GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress.

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses.This research was funded by the Instituto de Salud Carlos III: PI17-00576; Ministerio de Economia, Industria y Competitividad, Gobierno de Espana: SAF2017-84125-R; Ministerio de Economia, Industria y Competitividad, Gobierno de Espana: SAF2017-87301-R; Instituto de Salud Carlos III: CIBERCV CB16/11/00278; Instituto de Salud Carlos III: PI14-00435; Fundacion Ramon Areces and the Comunidad de Madrid: B2017/BMD-3671-INFLAMUNE.S

Pasado y futuro de la infección por VIH. Un documento basado en la opinión de expertos

[EN] HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection. [ES] La infección por VIH cumple ahora casi 40 años de existencia. En este tiempo, junto a la catástrofe y la tragedia que ha supuesto, ha representado también la capacidad de la sociedad moderna de asumir un reto de esta magnitud y de transformar, gracias al tratamiento antirretroviral, una enfermedad mayoritariamente letal en una enfermedad crónica, compatible con una vida personal y de relación prácticamente normales. Este aniversario parecía un momento idóneo para pararse a reflexionar sobre el futuro de la infección VIH, los retos que todavía quedan por abordar y las perspectivas para el inmediato futuro. Esa reflexión tiene que ir más allá de planteamientos meramente técnicos, de profesionales especializados, para abordar aspectos sociales y éticos. Por este motivo, la Fundación de Ciencias de la Salud convocó a un grupo de expertos en distintos aspectos de esta infección para discutir una serie de preguntas que parecieron pertinentes a todos los convocados. Cada pregunta era expuesta por uno de los participantes y discutida por el grupo. El documento que ofrecemos es el resultado de esa reflexión.For transparency purposes, we would like to inform you that GSK has contributed to the funding of this publication. Its content reflects the authors’ own opinions, criteria, conclusions and/or findings, which may not necessarily coincide with those of GSK. GSK always recommends that its products are used in accordance with the technical data sheet approved by the health authorities.S

CARACTERÍSTICAS DE LA FORMACIÓN DEPORTIVA DE LOS PARTICIPANTES EN LOS IV JUEGOS ESCOLARES CENTROAMERICANOS Y DEL CARIBE, ARMENIA 2013

Objetivo: Caracterizar la formación deportiva de participantes en los IV Juegos Deportivos EscolaresCentroamericanos y del Caribe, Armenia, 2013. Materiales y métodos: Estudio cuantitativo, prospectivo,con alcance descriptivo y de corte transversal. De un universo de 683 participantes, fue seleccionadaintencionalmente una muestra no probabilística de 233 deportistas (102 hombres y 131 mujeres),entre 15 y 17 años de edad, pertenecientes a nueve delegaciones participantes, quienes respondieronuna encuesta que indagaba sobre la formación deportiva. Resultados: Los deportistas encuestadosafirman que la organización del deporte en la escuela se da en clubes deportivos, los deportistaspertenecen a entidades deportivas independientes a su institución educativa y dichas entidades noposeen convenios con las instituciones educativas; el promedio de edad de inicio es 9,57 años, enentidades deportivas independientes de su institución; al 52,3 % de los deportistas se les realizaronpruebas para identificar talento; y de ellas las más utilizadas fueron las pruebas físicas. Dentro delcontrol se encuentra que el 89,2 % realizó pruebas permanentemente y las más utilizadas son las físicas,se identifica que los deportistas tienen un bagaje en competencias internacionales y un promediode 7 competencias por año; finalmente, se establece que el principal agente motivador son los padres

Plataforma basada en microprocesador para el aprendizaje de tecnologías inalámbricas RFID, NFC y Bluetooth

El Congreso TAEE 2010, organizado por la Universidad Nacional de Educación a Distancia (UNED) y la Universidad Politécnica de Madrid (UPM), se ha celebrado entre el 13 y el 15 de abril de 2010.En este trabajo se presenta el desarrollo de una plataforma, basada en un microprocesador de bajo coste, que pretende acercar a los alumnos al uso y desarrollo de aplicaciones basadas en las tecnologías inalámbricas RFID y Bluetooth. Mientras que el estándar NFC representa el ejemplo más claro del elevado crecimiento que están experimentado recientemente los dispositivos RFID, Bluetooth personifica el grado de desarrollo y uso que pueden alcanzar estas tecnologías inalámbricas gracias a los dispositivos electrónicos de uso cotidiano como son teléfonos mó viles, PDAs y PCs portátiles. Para mostrar a los alumnos el interés de ambas tecnologías, se ha desarrollado un sistema simple para la realización de trabajos prácticos en una asignatura denominada “Laboratorio de Instrumentación Electrónica”, adscrita a la titulación de Ingeniería de telecomunicaciones en la Escuela Superior de Ingenieros de la Universidad de Sevill

Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRY A B, M YOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 M FM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in M YOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis. (C) 2011 Elsevier B.V. All rights reserved

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Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.FUNDING: Grants from ISCIII, co-financed by the European Union (FEDER) (PI16/00156), Ramón and Cajal research program from MINECO (RYC-2013-14097) and FUNDACIÓN LUCHAMOS POR LA VIDA to JPV. Grants from ISCIII (RD06/0020/0107-RD012/0036/0060) to MAP. Grant from ISCIII (Ref. PIE15/00079) to JC & JPV. NGD is a recipient of a UC-IDIVAL pre-doctoral fellow. I.V. was also supported by the Ramón and Cajal research program

