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See detailAryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.
Daly, Adrian ULg; Vanbellinghen, Jean-François ULg; Khoo, Sok Kean et al

in Journal of Clinical Endocrinology and Metabolism (2007), 92(5), 1891-1896

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess ... [more ▼]

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA. [less ▲]

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See detailLe syndrome de Hutchinson-Gilford (progeria): analyse clinique et moleculaire chez une patiente d'origine africaine
Mutesa, Léon; Pierquin, Geneviève ULg; Cwiny-Ay, N. et al

in Revue Médicale de Liège (2007), 62(3), 155-8

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease characterized by an early onset of several clinical features including premature ageing in children. Approximately 80% of ... [more ▼]

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease characterized by an early onset of several clinical features including premature ageing in children. Approximately 80% of HGPS cases are caused by a de novo single-base pair substitution c.1824 C>T (GGC > GGT, p.Gly608Gly) within the exon 11 of the LMNA gene which codes for lamins A and C proteins. This mutation creates an abnormal splice donor site, leading to the formation of a truncated lamin A protein. Only a very few cases of African patients with HGPS have been reported, but none of them has been characterized at the molecular level. We report here a 12 year-old-girl African patient with HGPS, in whom the p.Gly608Gly heterozygous disease-causing mutation was found. [less ▲]

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See detailSufasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas
Robe, Pierre ULg; Nguyen-Khac, Minh-Tuan ULg; Lambert, Frédéric ULg et al

in International Journal of Oncology (2007), 30(1), 283-290

The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased ... [more ▼]

The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased the HSV-TK/ganciclovir bystander effect in C6, 9L and LN18 cells but not in U87 glioma cells. Using bi-compartmental culture devices and conditioned medium transfer experiments, we showed that in C6, 9L and LN18 cells but not in U87 cells, Sulfasalazine also unveiled a new, contact-independent mechanism of HSV-TK/ganciclovir bystander effect. Upon treatment with ganciclovir, human LN18-TK but not U87-TK cells synthetized and released TNF-alpha in the culture medium. Sulfasalazine sensitized glioma cells to the toxic effect of TNF-alpha. and enhanced its secretion in LN18-TK cells in response to GCV treatment. The caspase-8 inhibitor Z-IETD-FMK and a blocking antibody to TNF-alpha both inhibited the contact-independent bystander effect in LN18 cells. Taken together, these results suggest that TNF-alpha mediates the contact-independent bystander effect in LN18 cells. The treatment with GCV and/or Sulfasalazine of tumor xenografts consisting of a mix of 98% C6 and 2% C6-TK cells shows that Sulfasalazine is also a potent adjunct to the in vivo treatment of gliomas. [less ▲]

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See detailBiomarker discovery for inflammatory bowel disease, using proteomic serum profiling
Meuwis, Marie-Alice ULg; Fillet, Marianne ULg; Geurts, Pierre ULg et al

in Biochemical Pharmacology (2007), 73(9), 1422-1433

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic ... [more ▼]

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic and of unknown etiology. Clinical presentation is non-specific and diagnosis is based on clinical, endoscopic, radiological and histological criteria. Novel markers are needed to improve early diagnosis and classification of these pathologies. We performed a study with 120 serum samples collected from patients classified in 4 groups (30 Crohn, 30 ulcerative colitis, 30 inflammatory controls and 30 healthy controls) according to accredited criteria. We compared protein sera profiles obtained with a Surface Enhanced Laser Desorption Ionization-Time of Flight-Mass Spectrometer (SELDI-TOF-MS). Data analysis with univariate process and a multivariate statistical method based on multiple decision trees algorithms allowed us to select some potential biomarkers. Four of them were identified by mass spectrometry and antibody based methods. Multivariate analysis generated models that could classify samples with good sensitivity and specificity (minimum 80%) discriminating groups of patients. This analysis was used as a tool to classify peaks according to differences in level on spectra through the four categories of patients. Four biomarkers showing important diagnostic value were purified, identified (PF4, MRP8, FIBA and Hpalpha2) and two of these: PF4 and Hpalpha2 were detected in sera by classical methods. SELDI-TOF-MS technology and use of the multiple decision trees method led to protein biomarker patterns analysis and allowed the selection of potential individual biomarkers. Their downstream identification may reveal to be helpful for IBD classification and etiology understanding. [less ▲]

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See detailMutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas.
Barlier, Anne; Vanbellinghen, Jean-François ULg; Daly, Adrian ULg et al

in Journal of Clinical Endocrinology and Metabolism (2007), 92(5), 1952-5

CONTEXT: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel ... [more ▼]

CONTEXT: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. OBJECTIVE: The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. DESIGN: The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. Setting: The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. RESULTS: In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. CONCLUSIONS: AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects. [less ▲]

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See detailPharmacogenetics of infliximab in Crohn's disease
Dideberg, Vinciane ULg; Louis, Edouard ULg; Bours, Vincent ULg

in Acta Endoscopica (2007), 37(4), 521-530

Pharmacogenetic studies will certainly contribute to a better management of medication in inflammatory bowel diseases. Infliximab is the most efficient drug in refractory and fistulising Crohn's disease ... [more ▼]

Pharmacogenetic studies will certainly contribute to a better management of medication in inflammatory bowel diseases. Infliximab is the most efficient drug in refractory and fistulising Crohn's disease. However, about one third of the patients do not respond to this treatment. Several studies have been performed to identify predictive factors of the response to infliximab in CD. We attempt to summarize the current knowledge on the use of infliximab in CD and focus on the result of these studies and more particularly on pharmacogenetic aspects. [less ▲]

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See detailLes maladies inflammatoires chroniques intestinales : de la génétique au traitement
Louis, Edouard ULg; Bours, Vincent ULg; Dideberg, Vinciane ULg et al

in Revue Médicale de Liège (2007), 62

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See detailP2X1 receptors as new regulators of neutrophil life span
Faccinetto, Céline ULg; Lecut, Christelle ULg; Jacobs, Nathalie ULg et al

in Journal of Thrombosis and Haemostasis [=JTH] (2007)

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See detailIntrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells
Verhaeghe, Catherine ULg; Tabruyn, Sébastien ULg; Oury, Cécile ULg et al

in Biochemical and Biophysical Research Communications (2007), 356(3), 745-749

Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been ... [more ▼]

Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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See detailNeonatal screening for sickle cell disease in Central Africa: a study of 1825 newborns with a new enzyme-linked immunosorbent assay test
Mutesa, Léon; Boemer, François ULg; Ngendahayo, Louis et al

in Journal of Medical Screening (2007), 14(3), 113-116

Objectives To evaluate the feasibility of systematic neonatal screening for sickle cell disease in the region of Great Lakes in Central Africa using a new approach with limited costs. Methods Between July ... [more ▼]

Objectives To evaluate the feasibility of systematic neonatal screening for sickle cell disease in the region of Great Lakes in Central Africa using a new approach with limited costs. Methods Between July 2004 and July 2006, 1825 newborn dried blood samples were collected onto filter papers in four maternity units from Burundi, Rwanda and the East of the Democratic Republic of Congo. We tested for the presence of haemoglobin C and S in the eluted blood by an enzyme-linked immunosorbent assay (ELISA) test using a monoclonal antibody. All ELISA-positive samples (multiple of the median (MoM) >= 1.5) were confirmed by a simple molecular test. The statistica software version 7.1 was used to create graphics and to fix the MoM cut-off, and the chi(2) of Pearson was used to compare the genotype incidences between countries. Results Of the 1825 samples screened, 97 (5.32%) were positive. Of these, 60 (3.28%) samples were heterozygous for Hb S, and four (0.22%) for Hb C; two (0.11%) newborns were Hb SS homozygotes. Conclusions The lower cost and the high specificity of ELISA test are appropriate for developing countries, and such systematic screening for sickle cell anaemia is therefore feasible. [less ▲]

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See detailPrecocious puberty associated with partial trisomy 18q and monosomy 11q
Mutesa, Léon; Hellin, A. C.; Jamar, Michelle ULg et al

in Genetic Counseling (Geneva, Switzerland) (2007), 18(2), 201-207

We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication ... [more ▼]

We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication 18q but she has also some atypical anomalies such as precocious puberty, a retinal albinism and hypermetropia. Based on cytogenetics and FISH analysis, the karyotype of the proband was 46,XX,der(11)t(11;18)(q24;q13). To the best of our knowledge, this is the first report of precocious puberty associated with either dup(18q) or del(11q) syndromes. [less ▲]

