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Port-Saint-Louis-du-Rhône, France

Mahevas M.,University Paris Est Creteil | Chiche L.,Hopital de la Conception | Uzunhan Y.,Groupe Sarcoidose Francophone | Uzunhan Y.,University of Paris 13 | And 19 more authors.
Medicine | Year: 2011

The association of sarcoidosis and immune thrombocytopenia (ITP) has rarely been investigated. The aim of the current retrospective study was to investigate the clinical and biological phenotypes and outcome of this association in a large series of recent patients. Twenty patients (50% men) were included. Median age at sarcoidosis and ITP diagnosis was 36 (range, 10-83 yr) and 38 (range, 21-83 yr) years, respectively. In 11 of 20 (55%) patients, sarcoidosis onset preceded ITP (median interval, 48 mo; range, 6-216 mo). In 5 of 20 (25%) patients, the 2 conditions occurred concomitantly. In 4 of 20 (20%) patients, ITP onset preceded sarcoidosis (median interval, 68 mo; range, 15-153 mo). In 4 cases, sarcoidosis and ITP were not concomitant, since 1 condition was cured before the other was declared. In 12 of 20 (60%) patients there was a simultaneous onset or relapse of both ITP and sarcoidosis. Sarcoidosis phenotype was characterized by an acute onset in 40% of patients. The visceral involvement included thoracic sites in 19 of 20 (95%) patients and extrathoracic sites in 16 of 20 (80%) patients. At ITP onset, median platelet count was 11 × 10/L (range, 3-90); 17 (85%) patients had a platelet count <30 × 10/L. Seven (35%) patients had a bleeding score >8 without visceral bleeding.Nineteen of the 20 (95%) patients were treated specifically for ITP. After the first-line therapy (prednisone at 1 mg/kg per day for at least 3 consecutive weeks in all patients; with IVIg in addition for 10 patients with severe bleeding score), 12 of 19 (63%) patients achieved a complete response, 6 (31.5%) had a partial response, and only 1 patient failed to respond. At the end of ITP follow-up (median, 70 mo; range, 12-142 mo), 18 (90%) patients achieved a complete response, 1 achieved a partial response, and 1 had no response. After a median follow-up of 105 months, 13 of 20 (65%) patients had persistent sarcoidosis requiring prolonged therapy, and thus sarcoidosis represented the main long-term concern. Main conclusions were 1) ITP presentation was usually severe, but response to treatment was favorable in almost all cases, with no death and no severe bleeding, in contrast with older reports, 2) sarcoidosis was remarkable for the high proportion of cases with an acute onset, a chronic course, and the need for prolonged prednisone therapy, 3) sarcoidosis and ITP onset and evolution were not always synchronous. © 2011 by Lippincott Williams & Wilkins. Source

de la Grange P.,Center Hayem | Gratadou L.,French Institute of Health and Medical Research | Delord M.,Institut Universitaire de France | Dutertre M.,French Institute of Health and Medical Research | Auboeuf D.,French Institute of Health and Medical Research
Nucleic Acids Research | Year: 2010

It has been shown that alternative splicing is especially prevalent in brain and testis when compared to other tissues. To test whether there is a specific propensity of these tissues to generate splicing variants, we used a single source of high-density microarray data to perform both splicing factor and exon expression profiling across 11 normal human tissues. Paired comparisons between tissues and an original exon-based statistical group analysis demonstrated after extensive RT-PCR validation that the cerebellum, testis, and spleen had the largest proportion of differentially expressed alternative exons. Variations at the exon level correlated with a larger number of splicing factors being expressed at a high level in the cerebellum, testis and spleen than in other tissues. However, this splicing factor expression profile was similar to a more global gene expression pattern as a larger number of genes had a high expression level in the cerebellum, testis and spleen. In addition to providing a unique resource on expression profiling of alternative splicing variants and splicing factors across human tissues, this study demonstrates that the higher prevalence of alternative splicing in a subset of tissues originates from the larger number of genes, including splicing factors, being expressed than in other tissues. © The Author(s) 2010. Source

