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The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high NFE2L2 levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high NFE2L2 levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of NFE2L2 may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients., Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub, Descuento UCM

Background Psychological stress and increased permeability are implicated as contributing factors in the initiation and worsening of gastrointestinal diseases. A link between stress and intestinal permeability has been shown in animal models as well as in human small intestine, but stress effects on the human colorectal mucosal barrier has not been reported. Objective To investigate the potential effects of acute psychological stress on colorectal mucosal barrier function and to explore stress-induced molecular events in the rectal mucosa under healthy conditions. Methods Endoscopic biopsies were taken from the rectosigmoid region of healthy volunteers, who had been subjected to dichotomous listening stress and after a control session, respectively. Paracellular and transcellular permeability were assessed in modified Ussing chambers. RNA expression (microarray technology confirmed by quantitative real-time polymerase chain reaction) and biological pathway analysis were used to investigate the local mucosal response to acute stress. Results Dichotomous listening stress induced a subjective and objective stress response, and significantly increased paracellular but not transcellular permeability. We also identified a stress-induced reduction in RNA expression of genes related to immune cell activation and maturation (CR2, CD20, TCLA1, BANK1, CD22, FDCSP), signaling molecules of homing of immune cells to the gut (chemokines: CCL21, CXCL13, and CCL19, and receptors: CCR7, CXCR5), and innate immunity (DUOX2). Eight of the 10 top down-regulated genes are directly involved in B cell activation, signaling and migration. The systemic stress response correlated positively with paracellular permeability and negatively with DUOX2 expression. Conclusion Dichotomous listening stress increases paracellular permeability and modulates immune cell activity in the rectal mucosa. Further studies are warranted to identify the primary mechanisms of stress-mediated reduction of mucosal d, Funding Agencies|Fondo de Investigacion Sanitaria and CIBERehd, Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Economia y Competitividad [PI17/0190, PI19/01643]; Futurum, Region Jonkoping County [12406, 1460]; Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas [CB06/04/0021]; Vetenskapsradet [2014-02537, 2017-02475]; Forskningsradet i Sydostra Sverige [37841]

Introduction: The study of predictors of negative outcomes in patients with heart failure has included the combination of natriuretic peptides and red cell distribution width (RDW). Objective: To evaluate the combined use of the amino-terminal pro-brain natriuretic peptide (NT-proBNP) and RDW as a prognostic factor for death from any cause, prolonged hospitalization, and readmission one year after discharge in patients with decompensated acute heart failure (AHF). Methods: We conducted a retrospective observational study. We constructed a combined index = NT-ProBNP x RDW/100. ROC curves were constructed, sensitivity and specificity were estimated based on the cut-off points, and the relative risk was estimated to develop the outcomes studied. We compared the area under curve of combined index versus NT-proBNP and RDW, separately. Results: We analyzed data from 471 patients. The combined index had its best cut of 927.79 to predict death during the first year of admission. Those with values≥ 927,79 had a relative risk of 32.7 (95% CI: 4.8 – 222.3). To predict hospitalization ≥7 days, the cut-off point was 752.67; those with this value or higher had a relative risk of 22.4 (95% CI: 9.7 – 51.8). To predict readmission one year after discharge, the cutoff was 858.47 and the relative risk was 4.7 (95% CI: 3.3 – 6.8). Conclusions: The combined index used generate relative risks that show a strong strength of association for death from any cause, hospitalization ≥7 days, and readmissions one year after discharge. However, the superiority to discriminate was inconclusive with respect to the individual components, Introducción: El estudio depredictores de desenlaces negativos en pacientes con insuficiencia cardiaca ha incluido la combinación de péptidos natriuréticos y el ancho de distribución eritrocitaria (RDW). Objetivo: Evaluar el uso combinado de la porción N-terminal del propéptido natriurético tipo B (NT-proBNP) y el RDW como pronóstico de fallecimiento por cualquier causa, hospitalización prolongada y reingreso al año del alta en pacientes con insuficiencia cardiaca aguda (ICA) descompensada. Métodos: Realizamos un estudio observacional retrospectivo. Construimos un índice combinado = NT-proBNP x RDW/100. Elaboramos curvas ROC, se estimó la sensibilidad y especificidad en base a los puntos de corte y se estimó el riesgo relativo para desarrollar los desenlaces. Comparamos las áreas bajo las curvas del índice combinado versus el NT-proBNP y RDW, por separado. Resultados: Analizamos los datos de 471 pacientes. El índice combinado tuvo su mejor corte en 927,79 para pronosticar fallecimiento durante el primer año de ingreso. Aquellos convalores ≥ 927,79 tuvieron un riesgo relativo de 32,7 (IC95%: 4,8 - 222,3). Para hospitalización ≥7 días el punto de corte fue 752,67, aquellos con este valor o superiores tuvieron un riesgo relativo de 22,4 (IC95%: 9,7 – 51,8). Para pronosticar reingreso al año del alta el corte fue 858,47 y el riesgo relativo fue 4,7 (IC95%: 3,3 – 6,8). Conclusiones: El índice combinado generó riesgos relativos que muestran una fuerte fuerza de asociación para fallecimiento por cualquier causa, hospitalización≥7 días y reingresos al año del alta. Sin embargo, la superioridad para discriminar no fue concluyente respecto a los componentes individuales

