Aplicación de herramientas tecnológicas en la enseñanza de la ingeniería estructural

Traditionally it has been conceived that meaningful learning in students is achieved by understanding concepts or definitions through theory, laboratory, and field practices, as well as an enriching component, called creativity. With this background, this article aims to highlight that in addition to the elements of meaningful learning already mentioned, this process must be accompanied using technological tools, such as software, hardware, learning management systems, and internet connectivity, to expedite the activities that comprise each one of the goals involved in the Programs of the Academic Units (PUA) or also known as descriptive letters. This manuscript develops a case study in the area of ​​structural engineering, which is analyzed by the authors applying the three Laws of Newton or also called equilibrium, which is validated through the Opensees programming language, recognized for being Opensource. developed by the University of California Berkeley, the Midas Gen structural design and analysis software. The results obtained are approximate in the determination of reactions and internal forces, with a significant difference in solution times and availability of digital tools.Tradicionalmente se ha concebido que el aprendizaje significativo en los estudiantes se logra mediante la comprensión de conceptos o definiciones a través de la teoría, prácticas de laboratorio y campo, además de un componente enriquecedor que se denomina creatividad. Con este antecedente el presente artículo tiene como objetivo resaltar que además de los elementos del aprendizaje significativo ya enunciados, este proceso debe estar acompañado del uso de herramientas tecnológicas, tales como, software, hardware, sistemas del manejo del aprendizaje, la conectividad a internet, con el propósito agilizar las actividades que comprenden cada una de las metas involucradas en los Programas de las Unidades Académicas(PUA) o también conocidas como cartas descriptivas. En particular este manuscrito desarrolla un caso de estudio en el área de ingeniería estructural, el cual es analizado por los autores aplicando las tres Leyes de Newton o también denominadas de equilibrio, el cual es validado mediante el lenguaje de programación Opensees, reconocido por ser Opensource desarrollado por la Universidad de California Berkeley, el software de análisis y diseño estructural Midas Gen. Los resultados obtenidos son aproximados en la determinación de reacciones y fuerzas internas, con diferencia significativa en tiempos de solución y disponibilidad de herramientas digitales

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.</p

Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.This research was supported by the European Research Council (H2020) (CoG-2014-646903), the Agencia Estatal de Investigacion/European Re- ´ gional Development Fund (SAF2016-80481-R and SAF2016-75442-R), and the Catalunya Government (SGR330 and PERIS 2017) (P.M.), as well as the Asociacion Española Contra el C ´ ancer, Beca FERO, and the ´ ISCIII/FEDER (PI17/01028) (C.B.). P.M. also acknowledges institutional support from the Obra Social La Caixa-Fundacio Josep Carreras. J.G.P. ` holds a Miguel Servet contract (CP15/00014), and O.B.-L. is supported by an AGAUR-FI fellowship from the Catalan Government. P.M. is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).Peer reviewe

La restauración de la función de p53 retrasa el progreso de la Leucemia Mieloide Crónica causa por p210BCR-ABL en un modelo murino

[ES] Esta tesis busca entre sus objetivos: a) Caracterizar la cooperación entre la falta de función de p53 y el oncogén p210BCR-ABL en la progresión de la enfermedad causada por este estímulo oncogénico, en nuestro modelo p53ERTAMKI x Sca1-BCRABLp210. b) Determinar el estadio de la enfermedad en que la restauración de la funcionalidad de p53 ofrece una oportunidad terapéutica frente a la Leucemia Mieloide Crónica. c) Determinar si la restauración de p53 modifica fenotípicamente a la enfermedad. d) Estudiar las bases de los procesos celulares y moleculares del potencial efecto terapéutico de la restauración de p53.[EN] This thesis seeks among its objectives: a) To characterize the cooperation between the lack of function of p53 and the oncogene p210BCR-ABL in the progression of the disease caused by oncogenic stimuli, in our model p53ERTAMKI x Sca1-BCRABLp210. b) Determine the stage of the disease in which the restoration of p53 function provides a therapeutic opportunity against chronic myeloid leukemia. c) Determine whether the restoration of p53 phenotypic alterations to the disease. d) To study the basis of the cellular and molecular potential therapeutic effect of the restoration of p53

Deregulation of genes related to iron and mitochondrial metabolism in refractory anemia with ring sideroblasts

The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.</p

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NFκB, thus revealing a new putative strategy for therapeutically targeting AML cells

Most representative deregulated cellular functions in RARS patients respect to the RCUD group.

<p>Most representative deregulated cellular functions in RARS patients respect to the RCUD group.</p