874 resultados para STRENGTHENING MECHANISMS


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Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have been reported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a general agreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstream of EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However, there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKI efficacy. We recently monitored gene expression profiles and sub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin, epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cell sensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated (up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times) of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second, loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breast cancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells. In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene, oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 function also leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands, and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. The relevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypass the antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

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Durante los dos períodos de gobierno de Luis Inacio Da Silva en Brasil (2003-2010) el interés de este Estado se centró en la ampliación y fortalecimiento de su posición en Sudamérica a través de la lucha contra las amenazas que afectan su seguridad nacional. Puesto que muchas de estos detractores de la seguridad brasileña son compartidos con otras Estados en la región, destacándose entre estos el narcotráfico, tráfico de armas y la deforestación del Amazonas, el gobierno de Brasil dirigió su política exterior en materia de seguridad en Sudamérica a la lucha conjunta de estas amenazas, proponiendo mecanismos de defensa regionales con el fin de aumentar su liderazgo en la región y así poder aumentar su influencia en esta zona.

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Exposure to traumatic stress during childhood, in the form of abuse or neglect, is related to an increased vulnerability resulting in the development of several pathologies, this relation has been confi rmed by epidemiological studies; however, the neural mechanisms underlying such abnormalities are still unknown. Most of the research done has focused on the effects in the infant, and only recently it has begun to focus on the neurobiological changes in the abusive parents. In this article, I review some of the studies using animal models of early adverse trauma and present some of the data on neural changes. Further studies of brain abnormalities in abusive parents are still needed.

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Blood tissue is composed approximately in 45% by cells and its derivatives, with a life span of around 120 days for erythrocytes and 3 years for certain type of lymphocytes. This lost is compensated with the hematopoietic system activity and the presence of an immature primitive cell population known as Hematopoietic Stem Cells (HSCs) which perform the hematopoiesis, a process that is active from the beginning of the fetal life and produces near to 2 x 1011 eritrocytes and 1010 white blood cells per day (1). Hematopoietic Stem Cells are capable of both self-renewal and differentiation into multiple lineages, are located in a particular niche and are identified by their own cell surface markers, as the CD34 antigen. Recently it has been possible to advance in the understanding of self-renewal, differentiation and proliferation processes and in the involvement of the signaling pathways Hedgehog, Notch and Wnt. Studying the influence of these mechanisms on in vivo and in vitro behavior and the basic biology of HSCs, has given valuable tools for the generation of alternative therapies for hematologic disorders as leukemias.

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Los Estados recurren a la coordinación interagencial cuando enfrentan situaciones complejas como garantizar la legitimidad estatal en territorios recuperados militarmente. En el momento que dos o más entidades deciden cooperar, deben establecer mecanismos para la coordinación de sus acciones y relacionar los esfuerzos individuales con objetivos comunes. El gobierno Uribe ha definido como prioridad el establecimiento de instancias de coordinación interagencial para complementar la Política de Seguridad Democrática con acciones para fortalecer la gobernabilidad, legitimidad y confianza de los ciudadanos en el Estado, en el marco de la recuperación social del territorio.Este artículo (i) presenta una aproximación inicial a la teoría de coordinación interagencial y describe algunas experiencias internacionales y nacionales; (ii) define el fundamento legal y de política del trabajo cívico-militar coordinado en Colombia; (iii) presenta el trabajo para la recuperación social que realiza el Centro de Coordinación de Acción Integral de la Presidencia de la República –CCAI–, mostrando algunos avances en esta tarea; y (iv) finaliza concluyendo que la seguridad e inversión social no son excluyentes y deben ir de la mano, y es necesario consolidar y asegurar la sostenibilidad de la labor realizada.-----Modern states resort to interagency coordination when they face complex situations such as warranting state legitimacy in territories militarily reclaimed. When two or more agencies decide to cooperate, they must establish certain mechanisms to coordinate their actions and to unite individual efforts towards the achievement of common goals. One of the main priorities of President Uribe’s Administration is the establishment of interagency coordination groups to complement the Democratic Security Policy with actions aimed at strengthening governance, legitimacy and citizens’ trust in the State, all this within the general framework of the territories’ overall social recovery.This article (i) presents a first approach to interagency coordination theories and describes some relevant international and national experiences; (ii) defines the legal basis and policy framework behind the coordinated civil-military interagency work done in Colombia; (iii) presents the work being done by the Centro de Coordinación de Acción Integral de la Presidencia de la República (Comprehensive Action Coordination Center of the Colombian President’s Office, CCAI) for the social recovery of the national territory, highlighting some breakthroughs in this field; and (iv) concludes with the assertion that security issues and social investment should not be mutually exclusive, that they have to go hand in hand, and that it is necessary to consolidate and warrant the sustainability of the work done so far.

