Simvastatin and downstream inhibitors circumvent constitutive and stromal cell-induced resistance to doxorubicin in IGHV unmutated CLL cells

The immunoglobulin heavy-chain variable region (IGHV) mutational status is a strong determinant of remission duration in chronic lymphocytic leukemia (CLL). The aim of this work was to compare the multidrug resistance (MDR) signature of IGHV mutated and unmutated CLL cells, identifying biochemical and molecular targets potentially amenable to therapeutic intervention.We found that the mevalonate pathway-dependent Ras/ERK1-2 and RhoA/RhoA kinase signaling cascades, and the downstream HIF-1\u3b1/P-glycoprotein axis were more active in IGHV unmutated than in mutated cells, leading to a constitutive protection from doxorubicin-induced cytotoxicity. The constitutive MDR phenotype of IGHV unmutated cells was partially dependent on B cell receptor signaling, as shown by the inhibitory effect exerted by ibrutinib. Stromal cells further protected IGHV unmutated cells from doxorubicin by upregulating Ras/ERK1-2, RhoA/RhoA kinase, Akt, HIF-1\u3b1 and P-glycoprotein activities. Mevalonate pathway inhibition with simvastatin abrogated these signaling pathways and reversed the resistance of IGHV unmutated cells to doxorubicin, also counteracting the protective effect exerted by stromal cells. Similar results were obtained via the targeted inhibition of the downstream molecules ERK1-2, RhoA kinase and HIF-1\u3b1.Therefore, targeting the mevalonate pathway and its downstream signaling cascades is a promising strategy to circumvent the MDR signature of IGHV unmutated CLL cells

Nouvelle démographie médicale: quels défis pour les médecins formés à l’étranger ?

Les « Diplômés Internationaux en Médecine » (DIM), médecins pratiquant leur métier dans un pays dans lequel ils n’ont pas étudié, sont en augmentation à l’échelle globale comme à l’échelle suisse. Dans cet article, nous décrivons les défis rencontrés par les DIM : aspects liés à la communication, différences dans la formation médicale, variations dans la pratique clinique et difficultés de prise en charge de catégories spécifiques de patients en lien avec certaines valeurs sociétales. Ces défis rendent nécessaire un processus de transition professionnelle et culturelle de ces médecins étrangers, qui représentent un réel atout pour les pays d’accueil. En effet, ils participent à résoudre les problèmes de pénurie et de déserts médicaux en apportant leur riche expérience professionnelle et des compétences cliniques reconnues

Joint data analysis in nutritional epidemiology: identification of observational studies and minimal requirements

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well asminimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, t he minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition

Dietary macronutrient composition in relation to circulating HDL and non-HDL cholesterol : a federated individual-level analysis of cross-sectional data from adolescents and adults in 8 European studies

peer reviewedBACKGROUND: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined. OBJECTIVE: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data. METHODS: Dietary macronutrient intake was recorded using study-specific dietary assessment tools. Main outcome measures were lipoprotein cholesterol concentrations: HDL cholesterol (mg/dL) and non-HDL cholesterol (mg/dL). A cross-sectional analysis on 5919 participants (54% female) aged 13-80 y was undertaken using the statistical platform DataSHIELD that allows remote/federated nondisclosive analysis of individual-level data. Generalized linear models (GLM) were fitted to assess associations between replacing 5% of energy from carbohydrates with equivalent energy from total fats, SFAs, MUFAs, or PUFAs with circulating HDL cholesterol and non-HDL cholesterol. GLM were adjusted for study source, age, sex, smoking status, alcohol intake and BMI. RESULTS: The replacement of 5% of energy from carbohydrates with total fats or MUFAs was statistically significantly associated with 0.67 mg/dL (95% CI: 0.40, 0.94) or 0.99 mg/dL (95% CI: 0.37, 1.60) higher HDL cholesterol, respectively, but not with non-HDL cholesterol concentrations. The replacement of 5% of energy from carbohydrates with SFAs or PUFAs was not associated with HDL cholesterol, but SFAs were statistically significantly associated with 1.94 mg/dL (95% CI: 0.08, 3.79) higher non-HDL cholesterol, and PUFAs with -3.91 mg/dL (95% CI: -6.98, -0.84) lower non-HDL cholesterol concentrations. A statistically significant interaction by sex for the association of replacing carbohydrates with MUFAs and non-HDL cholesterol was observed, showing a statistically significant inverse association in males and no statistically significant association in females. We observed no statistically significant interaction by age. CONCLUSIONS: The replacement of dietary carbohydrates with fats had favorable effects on lipoprotein cholesterol concentrations in European adolescents and adults when fats were consumed as MUFAs or PUFAs but not as SFAs

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.status: publishe

Millennials en América Latina y el Caribe : ¿trabajar o estudiar?