El objetivo del proyecto es satisfacer las necesidades de una consulta clínica y de los roles que se desenvuelven dentro de ella. Busca dar una completitud a todas las perspectivas que conviven dentro de ella: desde la visión del médico, quien tendrá un abanico de posibilidades más global dentro del sistema, acceso a todas las herramientas de gestión humana, consultas y otros servicios. El punto de vista de los trabajadores del centro, tanto enfermeros como personal administrativo, quienes también tendrán soporte para facilitar su actividad en el día a día agilizando la gestión de pacientes y pudiendo tener un mecanismo de facturación sencillo. Y por último, la figura de los pacientes a los que se trata de acercar a la consulta y brindar la posibilidad de gestionar de forma autónoma sus necesidades en relación a la misma, siendo conocedor de la información almacenada en su historial o bien, solicitando una cita médica de forma totalmente trivial e intuitiva. Se ha buscado conseguir una aplicación web que pueda estar alojada en los ordenadores de la clínica con un sistema de identificación para que cada rol disponga de las herramientas que le van a ser más útiles y con un nivel de granularidad distinto en base a sus necesidades. Tiene como fin lograr que el trabajo diario sea más fácil de sostener y que la comunicación entre los pacientes y la clínica sea constante sin necesidad de soporte telefónico poniendo en contacto a los pacientes y a la clínica a través de ella., The objective of the project is to meet the needs of a clinical practice and the roles which are developed within it. It seeks to provide completeness to all the perspectives that coexist with it: from the doctor's point of view, who will have a more global range of possibilities within the system, access to all the human management tools, consultations, and other services. The center workers’ point of view, both nurses and administrative staff, who will also have support to facilitate their day-to-day activity by streamlining patient management and having a simple billing mechanism. And finally, the figure of the patients, who will be brought closer to the clinic and will have the possibility to manage their needs autonomously in relation to it, being aware of the information stored in the patient history or requesting a medical appointment in a completely trivial and intuitive way. We have sought to achieve a web application that can be hosted on the computers of the clinic with an identification system so that each role has the tools that will be most useful and with a different level of granularity based on their needs. It aims to make the daily work easier to sustain and to make communication between patients and the clinic constant without the need for telephone support by bringing patients and the clinic together through it.

