Identificación de la función y el mecanismo molecular del factor de transcripción SOX9 como regulador de las células madre tumorales. Perspectivas terapéuticas

237 p.La desregulación de genes esenciales en el desarrollo embrionario y mantenimiento de las células madre parece ser crítica en el desarrollo de los tumores y en el mantenimiento de las células madre tumorales (CMT), que son la responsable de la iniciación tumoral, metástasis, recurrencia y resistencia a las terapias. Hemos identificado que la expresión del factor de transcripción SOX9 está enriquecida en las CMT y sus altos niveles en biopsias tumorales están asociados a menor supervivencia de los pacientes de glioblastoma (GBM). Mediante estudios de análisis de transcriptoma en CMT con silenciamiento de SOX9 hemos identificado que STAT3 y PML son dianas transcripcionales de SOX9. En línea con este resultado hemos identificado que la expresión de SOX9 está asociada a la de STAT3 y PML en CMT y en muestras de pacientes afectos con cáncer de mama y GBM. El silenciamiento genético individual de cada uno de ellos reduce significativamente propiedades malignas como la proliferación, capacidad de auto-renovación y la actividad tumorogénica tanto de las células tumorales, como de las CMT, demostrando que son necesarios para el mantenimiento de las CMT. Además, hemos demostrado que existe un bucle regulatorio entre ellos.Asimismo, hemos observado que inhibidores farmacológicos específicos de SOX9, STAT3 y PML silencian la actividad de las CMT y reducen la iniciación y progresión tumoral.Estos resultados demuestran que SOX9-STAT3-PML es un eje crítico en el mantenimiento de las CMT, postulando que su inhibición es una estrategia prometedora para combatir la resistencia a la quimioterapia en el caso de GBM, y la progresión metastásica en el caso de cáncer de mama

Identificación de la función y el mecanismo molecular del factor de transcripción SOX9 como regulador de las células madre tumorales. Perspectivas terapéuticas

237 p.La desregulación de genes esenciales en el desarrollo embrionario y mantenimiento de las células madre parece ser crítica en el desarrollo de los tumores y en el mantenimiento de las células madre tumorales (CMT), que son la responsable de la iniciación tumoral, metástasis, recurrencia y resistencia a las terapias. Hemos identificado que la expresión del factor de transcripción SOX9 está enriquecida en las CMT y sus altos niveles en biopsias tumorales están asociados a menor supervivencia de los pacientes de glioblastoma (GBM). Mediante estudios de análisis de transcriptoma en CMT con silenciamiento de SOX9 hemos identificado que STAT3 y PML son dianas transcripcionales de SOX9. En línea con este resultado hemos identificado que la expresión de SOX9 está asociada a la de STAT3 y PML en CMT y en muestras de pacientes afectos con cáncer de mama y GBM. El silenciamiento genético individual de cada uno de ellos reduce significativamente propiedades malignas como la proliferación, capacidad de auto-renovación y la actividad tumorogénica tanto de las células tumorales, como de las CMT, demostrando que son necesarios para el mantenimiento de las CMT. Además, hemos demostrado que existe un bucle regulatorio entre ellos.Asimismo, hemos observado que inhibidores farmacológicos específicos de SOX9, STAT3 y PML silencian la actividad de las CMT y reducen la iniciación y progresión tumoral.Estos resultados demuestran que SOX9-STAT3-PML es un eje crítico en el mantenimiento de las CMT, postulando que su inhibición es una estrategia prometedora para combatir la resistencia a la quimioterapia en el caso de GBM, y la progresión metastásica en el caso de cáncer de mama

A pharmacometrics model to define docetaxel target in early breast cancer

Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75–100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300–350 mg/m2). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.Fil: Aldaz, Azucena. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aramendía, José Manuel. Universidad de Navarra; Españ

A pharmacometrics model to define docetaxel target in early breast cancer

Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients

Simples de Cristo y comedia de santos: El santo negro Rosambuco de Lope de Vega.

