Marcadores tumorales en neuroblastoma: un análisis retrospectivo

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Pediatria. Fecha de Lectura: 25-11-2021El cáncer pediátrico es, en su conjunto, una patología infrecuente que cumple criterios de enfermedad rara, y sin embargo es la primera causa de muerte por enfermedad en niños excluida la patología perinatal. El neuroblastoma es el tumor sólido extracraneal más frecuente en pediatría. Las formas de riesgo alto, que se dan en niños mayores de 18 meses, y que son habitualmente metastásicas (estadio M) y con genética desfavorable (principalmente amplificación del oncogen NMYC) presentan una elevada tasa de recaídas (mayor del 40%) y una supervivencia que apenas supera el 50% a pesar de tratamiento agresivo multimodal incluyendo inmunoterapia. El desarrollo de nuevas terapias dirigidas contra alteraciones específicas del neuroblastoma podía incrementar la supervivencia de pacientes de mal pronóstico. Las dos alteraciones más relevantes son la mutación de Kinasa de Linfoma Anaplásico (ALK), responsable de las formas familiares, y presente en aproximadamente el 10% de los neuroblastomas esporádicos, y la sobreexpresión de Aurora Kinasa A, proteína que estabiliza NMYC. Se ha realizado una revisión retrospectiva de los neuroblastomas diagnosticados y/o tratados en nuestro centro desde la implantación de protocolos estandarizados (1990-2016). Se ha comparado las características con las principales series internacionales, en particular con la base de datos del International Neuroblastoma Risk Group (INRG). Se ha estudiado asimismo la mutación de ALK (mediante secuenciación Sanger) y la sobreexpresión de AURKA (mediante PCR cuantitativa e inmunohistoquímica) en muestras parafinadas de pacientes estadio M. Nuestros pacientes son comparables, en características y supervivencia, a las series nacionales e internacionales publicadas. Hemos encontrado correlación entre inmunohistoquímica positiva para AURKA y amplificación de NMYC. Consideramos que los pacientes con amplificación de NMYC se podrían beneficiar de tratamiento dirigido con inhibidores de AURK

A Meta-analysis of Gut Microbiota in Children with Autism

Previous studies have reported dysbiosis in the gut microbiota (GM) of children with autism spectrum disorders (ASD), which may be a determining factor on child development through the microbiota-gut-brain axis. However, it is not clear if there is a specific group of dysbiotic bacteria in ASD. The aim of this study was to carry out a meta-analysis on the studies that analyze GM in children with ASD. 18 studies fulfilled our selection criteria. Our results showed a lower relative abundance of Streptococcus (SMD+ = − 0.999; 95% CI − 1.549, − 0.449) and Bifidobacterium genera (SMD+ = − 0.513; 95% CI − 0.953, − 0.073) in children with ASD. Overall, the Bifidobacterium genera is involved. However, differences found between studies are attributed to factors such as reporting bias

Image guided SBRT for multiple liver metastases with ExacTrac Adaptive Gating

AimTo report the outcome and toxicity of sequential stereotactic body radiotherapy (SBRT) for multiple liver metastases in patients treated with ExacTrac Adaptive Gating.BackgroundIn selected patients with a limited number of liver metastases, SBRT has been evaluated as a safe and effective treatment, with minimal toxicity and high rates of local control.Materials and methodsFrom April 2008 to October 2013, 21 patients with multiple (3–14) liver metastases (n[[ce:hsp sp="0.25"/]]=[[ce:hsp sp="0.25"/]]101) were treated sequentially with SBRT at our institution. Maximum tumor diameter was 7.5[[ce:hsp sp="0.25"/]]cm. Prior to treatment, internal markers were placed inside or near the tumor. CT or PET-CT simulation was used for the definition of gross tumor volume (GTV). Median planning target volume was 32.3[[ce:hsp sp="0.25"/]]cc (3.6–139.3[[ce:hsp sp="0.25"/]]cc). Treatment consisted of 3 fractions (12–20[[ce:hsp sp="0.25"/]]Gy/fraction) or 5 fractions (10[[ce:hsp sp="0.25"/]]Gy/fraction), prescribed to the 90–95% of the PTV volume. Daily intra-fraction image guidance was performed with ExacTrac Adaptive Gating. Regular follow-up included CT or PET-CT imaging.ResultsAfter a median of 23.2 months, the estimated local control rate was 94.4%, 80.6%, 65% and 65% after 1, 2, 3 and 4 years; the median overall survival was 62 months (95% CI 49.12–74.87) and the actuarial survival reached at 60 months was 57.6%. The univariate data analysis revealed that only primary histology other than colorectal adenocarcinoma was shown as an independent significant prognostic factor for local control (p[[ce:hsp sp="0.25"/]]=[[ce:hsp sp="0.25"/]]0.022). Number of treated metastases did not modify significantly the overall survival (p[[ce:hsp sp="0.25"/]]=[[ce:hsp sp="0.25"/]]0.51). No toxicity higher than G3 (1 patient with chest wall pain) and no radiation-induced liver disease were observed.ConclusionsSequential SBRT with ExacTrac Adaptive Gating for multiple liver metastases can be considered an effective, safe therapeutic option, with a low treatment-related toxicity. Excellent rates of local control and survival were obtained