Presenta los principales resultados de un proyecto regional que contó con la participación de más de 15.000 jóvenes de entre 15 y 24 años en nueve países (Brasil, Chile, Colombia, El Salvador, Haití, México, Paraguay, Perú y Uruguay). La novedad de este estudio es que va más allá de las variables que tradicionalmente levantan las encuestas de hogares, como ingresos o nivel de estudios, e incorpora otras menos convencionales: la información que los jóvenes manejan acerca del funcionamiento del mercado laboral, así como sus aspiraciones, expectativas y habilidades cognitivas y socioemocionales. Así, tratamos de entender mejor la decisión que toman los jóvenes respecto de solo estudiar, solo trabajar, combinar estudio y trabajo, o ni estudiar ni trabajar (ser nini), e impulsar medidas más acordes para desarrollar su potencial. Sobre la base de estos hallazgos, esta publicación sugiere qué acciones de política pueden ayudar a los jóvenes a realizar una transición exitosa desde sus estudios al mercado laboral. La investigación presentada en este libro se basa en información novedosa, de calidad y comparable que se obtuvo como parte del proyecto en los nueve países de la región. En particular, se diseñaron dos instrumentos. Uno es la encuesta “Millennials en América Latina y Caribe”, en la que participaron entre 2017 y 2018 jóvenes residentes en las zonas urbanas de Brasil, Chile, Colombia, El Salvador, Haití, México y Paraguay. A ellos se suman Perú y Uruguay, que participaron sobre la base de información longitudinal ya existente (Young Lives/Niños del Milenio en Perú y el Estudio Longitudinal del Bienestar en Uruguay). El segundo instrumento es un estudio cualitativo, basado en grupos focales en los nueve países, que permitió indagar con más detalle cómo los jóvenes han llegado a su actual situación de estudio y trabajo, así como cuáles son sus aspiraciones para el futuro. La medición de habilidades socioemocionales, aspiraciones y expectativas, además del análisis de su correlación con las decisiones educativas y laborales de los jóvenes, es uno de los aportes centrales de este libro. Las habilidades socioemocionales que mide este proyecto, también conocidas como habilidades blandas, incluyen, entre otras, la perseverancia, la confianza en las propias capacidades, la autoestima y el autocontrol. Para medirlas, se emplearon instrumentos y pruebas que ya han sido utilizados y validados ampliamente en psicología y, más reciente, en economía. Contar con evidencia de estas variables se justifica por dos razones principales: primero, existe una creciente literatura académica que sugiere que el desarrollo de estas habilidades permite una inserción educativa, laboral y social más exitosa de las personas; y, segundo, estas dimensiones pueden modificarse a bajo costo durante la juventud. Los resultados de esta investigación, una radiografía detallada sobre los jóvenes de América Latina y el Caribe, ofrecen un panorama alentador en la mayoría de los aspectos. En él no hay cabida para prejuicios y estereotipos, como los que pesan sobre los millennials o sobre los 20 millones de ninis que hay en América Latina y el Caribe. De acuerdo con los resultados de la encuesta, un 41% de los jóvenes en la región se dedica exclusivamente al estudio, un 21% solo trabaja, un 17% realiza ambas actividades y un 21% no estudia, se capacita o trabaja. Además, se observan diferencias en los años de educación que alcanzan los jóvenes en los distintos países de América Latina y el Caribe. Respecto a sus resultados laborales, los jóvenes muestran una temprana inserción laboral (a los 16 años, en promedio) y altas tasas tanto de informalidad como de rotación laboral. Asimismo, el análisis confirma el rezago en habilidades cognitivas de los jóvenes de la región que ya han detectado pruebas estandarizadas internacionales como PISA, independiente de su situación laboral y educativa. Por ejemplo, alrededor de un 40% de los encuestados no es capaz de realizar correctamente cálculos matemáticos muy sencillos, útiles para la vida diaria, como repartir un monto de dinero en partes iguales. También encontramos que, en promedio, los jóvenes del estudio carecen de algunas habilidades técnicas esenciales para el nuevo mercado laboral (por ejemplo, menos de un cuarto declara hablar fluidamente inglés), pero que a la vez poseen otras capacidades igualmente relevantes (por ejemplo, indican manejar dispositivos tecnológicos con facilidad). Además, este estudio devela que los jóvenes de América Latina y el Caribe son, en general, optimistas acerca de su futuro. De hecho, aunque la cobertura actual de la educación superior en la región se ubica en promedio alrededor del 40%, una mayoría abrumadora de los encuestados aspiran y declaran estar altamente seguros de completar la educación superior

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Significance Statement The mechanisms regulating the urinary excretion of uromodulin remain mostly unknown. A meta-GWAS conducted in 29,315 individuals from 13 cohorts identified two novel, genome-wide significant loci, KRT40 and WDR72, in addition to the previously known UMOD-PDILT locus, to be associated with urinary uromodulin. KRT40 colocalizes with uromodulin in TAL cells and functional studies showed that its expression affects the processing and apical excretion of uromodulin. WDR72, which does not colocalize with uromodulin, has been associated with kidney function, urinary acidification, and kidney stones. These studies provide novel insights into the biology of uromodulin and keratins and into the influence of the UMOD-PDILT locus on kidney function. Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E?08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E?88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function