Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle.

Background Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands. Scope of review The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time. Major conclusions Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.post-print3250 K

Integración del aprendizaje social (social learning) en las asignatras vinculadas al campo de conocimiento del Derecho del Trabajo y la Seguridad Social

Este proyecto trata de integrar las redes sociales como una herramienta colaborativa en la docencia de las materias relacionadas con el Derecho del Trabajo. De entre los recursos asociados a las plataformas "b-learning", e empleo de las redes sociales permite el intercambio de información en tiempo real. A través de este instrumento, los alumnos, guiados por el profesor, aportan su trabajo activo en relación con la materia seleccionada y poniéndolo en común mediante la herramienta elegida. En este proyecto nos decantamos por el empleo de Facebook. Esta metodología puede ser aplicada en cuantas disciplinas se vean especialmente vinculadas a la realidad económico-social, que por su naturaleza requieran de una permanente actualización. La recepción de esta metodología es evidente en aquellas materias que exijan del alumno un esfuerzo crítico que le permita acercarse en profundidad a los elementos novedosos de la materia

A New Natural Antimycotic Agent is Effective Against Oropharyngeal Candidiasis: The VIPROCAN Study.

Background: The incidence of community and nosocomial candidiasis has dramatically increased in the last two decades. There are multiple treatments for this infection, but the toxicity of some and the induction of resistant strains require the development of new compounds. Objectives: With the aim of reducing the Candida population in the oropharyngeal cavity, we have formulated a toothpaste with VG-01 agent, composed of a mixture of carnosic acid (CA) and propolis (PP). Methods: We investigated the ability of VG-01 toothpaste to minimize and stabilize fungal presence in 21 patients diagnosed with clinical oropharyngeal candidiasis. Results: Our data indicate that VG-01 toothpaste showed an effect not only against the most frequent species of Candida, C. albicans, but also in the other species analyzed. 82% of patients stated that they would continue using it outside the study. Conclusion: Our data demonstrate that VG-01, composed of CA and PP is a potential antimycotic agent effective against the most common species that cause oropharyngeal candidiasis present in clinical practicepost-print988 K

Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.post-print3439 K

Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic e ect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.post-print3309 K

The low affinity A2B adenosine receptor enhances migratory and invasive capacity in vitro and angiogenesis in vivo of glioblastoma stem-like cells.

Glioblastoma (GBM) is the most common and deadlymalignant brain tumor,with a median survival of 15 to 17 months for a patient. GBM contains a cellular subpopulation known as GBM stem-like cells (GSCs) that persist in hypoxic niches and are capable of infiltrating into healthy brain tissue. For this reason, GSCs are considered one of the main culprits for GBM recurrence. A hypoxic microenvironment increases extracellular adenosine levels, activating the low affinity A2B adenosine receptor (A2BAR). Adenosine, through A2BAR, is capable of modulating invasiveness. However, its role in the invasion/migration of hypoxic- GSCs is still unknown. This study aims to understand the importance of A2BAR in modulating themigratory/invasive capacity of GSCs under hypoxia. Data analysis from The Cancer Genome Atlas (TCGA) program correlates A2BAR expression with high-grade glioma and hypoxic necrotic areas. U87MG and primary culturederived GSCs under hypoxic conditions (0.5% O2) increased A2BAR mRNA and protein levels. As expected, the migratory and invasive capacity of GSCs increased under hypoxia, which was counteracted by blocking A2BAR, through the downregulation of MMP9 activity and epithelial–mesenchymal transition marker expression. Finally, in a xenograft mouse model, we demonstrate that treatment with MRS1754 did not affect the tumor volume but could decrease blood vessel formation and VEGF expression. Our results suggest that extracellular adenosine, through the activation of A2BAR, enhances the migratory and invasive capacity of GSCs in vitro under hypoxic conditions. Targeting A2BAR can be an effective therapy for GBM recurrence.post-print556 K

Uso de evaluación continua para incrementar la motivación del alumnado en asignaturas de Ingeniería

The guided and evaluated learning at the end of the course is a vestige inherited from the old curricula. With the reduction of the number of students, as well as with the implementation of the new curricula, the teaching system has to be changed, turning towards a way in which the student is the main actor and the teacher carries out a continuous feedback (guided process). In the present research it has been shown that the continued work of students, with real problems associated with Engineering, allows the learning process to be carried out with a greater motivation and, therefore, involvement by the students, improving their academic performanceEl aprendizaje guiado y evaluado al final del curso es un vestigio heredado de los antiguos planes de estudios. Con la reducción del número de alumnos, así como con la implementación de los nuevos planes de estudio se hace necesario cambiar el sistema de enseñanza, virando hacia un modeo en el que el alumno sea el protagonista y que el profesor lleve a cabo un proceso de retroalimentación (guiado) continuado. En el presente estudio queda demostrado que el trabajo continuo de los alumnos con problemas reales asociados a la Ingeniería permite que el proceso de aprendizaje lleve acarreado una mayor motivación y, por ende, implicación por parte de los estudiantes, mejorando el rendimiento de los mismos.Universidad de Sevilla. Ayuda 1.2.3 del III Plan Propio de Docenci

DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes− cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human gliomaWe are grateful for the financial support from the ‘Fondo de Investigaciones Sanitarias’ (FIS) (PI10/01069 and PI14/00077) and the ‘Miguel Servet Program’ (CP11/00147) from the ‘Instituto de Salud Carlos III’ (AAS), RTC-2015-3846-1 from Ministerio de Economía y Competitividad and FEDER fund

Cambios en la relación enseñanza-aprendizaje. Una experiencia a través del uso de YouTube y los procesos de evaluación en la Facultad de Educación.

Este proyecto de innovación docente emerge en un entorno digital que demanda una transformación en la relación enseñanza-aprendizaje, y especialmente en las Facultades de Educación, en las que cada vez más se exigen cambios en la actual formación inicial del profesorado. Para responder a los nuevos retos, y comprometidos con la mejora continua de la práctica docente, el proyecto otorgar un mayor protagonismo al alumnado en los procesos de construcción de conocimiento y en la evaluación de los mismos. Para ello se incide, por un lado, en el uso de YouTube como un recurso digital que permite que el alumnado se acerque a las asignaturas de una manera más activa y creativa. Por otro lado, se ponen en marcha procesos de evaluación online que permitan la auto-evaluación, la evaluación entre pares y la coevaluación. De esta forma, el proyecto contribuye al desarrollo de la competencia digital docente, que las instituciones educativas tanto nacionales como europeas, consideran clave para el desempeño de la función docente ante el nuevo entorno digital