Actualidad y prospectiva de la investigación científica en el Centro Universitario Amecameca de la Universidad Autónoma del Estado de México

Con responsabilidad, se organizó un programa cuya finalidad fuera publicitar con transparencia dichos avances, a través de un esfuerzo de rendición de cuentas a la comunidad inmediata, la universitaria, y a la comunidad abierta, la sociedad que la principal referencia para tal efecto. El programa se concretiza a través del presente libro, conformado con una inspiración de investigación multidisciplinaria; sin embargo, para llegar a tal fin, el reto es realizar el proceso de búsqueda y generación de conocimiento transitando hacia la colaboración de los cuerpos académicos, que puedan construir nuevos conocimientos fortalecidos por la convergencia de diferentes campos del saber. En consecuencia, la primera etapa de esta estrategia es la publicidad de los trabajos investigativos ejercidos, para hacer un balance al día, pero también proyectar el futuro de cada campo y área del conocimiento. La organización explicativa está organizada por tres bloques representativos del quehacer en la generación de conocimiento del Centro Universitario, un primer bloque centra el interés en las humanidades, educación y sustentabilidad; el segundo bloque lo integra la reflexión científica sobre la construcción democrática, derechos humanos y equidad de género; en el tercer segmento se destina a la seguridad alimentaria, salud pública y sistemas agropecuarios. La actualidad de la investigación eleva la producción lograda y lo que en el momento se encuentra en construcción y los alcances que produce para la docencia, la investigación misma, y para la sociedad en general. La prospectiva es un área que todos los capítulos desarrollan con el propósito de delinear los alcances innovadores por andar en teoría, metodología e incluso en los saberes mismo

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Chaperone-mediated autophagy ablation in pericytes reveals new glioblastoma prognostic markers and efficient treatment against tumor progression

[Background]: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment.[Methods]: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared.[Results]: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination.[Conclusion]: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.This work was mainly developed by SAF 2015-73923-JIN, funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” and Seneca 20840/PI/18 funded by Seneca Foundation “Agencia de Ciencia y Tecnología de la Región de Murcia” (to RV). It was also partially supported by RYC 2019-027520-I funded by MCIN/AEI/10.13039/501100011033, as ESF Investing in your future”; PID 2020-114010RB-I00 funded by MCIN/AEI/10.13039/501100011033 (to RV), RD16/0011/0010 and RD16/0011/0001 (to SM and JMM) funded by Instituto de Salud Carlos III and co-founded by European Regional Development Funds “una manera de hacer Europa”; SAF 2017-83702 (to SM).Peer reviewe

