The Role of Microenviroment in Glioblastoma Progression and Resistance Development

El glioblastoma (GBM) es un tumor cerebral primario altamente heterogéneo, con una tasa de supervivencia muy baja. Recientemente se ha demostrado que su microentorno tumoral complejo tiene un papel esencial en la progresión del tumor y la respuesta a la terapia. Por lo tanto, es crucial identificar todos los componentes y sus interacciones, e incorporarlos en modelos in vitro utilizados para estudios sobre GBM y el desarrollo de nuevas terapias. El desarrollo de nuevas tecnologías en las últimas décadas ha asegurado el progreso en ambos campos mencionados. Diferentes técnicas multiómicas permiten una caracterización detallada de las muestras de los pacientes. Por otro lado, la evolución de las técnicas de cultivo celular y los procesos de fabricación permiten la creación de sistemas in vitro más fisiológicos que el cultivo tradicional en placas de Petri (organ on chip). El principal objetivo de esta tesis fue estudiar el papel del microentorno en la respuesta del GBM al tratamiento con temozolomida (TMZ). Se modificaron dispositivos microfluídicos, desarrollados previamente dentro del grupo, para estudiar el impacto de la concentración de oxígeno en la progresión de GBM. Se demostró que la hipoxia es esencial para la formación del núcleo necrótico y protege a las células del efecto de TMZ. Además, se mejoró el diseño del dispositivo microfluídico para permitir la creación de un sistema más avanzado y controlable. Igualmente, el cultivo de esferoides nos proporcionó un modelo valioso para los estudios de desarrollo de quimio-resistencia. Tras la aplicación de dos ciclos de tratamiento clínico con TMZ, se observó la aparición de una población de esferoides resistentes. Morfológicamente, esos esferoides eran una combinación de esferoides control y esferoides tratados, que tenían un patrón de expresión génica específico. Por último, se utilizó una nueva técnica de transcriptómica espacial para caracterizar mejor las muestras de pacientes con GBM, correlacionando su expresión génica con la ubicación histológica. Esto permitió la identificación de clusters transcriptómicos diferenciales dentro de tejidos aparentemente homogéneos, confirmando la alta heterogeneidad de este tumor, no solo en el aspecto morfológico sino también molecular. Glioblastoma (GBM) is a highly heterogeneous primary brain tumor, with a very low survival rate. It has been shown recently that the complex tumor microenvironment has an essential role in tumor progression and therapy response. Hence, it is crucial to identify all the components and their interactions, and incorporate them in in vitro models used for GBM studies and therapy development. The development of new technologies in the last decades ensured progress in both mentioned fields. Different multiomics techniques allow detailed characterization of the patient samples. On the other hand, the evolution of cell culture techniques and fabrication processes enables the creation of more physiological in vitro systems than traditional Petri dish culture (organ on chip). The main aim of this thesis was to study the role of the microenvironment in the response of GBM to temozolomide (TMZ) treatment. Microfluidic devices, previously developed within the group, were modified to study the impact of oxygen concentration on GBM progression. Hypoxia was shown to be essential for the necrotic core formation and it protected cells from the TMZ effect. Moreover, the microfluidic device design was improved to enable the creation of a more advanced and controllable system. Furthermore, spheroid culture gave us a valuable model for chemoresistance development studies. After the application of two clinical TMZ treatment cycles, the presence of a population of resistant spheroids was observed. Morphologically, those spheroids were a combination of control and treated spheroids, and they had a specific gene expression pattern. Last but not least, a new spatial transcriptomics technique was used to characterize better GBM patient samples correlating their gene expression with the histological location. It enabled the identification of differential transcriptomic clusters within apparently homogeneous tissues, confirming the high heterogeneity of this tumor, not only in a morphological aspect but also molecularly.<br /

Prevention of Bone Loss in a Model of Postmenopausal Osteoporosis through Adrenomedullin Inhibition

Despite recent advances in the understanding and treatment options for osteoporosis, this condition remains a serious public health issue. Adrenomedullin (AM) is a regulatory peptide with reported activity on bone remodeling. To better understand this relationship we built an inducible knockout for AM. An outstanding feature of knockout mice is their heavier weight due, in part, to the presence of denser bones. The femur of knockout animals was denser, had more trabeculae, and a thicker growth plate than wild type littermates. The endocrine influence of AM on bone seems to be elicited through an indirect mechanism involving, at least, the regulation of insulin, glucose, ghrelin, and calcitonin gene-related peptide (CGRP). To confirm the data we performed a pharmacological approach using the AM inhibitor 16311 in a mouse model of osteoporosis. Ovariectomized females showed significant bone mass loss, whereas ovariectomized females treated with 16311 had similar bone density to sham operated females. In conclusion, we propose the use of AM inhibitors for the treatment of osteoporosis and other conditions leading to the loss of bone mass

La visita a personas privadas de libertad : primeros acercamientos a una población invisibilizada

