Dual regulation of P-glycoprotein expression by Trichostatin A in cancer cell lines

Background. It has been reported that the histone deacetylase inhibitor (iHDAc) trichostatin A (TSA) induces an increase in MDR1 gene transcription (ABCB1). This result would compromise the use of iHDACs in combination with other cytotoxic agents that are substrates of P-glycoprotein (Pgp). It has also been reported the use of alternative promoters by the ABCB1 gene and the existence of a traslational control of Pgp protein. Finally, the ABCB1 gene is located in a genetic locus with the nested gene RUNDC3B in the complementary DNA strand, raising the possibility that RUNDC3B expression could interfere with ABCB1 alternative promoter regulation. Methods. A combination of RT-PCR, real time RT-PCR, Western blot and drug accumulation assays by flow cytometry have been used in this study. Results. The iHDACs-induced increase in MDR1 mRNA levels is not followed by a subsequent increase in Pgp protein levels or activity in several pancreatic and colon carcinoma cell lines, suggesting a traslational control of Pgp in these cell lines. In addition, the MDR1 mRNA produced in these cell lines is shorter in its 5' end that the Pgp mRNA produced in cell lines expressing Pgp protein. The different size of the Pgp mRNA is due to the use of alternative promoters. We also demonstrate that these promoters are differentially regulated by TSA. The translational blockade of Pgp mRNA in the pancreatic carcinoma cell lines could be related to alterations in the 5' end of the MDR1 mRNA in the Pgp protein expressing cell lines. In addition, we demonstrate that the ABCB1 nested gene RUNDC3B expression although upregulated by TSA is independent of the ABCB1 alternative promoter used. Conclusions. The results show that the increase in MDR1 mRNA expression after iHDACs treatment is clinically irrelevant since this mRNA does not render an active Pgp protein, at least in colon and pancreatic cancer cell lines. Furthermore, we have demonstrated that TSA in fact, differentially regulates both ABCB1 promoters, downregulating the upstream promoter that is responsible for active P-glycoprotein expression. These results suggest that iHDACs such as TSA may in fact potentiate the effects of antitumoral drugs that are substrates of Pgp. Finally, we have also demonstrate that TSA upregulates RUNDC3B mRNA independently of the ABCB1 promoter in use.

Robust Solutions of MultiObjective Linear Semi-Infinite Programs under Constraint Data Uncertainty

The multiobjective optimization model studied in this paper deals with simultaneous minimization of finitely many linear functions subject to an arbitrary number of uncertain linear constraints. We first provide a radius of robust feasibility guaranteeing the feasibility of the robust counterpart under affine data parametrization. We then establish dual characterizations of robust solutions of our model that are immunized against data uncertainty by way of characterizing corresponding solutions of robust counterpart of the model. Consequently, we present robust duality theorems relating the value of the robust model with the corresponding value of its dual problem.

Palladium and organocatalysis: an excellent recipe for asymmetric synthesis

The dual activation of simple substrates by the combination of organocatalysis and palladium catalysis has been successfully applied in a variety of different asymmetric transformations. Thus, the asymmetric a-allylation of carbonyl compounds, a-fluorination of acyl derivatives, decarboxylative protonation of β-dicarbonyl compounds, cyclization reactions of alkynyl carbonyl compounds and β-functionalization of aldehydes have been efficiently achieved employing this double-catalytic methodology.

Dirección estratégica de la asignatura Dirección Estratégica de las Tecnologías de la Información

¿Se pueden utilizar las habilidades, las técnicas y los principios de la dirección estratégica en el diseño y ejecución de la programación docente de una asignatura? Esta es la pregunta que nos planteamos al diseñar la asignatura Dirección Estratégica de las Tecnologías de la Información perteneciente al Máster Universitario en Ingeniería Informática de la Universidad de Alicante. Estas técnicas las aplicaremos a aspectos clave de la innovación educativa: contrato pedagógico, objetivos, evaluación, trabajo en equipo y comunicación oral. Algunas de las propuestas innovadoras, que tienen el doble objetivo de ser un instrumento de la asignatura pero al mismo tiempo recoger aspectos de dirección y de mejora continua, son el SLA (“Service Level Agreement”) de aprendizaje, las actas de aprendizaje, el análisis de tendencias en las TI y el espacio para la creatividad. Tras dos cursos académicos de ajuste de la propuesta docente, en el curso 2014-2015 hemos analizado el nivel de satisfacción de los estudiantes con la misma y la autoevaluación crítica de los profesores que la han impartido. Los resultados han sido muy satisfactorios, con comentarios del estilo “ha sido una experiencia de aprendizaje efectivo”. Los estudiantes agradecen que los profesores prediquemos con el ejemplo. Nos hace más humanos y más creíbles.

New glimpses on convex infinite optimization duality

Given a convex optimization problem (P) in a locally convex topological vector space X with an arbitrary number of constraints, we consider three possible dual problems of (P), namely, the usual Lagrangian dual (D), the perturbational dual (Q), and the surrogate dual (Δ), the last one recently introduced in a previous paper of the authors (Goberna et al., J Convex Anal 21(4), 2014). As shown by simple examples, these dual problems may be all different. This paper provides conditions ensuring that inf(P)=max(D), inf(P)=max(Q), and inf(P)=max(Δ) (dual equality and existence of dual optimal solutions) in terms of the so-called closedness regarding to a set. Sufficient conditions guaranteeing min(P)=sup(Q) (dual equality and existence of primal optimal solutions) are also provided, for the nominal problems and also for their perturbational relatives. The particular cases of convex semi-infinite optimization problems (in which either the number of constraints or the dimension of X, but not both, is finite) and linear infinite optimization problems are analyzed. Finally, some applications to the feasibility of convex inequality systems are described.