Madrid como otras grandes ciudades tiene un gran tránsito de peatones cada día, atraídos por el ocio, el turismo, trabajo o simplemente para dar un paseo y disfrutar de esta ciudad llena de encanto. Debido a la pandemia el gran número de peatones que transitaban las calles de Madrid se redujo drásticamente, confinamientos y medidas restrictivas de movilización hicieron que los peatones se vieran limitados. En este proyecto se pretende estudiar el tránsito y densidad de peatones antes de la pandemia y como afectó esta al número de peatones que recorrían las calles de Madrid, empleando datos históricos recogidos de la web del ayuntamiento de Madrid y aplicando algoritmos de Machine Learning., Madrid, like other big cities, has a large pedestrian traffic every day, attracted by leisure, tourism, work or simply to take a walk and enjoy this city full of charm. Due to the pandemic, the number of pedestrians on the streets of Madrid was drastically reduced, since confinements and other restrictive mobility measures implied that pedestrians were limited. This project aims to study the traffic and density of pedestrians before the pandemic and how it affected the number of pedestrians walking the streets of Madrid, using historical data collected from the Madrid City Council website and applying Machine Learning algorithms.

El presente trabajo supone una herramienta de uso médico en la que poder gestionar un conjunto de pacientes, así como realizar predicciones de riesgo oncológico dadas ciertas variables de uso en la medicina, concretamente centradas en el campo de la urología. De manera específica, los usuarios, en este caso, doctores; tendrán la capacidad de acceder de manera ordenada a una lista de pacientes, sobre la que podrán añadir nuevos pacientes, modificar o eliminar los existentes o simplemente consultar el estado del paciente deseado. Además, tendrá la posibilidad de consultar, bien sobre cada uno de los pacientes mencionados, o bien sobre nuevos pacientes, sus probabilidades ante ciertos sucesos médicos, mediante el uso de una calculadora de riesgo con tecnologías de machine learning. El desarrollo mencionado está íntegramente creado en forma de aplicación web con acceso a base de datos., The present work represents a medical tool for managing a set of patients and making oncological risk predictions based on certain variables used in medicine, specifically focused on the field of urology. Specifically, users, in this case doctors, will have the ability to access an organized list of patients. They can add new patients, modify or delete existing ones, or simply check the status of a desired patient. Additionally, they will be able to consult the probabilities of certain medical events for each patient mentioned, or for new patients, using a risk calculator powered by machine learning technologies. The mentioned development is entirely created as a web application with database access.

La gran crisis global acaecida en la primera década del siglo XXI evidenció toda una serie de problemas que la profesión periodística arrastraba desde hacía décadas. En un contexto de incertidumbre generalizada, la industria afronta ahora una verdadera transformación en el concepto de empresa informativa donde no todas las opciones conocidas podrán pervivir y se abrirán paso otras nuevas. Entre las que se consolidan, llama la atención la evolución de aquellas que, en torno al denominado engaged journalism, buscan consolidar dinámicas que garanticen el beneficio económico (indispensable para garantizar su viabilidad e independencia) y reporten al mismo tiempo un fuerte beneficio social. Hablamos de un periodismo basado en relaciones entre los miembros de una comunidad que, respetando el reparto de roles de cada uno, contribuyen a la realización de cada individuo y, al mismo tiempo, generan dinámicas de mayor alcance en favor de la construcción de una identidad colectiva., The great global crisis that occurred in the first decade of the 21st century brought to the fore a range of problems that the journalistic profession had been sidestepping for many years. Against a backdrop of widespread uncertainty, the media is now fully immersed in a fundamental transformation that is redefining what we understand as an information company, meaning that not all the current options and formats will survive and new entrants will claim their place in the evolving landscape. In terms of consolidation, the progress being made by those outlets focused on engaged journalism as they seek to reinforce a dynamic that both ensures an economic return (essential to guaranteeing their viability and independence) and delivers a strong social benefit is striking. We are talking about a journalism that is built on the relationships among the members of a community who, while respecting the role played by each one, also contribute to the fulfillment of each other’s objectives, all the time amplifying the dynamics and breadth of scope that favor the construction of a collective identity.

