Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response.

AIMS/HYPOTHESIS: Although insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response. METHODS: Using a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k-nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study. RESULTS: We found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2, AASS, ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response. CONCLUSION/INTERPRETATION: Our results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies.

Breast Cancer Antiestrogen Resistance 3 (BCAR3) promotes tumor growth and progression in triple-negative breast cancer.

Triple-Negative Breast Cancers (TNBCs) constitute roughly 10-20% of breast cancers and are associated with poor clinical outcomes. Previous work from our laboratory and others has determined that the cytoplasmic adaptor protein Breast Cancer Antiestrogen Resistance 3 (BCAR3) is an important promoter of cell motility and invasion of breast cancer cells. In this study, we use both in vivo and in vitro approaches to extend our understanding of BCAR3 function in TNBC. We show that BCAR3 is upregulated in ductal carcinoma in situ (DCIS) and invasive carcinomas compared to normal mammary tissue, and that survival of TNBC patients whose tumors contained elevated BCAR3 mRNA is reduced relative to individuals whose tumors had less BCAR3 mRNA. Using mouse orthotopic tumor models, we further show that BCAR3 is required for efficient TNBC tumor growth. Analysis of publicly available RNA expression databases revealed that MET receptor signaling is strongly correlated with BCAR3 mRNA expression. A functional role for BCAR3-MET coupling is supported by data showing that both proteins participate in a single pathway to control proliferation and migration of TNBC cells. Interestingly, the mechanism through which this functional interaction operates appears to differ in different genetic backgrounds of TNBC, stemming in one case from potential differences in the strength of downstream signaling by the MET receptor and in another from BCAR3-dependent activation of an autocrine loop involving the production of HGF mRNA. Together, these data open the possibility for new approaches to personalized therapy for individuals with TNBCs.

Barriers and Facilitators to Antiretroviral Medication Adherence among HIV-Infected Paediatric Patients in Ethiopia: a Qualitative Study

Medication adherence is a complex behaviour with multiple determinants. Understanding the barriers and facilitators of adherence is invaluable for programme improvement; which assists the foundation of adherence intervention strategies. A qualitative study was conducted in six selected hospitals of Addis Ababa in 2008; to explore barriers and facilitators to antiretroviral medication adherence among HIV-infected paediatric patients. Twelve caregivers of adherent and non-adherent children and 14 key informants in five hospitals were included in the study. The findings revealed that over-dosage (heavy pill burden); fear of stigma and discrimination; cost and access to transportation; lack of understanding of the benefit of taking the medication; economic problems in the household; and lack of nutritional support were the barriers to adherence to HAART. The presence of mobile/wall alarm; the presence of follow-up counselling; improved health of the child; ART clinic setups; and disclosure of HIV serostatus were among the facilitators. This study indicated that paediatric adherence to antiretroviral therapy faces a huge challenge. It suggests the provision of income-generating schemes to caregivers for assisting HIV-infected children. Health care providers should address proper usage of medication reminders

Levels of 15-ketodihydroprostaglandin F2 alpha during experimental Toxoplasma gondii infection in non-pregnant ewe lambs.

In order to study the relation between prostaglandin F2 alpha levels and fever during Toxoplasma gondii infection, six non-pregnant ewe lambs were exposed orally to T. gondii oocysts and an additional four animals were used as non-inoculated controls. Rectal temperature was measured daily during four weeks and plasma samples were analysed for the content of 15-ketodihydroprostaglandin F2 alpha. As compared to controls, the inoculated animals had significantly elevated rectal temperatures on days 4-16 after infection, but no concomitant changes in prostaglandin F2 alpha metabolite levels were recorded.