29 research outputs found
Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia
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
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Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
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
Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
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
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
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
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
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
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
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E280A PS‐1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles
A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin‐1 (PS‐1) gene on chromosome 14 in affected individuals in each of seven Colombian early‐onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two‐point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS‐1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997. © 1997 Wiley‐Liss, Inc
Factores modificadores de la edad de inicio del Alzheimer familiar por mutación (e280a de la ps-1)
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