Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition

Endometrial cancer; Immunohistochemistry; Predictive markersCàncer d'endometri; Immunohistoquímica; Marcadors predictiusCáncer de endometrio; Inmunohistoquímica; Marcadores predictivosEndometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial

Quality Of Life Assessment In Children With Cerebral Palsy

Objectives: Evaluate the QoL of children with CP followed at Núcleo de Tratamento e Estimulação Precoce, in Fortaleza, Ceará, Brazil; identify the most affected domains of the Pediatric Quality of Life Inventory. Methods: This was a cross-sectional, of which target population consisted of parents of children with CP (N = 62). Data collection was carried out by applying the socioeconomic questionnaire and the Health-related Quality of Life tool – HRQoL-PedsQL version 4.0, module applied to parents. Data analysis was performed with SPSS statistical software, version 23.0. Results: The results after transformation of scores into a scale of 0 to 100 in PedsQL, the data showed statistical difference between QOL domains except for physical capacity and social aspect and in descending order of impairment, the domains were related to school activity, the emotional aspect, physical capacity and the social aspect. Conclusions: Given the above, to attain improvement in QoL indicators, it is reasonable to propose interdisciplinary intervention among healthcare professionals in order to develop improved strategies aiming to promote early integration of children with CP in schools, to obtain significant results

Estudio del mecanismo de supervivencia en ausencia de la actividad esencial ß-(1-3) glucán sintasa

Trabajo presentado en el XV Congreso Nacional de Micología, celebrado en Valencia (España), del 7 al 9 de septiembre de 202

Gate current analysis of AlGaN/GaN on silicon heterojunction transistors at the nanoscale

The gate leakage current of AlGaN/GaN (on silicon)high electron mobility transistor(HEMT) is investigated at the micro and nanoscale. The gate current dependence (25-310 °C) on the temperature is used to identify the potential conduction mechanisms, as trap assisted tunneling or field emission. The conductive atomic force microscopy investigation of the HEMT surface has revealed some correlation between the topography and the leakage current, which is analyzed in detail. The effect of introducing a thin dielectric in the gate is also discussed in the micro and the nanoscale

Microtubule stabilization reduces amyloid pathology and improves synaptic/memory deficits in APP/PS1 mice

Aims: Cognitive decline in Alzheimer's disease (AD) is highly related to synaptic/neuronal loss. Tau hyperphosphorylation destabilizes microtubules leading to axonal transport failure and generation of dystrophic neurites, thus contributing to synaptic dysfunction. The effect of microtubule stabilization on amyloid-beta pathology has not been assessed in vivo yet. This study evaluated the effect of the microtubule-stabilizing agent, Epothilone D (EpoD) in the pathology of an amyloidogenic mouse model. Methods: APP751SL/PS1M146L mice (3-month-old) were treated weekly with intraperitoneal injections of EpoD (2 mg/kg) or vehicle for 3 months. For memory performance, animals were tested on the objectrecognition, Y-maze and Morris water maze. Hippocampal proteinopathies were quantified by image analysis after immunostaining. Somatostatin (SOM)-numerical density was calculated by stereology. APPswe-N2a cells were treated with EpoD 100nM for 12/24 hours. Protein levels were analysed by Western/dot-blot. Results: EpoD-treated mice improved their performance of cognitive tests, while hippocampal phospho-tau and Ab (especially oligomers) accumulation decreased, together with synaptic/neuritic pathology. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Conclusions: EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Ab accumulation and promoting neuronal and cognitive protection, underlining the cross-talk between cytoskeleton pathology and proteinopathy. Therefore, microtubule-stabilizing drugs could be candidates for slowing AD at both tau and Ab pathologies.Supported by PI18/01557 (to AG) and PI18/01556 (to JV) grants from ISCiii of Spain, co-financed by FEDER funds (European Union), CIBERNED collaborative grant (to AG and JV), and by PPIT.UMA.B1.2017/26 grant (to RSV). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Entomopathogenic nematology in Latin America: A brief history, current research and future prospects

