miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

Non-Hodgkin lymphoma comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific miRNA whose expression is lost in numerous mature B-cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing class switch recombination and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell-cycle and B-cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 reexpression in human Burkitt (BL) and diffuse large B-cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment.This work was supported by a Ministerio de Economia y Competitividad's research training program (Formacion de Personal Investigador [FPI]) fellowship (N.B.-I.); the Ramon y Cajal program (RYC-2009-04503) funded by the Ministerio de Educacion, Cultura y Deporte and the European Research Council Proof of Concept program (HEAL-BY-MIRNA 713728) (V.G.d.Y.); the Centro Nacional de Investigaciones Cardiovaculares (CNIC) (A.F.A.-P., S.M.M., A.R.R.); the Ministerio de Economia y Competitividad (SAF2010-21394, SAF2013-42767-R), the European Research Council Starting Grant program (BCLYM-207844), and Proof of Concept program (HEAL-BY-MIRNA 713728) (A.R.R.); the People Programme-Marie Curie Actions (FP7-PIIF-2012-328177), Spanish Ministry of Economy and Competitiveness (MINECO; SAF2013-45787-R), and Gobierno de Navarra (GN-106/2014) (S.R.); and the Ministerio de Economia y Competitividad (BIO2012-37926 and BIO2015-67580-P), Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria [FIS] grants PRB2 [IPT13/0001, Proteo-Red], the Fundacion La Marato TV3, and Redes tematicas de investigacion cooperativa en salud [RETICS] [RD12/0042/00056, RIC]) (J.V.). This work has been cofunded by Fondo Europeo de Desarrollo Regional (FEDER) funds. The CNIC is supported by the and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8(N)/(C)EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy

Plant diversity patterns in neotropical dry forests and their conservation implications

This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record.Seasonally dry tropical forests are distributed across Latin America and the Caribbean and are highly threatened, with less than 10% of their original extent remaining in many countries. Using 835 inventories covering 4660 species of woody plants, we show marked floristic turnover among inventories and regions, which may be higher than in other neotropical biomes, such as savanna. Such high floristic turnover indicates that numerous conservation areas across many countries will be needed to protect the full diversity of tropical dry forests. Our results provide a scientific framework within which national decision-makers can contextualize the floristic significance of their dry forest at a regional and continental scale.This paper is the result of the Latin American and Caribbean Seasonally Dry Tropical Forest Floristic Network (DRYFLOR), which has been supported at the Royal Botanic Garden Edinburgh by a Leverhulme Trust International Network Grant (IN-074). This work was also supported by the U.K. Natural Environment Research Council grant NE/I028122/1; Colciencias Ph.D. scholarship 529; Synthesys Programme GBTAF-2824; the NSF (NSF 1118340 and 1118369); the Instituto Humboldt (IAvH)–Red colombiana de investigación y monitoreo en bosque seco; the Inter-American Institute for Global Change Research (IAI; Tropi-Dry, CRN2-021, funded by NSF GEO 0452325); Universidad Nacional de Rosario (UNR); and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). The data reported in this paper are available at www.dryflor.info. R.T.P. conceived the study. M.P., A.O.-F., K.B.-R., R.T.P., and J.W. designed the DRYFLOR database system. K.B.-R. and K.G.D. carried out most analyses. K.B.-R. R.T.P., and K.G.D. wrote the manuscript with substantial input from A.D.-S., R.L.-P., A.O.-F., D.P., C.Q., and R.R. All the authors contributed data, discussed further analyses, and commented on various versions of the manuscript. K.B.-R. thanks G. Galeano who introduced her to dry forest research. We thank J. L. Marcelo, I. Huamantupa, C. Reynel, S. Palacios, and A. Daza for help with fieldwork and data entry in Peru

Molecular Mechanisms of Activation Induced Deaminase Specificity

B lymphocytes are key effectors of the humoral immune response through the secretion of antibodies. The most distinctive event in mature B lymphocytes biology is the secondary diversification of their immunoglobulin genes during the germinal center (GC) reaction, which is fundamental to generate a repertoire of antibodies with virtually unlimited specificities. Activation Induced Deaminase (AID) initiates secondary antibody diversification in GC B cells through the deamination of cytosines on immunoglobulin genes. Remarkably, AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging, mostly because of the difficulty to detect AID-induced mutations, which occur at very low frequencies. In this work we have developed a novel capture-based approach to explore AID mutagenesis in a representation of the B cell genome. We have sequenced at very high depth 1588 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Further, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets, which has been experimentally validated. We have also found that Base Excision Repair and Mismatch Repair pathways back-up each other to faithfully repair most of AID-induced lesions. Finally, our data establishes a novel link between AID mutagenic activity and lymphomagenesis.N