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See detailThe Tnf/Adam 17 System: Implication of an Adam 17 Haplotype in the Clinical Response to Infliximab in Crohn's Disease
Dideberg, Vinciane ULg; Theatre, Emilie ULg; Farnir, Frédéric ULg et al

in Pharmacogenetics and Genomics (2006), 16(10), 727-734

Infliximab, a chimeric anti-tumour necrosis factor (TNF)-alpha antibody induces a clinical response in 70% of Crohn's disease patients and the response to infliximab therapy could be partially determined ... [more ▼]

Infliximab, a chimeric anti-tumour necrosis factor (TNF)-alpha antibody induces a clinical response in 70% of Crohn's disease patients and the response to infliximab therapy could be partially determined by genetic factors. The implication of both transmembrane and soluble forms of the TNF-alpha in the mechanism of action of infliximab has been demonstrated. The aim of our work was first to perform a complete study of TNF variants role in the response to infliximab in Crohn's disease. Secondly, considering the role of ADAM 17 in TNF-alpha shedding, the ADAM 17 locus was also studied. The response to infliximab was evaluated in 222 Caucasian Crohn's disease patients with a luminal (n=160) or fistulizing (n=62) form of the disease. Clinical and biological response evaluation was based on the Crohn's Disease Activity Index score and C-reactive protein level evolutions, respectively. The entire TNF gene was sequenced on the complete cohort. Twelve single nucleotide polymorphisms spanning the ADAM 17 locus were studied and haplotypes rebuilt. A clinical response was observed in 64% of the patients and biological response in 77.1% of patients. No association was found between the TNF gene and the response to infliximab. One haplotype in the ADAM 17 region was associated with a clinical response to infliximab in CD patients (adjusted P=0.045). In conclusion, our results exclude, with a reasonable power, an implication of the TNF gene in the response to infliximab in Crohn's disease, but reveal a potential role of the ADAM 17 gene in this response. [less ▲]

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See detailTranscriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB
Benoit, Valérie; de Moraes, E.; Dar, N. A. et al

in Oncogene (2006), 25(42), 5708-5718

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by ... [more ▼]

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-damaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (P < 0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE. [less ▲]

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See detailTranscription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia
Close, Pierre ULg; Hawkes, Nicola; Cornez, Isabelle ULg et al

in Molecular Cell (2006), 22(4), 521-531

Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only ... [more ▼]

Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients. [less ▲]

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See detailRaloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.
Olivier, Sabine ULg; Close, Pierre ULg; Castermans, Emilie ULg et al

in Molecular Pharmacology (2006), 69(5), 1615-1623

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of ... [more ▼]

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma. [less ▲]

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See detailLymphotoxin alpha gene in Crohn's disease patients: absence of implication in the response to infliximab in a large cohort study
Dideberg, Vinciane ULg; Louis, Edouard ULg; Farnir, Frédéric ULg et al

in Pharmacogenetics and Genomics (2006), 16(5), 369-373

A haplotype in the lymphotoxin alpha (LTA) gene has been associated with a lack of response to infliximab in a small cohort of Crohn's disease (CD) patients. The present study aimed to confirm the ... [more ▼]

A haplotype in the lymphotoxin alpha (LTA) gene has been associated with a lack of response to infliximab in a small cohort of Crohn's disease (CD) patients. The present study aimed to confirm the implication of this haplotype in the response to infliximab in a larger cohort of Caucasian patients. The response to the first infusion with infliximab was evaluated in 214 Caucasian patients with either luminal (n = 150) or fistulising (n = 64) CD. Clinical response was based on the decrease in CID Activity Index (luminal) or on the evolution in the fistula discharge (fistulising). Biological response was assessed in 139 patients who had elevated C-reactive protein (CRP) before treatment and for whom CRP values were also available after treatment. A positive biological response was defined as a decrease in CRP of at least 25%. The patients were genotyped for six polymorphisms in the LTA gene. A positive clinical response was present in 65.4% of the patients and a positive biological response was observed in 80.6% of the patients. No association was found with any of the studied polymorphisms, nor with the previously published LTA haplotype and the response to infliximab. We could not confirm an association between the LTA locus and clinical or biological response to infliximab in a large cohort of CID patients. Pharmacogenetics and Genomics 16:369-373 (c) 2006 Lippincott Williams [less ▲]

