Genome-wide profiling of methylation identifies novel targets with aberrant hyper-methylation and reduced expression in low-risk myelodysplastic syndromes

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. © 2013 Macmillan Publishers Limited All rights reserved

El proyecto de El Berrocal: síntesis preliminar

El Berrocal is an international research project on the natural radionuclide migration in a fissured granitic environment. This project is being carried out in the El Berrocal zone, north of the village of Nombela (Toledo). The gelogical formation studied is a granitic pluton with an epithermal vein-type mineralization comprising quartz, sphalerite, pyrite and chalcopyrite; and pitchblende, pyrite, carbonates and barite. The activities of the project are focused on the structural, lithological, geochemical, hydrochemical and hydrogeological aspects of the granite-U mineralization system, in order to establish a migration model of the natural radionuclides of the environment. The concurrence of the tectonic, hydrothermal and supergenic processes has originated several U remobilizations during the deuteric, hydrothermal and supergenic alteration phases, which affected the system. These phases are responsible of the mineralogical species and present distribution of this element within the system. The Th remobilization is much more limited, due to its different geochemical behavior. The present water-rock interaction processes account for the different types of water existing in the system, which are sulphatic, in the shallowest zones, and calcium bicarbonated in the deepest. The U contents in these waters vary from 1 to 100 ppb. The hydrogeology of the zone is controlled, at a local scale, by the topography and the fracture network, and the mineralized quartz dyke plays a major role on the groundwater flow. The isotopic analyses of the U and Th series in the infill materials seem to indicate recent sorption-desorption U processes and coprecipitation with carbonates.«El Berrocal», es un proyecto internacional de investigación sobre la migración de radionucleidos naturales en un medio granítico fisurado. Este proyecto se está desarrollando en la zona de El Berrocal, situada al norte de Nombela (Toledo), en un plutón granítico con una mineralización filoniana epitermal de uranio. El objetivo del proyecto es conocer los aspectos estructurales, litológicos, geoquímicos, hidroquímicos e hidrogeológicos del sistema granito-mineralización de U, a fin de establecer un modelo de migración de los radionucleidos naturales del medio. La convergencia de procesos tectónicos, hidrotermales y supergénicos ha dado lugar a sucesivas removilizaciones del uranio durante las fases deutérica, hidrotermal y supergénica, que afectaron al sistema. Estas fases son las responsables de la mineralogía y distribución actual de dicho elemento en el sistema. La removilización del torio es mucho más restringida debido a su diferente comportamiento geoquímico. Los procesos actuales de interacción agua-roca están condicionando los tipos de aguas existentes en el sistema que son: sulfatadas, en las zonas más superficiales y bicarbonatadas cálcicas, en las más profundas. Los contenidos en uranio en estas aguas están comprendidos entre 1 y 100 ppb. La hidrogeología de la zona está controlada, a nivel local, por la topografía y la red de fracturación, siendo el dique de cuarzo mineralizado un accidente con repercusión importante en la circulación de las aguas subterráneas. El análisis isotópico de las series del uranio y del torio en rellenos fisurales parece indicar procesos recientes de sorción-desorción de uranio y coprecipitación con carbonatos

Acceptability and feasibility of a virtual community of practice to primary care professionals regarding patient empowerment: A qualitative pilot study

