The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure

Systematic Analysis of Cis-Elements in Unstable mRNAs Demonstrates that CUGBP1 Is a Key Regulator of mRNA Decay in Muscle Cells

BACKGROUND: Dramatic changes in gene expression occur in response to extracellular stimuli and during differentiation. Although transcriptional effects are important, alterations in mRNA decay also play a major role in achieving rapid and massive changes in mRNA abundance. Moreover, just as transcription factor activity varies between different cell types, the factors influencing mRNA decay are also cell-type specific. PRINCIPAL FINDINGS: We have established the rates of decay for over 7000 transcripts expressed in mouse C2C12 myoblasts. We found that GU-rich (GRE) and AU-rich (ARE) elements are over-represented in the 3'UTRs of short-lived mRNAs and that these mRNAs tend to encode factors involved in cell cycle and transcription regulation. Stabilizing elements were also identified. By comparing mRNA decay rates in C2C12 cells with those previously measured for pluripotent and differentiating embryonic stem (ES) cells, we identified several groups of transcripts that exhibit cell-type specific decay rates. Further, whereas in C2C12 cells the impact of GREs on mRNA decay appears to be greater than that of AREs, AREs are more significant in ES cells, supporting the idea that cis elements make a cell-specific contribution to mRNA stability. GREs are recognized by CUGBP1, an RNA-binding protein and instability factor whose function is affected in several neuromuscular diseases. We therefore utilized RNA immunoprecipitation followed by microarray (RIP-Chip) to identify CUGBP1-associated transcripts. These mRNAs also showed dramatic enrichment of GREs in their 3'UTRs and encode proteins linked with cell cycle, and intracellular transport. Interestingly several CUGBP1 substrate mRNAs, including those encoding the myogenic transcription factors Myod1 and Myog, are also bound by the stabilizing factor HuR in C2C12 cells. Finally, we show that several CUGBP1-associated mRNAs containing 3'UTR GREs, including Myod1, are stabilized in cells depleted of CUGBP1, consistent with the role of CUGBP1 as a destabilizing factor. CONCLUSIONS: Taken together, our results systematically establish cis-acting determinants of mRNA decay rates in C2C12 myoblast cells and demonstrate that CUGBP1 associates with GREs to regulate decay of a wide range of mRNAs including several that are critical for muscle development

Blood pressure and associated factors in a North African adolescent population. a national cross-sectional study in Tunisia

<p>Abstract</p> <p>Background</p> <p>In southern and eastern Mediterranean countries, changes in lifestyle and the increasing prevalence of excess weight in childhood are risk factors for high blood pressure (BP) during adolescence and adulthood. The aim of this study was to evaluate the BP status of Tunisian adolescents and to identify associated factors.</p> <p>Methods</p> <p>A cross-sectional study in 2005, based on a national, stratified, random cluster sample of 1294 boys and 1576 girls aged 15-19 surveyed in home visits. The socio-economic and behavioral characteristics of the adolescents were recorded. Overweight/obesity were assessed by Body Mass Index (BMI) from measured height and weight (WHO, 2007), abdominal obesity by waist circumference (WC). BP was measured twice during the same visit. Elevated BP was systolic (SBP) or diastolic blood pressure (DBP) ≥ 90th of the international reference or ≥ 120/80 mm Hg for 15-17 y., and SBP/DBP ≥ 120/80 mm Hg for 18-19 y.; hypertension was SBP/DBP ≥ 95th for 15-17 y. and ≥ 140/90 mm Hg for 18-19 y. Adjusted associations were assessed by logistic regression.</p> <p>Results</p> <p>The prevalence of elevated BP was 35.1%[32.9-37.4]: higher among boys (46.1% vs. 33.3%; <it>P </it>< 0.0001); 4.7%[3.8-5.9] of adolescents had hypertension. Associations adjusted for all covariates showed independent relationships with BMI and WC: - obesity vs. no excess weight increased elevated BP (boys OR = 2.1[1.0-4.2], girls OR = 2.3[1.3-3.9]) and hypertension (boys OR = 3.5[1.4-8.9], girls OR = 5.4[2.2-13.4]), - abdominal obesity (WC) was also associated with elevated BP in both genders (for boys: 2nd vs. 1st tertile OR = 1.7[1.3-2.3], 3rd vs.1st tertile OR = 2.8[1.9-4.2]; for girls: 2nd vs. 1st tertile OR = 1.6[1.2-2.1], 3rd vs.1st tertile OR = 2.1[1.5-3.0]) but only among boys for hypertension. Associations with other covariates were weaker: for boys, hypertension increased somewhat with sedentary lifestyle, while elevated BP was slightly more prevalent among urban girls and those not attending school.</p> <p>Conclusion</p> <p>Within the limits of BP measurement on one visit only, these results suggest that Tunisian adolescents of both genders are likely not spared from early elevated BP. Though further assessment is likely needed, the strong association with overweight/obesity observed suggests that interventions aimed at changing lifestyles to reduce this main risk factor may also be appropriate for the prevention of elevated BP.</p

Breast cancer prognostic classification in the molecular era: the role of histological grade

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers. © 2010 BioMed Central Lt