 1995, based on three groups of variables: those related to their productive integration, others measuring their specific weight in the economy and finally some showing their economic dynamic. We also incorporate into the analysis the technological level, which being a categorical variable presents special methodological problems. All these questions are tackled applying a robust and fuzzy clustering analysis, which gives as a result a classification of sectors illustrating the role that each one plays in the Spanish economy.Key sectors, fuzzy clustering, input-output analysis, Spanish economy,

Spanish and European innovation diffusion: a structural hole approach in the input–output field

C67, D57, O33,