29 research outputs found

    Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia

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    Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41). Complex karyotype by cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL

    Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

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    Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

    Dilemas de la paz territorial en los tiempos del post-acuerdo: Experiencias territoriales en la región del eje cafetero

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    El presente libro, tejido a múltiples voces, perspectivas, abordajes teóricos y metodológicos, se inscribe en los proyectos editoriales de la región eje cafetero que se alejan de las lecturas dicotómicas o categóricas, por el contrario, transita los laberintos que se abren camino cuando una sociedad se traza la difícil tarea de construir una paz territorial en medio de los escenarios de la guerra. La memoria social, las voces de sobrevivientes, organizaciones sociales, medios de comunicación, posturas oficiales y cívicas, las apuestas pedagógicas por la paz, las lecturas territoriales del conflicto y las múltiples secuelas de las variadas violencias constituyen los horizontes temáticos de los 12 capítulos del presente libro, interpretando las complejas realidades presentes en el corazón de la región cafetera. Resultado de multiplicidad de voces, formaciones disciplinares y experiencias vitales, así como de la diversidad de organizaciones, entidades y universidades que acogieron el llamado del ¨Programa de Investigación en Transiciones, Violencias y Memoria¨ para construir una apuesta editorial recreada en los marcos de la sociología relacional, las cuales, a partir de perspectivas históricas, críticas y situadas, adelantaron análisis situados en la región cafetera en los tiempos del postacuerdo.Ruta Pacífica de las Mujeres ; Sistema Universitario del Eje Cafetero ; Universidad Católica de Manizales ; Universidad Católica de Pereira ; Vicerrectoría de Investigaciones, Innovación y Extensión Editorial Universidad Tecnológica de Pereira Pereira, Colombia.CONTENIDO Prólogo ....................................................................................................................6 Jefferson Jaramillo Marín Encrucijadas de una paz inacabada. A manera de introducción.....................12 Por: Luis Adolfo Martínez Herrera y Oscar Arango Gaviria PARTE I................................................................................................................20 Las tensiones de la memoria histórica y de los medios de comunicación en el contexto regional ..................................................................................................20 CAPÍTULO UNO.................................................................................................21 La memoria histórica en la región......................................................................22 Alberto Berón Ospina CAPÍTULO DOS .................................................................................................38 La mutación del periodismo en tiempos transicionales....................................39 Juan Antonio Ruiz Romero PARTE II..............................................................................................................73 Excombatientes, reintegrados y sobrevivientes del conflicto armado..............73 CAPÍTULO TRES...............................................................................................74 Una guerra silenciada: enunciaciones iniciales sobre los actores ...................75 y las dinámicas del conflicto armado en el Eje Cafetero ..................................75 Oscar Fernando Martínez Herrera y Miguel Gómez Bermeo CAPÍTULO CUATRO .....................................................................................106 Experiencia institucional de la Agencia para la Reincorporación y la Normalización en la atención de personas que se acogen a procesos de desarme, desmovilización, reintegración y reincorporación en el Eje Cafetero: 2003- 2020 .....................................................................................................................107 José Luis Medrano Benavides, Lina Marcela Duque Ossa, Oscar Fernando Sanmiguel CAPÍTULO CINCO..........................................................................................137 Entre víctimas y victimarios. Percepciones sociales de sobrevivientes del conflicto armado ................................................................................................................138 Luis Adolfo Martínez Herrera y Nicolás Muñoz Giraldo CAPÍTULO SEIS...............................................................................................173 Transición y reincorporación desde el Jimmy Tatamá: entre retórica y territorialidad.....................................................................................................174 Julio César Murillo García PARTE III...........................................................................................................197 Organizaciones sociales, historias y pedagogías regionales para la paz .......197 CAPÍTULO SIETE............................................................................................198 La Unión Patriótica: notas históricas sobre su acción política en el departamento de Risaralda, marzo 28 de 1984 - enero 6 de 1989 ..........................................199 Jahir Rodríguez Rodriguez CAPÍTULO OCHO ...........................................................................................250 Quinchía: memoria latente de un pueblo ultrajado. Reflexiones sobre la reparación simbólica..........................................................................................251 Gina M. Arias-Rodríguez y Érika V. Tobón-González CAPÍTULO NUEVE .........................................................................................279 La escuela de liderazgo para la paz: seis años al servicio dela educación para la paz ...................................................................................................................280 Oscar Arango Gaviria CAPÍTULO DIEZ..............................................................................................313 Una experiencia de formación para la paz ......................................................314 Claudia Mónica Londoño V. y Claudia Patricia Herrera G.. ........................314 PARTE IV...........................................................................................................338 Secuelas del conflicto armado y redefiniciones de las nociones de memoria y transiciones..........................................................................................................338 CAPÍTULO ONCE............................................................................................339 Comprensiones psicosociales sobre la desaparición forzada en Colombia...340 Mitzin Guadalupe Mata Mata y Mauricio Orozco Vallejo CAPÍTULO DOCE............................................................................................362 Narrativas, obsolescencias y hegemonías.........................................................363 Camilo Lozano River

