Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Produtos naturais ativadores de PPAR e marcadores associados ao processo inflamatório na Síndrome Metabólica

O processo inflamatório é o elo entre a síndrome metabólica e as doenças cardiovasculares. Para verificar a presença e o grau da inflamação, vários biomarcadores têm sido propostos e investigados. Este trabalho tem como objetivo revisar as recentes pesquisas que associam alguns marcadores expressos no tecido adiposo, enfatizando, dentre eles, a adiponectina, a resistina, a leptina e o transportador de glicose GLUT-4 na síndrome metabólica, a relação da inflamação decorrente desse conjunto de desordens metabólicas sob os receptores proliferadores peroxissomais (PPARs), bem como o efeito de diferentes extratos vegetais e produtos naturais bioativos na ativação desses receptores

Chemical Characterization Of Sapucaia Nuts (lecythis Pisonis Cambess.) From Zona Da Mata Mineira Region [caracterização Química Da Castanha De Sapucaia (lecythis Pisonis Cambess.) Da Região Da Zona Da Mata Mineira]

Currently the nuts have received special attention of researchers because they are natural sources of vitamins, minerals, protein and essential fatty acids, could also contribute to the diet of humans and animals. Recent research confirms that these foods are also sources of bioactive compounds, which can bring significant benefits to human health through regular consumption. This study evaluated the chemical composition of sapucaia nut (Lecythis pisonis Cambess.) of the state of Minas Gerais. We analyzed the chemical composition (lipids, proteins, carbohydrates, ash and moisture), and the mineral content by mass spectrometry, and the lipid profile by gas chromatography. The chemical composition showed 54,8% lipids; 26,82% protein; 5,01% carbohydrates; 3,17% ash and 10,2% moisture. The lipid, 43,1% were polyunsaturated fatty acids, monounsaturated fatty acids 41,7% and 15,2% saturated fatty acids. The minerals phosphorus, magnesium and manganese are highlighted by high levels, 941; 343 and 4,8 mg.100-1, respectively. Sapucaia nut is a potential protein-energy and minerals source, but its toxicity must be evaluated.286971977Bidlngmeyer, B.A., Cohen, S.A., Tarvin, T.L., Rapid analysis of aminoacids using pre-column derivatization (1984) Journal of Chromatography, 336 (1), pp. 93-104. , Amsterdan(1998) Princípios Gerais Para O Estabelecimento De Níveis Máximos De Contaminantes Químicos Em Alimentos, pp. 28-29. , BRASIL. Agência Nacional de Vigilância Sanitária - Ministério da Saúde. Portaria no 685 de 27 de agosto de 1998, Diário Oficial da União n° 165-E, Seção I, Brasília, agoChaves, M.H., Barbosa, A.S., Moita, N.J.M., Aued-Pimentel, S., Lago, J.H.G., Caracterizaçao química do óleo da amêndoa de Sterculia striata St Hill et Nauda (2004) Química Nova, 27 (3), pp. 404-408. , São PauloCosta, P.A., Ballus, C.A., Teixeira-Filho, J., Godoy, H.T., Phytosterols and tocopherols content of pulps and nuts of Brazilian fruits (2010) Food Research International, 43 (6), pp. 1-4. , TorontoDenadai, S.M.S., Hiane, P.A., Marangoni, S., Baldasso, P.A., Miguel, A.M.R.O., Macedo, M.L.R., In vitro digestibility of globulins from sapucaia (Lecythis pisonis Camb.) nuts by mammalian digestive proteinases (2007) Ciência E Tecnologia De Alimentos, 27 (3), pp. 535-543. , Campinas(1991), FAO/WHO. Report of a joint FAO/WHO expert consultation held in Bethseda, MD, USA. Dec 1989. Protein quality evaluation. FAO/Rome/ItalyFood additives and contaminants (2001) Joint FAO/WHO Food Standards ProgrammeALINORM, 1 (12 A), pp. 1-289. , FAO/WHO. Codex Alimentarius CommissionFitó, M., Guxens, M., Corella, D., Saez, G., Estruch, R., Effect of a traditional Mediterranean diet on lipoprotein oxidation: A randomized, controlled trial (2007) Archives of Internal Medicine, 167 (11), pp. 1195-1203. , ChicagoFolch, J., Lees, M., Stanley, S., A simple method for the isolation and purification of total lipids from animal tissues (1957) Journal of Biological