The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells

The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

ColPortal, an integrative multiomic platform for analysing epigenetic interactions in colorectal cancer

Abstract Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. Different pathological pathways and molecular drivers have been described and some of the associated markers are used to select effective anti-neoplastic therapy. More recent evidence points to a causal role of microbiota and altered microRNA expression in CRC carcinogenesis, but their relationship with pathological drivers or molecular phenotypes is not clearly established. Joint analysis of clinical and omics data can help clarify such relations. We present ColPortal, a platform that integrates transcriptomic, microtranscriptomic, methylomic and microbiota data of patients with colorectal cancer. ColPortal also includes detailed information of histological features and digital histological slides from the study cases, since histology is a morphological manifestation of a complex molecular change. The current cohort consists of Caucasian patients from Europe. For each patient, demographic information, location, histology, tumor staging, tissue prognostic factors, molecular biomarker status and clinical outcomes are integrated with omics data. ColPortal allows one to perform multiomics analyses for groups of patients selected by their clinical data

Georg Simmel, un siglo después : actualidad y perspectiva

Autor sin sucesores, Simmel fue uno de los más activos y lúcidos exponentes de la primera generación de sociólogos alemanes. Debido, tal vez, a la amplitud de temas, métodos y estructuras para sus escritos, las formas de leer su obra han sido tan múltiples como sus objetos y puntos de vista. Hoy, en vísperas de cumplirse un siglo de su muerte, y en un mundo signado por la individualidad, la diferenciación social, la economía monetaria, el retorno de lo religioso y la estetización de la vida, este libro se interroga por la actualidad del pensamiento simmeliano, por los significados que perduran y mantienen viva su teoría. ¿Cómo nos siguen interpelando sus textos? ¿Qué nos dice ese voluminoso cuerpo, por momentos enigmático, de escrituras sobre arte, filosofía, cultura, moral, economía y sociedad? En definitiva, ¿cuál es el peso de las ideas simmelianas ante la pregunta por el mundo socio-histórico de hoy? Compuesto por textos de autores de distintos países que tomaron para sí partes del legado de Simmel, este volumen retoma varias de las aristas que conforman la constelación temática del pensador berlinés, tales como la libertad, la personalidad, el dinero y el vitalismo. Hay también vinculaciones con sus propios contemporáneos, así como con los nuestros. La teoría de Simmel representa, en fin, un capítulo actual y palpitante del pensamiento occidental, cuyas dinámicas huellas retornan en estas páginas

First scientific observations with MEGARA at GTC

On June 25th 2017, the new intermediate-resolution optical IFU and MOS of the 10.4-m GTC had its first light. As part of the tests carried out to verify the performance of the instrument in its two modes (IFU and MOS) and 18 spectral setups (identical number of VPHs with resolutions R=6000-20000 from 0.36 to 1 micron) a number of astronomical objects were observed. These observations show that MEGARA@GTC is called to fill a niche of high-throughput, intermediateresolution IFU and MOS observations of extremely-faint narrow-lined objects. Lyman-α absorbers, star-forming dwarfs or even weak absorptions in stellar spectra in our Galaxy or in the Local Group can now be explored to a new level. Thus, the versatility of MEGARA in terms of observing modes and spectral resolution and coverage will allow GTC to go beyond current observational limits in either depth or precision for all these objects. The results to be presented in this talk clearly demonstrate the potential of MEGARA in this regard

Escala 1-1. Trayectos experimentales en el proceso de determinación del Proyecto Arquitectónico.

El proyecto de investigación llevado adelante por la Cátedra del Ciclo Básico del taller Valderrama, explora las posibilidades pedagógicas de una didáctica interdisciplinaria que introduce ejercitaciones a escala real como dispositivos de interfaz entre sucesivas instancias de transformación en el proceso de determinación de la arquitectura, como una sucesión de transformaciones encadenadas. A partir del monitoreo sistemático, se produjeron ajustes que mejoraron significativamente la performance de los estudiantes y la validez de la didáctica en su capacidad de generalización y aplicación en contextos diferenciados, introduciendo trayectos experimentales a escala 1:1 en una apuesta hacia el aprendizaje situado, incorporando una participación corporal legítima y un vínculo con la práctica artesanal. El contexto de pandemia nos exigió la readaptación de las exploraciones pedagógicas y devino en artefactos adaptados a los procedimientos y procesos de producción emanados de las condiciones del aislamiento social preventivo y obligatorio (ASPO), trabajando con técnicas mixtas, analógicas y digitales, donde se hibridaron los procesos experimentales a escala 1:1 con la inteligencia artificial y se propició un tipo de producción basada en “la expresión de lo disponible”. Se realizaron escaneos del territorio con fotogrametría, con maquetas digitales del lugar y experimentos a escala 1:1 utilizando materiales de descarte, encontrados en un radio de 100m de casa. También se propició y se trabajó en el reconocimiento de las cualidades de los distintos ambientes domésticos como lugares de laboratorio (luz, agua, temperatura, gravedad, fuego, hielo). La Pandemia Global generó un resquebrajamiento de los lazos sociales y dificultó la construcción colectiva del conocimiento; corrió el cuerpo de la escena del aula, impidiendo la producción de conocimientos desde la experimentación y la comprobación empírica a escala 1:1 y distorsionando la percepción del espacio con el propio cuerpo y la interrelación con el paisaje físico y simbólico. Las consecuencias de la pandemia nos ha forzado a re-pensar la disciplina. Entendemos que es urgente un giro onto-epistemológico que nos permita re-conectar los cuerpos, las materias, los artefactos y los territorios y profundizar la dimensión situada in-situ-in vivo y colectiva del proyecto arquitectónico