Alternative signaling network activation through different insulin receptor family members caused by pro-mitogenic antidiabetic insulin analogues in human mammary epithelial cells

INTRODUCTION: Insulin analogues are designed to have improved pharmacokinetic parameters compared to regular human insulin. This provides a sustained control of blood glucose levels in diabetic patients. All novel insulin analogues are tested for their mitogenic side effects, however these assays do not take into account the molecular mode of action of different insulin analogues. Insulin analogues can bind the insulin receptor and the insulin-like growth factor 1 receptor with different affinities and consequently will activate different downstream signaling pathways. METHODS: Here we used a panel of MCF7 human breast cancer cell lines that selectively express either one of the isoforms of the INSR or the IGF1R. We applied a transcriptomics approach to assess the differential transcriptional programs activated in these cells by either insulin, IGF1 or X10 treatment. RESULTS: Based on the differentially expressed genes between insulin versus IGF1 and X10 treatment, we retrieved a mitogenic classifier gene set. Validation by RT-qPCR confirmed the robustness of this gene set. The translational potential of these mitogenic classifier genes was examined in primary human mammary cells and in mammary gland tissue of mice in an in vivo model. The predictive power of the classifier genes was evaluated by testing all commercial insulin analogues in the in vitro model and defined X10 and glargine as the most potent mitogenic insulin analogues. CONCLUSIONS: We propose that these mitogenic classifier genes can be used to test the mitogenic potential of novel insulin analogues as well as other alternative molecules with an anticipated affinity for the IGF1R. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0600-5) contains supplementary material, which is available to authorized users

Structured ambivalence in grandchild care and the quality of life among European grandparents

This study employs the concept of structured ambivalence to analyse the effect of grandchild care on quality of life (QoL) in different cultural contexts. We define structured ambivalence as the contradiction between behaviour and cultural norms. The analysis is based on the Survey of Health, Ageing and Retirement in Europe with 14 countries in the sample. We focus on grandparents aged 50 and over with at least one grandchild 12 years old or younger (n = 12,740). In countries with high grandparent obligations, grandparents who did not look after their grandchildren reported a lower quality of life. Compliance with such grandparental obligations (e.g. providing grandchild care in a country with high grandparent obligations) was found to increase the QoL of grandparents. Family policy should consider family practices that better match the realities of current grandparents’ lives in order to reduce structured ambivalence and increase the QoL of grandparents

CHEK2*1100delC homozygosity in the Netherlands--prevalence and risk of breast and lung cancer

Item does not contain fulltextThe 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4-32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency

The expression of type III hyperlipoproteinemia: Involvement of lipolysis genes

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G>C and APOA5 -1131 T>C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (PC polymorphism and LPL c.27 G>A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 -1131 T>C, c.56 G>C and/or LPL c.27 G>A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval=1.8-7.5, PC/APOA5 -1131 T>C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2

Discutir saúde e imigração no contexto atual de intensa mobilidade humana

Este artigo aborda as relações entre imigração e saúde no Brasil, partindo de uma abordagem histórica que busca contextualizar o debate no país desde o século XIX até os dias atuais. A problematização dessas relações destaca os desafios das políticas sociais de acolhimento e integração dos imigrantes no mundo globalizado. Por meio da revisão bibliográfica sobre imigração e saúde no contexto brasileiro e internacional, buscamos prioridades que se impõem à saúde coletiva em face da intensa mobilidade humana atual. As desigualdades socioeconômicas marcam a experiência de parte dos imigrantes, expondo estas populações a uma maior vulnerabilidade, adoecimento e menor qualidade de vida. Apontamos a necessária promoção da equidade de acesso à saúde, prevenção contra a discriminação, ampliação das políticas públicas, formação dos profissionais e oferta de serviços adaptados, abordando a temática das migrações como determinante social de saúde