Background: Virtual communities of practice (vCoPs) facilitate online learning via the exchange of experiences and knowledge between interested participants. Compared to other communities, vCoPs need to overcome technological structures and specific barriers. Our objective was to pilot the acceptability and feasibility of a vCoP aimed at improving the attitudes of primary care professionals to the empowerment of patients with chronic conditions. Methods: We used a qualitative approach based on 2 focus groups: one composed of 6 general practitioners and the other of 6 practice nurses. Discussion guidelines on the topics to be investigated were provided to the moderator. Sessions were audio-recorded and transcribed verbatim. Thematic analysis was performed using the ATLAS-ti software. Results: The available operating systems and browsers and the lack of suitable spaces and time were reported as the main difficulties with the vCoP. The vCoP was perceived to be a flexible learning mode that provided up-to-date resources applicable to routine practice and offered a space for the exchange of experiences and approaches. Conclusions: The results from this pilot study show that the vCoP was considered useful for learning how to empower patients. However, while vCoPs have the potential to facilitate learning and as shown create professional awareness regarding patient empowerment, attention needs to be paid to technological and access issues and the time demands on professionals. We collected relevant inputs to improve the features, content and educational methods to be included in further vCoP implementation. Trial registration: ClinicalTrials.gov, NCT02757781. Registered on 25 April 2016.This study was financed by Instituto de Salud Carlos III and Cofinanced by Fondo Europeo de Desarrollo Regional (FEDER). Ministerio de Economía y Competitividad. Gobierno de España. (PI15/00164, PI15/00586, PI15/00566

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006

Acceptability and feasibility of a virtual community of practice to primary care professionals regarding patient empowerment : A qualitative pilot study

Background: Virtual communities of practice (vCoPs) facilitate online learning via the exchange of experiences and knowledge between interested participants. Compared to other communities, vCoPs need to overcome technological structures and specific barriers. Our objective was to pilot the acceptability and feasibility of a vCoP aimed at improving the attitudes of primary care professionals to the empowerment of patients with chronic conditions. Methods: We used a qualitative approach based on 2 focus groups: one composed of 6 general practitioners and the other of 6 practice nurses. Discussion guidelines on the topics to be investigated were provided to the moderator. Sessions were audio-recorded and transcribed verbatim. Thematic analysis was performed using the ATLAS-ti software. Results: The available operating systems and browsers and the lack of suitable spaces and time were reported as the main difficulties with the vCoP. The vCoP was perceived to be a flexible learning mode that provided up-to-date resources applicable to routine practice and offered a space for the exchange of experiences and approaches. Conclusions: The results from this pilot study show that the vCoP was considered useful for learning how to empower patients. However, while vCoPs have the potential to facilitate learning and as shown create professional awareness regarding patient empowerment, attention needs to be paid to technological and access issues and the time demands on professionals. We collected relevant inputs to improve the features, content and educational methods to be included in further vCoP implementation. Trial registration: ClinicalTrials.gov, NCT02757781. Registered on 25 April 2016

Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA

The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E−4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p < 0.001), offering DNA-DeepNGS a sensitivity of 92% and specificity of 82%. The clinical impact was studied in a cohort of 129 patients (n = 67 for CML and n = 62 for B-ALL patients). A total of 162 samples (n = 86 CML and n = 76 B-ALL) were studied. Of them, 27 out of 86 harbored mutations (6 in warning and 21 in failure) for CML, and 13 out of 76 (2 diagnostic and 11 relapse samples) did in B-ALL patients. In addition, in four cases were detected mutation despite BCR::ABL1 < 1%. In conclusion, we were able to detect KD ABL1 mutations with a 1.0E−4 sensitivity by NGS using DNA as starting material even in patients with low levels of disease.Tis project was funded in part by CRIS CANCER FOUNDATION

Latin American consumption of major food groups: Results from the ELANS study

Background The Latin American (LA) region is still facing an ongoing epidemiological transition and shows a complex public health scenario regarding non-communicable diseases (NCDs). A healthy diet and consumption of specific food groups may decrease the risk of NCDs, however there is a lack of dietary intake data in LA countries. Objective Provide updated data on the dietary intake of key science-based selected food groups related to NCDs risk in LA countries. Design ELANS (Latin American Study of Nutrition and Health) is a multicenter cross-sectional study assessing food consumption from an urban sample between15 to 65 years old from 8 LA countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Peru, and Venezuela). Two 24-HR were obtained from 9, 218 individuals. The daily intake of 10 food groups related to NCDs risk (fruits; vegetables; legumes/beans; nuts and seeds; whole grains products; fish and seafood; yogurt; red meat; processed meats; sugar-sweetened beverages (ready-to-drink and homemade)) were assessed and compared to global recommendations. Results Only 7.2% of the overall sample reached WHO's recommendation for fruits and vegetables consumption (400 grams per day). Regarding the dietary patterns related to a reduced risk of NCDs, among the overall sample legumes and fruits were the food groups with closer intake to the recommendation, although much lower than expected (13.1% and 11.5%, respectively). Less than 3.5% of the sample met the optimal consumption level of vegetables, nuts, whole grains, fish and yogurt. Largest country-dependent differences in average daily consumption were found for legumes, nuts, fish, and yogurt. Mean consumption of SSB showed large differences between countries. Conclusion Diet intake quality is deficient for nutrient-dense food groups, suggesting a higher risk for NCDs in the urban LA region in upcoming decades. These data provide relevant and up-to-date information to take urgent public health actions to improve consumption of critically foods in order to prevent NCDs. Copyright

Phenomenology of high-ozone episodes in NE Spain

Ground-level and vertical measurements (performed using tethered and non-tethered balloons), coupled with modelling, of ozone (O3), other gaseous pollutants (NO, NO2, CO, SO2) and aerosols were carried out in the plains (Vic Plain) and valleys of the northern region of the Barcelona metropolitan area (BMA) in July 2015, an area typically recording the highest O3 episodes in Spain. Our results suggest that these very high O3 episodes were originated by three main contributions: (i) the surface fumigation from high O3 reservoir layers located at 1500-3000 m a.g.l. (according to modelling and non-tethered balloon measurements), and originated during the previous day(s) injections of polluted air masses at high altitude; (ii) local/regional photochemical production and transport (at lower heights) from the BMA and the surrounding coastal settlements, into the inland valleys; and (iii) external (to the study area) contributions of both O3 and precursors. These processes gave rise to maximal O3 levels in the inland plains and valleys northwards from the BMA when compared to the higher mountain sites. Thus, a maximum O3 concentration was observed within the lower tropospheric layer, characterised by an upward increase of O3 and black carbon (BC) up to around 100-200 m a.g.l. (reaching up to 300 µg m−3 of O3 as a 10 s average), followed by a decrease of both pollutants at higher altitudes, where BC and O3 concentrations alternate in layers with parallel variations, probably as a consequence of the atmospheric transport from the BMA and the return flows (to the sea) of strata injected at certain heights the previous day(s). At the highest altitudes reached in this study with the tethered balloons (900-1000 m a.g.l.) during the campaign, BC and O3 were often anti-correlated or unrelated, possibly due to a prevailing regional or even hemispheric contribution of O3 at those altitudes. In the central hours of the days a homogeneous O3 distribution was evidenced for the lowest 1 km of the atmosphere, although probably important variations could be expected at higher levels, where the high O3 return strata are injected according to the modelling results and non-tethered balloon data. Relatively low concentrations of ultrafine particles (UFPs) were found during the study, and nucleation episodes were only detected in the boundary layer. Two types of O3 episodes were identified: type A with major exceedances of the O3 information threshold (180 µg m−3 on an hourly basis) caused by a clear daily concatenation of local/regional production with accumulation (at upper levels), fumigation and direct transport from the BMA (closed circulation); and type B with regional O3 production without major recirculation (or fumigation) of the polluted BMA/regional air masses (open circulation), and relatively lower O3 levels, but still exceeding the 8 h averaged health target. To implement potential O3 control and abatement strategies two major key tasks are proposed: (i) meteorological forecasting, from June to August, to predict recirculation episodes so that NOx and VOC abatement measures can be applied before these episodes start; (ii) sensitivity analysis with high-resolution modelling to evaluate the effectiveness of these potential abatement measures of precursors for O3 reduction

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3–5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. © 2021, The Author(s), under exclusive licence to Springer Nature Limited