Insulin receptor substrate adaptor proteins mediate prognostic gene expression profiles in breast cancer

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer

Cut off values of waist circumference & associated cardiovascular risk in egyptians

<p>Abstract</p> <p>Background</p> <p>Recent guidelines stressed the need to adopt different values of waist circumference (WC) measurements to define abdominal obesity in different ethnic groups. The aim of this study is to identify WC cutoff points in normotensive and hypertensive subjects which are diagnostic of abdominal obesity in a Middle Eastern population and the prevalence of abdominal obesity in a nationwide sample.</p> <p>Methods</p> <p>Data were collected during phase-2 of the Egyptians National Hypertension Project survey. Blood pressure, anthropometric measurements and laboratory studies were performed according to a standardized protocol by trained personnel. To derive the cutoff points for WC, we applied the factor analysis on CV risk factors: diabetes mellitus, decrease in HDL-C and increase in LDL-C, triglycerides and left ventricular mass index by echocardiography.</p> <p>Results</p> <p>The sample included 2313 individuals above the age of 25 years. WC values (mean ± SD) were 88 ± 14 cm and 95 ± 14 cm for normotensive (NT) and hypertensive (HT) men respectively, and 89.6 ± 14.7 cm and 95.7 ± 15.9 cm for NT and HT women respectively. Applying factor analysis, the weighted average cutoff points were 93.5 cm for both NT and HT men and 91.5 and 92.5 cm for NT and HT women respectively. Based on these thresholds, the prevalence of abdominal obesity was 48% in men and 51.5% in women.</p> <p>Conclusion</p> <p>This is the first report of specific abdominal obesity cutoff points in a Middle Eastern country. The cutoff points were different from the Europid standards. There is a high prevalence rate of abdominal obesity among Egyptians which is associated with increased prevalence of cardiometabolic risk factors.</p

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Analysis of gene expression data from non-small celllung carcinoma cell lines reveals distinct sub-classesfrom those identified at the phenotype level

Microarray data from cell lines of Non-Small Cell Lung Carcinoma (NSCLC) can be used to look for differences in gene expression between the cell lines derived from different tumour samples, and to investigate if these differences can be used to cluster the cell lines into distinct groups. Dividing the cell lines into classes can help to improve diagnosis and the development of screens for new drug candidates. The micro-array data is first subjected to quality control analysis and then subsequently normalised using three alternate methods to reduce the chances of differences being artefacts resulting from the normalisation process. The final clustering into sub-classes was carried out in a conservative manner such that subclasses were consistent across all three normalisation methods. If there is structure in the cell line population it was expected that this would agree with histological classifications, but this was not found to be the case. To check the biological consistency of the sub-classes the set of most strongly differentially expressed genes was be identified for each pair of clusters to check if the genes that most strongly define sub-classes have biological functions consistent with NSCLC

Obesity in total hip arthroplasty—does it really matter?: A meta-analysis

Discussion persists as to whether obesity negatively influences the outcome of hip arthroplasty. We performed a meta-analysis with the primary research question of whether obesity has a negative effect on short- and long-term outcome of total hip arthroplasty. We searched the literature and included studies comparing the outcome of hip arthroplasty in different weight groups. The methodology of the studies included was scored according to the Cochrane guidelines. We extracted and pooled the data. For continuous data, we calculated a weighted mean difference and for dichotomous variables we calculated a weighted odds ratio (OR). Heterogeneity was calculated using I(2) statistics. 15 studies were eligible for data extraction. In obese patients, dislocation of the hip (OR = 0.54, 95% CI: 0.38-0.75) (10 studies, n = 8,634), aseptic loosening (OR = 0.64, CI: 0.43-0.96) (6 studies, n = 5,137), infection (OR = 0.3, CI: 0.19-0.49) (10 studies, n = 7,500), and venous thromboembolism (OR = 0.56, CI: 0.32-0.98) (7 studies, n = 3,716) occurred more often. Concerning septic loosening and intraoperative fractures, no statistically significant differences were found, possibly due to low power. Subjective outcome measurements did not allow pooling because of high heterogeneity (I(2) = 68%). Obesity appears to have a negative influence on the outcome of total hip replacemen

Amyloid Precursor Protein and Proinflammatory Changes Are Regulated in Brain and Adipose Tissue in a Murine Model of High Fat Diet-Induced Obesity

Background: Middle age obesity is recognized as a risk factor for Alzheimer’s disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions. Methodology/Principal Findings: To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes. Conclusions/Significance: Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-a and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokin