SOCIAL AND BIOLOGICAL DETERMINANTS OF SHORT-TERM GROWTH VELOCITY AMONG PRESCHOOLERS OF RURAL GUATEMALA: A PATH ANALYSIS APPROACH (WEIGHT-GAIN, IRON DEFICIENCY, GASTROINTESTINAL SYMPTOMS)

This dissertation develops and tests through path analysis a theoretical model to explain how socioeconomic, socioenvironmental, and biologic risk factors simultaneously influence each other to further produce short-term, depressed growth in preschoolers. Three areas of risk factors were identified: child's proximal environment, maturational stage, and biological vulnerability. The theoretical model represented both the conceptual framework and the nature and direction of the hypotheses. Original research completed in 1978-80 and in 1982 provided the background data. It was analyzed first by nested-analysis of variance, followed by path analysis. The study provided evidence of mild iron deficiency and gastrointestinal symptomatology in the etiology of depressed, short-term weight gain. Also, there was evidence suggesting that family resources for material and social survival significantly contribute to the variability of short-term, age-adjusted growth velocity. These results challenge current views of unifocal intervention, whether for prevention or control. For policy formulations, though, the mechanisms underlying any set of interlaced relationships must be decoded. Theoretical formulations here proposed should be reassessed under a more extensive research design. It is suggested that studies should be undertaken where social changes are actually in progress; otherwise, nutritional epidemiology in developing countries operates somewhere between social reality and research concepts, with little grasp of its real potential. The study stresses that there is a connection between substantive theory, empirical observation, and policy issues. ^

BIM MEDIATES IMATINIB-INDUCED APOPTOSIS OF GASTROINTESTINAL STROMAL TUMORS: TRANSLATIONAL IMPLICATIONS

Gastrointestinal stromal tumors (GISTs) are oncogene-addicted cancers driven by activating mutations in the genes encoding receptor tyrosine kinases KIT and PDGFR-α. Imatinib mesylate, a specific inhibitor of KIT and PDGFR-α signaling, delays progression of GIST, but is incapable of achieving cure. Thus, most patients who initially respond to imatinib therapy eventually experience tumor progression, and have limited therapeutic options thereafter. To address imatinib-resistance and tumor progression, these studies sought to understand the molecular mechanisms that regulate apoptosis in GIST, and evaluate combination therapies that kill GISTs cells via complementary, but independent, mechanisms. BIM (Bcl-2 interacting mediator of apoptosis), a pro-apoptotic member of the Bcl-2 family, effects apoptosis in oncogene-addicted malignancies treated with targeted therapies, and was recently shown to mediate imatinib-induced apoptosis in GIST. This dissertation examined the molecular mechanism of BIM upregulation and its cytotoxic effect in GIST cells harboring clinically-representative KIT mutations. Additionally, imatinib-induced alterations in BIM and pro-survival Bcl-2 proteins were studied in specimens from patients with GIST, and correlated to apoptosis, FDG-PET response, and survival. Further, the intrinsic pathway of apoptosis was targeted therapeutically in GIST cells with the Bcl-2 inhibitor ABT-737. These studies show that BIM is upregulated in GIST cells and patient tumors after imatinib exposure, and correlates with induction of apoptosis, response by FDG-PET, and disease-free survival. These studies contribute to the mechanistic understanding of imatinib-induced apoptosis in clinically-relevant models of GIST, and may facilitate prediction of resistance and disease progression in patients. Further, combining inhibition of KIT and Bcl-2 induces apoptosis synergistically and overcomes imatinib-resistance in GIST cells. Given that imatinib-resistance and GIST progression may reflect inadequate BIM-mediated inhibition of pro-survival Bcl-2 proteins, the preclinical evidence presented here suggests that direct engagement of apoptosis may be an effective approach to enhance the cytotoxicity of imatinib and overcome resistance.

