Comprehensive analysis of the ErbB receptor family in pediatric nervous system tumors and rhabdomyosarcoma

Background: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. / Procedure: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. / Results: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%–30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. / Conclusions: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Marja-Liisa Lokki työryhmien Generation Scotland Consortium, LifeLines Cohort Study ja GIANT Consortium jäsenPeer reviewe

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Diminishing benefits of urban living for children and adolescents’ growth and development

AbstractOptimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.</jats:p

Suplementação de ácidos graxos ômega 3 em atletas de competição: impacto nos mediadores bioquímicos relacionados com o metabolismo lipídico Adición de ácidos grasos omega 3 en atletas de competición: impacto en los mediadores bioquímicos relacionados con el metabolismo lipídico Omega 3 fatty acids-supplementation to competition athletes: impact on the biochemical indicators related to the lipid metabolism

OBJETIVO: Avaliar o efeito da suplementação dos ácidos graxos ômega 3 em atletas de natação sobre indicadores bioquímicos. MÉTODOS: Nadadores de elite (n = 14) do sexo masculino foram avaliados em estudo randomizado, controlado por placebo pelo período de seis semanas (45 dias). O grupo placebo (GP) recebeu óleo mineral (n = 6) e o grupo suplementado (n = 8), óleo de peixe (GOP) contendo, no total, 950mg de ácido eicosapentaenóico e 500mg de ácido docosapentaenóico. Amostras de sangue foram coletadas imediatamente antes (T0), aos 15 (T15), aos 30 (T30) e aos 45 (T45) dias de suplementação para análise da composição dos ácidos graxos por cromatografia gasosa e para quantificação das lipoproteínas plasmáticas através de kits comerciais específicos. RESULTADOS: Os resultados revelaram um desajuste na dieta dos atletas considerando a ingestão g/kg de massa corporal dos macronutrientes. A análise do questionário de freqüência de consumo mostrou que os atletas não ingeriram regularmente fontes alimentares de ômega 3 e que o consumo de peixes, em 85% da amostra, era inferior ou igual a uma vez na semana. O perfil de ácidos graxos plasmáticos evidenciou aumento dos ácidos graxos poliinsaturados ômega 3 (P < 0,05) e redução do ácido araquidônico no grupo suplementado (P < 0,05). A suplementação com óleo de peixe ocasionou efeito hipocolesterolêmico, com redução nos teores sanguíneos de VLDL, LDL e colesterol total. Os valores de HDL não apresentaram diferenças significativas entre os grupos em nenhum momento estudado (P > 0,05). CONCLUSÃO: A suplementação de ácidos graxos N-3 em atletas nadadores altera os indicadores bioquímicos do metabolismo lipídico, influenciando na redução das lipoproteínas plasmáticas, ricas em colesterol e na prevenção de doenças cardiovasculares.<br>OBJETIVO: Evaluar el efecto suplementar de los ácidos grasos omega 3 en atletas de natación sobre indicadores bioquímicos. MÉTODOS: Nadadores de elite (n = 14) del sexo masculino fueron evaluados en estudio aleatorio, controlado por placebo por un período de 6 semanas (45 días). El grupo placebo (GP) recibió aceite mineral (n = 6) y el grupo suplementado (n = 8) recibió aceite de pescado (GOP) conteniendo en total 950 mg de ácido eicosapentaenóico y 500 mg de ácido docosapentaenóico. Muestras de sangre fueron colectadas inmediatamente antes (T0), a los quince (T15), a los treinta (T30) y a los cuarenta y cinco (T45) días de suplementación para análisis de la composición de los ácidos grasos por cromatografía gaseosa y para cuantificación de las lipoproteínas plasmáticas a través de kits comerciales específicos. RESULTADOS: Los resultados revelaron un desajuste en la dieta de los atletas considerando la ingestión g/kg de masa corporal de los macro nutrientes. El análisis del cuestionario de frecuencia de consumo mostró que los atletas no ingirieron regularmente fuentes alimentares de omega 3 y que el consumo de pescado, en 85% de la muestra, era inferior o igual a 1 vez por semana. El perfil de ácidos grasos plasmáticos mostró un aumento de los ácidos grasos poliinsaturados omega 3 (P < 0,05) y reducción del ácido araquidónico en el grupo suplementado (P < 0,05). La suplementación con aceite de pescado ocasionó efecto hipocolesterolémico, con reducción en los grados sanguíneos de VLDL, LDL y colesterol total. Los valores de HDL no presentaron diferencias significativas entre los grupos en ningún momento estudiado (P > 0,05). CONCLUSIÓN: La suplementación de ácidos grasos N-3 en atletas de natación altera los indicadores bioquímicos del metabolismo lipídico, influyendo en la reducción de las lipoproteínas plasmáticas, ricas en colesterol y en la prevención de enfermedades cardiovasculares.<br>PURPOSE: To assess the effects of omega 3 fatty acid supplementation to swimmers on biochemical indicators. METHODS: Male elite swimmers (n = 14) were assessed in a placebo-controlled randomized study over a 6-week (45-day) experimental period. The placebo group (GP) received mineral oil (n = 6) and the supplemented group (GOP) received fish oil (n = 8) containing a total of 950 mg of eicosapentaenoic acid and 500 mg of docosapentaenoic acid. Immediately before starting the supplementation (T0), as well as 15 (T15), 30 (T30) and 45 (T45) days after that point, blood samples were collected and analyzed by gas chromatography for fatty acids composition, and by specific commercial kits for plasmatic lipoproteins. RESULTS: The results showed that the diets of the swimmers were unbalanced regarding the macronutrient ingestion/body weight ratio (g/kg). The analysis of the consumption frequency questionnaire showed that (1) the swimmers have not regularly ingested omega 3 dietary sources and (2) the fish consumption was below once a week for 85% of the sample. The plasmatic fatty acids profile presented an increase in omega 3 polyunsaturated fatty acids (p < 0.05) and decrease in arachidonic fatty acid in the supplemented group (p < 0.05). The fish oil supplementation led to a hypocholesterolemic effect, with a decrease in VLDL, LDL and total cholesterol blood levels. The HDL levels presented no significant differences between the groups in any moment of the study (p > 0.05). CONCLUSION: N-3 fatty acids supplementation to swimmers alters the biochemical indicators of the lipid metabolism, with an influence in the decrease of the cholesterol-rich plasmatic lipoproteins, so preventing cardiovascular diseases