Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patientsHorizon 2020 856620Instituto de Salud Carlos III Spanish GovernmentMarie Curie Actions PI17/02256 PI20/01845Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades y FEDER PY20/01282United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P50 CA97274 R01 CA9215

Fotosensibilización y fototerapia con furocumarinas: Un estudio mecano-cuántico.

RESUMEN La Fototerapia es uno de los campos de la Medicina que ha experimentado un mayor desarrollo en las últimas décadas, ampliándose cada vez más el rango de enfermedades que pueden ser tratadas de esta forma. Quizás esta terapia representa como ninguna otra la combinación entre la Física (radiación electromagnética) y la Química (el fármaco empleado o fotosensibilizador) para combatir enfermedades. El objeto de la presente Tesis Doctoral es el estudio teórico de compuestos empleados como fármacos en la denominada terapia PUVA, denominados furocumarinas. El estudio teórico químico-cuántico de los estados electrónicos excitados de estas moléculas permite hallar alguna de las claves del mecanismo de acción fototerapéutica, que, según la literatura, se basa en la fotoconjugación con las bases pirimidínicas del ADN por un lado y en la reacción con el oxígeno molecular del medio celular produciendo oxígeno singlete tóxico por otro (terapia fotodinámica). Nuestro estudio del mecanismo tiene como principales objetivos proponer mejores fotosensibilizadores y desentrañar el mecanismo fotoquímico subyacente en este tipo de fotoquimioterapia. Inicialmente hemos centrado nuestros cálculos, mediante la metodología CASPT2//CASSCF, en el estudio de los estados excitados singletes y tripletes cuya participación en los procesos fotoquímicos radiativos y no radiativos es más probable a fin de estudiar las principales propiedades fotofísicas de los compuestos (espectros de absorción y emisión, fuerzas de oscilador, momentos dipolares, tiempos de emisión radiativa, orígenes de banda, acoplamiento espín-órbita), en un primer paso para racionalizar su mecanismo de actuación. Una vez analizado si se puebla eficientemente el estado excitado triplete (protagonista de la acción fotosensibilizadora) de cada molécula, estudiaremos cómo interaccionan estos fármacos con la timina del ADN y con el oxígeno molecular. Por último, se ha estudiado la formación de los dímeros de timina, una de las lesiones más frecuentes en el ADN, y cuya formación sigue un mecanismo similar a la correspondiente a la interacción entre las furocumarinas y la propia timina. Para ello será clave el análisis de las hipersuperficies de energía potencial de los estados implicados en un proceso dado, así como los cruces entre las mismas y las barreras energéticas para pasar de una región a otra de la hipersuperficie. De hecho, la Fotofísica y la Fotoquímica modernas están basadas en el estudio de las hipersuperficies, las cuales pueden ser consideradas como el terreno de juego donde tienen lugar los procesos físicos y químicos. __________________________________________________________________________________________________This thesis is focused on studying the photochemical behaviour of the furocoumarins in order to propose the best photosensitizer. Firstly the photophysics of psoralen, the parent molecule, will be studied. Afterwards how the lowest triplet excited state is populated will be analized, in both psoralen and thymine, since this state is the responsible for the photosensitizing action. The next step is studying the photocycloaddition between psoralen and thymine that culminates in the formation of monoadducts and diadducts in DNA, which is the key point in the photosensitizing ability of these compounds. A parallel study of other furocoumarins (8-MOP, 5-MOP, TMP, khellin and 3-CPS) will be carried out in order to rationalize which is the best drug from a quantum-chemical viewpoint. We will consider the other side of PUVA therapy as well: the interaction of furocoumarins with molecular oxygen through energy transfer to yield singlet oxygen, which is a strong electrophilic species that reacts with some components of the cellular membrane causing cell death by apoptosis. Finally, the properties of thymine dimers, formed via another sort of photocycloaddition reaction, will be studied. The overwhelming majority of the calculations presented here will be carried out with the CASPT2//CASSCF methodology, that is, energies at CASPT2 level and geometries at CASSCF level. Specifically, we will compute the lowest-lying singlet and triplet excited states, in order to rationalize the photophysical (electronic energies, oscillator strengths, dipole moments, radiative lifetimes, band origins, spin-orbit coupling) and photochemical properties (photocycloaddition, energy transfer) of furocoumarins

Public sector wage gaps in Spanish regions

This paper provides an approximation to the measurement of public sector wage gaps in Spanish regions. By using data from the European Community Household Panel, it is shown that the balance between what private firms pay in the local market and what the public sector pays, differs substantially in different areas of the country. Public sector wage differences among Spanish regions are mostly due to differences in returns, not to differences in characteristics or to selection effects, and are not constant across gender, educational levels, or occupations. Moreover, in those regions where Regional Governments have a higher weight in public employment, public wage gaps are higher and public employers pay higher returns. There also seems to be a cross regional positive correlation between public wage gaps and unemployment, and a negative one between labour productivity and public wage gaps. Hence, a tentative conclusion is that the incentives to select into the public sector are higher in the low productivity regions, precisely those where scarcity of human capital in the private sector may be the most important factor for explaining economic backwardness

