CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldA T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size

Use of complementary and alternative medicine in cancer patients: a European survey

Background: The aim of this study was to explore the use of complementary and alternative medicine (CAM) in cancer patients across a number of European countries. Methods: A descriptive survey design was developed. Fourteen countries participated in the study and data was collected through a descriptive questionnaire from 956 patients. Results: Data suggest that CAM is popular among cancer patients with 35.9% using some form of CAM (range among countries 14.8% to 73.1%). A heterogeneous group of 58 therapies were identified as being used. Herbal medicines and remedies were the most commonly used CAM therapies, together with homeopathy, vitamins/minerals, medicinal teas, spiritual therapies and relaxation techniques. Herbal medicine use tripled from use before diagnosis to use since diagnosis with cancer. Multivariate analysis suggested that the profile of the CAM user was that of younger people, female and with higher educational level. The source of information was mainly from friends/family and the media, while physicians and nurses played a small part in providing CAM-related information. The majority used CAM to increase the body's ability to fight cancer or improve physical and emotional well-being, and many seemed to have benefited from using CAM (even though the benefits were not necessarily related to the initial reason for using CAM). Some 4.4% of patients, however, reported side-effects, mostly transient. Conclusions: It is imperative that health professionals explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provisio

Co-creation and regional adaptation of a resilience-based universal whole-school program in five European regions

The co-creation of educational services that promote youth resilience and mental health is still scarce. UPRIGHT (Universal Preventive Resilience Intervention Globally implemented in schools to improve and promote mental Health for Teenagers) is a research and intervention program in the Basque Country (Spain), Trentino (Italy), Low Silesia (Poland), Denmark and Reykjavik (Iceland). UPRIGHT implemented a co-creation research process whose results, outcomes and policy implications are presented here. The co-creation had a mixed-methods participatory research design with nine specific objectives linked to paired strategies of inquiry for adolescents, families, teachers and school staff. The overarching objective was to generate a valid and feasible regional adaptation strategy for UPRIGHT intervention model. Participants answered surveys (n= 794) or attended 16 group sessions (n= 217). The results integrate quantitative and qualitative information to propose a regional adaptation strategy that prioritizes resilience skills, adolescents' concerns, and preferred methods for implementation across countries and in each school community. In conclusion, a whole-school resilience program must innovate, include and connect different actors, services and communities, and must incorporate new technologies and activities outside the classroom. A participatory co-creation process is an indispensable step to co-design locally relevant resilience interventions with the involvement of the whole-school community

Proteomic prediction of incident heart failure and its main subtypes

AimTo examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.Methods and resultsIn the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study.ConclusionA small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.The ability of the deep circulating proteome to predict future heart failure (HF) events, including its primary subtypes, in relation to event time and known HF-associated clinical factors was studied in two prospective population-based cohorts. AGES-RS, Age, Gene/Environment Susceptibility Reykjavik Study; CHS, Cardiovascular Health Study; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LASSO, least absolute shrinkage and selection operator; ROC, receiver operating characteristic.dagger imageVascular Surger

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer’s disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets

A Novel Adaptive Method for the Analysis of Next-Generation Sequencing Data to Detect Complex Trait Associations with Rare Variants Due to Gene Main Effects and Interactions

There is solid evidence that rare variants contribute to complex disease etiology. Next-generation sequencing technologies make it possible to uncover rare variants within candidate genes, exomes, and genomes. Working in a novel framework, the kernel-based adaptive cluster (KBAC) was developed to perform powerful gene/locus based rare variant association testing. The KBAC combines variant classification and association testing in a coherent framework. Covariates can also be incorporated in the analysis to control for potential confounders including age, sex, and population substructure. To evaluate the power of KBAC: 1) variant data was simulated using rigorous population genetic models for both Europeans and Africans, with parameters estimated from sequence data, and 2) phenotypes were generated using models motivated by complex diseases including breast cancer and Hirschsprung's disease. It is demonstrated that the KBAC has superior power compared to other rare variant analysis methods, such as the combined multivariate and collapsing and weight sum statistic. In the presence of variant misclassification and gene interaction, association testing using KBAC is particularly advantageous. The KBAC method was also applied to test for associations, using sequence data from the Dallas Heart Study, between energy metabolism traits and rare variants in ANGPTL 3,4,5 and 6 genes. A number of novel associations were identified, including the associations of high density lipoprotein and very low density lipoprotein with ANGPTL4. The KBAC method is implemented in a user-friendly R package

Turnover of BRCA1 Involves in Radiation-Induced Apoptosis

Background: Germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) increase the susceptibility to tumorigenesis. The function of BRCA1 is to regulate critical cellular processes, including cell cycle progression, genomic integrity, and apoptosis. Studies on the regulation of BRCA1 have focused intensely on transcription and phosphorylation mechanisms. Proteolytic regulation of BRCA1 in response to stress signaling remains largely unknown. The manuscript identified a novel mechanism by which BRCA1 is regulated by the ubiquitin-dependent degradation in response to ionization. Methodology/Principal Findings: Here, we report that severe ionization triggers rapid degradation of BRCA1, which in turn results in the activation of apoptosis. Ionization-induced BRCA1 turnover is mediated via an ubiquitin-proteasomal pathway. The stabilization of BRCA1 significantly delays the onset of ionization-induced apoptosis. We have mapped the essential region on BRCA1, which mediates its proteolysis in response to ionization. Moreover, we have demonstrated that BRCA1 protein is most sensitive to degradation when ionization occurs during G2/M and S phase. Conclusions/Significance: Our results suggest that ubiquitin-proteasome plays an important role in regulating BRCA1 during genotoxic stress. Proteolytic regulation of BRCA1 involves in ionization-induced apoptosis. © 2010 Liu et al