Les glioblastomes, un exemple de recherche translationnelle?

in Revue Médicale de Liège (2008), 63(5-6), 251-6

Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most ... [more ▼]

Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most aggressive tumour of the Central Nervous System. A better understanding of the mechanisms by which these tumours relapse could promote the use of preventive therapy and could increase patients' survival. GBM stem cells have been recently described and it was demonstrated that they are specifically implied in the experimental tumorigenesis. It is thus very attractive to speculate on a possible relationship between these GBM stem cells and the neural stem cells which are persisting in the neurogenic zones of the adult brain. In this review, we formulate and discuss the hypothesis by which, in a patient with GBM, malignant stem cells might be present in the neurogenic zones, away from the tumour mass. This hypothesis could explain the tumour relapse observed after the first treatments. [less ▲]

Management of diffuse glioma in children: a retrospective study of 27 cases and review of literature.

in Acta Neurologica Belgica (2008), 108(2), 35-43

Gliomas are the most common CNS tumours in children and present either as circumscribed tumours or diffusely infiltrative neoplasms. Diffuse gliomas develop both in the cerebral hemispheres and the ... [more ▼]

Gliomas are the most common CNS tumours in children and present either as circumscribed tumours or diffusely infiltrative neoplasms. Diffuse gliomas develop both in the cerebral hemispheres and the brainstem and have a poor prognosis. Guidelines for the therapy of these tumours are still debated. In this study, we reviewed the clinical features of 27 consecutive patients with diffuse gliomas admitted to the Department of Paediatrics of CHR Citadelle, University of Liege, between 1985 and 2005. We review their clinical presentation, diagnosis, treatment and outcome with reference to the published literature. [less ▲]

Chromosomal profiles of gene expression in Huntington's disease.

in Brain : A Journal of Neurology (2008), 131(Pt 2), 381-8

Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread ... [more ▼]

Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread transcriptional dysregulation. Mutant huntingtin also interacts with histone acetyltransferases, consequently interfering with the acetylation and deacetylation states of histones. Because histone modifications and chromatin structure coordinate the expression of gene clusters, we have applied a novel mathematical approach, Chromowave, to analyse microarray datasets of brain tissue and whole blood to understand how genomic regions are altered by the effects of mutated huntingtin on chromatin structure. Results show that, in samples of caudate and whole blood from Huntington's disease patients, transcription is indeed deregulated in large genomic regions in coordinated fashion, that transcription in these regions is associated with disease progression and that altered chromosomal clusters in the two tissues are remarkably similar. These findings support the notion of a common genome-wide mechanism of disruption of RNA transcription in the brain and periphery of Huntington's disease patients. [less ▲]

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra.

in Acta Neuropathologica (2007), 113(3), 253-63

The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the ... [more ▼]

The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be up-regulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly(ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD. [less ▲]

Treating gliomas with glucocorticoids: from bedside to bench

in Acta Neuropathologica (2006), 112(6), 651-664

Glucocorticoids are used in the treatment of gliomas to decrease tumour-associated oedema and to reduce the risk of acute encephalopathy associated with radiotherapy. However, the mechanisms by which ... [more ▼]

Glucocorticoids are used in the treatment of gliomas to decrease tumour-associated oedema and to reduce the risk of acute encephalopathy associated with radiotherapy. However, the mechanisms by which glucocorticoids work are still largely unknown. In this paper, we survey the experimental and clinical evidence for the effects of glucocorticoids on tumour cell proliferation, apoptosis and sensitivity to chemotherapy, angiogenesis and vascular permeability. We then review current guidelines on the choice of molecule, dose and duration of glucocorticoid treatment for gliomas. [less ▲]

Chromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas.

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 ▲]

The epileptic syndromes with continuous spikes and waves during slow sleep: definition and management guidelines.

in Acta Neurologica Belgica (2006), 106(2), 52-60

The authors propose to define the epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) as a cognitive or behavioral impairment acquired during childhood, associated with a strong ... [more ▼]

The authors propose to define the epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) as a cognitive or behavioral impairment acquired during childhood, associated with a strong activation of the interictal epileptiform discharges during NREM sleep--whatever focal or generalized--and not related to another factor than the presence of CSWS. The type of syndrome will be defined according to the neurological and neuropsychological deficit. These syndromes have to be classified among the localization-related epileptic syndromes. Some cases are idiopathic and others are symptomatic. Guidelines for work-up and treatment are proposed. [less ▲]

Increased incidence of sporadic Creutzfeldt-Jakob disease in the age groups between 70 and 90 years in Belgium.

in European Journal of Epidemiology (2006), 21(6), 443-7

From 1998 a prospective surveillance study of Creutzfeldt-Jakob disease (CJD) has been initiated in Belgium. In addition to epidemiological data, information on cerebrospinal fluid biomarkers, prion ... [more ▼]

From 1998 a prospective surveillance study of Creutzfeldt-Jakob disease (CJD) has been initiated in Belgium. In addition to epidemiological data, information on cerebrospinal fluid biomarkers, prion protein gene and brain neuropathology was collected. From 1-1-1998 to 31-12-2004, 188 patients were referred to the surveillance system. In 85 patients a 'definite' diagnosis of sporadic CJD (sCJD) could be made, whereas 26 patients remained 'probable'. We further identified two unrelated patients with an E200K mutation, and two patients with a seven octapeptide repeat insertion in one family. In one patient a familial history was noted but genetic analysis was not performed. In 72 patients different final diagnoses were made, Alzheimer's disease being the most frequent (N = 20). The demographic parameters of the Belgian population were similar to those observed in the rest of Europe. We did notice a significantly increased age-specific incidence (> 6/10(6)/year) of sCJD patients between 70 and 90 years old in the period 2002-2004 compared to 1998-2001 and retrospectively obtained data (1990-1997, p < 0.01). We undertook a detailed clinical and biochemical analysis to investigate this increase but could not identify any reason other than an increased vigilance for the diagnosis.In conclusion, our study identified that in the past sCJD may have been underestimated in patients over age 70 although these patients are both clinically and neurobiochemically similar to the general sCJD phenotype. [less ▲]

Pathologie inflammatoire de l'hypophyse et grossesse

in Pathologie hypophysaire et grossesse (2006)

Les affections hypophysaires, tumorales ou non tumorales, sont classiquement responsables d'infertilité. Grâce aux progrès des traitements médicaux et chirurgicaux développés pour le traitement de ces ... [more ▼]

Les affections hypophysaires, tumorales ou non tumorales, sont classiquement responsables d'infertilité. Grâce aux progrès des traitements médicaux et chirurgicaux développés pour le traitement de ces affections hypophysaires, les grossesses sont de plus en plus fréquentes chez les patientes ayant en particulier un adénome hypophysaire sécrétant ou une insuffisance anté-hypophysaire ou un diabète insipide central. Cependant, les conséquences de l'affection hypophysaire et des traitements pour la mère ou le f¿tus sont toujours discutés par les endocrinologues, les gynécologues, les obstétriciens et les pédiatres. Le but de cet ouvrage unique en français est une mise au point de nos connaissances sur le sujet, et tout particulièrement sur le diagnostic hormonal et radiologique d'un syndrome d'hypersécrétion ou d'une insuffisance hypophysaire au cours d'une grossesse, ainsi que sur la prise en charge des patientes présentant une pathologie hypophysaire tumorale ou non tumorale, désirant ou présentant une grossesse. [less ▲]

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson's disease.

in Neurogenetics (2006), 7(3), 139-48

There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important ... [more ▼]

There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well. [less ▲]