Impact of targeting MYC in metabolic reprogramming and differentiation of cancer

Alterations in several metabolic pathways due to increased energy and biomass demand, as consequence of the uncontrolled proliferation of cancer cells, is known as metabolic reprogramming. Mutations in tumor suppressor genes and oncogenes that initiate cancer development, are responsible directly and indirectly of the changes in major cellular energy production processes, including glycolysis, glutaminolysis, and lipid metabolism. Neuroblastoma (NB) is a solid tumor that develops extracranially in the sympathetic nervous system, and the most diagnosed cancer during the first year of life. Among several genetic alterations, MYCN-amplification occurs in approximately 25% of all cases, associated with poor survival rate. Although the MYCN protein plays a crucial role in NB progression, no inhibitors have been approved for clinical use, as targeting MYCN has proven to be challenging. Thus, other indirect strategies, such as targeting downstream processes controlled by MYCN including metabolism and differentiation, represent alternatives to overcome the drawbacks of directly targeting this oncoprotein. In clear cell renal cell carcinoma (ccRCC), loss of the von Hippel-Lindau (VHL) gene provokes constitutive activation of hypoxia inducible factors (HIFs). Due to disruptions in a myriad of metabolic pathways, and in part, as consequence of the continuous stabilization of HIFs, ccRCC is considered a metabolic disease. Moreover, although MYC amplification is found only in 5-10 % of the cases, increased MYC signaling has been associated with development of aggressive forms of ccRCC. In paper I we investigated the metabolic changes induced by MYCN amplification in NB. By combining proteomics, transcriptome analysis and functional metabolic assays, we demonstrated that MYCN induced changes in several metabolic enzymes, increasing glycolysis and oxidative phosphorylation. We also found that fatty acids were the preferred mitochondrial fuel for energy production in MYCN-amplified cells. Moreover, data from tracing experiments with 13C-labeled glucose or glutamine indicated that MYCN-amplified NB cells synthetized glutamine de novo. Furthermore, targeting fatty acid oxidation resulted in reduction of viability in NB cells with MYCN-amplification in vitro and in reduction of tumor burden in vivo. Since we found that fatty acid oxidation was relevant for MYCN-amplified NB, we further studied the effects of inhibiting de novo fatty acids synthesis in paper II. Using five different inhibitors targeting two consecutive enzymes in the process, we described that inhibition of the synthesis of fatty acids resulted in striking neuronal differentiation associated with activation of ERK signaling, and reduction of MYCN and MYC levels. Moreover, lipid composition as well as mitochondrial function and morphology of NB cells was altered. In addition, fatty acid synthesis inhibition led to reduced tumor formation and increased differentiation markers in several NB xenograft models. Together, the results in paper I and II suggested that targeting lipid metabolism could be a potential therapeutic approach for NB patients. In paper III we further analyzed the potential differentiation of NB cells induced by activation of nuclear hormone receptors (NHRs). Our data showed that the simultaneous activation of glucocorticoid receptor (GR), estrogen receptor α (ERα) and retinoic acid receptor α (RARα) potentiated neurite outgrowth, induced changes in the glycolytic and mitochondrial functions, accompanied with lipid droplet accumulation, and reduced proliferation in vitro as well as tumor burden in vivo. In addition, single cell nuclei analysis revealed a sequential expression of the three NHRs during adrenal gland development. Notably, in silico analysis of patient cohorts demonstrated that high expression of these NHRs were correlated with better overall survival. Thus, combination therapy with the concurrent activation of GR, ERα and RARα represents a promising strategy to induce differentiation in NB patients. Paper IV describes the mechanism behind lipid droplet (LD) accumulation induced by MYC inhibition during hypoxia in clear cell renal cell carcinoma (ccRCC). We found that HIF expression together with MYC inhibition resulted in LD deposition. Our results showed that due to HIF stabilization, glutamine-derived carbons were directed for synthesis of fatty acids, further accumulating in LDs. Importantly, we identified that the hypoxia inducible lipid droplet associated (HILPDA) gene, was overexpressed upon HIF induction and MYC inhibition, controlling LD formation in ccRCC cells. Hence, our study characterizes the molecular mechanism of LD accumulation in relation to hypoxia and MYC signaling, providing new understanding of metabolic adaption in ccRCC. Altogether, the data compiled in this thesis describes the important role of the MYC family of proteins in differentiation and metabolism of NB and in the metabolic reprogramming of ccRCC providing new knowledge and potential targets for development of novel therapeutic approaches

