Estudio clínico-genético de patologías asociadas a malformaciones linfáticas: Síndrome CLAPO y anomalía linfática generalizada

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 15-03-2019Las malformaciones vasculares son anomalías congénitas que se clasifican en función del tipo de vaso afectado en: capilares, linfáticas, venosas y arteriovenosas. El Síndrome CLAPO (Capillary malformation of the lower lip, Lymphatic malformation predominant on the face and neck, Asymmetry, and Partial/generalized Overgrowth) y la Anomalía Linfática Generalizada o GLA (Generalized Lymphatic Anomaly), son dos enfermedades raras de etiologías desconocidas que presentan malformaciones linfáticas como una de sus características clínicas principales. Ambas enfermedades presentan un patrón segmentario de manifestaciones clínicas y una alta heterogeneidad fenotípica, que apuntan a la presencia de un mosaicismo somático (mutaciones post-cigóticas) como mecanismo patogénico. En la presente tesis, se evaluó clínica y molecularmente dos cohortes de pacientes con diagnóstico de CLAPO y GLA con el objetivo de ampliar el conocimiento clínico, describir su causa genética, y desarrollar un protocolo experimental para el estudio de patologías causadas por alteraciones en mosaico somático. Para ello, se llevó a cabo el estudio retrospectivo de los pacientes incluidos en la cohorte, y se analizaron muestras pareadas sangre/tejido de 11 pacientes con CLAPO y 9 pacientes con GLA, utilizando paneles de genes de secuenciación masiva y un algoritmo bioinformático específico para la detección de variantes en mosaico. Además, se desarrolló un protocolo para el aislamiento y caracterización de células endoteliales linfáticas (LECs), y se generó un modelo de ratón para el estudio específico de la patología GLA. La reevaluación fenotípica de los pacientes con CLAPO y GLA permitió definir mejor las características clínicas y criterios diagnósticos, así como establecer posibles pautas de seguimiento. Gracias a los estudios moleculares se identificaron por primera vez mutaciones patogénicas activantes, en forma de mosaicismo somático, en el gen PIK3CA, en el 64% de los pacientes con CLAPO y el 56% de los pacientes con GLA. El aislamiento y caracterización de LECs a partir de tejido linfático, así como la generación del primer modelo animal específico de GLA, permitió validar funcionalmente los resultados genéticos y proporcionar evidencia preclínica y clínica para apoyar el uso de Rapamicina, para el tratamiento en pacientes GLA. Por último, se desarrolló un protocolo experimental y bioinformático para el estudio genético de pacientes con patologías asociadas a malformaciones vasculares que pudo ser extrapolado tanto al diagnóstico asistencial, como a la investigación, de patologías causadas por mutaciones en forma de mosaicismo somático.Vascular malformations are congenital vascular defects produced during the embryological development of the vascular system. They can be divided according to the type of affected vessel into capillary, lymphatic, venous, and arteriovenous malformations. CLAPO syndrome (Capillary malformation of the lower lip, Lymphatic malformation predominant on the face and neck, Asymmetry, and Partial/generalized Overgrowth) and GLA (Generalized Lymphatic Anomaly), are two complex diseases that present lymphatic malformations as one of their main clinical features. The etiology of both diseases is unknown. However, the segmental pattern of clinical manifestations in addition to the high phenotypic heterogeneity observed, seem to point towards somatic mosaicism (post-zygotic alterations) as the pathogenic mechanism. In this project, two cohorts of patients with CLAPO and GLA were clinically and molecularly evaluated with the aim of expanding the clinical knowledge, describing their genetic cause, and developing an experimental protocol for the study of diseases caused by somatic mosaicism. Hence, we analyzed paired blood/tissue samples from 11 and 9 patients with CLAPO and GLA respectively, using custom high-throughput sequencing panels and an inhouse bioinformatic algorithm for the detection of mosaic variants. In addition, a specific protocol for the isolation of lymphatic endothelial cells (LECs) from lymphatic tissues was developed, and a mouse model was generated for the functional analysis of variants. The phenotypic re-evaluation of the patients with CLAPO and GLA allowed us to better define the clinical features and guided the development of follow-up guidelines. Molecular studies identified for the first time activating pathogenic mutations in the PIK3CA gene in 64% and 56% of patients with CLAPO and GLA respectively. All variants were detected in the form of somatic mosaicism. The isolation and characterization of LECs, as well as the generation of a specific animal model of GLA, allowed the functional validation of our genetic results, and provided preclinical and clinical evidences to support the use of rapamycin, a specific inhibitor of mTOR, for the treatment in GLA. Finally, a combined experimental and bioinformatic protocol for the genetic study of patients with pathologies associated with vascular malformations has been developed and tested, and it could be extrapolated to the study of somatic mosaicism disorders

Analysis of the information and communication technologies (ICTs) as viable resources in the development of the speaking skill

The study aims to analyze the Information and Communication Technologies (ICTs)as viable resources in the development of the speaking skill in 8th graders at Ulises Tapia Roa School, Nindiri in the second semester 2020. There were selected 20 high school students and 1 teacher to participate in this work. The instruments that were used to collect reliable information were students survey, teacher’s interview and an observation guide. Afterward, in order to analyze the information gathered through the process of this research, it was used IBM SPSS Statistics 20 Software. This program helped to illustrate the information and results obtained from the tools mentioned above in an organized way through graphics organizer. The results indicated that the Information and Communication Technologies (ICTs) can be considered as viable resources in the development of the speaking skill and improve the Learning process. Moreover, ICTs tools give students and teachers an interactive and collaborative English class. Using technology teachers have more opportunities to enhance their traditional teaching methods for innovative classes. The use of technology has become an important part of the learning process in and out the class. Technology enables teachers to adapt classroom activities, thus enhancing the language learning process of the students. Technology continues to grow in importance as a tool to help teachers facilitate the language learning for their learners. Finally, some recommendations are given to the teacher and students to the integration of the ICTs tools into the classroom and help in the acquisition of the foreign languag

BIM en la construcción

244 páginas.En la actualidad, con la metodología BIM (Building Information Modeling), todos los sistemas de información de los procesos productivos en la obra se han integrado, la información se puede compartir a distancia y en tiempo real con todos los actores involucrados en el proyecto. En estas condiciones, las instituciones generadoras de obras y las empresas prestadoras de servicios se están rediseñando con nuevos modelos de negocios enfocados en satisfacer las actuales demandas y experiencias de los clientes. El libro que aquí se presenta reúne el trabajo de investigación referente a BIM de la Red Académica de Diseño Construcción integrada por académicos de la Facultad de Ingeniería de la Universidad Autónoma de Yucatán, México (UADY), el Worcester Polytechnical Institute (WPI) de Massachusetts, Estados Unidos y del Área de Administración y Tecnología para el Diseño de la Universidad Autónoma Metropolitana, Unidad Azcapotzalco (UAM). También han colaborado con la Red investigadores de la Universidad Politécnica de Madrid (UPM), España y, dentro de la UAM, académicos de la División de Ciencias Básicas e Ingeniería, Departamento de Materiales, del Área de Construcción. Cabe mencionar que los artículos ya han sido publicados con anterioridad en los Anuarios de Administración y Tecnología para el Diseño y las Compilaciones de Artículos de Investigación en Administración y Tecnología para la Arquitectura, Diseño e Ingeniería, productos del trabajo de investigación del Área que edita anualmente desde 1999, como se indica en el índice del presente libro

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Impact of NGS in the medical sciences: genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies

The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes