Predicción de la respuesta al tratamiento con Paclitaxel semanal y Bevacizumab en mujeres con cáncer de mama diseminado a través de un perfil de expresión génica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 18-12-2015Esta tesis ha sido financiada por el Ministerio de Sanidad (proyecto EC 10-342) y el laboratorio Roche-Farm

Cajal´s achievements in the field of the development of dendritic arbors

13 páginas, 7 figuras.In 1909, Cajal published an up-dated version in French (Cajal, 1909-1911) of his main work Texture of the Nervous System of Man and Vertebrates (Cajal, 1899-1904), considered the most important book devoted to the nervous system. Owing that last year was the centenary of this publication, we decided to produce an article focused on Cajal´s description of the morphological changes that dendritic trees undergo during development. We will emphasize his brilliant hypotheses explaining the modelling of dendritic trees (the neurotropic hypothesis and the role of neuronal activity in the patterning of the dendritic trees), and the status of this topic in present day Neuroscience. Here, we will show original photographs taken from a selected collection of Cajal´s slides housed in the Cajal Museum (Instituto Cajal, CSIC, Madrid, Spain) illustrating the principal changes in neuronal morphology at different stages of development of the spinal cord, cerebellum and cerebral cortex. We will also discuss Cajal’s initial proposals regarding the influence of neurotropic substances (chemotactic hypothesis) and neural activity in the modelling of the dendritic tree, as well as the evidence that later confirmed these theories.P. GL. is supported by the Fundación Caixa Galicia. This study was supported by grants from Spain´s Ministry of Science and Innovation (SAF2007- 60010) and the Instituto de Salud Carlos III (RETICS, RENEVAS, RD06/ 0026/1001).Peer reviewe

Bases biológicas del deterioro de la función cognitiva inducido por los tratamientos antineoplásicos

Often patients treated with chemotherapy and/or radiotherapy suffer memory and attention problems. The exact mechanisms of action are unknown, although several explanations have been proposed. Both chemotherapy and radiotherapy have a direct toxic effect in the CNS, especially neural progenitor cells and the glia, which are responsible for maintaining neurogenesis in the hippocampus and white matter integrity. Besides the treatments can induce vascular damage in the brain, altering the immune response mediated by cytokines, and hormonal changes secondary to either chemotherapy or hormone therapy itself. The intensity of these effects would be modulated by several genetic factors that influence the ability of neuronal repair, pharmacodynamics and activity of neurotransmitters.A menudo los pacientes que reciben tratamiento con quimioterapia y/o radioterapia presentan problemas de memoria y de atención. Se desconocen los mecanismos exactos por los que esto se produce, aunque se han propuesto diversas explicaciones. Tanto la quimioterapia como la radioterapia poseen una acción tóxica directa en el SNC, especialmente sobre las células progenitoras neurales y las de la glía, que son las responsables de mantener la neurogénesis del hipocampo y la integridad de la sustancia blanca. A ello cabe añadir el daño que pueden inducir los tratamientos en la vascularización cerebral, la alteración de la respuesta inmune mediada por citoquinas, y los cambios hormonales ya sean secundarios a la quimioterapia o a la propia hormonoterapia. La intensidad de estos efectos estaría modulada por diversos factores genéticos que influyen sobre la capacidad de reparación neuronal, la farmacodinamia y la actividad de los neurotransmisores

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022)

Avapritinib; Imatinib; RipretinibAvapritinib; Imatinib; RipretinibAvapritinib; Imatinib; RipretinibGastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers

Assessing hydromorphological and floristic patterns along a regulated Mediterranean river : The Serpis River (Spain)

In the European context, several methodologies have been developed to assess the ecological status and, specifically, the hydromorphological status of running surface waters. Although these methodologies have been widely used, few studies have focused on hydrologically altered water bodies and the factors that may determine their status. In this study, the Serpis River was divided into 16 segments from the Beniarr'es dam (40 km from the river mouth) to the sea, all of which are affected by flow regulation, but with different severity. In each segment, an inventory of the flora was conducted, and hydromorphological indices (QBR, Riparian Habitat Quality Index; and IHF, River Habitat Index) were applied. The objectives of the study were (A) to identify relationships between floristic composition and QBR components and (B) between instream habitat characteristics and IHF components as well as (C) to determine the main factors controlling the floristic composition and riparian habitat quality (QBR) and the factors controlling instream habitat characteristics and heterogeneity (IHF). A cluster analysis allowed grouping sites according to their floristic composition and instream habitat characteristics, and non-metric multidimensional scaling (NMDS) was used to ordinate the sites, obtaining the biotic and instream habitat characteristics, as well as the QBR and IHF subindices, which better explained the spatial patterns. Finally, a canonical correspondence analysis (CCA) with predictor variables (geographical, hydrological, geomorphological and human pressures) indicated the main factors controlling the spatial patterns of the floristic composition, instreamhabitat characteristics, riparian habitat quality and instream habitat heterogeneity. A gradient of riparian and instream habitat quality was identified. Our results suggest that physical constraints (presence of a gorge) have protected sites from severe human impacts, resulting in good ecological quality, despite hydrological alteration. This area, where there is geomorphological control, could be potentially reclassified into a different ecotype because regular monitoring could be using incorrect references for index scores, and naturally high scores could be confused with recovery from hydrological alteration or other pressures. The sites with the worst quality were near the river mouth and were characterised by an artificial and highly variable flow regime (related to large autumnal floods and frequent human-induced periods of zero flow). This artificial flow variability as well as the presence of lateral structures in the river channel and geomorphological characteristics were identified as the main factors driving the hydromorphological and floristic pattern in this regulated river.Diversas metodologías han sido desarrolladas en el contexto europeo para evaluar el estado ecológico, y específicamente el estado hidromorfológico de las aguas superficiales. Aunque éstas han sido ampliamente utilizadas, pocos estudios se han centrado en masas de agua hidrológicamente alteradas y en los factores que condicionan su estado. En este estudio, el río Serpis fue dividido en 16 segmentos desde la presa de Beniarrés (a 40 km de la desembocadura) hasta el mar, todos ellos afectados por la regulación de caudales con distinta severidad. En cada segmento se realizó un inventario florístico y se aplicaron índices hidromorfológicos (QBR, Calidad del Bosque de Ribera, e IHF, Índice de Hábitat Fluvial). Los objetivos del estudio fueron (A) identificar relaciones entre la composición florística y los componentes del QBR, (B) entre las caracteríısticas del hábitat fluvial y los componentes del IHF, (C) determinar los principales factores que controlan la composición florística y la calidad del hábitat ripario (QBR), y las características del hábitat fluvial y su heterogeneidad (IHF). Un cluster permitió agrupar los puntos de muestreo según su composición florística y las características del hábitat fluvial, y un escalado multidimensional no-métrico (NMDS) fue usado para ordenar los puntos, obteniendo las variables bióticas y características del hábitat y los subindices del QBR e IHF, respectivamente, que explicaban mejor los patrones espaciales. Finalmente, un análisis de correspondencias canónicas (CCA) con variables predictoras (geográficas, hidrológicas, geomorfológicas y presiones humanas) indicó los principales factores que controlan los patrones espaciales de la composición florística, las características del hábitat fluvial, la calidad del hábitat ripario y la heterogeneidad del hábitat fluvial. Se identificó un gradiente de calidad del hábitat ripario y fluvial. Los resultados sugieren que las limitaciones físicas (presencia de un cañón) han protegido a los tramos de impactos humanos severos, resultando en una buena calidad ecológica a pesar de la alteración hidrológica. Esta zona podría potencialmente ser reclasificada en un ecotipo diferente, ya que un monitoreo regular podría estar usando referencias incorrectas para los índices y sus altas puntuaciones naturales se podrían estar confundiendo con una recuperación de la alteración hidrológica o de otras presiones. Los puntos de muestreo con peor calidad estuvieron cerca de la desembocadura y tuvieron un régimen de caudales alterado y muy variable. Esta variabilidad artificial del caudal, junto con la presencia de estructuras laterales en el cauce y las características geomorfológicas fueron identificadas como los principales factores determinantes del patrón hidromorfológico y florístico en este río regulado

Expresión corporal y aprendizaje de la Música en Educación Secundaria. Diferencias y relaciones según la edad, sexo, y gusto por la Música

