Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.[Significance] Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.This work was supported, in part, by grants from Asociación Española Contra el Cáncer (F.X. Real), Spanish Ministry of Economy and Competitivity, Plan Estatal de I+D+I 2013-2016, ISCIII (FIS PI15/00045 to A. Carnero), RTICC (Instituto de Salud Carlos III, grants RD12/0036/0034 to F.X. Real and A. Carnero, respectively), and CIBERONC (CB16/12/00453 and CD16/12/00275 to F.X. Real and A. Carnero, respectively), cofunded by FEDER from Regional Development European Funds (European Union) and Inserm (Institut national de la santé et de la recherche médicale). M. Marqués was supported by a Sara Borrell Fellowship from Instituto de Salud Carlos III. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

¿Están alterando las estaciones depuradoras de aguas residuales nuestros ríos?

A methodology is presented to characterize the hydrological alteration due to wastewater treatment plant (WWTP) from data of daily average flows obtained from the Official Network of Stream gauges. As indicators of hydrological alteration, the following are used: i) the ratios proposed by the MAPAMA, ii) the results of the IAHRIS software, and iii) new ratios at monthly and seasonal scales proposed by the authors of this study. As examples of application, three cases of the Community of Madrid are presented: Sur WWTP in the Manzanares River, El Chaparral WWTP in the Guadarrama River and Arroyo Culebro Cuenca Baja WWTP in the Culebro Stream. The analyzed cases reflect: (i) a value of 0.3 is endorsed as a significant alteration threshold in all the ratios; ii) in intensely altered sections it is difficult to differentiate the effect of the WWTP from the rest of the disturbances; iii) in sections only affected by WWTPs, the alteration is more pronounced in dry periods, when minimum flows can reach increases of the order of 130%. In other cases, the character of a seasonal river is lost when the periods of zero flow disappear; iv) in sections with significant amounts of wastewater discharges have been observed increases of up to 14 times in the annual volumes and 20 times in the monthly.Se presenta una metodología para caracterizar la alteración hidrológica debida a las EDAR a partir de datos de caudales medios diarios obtenidos de la Red Oficial de Estaciones de Aforo. Como indicadores de alteración hidrológica se utilizan: i) los ratios propuestos por el MAPAMA, ii) los resultados del software IAHRIS y iii) nuevos ratios a escalas mensual y estacional propuestos por los autores de este estudio. Como ejemplos de aplicación se presentan tres casos en la Confederación Hidrográfica del Tajo: EDAR Sur en el río Manzanares, EDAR El Chaparral en el río Guadarrama y EDAR Arroyo Culebro Cuenca Baja en el Arroyo Culebro. Los casos analizados reflejan: (i) un valor de 0,3 se refrenda como umbral de alteración significativa en todos los ratios; ii) en tramos intensamente alterados es difícil diferenciar el efecto de las depuradoras del resto de perturbaciones; iii) en tramos sólo afectados por EDARs la alteración se manifiesta con más intensidad en los períodos secos, cuando los caudales mínimos pueden llegar a experimentar incrementos del orden del 130%. En otros casos se pierde el carácter de río estacional al desaparecer los períodos de flujo cero; iv) en tramos con cuantías importantes de vertidos se han observado incrementos de hasta 14 veces en las aportaciones anuales y 20 veces en las mensuales

Síndrome de la cuenca urbanizada vs dinámica morfológica fluvial: un caso práctico

