964 resultados para Friedrich II, Landgrave of Hesse-Cassel, 1720-1785.


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The human GSTP1 gene has been shown, conclusively, to be polymorphic. The three main GSTP1 alleles, GSTP1*A, GSTP1*B, and GSTP1*C, encode proteins which differ in the 3-dimensional structure of their active sites and in their function in phase II metabolism of carcinogens, mutagens, and anticancer agents. Although, it is well established that GSTP1 is over expressed in many human tumors and that the levels of GSTP1 expression correlate directly with tumor resistance to chemotherapy and inversely with patient survival, the significance of the polymorphic GSTP1 gene locus on tumor response to chemotherapy remains unclear. The goal of this project was to define the role and significance of the polymorphic GSTP1 gene locus in GSTP1-based tumor drug resistance and as a determinant of patient response to chemotherapy. The hypothesis to be tested was that the polymorphic GSTP1 gene locus will confer to tumors a differential ability to metabolize cisplatin resulting in a GSTP1 genotype-based sensitivity to cisplatin. The study examined: (a) whether the different GSTP 1 alleles confer different levels of cellular protection against cisplatin-induced cytotoxicity, (b) whether the allelic GSTP1 proteins metabolize cisplatin with different efficiencies, and (c) whether the GSTP1 genotype is a determinant of tumor response to cisplatin therapy. The results demonstrate that the GSTP1 alleles differentially protect tumors against cisplatin-induced apoptosis and clonogenic cell kill in the rank order: GSTP1*C > GSTP1*B > GSTP1*A. The same rank order was observed for the kinetics of GSTP1-catalyzed cisplatin metabolism, both in cell-free and cellular systems, to the rate-limiting monoglutathionyl-platinum metabolite, which was characterized, for the first time, by mass spectral analysis. Finally, this study demonstrates that both GSTP1 genotype and the level of GSTP1 expression significantly contribute to tumor sensitivity to cisplatin treatment. Overall, the results of this project show that the polymorphic GSTP1 gene locus plays a significant role in tumor sensitivity to cisplatin treatment. Furthermore, these studies have contributed to the overall understanding of the significance of the polymorphic GSTP1 gene locus in tumor resistance to cancer chemotherapy and have provided the basis for further investigations into how this can be utilized to optimize and individualize cancer chemotherapy for cancer patients. ^

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Advances in therapy for colorectal cancer have been hampered by development of resistance to chemotherapy. The Src family of protein tyrosine kinases has been associated with colorectal cancer development and progression. Activation of the prototypic member of the family, Src, occurs in advanced colorectal cancer and is associated with a worse outcome. This work tests the hypotheses that Src activation contributes to chemoresistance in some colon tumors and that this resistance can be overcome by use of Src inhibitors. The aims of the proposal were to (1) determine if constitutive Src activation is sufficient to induce oxaliplatin resistance; (2) evaluate the role of reactive oxygen species (ROS) in the activation of Src after oxaliplatin treatment; (3) determine the frequency of Src activation in liver metastases after oxaliplatin treatment; and (4) evaluate the safety, preliminary efficacy, and pharmacodynamics of the combination of dasatinib with oxaliplatin-based therapy in patients with metastatic colorectal cancer. ^ Using a panel of colon cancer cell lines and murine models, I demonstrate that administration of oxaliplatin, a commonly utilized chemotherapy for colorectal cancer, results in an increased activation of Src. The activation occurs acutely in some, but not all, colorectal carcinoma cell lines. Cell lines selected for oxaliplatin resistance are further increased in Src activity. Treatment of cell lines with dasatinib, a non-selective pharmacologic inhibitor of the Src family kinases synergistically killed some, but not all cell lines. Cell lines with the highest acute activation of Src after oxaliplatin administration were the most sensitive to the combination therapy. Previous work demonstrated that siRNA to Src increased sensitivity to oxaliplatin, suggesting that the effects of dasatinib are primarily due to its ability to inhibit Src in these cell lines. ^ To examine the mechanism underlying these results, I examined the effects of reactive oxygen species (ROS), as previous studies have demonstrated that platinum chemotherapeutics result in intracellular oxidative stress. I demonstrated that oxaliplatin-induced reactive oxygen species were higher in the cell lines with Src activation, relative to those in which Src was not activated. This oxaliplatin-induced Src activation was blocked by the administration of anti-oxidants, thereby demonstrating that synergistic killing between dasatinib and oxaliplatin was associated with the ability of the latter to generate ROS. ^ In a murine model of colorectal cancer metastasis to the liver, the combination of dasatinib and oxaliplatin was more effective in reducing tumor volume than either agent alone. However, when oxaliplatin resistant cell lines were treated with a combination of oxaliplatin and AZD0530, an inhibitor in the clinic with increased specificity for Src, no additional benefit was seen, although Src was activated by oxaliplatin and Src substrates were inhibited. The indolent growth of oxaliplatin-resistant cells, unlike the growth of oxaliplatin resistant tumors in patients, precludes definitive interpretation of these results. ^ To further explore Src activation in patients with oxaliplatin exposure and resistance, an immunohistochemistry analysis of tumor tissue from resected liver metastases of colorectal cancer was performed. Utilizing a tissue microarray, staining for phosphorylated Src and FAK demonstrated strong staining of tumor relative to stromal and normal liver. In patients recently exposed to oxaliplatin, there was increased FAK activation, supporting the clinical relevance of the prior preclinical studies. ^ To pursue the potential clinical benefit of the combination of Src inhibition with oxaliplatin, a phase IB clinical trial was completed. Thirty patients with refractory metastatic colorectal cancer were treated with a combination of 5-FU, oxaliplatin, an epidermal-growth factor receptor monoclonal antibody, and dasatinib. The recommended phase II dose of dasatinib was established, and toxicities were quantified. Pharmacodynamic studies demonstrated increased phosphorylation of the Src substrate paxillin after dasatinib therapy. Tumor biopsies were obtained and Src expression levels were quantitated. Clinical benefit was seen with the combination, including a response rate of 20% and disease control rate of 56%, prompting a larger clinical study. ^ In summary, although Src is constitutively activated in metastatic colorectal cancer, administration of oxaliplatin chemotherapy can further increase its activity, through a reactive oxygen species dependent manner. Inhibition of Src in combination with oxaliplatin provides additional benefit in vitro, in preclinical animal models, and in the clinic. Further study of Src inhibition in the clinic and identification of predictive biomarkers of response will be required to further advance this promising therapeutic target. ^