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See detailCan NF-kappaB be a target for novel and efficient anti-cancer agents?
Olivier, Sabine ULg; Robe, Pierre ULg; Bours, Vincent ULg

in Biochemical Pharmacology (2006), 72(9), 1054-1068

Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in ... [more ▼]

Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in most cases, protect transformed cells from apoptosis and therefore participate in the onset or progression of many human cancers. Molecular studies demonstrated that ancient widely used drugs, known for their chemopreventive or therapeutic activities against human cancers, inhibit NF-kappaB, usually among other biological effects. It is therefore considered that the anti-cancer activities of NSAIDs (non-steroidal anti-inflammatory drugs) or glucocorticoids are probably partially related to the inhibition of NF-kappaB and new clinical trials are being initiated with old compounds such as sulfasalazine. In parallel, many companies have developed novel agents acting on the NF-kappaB pathway: some of these agents are supposed to be NF-kappaB specific (i.e. IKK inhibitors) while others have wide-range biological activities (i.e. proteasome inhibitors). Today, the most significant clinical data have been obtained with bortezomib, a proteasome inhibitor, for the treatment of multiple myeloma. This review discusses the preclinical and clinical data obtained with these various drugs and their putative future developments. [less ▲]

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See detailChromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas.
Turkheimer, Federico E; Roncaroli, Federico; Hennuy, Benoît ULg et al

in BMC Bioinformatics (2006), 7

BACKGROUND: Expression microarrays represent a powerful technique for the simultaneous investigation of thousands of genes. The evidence that genes are not randomly distributed in the genome and that ... [more ▼]

BACKGROUND: Expression microarrays represent a powerful technique for the simultaneous investigation of thousands of genes. The evidence that genes are not randomly distributed in the genome and that their coordinated expression depends on their position on chromosomes has highlighted the need for mathematical approaches to exploit this dependency for the analysis of expression data-sets. RESULTS: We have devised a novel mathematical technique (CHROMOWAVE) based on the Haar wavelet transform and applied it to a dataset obtained with the Affymetrix HG-U133_Plus_2 array in 27 gliomas. CHROMOWAVE generated multi-chromosomal pattern featuring low expression in chromosomes 1p, 4, 9q, 13, 18, and 19q. This pattern was not only statistically robust but also clinically relevant as it was predictive of favourable outcome. This finding was replicated on a data-set independently acquired by another laboratory. FISH analysis indicated that monosomy 1p and 19q was a frequent feature of tumours displaying the CHROMOWAVE pattern but that allelic loss on chromosomes 4, 9q, 13 and 18 was much less common. CONCLUSION: The ability to detect expression changes of spatially related genes and to map their position on chromosomes makes CHROMOWAVE a valuable screening method for the identification and display of regional gene expression changes of clinical relevance. In this study, FISH data showed that monosomy was frequently associated with diffuse low gene expression on chromosome 1p and 19q but not on chromosomes 4, 9q, 13 and 18. Comparative genomic hybridisation, allelic polymorphism analysis and methylation studies are in progress in order to identify the various mechanisms involved in this multi-chromosomal expression pattern. [less ▲]

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See detailInositide-specific phospholipase c beta1 gene deletion is a rare event in myelodysplastic syndromes.
Herens, Christian ULg; Ketelslegers, O.; Tassin, Françoise ULg et al

in Leukemia (2006), 20(3), 521-2522-3

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See detailPeroxisome proliferator-activated receptor-gamma1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis
Relic, Biserka ULg; Benoit, Valerie; Franchimont, Nathalie et al

in Journal of Biological Chemistry (2006), 281(32), 597-604

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has ... [more ▼]

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that BAY 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR-gamma agonist 15d-PGJ2; the expression of PPAR-gamma in these cells was studied. Both PPAR-gamma1 and PPAR-gamma2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-gamma1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of BAY 11-7085 treatment, a PPAR-gamma1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, BAY 11-7085-induced PPAR-gamma1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-gamma1 protein degradation. PPAR-gamma1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-gamma1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-gamma1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies BAY 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from BAY 11-7085-induced apoptosis, and reversed both PPAR-gamma dephosphorylation and degradation. Furthermore, PPAR-gamma antagonist BADGE induced PPAR-gamma1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-gamma1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-gamma1 dephosphorylation but before PPAR-gamma1 degradation, dephosphorylation event might be enough to mediate BAY 11-7085-induced apoptosis in synovial fibroblasts. [less ▲]

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