Luxembourg, Luxembourg
Luxembourg, Luxembourg

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Devaux Y.,Laboratory of Cardiovascular Research | Vausort M.,Laboratory of Cardiovascular Research | Goretti E.,Laboratory of Cardiovascular Research | Nazarov P.V.,Microarray Center | And 7 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI. METHODS: Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls. RESULTS: miRNA-208b and miR-499 were highly increased in MI patients (>10 5-fold, P < 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n=397) had higher miRNA concentrations than patients with non-ST-elevation MI (n =113) (P < 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P <10 -9). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented <3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P = 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15). CONCLUSIONS: Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain. © 2011 American Association for Clinical Chemistry.

Janji B.,Laboratory of Experimental Hemato Oncology LHCE | Janji B.,Microarray Center | Vallar L.,Microarray Center | Tanoury Z.A.,Microarray Center | And 9 more authors.
Journal of Cellular and Molecular Medicine | Year: 2010

We used a tumour necrosis factor (TNF)-α resistant breast adenocarcinoma MCF-7 cell line to investigate the involvement of the actin cytoskeleton in the mechanism of cell resistance to this cytokine. We found that TNF resistance correlates with the loss of cell epithelial properties and the gain of a mesenchymal phenotype, reminiscent of an epithelial-to-mesenchymal transition (EMT). Morphological changes were associated with a profound reorganization of the actin cytoskeleton and with a change in the repertoire of expressed actin cytoskeleton genes and EMT markers, as revealed by DNA microarray-based expression profiling. L-plastin, an F-actin cross-linking and stabilizing protein, was identified as one of the most significantly up-regulated genes in TNF-resistant cells. Knockdown of L-plastin in these cells revealed its crucial role in conferring TNF resistance. Importantly, overexpression of wild-type L-plastin in TNF-sensitive MCF-7 cells was sufficient to protect them against TNF-mediated cell death. Furthermore, we found that this effect is dependent on serine-5 phosphorylation of L-plastin and that non-conventional protein kinase C isoforms and the ceramide pathway may regulate its phosphorylation state. The protective role of L-plastin was not restricted to TNF-α resistant MCF-7 cells because a correlation between the expression of L-plastin and the resistance to TNF-α was observed in other breast cancer cell lines. Together, our study discloses a novel unexpected role of the actin bundling protein L-plastin as a cell protective protein against TNF-cytotoxicity. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Vetter G.,University of Luxembourg | Saumet A.,French Institute of Health and Medical Research | Moes M.,University of Luxembourg | Vallar L.,Microarray Center | And 7 more authors.
Oncogene | Year: 2010

Epithelial to mesenchymal transition (EMT) is a key step toward metastasis. MCF7 breast cancer cells conditionally expressing the EMT master regulator SNAI1 were used to identify early expressed microRNAs (miRNAs) and their targets that may contribute to the EMT process. Potential targets of miRNAs were identified by matching lists of in silico predicted targets and of inversely expressed mRNAs. MiRNAs were ranked based on the number of predicted hits, highlighting miR-661, a miRNA with so far no reported role in EMT. MiR-661 was found required for efficient invasion of breast cancer cells by destabilizing two of its predicted mRNA targets, the cell-cell adhesion protein Nectin-1 and the lipid transferase StarD10, resulting, in turn, in the downregulation of epithelial markers. Reexpression of Nectin-1 or StarD10 lacking the 3′-untranslated region counteracted SNAI1-induced invasion. Importantly, analysis of public transcriptomic data from a cohort of 295 well-characterized breast tumor specimen revealed that expression of StarD10 is highly associated with markers of luminal subtypes whereas its loss negatively correlated with the EMT-related, basal-like subtype. Collectively, our non-a priori approach revealed a nonpredicted link between SNAI1-triggered EMT and the down-regulation of Nectin-1 and StarD10 through the up-regulation of miR-661, which may contribute to the invasion of breast cancer cells and poor disease outcome. © 2010 Macmillan Publishers Limited All rights reserved.