Resultados académicos de la educación asturiana 2014/2015

Se recogen los datos de las Enseñanzas no universitarias del sistema educativo asturiano. La publicación permite moverse por el documento a través de hipervínculos, lo que facilita el acceso a la información. Incluye un análisis de cada etapa, presentando datos correspondientes al curso académico 2014-2015, las tendencias evolutivas de promoción y titulación y los resultados segregados por sexo. La información recogida se centra en el alumnado matriculado y evaluado, así como en su promoción y titulación por cada etapa y modalidad educativa. Los indicadores confirman unos buenos resultados y estabilidad de los datos, particularmente en las Enseñanzas de Régimen General. La Educación Primaria marca una tasa global de promoción en el entorno del 96% mientras que la tasa de titulación en Educación Secundaria Obligatoria se sitúa en el 87%. En Bachillerato la titulación es cercana al 84%, en Ciclos Formativos de Grado Superior se sitúa en el 78%, y los resultados correspondientes a Ciclos Formativos de Grado Medio registran un 76% de titulación. La comparación de los resultados por sexo confirma, una edición más, unos mejores resultados de las alumnas. Los resultados se asocian a los de las tendencias evolutivas, confirmando los buenos datos del servicio educativo asturiano, puestos de manifiesto en la comparación de los diferentes indicadores estatales del Ministerio de Educación, Cultura y Deporte.ES

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8(N)/(C)EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy

Caracterización de la investigación, el desarrollo tecnológico y la innovación en el sector productivo de la región fronteriza colombo venezolana. Volumen 2

En este libro en su segundo volumen, se presenta la recopilación de proyectos de Investigación e Innovación Tecnológica como resultado del desarrollo de actividades investigativas, en las cuales se involucran grupos de investigación y semilleros, instructores investigadores, docentes universitarios, administrativos, aprendices, estudiantes universitarios y empresarios del ámbito regional, nacional e internacional, quienes motivados por su espíritu emprendedor e innovador le apostaron a involucrarse en proyectos desde las áreas de automatización, electrónica y telecomunicaciones, gestión del hábitat, Diseño e implementación de soluciones en TIC, Gestión del negocio emprendimiento y empresarismo, Innovación educativa y Diseño de vestuario.In this book in its second volume, the compilation of Research and Technological Innovation projects is presented as a result of the development of research activities, in which research groups and seedbeds, research instructors, university teachers, administrators, apprentices, university students are involved. and regional, national and international entrepreneurs, who, motivated by his entrepreneurial and innovative spirit, bet him to get involved in projects from the areas of automation, electronics and telecommunications, habitat management, Design and implementation of ICT solutions, Entrepreneurship business management and entrepreneurship, educational innovation and costume design.Desarrollo de un sistema de información para los laboratorios de servicios tecnológicos basado en normatividad ISO/IEC 7025:2017 -- Implementación de tecnologías de realidad aumentada para mejorar el proceso de enseñanza aprendizaje de las operaciones logísticas de almacenamiento -- Automatización de un sistema hidropónico para la optimización de la producción de hortalizas de hoja -- Desarrollo y control de posicionamiento de un seguidor solar por seguimiento de carta solar y por maximo punto de radiación solar por lógica difusa -- Diseño de un sistema de control cinemático con open-hardware del manipulador didáctico pegasus amatrol -- Diseño de un sistema fotovoltaico híbrido grid-tied con respaldo de baterías para iluminación -- Implementación de un banco para la detección de fallas en motores trifásicos con inteligencia artificial -- Oilmaster dispositivo de detección de fallo en el sistema de lubricación en motocicletas -- Regulador de carga para picocentral hidroeléctrica -- Diseño de un sistema de percepción del impacto de choques mecánicos y golpes en el cerebro -- Crema humectante antiedad con principios activos naturales y subproductos del coee “silverskin” en sena, antioquia -- Formulación de barra de cereal partir de los subproductos del café, cacao, y sacha inchi -- Videojuego en realidad virtual como estrategia de formación para organización de eventos -- Fortalecimiento de las industrias culturales de dulces típicos en montería - departamento de córdobana199 página

Impacto de la COVID-19 en el tratamiento del infarto agudo de miocardio con elevación del segmento ST. La experiencia Española

The COVID-19 outbreak has had an unclear impact on the treatment and outcomes of patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to assess changes in STEMI management during the COVID-19 outbreak. Using a multicenter, nationwide, retrospective, observational registry of consecutive patients who were managed in 75 specific STEMI care centers in Spain, we compared patient and procedural characteristics and in-hospital outcomes in 2 different cohorts with 30-day follow-up according to whether the patients had been treated before or after COVID-19. Suspected STEMI patients treated in STEMI networks decreased by 27.6% and patients with confirmed STEMI fell from 1305 to 1009 (22.7%). There were no differences in reperfusion strategy (> 94% treated with primary percutaneous coronary intervention in both cohorts). Patients treated with primary percutaneous coronary intervention during the COVID-19 outbreak had a longer ischemic time (233 [150-375] vs 200 [140-332] minutes, P < .001) but showed no differences in the time from first medical contact to reperfusion. In-hospital mortality was higher during COVID-19 (7.5% vs 5.1%; unadjusted OR, 1.50; 95%CI, 1.07-2.11; P < .001); this association remained after adjustment for confounders (risk-adjusted OR, 1.88; 95%CI, 1.12-3.14; P = .017). In the 2020 cohort, there was a 6.3% incidence of confirmed SARS-CoV-2 infection during hospitalization. The number of STEMI patients treated during the current COVID-19 outbreak fell vs the previous year and there was an increase in the median time from symptom onset to reperfusion and a significant 2-fold increase in the rate of in-hospital mortality. No changes in reperfusion strategy were detected, with primary percutaneous coronary intervention performed for the vast majority of patients. The co-existence of STEMI and SARS-CoV-2 infection was relatively infrequent.S