Objective: The objective of this article is to recognize what characteristics define the Castilian and Portuguese border societies in the Atlantic that, during the aggregation of Portugal to the Hispanic Monarchy, were closely connected to each other. The object of study are the islands of Macaronesia in the period of consolidation of the Atlantic world, with the aim of clarifying the particularities of the insular identity built from ties of complementarity between archipelagos ruled by different kingdoms within a dynamic and related ocean. Methodology: The insular chronicles, both Castilian and Portuguese, contemporary to the period have been analyzed since these texts reflect in writing the social perception of the insular about their closest environment. In a complementary way, primary sources from the local administrations of different archipelagos and Canary Islands notarial protocols have been used to deepen the study of socioeconomic contacts and complementary ties between the different Macaronesian island spaces. Originality: The purpose of this study is to apply a supranational observation method on a border society whose inhabitants were subjects of two kingdoms and at the same time made up a single region. Conclusions: These chroniclers understand that there is a common insular entity that relates them, socially and economically. It is from these stories that Macaronesia begins to define itself in historical terms., Objetivo: este artigo reconhece quais são as características que definem as sociedades fronteiriças castelhanas e portuguesas no Atlântico que, durante a agregação de Portugal à Monarquia Hispânica, estiveram intimamente ligadas entre si. O objeto de estudo são as ilhas da Macaronésia no período de consolidação do mundo atlântico com o objetivo de esclarecer as particularidades da identidade insular construída a partir de laços complementares entre arquipélagos governados por diferentes reinos num oceano dinâmico e relacional. Metodologia: foram analisadas as crônicas insulares contemporâneas ao período, tanto castelhanas quanto portuguesas, uma vez que esses textos refletem na escrita a percepção social dos insulares sobre seu entorno mais próximo. De forma complementar, foram utilizadas fontes primárias das administrações locais de diferentes arquipélagos e protocolos notariais das Ilhas Canárias para aprofundar o estudo dos contatos socioeconômicos e os laços complementares entre os diferentes espaços insulares da Macaronésia. Originalidade: o objetivo deste estudo é aplicar um método de observação supranacional a uma sociedade de fronteira cujos habitantes eram súditos de dois reinos e, ao mesmo tempo, formavam uma única região. Conclusões: estes cronistas entendem que existe uma entidade insular comum que os relaciona, social e economicamente. É a partir destas histórias que a Macaronésia começa a definir-se em termos históricos., Objetivo: el objetivo de este artículo es reconocer qué características definen a las sociedades fronterizas castellanas y portuguesas en el Atlántico que, durante la agregación de Portugal a la Monarquía Hispánica, estuvieron estrechamente conectadas entre sí. El objeto de estudio son las islas de la Macaronesia en el periodo de consolidación del mundo atlántico con el objetivo de esclarecer las particularidades de la identidad insular construida a partir de lazos de complementariedad entre archipiélagos regidos por distintos reinos en el interior de un océano dinámico y relacionante. Metodología: se han analizado las crónicas insulares, tanto castellanas como portuguesas, coetáneas al periodo ya que estos textos plasman por escrito la percepción social del insular sobre su entorno más cercano. Subsidiariamente, se han empleado fuentes primarias de las administraciones locales de distintos archipiélagos y protocolos notariales canarios para profundizar en el estudio de los contactos socioeconómicos y los lazos de complementariedad entre los distintos espacios insulares macaronésicos. Originalidad: la finalidad de este estudio es aplicar un método de observación supranacional sobre una sociedad fronteriza cuyos moradores fueron súbditos de dos reinos y a la vez conformaron una única región. Conclusiones: entienden estos cronistas que existe una entidad común insular que los relaciona social y económicamente. Es, a partir de estos relatos, cuando comienza a definirse, en términos históricos, la Macaronesia.

