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PubMed | Institute Paoli Calmettes, Hopital Henri Mondor, University of Versailles, Institute Bergonie and 9 more.
Type: | Journal: Cancer | Year: 2016

We recently reported that peroxisome proliferator-activated receptor agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification.CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MRTwenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4g/dL in hemoglobin concentration. The cumulative incidence of MRPioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009-011675-79). Cancer 2016. 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.


PubMed | Nancy University Hospital Center, Service de Genetique Clinique, Laboratoire Of Cytogenetique Constitutionnelle Et Prenatale, Departement de Genetique Medicale and 22 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228kb to 11.7Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n=20), reduced volume of the white matter (WM) (n=12), ventricular dilatation (n=9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n=6), and vermis hypoplasia (n=5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.


PubMed | University of Minnesota, University Utrecht, Radboud University Nijmegen, Texas Tech University Health Sciences Center and 13 more.
Type: | Journal: Journal of medical genetics | Year: 2017

Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations.Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.


Chaieb K.,University of Monastir | Chaieb K.,Laboratoire Of Biologie Moleculaire | Zmantar T.,University of Monastir | Souiden Y.,Laboratoire Of Biologie Moleculaire | And 2 more authors.
Microbial Pathogenesis | Year: 2011

To analyze the degree of biofilm formation on three ica-positives Staphylococcus epidermidis as a function of biocides, the medium was supplemented with increasing concentrations of isopropanol, ethanol, and methanol at 0, 1, 4, 6, 8, 10, 12 and 14% (v/v), hydrogen peroxide (0, 0.125, 0.25, 0.5, 1, 2, 3, 4 and 5% v/v) and benzalkonium chloride (0, 0.125, 0.25, 0.5, 1, 2, 3, 4 and 6μgml-1).In biocide-free biofilms, the results showed that two strains (S. epidermidis CIP106510 and E24) were strongly biofilm positive displaying a high oxidative activity (1.254 and 0.855, respectively) in comparison with the non-adherent one (S22). In addition biofilm formation was induced with 1% alcohol (isopropanol and ethanol) supplementation. The three studied strains cultured in TSB supplemented with 2% methanol displayed a strong oxidative activity (P=0.008).Moreover wells with 0.125% hydrogen peroxide enhanced increasing oxidative activity of S. epidermidis CIP106510 and S22. A significant induction of biofilm was noted after treatment with 1μgml-1 of benzalkonium chloride. This study suggests that some biocides currently used in hospitals are ineffective against nosocomial pathogens growing in biofilms when used at weak concentration and fail to control this reservoir for hospital-acquired infection. © 2010 Elsevier Ltd.


Souiden Y.,Laboratoire Of Biologie Moleculaire | Bouraoui A.,University of Monastir | Chaieb K.,Laboratoire Of Biologie Moleculaire | Mahdouani K.,Laboratoire Of Biologie Moleculaire
Bulletin du Cancer | Year: 2010

Advances in chromosome dynamics have increased our understanding of the significant role of telomeres and telomerase in cancer. Telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. Therefore, telomerase is an important target for the design of therapeutic agents that might have minimal side effects. Herein, we evaluate current approaches to telomerase/telomere-targeted therapy, discuss the benefits and disadvantages, and speculate on the future direction of telomerase inhibitors as cancer therapeutics. ©John Libbey Eurotext.


Mrad M.,Tunis el Manar University | Mrad M.,Laboratoire Of Biologie Moleculaire | Fekih-Mrissa N.,Laboratoire Of Biologie Moleculaire | Wathek C.,Tunis el Manar University | And 4 more authors.
Journal of Stroke and Cerebrovascular Diseases | Year: 2014

