A new ETV6-RUNX1 in vivo model produces a phenocopy of the human Pb-ALL

Resumen del trabajo presentado al 57th American Society of Hematology (ASH) Annual Meeting and Exposition, celebrado en Orlando (Florida-US) del 5 al 8 de diciembre de 2015.-- et al.[Introduction]: The ETV6-RUNX1 fusion gene, the most common subtype of childhood pB-ALL, is acquired in utero, producing a persistent and hidden preleukemic clone. However, the underlying mechanism explaining how the preleukemic clone evolves to pB-ALL remains to be identified. The lack of genetically engineered human-like ETV6-RUNX1pB-ALL models has hampered our understanding of the pathogenesis of this disease. [Methods]: We have used a novel experimental approach to generate a murine strain that mimics the human ETV6-RUNX1 pB-ALL. We expressed ETV6-RUNX1 specifically in hematopoietic stem cells (HSC) of C57BL/6 x CBA mice by placing ETV6-RUNX1 under the control of the Sca1 promoter. Two founder mice were obtained for the Sca1-ETV6-RUNX1 transgene, which had normal gestation, were viable and developed normally. Sca1-ETV6-RUNX1 transgenic mice were characterized with respect to clinical, immunephenotypic and genetic characteristics. For the detection of shared secondary genomic alterations we analyzed three murine Sca1-ETV6-RUNX1 and 11 ETV6-RUNX1positive human pB-ALL and corresponding germline by whole-exome (WES) and whole-genome sequencing using a HiSeq 2500 (Illumina) platform.[Results]: In our transgenic murine model Sca1-ETV6-RUNX1 transgene expression was detected in HSCs, while there was no detectable expression in pro B cells or later stages of B-cell development, which mimics human ETV6-RUNX1 preleukemic biology. Sca1-ETV6-RUNX1 mice developed exclusively pB-ALL at a low penetrance (7.5%; 3 out of 40) with a CD19+B220+IgM- cell surface phenotype. Overall survival was not significantly reduced compared to wild-type mice (P value = 0.7901). pB-ALL in Sca1-ETV6-RUNX1 mice manifested with splenomegaly, disruption of splenic architecture, and appearance of blast cells in the peripheral blood (PB). All leukemic cells displayed clonal immature BCR rearrangement. Tumor pro B cells grew independent of IL-7 and were able to propagate the disease when transplanted into sub-lethally irradiated syngeneic recipient mice. Whole-exome sequencing of murine pB-ALL revealed in one mouse a deletion of three amino acids in the B-cell differentiation factor EBF1, which is well known in the context of human ETV6-RUNX1 leukemia. Additionally we found mutations in genes implicated in histone modification, i.e. in KDM5Ccausing a premature translation stop. We compared the genomic alterations detected in the mouse model to published genomic data of pediatric ETV6-RUNX1 pB-ALL and identified multiple copy number variations, which are shared between the murine and human ETV6-RUNX1 pB-ALL. Among them were copy number gains and losses including i.e. the tumorsuppressor locus CDKN2A/B with a well-known role in human and mouse pB-ALL. A high proportion of genes implicated in histone modification was also mutated in published data of human ETV6-RUNX1 positive pB-ALL. We validated this novel finding of recurrent alterations of histone modifying genes in both the murine model and the human disease using an independent human ETV6-RUNX1 cohort of 11 patients. In this cohort were able to reproduce this finding. Similar to the murine model, we also detected a missense mutation in the methyltransferase KDM5C in one patient of our cohort of ETV6-RUNX1positive patients.[Conclusion]: In summary, we have characterized a new Sca1-ETV6-RUNX1 mouse model and this is, to our knowledge the first model, which represents a phenocopy of the human pB-ALL. Sca1-ETV6-RUNX1 mice develop exclusively pB-ALL at a very low penetrance as it is the case in human ETV6-RUNX1 positive pB-ALL. The acquisition of secondary mutations in pB-ALL with a high proportion in histone modifying genes confers the second hit for the conversion of a preleukemic clone into the clinically overt ETV6-RUNX1 positive pB-ALL disease. These findings are important for encouraging novel interventions that might help to prevent or treat ETV6-RUNX1 positive childhood leukemias.Peer Reviewe

Predictors of Loss of Functional Independence in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group

COPPADIS Study Group.[Background and objective] The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson’s disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD).[Patients and Methods] PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%.[Results] In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen’s effect size = −0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2.[Conclusions] In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.Fundación Curemos el Parkinson (www.curemoselparkinson.org).Peer reviewe

Hacia una internacionalización de calidad. Buenas prácticas para la integración académica y personal del estudiante Erasmus en el Grado de Español: Lengua y Literatura (Fase I)

