Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

Low–moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in ∼1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted Pdominant=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case–control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80–0.99) and remained statistically significant (Pdominant=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (Pglobal=0.034) and a haplotype in BRAF that had a protective effect (Pglobal=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC

Prior mucosal exposure to heterologous cells alters the pathogenesis of cell-associated mucosal feline immunodeficiency virus challenge

<p>Abstract</p> <p>Background</p> <p>Several lines of research suggest that exposure to cellular material can alter the susceptibility to infection by HIV-1. Because sexual contact often includes exposure to cellular material, we hypothesized that repeated mucosal exposure to heterologous cells would induce an immune response that would alter the susceptibility to mucosal infection. Using the feline immunodeficiency virus (FIV) model of HIV-1 mucosal transmission, the cervicovaginal mucosa was exposed once weekly for 12 weeks to 5,000 heterologous cells or media (control) and then cats were vaginally challenged with cell-associated or cell-free FIV.</p> <p>Results</p> <p>Exposure to heterologous cells decreased the percentage of lymphocytes in the mucosal and systemic lymph nodes (LN) expressing L-selectin as well as the percentage of CD4+ CD25+ T cells. These shifts were associated with enhanced ex-vivo proliferative responses to heterologous cells. Following mucosal challenge with cell-associated, but not cell-free, FIV, proviral burden was reduced by 64% in cats previously exposed to heterologous cells as compared to media exposed controls.</p> <p>Conclusions</p> <p>The pathogenesis and/or the threshold for mucosal infection by infected cells (but not cell-free virus) can be modulated by mucosal exposure to uninfected heterologous cells.</p

Association analysis identifies 65 new breast cancer risk loci

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec, and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH Grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combining of the GWAS data was supported in part by The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative)

Late-Quaternary recharge determined from chloride in shallow groundwater in the central Great Plains

An extensive suite of isotopic and geochemical tracers in groundwater has been used to provide hydrologic assessments of the hierarchy of flow systems in aquifers underlying the central Great Plains (southeastern Colorado and western Kansas) of the United States and to determine the late Pleistocene and Holocene paleotemperature and paleorecharge record. Hydrogeologic and geochemical tracer data permit classification of the samples into late Holocene, late Pleistocene-early Holocene, and much older Pleistocene groups. Paleorecharge rates calculated from the Cl concentration in the samples show that recharge rates were at least twice the late Holocene rate during late Pleistocene-early Holocene time, which is consistent with their relative depletion in 16O and D. Noble gas (Ne, Ar, Kr, Xe) temperature calculations confirm that these older samples represent a recharge environment approximately 5°C cooler than late Holocene values. These results are consistent with the global climate models that show a trend toward a warmer, more arid climate during the Holocene. (C) 2000 University of Washington

Late-Quaternary recharge determined from chloride in shallow groundwater in the central Great Plains

An extensive suite of isotopic and geochemical tracers in groundwater has been used to provide hydrologic assessments of the hierarchy of flow systems in aquifers underlying the central Great Plains (southeastern Colorado and western Kansas) of the United States and to determine the late Pleistocene and Holocene paleotemperature and paleorecharge record. Hydrogeologic and geochemical tracer data permit classification of the samples into late Holocene, late Pleistocene-early Holocene, and much older Pleistocene groups. Paleorecharge rates calculated from the Cl concentration in the samples show that recharge rates were at least twice the late Holocene rate during late Pleistocene-early Holocene time, which is consistent with their relative depletion in 16O and D. Noble gas (Ne, Ar, Kr, Xe) temperature calculations confirm that these older samples represent a recharge environment approximately 5°C cooler than late Holocene values. These results are consistent with the global climate models that show a trend toward a warmer, more arid climate during the Holocene. (C) 2000 University of Washington

Intervenções de enfermagem relacionadas à promoção da saúde em portadores de hipertensão Intervenciones de enfermería relacionadas a la promoción de la salud en portadores de hipertensión Nursing interventions related to health promotion in hypertensive patients

OBJETIVOS: Identificar as competências de promoção da saúde em intervenções de enfermagem em portadores de hipertensão arterial. MÉTODOS: Seguiu-se a metodologia de revisão integrativa da literatura, utilizando as oito competências para a prática de promoção da saúde definidas na Conferência de Galway. Foram analisados 16 artigos. RESULTADOS: Os domínios de competência para a prática de promoção da saúde mais evidenciados foram Catalisar mudanças, Avaliação das necessidades e Parcerias. Apenas um artigo mencionou o uso das taxonomias de enfermagem para o planejamento da assistência em portadores de hipertensão arterial. CONCLUSÃO: Os resultados deste estudo poderão subsidiar as competências dos enfermeiros para a prática da promoção da saúde em portadores de hipertensão arterial.<br>OBJETIVOS: Identificar las competencias de promoción de la salud en intervenciones de enfermería en portadores de hipertensión arterial. MÉTODOS: Se siguió la metodología de La revisión integrativa de la literatura, utilizando las ocho competencias para la práctica de la promoción de la salud definidas en la Conferencia de Galway. Fueron analizados 16 artículos. RESULTADOS: Los dominios de competencia para la práctica de promoción de la salud más evidenciados fueron Catalizar cambios, Evaluación de las necesidades y sociedades. Sólo un artículo mencionó el uso de las taxonomías de enfermería para la planificación de la asistencia en portadores de hipertensión arterial. CONCLUSIÓN: Los resultados de este estudo pueden subsidiar las competencias de los enfermeros para la práctica de la promoción de la salud en portadores de hipertensión arterial.<br>OBJECTIVES: To identify the health promotion compentencies of nursing interventions for patient with hypertension. METHODS: The methodology of an integrative literature review was followed, using the eight competencies for the practice of health promotion that were defined at the Galway Consensus Conference. Sixteen articles were analyzed. RESULTS: The domains of competence for health promotion practice that were most evident were: catalyzing change, assessment of needs, and partnerships. Only one article mentioned the use of nursing taxonomies for planning care in patients with hypertension. CONCLUSION: The results of this study will support nursing competencies for practicing health promotion in patients with hypertension