12 resultados para pro-drug
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Background -- N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a synthetic retinoid with potent pro-apoptotic activity against several types of cancer, but little is known regarding mechanisms leading to chemoresistance. Ceramide and, more recently, other sphingolipid species (e.g., dihydroceramide and dihydrosphingosine) have been implicated in 4-HPR-mediated tumor cell death. Because sphingolipid metabolism has been reported to be altered in drug-resistant tumor cells, we studied the implication of sphingolipids in acquired resistance to 4-HPR based on an acute lymphoblastic leukemia model. Methods -- CCRF-CEM cell lines resistant to 4-HPR were obtained by gradual selection. Endogenous sphingolipid profiles and in situ enzymatic activities were determined by LC/MS, and resistance to 4-HPR or to alternative treatments was measured using the XTT viability assay and annexin V-FITC/propidium iodide labeling. Results -- No major crossresistance was observed against other antitumoral compounds (i.e. paclitaxel, cisplatin, doxorubicin hydrochloride) or agents (i.e. ultra violet C, hydrogen peroxide) also described as sphingolipid modulators. CCRF-CEM cell lines resistant to 4-HPR exhibited a distinctive endogenous sphingolipid profile that correlated with inhibition of dihydroceramide desaturase. Cells maintained acquired resistance to 4-HPR after the removal of 4-HPR though the sphingolipid profile returned to control levels. On the other hand, combined treatment with sphingosine kinase inhibitors (unnatural (dihydro)sphingosines ((dh)Sph)) and glucosylceramide synthase inhibitor (PPMP) in the presence or absence of 4-HPR increased cellular (dh)Sph (but not ceramide) levels and were highly toxic for both parental and resistant cells. Conclusions -- In the leukemia model, acquired resistance to 4-HPR is selective and persists in the absence of sphingolipid profile alteration. Therapeutically, the data demonstrate that alternative sphingolipid-modulating antitumoral strategies are suitable for both 4-HPR-resistant and sensitive leukemia cells. Thus, whereas sphingolipids may not be critical for maintaining resistance to 4-HPR, manipulation of cytotoxic sphingolipids should be considered a viable approach for overcoming resistance.
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[ES] En este trabajo se estudia gár como marcador del discurso en un corpus del griego ático, el discurso Pro corona de Demóstenes. Gár introduce secciones informativas tanto en el nivel local como en el global. En el primero añade información complementaria, mientras que en el segundo indica la introducción de un nuevo tema como desarrollo de una información preliminar. La función común de gár en los dos casos es marcar la información que introduce como suplementaria.
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3 cartas (mecanografiadas) ; entre 220x340mm y 220x310mm. Ubicación: Caja 1 - Carpeta 11
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Introduction: Acinetobacter baumannii is opportunistic in debilitated hospitalised patients. Because information from some South American countries was previously lacking, this study examined the emergence of multi-resistant A. baumannii in three hospitals in Cochabamba, Bolivia, from 2008 to 2009. Methodology: Multiplex PCR was used to identify the main resistance genes in 15 multi-resistant A. baumannii isolates. RT-PCR was used to measure gene expression. The genetic environment of these genes was also analysed by PCR amplification and sequencing. Minimum inhibitory concentrations were determined for key antibiotics and some were determined in the presence of an efflux pump inhibitor, 1-(1-napthylmethyl) piperazine. Results: Fourteen strains were found to be multi-resistant. Each strain was found to have the bla(OXA-58) gene with the ISAba3-like element upstream, responsible for over-expression of the latter and subsequent carbapenem resistance. Similarly, ISAba1, upstream of the bla(ADC) gene caused over-expression of the latter and cephalosporin resistance; mutations in the gyrA(Ser83 to Leu) and parC (Ser-80 to Phe) genes were commensurate with fluoroquinolone resistance. In addition, the adeA, adeB efflux genes were over-expressed. All 15 isolates were positive for at least two aminoglycoside resistance genes. Conclusion: This is one of the first reports analyzing the multi-drug resistance profile of A. baumannii strains isolated in Bolivia and shows that the over-expression of thebla(OXA-58), bla(ADC) and efflux genes together with aminoglycoside modifying enzymes and mutations in DNA topoisomerases are responsible for the multi-resistance of the bacteria and the subsequent difficulty in treating infections caused by them.
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El objetivo general que se pretende alcanzar con la realización de este proyecto, consiste en el diseño del sistema de suspensión trasera regulable y el prediseño de un basculante para una motocicleta de competición de 250cc y 4 tiempos, englobado dentro de la competición MotoStudent promovida por la Fundación Moto Engineering Foundation. Más concretamente se pretende diseñar un sistema de suspensión con un buen comportamiento dinámico que facilite el manejo de la moto, regulable para que se pueda adaptar a las características de los diferentes circuitos y a la forma de conducción de los pilotos, y el prediseño de un basculante con una buena relación rigidez - peso.
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[ES]Mediante este trabajo se va a diseñar un mecanismo para crear un sistema de suspensión progresiva para la suspensión trasera de una motocicleta a partir de un muelle lineal. El muelle introducido en la suspensión será lineal, por lo tanto, tendrá una sola rigidez, constante y la cual delimita el muelle, pero gracias a un mecanismo diseñado especialmente para la suspensión trasera de una moto, se va conseguir que la rigidez varíe. El mecanismo utilizado para este trabajo se llama Pro-Link y la empresa que lo emplea es Honda. Para ello, se creará un esquema del mecanismo en sí y tras un análisis cinemático mediante el programa Creo Parametric, y haciendo varios cambios en el sistema para ajustarlo a la mejor progresividad posible, se obtendrá la gráfica en la que se observará la curva que marca la rigidez progresiva. Esto es, se verá la evolución de la nueva rigidez dependiendo de la oscilación vertical de la rueda. Por otra parte, gracias a un análisis dinámico del mismo programa se conseguirán las reacciones del sistema y se calcularán los elementos auxiliares de éste para el buen funcionamiento del mismo. Finalmente, se creará el diseño del triángulo y un diseño preliminar del basculante mediante el método de elementos finitos del programa.
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El objetivo de este proyecto ha sido el de diseñar un sistema de suspensión englobado en el ámbito de la competición interuniversitaria MotoStudent. Además de la normativa de la competición, dicha suspensión debe cumplir una serie de requisitos extra impuestos por el equipo de MotoStudent de la ETSI de Bilbao. Las características principales de la suspensión en cuestión deben ser las siguientes: La rigidez del sistema de suspensión debe ser progresiva, de forma que se comporte como una suspensión blanda a bajas solicitaciones, y como una suspensión dura a altas solicitaciones. A fin de poder adaptar la suspensión de la moto a diferentes circuitos, el esta deberá estar dotada de un sistema de regulación. Para ello el sistema de suspensión elegido es el sistema por bieletas tipo Pro- Link, cuya principal característica es que, en dicha solución, el balancín no solo tiene movimiento angular, sino que tiene también movimiento lineal, de forma que es mucho más versátil a la hora de diseñar. Figura[
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Background: Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings: This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: "NICUs description - Level of care'' (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience'' (12), "Scientific competencies and area of expertise'' (8), "Quality Management'' (16), "Training and educational capacity'' (8) and "Public involvement'' (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion: A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points: 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - "NICUs description - Level of care'' (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience'' (12), "Scientific competencies and area of expertise'' (8), "Quality Management'' (16), "Training and educational capacity'' (8) and "Public involvement'' (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network.
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172 p.
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237 p.
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208 p.
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César Fornis, Julián Gallego, Pedro López Barja, Miriam Valdés (eds.)