Cuando pensamos en los efectos que produce la pena de prisión, usualmente consideramos las afectaciones que produce en personas privadas de la libertad. No obstante, el traslado de las cárceles de Córdoba hacia las afueras de la ciudad y la impermeabilidad de los muros de la cárcel ha hecho emerger la necesidad de reestructuración de nuestro campo de análisis, permitiendo observar una problemática invisibilizada: el sufrimiento que produce a familiares y allegadxs de sujetxs privadxs de libertad las condiciones actuales de la situación de la visita, debido a los rituales y ceremonias institucionales que deben atravesar. Desde la sociología clínica, nos interesa la vivencia de familiares y allegadxs y lo que tienen para decir sobre este fenómeno social que los involucra. Por ello, en esta presentación nos interesa discutir las diferentes estrategias metodológicas de establecer relación con esta población teniendo en cuenta las contingencias del encuentro en la situación de la visita. En la tentativa de abordar esta complejidad, concretamos observaciones no participantes y conversaciones informales con ellxs en la terminal donde parten los colectivos hacia la cárcel de Bouwer, viajando con ellxs ocasionalmente. Los primeros resultados revelan la vivencia de un sufrimiento psicosocial producido por prácticas institucionales (requisa, traslados) y sociales (vergüenza, estigma) que se naturalizan por la insistencia en lo cotidiano de situaciones denigrantes para estxs sujetxs, quienes manifiestan una necesidad concreta de ser escuchadxs por las diversas agencias del Estado. A raíz de este primer acercamiento construimos la noción de espacio carcelar, desde la cual consideramos la relación adentro-afuera de la cárcel como un continuo, cuyos efectos poseen un alcance indeterminado. De esta forma, el espacio carcelar afecta tanto a quienes se encuentran dentro de las paredes de la cárcel, como la de sus familiares y allegadxs quienes no quedan por fuera de sus efectos deteriorantes.Fil: Páez, José Ignacio. Universidad Nacional de CórdobaFil: Ochoa Valor, María Victoria. Universidad Nacional de Córdob

Las caminatas aleatorias no son de este mundo. Teoría y revisión bibliográfica sobre evidencia empírica.

La evidencia empírica presentada en relación con la hipótesis de que los retornos de los activos financieros siguen un proceso de caminata aleatoria soporta la afirmación de que éstas no son de este mundo. Independientemente de que el estudio se haya realizado en un mercado desarrollado o en uno emergente, la conclusión es la misma. Se rechaza la hipótesis de caminata aleatoria para todos los mercados, pues se evidencia la presencia de autocorrelación en las distintas series analizadas y, ciertamente, los retornos no siguen una distribución definida, independiente e idéntica, mucho menos una distribución normal. La diferencia entre mercados desarrollados y emergentes radica más bien en la magnitud de la dependencia serial, que por ser pequeña no permite la obtención de ganancias extraordinarias en los primeros.The empirical evidence gathered in this survey related to the hypothesis that stock returns follow a random walk, led us to the conclusion that random walks are not from this world. Besides the fact that the study was performed in a developed or an emerging market, the conclusion is the same. The random walk hypothesis is rejected since the series of stock returns covered by these studies do not follow an identical, independent distribution, and these exhibit some level of autocorrelation. The difference between developed and emerging markets is rather due to the magnitude of the serial dependence which prevents agents from obtaining excess returns in the first type of markets

Expectile depth: Theory and computation for bivariate datasets

Expectiles are the solution to an asymmetric least squares minimization problem for univariate data. They resemble the quantiles, and just like them, expectiles are indexed by a level α in the unit interval. In the present paper, we introduce and discuss the main properties of the (multivariate) expectile regions, a nested family of sets, whose instance with level 0 < α ≤ 1/2 is built up by all points whose univariate projections lie between the expectiles of levels α and 1 − α of the projected dataset. Such level is interpreted as the degree of centrality of a point with respect to a multivariate distribution and therefore serves as a depth function. We propose here algorithms for determining all the extreme points of the bivariate expectile regions as well as for computing the depth of a point in the plane. We also study the convergence of the sample expectile regions to the population ones and the uniform consistency of the sample expectile depth. Finally, we present some real data examples for which the Bivariate Expectile Plot (BExPlot) is introduced.This research was partially supported by the Spanish Ministry of Science and Innovation under grant ECO2015-66593-P

Multivariate expectile trimming and the BExPlot

Expectiles are the solution to an asymmetric least squares minimization problem for univariate data. They resemble some similarities with the quantiles, and just like them, expectiles are indexed by a level α. In the present paper, we introduce and discuss the main properties of the expectile multivariate trimmed regions, a nested family of sets, whose instance with trimming level α is built up by all points whose univariate projections lie between the expectiles of levels α and 1 − α of the projected dataset. Such trimming level is interpreted as the degree of centrality of a point with respect to a multivariate distribution and therefore serves as a depth function. We study here the convergence of the sample expectile trimmed regions to the population ones and the uniform consistency of the sample expectile depth. We also provide efficient algorithms for determining the extreme points of the expectile regions as well as for computing the depth of a point in R2. These routines are based on circular sequence constructions. Finally, we present some real data examples for which the Bivariate Expectile Plot (BExPlot) is introduced.This research was partially supported by the Spanish Ministry of Science and Innovation under grant ECO2015-66593-P

