Analysis of Intratumoral Heterogeneity in Myelodysplastic Syndromes with Isolated del(5q) Using a Single Cell Approach

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological diseases. Among them, the most well characterized subtype is MDS with isolated chromosome 5q deletion (MDS del(5q)), which is the only one defined by a cytogenetic abnormality that makes these patients candidates to be treated with lenalidomide. During the last decade, single cell (SC) analysis has emerged as a powerful tool to decipher clonal architecture and to further understand cancer and other diseases at higher resolution level compared to bulk sequencing techniques. In this study, a SC approach was used to analyze intratumoral heterogeneity in four patients with MDS del(5q). Single CD34+CD117+CD45+CD19- bone marrow hematopoietic stem progenitor cells were isolated using the C1 system (Fluidigm) from diagnosis or before receiving any treatment and from available follow-up samples. Selected somatic alterations were further analyzed in SC by high-throughput qPCR (Biomark HD, Fluidigm) using specific TaqMan assays. A median of 175 cells per sample were analyzed. Inferred clonal architectures were relatively simple and either linear or branching. Similar to previous studies based on bulk sequencing to infer clonal architecture, we were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS del(5q) and the importance of patient-specific molecular characterization

Factores sociales asociados a la hiperfrecuentación en Centros de Atención Primaria de Salud: un estudio desde el Trabajo Social Sanitario

El objetivo de este trabajo es analizar si existen características de disfunción socio-familiar comunes a los hiperfrecuentadores, y diferentes a las de la población general, que puedan explicar la necesidad de acudir repetidamente a las consultas. Con dicha finalidad, se ha llevado a cabo un estudio de casos y controles transversal, en el Servicio de Atención Primaria (SAP) Esquerra de Barcelona. En concreto, mediante la realización de 162 entrevistas personales a 84 pacientes clasificados como hiperfrecuentadores entre el 1 de septiembre de 2007 y el 31 de agosto de 2008 (visitas CP y/o URG >= 18 (percentil 95 de la distribución de visitas CP y/o URG de los usuarios del SAP) y 78 como no hiperfrecuentadores se aparearon por edad y sexo. Se administraron cuatro cuestionarios: uno de datos sociodemográficos, el test APGAR familiar, las escalas de ansiedad y depresión de Goldberg y la escala de apoyo social funcional de Duke. The objective of this article is to analyze if there exist socio-familiar features common to frequent attenders and different from those of the general population, with the aim to propose a appropriate intervention. In order to develop quantitative study based in an intervention group and a control group, and cross sectional study, in the Primary Health Care Service from a great urban area. Specifically, patients classed as frequent attenders between September 1, 2007 and August 31, 2008 (previous appointments and/or out-of-hours visits > = 18) (Percentile 95 of the distributions of previous appointments and/or out-of-hours visits of the PHCS users). Frequent attenders were joined by age and sex. By means of a personal interview they were administered four questionnaires to a patient’s representative sample: 1. Sociodemographic data index, 2. Family APGAR index, 3. Anxiety-depression Goldberg Scale, and 4. Duke-UNC Functional Questionnaire

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Analysis of Intratumoral Heterogeneity in Myelodysplastic Syndromes with Isolated del(5q) Using a Single Cell Approach

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological diseases. Among them, the most well characterized subtype is MDS with isolated chromosome 5q deletion (MDS del(5q)), which is the only one defined by a cytogenetic abnormality that makes these patients candidates to be treated with lenalidomide. During the last decade, single cell (SC) analysis has emerged as a powerful tool to decipher clonal architecture and to further understand cancer and other diseases at higher resolution level compared to bulk sequencing techniques. In this study, a SC approach was used to analyze intratumoral heterogeneity in four patients with MDS del(5q). Single CD34+CD117+CD45+CD19- bone marrow hematopoietic stem progenitor cells were isolated using the C1 system (Fluidigm) from diagnosis or before receiving any treatment and from available follow-up samples. Selected somatic alterations were further analyzed in SC by high-throughput qPCR (Biomark HD, Fluidigm) using specific TaqMan assays. A median of 175 cells per sample were analyzed. Inferred clonal architectures were relatively simple and either linear or branching. Similar to previous studies based on bulk sequencing to infer clonal architecture, we were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS del(5q) and the importance of patient-specific molecular characterization

Analysis of Intratumoral Heterogeneity in Myelodysplastic Syndromes with Isolated del(5q) Using a Single Cell Approach

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by ineffective differentiation of one or more bone marrow cell lineages. Only 50% of patients with de novo MDS will be found to have cytogenetic abnormalities, of which del(5q) is the most common. In 10% of MDS cases, del(5q) is found as a sole abnormality. In this work, a single cell approach was used to analyze intratumoral heterogeneity in four patients with MDS with isolated del(5q). We were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS with isolated del(5q) and the importance of patient-specific molecular characterization. Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological diseases. Among them, the most well characterized subtype is MDS with isolated chromosome 5q deletion (MDS del(5q)), which is the only one defined by a cytogenetic abnormality that makes these patients candidates to be treated with lenalidomide. During the last decade, single cell (SC) analysis has emerged as a powerful tool to decipher clonal architecture and to further understand cancer and other diseases at higher resolution level compared to bulk sequencing techniques. In this study, a SC approach was used to analyze intratumoral heterogeneity in four patients with MDS del(5q). Single CD34+CD117+CD45+CD19- bone marrow hematopoietic stem progenitor cells were isolated using the C1 system (Fluidigm) from diagnosis or before receiving any treatment and from available follow-up samples. Selected somatic alterations were further analyzed in SC by high-throughput qPCR (Biomark HD, Fluidigm) using specific TaqMan assays. A median of 175 cells per sample were analyzed. Inferred clonal architectures were relatively simple and either linear or branching. Similar to previous studies based on bulk sequencing to infer clonal architecture, we were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS del(5q) and the importance of patient-specific molecular characterization

A genetic analysis of a Spanish population with early onset Parkinson's disease.

IntroductionBoth recessive and dominant genetic forms of Parkinson's disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson's disease in a cohort from central Spain.Methods/patientsWe analyzed a cohort of 117 unrelated patients with early onset Parkinson's disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson's disease and other Parkinsonisms and CNV screening.ResultsTwenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes.ConclusionsOur results contribute to the understanding of the genetic architecture associated with early onset Parkinson's disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson's disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson's disease

. 11-12 Año 6 (2017) enero-agosto. CR. Conservación y restauración

- Editorial por Manuel Alejandro González Gutiérrez y Magdalena Rojas Vences. -Proyecto de atención del acervo documental de Ixcamilpa de Guerrero por Patricia de la Garza Cabrera, Marie Vander Meeren, Laura Olivia Ibarra Carmona, Nora A. Pérez Castellanos, Carlos Orejel Delgadillo, Silvia Yocelin Pérez Ramírez, Débora Y. Ontiveros Ramírez, Denisse Ochoa Gutiérrez, Hugo Arriaga González y Gerardo Gutiérrez. - Haciendo frente a los embates medioambientales: conservación integral del sitio rupestre Cuevas Pintas,Baja California Sur por Sandra Cruz Flores, Alejandra Bourillón Moreno, Anacaren Morales Ortiz, Rodrigo Ruiz Herrera y María Fernanda López-Armenta. - Estrategia para la accesibilidad e inclusión de las personas con discapacidad a zonas arqueológicas “El pasado es de todos” por Daniela Tovar Ortiz y Luis Antonio Huitrón Santoyo. - Atención a grupos sociales. Sistematización de actividades por Manuel González Gutiérrez y Denisse Ochoa Gutiérrez. - Tañendo campanas: trabajando en equipo. Intervención de las campanas robadas en la capilla de Nuestra Señora de la Concepción, Escobedo, Nuevo León por Gabriela Peñuelas Guerrero, Carlos I. Cañete Ibáñez, Claudia Sánchez Gándara, Jannen Contreras Vargas e Ingrid K. Jiménez Cosme. - La apropiación del patrimonio cultural de El Ocote. Una aportación etnográfica para la sostenibilidad por Hugo Arriaga González. - Churubusco. 50 años en la memoria. Una muestra conmemorativa de la conservación en el INAH por Mónica Badillo Leal, Gabriela Gómez Llorente y Mariana Pascual Cáceres. - Los órganos y su conservación en la CNCPC por Norma Cristina Peña Peláez, Sandra María Álvarez Jacinto, José Luis Acevedo Guzmán y Fanny Magaña Nieto. - Conservación de cestería en espiral proveniente de la Cueva de la Candelaria, Torreón, Coahuila: criterios, tratamientos y líneas de investigación por Gloria Martha Sánchez Valenzuela, Miriam Elizabeth Castro Rodríguez y Adriana Reyes García. - Evaluación de recubrimientos de protección para metales. Caso de estudio: Imagen de México, relieve escultórico del Museo Nacional de Antropología. Primera etapa por Aline Moreno Núñez, Arturo A. Egea Salas, Gilda E. Salgado Manzanares, Mauricio B. Jiménez Ramírez, Armando Arciniega Corona y Nora A. Pérez Castellanos. - Patrimonio arqueológico digital. Uso de las tecnologías de la información y la comunicación para la divulgación del patrimonio arqueológico por Eduardo Andrés Escalante Carrillo y Luis Antonio Huitrón Santoyo. - El laboratorio de documentación y análisis tridimensional de la CNCPC. Resultados a un año de operación María Fernanda López-Armenta, Gilberto García Quintana y Celedonio Rodríguez Vidal. - La conservación-restauración de los bienes culturales en el Museo Regional de Querétaro: retos y perspectivas por María del Rosario Bravo Aguilar Conocer y reconocer a los actores sociales en la conservación de los bienes patrimoniales por Mitzi Vania García Toribio y Fanny Magaña Nieto. - Foro Anual de Trabajo. Una historia sin historia en el archivo de la CNCPC por Débora Y. Ontiveros Ramírez. - Expediente de incidentes en el tiempo. El Ehécatl-Quetzalcóatl de Coyoacán y cómo su caso puede ser usado para difundir la conservación en museos por Roberto Velasco Alonso. - Conservación en la vida cotidiana por María Bertha Peña Tenorio. - La Mediateca del INAH por Thalía E. Velasco Castelán. - Finaliza CNCPC la recuperación de sillares simulados originales en la bóveda del templo franciscano de Huaquechula, Puebla por Oscar Adrián Gutiérrez Vargas. - San Francisco de Asís en Huejotzingo, Puebla María Eugenia Rivera Pérez. - Investiga INAH factores de deterioro en la pirámide de la Serpiente Emplumada por Oscar Adrián Gutiérrez Vargas. - Lo que querías saber y no te atrevías a preguntar sobre el INAH en El Ocote por Oscar Adrián Gutiérrez Vargas. - Para saber más de El Caballito por Oscar Adrián Gutiérrez Vargas