Chemistry, 226 (1), pp. 497-509. , BostonFreitas, J.B., Naves, M.M.V., Composição química de nozes e sementes comestíveis e sua relação com a nutrição e saúde (2010) Revista De Nutrição, 23 (2), pp. 269-279. , CampinasHartmann, L., Lago, R.C.A., Rapid preparation of fatty acid methyl esters from lipids (1973) Laboratory Practices, 22 (6), pp. 475-477. , LondresMétodos Físico-químicos Para Análise De Alimentos, 2008, p. 1020. , INSTITUTO ADOLFO LUTZ, 4a ed. São PauloJenkins, D.J., Kendall, C.W., Marchie, A., Josse, A.R., Nguyen, T.H., Faulkner, D., Lapsely, K.G., Blumberg, J., Almonds reduce biomarkers of lipid peroxidation in older hyperlipidemic subjects (2008) Journal of Nutrition, 138 (5), pp. 908-913. , BethesdaJenkins, D.J., Kendall, C.W., Marchie, A., Parker, T.L., Connelly, P.W., Qian, W., Haight, J.S., Spiller, G.A., Dose response of almonds on coronary heart disease risk factors: Blood lipids, oxidized lowdensity lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: A randomized, controlled, crossover trial (2002) Circulation, 106 (10), pp. 1327-1332. , DallasJiang, R., Jacobs, D.R., Mayer-Davis, E., Szklo, M., Herrington, D., Jenny, N.S., Kronmal, R., Graham, B.R., Nut and seed consumption and inflammatory markers in the Multi-Ethnic Study of Atherosclerosis (2006) American Journal of Epidemiology, 163 (3), pp. 222-231. , OxfordJohn, J.A., Shahidi, F., Phenolic compounds and antioxidant activity of Brazil nut (Bertholletia excelsa) (2010) Journal of Functional Foods, 2 (3), pp. 196-209. , ShanghaiLorenzi, H., (1992) Árvores Brasileiras: Manual De Identificação E Cultivo De Plantas Arbóreas Nativas Do Brasil, p. 352. , 1a ed., São Paulo, PlantarumMachado, S.S., Bueno, P.R.M., Oliveira, M.B., Moura, C.J., Concentração de chumbo em alface cultivada com diferentes adubos orgânicos (2008) Revista Brasileira De Produtos Agroindustriais, 10 (1), pp. 63-70. , Campina GrandePantano, A.P., (2010) Sapucaia - Lecythis Ollaria Ou L. Pisonis, , http://www.jardimdeflores.com.br/floresefolhas/A47sapucaia.htm, Disponível em:, Acesso em: 01 de junRos, E., Mataix, J., Fatty acid composition of nuts - implications for cardiovascular health (2006) British Journal of Nutrition, 96 (2), pp. 29-35. , CambrigdeRos, E., Nuts and novel biomarkers os cardiovascular disease (2009) American Journal of Clinical Nutrition, 89, pp. 1649-1656. , BethesdaRosa, J.C., Izumi, C., Beltramini-Sabbag, L.M., Greene, L.J., Quantitative HPLC analysis of phenylisothio-carbamyl-amino acids at picomol levels (1987) Arquivos De Biologia E Tecnologia, 30 (1), p. 35. , CuritibaRyan, E., Galvin, K., O'connor, T.P., Maguire, A.R., O'Brien, N.M., Fatty acid profile, tocopherol, squalene and phytosterol content of brazil, pecan, pine, pistachio and cashew nuts (2006) International Journal of Food Sciences and Nutrition, 57 (3), pp. 219-228. , LondonSinha, R., Radha, C., Prakash, J., Kaul, P., Whey protein hydrolysate: Functional properties, nutritional quality and utilization in beverage formulation (2007) Food Chemistry, 101 (4), pp. 1484-1491. , BarkingSouza, V.A.B., Carvalho, M.G., Santos, K.S., Ferreira, C.S., Características físicas de frutos e amêndoas e características químico-nutricionais de amêndoas de acessos de sapucaia (2008) Revista Brasileira De Fruticultura, 30 (4), pp. 946-952. , JaboticabalVallilo, M.I., Tavares, M., Pimentel, S.A., Campos, N.C., Moita, N.J.M., Lecythis pisonis Camb. nuts: Oil characterization, fatty acids and minerals (1999) Food Chemstry, 66, pp. 197-200. , BarkingVallilo, M.I., Tavares, M., Pimentel, S.A., Badolato, E.S.G., Inomata, E.I., Caracterização química parcial das sementes de Lecythis pisonis Camb. (SAPUCAIA) (1998) Acta Amazonica, 28 (2), pp. 131-140. , ManausVenkatachalam, M., Sathe, S.K., Chemical composition of selected edible nut seeds (2006) Journal of Agriculture and Food Chemistry, 54 (13), pp. 4705-4714. , WashingtonYang, J., Brazil nuts and associated health benefits: A review (2009) Food Science and Technology, 42, pp. 1573-1580. , Oxfor

