Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status

OBJECTIVE: There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status. MATERIAL AND METHODS: Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction. RESULTS: We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status. DISCUSSION AND CONCLUSIONS: Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.     

Erythrocytic profile of rats infected with T. brucei brucei and treated with a combination of Azadirachta indica leaf extract and diminazene diaceturate

This study investigated the erythrocytic profile of rats experimentally infected with Trypanosoma brucei brucei and treated with a combination of methanolic leaf extract of Azadirachta indica and diminazene diaceturate (DDA). Acute toxicity study of the drug and extract combinations was carried; selection of the best drug and extract combinations was carried out using 54 rats of both sexes separated into nine groups. Three dose combinations were derived from the selection of the best drug and extract combinations used for the final study, viz: 7?mg/kg body weight (bw) DDA plus 125?mg/kg bw extract (group B), 3.5?mg/kg bw DDA plus 250?mg/kg bw extract (group C) and 1.8?mg/kg bw DDA plus 500?mg/kg bw extract (group D). The final study had, in addition to the three groups derived from the dose–response study, four other groups, viz: uninfected untreated negative control (group F), infected and treated with 3,000?mg/kg bw extract alone (group E), infected and treated with 7?mg/kg bw DDA alone (group A) and infected untreated positive control (group G). The parameters assessed were onset of parasitaemia (OP), level of parasitaemia (LOP), clearance of parasites posttreatment (COPPT), relapse of infection period (RIP), red blood cell counts (RBC) and packed cell volume (PCV). There was no significant difference (p?<?0.05) in OP between the groups. A day following treatment, the LOP of groups A, B and C was found to be significantly lower (p?<?0.05) than that of group D (p?<?0.05) which in turn was lower (p?<?0.05) than that of group E and G, respectively. The mean LOP of group E was significantly (p?<?0.05) lower than group G (p?<?0.05) 2?days posttreatment, and this trend continued throughout the experimental period. Mean COPPT of group D was significantly (p?<?0.05) longer than that of groups A, C and B. There was no significant difference (p?<?0.05) in the mean COPPT among groups B, C and A. The mean RIP of group D was significantly shorter (p?<?0.05) than group C, and that of group C was significantly shorter (p?<?0.05) than group A. There was no relapse of infection in group B rats. Group B rats had significantly higher (p?<?0.05) PCV and RBC counts when compared to other infected groups. Group E rats had significantly higher (p?<?0.05) PCV and RBC counts when compared to group G rats. It was concluded that dose combination of 125?mg/kg bw extract plus 7?mg/kg bw DDA led to significant enhancement of erythrocytic profile and potentiation of diminazene in its trypanocidal activity. This combination therapy proved to be better than single therapy of DDA.     

Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes - role of the redox-regulated transcription factor Nrf2

Background  

Both resveratrol and vitamin C (ascorbic acid) are frequently used in complementary and alternative medicine. However, little is known about the underlying mechanisms for potential health benefits of resveratrol and its interactions with ascorbic acid.     

Class Evolution Tree: a graphical tool to support decisions on the number of classes in exploratory categorical latent variable modeling for rehabilitation research

The aim of our study was to develop a graphical tool that can be used in addition to standard statistical criteria to support decisions on the number of classes in explorative categorical latent variable modeling for rehabilitation research. Data from two rehabilitation research projects were used. In the first study, a latent profile analysis was carried out in patients with cancer receiving an inpatient rehabilitation program to identify prototypical combinations of treatment elements. In the second study, growth mixture modeling was used to identify latent trajectory classes based on weekly symptom severity measurements during inpatient treatment of patients with mental disorders. A graphical tool, the Class Evolution Tree, was developed, and its central components were described. The Class Evolution Tree can be used in addition to statistical criteria to systematically address the issue of number of classes in explorative categorical latent variable modeling.     

Cognitive development and risk factors in bilingual pre-school children from an immigrant background

A sample of N=126 preschool children ages 57 to 72 months were examined to explore whether bilingual children from an immigrant background have a higher risk of developing specific developmental problems of educational ability and whether specific precursors could be identified. 63 children with bilingualism and immigrant background were compared to 63 controls matched for age, sex and length of stay in kindergarten. All children were tested with the BASIC-Preschool, a screening tool which assesses specific and non-specific precursors of school problems. Significantly higher risks for developing specific educational problems were found for children growing up bilingually. The subgroup of children with a Turkish background showed the poorest results. Not only language-based subtests of the BASIC-Preschool, but numeracy and visual spatial subtests were affected as language is necessary to understand and/or solve the tasks. For children with immigration background a differentiated analysis of individual resources and risk factors including the consideration of their primary language is required and no universal interventions can be recommended.     

Lipoprotein apheresis – More than just cholesterol reduction?

Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe.     

The retinoid‐related orphan receptor alpha is essential for the end‐stage effector phase of experimental epidermolysis bullosa acquisita

Genetic studies have added to the understanding of complex diseases. Here, we used a combined genetic approach for risk‐loci identification in a prototypic, organ‐specific, autoimmune disease, namely experimental epidermolysis bullosa acquisita (EBA), in which autoantibodies to type VII collagen (COL7) and neutrophil activation cause mucocutaneous blisters. Anti‐COL7 IgG induced moderate blistering in most inbred mouse strains, while some showed severe disease or were completely protected. Using publicly available genotyping data, we identified haplotype blocks that control blistering and confirmed two haplotype blocks in outbred mice. To identify the blistering‐associated genes, haplotype blocks encoding genes that are differentially expressed in EBA‐affected skin were considered. This procedure identified nine genes, including retinoid‐related orphan receptor alpha (RORα), known to be involved in neurological development and function. After anti‐COL7 IgG injection, RORα+/? mice showed reduced blistering and homozygous mice were completely resistant to EBA induction. Furthermore, pharmacological RORα inhibition dose‐dependently blocked reactive oxygen species (ROS) release from activated neutrophils but did not affect migration or phagocytosis. Thus, forward genomics combined with multiple validation steps identifies RORα to be essential to drive inflammation in experimental EBA. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

B cell subsets are modulated during allergic airway inflammation but are not required for the development of respiratory tolerance in a murine model

Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild‐type (WT) and B cell‐deficient (μMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma‐like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen‐specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen‐specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, μMT mice developed asthma‐like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma‐like and respiratory tolerant phenotypes, B cells are not required for tolerance induction.