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El interés de este Estudio de Caso es investigar la manera en que la Misión de Paz de la ONU en Sierra Leona (UNAMSIL) redireccionó el programa Desarme, Desmovilización y Reintegración (DDR) hacia los niños soldados durante el post-conflicto en el país. Se analiza cómo a través de la coordinación de diferentes Agencias y Organizaciones Internacionales con UNAMSIL, el Gobierno y la Sociedad Civil hace posible que se refuerce el rol de los Interim Care Centers (ICCs) en donde se enfrentaron las necesidades esenciales de los menores excombatientes para lograr un mejor proceso de su desmovilización y reintegración. Se explica de igual forma, las diferentes herramientas que sirven para llevar a cabo la resolución del conflicto y la reconstrucción de la paz, enfocándose en el peacekeeping, peacemaking y peacebuilding, como mecanismos que ayudaron a crear un espacio seguro para los niños exsoldados. Por último, se exponen los alcances y límites de los ICCs con respecto a la reintegración de los menores excombatientes

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This paper studies the effect of strengthening democracy, as captured by an increase in voting rights, on the incidence of violent civil conflict in nineteenth-century Colombia. Empirically studying the relationship between democracy and conflict is challenging, not only because of conceptual problems in defining and measuring democracy, but also because political institutions and violence are jointly determined. We take advantage of an experiment of history to examine the impact of one simple, measurable dimension of democracy (the size of the franchise) on con- flict, while at the same time attempting to overcome the identification problem. In 1853, Colombia established universal male suffrage. Using a simple difference-indifferences specification at the municipal level, we find that municipalities where more voters were enfranchised relative to their population experienced fewer violent political battles while the reform was in effect. The results are robust to including a number of additional controls. Moreover, we investigate the potential mechanisms driving the results. In particular, we look at which components of the proportion of new voters in 1853 explain the results, and we examine if results are stronger in places with more political competition and state capacity. We interpret our findings as suggesting that violence in nineteenth-century Colombia was a technology for political elites to compete for the rents from power, and that democracy constituted an alternative way to compete which substituted violence.

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Este documento presenta los resultados del componente cuantitativo de la evaluación del Programa de Educación para la Sexualidad y Construcción de Ciudadanía (PESCC) del Ministerio de Educación Nacional de Colombia (MEN). Para identificar el efecto, la estrategia empírica explota la variación en la implementación del componente pedagógico del PESCC entre los colegios y la variación en el componente de fortalecimiento institucional del programa a nivel departamental. El principal hallazgo de este trabajo es que el PESCC mejora las prácticas docentes de planeación y los conocimientos de los estudiantes en servicios en salud sexual y reproductiva y en derechos humanos sexuales y reproductivos. No hay efectos significativos en otros índices de Conocimientos, Actitudes o Prácticas (CAP) de profesores o estudiantes.

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L'activació d'oxigen que té lloc en els éssers vius constitueix una font d'inspiració pel desenvolupament d'alternatives als oxidants tradicionals, considerats altament tòxics i nocius. En aquesta treball s'utilitzen compostos sintètics com a models del centre actiu de proteïnes dinuclears de coure i mononuclears de ferro de tipus no-hemo que participen en l'activació d'oxigen en els éssers vius. Els sistemes dinuclears de coure mostren un centre de tipus coure(III) bis(oxo) que és capaç de dur a terme l'ortho-hidroxilació de fenols de manera similar a la reacció que catalitza la proteïna tirosinasa. Per altra banda, els sistemes de ferro desenvolupats en aquest treball actuen com a models de les dioxigenases de Rieske i poden dur a terme l'hidroxilació estereoespecífica d'alcans i l'epoxidació i cis-dihidroxilació d'olefines utilitzant peròxid d'hidrogen com a agent oxidant. Tot plegat demostra que el desenvolupament de sistemes model constitueix una bona estratègia per l'estudi dels sistemes naturals.

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