The aim of this study was to know the opinion of secondary school students about the employment of body expression in music class and if it differed or was associated differently depending on the age, sex, and interest in music. A total of 2,017 secondary school students participated in the study by completing the Body Expression and Music Learning in Secondary School questionnaire. The statistical tests employed were the factor analysis, ANOVA analysis, Student’s T and linear regression analysis. The data showed a high validity and internal consistency in each of three obtained factors: music learning (F1), relationship with classmates (F2) and motivation towards music (F3). The results were higher in girls and in students with more interest in music for all the three factors. Music learning through body expression (F1) and motivation (F3) decreased when age increased. The relationship with classmates (F2) was similar in all ages. An increase of body movement during music lessons is suggested. These activities must be performed mainly in younger students and additional motivational measures should be established to involve both boys and young learners who demonstrate less interest in this subject.El objetivo del presente estudio fue conocer la opinión del alumnado de Educación Secundaria sobre el empleo de la expresión corporal en la asignatura de Música, y si esta difería o se asociaba de forma diferente en función de la edad, el sexo, y su gusto por la música. Participaron 2017 estudiantes que cumplimentaron el cuestionario “Expresión corporal y aprendizaje de la Música en Educación Secundaria”. Se empleó análisis factorial, ANOVA de un factor, prueba T de Student, y análisis de regresión. Los datos presentaron una alta validez y consistencia interna en cada una de las tres dimensiones obtenidas: Aprendizaje de la Música (F1), relación con los compañeros (F2) y motivación hacia la Música (F3). En los 3 factores, la puntuación fue más alta en chicas y en el alumnado que manifestó tener más gusto por la Música. Tanto el aprendizaje de la Música mediante la expresión corporal (F1), como la motivación provocada (F3), disminuían a medida que aumentaba la edad. La relación con los compañeros (F2) era similar en todas las edades. Se sugiere, un incremento de las prácticas que implique movimiento corporal durante las clases de Música. Estas actividades deben llevarse a cabo prioritariamente en los más jóvenes, y establecer medidas adicionales de motivación para involucrar tanto a los chicos como a aquellos jóvenes que manifiestan tener un menor gusto por esta asignatura

Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas

Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.This study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) under the grant SAF2016-76520-R. ME is recipient of a postdoctoral contract Juan de la Cierva; DL and NRA of a FPU contract of MINECO; MP and RFG of a FPI contracts of Autonomous University of Madrid. RG has been funded by the AECC Scientific Foundation

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients' clinical and genetic risk factors for thrombosis. We included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared. We recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Khorana score (AUC 0.73 vs. 0.58, sensitivity 49 vs. 22%, specificity 81 vs. 82%, PPV 37 vs. 22%, and NPV 88 vs. 82%). TiC-Onco risk score performed significantly better than Khorana score at identifying cancer patients at high risk of VTE who would benefit from personalised thromboprophylaxis

p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming

[EN] The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming.S

The Relationship between Depressive Symptoms, Quality of Life and miRNAs 8 Years after Bariatric Surgery

Altres ajuts: Universidad de Málaga, UMA20-FEDERJA-144; Junta de Andalucia, PI-0194-2017, C-0028-2018, RC-005-2020, DOC_00288 and DOC_01095Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive symptomatology in studied patients at the 8-year follow-up after BS, as well as their relationship with different serum proteins and miRNAs. Methods: A total of 53 patients with class III obesity who underwent BS, and then classified into "good responders" and "non-responders" depending on the percentage of excess weight lost (%EWL) 8 years after BS (%EWL ≥ 50% and %EWL < 50%, respectively), were included. Basal serum miRNAs and different proteins were analysed, and patients completed tests to evaluate QoL/depressive symptomatology at 8 years after BS. Results: The good responders group showed higher scores on SF-36 scales of physical functioning, role functioning-physical, role functioning-emotional, body pain and global general health compared with the non-responders. The expression of hsa-miR-101-3p, hsa-miR-15a-5p, hsa-miR-29c-3p, hsa-miR-144-3p and hsa-miR-19b-3p were lower in non-responders. Hsa-miR-19b-3p was the variable associated with the response to BS in a logistic regression model. Conclusions: The mental health of patients after BS is limited by the success of the intervention. In addition, the expression of basal serum miRNAs related to depression/anxiety could predict the success of BS