Data depth and multiple output regression, the distorted M-quantiles approach

For a univariate distribution, its M-quantiles are obtained as solutions to asymmetric minimization problems dealing with the distance of a random variable to a fixed point. The asymmetry refers to the different weights for the values of the random variable at either side of the fixed point. We focus on M-quantiles whose associated losses are given in terms of a power. In this setting, the classical quantiles are obtained for the first power, while the expectiles correspond to quadratic losses. The M-quantiles considered here are computed over distorted distributions, which allows to tune the weight awarded to the more central or peripheral parts of the distribution. These distorted M-quantiles are used in the multivariate setting to introduce novel families of central regions and their associated depth functions, which are further extended to the multiple output regression setting in the form of conditional regression regions and conditional depths

In vitro growth of human follicles: current and Future Perspectives

Ovarian tissue cryopreservation is gaining importance as a successful method to restore fertility to girls and young women at high risk of sterility. However, there are concerns regarding the safety of transplantation after ovarian tissue cryopreservation due to the high risk of reintroducing cancer cells and causing disease recurrence. In these cases, the development of culture systems that support oocyte development from the primordial follicle stage is required. Notable achievements have been reached in human follicle in vitro growth in the past decade. Currently, systems for the in vitro culture of ovarian tissue are based on two-dimensional substrates that do not support the survival of follicles or recapitulate the mechanical heterogenicity in the mammalian ovary. Recognition of the importance of special arrangements between cells has spurred research in three-dimensional culture systems, and the provision of a precise culture system that maximizes the diffusion of nutrients and gases through the follicles has raised interest in advanced biomimetic models. The current review critically examines various culture systems employed for the in vitro development of follicles, with a particular focus on solutions utilizing Organ-on-a-Chip (OOC) technology. The emphasis on OOC technology underscores its role as a promising avenue in ensuring the successful cultivation and maintenance of follicular structures during the culture period

Estudio numérico de un tubo receptor de un colector cilindro parabólico mediante Fluent

En este trabajo se realiza un estudio termodinámico del tubo receptor de un colector solar cilindro parabólico, mediante el empleo de un modelo tridimensional. Se asume una distribución de radiación sobre el absorbedor no uniforme, y se utiliza el software de simulación “Fluent” para obtener los resultados finales. Para ello se modeliza el receptor del colector solar LS2 y se emplea el aceite térmico Syltherm 800 como fluido de trabajo. Igualmente, se analizan las diferencias de las soluciones obtenidas para otros aceites térmicos, como el Therminol 55, el Therminol VP1 y la sal orgánica Hitec XL, estudiando las diferencias en la temperatura de salida del fluido del receptor. Se obtienen unos resultados satisfactorios que suponen un avance más en esta línea de investigación.The present study investigates the thermodynamic processes in the receiver tube of a parabolic solar collector using a three-dimensional model. A non-uniform solar energy flux distribution is assumed, and the simulation software “Fluent” is used to calculate the final results. With this purpose, LS2 solar collector is modeled and Syltherm 800 oil is employed. Differences in the results obtained for other thermal oils, such as Therminol 55, Therminol VP1, and for the organic salt Hitec XL are also analysed, studying the differences in the outlet temperature of the fluid. Satisfactory results are obtained, what constitutes a step forward in this line of research.Ingeniería en Tecnologías Industriale

Escultura urbana. Chillida: el arquitecto del vacío

La arquitectura y la escultura han estado ligadas desde sus inicios hace ya miles de años. Esta relación ha ido evolucionando a lo largo de la historia. Es en el siglo pasado cuando ambas disciplinas, y en general todas las artes, evolucionan y transforman los conceptos de lo que hasta entonces se entendía como ‘arquitectura’ y ‘escultura’ desdibujando los límites que previamente las diferenciaban de forma clara. En este trabajo de investigación se estudiará, a través de la obra del escultor Eduardo Chillida, la transgresión de los límites entre ambas disciplinas. Se analizará el trabajo escultórico del autodenominado ‘arquitecto del vacío’ y su relación, no solo con la arquitectura como tal, sino también con la ciudad y su repercusión urbana. De este modo se espera encontrar las claves proyectuales que el artista utilizaba para su creación y que de alguna manera se puedan extrapolar a la proyectación arquitectónica.Architecture and sculpture have been linked since their beginnings thousands of years ago. This relationship has evolved throughout history. It was in the last century when both disciplines, and in general all the arts, evolved and transformed the concepts of what was previously understood as ‘architecture’ and ‘sculpture’, blurring the limits that previously clearly differentiated them. This research project will study, through the work of the sculptor Eduardo Chillida, the transgression of the limits between the two disciplines. It will analyse the sculptural work of the self-styled ‘architect of the void’ and his relationship, not only with architecture as such, but also with the city and its urban repercussions. In this way it is hoped to find the design keys that the artist used for his creations and which can be extrapolated in some way to architectural design.Universidad de Sevilla. Grado en Fundamentos de la Arquitectur