    Toxic and therapeutic effects of Nifurtimox and Benznidazol on Trypanosoma cruzi ex vivo infection of human placental chorionic villi explants

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    Artículo de publicación ISINifurtimox (Nfx) and Benznidazole (Bnz) are the only available drugs in use for the treatment of Chagas disease. These drugs are recommended but not fully validated in evidence-based medicine and reports about the differential toxicity of both drugs are controversial. Here, we evaluated the toxic and therapeutic effects of Nfx and Bnz on human placental chorionic villi explants (HPCVE) during ex vivo infection of Trypanosoma cruzi, performing histopathological, histochemical, immunohistochemical as well as immunofluorescence analysis of the tissue. Additionally, we determined the effect of both drugs on parasite load by real time PCR. Bnz prevents the parasite induced tissue damage in ex vivo infected HPCVE compared to Nfx, which is toxic per se. The presence of T. cruzi antigens and DNA in infected explants suggests that these drugs do not impair parasite invasion into the HPCVE. Additionally, our results confirm reports suggesting that Bnz is less toxic than Nfx and support the need for the development of more effective and better-tolerated drugs.This study was supported by grants 1120230 (to UK), 1130113 (to NG), 1130189 (to JM), 11110182 (to RL) from FONDECYT, Chile and by grant CONICYT-PBCT Anillo ACT 112, Chile

    Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications

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    Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research

    Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

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    Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established WHO disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS

    A Hybrid Model for COVID-19 Monitoring and Prediction

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    COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has a case-fatality rate of 2–3%, with higher rates among elderly patients and patients with comorbidities. Radiologically, COVID-19 is characterised by multifocal ground-glass opacities, even for patients with mild disease. Clinically, patients with COVID-19 present respiratory symptoms, which are very similar to other respiratory virus infections. Our knowledge regarding the SARS-CoV-2 virus is still very limited. These facts make it vitally important to establish mechanisms that allow to model and predict the evolution of the virus and to analyze the spread of cases under different circumstances. The objective of this article is to present a model developed for the evolution of COVID in the city of Manizales, capital of the Department of Caldas, Colombia, focusing on the methodology used to allow its application to other cases, as well as on the monitoring tools developed for this purpose. This methodology is based on a hybrid model which combines the population dynamics of the SIR model of differential equations with extrapolations based on recurrent neural networks. This combination provides self-explanatory results in terms of a coefficient that fluctuates with the restraint measures, which may be further refined by expert rules that capture the expected changes in such measures

    Factores modificadores de la edad de inicio del Alzheimer familiar por mutación (e280a de la ps-1)

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    IP 1115-04-007-99Incluye anexosARTICULO(S) EN REVISTA: Factores modificadores de la edadde inicio de laenfermedad de alzheimer por;mutacion E280A de la presenilina-1 / Silvia Mejia, Francisco Lopera, DavidPineda, Alfredo Ardila, Sonia;Moreno, Liliana Cadavid. - En: Neuropsicologia, Neuropsiquiatriay Neurociencias vol. 1 No 2 p. 167-176. -;Cognitive decline in patients wite familial alzheimer's diseaseassociatedwith E280a presenilin-1 mutation: a;longitudinal study / Monica Rosselli, Alfredo Ardila, Sonia Moreno, Virginia Standish, Juan Carlos Arango;Lasprilla, Victoria Tirado, Jorge Ossa, Alison M. Goate, KennethS. Kosik,Francisco Lopera. - En: Journal of;Clinical and Experimental Neuropsychology vol. 22 No 4 (2000);p. 483-495.'- Age of onset in familial;alzheimer's disense: eduentional effects / Silvia Mejia, DavidPineda, Alfredo Ardila, M. Giraldo, Francisco;Lopera. - En: Journal of the International NeuropsychologicalSociety. - ISSN 13556177. - Alteraciones en el;SPECT cerebral antes del inicio de la enfermedad de alzheimerprecoz producida por la mutacion E280A de la PS1;/ Francisco Lopera, Isolda Siegert, Mauricio Arcos Burgos,Alejandro Rios.'- en: Acta Medica colombiana vol.;25 No 3 (2000 : may-jun); p. 144-149
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