Background Retinal vein occlusion (RVO) is the second most common cause of vision loss because of retinal vascular disease. There are 2 types of RVO: branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). The pathogenesis of RVO is multifactorial. The role of factor V Leiden (FVL) and prothrombin mutations was examined in patients with CRVO and BRVO. Methods FVL and prothrombin were investigated by extracting DNA of 88 patients with RVO. Sixteen of the patients were diagnosed with CRVO, 4 with hemispheric retinal vein occlusion, and 68 with BRVO. The genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Results Significant differences were found in the frequencies of the genotypes for both the FVL (G1691A) (P < 10-3, odds ratio [OR] = 17.4, confidence interval [CI] = 6.20-59) and prothrombin (G20210A) (P =.007, OR = 5.11, CI = 1.30-29) polymorphisms between RVO patients and healthy controls. Additionally, the frequency of the GA genotype for the G1691A polymorphism was significantly higher among the patients in a subset of BRVO compared with controls (P < 10-3, OR = 21.4, CI = 7.34-74.2). However, no statistically significant differences were found in the frequencies of the prothrombin G20210A polymorphism between the BRVO group and healthy controls (P =.09, OR = 3.13, CI = 64-19.9). The frequency of both G1691A and G20210A genotypes among the patients of a CRVO subgroup was significantly higher compared with controls (P < 10-3, OR = 11.4, CI = 2.94-44.2; P =.007, OR = 10.8, CI = 2.15-54.1, respectively), suggesting an association between these polymorphisms and CRVO. Conclusions Large study would be required to understand completely the contribution of these markers in the risk of all types of RVO. © 2014 by National Stroke Association.


Kouidhi B.,University of Monastir | Zmantar T.,University of Monastir | Mahdouani K.,Laboratoire Of Biologie Moleculaire | Hentati H.,University of Monastir | Bakhrouf A.,University of Monastir
BMC Microbiology | Year: 2011

Abstract. Background: Enterococci are increasingly associated with opportunistic infections in Humans but the role of the oral cavity as a reservoir for this species is unclear. This study aimed to explore the carriage rate of Enterococci in the oral cavity of Tunisian children and their antimicrobial susceptibility to a broad range of antibiotics together with their adherence ability to abiotic and biotic surfaces. Results: In this study, 17 E. faecalis (27.5%) and 4 E. faecium (6.5%) were detected. The identified strains showed resistance to commonly used antibiotics. Among the 17 isolated E. faecalis, 12 strains (71%) were slime producers and 5 strains were non-producers. Among the 4 E. faecium, 2 strains were slime producers. All the tested strains were able to adhere to at least one of the two tested cell lines. Our result showed that 11 E. faecalis and 2 E. faecium strains adhered strongly to Hep-2 as well as to A549 cells. Conclusions: Drugs resistance and strong biofilm production abilities together with a high phenotypic adhesion to host cells are important equipment in E. faecalis and E. faecium which lead to their oral cavity colonization and focal infections. © 2011 Kouidhi et al; licensee BioMed Central Ltd.


PubMed | Laboratoire Of Biologie Moleculaire, University of Paris Descartes and Gynecologie Obstetricale
Type: Journal Article | Journal: Pediatric research | Year: 2015

Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis.We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on target genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected target.We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4.Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary.


PubMed | Laboratoire Of Biologie Moleculaire, Tunis el Manar University and University of Monastir
Type: | Journal: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis | Year: 2016

Apolipoprotein E (APOE) is a member of the apolipoprotein gene family. APOE is polymorphic with 3 main allelic types: 2, 3, and 4. Certain of these alleles have been associated with higher vascular risk. However, the association of APOE genotypes with retinal biomarkers and risk of retinal stroke is less clear. This study evaluated the role of APOE polymorphisms in retinal vein occlusion (RVO). In the present study, 2-point mutations coding amino acid residues 112 and 158 were amplified using the polymerase chain reaction (PCR) from DNA extracted from Tunisian participants. APOE genotypes were determined by multiplex PCR followed by molecular hybridization. Eighty-eight patients (26 women and 62 men) and 100 age- and gender-matched healthy participants were enrolled. The statistical study revealed a higher frequency of the 4 allele in patients as compared to controls (27.3% vs 9%) with a significant association of the 4 allele with the disease (P < 10


PubMed | Laboratoire Of Biologie Moleculaire and Service de Cardiologie
Type: | Journal: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis | Year: 2016

Coronary artery disease (CAD), also known as atherosclerotic heart disease, is a leading cause of mortality and morbidity throughout the world. The role of insertion/deletion (I/D) polymorphisms of the angiotensin-converting enzyme (ACE) gene in the etiology of CAD remains to be more completely clarified. The aim of this study was to determine the role of the ACE I/D polymorphism in patients with CAD and to study the association together with traditional risk factors in assessing the risk of CAD.Our study population included 145 Tunisian patients with symptomatic CAD and a control group of 300 people matched for age and sex. All participants in the study were genotyped for the ACE I/D polymorphisms obtained by polymerase chain reaction amplification on genomic DNA.Our analysis showed that the ACE D allele frequency (P < 10The ACE D allele may be predictive in individuals who may be at risk of developing CAD. Further investigations of these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.

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