Urbanization processes can generate important effects on fluvial systems as a consequence of the increase of the impermeable surface. The most appreciable and immediate effect is the flow regimes alteration. This change causes variations in the sedimentological processes that affect fluvial morphology. The responses derived from urbanization have been identified with the name of Urban Stream Syndrome (USS). In Spain the 70% of the population lives in large urban areas. Nevertheless, there are almost any geomorphological studies in channels affected by USS. The study of this syndrome is presented using the case of Trofa stream (Madrid). The basin of this stream has two characteristics that make it a perfect study case of USS effects. On one hand since the late seventies the headwaters basin has supported an important urban development. On the other hand, a third of the basin, closed to the confluence and with a restricted use, keep itself intact of human activities. This work address the characterization of the geomorphological dynamics in the plant and section of the stream by the application of morphometric parameters, and identifies and quantifies the effects of the USS on the fluvial morphology and its dynamics.El cambio de uso del suelo debido a la urbanización puede generar importantes efectos sobre los sistemas fluviales. El más apreciable e inmediato es la alteración del régimen hidrológico el cual, provoca a su vez cambios en los regímenes sedimentológicos que afectan a la morfología fluvial. Estas respuestas derivadas de la urbanización se han identificado como Síndrome de la Cuenca Urbanizada (SCU). En España los estudios geomorfológicos en cauces afectados por SCU son casi inexistentes, a pesar de que el 70% de la población vive en grandes áreas urbanas. Este estudio presenta el caso del arroyo de Trofa (Madrid). La cuenca de este arroyo presenta dos características que la hacen un caso perfecto para el estudio del SCU: la cabecera de cuenca ha soportado, desde finales de los años setenta, un importante desarrollo urbanístico, y sin embargo, el tercio inferior de la cuenca se encuentra intacta en lo referente a modificaciones directas humanas. Este trabajo presenta la caracterización de la dinámica geomorfológica en planta y sección de un tramo del arroyo mediante la aplicación de parámetros morfométricos, e identifica y cuantifica los efectos del SCU en la morfología fluvial y su dinámica

¿Cómo plantear el seguimiento de las actuaciones de restauración fluvial?: Caso del río Manzanares en el entorno del Real Sitio del Pardo (Madrid)

We presented the methodology carried out for the elaboration of the monitoring program of the hydromorphological actions included in the Project of river restoration of the Manzanares river, in the surroundings of the Real Site of El Pardo (Madrid). The effectiveness of these actions are measured through a set of 18 indicators, all proposed following criteria that ensure their effectiveness and applicability. As an example, the file corresponding to one of the indicators is presented, specifying its objective, valuation thresholds, calculation methodology in the field and / or cabinet, location and periodicity. In a global way, the program proposes the division of the scope of the project into sections and sub-sections, according to the most relevant environmental characteristics prior to the execution of the project. As tasks are scheduled the realization of three geo-referenced drone flights for the estimation of various variables, 16 bathymetries in selected sections, 3 campaigns of sampling of benthos in 5 representative sections and 4 precincts for the characterization of the vegetation. In this way, there is an adaptive management tool that, over the 3 years programmed, will make it possible to demonstrate the effectiveness of the actions, proposes improvements and generates guidelines for other similar projectsSe presenta la metodología seguida en la elaboración del programa de seguimiento de las actuaciones de carácter hidromorfológico enmarcadas en el Proyecto de restauración fluvial del río Manzanares en el entorno del Real Sitio de El Pardo (Madrid). La eficacia de dichas actuaciones se medirá mediante un conjunto de 18 indicadores, todos ellos propuestos siguiendo unos criterios que aseguren su eficacia y aplicabilidad. A modo de ejemplo se presenta la ficha correspondiente a uno de los indicadores donde se especifica su objetivo, umbrales de valoración, metodología de cálculo en campo y/o gabinete, localización y periodicidad. De manera global el programa propone la división del ámbito del proyecto en tramos y subtramos, acordes a las características ambientales más relevantes previas a la ejecución del proyecto. Como tareas se programan la realización de tres vuelos dron georeferenciados para la estimación de diversas variables, 16 batimetrías en secciones seleccionadas, 3 campañas de muestreo de bentos en 5 secciones representativas y 4 recintos para la caracterización de la vegetación. De este modo se dispone de un instrumento de gestión adaptativa que a lo largo de los 3 años programados permitirá demostrar la eficacia de las actuaciones, proponer mejoras y generar pautas para otros proyectos similares