Memoria del Proyecto de Innovación Docente Hacia una internacionalización de calidad. Buenas prácticas para la integración académica y personal del estudiante Erasmus en el Grado en Español: Lengua y Literatura(Fase I), desarrollado en la Facultad de Filología de la Universidad Complutense de Madrid durante el curso académico 2018-2019. El proyecto buscó incrementar el grado de integración personal y académica del estudiante de intercambio Erasmus del Grado en Español: Lengua y Literatura de la UCM a través de una serie de acciones conjuntas que incluyeron, entre otras: el desarrollo de tutorías individuales y talleres y actividades interculturales, la puesta en marcha de un sistema de mentorías imbricado en el plan intergeneracional de la UCM, la elaboración de Guías para el estudiante Erasmus entrante y saliente, reuniones informativas, la realización de cuestionarios de satisfacción académica y personal, la promoción de los Premios para alumnos internacionales de la Facultad de Filología de la UCM o la celebración de una pionera jornada sobre "La internacionalización de los Grados de Estudios Hispánicos: Seminario de buenas prácticas en la gestión de la movilidad", según se detalla en la Memoria

Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas

TFG 2014/2015

Amb aquesta publicació, EINA, Centre universitari de Disseny i Art adscrit a la Universitat Autònoma de Barcelona, dóna a conèixer el recull dels Treballs de Fi de Grau presentats durant el curs 2014-2015. Voldríem que un recull com aquest donés una idea més precisa de la tasca que es realitza a EINA per tal de formar nous dissenyadors amb capacitat de respondre professionalment i intel·lectualment a les necessitats i exigències de la nostra societat. El treball formatiu s’orienta a oferir resultats que responguin tant a paràmetres de rigor acadèmic i capacitat d’anàlisi del context com a l’experimentació i la creació de nous llenguatges, tot fomentant el potencial innovador del disseny.Con esta publicación, EINA, Centro universitario de diseño y arte adscrito a la Universidad Autónoma de Barcelona, da a conocer la recopilación de los Trabajos de Fin de Grado presentados durante el curso 2014-2015. Querríamos que una recopilación como ésta diera una idea más precisa del trabajo que se realiza en EINA para formar nuevos diseñadores con capacidad de responder profesional e intelectualmente a las necesidades y exigencias de nuestra sociedad. El trabajo formativo se orienta a ofrecer resultados que respondan tanto a parámetros de rigor académico y capacidad de análisis, como a la experimentación y la creación de nuevos lenguajes, al tiempo que se fomenta el potencial innovador del diseño.With this publication, EINA, University School of Design and Art, affiliated to the Autonomous University of Barcelona, brings to the public eye the Final Degree Projects presented during the 2014-2015 academic year. Our hope is that this volume might offer a more precise idea of the task performed by EINA in training new designers, able to speak both professionally and intellectually to the needs and demands of our society. The educational task is oriented towards results that might respond to the parameters of academic rigour and the capacity for contextual analysis, as well as to considerations of experimentation and the creation of new languages, all the while reinforcing design’s innovative potential

New records of the invasive alien plant pest Halyomorpha halys (Stål, 1855) in the Iberian Peninsula (Heteroptera: Pentatomidae)

Se cita per primera vegada l'espècie invasora Halyomorpha halys (Stål, 1855) a la província de Barcelona. Les noves localitats són a un centenar de kilòmetres més al sud de la primera troballa de l'espècie a la península Ibèrica. S'alerta de la importància econòmica que comporta aquesta plaga en cultius extensius, de fruiters o d'horta. No cal menysprear les molèsties per a la població quan l'insecte es congrega en els edificis per a hibernar-hi.The brown marmorated stink bug Halyomorpha halys (Stål, 1855) is reported in the province of Barcelona for the first time. Now locations are a hundred kilometer southwards from the first report in the Iberian Peninsula. An alert is made due to the economic importance that this plant pest species has on field, fruit and vegetable crops. Nuisance to people when insects congregate inside buildings to overwinter is not negligible either

Cancer stem cells as a result of a reprogramming-like mechanism: implications in tumor development and treatment

Several recent studies of the effect of oncogenes in stem cells in cancer development implicate that tumor reprogramming (where the maintenance of oncogene expression is not critical for the generation of differentiated tumor cells) might represent a potentially important mechanism of tumor development for many types of cancer and that, if this is the case, the oncogenes that initiate tumor formation might be dispensable for tumor progression and/or maintenance. The practical implications that this new point of view has for the therapy of cancer are obviously enormous. This chapter addresses the impact of these results toward a better understanding of carcinogenesis and proposes research avenues for tackling these issues in the future.Peer Reviewe

Tumoral stem cell reprogramming as a driver of cancer: Theory, biological models, implications in cancer therapy

Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumor cells. However, recent evidences have revealed that cancer stem cells could arise through a tumor stem cell reprogramming mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of cancer development and proposes new approaches to treat cancer in the future.Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), the ARIMMORA Project (FP7-ENV-2011, European Union Seventh Framework Program), by Junta de Castilla y Leon (BIO/SA06/13) and by proyecto en red de investigación en celulas madre tumorales supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. ISG is an API lab of the EuroSyStem project and a partner within the Marie Curie Initial Training Network DECIDE (decision-making within cells and differentiation entity therapies). LRR was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI020-12).Peer Reviewe

Genetic background affects susceptibility to tumoral stem cell reprogramming

The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRA BLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRA BLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRA BLp210 FVB mice developed thymomas that were not seen in the Sca1- BCRA BLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control.Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by MEC OncoBIO ConsoliderIngenio 2010 (Ref. CSD2007-0017), by NIH grant (R01CA109335-04A1), the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and by proyecto en red de investigación en celulas madre tumorales supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER program.Peer Reviewe