Critical appraisal of pralatrexate in the management of difficult-to-treat peripheral T cell lymphoma

Aggressive T cell lymphomas are a subgroup of lymphomas with a particularly poor prognosis. This is especially true for patients with recurrent or refractory disease, who typically have limited response to salvage therapy and extremely poor overall survival. For this reason, there is a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T cell lymphomas. The dose-limiting toxicity for pralatrexate is mucositis, which can be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is the first single agent approved for the treatment of patients with relapsed or refractory peripheral T cell lymphoma. This approval was based on an overall objective response rate observed in the pivotal study. The overall response rate was 29%, with a median duration of 10.1 months. This article reviews the biochemistry, preclinical experience, metabolism, and pharmacokinetics of pralatrexate, including the clinical experience with this agent in lymphoma. Future areas of development are now focused on identifying synergistic combinations of pralatrexate with other agents and the evaluation of predictive markers for clinical benefit

Evaluación de las necesidades hídricas de tres variedades de fresas y de su respuesta frente a un recorte hídrico moderado

Instituto Nacional de Investigaciones RTA2012-00001-00-00FEDER CC10-009-C02-0

Experiencia del Programa Mentor. ¿Altruismo o Trueque?

Este artículo describe las lecciones aprendidas al implantar en nuestra Escuela el programa Mentor, cuya finalidad es que estudiantes de cursos avanzados guíen y apoyen personalmente a estudiantes de nuevo ingreso, así como a estudiantes de programas de movilidad. Este programa nace como respuesta a las necesidades de los estudiantes de nuevo ingreso y de programas de movilidad que, especialmente al comenzar su vida académica, suelen hallarse un poco perdidos y encuentran dificultades en tareas académicas, administrativas e incluso en la inserción social en la universidad. Para solucionar estas dificultades, los mentores ayudan a integrar a los estudiantes en la comunidad universitaria no solo en labores académicas o administrativas, sino también a través de actividades sociales y culturales. Este programa tiene dos características principales que lo diferencian de sus homólogos en otras universidades: en primer lugar, no se otorgan créditos ni ningún otro tipo de contraprestación por formar parte del programa fomentando, así, la competencia transversal de compromiso social, a diferencia de otras universidades que otorgan algún reconocimiento pero imposibilitan la participación en ediciones sucesivas del mentor, perdiendo su experiencia y frenando su altruismo. Por otra parte, los estudiantes de primer curso y programas de movilidad no están inscritos por defecto al programa, sino que su participación es voluntaria, ya que se considera que la verdadera ayuda es aprovechada por quien es suficientemente maduro y valiente para pedirla y valorarla. El artículo describe las lecciones aprendidas durante el primer curso de implantación de este proyecto, así como las nuevas iniciativas emprendidas en este curso por los mentores, como los grupos de estudio y apoyo o el festival de talentos.This paper describes the lessons learned after implementing the Mentor program, whose goal is to allow the elder students guide and encourage the newcomers and students from any international mobility program. This program attempts to deal with the needs of these students, who are often lost and normally find many difficulties in academic and administrative tasks and even in their own social inclusion. The mentors help solve these problems by helping these students to become integrated into the university community, not only in academic or administrative tasks but also in social and cultural activities. This Mentor program has two main characteristics that makes it different from other similar projects: first, no credit or other rewards are given to the mentors participating in this program, thus promoting the transversal competency of social commitment, unlike other universities which reward them and henceforth do not allow students to participate in successive editions. This way, the mentors cannot apply their own experience and know-how nor their altruism is enhanced. Second, newcomers and students involved in international mobility programs are not by default enrolled in the program. Their participation is fully optional, since we consider that only a sufficiently brave and mature person is capable of making the most of the help received and valuing it sufficiently. This paper describes the lessons learned during the first year of implementation of this project, along with the new efforts made and initiatives undertaken by the mentors during this year, like the study groups and the talents festival.Este trabajo ha sido financiado por los proyectos GINSENG (TIN2015-70259-C2-1-R) y SEQUOIA (TIN2015-63502-C3-1-R) a través del Ministerio de Economía y Competitividad (MINECO) y el Fondo Europeo de Desarrollo Regional (FEDER)

Study protocol for the evaluation of the health effects of superblocks in barcelona : The "salut als carrers" (health in the streets) project