Halavatyi A.A.,University of Luxembourg | Nazarov P.V.,Microarray Center | Al Tanoury Z.,University of Luxembourg | Apanasovich V.V.,Belarusian State University | And 2 more authors.
European Biophysics Journal | Year: 2010

A novel mathematical model of the actin dynamics in living cells under steady-state conditions has been developed for fluorescence recovery after photobleaching (FRAP) experiments. As opposed to other FRAP fitting models, which use the average lifetime of actins in filaments and the actin turnover rate as fitting parameters, our model operates with unbiased actin association/dissociation rate constants and accounts for the filament length. The mathematical formalism is based on a system of stochastic differential equations. The derived equations were validated on synthetic theoretical data generated by a stochastic simulation algorithm adapted for the simulation of FRAP experiments. Consistent with experimental findings, the results of this work showed that (1) fluorescence recovery is a function of the average filament length, (2) the F-actin turnover and the FRAP are accelerated in the presence of actin nucleating proteins, (3) the FRAP curves may exhibit both a linear and non-linear behaviour depending on the parameters of actin polymerisation, and (4) our model resulted in more accurate parameter estimations of actin dynamics as compared with other FRAP fitting models. Additionally, we provide a computational tool that integrates the model and that can be used for interpretation of FRAP data on actin cytoskeleton. © 2009 European Biophysical Societies' Association.

Reinsbach S.E.,University of Luxembourg | Nazarov P.V.,Microarray Center | Philippidou D.,University of Luxembourg | Schmitt M.,University of Luxembourg | And 5 more authors.
RNA Biology | Year: 2012

MicroRNAs are major players in post-transcriptional gene regulation. Even small changes in miRNA levels may have profound consequences for the expression levels of target genes. Hence, miRNAs themselves need to be tightly, albeit dynamically, regulated. Here, we investigated the dynamic behavior of miRNAs over a wide time range following stimulation of melanoma cells with interferonγ (IFNγ), which activates the transcription factor STAT1. By applying several bioinformatic and statistical software tools for visualization and identification of differentially expressed miRNAs derived from time-series microarray experiments, 8.9% of 1105 miRNAs appeared to be directly or indirectly regulated by STAT1. Focusing on distinct dynamic expression patterns, we found that the majority of robust miRNA expression changes occurred in the intermediate time range (24-48 h). Three miRNAs (miR-27a, miR-30a and miR-34a) had a delayed regulation occurring at 72 h while none showed significant expression changes at early time points between 30 min and 6 h. Expression patterns of individual miRNAs were altered gradually over time or abruptly increased or decreased between two time points. Furthermore, we observed coordinated dynamic transcription of most miRNA clusters while few were found to be regulated independently of their genetic cluster. Most interestingly, several "star" or passenger strand sequences were specifically regulated over time while their "guide" strands were not. © 2012 Landes Bioscience.

Tsao J.,Microarray Center | Yau P.,Microarray Center | Winegarden N.,Microarray Center
Methods in Molecular Biology | Year: 2010

The complex mechanisms involved in the regulation of both gene and protein expressions are still being understood. When microarray technology was first introduced during the early to mid 1990s, they heralded a tremendous opportunity to study transcription on a global scale. Despite this promise, however, one thing that has become clear is that the expression of protein coding genes is not the only aspect of the transcriptome that researchers need pay attention to. Small noncoding RNAs, such as microRNAs, are now known to play a pivotal role in the control of both gene and protein expressions. Each microRNA may act upon a plurality of different targets, which makes the measurement of their expression levels a highly important part of understanding the entire cellular response. It has only been recently, however, that advancements and modifications to microarray technology have allowed us to study these important molecules in a high throughput and parallel manner. © 2010 Humana Press, a part of Springer Science+Business Media, LLC.

Jackson K.,Microarray Center | Paris J.,Microarray Center | Takahashi M.,Microarray Center
Methods in Molecular Biology | Year: 2010

The regulation of gene expression impacts all aspects of cell biology and biochemistry. As we gain a greater understanding of the mechanisms involved in this process, we also begin to unveil its complexities. The delicate balancing act played out by the multitude of DNA interacting proteins can easily become unhinged. The implications of this may potentially lead to cell death or a diseased state. Recent microarray technologies are now allowing scientists to begin the journey into characterizing the relationship between gene expression and DNA modifying proteins. For example, genome-wide studies of protein-DNA interactions, such as Chromatin Immunoprecipitation on arrays (also referred to as ChIP-chip), allow for a global view of where and when DNA binding proteins interact. A number of microarray based genome wide methodologies have emerged based upon these same principles. Here, we outline a methodology that we have developed using the ChIP-chip technique. Application of this methodology is easily adaptable to different cell types, antibodies, and to a variety of array platforms. © 2010 Humana Press, a part of Springer Science+Business Media, LLC.

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