MicroRNA-155 expression is independently predictive of outcome in chordoma.

BackgroundChordoma pathogenesis remains poorly understood. In this study, we aimed to evaluate the relationships between microRNA-155 (miR-155) expression and the clinicopathological features of chordoma patients, and to evaluate the functional role of miR-155 in chordoma.MethodsThe miRNA expression profiles were analyzed using miRNA microarray assays. Regulatory activity of miR-155 was assessed using bioinformatic tools. miR-155 expression levels were validated by reverse transcription-polymerase chain reaction. The relationships between miR-155 expression and the clinicopathological features of chordoma patients were analyzed. Proliferative, migratory and invasive activities were assessed by MTT, wound healing, and Matrigel invasion assays, respectively.ResultsThe miRNA microarray assay revealed miR-155 to be highly expressed and biologically active in chordoma. miR-155 expression in chordoma tissues was significantly elevated, and this expression correlated significantly with disease stage (p = 0.036) and the presence of metastasis (p = 0.035). miR-155 expression also correlated significantly with poor outcomes for chordoma patients (hazard ratio, 5.32; p = 0.045). Inhibition of miR-155 expression suppressed proliferation, and the migratory and invasive activities of chordoma cells.ConclusionsWe have shown miR-155 expression to independently affect prognosis in chordoma. These results collectively indicate that miR-155 expression may serve not only as a prognostic marker, but also as a potential therapeutic target in chordoma

Inositol phosphatase SHIP1 is a primary target of miR-155

MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3′UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3′UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155−/− primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology

Low Income Families and Opportunity

Despite considerable progress over last several decades, low-income families continue to face many barriers to opportunity. In 2004 the number and rate of people in poverty increased for the fourth consecutive year. This is just one sign that opportunity for low-income and working poor families is in crisis

Association between one-hour post-load plasma glucose levels and vascular stiffness in essential hypertension

Objectives: Pulse wave velocity (PWV) is a surrogate end-point for cardiovascular morbidity and mortality. A plasma glucose value $155 mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high-risk for type-2 diabetes (T2D) and for subclinical organ damage. Thus, we addressed the question if 1-hour post-load plasma glucose levels, affects PWV and its central hemodynamic correlates, as augmentation pressure (AP) and augmentation index (AI). Methods: We enrolled 584 newly diagnosed hypertensives. All patients underwent OGTT and measurements of PWV, AP and AI. Insulin sensitivity was assessed by Matsuda-index. Results: Among participants, 424 were NGT and 160 had impaired glucose tolerance (IGT). Of 424 NGT, 278 had 1-h postload plasma glucose ,155 mg/dl (NGT,155) and 146 had 1-h post-load plasma glucose$155 mg/dl (NGT$155). NGT$155 had a worse insulin sensitivity and higher hs-CRP than NGT,155, similar to IGT subjects. In addition, NGT $155 in comparison with NGT,155 had higher central systolic blood pressure (134612 vs 131610 mmHg), as well as PWV (8.463.7 vs 6.761.7 m/s), AP (12.567.1 vs 9.865.7 mmHg) and AI (29.4611.9 vs 25.1612.4 regression analysis, 1-h post-load plasma glucose resulted the major determinant of all indices of vascular stiffness. Conclusion: Hypertensive NGT$155 subjects, compared with NGT,155, have higher PWV and its hemodynamic correlates that increase their cardiovascular risk profile

MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis

MicroRNA-155 (miR-155) is an important regulator of B cells in mice. B cells have a critical role in the pathogenesis of rheumatoid arthritis (RA). Here we show that miR-155 is highly expressed in peripheral blood B cells from RA patients compared with healthy individuals, particularly in the IgD-CD27- memory B-cell population in ACPA+ RA. MiR-155 is highly expressed in RA B cells from patients with synovial tissue containing ectopic germinal centres compared with diffuse synovial tissue. MiR-155 expression is associated reciprocally with lower expression of PU.1 at B-cell level in the synovial compartment. Stimulation of healthy donor B cells with CD40L, anti-IgM, IL-21, CpG, IFN-α, IL-6 or BAFF induces miR-155 and decreases PU.1 expression. Finally, inhibition of endogenous miR-155 in B cells of RA patients restores PU.1 and reduces production of antibodies. Our data suggest that miR-155 is an important regulator of B-cell activation in RA

MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis

Objectives: To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in rheumatoid arthritis (RA); and thereby is associated with disease activity. Methods: miR-155 copy-number in monocytes from peripheral blood (PB) of healthy (n=22), RA (n=24), and RA synovial fluid (SF; n=11) were assessed by real time- PCR using synthetic miR-155 as quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic and the effect on transcript levels, and production of chemokines was evaluated by TLDA and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155-/- and wild-type murine (CD115+Ly6C+Ly6G-) monocytes. Results: Compared with healthy monocytes, miR-155 copy-number was higher in RA PB and SF monocytes (PB p<0.01, and SF p<0.0001). MiR-155 copy-number in RA PB monocytes were higher in ACPA positive compared with ACPA negative patients (p=0.033) and correlated (95% C.I.) with DAS28 (ESR), R=0.728 (0.460, 0.874), with tender, R=0.631 (0.306, 0.824) and swollen, R=0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5, CCL8; up-regulated CCR7 expression and down-regulated CCR2. Conversely, miR155-/- monocytes showed down-regulated CCR7 and upregulated CCR2 expression. Conclusions: Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium

Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder

Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficiency of miR-155 to drive GM expansion, enforced expression in mouse bone marrow cells caused GM proliferation in a manner reminiscent of LPS treatment. However, the miR-155–induced GM populations displayed pathological features characteristic of myeloid neoplasia. Of possible relevance to human disease, miR-155 was found to be overexpressed in the bone marrow of patients with certain subtypes of acute myeloid leukemia (AML). Furthermore, miR-155 repressed a subset of genes implicated in hematopoietic development and disease. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress

MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes

Another construction of BV solutions to rate-independent systems

We study one kind of weak solutions to rate-independent systems, which is constructed by using the local minimality in a small neighborhood of order ε and then taking the limit ε → 0. We show that the resulting solution satisfies both the weak local stability and the new energy-dissipation balance, similarly to the BV solutions constructed by vanishing viscosity introduced recently by Mielke, Rossi and Savare

Visibility graphs and landscape visibility analysis

Visibility analysis based on viewsheds is one of the most frequently used GIS analysis tools. In this paper we present an approach to visibility analysis based on the visibility graph. A visibility graph records the pattern of mutual visibility relations in a landscape, and provides a convenient way of storing and further analysing the results of multiple viewshed analyses for a particular landscape region. We describe how a visibility graph may be calculated for a landscape. We then give examples, which include the interactive exploration ofa landscape, and the calculation of new measures of a landscape?s visual properties based on graph metrics ? in particular, neighbourhood clustering coefficient and path length analysis. These analyses suggest that measures derived from the visibility graph may be of particular relevance to the growing interest in quantifying the perceptual characteristics of landscapes