Superblocks are currently being introduced in Barcelona to respond to the city's scarcity of green spaces and high levels of air pollution, traffic injuries, and sedentariness. The aim is to calm the streets by reducing the number of square meters dedicated to private vehicles and to reclaim part of this public space for people. Salut als Carrers (Health in the Streets) is a project to evaluate the potential environmental and health effects of the superblock model with an equity perspective in Barcelona. This study aims to explain the various interventions implemented in different neighborhoods in Barcelona and the methods that will be used to evaluate them in a quasi-experimental and health impact assessment (HIA) approaches. Given the complexity of the intervention evaluated, the project employs mixed methodologies. Quantitative methods include: (a) a pre-post health survey of 1200 people randomly selected from the municipal register asked about self-perceived health and quality of life, social support, mental health, mobility, physical activity, neighborhood characteristics, and housing; (b) pre-post environmental measurements, mainly of nitrogen dioxide (NO), particulate matter of less than 10 µm (PM), and particulate matter of less than 2.5 µm (PM) and black carbon; (c) pre-post environmental walkability measures using the Microscale Audit of Pedestrian Streetscapes (MAPS) tool; (d) use of public space and physical activity levels using the System for Observing Play and Recreation in Communities (SOPARC), a validated observation tool; (e) pre-post traffic injury measures with a comparison group; and (f) the comparison and integration of pre-post assessment with previous HIAs and the improvement of future HIAs. Qualitative studies will be performed to analyze residents' perception of these effects by using: (a) various focus groups according to different participant characteristics who are more or less likely to use the superblocks; and (b) a guerrilla ethnography, which is a method that combines ethnographic observation and semi-structured interviews. This study, which evaluates the impact of an ambitious urban-renewal program on health, will help to assess the effectiveness of public policy in terms of health and health inequalities

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Analysis of SNP-SNP interactions and bone quantitative ultrasound parameter in early adulthood

Background: Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease. Methods: The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound attenuation (BUA, dB/MHz). A total of 32 SNPs mapping to loci that have been characterized as genetic markers for QUS and/or BMD parameters were selected as genetic markers in this study. The association of all possible SNP pairs with QUS was assessed by linear regression and a SNP-SNP interaction was defined as a significant departure from additive effects. Results: The pairwise SNP-SNP analysis showed multiple interactions. The interaction comprising SNPs rs9340799 and rs3736228 that map in the ESR1 and LRP5 genes respectively, revealed the lowest p value after adjusting for confounding factors (p-value = 0.001, β (95% CI) = 14.289 (5.548, 23.029). In addition, our model reported others such as TMEM135-WNT16 (p = 0.007, β(95%CI) = 9.101 (2.498, 15.704), ESR1-DKK1 (p = 0.012, β(95%CI) = 13.641 (2. 959, 24.322) or OPG-LRP5 (p = 0.012, β(95%CI) = 8.724 (1.936, 15.512). However, none of the detected interactions remain significant considering the Bonferroni significance threshold for multiple testing (p<0.0001). Conclusion: Our analysis of SNP-SNP interaction in candidate genes of QUS in Caucasian young adults reveal several interactions, especially between ESR1 and LRP5 genes, that did not reach statistical significance. Although our results do not support a relevant genetic contribution of SNP-SNP epistatic interactions to QUS in young adults, further studies in larger independent populations would be necessary to support these preliminary findings.This study was supported by a grant PI-0414-2014 from Consejería de Salud (Junta de Andalucía, Spain). Correa-Rodríguez M is a predoctoral fellow (FPU13/ 00143) from the Ministerio de Educación, Cultura y Deporte (Programa de Formación del Profesorado Universitario)

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

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

Egg rejection in blackbirds Turdus merula: a by-product of conspecific parasitism or successful resistance against interspecific brood parasites?

Traditional theory assumes that egg recognition and rejection abilities arise as a response against interspecific brood parasitism (IBP). However, rejection also appears in some species that are currently not exploited by interspecific parasites, such as Turdus thrushes. Recent evidences suggest that rejection abilities evolved in these species as a response to conspecific brood parasitism (CBP). To test these two alternative hypotheses, we performed an experimental study by parasitizing nests of the common blackbird (Turdus merula) with conspecifics or heterospecific eggs under different risk of parasitism (presence of interspecific or conspecific parasites near the nest). Common blackbird is a potential host of the common cuckoo (Cuculus canorus) but suffers low levels of CBP too. Results: We found that blackbirds were able to recognize and eject heterospecific eggs at high rates whereas most of conspecifics eggs were not recognized and, therefore, accepted. Ejection rates of conspecific eggs did not exceed 13 %, even in situations of high risk of CBP (blackbird female placed near the nest), which contradict the main prediction derived from the CBP hypothesis. Conversely, ejection rates of experimental eggs simulating IBP were much higher (80–100 %). Furthermore, female blackbirds were more aggressive towards cuckoos than towards blackbird dummies. Conclusions: Our results considered together support the IBP hypothesis, indicating that recognition and rejection of parasitic eggs in blackbirds have probably evolved due to previous cuckoo parasitism. The current absence of IBP in blackbirds may be due to the highly efficient rejection abilities in this species. Thus, these abilities have been retained in absence of brood parasitism as a consequence of the low costs involved for blackbirds, resulting in a successful resistance against interspecific brood parasitism.Financial support has been provided by the Consejería Economía, Innovación, Ciencia y Empleo. Junta de Andalucia (research project CVI-6653)

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