A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Las elecciones 2009, en perspectiva

Este trabajo es fundamentalmente una descripción del comportamiento electoral en los comicios de 2009. Para ello se adopta una perspectiva diacrónica que retrocede hasta 1994, año en que se realizaron las primeras elecciones libres, justas y competitivas de la historia salvadoreña. El examen recae en participación electoral, la competitividad de las elecciones, la concentración del voto, el formato del sistema de partidos, la polarización de la competencia, la fluidez de la oferta partidista y la volatividad electoral. También se adopta una visión comparatista al poner en perspectiva regional el sistema de partidos salvadoreño y contrastarlo con los sistemas de partidos del resto de Centroamérica. Finalmente el autor hace una breve reflexión sobre la coyuntura 2009-2014

Fluidez y volatilidad en la institucionalización de los sistemas de partidos (Notas metodológicas para su medición)

[ES] En este artículo se propone la necesidad teórica de realizar una distinción entre fluidez y volatilidad en los estudios sobre institucionalización de los sistemas de partidos. Se insiste en que son dos facetas de un mismo problema pero que deben ser estudiadas separadamente. Incluso una antes que la otra. Con este objetivo, el autor propone tres índices para medir la fluidez de los sistemas de partidos: la natalidad partidista (Np), la mortalidad partidista (Mp) y la fluidez (fp) que el sistema de partidos causa en el ámbito parlamentario. En términos empíricos, esos tres índices son calculados para los casos centroamericanos entre los cuales se constata cómo es posible encontrarse con sistemas fluidos (a nivel de la «oferta») y con baja volatilidad (a nivel de «demanda»). Ello es así, justamente, porque se trata de dos problemas distintos.[EN] This article suggest the need to do the theoretical and analytical distinction between fluidity and volatility in the study of the institucionalization of party system. They are two dimensions of the same problem, but should the studied separately, or, even better, one before the other. The author develops three indexes two measurs the degree of fluidity of party systems: the party birth rate index (Np), the party death rate index (Mp) and the index of fluidity (Fp) of the parliamentary party system. These three indexes are applied to analyse the Centroamerican party system. The results show that it is possible to find a conbination of fluid systems (at the level of the offer) with low levels of volatility (at the level of the demand). This is so, precisely because the two are different issues that should be addressed separately

Fluidez y volatilidad en la institucionalización de los sistemas de partidos (Notas metodológicas para su medición)

<p>RESUMEN: En este artículo se propone la necesidad teórica de realizar una distinción entre fluidez y volatilidad en los estudios sobre institucionalización de los sistemas de partidos. Se insiste en que son dos facetas de un mismo problema pero que deben ser estudiadas separadamente. Incluso una antes que la otra. Con este objetivo, el autor propone tres índices para medir la fluidez de los sistemas de partidos: la natalidad partidista (Np), la mortalidad partidista (Mp) y la fluidez (fp) que el sistema de partidos causa en el ámbito parlamentario.</p><p>En términos empíricos, esos tres índices son calculados para los casos centroamericanos entre los cuales se constata cómo es posible encontrarse con sistemas fluidos (a nivel de la «oferta») y con baja volatilidad (a nivel de «demanda»). Ello es así, justamente, porque se trata de dos problemas distintos.</p><p>ABSTRACT: This article suggest the need to do the theoretical and analytical distinction between fluidity and volatility in the study of the institucionalization of party system. They are two dimensions of the same problem, but should the studied separately, or, even better, one before the other. The author develops three indexes two measurs the degree of fluidity of party systems: the party birth rate index (Np), the party death rate index (Mp) and the index of fluidity (Fp) of the parliamentary party system.</p><p>These three indexes are applied to analyse the Centroamerican party system. The results show that it is possible to find a conbination of fluid systems (at the level of the offer) with low levels of volatility (at the level of the demand). This is so, precisely because the two are different issues that should be addressed separately.</p