The Genome in a Three-Dimensional Context : Deciphering the Contribution of Noncoding Mutations at Enhancers to Blood Cancer

Altres ajuts: AR-M is funded by the José Carreras Leukämie-Stiftung (08R/2019). BJ is funded by La Caixa Banking Foundation Junior Leader project (LCF/BQ/PI19/11690001), by the José Carreras Leukämie-Stiftung (08R/2019), and by the European Hematology Association Advance Research Grant.Associations between blood cancer and genetic predisposition, including both inherited variants and acquired mutations and epimutations, have been well characterized. However, the majority of these variants affect noncoding regions, making their mechanisms difficult to hypothesize and hindering the translation of these insights into patient benefits. Fueled by unprecedented progress in next-generation sequencing and computational integrative analysis, studies have started applying combinations of epigenetic, genome architecture, and functional assays to bridge the gap between noncoding variants and blood cancer. These complementary tools have not only allowed us to understand the potential malignant role of these variants but also to differentiate key variants, cell-types, and conditions from misleading ones. Here, we briefly review recent studies that have provided fundamental insights into our understanding of how noncoding mutations at enhancers predispose and promote blood malignancies in the context of spatial genome architecture

Effective Theory Approach to the Spontaneous Breakdown of Lorentz Invariance

We generalize the coset construction of Callan, Coleman, Wess and Zumino to theories in which the Lorentz group is spontaneously broken down to one of its subgroups. This allows us to write down the most general low-energy effective Lagrangian in which Lorentz invariance is non-linearly realized, and to explore the consequences of broken Lorentz symmetry without having to make any assumptions about the mechanism that triggers the breaking. We carry out the construction both in flat space, in which the Lorentz group is a global spacetime symmetry, and in a generally covariant theory, in which the Lorentz group can be treated as a local internal symmetry. As an illustration of this formalism, we construct the most general effective field theory in which the rotation group remains unbroken, and show that the latter is just the Einstein-aether theory.Comment: 45 pages, no figures

Seroprevalencia de marcadores de infecciones transmisibles por vía transfusional en banco de sangre de Colombia

OBJETIVO: Determinar la seroprevalencia de marcadores de infecciones transmisibles por vía transfusional. MÉTODOS: Estudio transversal con fuente de información secundaria, basada en los resultados de pruebas biológicas en los donantes de un banco de sangre de Medellín, Colombia, de 2007 a 2010. Se determinó la seroprevalencia de los marcadores de infección y se compararon según sexo y tipo de donante a través de análisis de frecuencias, chi cuadrado, Fisher y razones de prevalencia. RESULTADOS: La población de base estuvo conformada por 65.535 donantes de los cuales, 3,3% presentaran al menos una prueba biológica positiva. El marcador más prevalente en las pruebas del banco de sangre fue sífilis (1,2%), seguido de tripanosomiasis (1,0%), virus de la hepatitis C (VHC) (0,6%), virus de la inmunodeficiencia humana (VIH) (0,5%) y virus de la hepatitis B (VHB) (0,2%). Con base en el laboratorio de referencia se halló una prevalencia de 0,6% para sífilis, 0,1% para VHB y 0% para VHC, VIH y Chagas. Se hallaron diferencias estadísticas en la prevalencia de VHB y sífilis según sexo y tipo de donante. CONCLUSIONES: Los resultados son coherentes con las prevalencias dadas por la Organización Panamericana de la Salud (OPS) y se pueden correlacionar con la prevalencia mundial de las infecciones transmisibles por via transfusional. Los resultados hallados en las pruebas del banco de sangre posibilitan la disminución del riesgo transfusional pero limitan la optimización de recursos al excluir donantes clasificados como falsos positivos

Exclusive Photoproduction of the Cascade (Xi) Hyperons

We report on the first measurement of exclusive Xi-(1321) hyperon photoproduction in gamma p --> K+ K+ Xi- for 3.2 < E(gamma) < 3.9 GeV. The final state is identified by the missing mass in p(gamma,K+ K+)X measured with the CLAS detector at Jefferson Laboratory. We have detected a significant number of the ground-state Xi-(1321)1/2+, and have estimated the total cross section for its production. We have also observed the first excited state Xi-(1530)3/2+. Photoproduction provides a copious source of Xi's. We discuss the possibilities of a search for the recently proposed Xi5-- and Xi5+ pentaquarks.Comment: submitted to Phys. Rev.

Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Neuroblastoma is the most common, pediatric, extra-cranial, malignant solid tumor. Despite multimodal therapeutic protocols, outcome for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. Hereby, we evaluated the potential of non-coding RNA expression to predict outcome in high-risk, stage 4 neuroblastoma.</p> <p>Methods</p> <p>We analyzed expression of 481 Ultra Conserved Regions (UCRs) by reverse transcription-quantitative real-time PCR and of 723 microRNAs by microarrays in 34 high-risk, stage 4 neuroblastoma patients.</p> <p>Results</p> <p>First, the comparison of 8 short- versus 12 long-term survivors showed that 54 UCRs were significantly (<it>P </it>< 0.0491) over-expressed in the former group. For 48 Ultra Conserved Region (UCRs) the expression levels above the cut-off values defined by ROC curves were strongly associated with good-outcome (OS: 0.0001 <<it>P </it>< 0.0185, EFS: 0.0001 <<it>P </it>< 0.0491). Then we tested the Transcribed-UCR (T-UCR) threshold risk-prediction model on an independent cohort of 14 patients. The expression profile of 28 T-UCRs was significantly associated to prognosis and at least 15 up-regulated T-UCRs are needed to discriminate (<it>P </it>< 0.0001) short- from long-survivors at the highest sensitivity and specificity (94.12%). We also identified a signature of 13 microRNAs differently expressed between long- and short-surviving patients. The comparative analysis of the two classes of non-coding RNAs disclosed that 9 T-UCRs display their expression level that are inversely correlated with expression of 5 complementary microRNAs of the signature, indicating a negative regulation of T-UCRs by direct interaction with microRNAs. Moreover, 4 microRNAs down-regulated in tumors of long-survivors target 3 genes implicated in neuronal differentiation, that are known to be over-expressed in low-risk tumors.</p> <p>Conclusions</p> <p>Our pilot study suggests that a deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma. After further validation on a larger independent set of samples, such findings may be applied as the first T-UCR prognostic signature for high-risk neuroblastoma patients.</p

Geographical variations in the benefit of applying a prioritization system for cataract surgery in different regions of Spain

<p>Abstract</p> <p>Background</p> <p>In Spain, there are substantial variations in the utilization of health resources among regions. Because the need for surgery differs in patients with appropriate surgical indication, introducing a prioritization system might be beneficial. Our objective was to assess geographical variations in the impact of applying a prioritization system in patients on the waiting list for cataract surgery in different regions of Spain by using a discrete-event simulation model.</p> <p>Methods</p> <p>A discrete-event simulation model to evaluate demand and waiting time for cataract surgery was constructed. The model was reproduced and validated in five regions of Spain and was fed administrative data (population census, surgery rates, waiting list information) and data from research studies (incidence of cataract). The benefit of introducing a prioritization system was contrasted with the usual first-in, first-out (FIFO) discipline. The prioritization system included clinical, functional and social criteria. Priority scores ranged between 0 and 100, with greater values indicating higher priority. The measure of results was the waiting time weighted by the priority score of each patient who had passed through the waiting list. Benefit was calculated as the difference in time weighted by priority score between operating according to waiting time or to priority.</p> <p>Results</p> <p>The mean waiting time for patients undergoing surgery according to the FIFO discipline varied from 1.97 months (95% CI 1.85; 2.09) in the Basque Country to 10.02 months (95% CI 9.91; 10.12) in the Canary Islands. When the prioritization system was applied, the mean waiting time was reduced to a minimum of 0.73 months weighted by priority score (95% CI 0.68; 0.78) in the Basque Country and a maximum of 5.63 months (95% CI 5.57; 5.69) in the Canary Islands. The waiting time weighted by priority score saved by the prioritization system varied from 1.12 months (95% CI 1.07; 1.16) in Andalusia to 2.73 months (95% CI 2.67; 2.80) in Aragon.</p> <p>Conclusion</p> <p>The prioritization system reduced the impact of the variations found among the regions studied, thus improving equity. Prioritization allocates the available resources within each region more efficiently and reduces the waiting time of patients with greater need. Prioritization was more beneficial than allocating surgery by waiting time alone.</p

Determinants of bed net use in children under five and household bed net ownership on Bioko Island, Equatorial Guinea

BACKGROUND: As part of comprehensive malaria control strategies, the Bioko Island Malaria Control Project (BIMCP) distributed 110,000 long-lasting insecticide-treated nets (LLIN) in late 2007 with the aim of providing one net for each sleeping area. Despite attaining initially very high levels of net coverage and net use, many children under five years of age did not sleep under a net by 2009, according to annual malaria indicator surveys. The aim of this study was to assess the determinants of bed net use in children under five and bed net ownership of the households in which they live. METHODS: Using data from annual cross-sectional household surveys of 2008 and 2009, we investigated factors associated with sleeping under a mosquito net the night prior to the survey, and a households owning at least one net, in all households which had at least one child under five years. Amongst others, caregiver's knowledge of malaria and household characteristics including a socio-economic score (SES), based on ownership of household assets, were analysed for their effect on net ownership and use. RESULTS: There was a decline of around 32% in the proportion of households that owned at least one net between 2008 and 2009. Higher household bed net ownership was associated with knowing how malaria was prevented and transmitted, having the house sprayed in the previous 12 months, having fewer children under five in the household, and children being sick at some point in the previous 14 days. Higher bed net use in children < 5 was associated with being sick at some point in the last 14 days prior to the survey, living in an urban area, more years of education of the head of the household, household ownership of at least one ITN (as opposed to an untreated net) and the year in which the survey took place. CONCLUSIONS: The big fall in bed net use from 2008 to 2009 was attributable to the striking decline in ownership. Although ownership was similar in rural and urban areas, rural households were less likely to protect their children with bed nets. Knowledge about malaria was an important determinant of bed net ownership. Further research is needed to elucidate the decline in bed net ownership between 2008 and 2009