En el presente trabajo se analiza una comedia del siglo de Oro tejida sobre el tema de los locos y simples de Cristo: El Santo negro Rosambuco de la ciudad de Palermo, de Lope de Vega. Tras situar el tema de los simples de Cristo en la tradición hagiográfica y ofrecer una breve semblanza sobre la figura del personaje del negro en la literatura castellana del Siglo de Oro, se plantea el estudio de la obra, atento a los detalles de su datación y de su relación con la biografía del santo, así como a la novedad de algunos pasajes añadidos por Lope y a los temas religiosos que afloran en sus páginas. <br /

Las huellas de Celestina. Alcahuetería y hechicería en la Tragicomedia y en tres obras celestinescas.

El siguiente Trabajo Fin de Grado pretende indagar el modo en el que las funciones de Celestina en la Tragicomedia de Rojas alcahuetería y hechicería fundamentalmente se transforman o evolucionan en la literatura celestinesca. Se estudia la huella de La Celestina en tres textos renacentistas: la Comedia Tidea, el Auto de Clarindo y la Penitencia de amor, que presentan una redefinición de los oficios de Celestina. Si en la Comedia Tidea y el Auto de Clarindo reaparece el tema de la magia, aunque esta no se muestra operativa en el primer caso, en la Penitencia de amor la labor de alcahuetería es asumida por los criados.<br /

Dos aproximaciones jurisprudenciales al problema de la maternidad subrogada: Tribunal Europeo de Derechos Humanos y Tribunal Supremo.

Se trata de analizar el problema que surge al realizar un contrato de maternidad subrogada en el extranjero y querer después inscribir a los menores en el Registros Civil español. El TS considera que este contrato es contrario al orden público y no se puede inscribir a los menores en cambio la DGRN si que acepta la inscripción si se cumplen ciertos requisitos. Se compara una Sentencia del TEDH similar al caso español, se trata de comprobar si el TS podría haber resuelto de la misma manera que el TEDH

Do Spanish students become more sustainable after the implementation of sustainable practices by universities?

Higher Education Institutions (HEIs) are a critical component to develop and promote sustainable solutions for both society and the planet. A challenge to HEIs is to provide students with the knowledge and skills required to achieve Sustainable Development (SD), as they are important stakeholders. In order for a person to take responsibility for a sustainable future, it is not only important to implement SDs in higher education, but to follow the progress of the individuals’ awareness of the sustainable world and lifestyle. This study aimed to analyze students of Universidad Autónoma de Madrid (UAM), focusing on their attitudes, behaviors, and level of knowledge concerning education for sustainable development (ESD), to better understand the situation of students in terms of learning and applying sustainability. The students’ perception of the University practices and initiatives, as well as pedagogical methodologies for promoting and learning SD, were also examined. An online survey was applied to undergraduate students from several faculties at UAM, and a sample of 504 students returned from a total population of 30,000 students. Descriptive and inferential analyses were carried out and included Chi-square tests, correlation analyses, and ANOVA analyses for independent and repeated measures. The results reveal good levels for the three dimensions (global Index > 3.5), with consistency demonstrating the highest correlation between attitudes and behaviors, although differences between faculties were identified. Knowledge has the highest score among all faculties. In addition, the results point to a need to better communicate the initiatives promoted, as well as to realign some learning methodologies with students’ preferences. The most important contributions of the paper are as follows: Shedding fresh light on the knowledge, attitudes, and behavioral dispositions of university students and improving strategies concerning education in higher education institutions. Furthermore, it is relevant to say that UAM has pushed sustainability in environmental management and education, so it is also important to assess the impact of these initiatives. Our research aimed to help understand how students incorporate sustainability into their attitudes and behaviors, and whether this incorporation depends on the type of faculty. It also makes it possible to verify whether the sustainability measures implemented by universities are identified and applied by their students.info:eu-repo/semantics/publishedVersio

Inter- and intracontinental migrations and local differentiation have shaped the contemporary epidemiological landscape of canine parvovirus in South America