Suicide and dementia: Systematic review and meta-analysis

Introducción: Analizar la posible relación entre demencia en el anciano y el posterior desarrollo de ideas, intentos y/o suicidios consumados. Métodos: Revisión sistemática y metaanálisis. Criterios de selección: estudios que analizaran la relación entre demencia y suicidio. Estrategia de búsqueda: i) en PubMed, EMBASE, CINAHL, IME y LILACS hasta diciembre de 2018; ii) búsqueda manual de la bibliografía de artículos seleccionados; iii) contacto con principales autores. Revisión independiente por pares para la selección de artículos y extracción de datos según protocolo de registro, incluyendo la evaluación del riesgo de sesgos. Cálculo del índice del tamaño del efecto mediante razón de ventajas (RV) y su intervalo de confianza del 95% (IC 95%) (modelo de efectos aleatorios). La heterogeneidad se evaluó con forest plots, Q de Cochran e índice I2. Valoración del sesgo de publicación mediante funnel plots (método «trim-and-fill») y el test de Egger. El análisis de variables moderadoras se realizó mediante un modelo de metarregresión múltiple de efectos mixtos. Resultados: Se identificaron 37 estudios y 47 unidades básicas de estudio. Tamaño del efecto de la asociación de demencia con: ideación suicida RV = 1,37 (IC 95%: 0,78-2,39); intento de suicidio: RV = 2,24 (IC 95%: 1,01-4,97); y suicidio consumado: RV = 1,28 (IC 95%: 0,77-2,14). Se descartó un posible sesgo de publicación. Conclusiones: Se identifica una tendencia hacia la aparición de eventos suicidas, especialmente intento de suicidio en personas con demencia. Sería recomendable una mayor atención y cuidado tras un diagnóstico reciente de demencia, especialmente con adecuada valoración de comorbilidades, que pudieran influir en aparición y desenlace de eventos suicidas.Introduction: To analyse the possible relationship between dementia in the elderly and the subsequent development of suicide ideation, attempts and / or completed suicides. Methods: Systematic review and meta-analysis. Selection criteria: studies that analysed the relationship between dementia and suicide. Search strategy: i) in PubMed, EMBASE, CINAHL, IME and Lilacs until December 2018; ii) manual search of the bibliography of selected articles; iii) contact with leading authors. Article selection and data extraction according to a predefined protocol, including bias risk assessment, were performed by independent peer reviewers. The effect size index was calculated using Odds Ratio (OR) and its 95% confidence interval (random-effects model). Heterogeneity was evaluated with forest plots, Cochran's Q and I2 index. Assessment of publication bias using funnel plots (“trim-and-fill” method) and the Egger test. The analysis of moderating variables was performed using a multiple meta-regression under a mixed-effects model. Results: 37 studies and 47 basic units of study were identified. Effect size of the association of dementia with: Suicidal Ideation OR = 1.37 (95% CI: .78-2.39); Suicide Attempt: OR = 2.24 (95% CI: 1.01-4.97); and Completed Suicide: OR = 1.28 (95% CI: .77-2.14). Possible publication bias was ruled out. Conclusions: A trend towards suicidal events is identified, especially suicide attempts in people with dementia. Greater attention and care are recommended after a recent diagnosis of dementia, especially with adequate assessment of comorbidities, which could influence the occurrence and outcome of suicidal events

Desarrollo de actividades de estudio e investigación para la enseñanza-aprendizaje de Matemáticas para el Diploma de formación para jóvenes con discapacidad intelectual (Diploma Liceo) y de formación matemático-didáctica para sus docentes

Proyecto de innovación UCMDepto. de Didáctica de las Ciencias Experimentales , Sociales y MatemáticasDepto. de Sistemas Informáticos y ComputaciónFac. de EducaciónFac. de InformáticaFALSEsubmitte

Nuevos escenarios para la innovación educativa : el Grupo CREA (Centros en Red para las Enseñanza Activas) y la renovación metodológica de los centros educativos

Convocatoria Proyectos de innovación de Extremadura 2018/2019Proyecto que agrupa a cinco centros educativos: el IES Jaranda (Jarandilla de la Vera, Cáceres), el IESO Sierra la Mesta (Santa Amalia, Badajoz), el IES Albarrega (Mérida, Badajoz), el IESO Val de Xálima (Valverde del Fresno, Badajoz), IESO Matías Ramón Martínez (Burguillos del Cerro, Badajoz) que conforman el Grupo CREA y que comparten una trayectoria común: el uso de metodologías educativas activas. A las iniciativas innovadoras llevadas a cabo colectivamente se suman las individuales de cada centro debido a la particularidad de cada uno de ellos. Los objetivos principales del proyecto son: la creación de una estructura organizativa y de coordinación entre los distintos centros participantes que permita la planificación y puesta en marcha de acciones educativas conjuntas; la introducción de cambios organizativos, funcionales, espaciales y metodológicos para llevar a cabo aprendizajes basados en proyectos, orientados al servicio a la comunidad y a los problemas sociales, centrados en el aprendizaje cooperativo, etc.; el diseño y desarrollo de programas de innovación coordinados entre los distintos centros educativos participantes; el establecimiento de mecanismos de coordinación para hacer efectiva la comunicación, el intercambio de información, el análisis y la reflexión del profesorado participante en los programas de innovación de cada uno de los centros; la formación conjunta del profesorado; el desarrollo de proyectos conjuntos para los alumnos participantes, su conexión en entornos virtuales, el intercambio de experiencias en encuentros periódicos, etc. y la generación y fomento de una nueva red creando un portal web y un espacio de comunicación e intercambio de documentaciónExtremaduraES

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women