Determinants of activity and efficacy of anti-PD1/PD-L1 therapy in patients with advanced solid tumors recruited in a clinical trials unit: a longitudinal prospective biomarker-based study

Immune checkpoint inhibitors; Immunotherapy; Solid tumorsInhibidores de puntos de control inmunitarios; Inmunoterapia; Tumores sólidosInhibidors del punt de control immunitari; Immunoteràpia; Tumors sòlidsImmune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored

Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling

All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism

Influencia de la hipoxia hipobárica aguda en el ciclo menstrual de mujeres jóvenes en el año 2018

OBJETIVO: Determinar la influencia de la hipoxia hipobárica aguda en el ciclo menstrual de mujeres jóvenes. MATERIALES Y MÉTODOS: Diseño observacional. Se seleccionaron 21 mujeres, divididas en dos grupos. A 15 participantes en fase menstrual (G1) se les proporcionó un sistema de puntuación (pictograma) que midió el flujo menstrual y un test de escala del dolor. Las mediciones se realizaron a 34 m s.n.m y posteriormente a más de 2500 m s.n.m; utilizándose la prueba de Mann-Whitney con p&lt;0.05. A 6 participantes (G2) se les realizó una ecografía antes y después de la exposición a gran altura con el fin de conocer su influencia sobre la ovulación mediante la Prueba Exacta de Fisher con p&lt;0.05. RESULTADOS: La puntuación promedio del pictograma obtenida en G1 a 34 m s.n.m fue de 17.033, mientras que a más de 2500 m s.n.m se obtuvo 13.967 (p=0.349). Para el test de escala del dolor p=0.3436. Las ecografías a 34 m.s.n.m mostraron en G2 folículo óptimo (&gt; 18 mm) para la ovulación. Después de la exposición a gran altura, en 4 de las participantes se observó folículos entre 2-6 mm, con ausencia de cuerpo lúteo; por el contrario, en las restantes se evidenció la presencia del cuerpo lúteo. El análisis estadístico para G2 mostró p= 0.03. CONCLUSIONES: No se encontró una relación significativa entre la hipoxia hipobárica aguda y variación del flujo y dolor menstrual debido al limitado tamaño muestral. Sin embargo, se evidenció una influencia negativa de la hipoxia hipobárica aguda sobre el desarrollo de la ovulación.PALABRAS CLAVE: hipoxia hipobárica aguda, ciclo menstrual

Anexo II. Fichas de los ítems

El presente documento contiene uno de los anexos a la publicación impresa titulada "Recuperando la ciudad. Estrategia para el diseño y la evaluación de planes y programas de regeneración urbana integrada" —ISBN: 978-84-9728-5585-1— libro que es uno de los resultados obtenidos del proyecto financiado por el Plan Nacional I+D+i para el periodo 2013-2015, titulado "Estrategia para el diseño y evaluación de planes y programas de regeneración urbana integrada. La intervención en las periferias españolas a través de las áreas de rehabilitación integral y el programa URBAN" (BIA2012-31905). Dicho proyecto se ha realizado en el Departamento de Urbanística y Ordenación del Territorio de la Escuela Técnica Superior de Arquitectura de Madrid, mediante la financiación del Ministerio de Economía y Competitividad, a través del Plan Nacional de I+D+i 2008-2011 (Subprograma de Proyectos de Investigación Fundamental no Orientada). En este segundo anexo se realiza una caracterización y descripción de cada uno de los ítems que forman parte cada una de las categorías pertenecientes a las cuatro áreas principales, facilitando así el uso de la herramienta en los casos en los que se requiera de un mayor nivel de detalle

Recuperando la ciudad. Estrategia para el diseño y la evaluación de planes programas de regeneración urbana integrada

El presente documento es uno de los resultados obtenidos del proyecto financiado por el Plan Nacional I+D+i para el periodo 2013-2015, titulado Estrategia para el diseño y evaluación de planes y programas de regeneración urbana integrada. La intervención en las periferias españolas a través de las áreas de rehabilitación integral y el programa URBAN (BIA2012-31905), realizado en el Departamento de Urbanística y Ordenación del Territorio de la Escuela Técnica Superior de Arquitectura de Madrid. El objetivo del proyecto fue desarrollar una “herramienta de evaluación” de los planes y programas de Rehabilitación Urbana Integrada y se materializa en un árbol de conceptos que deberían ser analizados tanto antes como después del plan o proyecto. Su intención es facilitar la comunicación entre los distintos actores de la rehabilitación: vecinos, técnicos y administración, que al disponer de un modelo de análisis común (que deberá ser ratificado de forma consensuada desde las fases previas de la operación) puedan llegar a consensos sobre cuáles son los elementos fundamentales y los secundarios de la operación, lo que permitiría determinar (en un marco de recursos limitados), el porqué y las consecuencias de la elección de alguno de los elementos del modelo en detrimento de otros. El modelo se construye en una doble dimensión. La espacial en la que se reflexiona sobre los distintos niveles de integración, desde el área urbana en la que se enclava, al espacio público del barrio sobre el que se pretende actuar, para llegar a la edificación y la vivienda, incluyendo a los propios habitantes. Pero esta estructura tiene la capacidad de garantizar la segunda dimensión, la integralidad de las operaciones, diferenciándose ésta en tres niveles: áreas, categorías e ítems. Se definen cuatro áreas, Marco Urbano y Territorial, Diseño urbano y Medio ambiente local, Edificación y Socio-Económica, que establecen el marco básico de la calidad urbana. Las categorías, en las que se divide cada área, representan un marco conceptual consistente que establece los temas que tienen que ser considerados y analizados en el proceso si queremos garantizar la integralidad de la actuación. Las categorías se dividen en ítems que son los elementos que en cada caso se utilizarán para garantizar la calidad final del plan o programa. Se han considerado los ítems como contextuales porque se conformarán en detalle y con matices diferenciados en función de cada proyecto o acción concreta, por lo que podrán coincidir con los ítems elaborados durante el desarrollo de esta herramienta o ser diferentes por necesidades específicas. El presente documento se completa con dos anexos: Anexo I: Informe de la encuesta sobre experiencias de rehabilitación urbana en las ciudades españolas. Resultados. URL: http://oa.upm.es/43244/ Anexo II: Fichas de los ítems. URL: http://oa.upm.es/43247

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía

El PIMCD Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía se ocupa de conceptos que generalmente han tendido a ser eludidos en la enseñanza académica de filosofía. Se trata de la tercera edición de un PIMCD que ha venido recibiendo financiación en las últimas convocatorias PIMCD UCM, de los que se han derivado publicaciones colectivas publicadas por Ediciones Complutense y Siglo XXI

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics