Spatial distribution and functional relevance of FGFR1 and FGFR2 expression for glioblastoma tumor invasion.

Glioblastoma is the most lethal brain cancer in adults. These incurable tumors are characterized by profound heterogeneity, therapy resistance, and diffuse infiltration. These traits have been linked to cancer stem cells, which are important for glioblastoma tumor progression and recurrence. The fibroblast growth factor receptor 1 (FGFR1) signaling pathway is a known regulator of therapy resistance and cancer stemness in glioblastoma. FGFR1 expression shows intertumoral heterogeneity and higher FGFR1 expression is associated with a significantly poorer survival in glioblastoma patients. The role of FGFR1 in tumor invasion has been studied in many cancers, but whether and how FGFR1 mediates glioblastoma invasion remains to be determined. Here, we investigated the distribution and functional relevance of FGFR1 and FGFR2 in human glioblastoma xenograft models. We found FGFR1, but not FGFR2, expressed in invasive glioblastoma cells. Loss of FGFR1, but not FGFR2, significantly reduced cell migration in vitro and tumor invasion in human glioblastoma xenografts. Comparative analysis of RNA-sequencing data of FGFR1 and FGFR2 knockdown glioblastoma cells revealed a FGFR1-specific gene regulatory network associated with tumor invasion. Our study reveals new gene candidates linked to FGFR1-mediated glioblastoma invasion.

The transcription factor ZEB1 regulates stem cell self-renewal and cell fate in the adult hippocampus.

Radial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cell-autonomous factors regulating neuronal and astroglial differentiation are incompletely understood. Here, we evaluate the functions of the transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells. Genetic deletion of Zeb1 causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric division.

Identifying subpopulations in multicellular systems by quantitative chemical imaging using label-free hyperspectral CARS microscopy.

Quantitative hyperspectral coherent Raman scattering microscopy merges imaging with spectroscopy and utilises quantitative data analysis algorithms to extract physically meaningful chemical components, spectrally and spatially-resolved, with sub-cellular resolution. This label-free non-invasive method has the potential to significantly advance our understanding of the complexity of living multicellular systems. Here, we have applied an in-house developed hyperspectral coherent anti-Stokes Raman scattering (CARS) microscope, combined with a quantitative data analysis pipeline, to imaging living mouse liver organoids as well as fixed mouse brain tissue sections xenografted with glioblastoma cells. We show that the method is capable of discriminating different cellular sub-populations, on the basis of their chemical content which is obtained from an unsupervised analysis, i.e. without prior knowledge. Specifically, in the organoids, we identify sub-populations of cells at different phases in the cell cycle, while in the brain tissue, we distinguish normal tissue from cancer cells, and, notably, tumours derived from transplanted cancer stem cells versus non-stem glioblastoma cells. The ability of the method to identify different sub-populations was validated by correlative fluorescence microscopy using fluorescent protein markers. These examples expand the application portfolio of quantitative chemical imaging by hyperspectral CARS microscopy to multicellular systems of significant biomedical relevance, pointing the way to new opportunities in non-invasive disease diagnostics.

FGF2: a novel druggable target for glioblastoma?

Introduction: Fibroblast growth factors (FGFs) are key mitogens in tissue homeostasis and cancer. FGF2 regulates self-renewal of multiple stem-cell types, is widely used in stem cell culture paradigms and has been adopted for cultivating the growth of cancer stem cells ex vivo. Research has shed light on the functions of FGF2 in brain tumors, particularly malignant glioma, and this has demonstrated that FGF2 increases self-renewal of glioblastoma stem cells.Areas covered: This review examines the potential targeting of FGF2 signaling as a possible treatment avenue for glioblastoma. The expression of FGF ligands and the FGFR family of receptor tyrosine kinases in the normal brain and in glioblastoma is described. Moreover, the paper sheds light on FGF/FGFR signaling, including the function of heparin/heparan sulfate proteoglycans in facilitating FGF signaling. We speculate on potential avenues for the therapeutic targeting of the FGF2-FGF receptor signaling axis in glioblastoma and the associated challenges envisioned with these approaches.Expert opinion: Precision targeting of FGF/FGFR signaling could improve prospective glioblastoma therapeutics and moderate adverse effects. Shrewd development of experimental models and FGF2 inhibitors could provide a 'pharmacological toolbox' for targeting diverse ligand/receptor combinations.

ADAMDEC1 and FGF2/FGFR1 signaling constitute a positive feedback loop to maintain GBM cancer stem cells.

Identification of targetable mechanisms that maintain glioblastoma cancer stem cells (CSCs) remain a priority. Our study reveals a new mechanism by which a disintegrin and metalloproteinase domain-like protein decysin 1 promotes CSC maintenance through the activation of a fibroblast growth factor autocrine signaling loop, which can be blocked pharmacologically.

ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells.

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. SIGNIFICANCE: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.This article is highlighted in the In This Issue feature, p. 1469.

Fibroblast Growth Factor Receptor Functions in Glioblastoma.

Glioblastoma is the most lethal brain cancer in adults, with no known cure. This cancer is characterized by a pronounced genetic heterogeneity, but aberrant activation of receptor tyrosine kinase signaling is among the most frequent molecular alterations in glioblastoma. Somatic mutations of fibroblast growth factor receptors (FGFRs) are rare in these cancers, but many studies have documented that signaling through FGFRs impacts glioblastoma progression and patient survival. Small-molecule inhibitors of FGFR tyrosine kinases are currently being trialed, underlining the therapeutic potential of blocking this signaling pathway. Nevertheless, a comprehensive overview of the state of the art of the literature on FGFRs in glioblastoma is lacking. Here, we review the evidence for the biological functions of FGFRs in glioblastoma, as well as pharmacological approaches to targeting these receptors.

Continuidad en la atención terapéutica a adolescentes con trastorno del espectro autista / Continuing the therapeutic care in autistic adolescents / Continuïtat en l’atenció terapèutica a adolescents amb trastorn de l'espectre autista

Se exponen algunos de los problemas detectados durante un año en un grupo de adolescentes diagnosticados de trastorno del espectro autista (TEA) y sus familias: necesidad de mantener una intervención terapéutica incluyendo también a los padres; necesidad de estar al tanto de las vicisitudes por las que pasan (cambios físicos y psíquicos), del posible incremento de ciertos mecanismos de defensa (primitivos) y el peligro de dependencia; a nivel escolar, importancia de trabajar en las dificultades metodológicas y contar con una figura de referencia

After treating an Autism Spectrum Disorder (ASD) teenage group and their families during a year, the following problems have been detected: the need to maintain a therapeutic intervention both for teenagers and their parents; the need to be aware of their vicissitudes (physical and psychic changes), the possible increase of certain (primitive) defence mechanisms and the danger that dependency can lead to. Working on the methodological difficulties at school and having a figure of reference were also detected during the treatment

S’exposen alguns dels problemes detectats durant un any en un grup d’adolescents diagnosticats de trastorn de l’espectre autista (TEA) i les seves famílies: necessitat de mantenir una intervenció terapèutica incloent també els pares; necessitat d’estar al corrent de les vicissituds per les quals passen (canvis físics i psíquics), del possible increment de certs mecanismes de defensa (primitius) i el perill de dependència; a nivell escolar, importància de treballar en les dificultats metodològiques i comptar amb una figura de referència

Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma.

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

Evaluación del Hospital de Día Infanto Juvenil / Evaluation of the child and adolescent psychiatrc day hospital

El Hospital de Día Infanto Juvenil (HDDIJ) basa su modelo de intervención en la terapia institucional. Este recurso ha sido ampliamente validado en el tratamiento de diferentes trastornos mentales de la infancia y adolescencia, y se propone para la intervención de la patología mental grave en esta población. Sin embargo, la estructura óptima de este dispositivo no ha sido bien establecida. En este trabajo presentamos a modo de ejemplo un posible esquema para estructurar la guía de actuación interna de un hospital de día infanto juvenil y del plan de intervención individualizado de trabajo con cada niño, basado en la experiencia del Hospital Mancha Centro. Así mismo, presentamos el proyecto de investigación actualmente en marcha en nuestra unidad de elaboración de un algoritmo de evaluación neuropsicológica para Trastornos del Espectro Autista en el HDDIJ. Abrimos igualmente el debate para la propuesta de posibles indicadores clínicos de evolución en HDDIJ (AU)

Child and Adolescent psychiatric Day Hospital (CAPDH)bases its intervention model in institutional therapy. This intervention has been extensively validated in the treatment of various mental disorders in childhood and adolescence, and it has been proposed for the intervention of severe mental illness in this population. However , the optimal structure of this device has not been well established. We present a possible structural scheme for a clinical actuation guide in child and adolescent day hospital and individual action plan work, based on the experience of the Hospital Mancha Centro. Also , we present the research project currently underway in our unit developing a neuropsychological evaluation algorithm for Autism Spectrum Disorders in (CAPDH). Also we opened the discussion for the proposed clinical indicators of possible developments in HDDIJ (AU)

Experiencias tempranas y patología mental grave en la infancia / Early experiences and severe mental illness in childhood

Este trabajo pretende evaluar las asociaciones de los factores de riesgo (ODAT) en los primeros años de vida y gravedad de la patología mental del niño, a través de un estudio trasversal, descriptivo y analítico de caso control, con una selección de los sujetos mediante un muestreo aleatorio estratificado. Se seleccionaron tres grupos de niños, uno con trastorno mental grave, otro con trastornos mentales no catalogados como graves y un último grupo de niños que acuden al reconocimiento del niño sano. Las alteraciones biológicas detectadas en los periodos iniciales de la vida se asocian sobre todo a la patología mental de mayor gravedad. La convivencia con ambos padres y parientes próximos, la patología mental y la situación laboral de los padres, las pérdidas de personas significativas también parecen contribuir significativamente en la patología mental del niño. Por contra factores como la incorporación temprana a guardería, no aparecen como relevantes (AU)

This work aims to evaluate the factors of risk (ODAT) associations in the first years of life and severity of mental pathology of the child, cross-sectional, descriptive and analytical case-control study, with a selection of subjects by means of a stratified random sampling. We selected three groups of children, one with serious mental disorder, other mental disorders not classified as serious and a last group of children who come to the recognition of the healthy child. Biological alterations detected in the initial periods of life are especially associated with more severe mental pathology. Living with both parents and close relatives, mental pathology and the employment situation of the parents, the loss of significant people also seem to contribute significantly in the child mental pathology. Against factors such as the early incorporation into child care, do not appear as relevant (AU)

Dispositivos de internamiento terapeutico para patologia mental grave de niños y adolescentes / Therapeutical internment devices for serious mental pathologie in children and teenagers

La existencia de problemas y descompensaciones de conducta graves en niños y adolescentes debido a tras tornos mentales, plantea la necesidad de dispositivos de internamiento sanitarios y socio- educativos- sanitarios, con la participación conjunta y la integración funcional de las tres instituciones implicadas. El grupo de trabajo tras dos años de reuniones ha elaborado el siguiente documento donde se describen estos diferentes dispositivos de internamiento, pero partiendo previamente de la necesidad de la existencia de una clara y suficiente red asistencial de salud mental infanto juvenil, dando además una especial importancia a las políticas preventivas y de detección precoz (AU)

Detección y atención precoz de la patología mental en la primera infancia / Early detection and care of mental pathology in early childhood

No disponible

Hospital de día psiquiátrico para niños y adolescentes / Psychiatric day Hospital for choldren and adolescents

No disponible