Modelling and Terrestrial Laser Scanning Methodology (2009–2018) on Debris Cones in Temperate High Mountains

Producción CientíficaDebris cones are a very common landform in temperate high mountains. They are the most representative examples of the periglacial and nival processes. This work studies the dynamic behavior of two debris cones (Cone A and Cone B) in the Picos de Europa, in the north of the Iberian Peninsula. Their evolution was measured uninterruptedly throughout each August for 10 years (2009–2018) using the Terrestrial Laser Scanning (TLS) technique. The observations and calculations of the two debris cones were treated independently, but both showed the same behavior. Therefore, if these results are extrapolated to other debris cones in similar environments (temperate high mountain), they should show behavior similar to that of the two debris cones analyzed. Material falls onto the cones from the walls, and transfer of sediments follows linear trajectories according to the maximum slope. In order to understand the linear evolution of the two debris cones, profiles were created along the maximum slope lines of the Digital Elevation Model (DEM) of 2009, and these profile lines were extrapolated to the remaining years of measurement. In order to determine volumetric surface behavior in the DEMs, each year for the period 2009–2018 was compared. In addition, the statistical predictive value for position (Z) in year 2018 was calculated for the same planimetric position (X,Y) throughout the profiles of maximum slopes. To do so, the real field data from 2009–2017 were interpolated and used to form a sample of curves. These curves are interpreted as the realization of a functional random variable that can be predicted using statistical techniques. The predictive curve obtained was compared with the 2018 field data. The results of both coordinates (Z), the real field data, and the statistical data are coherent within the margin of error of the data collection.Fondo Europeo de Desarrollo Regional - Agencia Estatal de Investigación (grant TIN2016-76843-C4-2-R)Ministerio de Economía, Industria y Competitividad - Fondo Europeo de Desarrollo Regional (grant CGL2015-68144-R

UPCT-Bloopbusters: Teaching Science and Technology through Movie Scenes and related Experiments

[EN] In order to change the preconceptions of youth towards science and technology subjects (which, usually, are perceived as difficult or boring), new educational methods aimed at motivating and engaging students in learning are becoming more and more necessary. In this sense, an educational project called ‘UPCT-Bloopbusters’ through which a group of professors of the Universidad Politécnica de Cartagena (UPCT), Spain, use science fiction movie scenes ─as well as experiments─ within the lecture room to teach both physics and engineering technology is hereby presented. The methodology of the project is properly described and the results of a survey carried out among the students of a course in which such methodology has been used are shown. In view of this survey, it can be concluded that the project has been more than welcome by the students while at the same time has favored the learning of a great deal of physics and technology concepts.http://ocs.editorial.upv.es/index.php/HEAD/HEAD18Rodríguez, J.; Castro-Rodríguez, E.; Sánchez-Pérez, J.; Serrano-Martínez, J. (2018). UPCT-Bloopbusters: Teaching Science and Technology through Movie Scenes and related Experiments. Editorial Universitat Politècnica de València. 347-353. https://doi.org/10.4995/HEAD18.2018.7992OCS34735

Geomatic methods applied to the change study of the la Paúl Rock Glacier, Spanish Pyrenees

Producción CientíficaRock glaciers are one of the most important features of the mountain permafrost in the Pyrenees. La Paúl is an active rock glacier located in the north face of the Posets massif in the La Paúl glacier cirque (Spanish Pyrenees). This study presents the preliminary results of the La Paúl rock glacier monitoring works carried out through two geomatic technologies since 2013: Global Navigation Satellite System (GNSS) receivers and Terrestrial Laser Scanning (TLS) devices. Displacements measured on the rock glacier surface have demonstrated both the activity of the rock glacier and the utility of this equipment for the rock glaciers dynamic analysis. The glacier has exhibited the fastest displacements on its west side (over 35 cm yr-1), affected by the Little Ice Age, and frontal area (over 25 cm yr-1). As an indicator of permafrost in marginal environments and its peculiar morphology, La Paúl rock glacier encourages a more prolonged study and to the application of more geomatic techniques for its detailed analysis.Ministerio de Economía, Industria y Competitividad - Fondo Europeo de Desarrollo Regional (project CGL2015-68144-R)Junta de Extremadura - Fondo Europeo de Desarrollo Regional (project GR10071

Some Notes about Inference for the Lognormal Diffusion Process with Exogenous Factors

Different versions of the lognormal diffusion process with exogenous factors have been used in recent years to model and study the behavior of phenomena following a given growth curve. In each case considered, the estimation of the model has been addressed, generally by maximum likelihood (ML), as has been the study of several characteristics associated with the type of curve considered. For this process, a unified version of the ML estimation problem is presented, including how to obtain estimation errors and asymptotic confidence intervals for parametric functions when no explicit expression is available for the estimators of the parameters of the model. The Gompertz-type diffusion process is used here to illustrate the application of the methodology.This work was supported in part by the Ministerio de Economía, Industria y Competitividad, Spain, under Grants MTM2014-58061-P and MTM2017-85568-P