Brazilian Biologic Registry: Biobada Brasil Implementation Process And Preliminary Results

Objectives: The present study aimed at describing the implementation process of a national registry in a developing country (Brazil) and at reporting the main preliminary results of the BiobadaBrasil registry. Material and methods: Through a PANLAR agreement, the Biobadaser protocol was used as a model for implementing the new registry in our country. During the first two years of this effort, the original protocol was adapted, translated, and presented to all Brazilian rheumatologists. For ten months, data of 1,037 patients (750 subjects treated with biological drugs and 287 control subjects) from 15 centers were collected. Results: Most patients had rheumatoid arthritis (RA) (n = 723). Infliximab was the most frequently used anti-TNF agent, and the total exposure to biologic drugs was 2,101 patient-years. The most common reason for interrupting drug use was lack or loss of efficacy (50%), while 30% withdrew from the treatment arm due to adverse events. Three cases of tuberculosis were observed in the biologic group, with an incidence higher than that of the general Brazilian population. Infections were observed in 23% of the biologic group, and the upper respiratory tract was the most commonly affected site. Only one case of tuberculoid leprosy was observed. No deaths or malignancies attributed to drug effects were observed as of February 2010. Conclusions: The implementation of the BiobadaBrasil registry was successful, and, although recent, the registry has provided important data. ©Elsevier Editora Ltda.51214515

Salacia campestris root bark extract: peroxidase inhibition, antioxidant and antiradical profile

Reactive oxygen species (ROS) and free radical species have been implicated in initiating or accompanying many diseases in living organisms; there is thus, a continual need for antioxidants molecules to inactivate ROS/free radicals. Many studies of plants crude extracts have demonstrated free-radical scavenging and antioxidant action. Salacia species have long been used, in several countries, as traditional medicines against certain diseases and for their anti-inflammatory properties. In this study, Salacia campestris Walp (Hippocrateaceae) root bark ethanol extract (ScEtOH) was assessed for its ability to scavenge free radicals and reactive oxygen species; the results were expressed as percentage inhibition of the active species. ScEtOH was efficient against studied species: DPPH radical (obtained inhibition = 30%), ABTS•+ (IC50 = 1.8±0.8 &#956;g/mL), HOCl (IC50 = 1.7 ± 0.1 &#956;g/mL), O2•- (obtained inhibition = 32%), and NO• (obtained inhibition = 18 %). Peroxidase activity inhibition was evaluated through the guaiacol oxidation reaction catalyzed by hemin, HRP and myeloperoxidase (MPO); data showed that ScEtOH at 10 &#956;g/mL led to 54 and 51% of inhibition, respectively, for the hemin and HRP systems. In the MPO system, ScEtOH promoted a 50% inhibition at 8.9 &#956;g/mL, whereas quercetin, a powerful MPO inhibitor, inhibited this system at 1.35 &#956;g/mL.<br>Espécies reativas do oxigênio (ERO) e radicais livres estão relacionados ao início ou à exacerbação de muitas doenças em organismos vivos; existindo portanto uma necessidade contínua por moléculas antioxidantes que inativem as ERO e radicais livres. Muitos estudos com extratos brutos de plantas têm demonstrado propriedades antioxidantes e seqüestradoras de radicais livres. Espécies de Salacia são utilizadas, em muitos países, como remédio tradicional contra certas doenças e por suas propriedades antiinflamatórias. Neste estudo, o extrato bruto etanólico da casca da raiz da Salacia campestris Walp (Hippocrateaceae) foi avaliado quanto à sua habilidade em seqüestrar radicais livres e espécies reativas do oxigênio; os resultados são expressos como porcentagem de inibição das espécies ativas. ScEtOH mostrou-se eficiente frente as espécies estudadas: radical DPPH (inibição obtida = 30%), ABTS•+ (IC50 = 1,8±0,8 &#956;g/mL), HOCl (IC50 = 1,7 ± 0,1 &#956;g/mL), O2•- (inibição obtida = 32%), and NO• (inibição obtida = 18%). A inibição da atividade peroxidásica foi avaliada através da oxidação do guaiacol catalisada pela hemina, HRP e mieloperoxidase (MPO); os dados mostram que 10 &#956;g/mL de ScEtOH promovem 54 e 51% de inibição, respectivamente para os sistemas da hemina e da HRP. No sistema da MPO, ScEtOH promoveu 50% de inibição na dose de 8,9 &#956;g/mL, enquanto a quercetina, um potente inibidor da MPO promoveu tal inibição com 1,35 &#956;g/mL

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.</p