Downregulation of miR-92a Is Associated with Aggressive Breast Cancer Features and Increased Tumour Macrophage Infiltration

BACKGROUND: MicroRNAs are small non-coding RNAs involved in the regulation of gene expression on a posttranscriptional level. These regulatory RNAs have been implicated in numerous cellular processes and are further deregulated in different cancer types, including breast cancer. MiR-92a is part of the miR-17∼92 cluster, which was first reported to be linked to tumourigenesis. However, little is known about the expression of miR-92a in breast cancer and potential associations to tumour properties. The expression of miR-92a was therefore characterized in 144 invasive breast cancer samples using in situ hybridization and related to clinico-pathological data as well as to selected key properties of the tumour stroma, including the presence of macrophages (CD68) and cancer activated fibroblasts (alpha-SMA). METHODOLOGY/PRINCIPAL FINDINGS: To measure miR-92a levels, an in situ hybridisation protocol was developed and validated using cell lines and miR-92a inhibitors. The expression in the tumour samples was objectively evaluated using digital image analysis program subtracting background activities. We found that the miR-92a expression varied between tumours and was inversely correlated to tumour grade (r = -0.276, p = 0.003) and recurrence-free survival (p = 0.008) and provided independent prognostic information in multivariate Cox analysis (HR: 0.375, CI: 0.145-0.972, p = 0.043). MiR-92a was moreover inversely correlated to the number of infiltrating macrophages in the tumour stroma (r = -0.357, p<0.001), and downregulation of miR-92a promoted cell migration (p<0.01). CONCLUSIONS/SIGNIFICANCE: This study demonstrates that downregulation of miR-92a in breast cancer is linked to key epithelial and stromal properties as well as clinical outcome

Increased shear in the North Atlantic upper-level jet stream over the past four decades

Earth’s equator-to-pole temperature gradient drives westerly mid-latitude jet streams through thermal wind balance. In the upper atmosphere, anthropogenic climate change is strengthening this meridional temperature gradient by cooling the polar lower stratosphere and warming the tropical upper troposphere acting to strengthen the upper-level jet stream. In contrast, in the lower atmosphere, Arctic amplification of global warming is weakening the meridional temperature gradient acting to weaken the upper-level jet stream. Therefore, trends in the speed of the upper-level jet stream represent a closely balanced tug-of-war between two competing effects at different altitudes. It is possible to isolate one of the competing effects by analysing the vertical shear—the change in wind speed with height—instead of the wind speed, but this approach has not previously been taken. Here we show that, although the zonal wind speed in the North Atlantic polar jet stream at 250 hectopascals has not changed since the start of the observational satellite era in 1979, the vertical shear has increased by 15 per cent (with a range of 11–17 per cent) according to three different reanalysis datasets. We further show that this trend is attributable to the thermal wind response to the enhanced upper-level meridional temperature gradient. Our results indicate that climate change may be having a larger impact on the North Atlantic jet stream than previously thought. The increased vertical shear is consistent with the intensification of shear-driven clear-air turbulence expected from climate change which will affect aviation in the busy transatlantic flight corridor by creating a more turbulent flying environment for aircraft. We conclude that the effects of climate change and variability on the upper-level jet stream are being partly obscured by the traditional focus on wind speed rather than wind shear

Warmer Weather Linked to Tick Attack and Emergence of Severe Rickettsioses

The impact of climate on the vector behaviour of the worldwide dog tick Rhipicephalus sanguineus is a cause of concern. This tick is a vector for life-threatening organisms including Rickettsia rickettsii, the agent of Rocky Mountain spotted fever, R. conorii, the agent of Mediterranean spotted fever, and the ubiquitous emerging pathogen R. massiliae. A focus of spotted fever was investigated in France in May 2007. Blood and tissue samples from two patients were tested. An entomological survey was organised with the study of climatic conditions. An experimental model was designed to test the affinity of Rh. sanguineus for biting humans in variable temperature conditions. Serological and/or molecular tools confirmed that one patient was infected by R. conorii, whereas the other was infected by R. massiliae. Dense populations of Rh. sanguineus were found. They were infected with new genotypes of clonal populations of either R. conorii (24/133; 18%) or R. massiliae (13/133; 10%). April 2007 was the warmest since 1950, with summer-like temperatures. We show herein that the human affinity of Rh. sanguineus was increased in warmer temperatures. In addition to the originality of theses cases (ophthalmic involvements, the second reported case of R. massiliae infection), we provide evidence that this cluster of cases was related to a warming-mediated increase in the aggressiveness of Rh. sanguineus, leading to increased human attacks. From a global perspective, we predict that as a result of globalisation and warming, more pathogens transmitted by the brown dog tick may emerge in the future

Dynamical Boson Stars

The idea of stable, localized bundles of energy has strong appeal as a model for particles. In the 1950s John Wheeler envisioned such bundles as smooth configurations of electromagnetic energy that he called {\em geons}, but none were found. Instead, particle-like solutions were found in the late 1960s with the addition of a scalar field, and these were given the name {\em boson stars}. Since then, boson stars find use in a wide variety of models as sources of dark matter, as black hole mimickers, in simple models of binary systems, and as a tool in finding black holes in higher dimensions with only a single killing vector. We discuss important varieties of boson stars, their dynamic properties, and some of their uses, concentrating on recent efforts.Comment: 79 pages, 25 figures, invited review for Living Reviews in Relativity; major revision in 201

Ethnicity and Cutaneous Melanoma in the City of Sao Paulo, Brazil: A Case-Control Study

Background: Over the last century the incidence of cutaneous melanoma has increased worldwide, a trend that has also been observed in Brazil. The identified risk factors for melanoma include the pattern of sun exposure, family history, and certain phenotypic features. In addition, the incidence of melanoma might be influenced by ethnicity. Like many countries, Brazil has high immigration rates and consequently a heterogenous population. However, Brazil is unique among such countries in that the ethnic heterogeneity of its population is primarily attributable to admixture. This study aimed to evaluate the contribution of European ethnicity to the risk of cutaneous melanoma in Brazil. Methodology/Principal Findings: We carried out a hospital-based case-control study in the metropolitan area of Sao Paulo, Brazil. We evaluated 424 hospitalized patients (202 melanoma patients and 222 control patients) regarding phenotypic features, sun exposure, and number of grandparents born in Europe. Through multivariate logistic regression analysis, we found the following variables to be independently associated with melanoma: grandparents born in Europe-Spain (OR = 3.01, 95% CI: 1.03-8.77), Italy (OR = 3.47, 95% CI: 1.41-8.57), a Germanic/Slavic country (OR = 3.06, 95% CI: 1.05-8.93), or &gt;= 2 European countries (OR = 2.82, 95% CI: 1.06-7.47); eye color-light brown (OR = 1.99, 95% CI: 1.14-3.84) and green/blue (OR = 4.62; 95% CI 2.22-9.58); pigmented lesion removal (OR = 3.78; 95% CI: 2.21-6.49); no lifetime sunscreen use (OR = 3.08; 95% CI: 1.03-9.22); and lifetime severe sunburn (OR = 1.81; 95% CI: 1.03-3.19). Conclusions: Our results indicate that European ancestry is a risk factor for cutaneous melanoma. Such risk appears to be related not only to skin type, eye color, and tanning capacity but also to others specific characteristics of European populations introduced in the New World by European immigrants.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [06-52041-9, 5-56069-2]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - Brasil (National Counsel of Technological and Scientific Development - Brazil) - CNPq [478239/03-3]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico Brasil (National Counsel of Technological and Scientific Development Brazil) CNP

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Molecular Biomarkers of Vascular Dysfunction in Obstructive Sleep Apnea

Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%–90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients