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Hôpital-Camfrout, France

Coyaud E.,French Institute of Health and Medical Research | Coyaud E.,University Paul Sabatier | Struski S.,Toulouse University Hospital Center | Prade N.,French Institute of Health and Medical Research | And 29 more authors.

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and commonrecurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event. © 2010 by The American Society of Hematology. Source

Chaoui A.,French Institute of Health and Medical Research | Chaoui A.,University Paris Est Creteil | Watanabe Y.,French Institute of Health and Medical Research | Watanabe Y.,University Paris Est Creteil | And 9 more authors.
Human Mutation

Waardenburg syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action. © 2011 Wiley Periodicals, Inc. Source

Persu A.,Catholic University of Louvain | Giavarini A.,Hypertension Unit | Giavarini A.,University of Milan | Touze E.,University of Caen Lower Normandy | And 12 more authors.
Journal of Hypertension

The main objectives of this expert consensus are to raise awareness about fibromuscular dysplasia, which is more frequent and more often systemic than previously thought and can sometimes have devastating consequences; to provide up-to-date recommendations for the diagnosis, evaluation, and management of the disease; and to identify research priorities. The emphasis has been put on recommendations for daily practice. The main topics covered include definition, classification, diagnosis, and management of fibromuscular dysplasia in adult patients with symptomatic involvement of the renal arteries, supraaortic trunks, and digestive and peripheral arteries. © Lippincott Williams & Wilkins. Source

Demanget N.,French Institute of Health and Medical Research | Avril S.,French Institute of Health and Medical Research | Badel P.,French Institute of Health and Medical Research | Orgeas L.,Grenoble Institute of Technology | And 3 more authors.
Journal of the Mechanical Behavior of Biomedical Materials

Secondary interventions after endovascular repair of abdominal aortic aneurysms are frequent because stent-graft (SG) related complications may occur (mainly endoleak and SG thrombosis). Complications have been related to insufficient SG flexibility, especially when devices are deployed in tortuous arteries. Little is known on the relationship between SG design and flexibility. Therefore, the aim of this study was to simulate numerically the bending of two manufactured SGs (Aorfix-Lombard Medical (A) and Zenith-Cook Medical Europe (Z)) using finite element analysis (FEA). Global SG behavior was studied by assessing stent spacing variation and cross-section deformation. Four criteria were defined to compare flexibility of SGs: maximal luminal reduction rate, torque required for bending, maximal membrane strains in graft and maximal Von Mises stress in stents. For angulation greater than 60°, values of these four criteria were lower with A-SG, compared to Z-SG. In conclusion, A-SG was more flexible than Z-SG according to FEA. A-SG may decrease the incidence of complications in the setting of tortuous aorto-iliac aneurysms. Our numerical model could be used to assess flexibility of further manufactured as well as newly designed SGs. © 2011 Elsevier Ltd. Source

Magdoud K.,University of Monastir | Herbepin V.G.,CHU Hopital Nord | Touraine R.,CHU Hopital Nord | Almawi W.Y.,Arabian Gulf University | Mahjoub T.,University of Monastir
American Journal of Reproductive Immunology

Problem: Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis, and the common promoter region variants -675G/A (4G/5G) and -844G/A are associated with increased thrombotic risk. Despite evidence linking altered fibrinolysis with adverse pregnancy events, including idiopathic recurrent pregnancy loss (RPL), the contribution of PAI-1 variants to RPL risk remains controversial. We investigated the association between the PAI-1 -844G/A and 4G/5G (-675G/A) variants with altered risk of RPL. Method of study: This was a case-control study involving 304 women with confirmed RPL and 371 age- and ethnically matched control women. PAI-1 genotyping was performed by PCR single-specific primer -675 (G/A) and real-time PCR (-844G/A) analysis. Results: Minor allele frequency (MAF) of 4G/5G (P < 0.001), but not -844G/A (P = 0.507), was higher in RPL cases. PAI-1 4G/5G single-nucleotide polymorphism (SNP) was significantly associated with RPL under additive, dominant, and recessive genetic models; no association of -844G/A with RPL was seen irrespective of the genetic model tested. Taking common -844G/5G haplotype as reference (OR = 1.00), multivariate analysis confirmed the association of 4G-containing -844A/4G (P < 0.001) and -844G/4G (P = 0.011) haplotypes with increased RPL risk. Conclusion: 4G/5G, but not -844G/A, PAI-1 variant is associated with an increased risk of RPL. © 2013 John Wiley & Sons Ltd. Source

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