ANTI-TUMOR EFFECTS OF THE NOTCH PATHWAY IN GASTROINTESTINAL STROMAL TUMORS

Gastrointestinal Stromal Tumors (GIST) are sarcomas driven by gain-of-function mutations of KIT or PDGFRA. Although, the introduction of tyrosine kinase inhibitors has dramatically changed the history of this disease, evidences emerge that inhibition of KIT or PDGFRA are not sufficient to cure patients. The developmental pathway Notch has a critical role in the cell fate, regulating cell proliferation and differentiation. Dysregulation of Notch pathway has been implicated in a wide variety of cancers functioning as a tumor promoter or a tumor suppressor in a cell context dependent manner. Given that Notch activation deregulates the morphogenesis of mesenchymal cells in the GI track, that Notch acts as a tumor suppressor in neuroendocrine tumors, and finally that the cell of origin of GIST are the Interstitial Cell of Cajal that arise from a mesenchymal origin with some neuroendocrine features, we hypothesized that Notch pathway signaling may play a role in growth, survival and differentiation of GIST cells. To test this hypothesis, we genetically and pharmacologically manipulated the Notch pathway in human GIST cells. In this study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) expression potently induced growth arrest and downregulated KIT expression. We have performed a retrospective analysis of 15 primary GIST patients and found that high mRNA level of Hes1, a major target gene of Notch pathway, correlated with a significantly longer relapse-free survival. Therefore, we have established that treatment with the FDA approved histone deacetylase inhibitor SAHA (Vorinostat) caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch with dominant negative Hes-1 as well as pharmacological inhibition of Notch pathway with a γ-secretase inhibitor partially rescued GIST cells from SAHA treatment. Taken together these results identify anti-tumor effect of Notch1 and a negative cross-talk between Notch1 and KIT pathways in GIST. Consequently, we propose that activation of this pathway with HDAC inhibitors may be a potential therapeutic strategy for GIST patients.

Economía de la regulación del tránsito

En este trabajo, se busca contribuir con elementos técnicos para la acertada regulación del tránsito en Mendoza. Específicamente se propone el análisis económico comparativo entre las leyes 6082 y 7680 utilizadas para regular el tránsito en la provincia. Un objetivo necesario de la regulación del tránsito es minimizar la cantidad y gravedad de las colisiones. El propósito de este trabajo es determinar si la ley 7680 alcanzará este objetivo eficientemente en relación a su antecesora. En el primer capítulo se desarrolla la justificación económica de la intervención del tránsito. Para ello se modela el comportamiento de usuarios y autoridades, se establece como marco teórico el enfoque de la Nueva Economía Institucional, se tiene presente la teoría económica de la regulación y se explicitan pautas para medir el impacto económico de los cambios en el sistema normativo. En el apartado dos se exponen características de las colisiones en Mendoza, se plantea una función de producción de colisiones, se detallan las variables de control y se proponen indicadores de la eficacia de la regulación. En el tercer apartado se comenta la evolución de la regulación mendocina desde 1978 hasta 2011, se propone una explicación del fracaso de la ley 6082 y se analizan costos y beneficios de la entrada en vigencia de la ley 7680. En el capítulo cuatro, se comentan aspectos de la regulación que jamás han sido criticados por la Legislatura aunque son optimizables desde la perspectiva económica. En el capítulo cinco se exponen resultados y conclusiones. Finalmente se acompaña un Anexo que mediante cuadros, tablas y gráficos complementa la exposición.

Andrés Neuman : Una literatura en tránsito

La literatura nos ha dado algunos ejemplos de escritores que manifiestan su pertenencia a dos orillas: una española y una argentina, que escriben desde los márgenes y borran, desatienden, niegan la posibilidad de pensarse desde un único lugar. Este es el caso de Andrés Neuman (1977), argentino, ahora nacionalizado español, partícipe ya de un canon literario y cultural disputado que piensa, lee, y escribe desde esta doble identidad. En este trabajo me propongo analizar la obra narrativa de Andrés Neuman en virtud de una estética afianzada en lo breve y en una tradición literaria en continuo tránsito y que hace de esta transitoriedad su propia esencia

Las prácticas profesionales de formación como experiencias de pasaje y tránsito identitario

El presente artículo tiene por objeto compartir algunas ideas sobre las prácticas profesionales de formación a partir de relatos de estudiantes y referencias teóricas que replantean algunos supuestos generalizados en el campo de la formación profesional. Con la intención de interrogar la imagen que muchas veces se plantea de las prácticas como ámbitos de integración y aplicación de saberes teóricos y procedimentales, los relatos e itinerarios teóricos propuestos en el texto, las muestran como tiempos de formación que suponen el abandono de una posición identitaria conocida -la de ser estudiante- para arriesgar allí otro rostro, otra palabra -la del profesional que quiere llegarse a ser-. En este tránsito se asoma algo del recién llegado, del extranjero, de aquel que emigra por primera vez de la propia casa para explorar otros mundos y dejarse sorprender en la difícil tarea de descubrirse a 'sí mismo' siendo 'otro'. En esta perspectiva, el artículo pretende aportar una mirada que abona la reflexión sobre los procesos de socialización y transmisión cultural que se desarrollan en las prácticas y sobre los efectos que esta experiencia genera en el plano identitario. Como corolario de este desarrollo plantea algunas consideraciones sobre la alternancia como estrategias de formación para el trabajo de claro potencial formativo y de alta complejidad en el plano organizativo y pedagógico