La búsqueda y el tratamiento de la valentía han sido llevados a cabo por Platón en numerosos diálogos, desde la temprana Apología hasta las Leyes, lo que indica la gran importancia que el filósofo ateniense concedía a esta cuestión. Por otro lado, la valentía es tratada en numerosos contextos diferentes —con diferentes interlocutores, diferentes temas y diferentes objetivos— que dan lugar a un nutrido número de aproximaciones a partir de las cuales cabe construir una visión bastante completa de lo que Platón entendía por valentía (andreía).

The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high NFE2L2 levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high NFE2L2 levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of NFE2L2 may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients.

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

The objective of this study is the elaboration of a questionnaire for the evaluation of the fear of recurrence of cancer in Spanish. Method: A pilot study with a cross-sectional correlational design is presented, elaborated in two phases: 1) creation of the Fear Cancer recurrence Questionnaire (CMRC) and the General Scale of Fear of Cancer Recurrence (EGMRC); 2) evaluation of their psychometric properties. Results: for the elaboration of the questionnaires, the agreement between experts was used, measured by Aiken’s V. The CMRC questionnaire is finally configured with 8 items that are answered with a Likert-type scale of 0-4 and a Cronbach’s Alpha of 0.851. The EGMRC consists of a single question that is answered with a scale of 0-100 correlates up to 0.84 with the CMRC. A sample of 50 female survivors of gynecological cancer selected from the Hospital Universitario Clínico San Carlos in Madrid was used. Both scales correlate with the level of anxiety of the patients and the emotional function of quality of life. No correlations with levels of depression were found. Conclusions: The CMRC and the EGMRC are two instruments that may be valid for the evaluation of FCR in Spanish for survivors of gynecological cancer., El objetivo de este estudio es la elaboración de un cuestionario de evaluación del miedo a la recurrencia del cáncer en español. Método: se presenta un estudio piloto de diseño correlacional trasversal elaborado en dos fases: 1) creación del cuestionario del miedo a la recurrencia del cáncer (CMRC) y de la Escala General del Miedo a la Recurrencia del Cáncer (EGMRC); 2) evaluación de sus propiedades psicométricas. Resultados: para la elaboración de los cuestionarios se utilizó el acuerdo entre expertos medido por la V de Aiken. El CMRC queda finalmente configurado con 8 ítems que se responden con una escala tipo Likert de 0-4 y un Alfa de Cronbach de 0,85. La EGMRC de una sola pregunta que se responde con una escala de 0-100 correlaciona hasta un 0,84 con el CMRC. Se utilizó una muestra de 50 mujeres supervivientes de cáncer ginecológico seleccionadas en el Hospital Universitario Clínico San Carlos de Madrid. Ambas escalas correlacionan con el nivel de ansiedad de las pacientes y la función emocional de calidad de vida. No se hallan correlaciones con los niveles de depresión. Conclusiones: El CMRC y la EGMRC son dos instrumentos que pueden ser válidos para la evaluación del miedo a la recurrencia del cáncer en pacientes supervivientes de cáncer ginecológico.

There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions.

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The aim of this short note is to show that Denoising Diffusion Probabilistic Model DDPM, a non-homogeneous discrete-time Markov process, can be represented by a time-homogeneous continuous-time Markov process observed at non-uniformly sampled discrete times. Surprisingly, this continuous-time Markov process is the well-known and well-studied Ornstein-Ohlenbeck (OU) process, which was developed in 1930's for studying Brownian particles in Harmonic potentials. We establish the formal equivalence between DDPM and the OU process using its analytical solution. We further demonstrate that the design problem of the noise scheduler for non-homogeneous DDPM is equivalent to designing observation times for the OU process. We present several heuristic designs for observation times based on principled quantities such as auto-variance and Fisher Information and connect them to ad hoc noise schedules for DDPM. Interestingly, we show that the Fisher-Information-motivated schedule corresponds exactly the cosine schedule, which was developed without any theoretical foundation but is the current state-of-the-art noise schedule.