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El objetivo de este trabajo fue evaluar el efecto del riego complementario sobre el rendimiento de materia seca del cultivo de maíz. Se usó un diseño completamente al azar con 5 tratamientos y 4 repeticiones. Para efectuar la programación de los diferentes tratamientos de riego se dividió el ciclo del cultivo en tres etapas (precrítico, crítico y poscrítico). Para la determinación del momento de riego se realizó un balance hídrico con datos climáticos obtenidos de la Estación Meteorológica ubicada en el lugar del ensayo. El riego se efectuó con un equipo presurizado de avance lateral. El maíz cumplió su ciclo en 138 días en todos los tratamientos y requirió 1660,6 grados día para alcanzar madurez fisiológica. El rendimiento de materia seca tuvo diferencias significativas (a = 0,05) entre los distintos tratamientos regados y entre éstos y el testigo. Los valores extremos de producción fueron de 34.628 kg.ha-1 en el tratamiento 1 y 20.414 kg.ha-1 en el tratamiento sin riego. La cantidad de agua aplicada varió entre 360 y 300 mm y el agua total consumida en el ciclo del cultivo, según el balance hídrico, fue para los tratamientos con riego de 575 mm ± 15 mm y para el testigo sin riego de 308 mm. La eficiencia de uso de agua para materia seca tuvo diferencias significativas (a = 0,05) entre los tratamientos regados (5,7 kg.m-3) y no regados (6,6 kg.m-3). El índice de cosecha fue de 0,49.

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Por el éxito y trascendencia de sus eventos anteriores, el Instituto CIFOT siente la obligación de hacer conocer las principales conclusiones del II Seminario de Ordenamiento Territorial, el que comienza a marcar pautas a partir de las preocupaciones comunes, enfoques teórico-metodológicos prevalecientes en el Ordenamiento Territorial, la planificación Estratégica y Ambiental, como también sobre las prácticas de gestión de la información territorial. Se sintetiza la idea central de las conferencias Magistrales: - Dr. Juan Gastó- Pontificia Universidad Católica de Chile- presenta “ La Ordenación Territorial como eje del Desarrollo Rural", cuyo punto central es la imposibilidad de separar la problemática territorial urbana de la rural. - Dr. Eduardo Salinas- Universidad de La Habana , Cuba- en “El Ordenamiento Territorial como instrumento de la Planificación y Gestión Ambiental" establece la necesidad de una planificación sustentable ambientalmente, con una concepción sistémica y holística de los problemas. -Dra. Elsa Laurelli -Universidad de La Plata , Argentina- en “Nuevas Tendencias del Ordenamiento Territorial en una Economía de Mercado. Limitaciones y posibilidades" plantea coexistencia de áreas receptoras de IDE vs espacios degradados y con problemáticas sociales y reflexiona sobre el rol del Estado para atenuar los efectos del mercado en el territorio y la sociedad. - Dr. Pablo Ciccolella -UBA-, Argentina. En “ Desafíos y opciones en la Gestión Urbana bajo el Capitalismo Global: Planificación Estratégica y Desarrollo Económico-Territorial" alerta sobre la planificación llave en mano que genera un desarrollo elitista, banal y efímero. - Dr. Mariano Zamorano -Universidad Nacional de Cuyo, Mendoza- presenta “ Una propuesta de Regionalización de la Provincia de Mendoza sobre la base de la Lógica Territorial " destinada a optimizar la gestión municipal y provincial. Al II Seminario de Ordenamiento Territorial concurren alrededor de 140 personas y se exponen 43 trabajos en las siguientes áreas temáticas : - 1 Nuevas tendencias en el Ordenamiento territorial . - 2 Ambiente y Ordenamiento Territorial. - 3 El Ordenamiento Territorial en el ámbito urbano. - 4 El Ordenamiento Territorial en el ámbito rural. - 5 La gestión de la información en el Ordenamiento Territorial. - 6 El rol de las Instituciones en el Ordenamiento Territorial. Conclusiones De l rico debate e intercambio de ideas realizado durante el II Seminario, se extraen tres grandes temas: - La necesidad de una visión general y holística del territorio, evitando la fragmentación disciplinar. - La interdisciplina, como campo de convergencia de problemáticas complejas. La planificación estratégica como instancia participativa y visión integral del territorio. - La metodología para el Ordenamiento Territorial debe ser verdaderamente aplicada. No se puede seguir planificando con una racionalidad limitada en busca de una imagen objetivo rígida mientras el territorio, conformado por sistemas complejos y abiertos, está en constante cambio por exigencias propias de lo global. - Un Estado en retirada no contiene la estructura necesaria ni el consenso para imponerse en sociedades democráticas con dominio absoluto de tipo capitalista.

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