Since the 1980s, research into entomopathogenic nematodes (EPNs) in Latin America has produced many remarkable discoveries. In fact, 16 out of the 117 recognized species of EPNs have been recovered and described in the subcontinent, with many more endemic species and/or strains remaining to be discovered and identified. In addition, from an applied perspective, numerous technological innovations have been accomplished in relation to their implementation in biocontrol. EPNs have been evaluated against over 170 species of agricultural and urban insects, mites, and plant-parasitic nematodes under laboratory and field conditions. While much success has been recorded, many accomplishments remain obscure, due to their publication in non-English journals, thesis dissertations, conference proceedings, and other non-readily available sources. The present review provides a brief history of EPNs in Latin America, including current findings and future perspectives.Fil: San Blas, Ernesto. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Campos Herrera, Raquel. Consejo Superior de Investigaciones Científicas; EspañaFil: Dolinski, Claudia. Universidade Estadual Do Norte Fluminense Darcy Ribeiro; BrasilFil: Monteiro, Caio. Universidade Federal de Goiás; BrasilFil: Andaló, Vanessa. Universidade Federal de Uberlandia; BrasilFil: Leite, Luis Garrigós. Universidade Estadual de Campinas; BrasilFil: Rodríguez, Mayra G.. Centro Nacional de Sanidad Agropecuaria; CubaFil: Morales Montero, Patricia. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Sáenz Aponte, Adriana. Pontificia Universidad Javeriana; ColombiaFil: Cedano, Carolina. Universidad Nacional de Trujillo; PerúFil: López Nuñez, Juan Carlos. Centro Nacional de Investigaciones del Café; ColombiaFil: del Valle, Eleodoro Eduardo. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Doucet, Marcelo Edmundo. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Zoología Aplicada; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Lax, Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Zoología Aplicada; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Navarro, Patricia D.. Instituto de Investigaciones Agropecuarias; ChileFil: Báez, Francisco. Instituto Nacional Autonomo de Investigaciones Agropecuarias; EcuadorFil: Llumiquinga, Pablo. Instituto Nacional Autonomo de Investigaciones Agropecuarias; EcuadorFil: Ruiz Vega, Jaime. Instituto Politécnico Nacional ; MéxicoFil: Guerra Moreno, Abby. Laboratorio de Biotecnología; PanamáFil: Stock, S. Patricia. University of Arizona; Estados Unido

Survival of Late Pleisticene Hunter-gatherer ancestry in the Iberian Peninsula

The Iberian Peninsula in southwestern Europe represents an important test case for the study of human population movements during prehistoric periods. During the Last Glacial Maximum (LGM), the peninsula formed a periglacial refugium for hunter-gatherers (HGs) and thus served as a potential source for the re-peopling of northern latitudes. The post-LGM genetic signature was previously described as a cline from Western HG (WHG) to Eastern HG (EHG), further shaped by later Holocene expansions from the Near East and the North Pontic steppes. Western and central Europe were dominated by ancestry associated with the 14,000-year-old individual from Villabruna, Italy, which had largely replaced earlier genetic ancestry, represented by 19,000-15,000-year-old individuals associated with the Magdalenian culture. However, little is known about the genetic diversity in southern European refugia, the presence of distinct genetic clusters, and correspondence with geography. Here, we report new genome-wide data from 11 HGs and Neolithic individuals that highlight the late survival of Paleolithic ancestry in Iberia, reported previously in Magdalenian-associated individuals. We show that all Iberian HGs, including the oldest, a 19,000-year-old individual from El Mirón in Spain, carry dual ancestry from both Villabruna and the Magdalenian-related individuals. Thus, our results suggest an early connection between two potential refugia, resulting in a genetic ancestry that survived in later Iberian HGs. Our new genomic data from Iberian Early and Middle Neolithic individuals show that the dual Iberian HG genomic legacy pertains in the peninsula, suggesting that expanding farmers mixed with local HGs

Common Genetic Variants, Acting Additively, Are a Major Source of Risk for Autism

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability

LITIO COMO TERAPIA NEUROPROTECTORA EN EL MODELO APPSL/PS1M146L DE LA ENFERMEDAD DE ALZHEIMER

El litio se utiliza desde hace varias décadas en el tratamiento de trastornos bipolares y la depresión, y recientemente se debate su uso potencial en patologías neurodegenerativas como la enfermedad de Alzheimer (AD). Diversos estudios han puesto de manifiesto su efecto positivo como potente inhibidor de GSK3beta disminuyendo la fosforilación de tau, la producción de Abeta e incrementando plasticidad sináptica. Sin embargo, su posible efecto neuroprotector previniendo la muerte neuronal in vivo no ha sido aun demostrado ya que la mayoría de los modelos transgénicos de AD no presentan pérdida neuronal. Nuestro modelo APPSL/PS1M146L sufre una pérdida significativa de neuronas SOM/NPY en hipocampo y corteza entorrinal desde edades tempranas (6 meses) con un marcado desarrollo de distrofias axonales. En este trabajo hemos estudiado el posible efecto neuroprotector del litio en este modelo animal mediante tratamiento crónico en la dieta desde los 3 hasta los 9 meses de edad. Se han utilizado técnicas imnunohistoquímicas, western blots y análisis por RT-PCR, y además se ha determinado la carga amiloide, el grado de compactación y el tamaño de las placas. El resultado más relevante de este estudio fue la preservación de la población de interneuronas SOM/NPY tanto en hipocampo como corteza entorrinal en los animales tratados, mientras que en los no tratados existió una pérdida significativa de esta supoblación neuronal. El efecto neuroprotector del litio se manifestó también en una marcada disminución de tau fosforilado, distrofias axonales y marcadores sinápticos, junto con una mejora cognitiva de los animales utilizando el test de reconocimiento de objetos. Este efecto preventivo del litio parece estar asociado con cambios en la formación de placas de Abeta que podrían afectar a su toxicidad, ya que los animales tratados presentaron placas más pequeñas y apariencia más compacta. Financiación: FIS PI12/01431 (AG) y FIS PI12/01439 (JV).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Common genetic variants, acting additively, are a major source of risk for autism

Abstract Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.http://deepblue.lib.umich.edu/bitstream/2027.42/112370/1/13229_2012_Article_55.pd