Canine parvovirus (CPV) is a fast-evolving single-stranded DNA virus that causes one of the most significant infectious diseasesof dogs. Although the virus dispersed over long distances in the past, current populations are considered to be spatiallyconfined and with only a few instances of migration between specific localities. It is unclear whether these dynamicsoccur in South America where global studies have not been performed. The aim of this study is to analyze the patterns ofgenetic variability in South American CPV populations and explore their evolutionary relationships with global strains.Genomic sequences of sixty-three strains from South America and Europe were generated and analyzed using a phylodynamicapproach. All the obtained strains belong to the CPV-2a lineage and associate with global strains in four monophyleticgroups or clades. European and South American strains from all the countries here analyzed are representative of awidely distributed clade (Eur-I) that emerged in Southern Europe during 1990?98 to later spread to South America in theearly 2000s. The emergence and spread of the Eur-I clade were correlated with a significant rise in the CPV effective populationsize in Europe and South America. The Asia-I clade includes strains from Asia and Uruguay. This clade originated in Asia during the late 1980s and evolved locally before spreading to South America during 2009?10. The third clade (Eur-II)comprises strains from Italy, Brazil, and Ecuador. This clade appears in South America as a consequence of an early introductionfrom Italy to Ecuador in the middle 1980s and has experienced extensive local genetic differentiation. Some strainsfrom Argentina, Uruguay, and Brazil constitute an exclusive South American clade (SA-I) that emerged in Argentina in the1990s. These results indicate that the current epidemiological scenario is a consequence of inter- and intracontinentalmigrations of strains with different geographic and temporal origins that set the conditions for competition and local differentiationof CPV populations. The coexistence and interaction of highly divergent strains are the main responsible for thedrastic epidemiological changes observed in South America in the last two decades. This highlights the threat of invasionfrom external sources and the importance of whole-genome resolution to robustly infer the origin and spread of new CPVvariants. From a taxonomic standpoint, the findings herein show that the classification system that uses a single aminoacid to identify variants (2a, 2b, and 2c) within the CPV-2a lineage does not reflect phylogenetic relationships and is not suitableto analyze CPV evolution. In this regard, the identification of clades or sublineages within circulating CPV strains is thefirst step towards a genetic and evolutionary classification of the virus.Fil: Grecco, Sofia. Universidad de la República; UruguayFil: Iraola, Gregorio. Universidad de la República; UruguayFil: Decaro, Nicola. Università degli Studi di Bari; ItaliaFil: Alfieri, Alice. Universidade Estadual de Londrina; BrasilFil: Alfieri, Amauri. Universidade Estadual de Londrina; BrasilFil: Gallo Calderon, Marina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: da Silva, Ana Paula. Universidade Estadual de Londrina; BrasilFil: Name, Daniela. Universidad de la República. Facultad de Ciencias; UruguayFil: Aldaz, Jaime. Universidad Estatal de Bolivar; EcuadorFil: Calleros, Lucia. Universidad de la República. Facultad de Ciencias; UruguayFil: Marandino, Ana. Universidad de la República. Facultad de Ciencias; UruguayFil: Gonzalo, Tomas. Universidad de la República. Facultad de Ciencias; Urugua

Transport at Strong Coupling and Black Hole Dynamics

In this thesis we study aspects of transport in strongly coupled quantum systems with broken translational symmetry. Using holographic duality, we also examine the associated dynamical problem in asymptotically Anti-de Sitter, spatially modulated black holes. More precisely, in chapter 2 we consider the transport of conserved charges in spatially inhomogeneous quantum systems with a discrete lattice symmetry. When the DC conductivities are finite, we derive a set of generalised Einstein relations, relating the diffusion constants of the conserved charges to the DC conductivities and static susceptibilities. We also develop a long-wavelength expansion in order to explicitly construct the heat and charge diffusive modes within hydrodynamics on curved manifolds. In chapter 3 we used analogous techniques to construct the thermoelectric diffusive quasinormal modes in a large class of black hole spacetimes that are holographically dual to strongly coupled field theories in which spatial translations are broken explicitly. These modes satisfy a set of constraints on the black hole horizon, from which we find that their dispersion relations are given by the generalised Einstein relations. In chapter 4 we define a boost incoherent current in spontaneously modulated phases, and we show that in holographic theories, its DC conductivity can be obtained from solving a system of horizon Stokes equations