Pesson M.,French Institute of Health and Medical Research | Eymin B.,Joseph Fourier University | De La Grange P.,Center Hayem | Simon B.,French Institute of Health and Medical Research | Corcos L.,French Institute of Health and Medical Research
Molecular Cancer | Year: 2014

Alternative pre-mRNA splicing (AS) widely expands proteome diversity through the combinatorial assembly of exons. The analysis of AS on a large scale, by using splice-sensitive microarrays, is a highly efficient method to detect the majority of known and predicted alternative transcripts for a given gene. The response to targeted anticancer therapies cannot easily be anticipated without prior knowledge of the expression, by the tumor, of target proteins or genes. To analyze, in depth, transcript structure and levels for genes involved in these responses, including AKT1-3, HER1-4, HIF1A, PIK3CA, PIK3R1-2, VEGFA-D and PIR, we engineered a dedicated gene chip with coverage of an average 185 probes per gene and, especially, exon-exon junction probes. As a proof of concept, we demonstrated the ability of such a chip to detect the effects of over-expressed SRSF2 RNA binding protein on the structure and abundance of mRNA products in H358 lung cancer cells conditionally over-expressing SRSF2. Major splicing changes were observed, including in HER1/EGFR pre-mRNA, which were also seen in human lung cancer samples over-expressing the SRSF2 protein. In addition, we showed that variations in HER1/EGFR pre-mRNA splicing triggered by SRSF2 overexpression in H358 cells resulted in a drop in HER1/EGFR protein level, which correlated with increased sensitivity to gefitinib, an EGFR tyrosine kinase inhibitor. We propose, therefore, that this novel tool could be especially relevant for clinical applications, with the aim to predict the response before treatment. © 2014 Pesson et al.; licensee BioMed Central Ltd. Source

Llorian M.,University of Cambridge | Schwartz S.,Tel Aviv University | Clark T.A.,Affymetrix | Hollander D.,Tel Aviv University | And 9 more authors.
Nature Structural and Molecular Biology | Year: 2010

To gain global insights into the role of the well-known repressive splicing regulator PTB, we analyzed the consequences of PTB knockdown in HeLa cells using high-density oligonucleotide splice-sensitive microarrays. The major class of identified PTB-regulated splicing event was PTB-repressed cassette exons, but there was also a substantial number of PTB-activated splicing events. PTB-repressed and PTB-activated exons showed a distinct arrangement of motifs with pyrimidine-rich motif enrichment within and upstream of repressed exons but downstream of activated exons. The N-terminal half of PTB was sufficient to activate splicing when recruited downstream of a PTB-activated exon. Moreover, insertion of an upstream pyrimidine tract was sufficient to convert a PTB-activated exon to a PTB-repressed exon. Our results show that PTB, an archetypal splicing repressor, has variable splicing activity that predictably depends upon its binding location with respect to target exons. © 2010 Nature America, Inc. All rights reserved. Source

Gandoura S.,French Institute of Health and Medical Research | Gandoura S.,University Paris Diderot | Weiss E.,French Institute of Health and Medical Research | Weiss E.,University Paris Diderot | And 29 more authors.
Journal of Hepatology | Year: 2013

Background & Aims: Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells. Methods: Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-stimulated PBMCs from 52 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients. Results: Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1588 downregulated genes. In LPS-stimulated "healthy" cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and "healthy" cells were involved in cytokine production/activity and induction of "immune paralysis". Comparison of functions associated with the 1356 genes, specifically regulated by LPS in cirrhotic cells, to functions of the 1049 genes, specifically regulated in "healthy" cells, allowed to define a cirrhosis-specific phenotype. Unlike in "healthy" cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex vivo LPS-induction of the inflammatory genes IL6 and CXCL5 was a significant predictor of mortality. Conclusions: Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

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