Is there a common pattern of dental specialties in the world? Orthodontics, the constant element

Background There is a lack of studies comparing the status of dental specialties worldwide. Therefore, this study aimed to analyze the differences and similarities between the number and types of dental specialties in 31 countries, including every continent, in the world. Materials and methods Available official documents and webpages from regulatory bodies, official colleges and councils, and dental institutions were collected from 31 countries and analyzed to obtain reliable data on dental specialties. Differences were analyzed using the Lorentz curve and Gini test. Additionally, a cluster analysis was performed to obtain groups of countries with similar patterns in the number and types of dental specialties. Results A total of 32 different specialties were officially recognized among all the analyzed countries. Orthodontics and oral surgery (100% and 93.1%, respectively) were the two most frequently officially recognized dental specialties worldwide. The total global degree of inequality in the 31 analyzed countries was 42.4%. The Anglo-Saxon countries showed the greatest similarity, approximately 15-fold higher than the European countries. Cluster analysis differentiated six main groups of countries according to the number and types of dental specialties. European countries formed one of the two largest clusters, and the other cluster was of Anglo-Saxon, Asian, African, and several Eastern European countries with a high number of specialties. Conclusions Officially recognized dental specialties in the different continents and countries show an asymmetric organization. The number, names, and skills of officially recognized dental specialties exhibited significant differences, showing inequalities in their organization. The Anglo-Saxon pattern of dental specialties showed greater equality than the European pattern. Orthodontics was the only constant element among the different patterns

Régimen térmico de suelos del macizo central de Picos de Europa (España)

The study of ground temperatures in a wet and temperate high mountain has got large interest because determines significant geomorphological processes in a periglacial environment. The aim of the research is to analyse the main thermal processes of ground along the year at different altitudes in the central massif of Picos de Europa (43°18’ - 43°7’N; 5°7’ - 4°36’W). Methodology has been used in the Alps and consists in temperature data that were obtained by 12 temperature data loggers undertaken at 10 cm with diverse locations between 1110 and 2535 m a.s.l. searching for altitudinal stepping and the coldest locations. The paper show the next parameters: thermal regime, freeze and thaw cycles, freeze index, duration and depth freeze. The thermal regime varies according topoclimatic conditions but it was possible to determinate four annual phases in function of snow cover behavior induced through the thermal registers. The year period best analyzed has been winter and spring, when the ground is protected by a big snow cover and in consequence there are not freeze and thaw cycles. During this period registers allow to asseverate the evidence of seasonal freeze grounds in five locations and the possibility in another six. However the data were not enough to discover permafrost.El estudio de las temperaturas del suelo en la alta montaña húmeda templada tiene un gran interés porque determina gran parte de los procesos geomorfológicos en un ámbito periglaciar. El objetivo de la investigación es analizar los principales procesos térmicos del suelo a lo largo del año en diferentes altitudes y emplazamientos en el macizo central de Picos de Europa (43°18’ - 43°7’N; 5°7’ - 4°36’O). La metodología ha sido ya aplicada en los Alpes y ha consistido en la obtención de temperaturas a través de 12 microsensores térmicos enterrados a 10 cm con emplazamientos muy diversos entre los 1.110 y 2.535 m.s.n.m. distribuidos buscando el escalonamiento altitudinal y los emplazamientos más fríos. En el artículo se presentan los siguientes parámetros: régimen térmico, ciclos de hielo y deshielo, índice de helada, duración y profundidad de la helada. El régimen térmico varía de acuerdo a las condiciones topoclimáticas de cada emplazamiento aunque se han podido estimar cuatro fases anuales en función del comportamiento del manto nival que se induce de los registros térmicos. El período del año mejor analizado ha sido el invierno y la primavera, cuando el suelo se encuentra protegido por un grueso manto nival y, en consecuencia, los ciclos de hielo y deshielo se anulan. Durante este período los registros nos han permitido afirmar la existencia de suelos helados estacionales en cinco emplazamientos y la posibilidad en otros seis. Sin embargo, no han sido suficientes para encontrar evidencias de permafrost

A theoretical insight into the photophysics of psoralen

Psoralen photophysics has been studied on quantum chemistry grounds using the multiconfigurational second-order perturbation method CASPT2. Absorption and emission spectra of the system have been rationalized by computing the energies and properties of the low-lying singlet and triplet excited states. The S1 ππ* state has been determined to be responsible of the lowest absorption and fluorescence bands and to initially carry the population in the photophysical processes related to the phototherapeutic properties of psoralen derivatives. The low-lying T1 ππ* state is, on the other hand, protagonist of the phosphorescence, and its prevalent role in the reactivity of psoralen is suggested to be related to the elongation of the pyrone ring C3–C4 bond, where the spin density is distributed on both carbon atoms. Analysis of energy gaps and spin-orbit coupling elements indicates that the efficient photophysical process leading to the population of the lowest triplet state does not take place at the Franck-Condon region but along the S1 relaxation [email protected] [email protected] [email protected]