Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program

Glioblastoma (GBM) still remains an incurable disease being radiotherapy (RT) the mainstay treatment. Glioblastoma intra-tumoral heterogeneity and GlioblastomaInitiating Cells (GICs) challenge the design of effective therapies. We investigated GICs and non-GICs response to RT in a paired in-vitro model and addressed molecular programs activated in GICs after RT. Established GICs heterogeneously expressed several GICs markers and displayed a mesenchymal signature. Upon fractionated RT, GICs reported higher radioresistance compared to non-GICs and showed lower α- and β-values, according to the Linear Quadratic Model interpretation of the survival curves. Moreover, a significant correlation was observed between GICs radiosensitivity and patient disease-free survival. Transcriptome analysis of GICs after acquisition of a radioresistant phenotype reported significant activation of Proneural-to-Mesenchymal transition (PMT) and pro-inflammatory pathways, being STAT3 and IL6 the major players. Our findings support a leading role of mesenchymal GICs in defining patient response to RT and provide the grounds for targeted therapies based on the blockade of inflammatory pathways to overcome GBM radioresistance

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Epigenetic loss of RNA‑methyltransferase NSUN5 in glioma targets ribosomes to drive stress adaptive translational program

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM

Coordinación vertical entre asignaturas dirigidas hacia la mejora de la salud mediante la práctica de actividad física. Propuesta de conexión y abordaje de los errores localizados

Dentro de los estudios de grado es fundamental la progresión y coordinación vertical entre asignaturas para garantizar una formación completa y competente del alumnado. Esta coordinación es evidente entre las asignaturas que conforman el plan de estudios del grado en ciencias de la actividad física y el deporte, tales como Actividad física y Calidad de Vida (AFCV) y Prescripción de Actividad Física en Poblaciones Especiales (PAFPE). El presente estudio se plantea con el objetivo de conocer la opinión de profesores y alumnos sobre la coordinación y planteamiento de ambas asignaturas para poder detectar y corregir los posibles errores y problemáticas de planificación de ambas asignaturas. 48 alumnos (22 de PAFPE y 26 AFCV) y 4 profesores, respondieron a un cuestionario mixto de valoración (escala Likert y preguntas abiertas). Los resultados permitieron conocer como profesores y alumnos coinciden en la importancia y buen planteamiento de los contenidos tratado. Sin embargo dada la complejidad de los temas, la duración de un cuatrimestre es insuficiente para la correcta asimilación y compresión los contenidos. La inclusión de estudios complementarios así como de espacios específicos para la docencia se presentan como posibles soluciones.El presente estudio está financiado por Xarxes-I3CE 19-20 (Universidad de Alicante

The Solutrean Antlerworking in Hort de Cortés–Volcán del Faro (Valencia, Spain) in the Southwest Europe Context: a Preliminary Study

In this work, we present a preliminary analysis of the Solutrean antlerworking at Hort de Cortés–Volcán del Faro (Valencia, Spain) (ca. 26–21 ka cal BP). A restudy of its archaeological sequence, which came to encompass the Early Upper Palaeolithic to the Magdalenian period, has been a mandatory subject in the last years. This site became an archaeological reference since the beginning of its excavation in the 1960s but has not been systematically studied. The implementation of more specialized studies is used a) to observe the distribution of technical pieces in the stratigraphy and identify possible stratigraphic alterations and b) to restudy a huge lithic, osseous, and faunal collection which can provide new information that may clarify them. The aim is to develop a systematic study, from a technological point of view, to identify and characterize operational schemes and to define the modalities of antlerworking. The technological analysis of waste products, blanks, roughouts, and objects allows us to observe how raw material is obtained and transformed into a toolkit following the refitting by default method. It will help us analyze some questions about the raw material acquisition and transformation like (1) selection between hunted and shed antlers and its possible explanation, (2) the existence of planning of tool manufacture, and (3) the step-by-step production of the debitage. We will extract conclusions and analyze different social aspects: (1) by identifying technical traditions and comparing them with other studied sites and periods and (2) by knowing a new aspect of the way of life of these human groups