In-loop Feature Tracking for Structure and Motion with Out-of-core Optimization

In this paper, a novel and approach for obtaining 3D models from video sequences captured with hand-held cameras is addressed. We define a pipeline that robustly deals with different types of sequences and acquiring devices. Our system follows a divide and conquer approach: after a frame decimation that pre-conditions the input sequence, the video is split into short-length clips. This allows to parallelize the reconstruction step which translates into a reduction in the amount of computational resources required. The short length of the clips allows an intensive search for the best solution at each step of reconstruction which robustifies the system. The process of feature tracking is embedded within the reconstruction loop for each clip as opposed to other approaches. A final registration step, merges all the processed clips to the same coordinate fram

Programa de Prevención de la Dependencia y Envejecimiento Activo: Un Modelo de Formación de Psicohabilidades en un entorno B-Learning.

Un estilo de vida vitalista o en su defecto los programas de envejecimiento activo, son las mejores herramientas para la prevención de la dependencia causada por el envejecimiento. Con la evolución del ciclo vital se agudizan las enfermedades no trasmisibles (ENT), que generan la dependencia. Es posible crear programas de prevención de la dependencia y el fomento del envejecimiento activo, a través de una formación en modalidad b-learning. La plataforma de formación Moodle, en sus versiones 1.9 y 2.0, ofrecen las herramientas de seguimiento y diagnóstico perfectas, para la trasmisión de conocimientos teóricos y la formación en psicohabilidades, cubriendo las necesidades de una formación en salud preventiva, fundamentado en las dimensiones de la salud integral, es decir en las 5 “eses”: Salud Física, Salud Espiritual, Salud Psicológica, Salud Social y Salud Emocional.[ABSTRACT] Abstract: A vitalistic lifestyle or else active aging programs are the best tools for the prevention of dependency caused by aging. With the development life cycle are exacerbated non-communicable diseases (NCDs), which generate dependency. We can create programs to prevent dependency and promote healthy aging through training in b-learning mode. The Moodle learning platform in their versions 1.9 and 2.0, provide the diagnostic tools to monitor and perfect for the transmission of knowledge and training in psychosocial skills, meeting the needs of a preventive health education, based on the size of the comprehensive health, in the 5 "Hs" Physical Health, Spiritual Health, Psychological Health, Social Health and Emotional Health

The effects of a manipulation of memory confidence on urges to check

One of the most common compulsions in obsessive-compulsive disorder (OCD) is repeated checking. Although individuals often report that they check to become more certain, checking has been shown to have the opposite effect - increased checking causes increased uncertainty. However, checking may also be thought of as beginning because of memory uncertainty. Beliefs about memory were manipulated to test whether or not they affected urges to check. Ninety one undergraduate participants received (positive or negative) false feedback about their performance on aspects of a standardized memory test, and then completed three additional tasks. Their urges to check and levels of memory vividness and detail following these tasks were assessed. Results were generally consistent with our hypotheses, as individuals in the low memory confidence condition had greater urges to check on most tasks than those in the high memory confidence condition. Low memory confidence led to reduced memory vividness and detail for only one of the memory tasks. Results and implications are discussed in terms of cognitive-behavioural models of and treatments for OCD

MUSEO DE LA TELECOMUNICACIÓN DE LA UPV: PROBLEMÁTICA DE ALMACENAJE Y PROPUESTA DE CONSERVACIÓN PREVENTIVA

[ES] A través del presente estudio, se analiza el sistema de almacenaje actual de los equipos ubicados en el museo de la telecomunicación Vicente Miralles Segarra, situado en el edificio 4D, de la ETSIT en la Universidad Politécnica de Valencia. Se han evaluado las medidas de conservación de las piezas emplazadas en este espacio, observando los criterios de almacenaje y etiquetado utilizados en la actualidad, con el fin de establecer un plan de deficiencias y mejoras. El trabajo se ha organizado en dos partes: en primer lugar, se realiza un estudio de la historia del museo, haciendo también un análisis de los almacenes y la problemática que estos presentan. Se ha evaluado su situación, la ubicación de las piezas que albergan y los materiales principales que las componen, información clave a la hora de realizar una buena conservación de estas. De la misma manera, se ha realizado un listado de posibles agentes de deterioro que puedan afectar a las piezas pertenecientes a la colección. En la segunda parte del trabajo, como resultado del análisis previo realizado, se muestra un plan integral de conservación preventiva atendiendo a las necesidades que se han observado, con el fin de facilitar su conservación futura.[EN] Through this study, the current storage system of the equipment located in the Vicente Miralles Segarra telecommunication museum, located in the 4D building, of the ETSIT at the Polytechnic University of Valencia is analyzed. The conservation measures of the pieces located in this space have been evaluated, observing the storage and labeling criteria currently used, in order to establish a plan for deficiencies and improvements. The work has been organized in two parts: first, a study of the history of the museum is carried out, also making an analysis of the stores and the problems they present. Their situation, the location of the pieces they house and the main materials that compose them have been evaluated, key information when it comes to maintaining them. In the same way, a list of possible deteriorating agents that could affect the pieces belonging to the collection has been made. In the second part of the work, as a result of the previous analysis carried out, a comprehensive preventive conservation plan is shown in response to the needs that have been observed, in order to facilitate its future conservation.Martínez Alcolado, A. (2020). MUSEO DE LA TELECOMUNICACIÓN DE LA UPV: PROBLEMÁTICA DE ALMACENAJE Y PROPUESTA DE CONSERVACIÓN PREVENTIVA. http://hdl.handle.net/10251/150196TFG