SARS-CoV-2 mutant spectra reveal differences between COVID-19 severity categories

Trabajo presentado en el XVI Congreso Nacional de Virología, celebrado en Málaga (España) del 06 al 09 de septiembre de 2022.RNA virus populations are composed of complex mixtures of genomes that are termed mutant spectra. SARS-CoV-2 replicates as a viral quasispecies, and mutations that are detected at low frequencies in a host can be dominant in subsequent variants. We have studied mutant spectrum complexities of SARS-CoV-2 populations derived from thirty nasopharyngeal swabs of patients infected during the first wave (April 2020) in the Hospital Universitario Fundación Jiménez Díaz. The patients were classified according to the COVID-19 severity in mild (non-hospitalized), moderate (hospitalized) and exitus (hospitalized with ICU admission and who passed away due to COVID-19). Using ultra-deep sequencing technologies (MiSeq, Illumina), we have examined four amplicons of the nsp12 (polymerase)-coding region and two amplicons of the spike-coding region. Ultra-deep sequencing data were analyzed with different cut-off frequency for mutation detection. Average number of different point mutations, mutations per haplotype and several diversity indices were significantly higher in SARS-CoV-2 isolated from patients who developed mild disease. A feature that we noted in the SARS-CoV-2 mutant spectra from diagnostic samples is the remarkable absence of mutations at intermediate frequencies, and an overwhelming abundance of mutations at frequencies lower than 10%. Thus, the decrease of the cut-off frequency for mutation detection from 0.5% to 0.1% revealed an increasement (50- to 100 fold) in the number of different mutations. The significantly higher frequency of mutations in virus from patients displaying mild than moderate or severe disease was maintained with the 0.1% cut- off frequency. To evaluate whether the frequency repertoire of amino acid substitutions differed between SARS-CoV-2 and the well characterized hepatitis C virus (HCV), we performed a comparative study of mutant spectra from infected patients using the same bioinformatics pipelines. HCV did not show the deficit of intermediate frequency substitutions that was observed with SARS-CoV-2. This difference was maintained when two functionally equivalent proteins, the corresponding viral polymerases, were compared. In conclusion, SARS-CoV-2 mutant spectra are rich reservoirs of mutants, whose complexity is not uniform among clinical isolates. Virus from patients who developed mild disease may be a source of new variants that may acquire epidemiological relevance.This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and In-novation (COVID-19 Research Call COV20/00181), and co-financed by European Development Regional Fund ‘A way to achieve Europe’. The work was also supported by grants CSIC-COV19-014 from Consejo Superior de Investigaciones Científicas (CSIC), project 525/C/2021 from Fundació La Marató de TV3, PID2020-113888RB-I00 from Ministerio de Ciencia e Innovación, BFU2017-91384-EXP from Ministerio de Ciencia, Innovación y Universidades (MCIU), PI18/00210 and PI21/00139 from Instituto de Salud Carlos III, and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER). C.P., M.C., and P.M. are supported by the Miguel Servet programme of the Instituto de Salud Carlos III (CPII19/00001, CPII17/00006, and CP16/00116, respectively) co-financed by the European Regional Development Fund (ERDF). CIBERehd (Centro de Investi-gación en Red de Enfermedades Hepáticas y Digestivas) is funded by Instituto de Salud Carlos III. Institutional grants from the Fundación Ramón Areces and Banco Santander to the CBMSO are also acknowledged. The team at CBMSO belongs to the Global Virus Network (GVN). B.M.-G. is supported by predoctoral contract PFIS FI19/00119 from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo) cofinanced by Fondo Social Europeo (FSE). R.L.-V. is supported by predoctoral contract PEJD-2019-PRE/BMD-16414 from Comunidad de Madrid. C.G.-C. is sup-ported by predoctoral contract PRE2018-083422 from MCIU. BS was supported by a predoctoral research fellowship (Doctorados Industriales, DI-17-09134) from Spanish MINECO

Pasado y futuro de la infección por VIH. Un documento basado en la opinión de expertos

[EN] HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.[ES] La infección por VIH cumple ahora casi 40 años de existencia. En este tiempo, junto a la catástrofe y la tragedia que ha supuesto, ha representado también la capacidad de la sociedad moderna de asumir un reto de esta magnitud y de transformar, gracias al tratamiento antirretroviral, una enfermedad mayoritariamente letal en una enfermedad crónica, compatible con una vida personal y de relación prácticamente normales. Este aniversario parecía un momento idóneo para pararse a reflexionar sobre el futuro de la infección VIH, los retos que todavía quedan por abordar y las perspectivas para el inmediato futuro. Esa reflexión tiene que ir más allá de planteamientos meramente técnicos, de profesionales especializados, para abordar aspectos sociales y éticos. Por este motivo, la Fundación de Ciencias de la Salud convocó a un grupo de expertos en distintos aspectos de esta infección para discutir una serie de preguntas que parecieron pertinentes a todos los convocados. Cada pregunta era expuesta por uno de los participantes y discutida por el grupo. El documento que ofrecemos es el resultado de esa reflexión.For transparency purposes, we would like to inform you that GSK has contributed to the funding of this publicationPeer reviewe