Beliefs about Memory in Compulsive Checking and Obsessive-Compulsive Disorder: Assessment and Intervention

Checking is one of the most common compulsions in obsessive-compulsive disorder (OCD). Some have suggested that individuals who check repeatedly may have memory deficits, but findings of memory-related investigations have been inconsistent. In contrast, beliefs about memory have been shown to relate closely to checking behaviour. Thus, it is possible that mixed findings regarding the presence of memory deficits in association with OCD may be related to maladaptive beliefs influencing performance. Currently no measure exists to assess these beliefs, nor does an intervention to improve them, despite the existence of such measures and interventions for other known maladaptive beliefs central to OCD. The present studies were thus designed to measure and examine the relationships between beliefs about memory, actual memory performance, and checking compulsions. The first study encompassed the development of the Beliefs About Memory Inventory (BAMI) to assess maladaptive beliefs that individuals hold about their memory. Non-clinical (N = 697) and clinical (N = 24) participants completed the candidate items for the BAMI along with other relevant questionnaires to determine its psychometric properties. Results showed that the psychometrically-sound measure is comprised of two factors: beliefs about memory ability, and beliefs about the importance of memory. Furthermore, the BAMI was able to predict checking symptoms over and above existing belief domains known to be relevant to OCD. The second study examined whether a brief cognitive intervention designed to improve beliefs about memory in a sample of compulsive checkers could decrease checking and increase memory performance. Individuals with OCD (N = 24) who exhibited clinical levels of checking symptoms monitored their checking behaviour over the course of a two-session intervention. Half were randomly assigned to the treatment condition, while the other half were randomly assigned to a waitlist control condition. Participants also completed neuropsychological tests pre- and post-treatment/waitlist. Results demonstrated that compared to those in the waitlist condition, individuals in the treatment condition decreased their maladaptive beliefs about memory, checking behaviour, and symptoms, while increasing their memory performance. The results of these studies are discussed in the context of implications for cognitive-behavioural theories of and interventions for OCD

Efectos de los estilos de humor, en el burnout y la satisfacción laboral.

The scientific literature has until recently considered humor as a merely positive construct; however, multiple investigations have shaped a model of sense of humor characterized by four different styles. So far, most studies delving into the sense of humor at work are based on the first conception. The present study investigates the relationships between the different styles of sense of humor and organizational variables; job satisfaction and burnout syndrome, using an adaptation of the Humor Style Questionnaire, the IBM General survey and the s10/12 job satisfaction questionnaire. The sample consisted of a group of 120 workers. The results showed significant differences between the different styles of sense of humor and the dimensions of burnout syndrome, as well as job satisfaction. This shows that sense of humor is a complex variable, that needs further study of its possible implications in the organizational field.La literatura científica ha considerado el humor hasta brevemente un constructo meramente positivo, sin embargo, múltiples investigaciones han conformado un modelo de sentido del humor caracterizado por cuatro estilos diferentes. Hasta ahora la mayoría de los estudios que ahondan el sentido del humor en el trabajo se basan en la primera concepción. En el presente estudio se investigan las relaciones entre los diferentes estilos de sentido del humor y las variables organizacionales; satisfacción laboral y síndrome de burnout. Para ello, se empleó una adaptación del Humor Style Questtionare, el IBM General survey y cuestionario de satisfacción laboral s10/12. La muestra se conformaba por un grupo de 120 trabajadores. Los resultados obtuvieron diferencias significativas entre los diferentes estilos de sentido del humor y las dimensiones del síndrome del burnout, así como de la satisfacción laboral. Ello muestra que el sentido del humor es una compleja variable que necesita un mayor estudio de sus posibles implicaciones sobre el campo organizacional