Implication des modifications épigénétiques dans les cancers : développement de nouvelles approches thérapeutiques

Involvement of epigenetic modifications in cancers: development of new therapeutic approaches. Since cancer is the second cause of death after cardiovascular diseases in industrialized countries, it is urgent to elaborate new therapeutic approaches. Besides DNA mutations of essential genes, expansion of a cancer cell is frequently associated with epigenetic modifications i.e. not directly coded by the DNA sequence. Amongst epigenetic modifications, histones acetylation and DNA methylation are known to play important roles. In this context, a very promising anticancer therapy would be to correct epigenetic errors using compounds modulating histone acetylation and DNA methylation alone or in combination with other chemotherapeutic agents

Observations of plasma dynamics in the coma of P/Halley by the Giotto Ion Mass Spectrometer

Observations in the coma of P/Halley by the Giotto Ion Mass Spectrometer (IMS) are reported. The High Energy Range Spectrometer (HERS) of the IMS obtained measurements of protons and alpha particles from the far upstream region to the near ionopause region and of ions from mass 12 to 32 at distances of about 250,000 to 40,000 km from the nucleus. Plasma parameters from the High Intensity Spectrometer (HIS) of the IMS obtained between 150,000 to 5000 km from the nucleus are also discussed. The distribution functions of water group ions (water group will be used to refer to ions of 16 to 18 m/q, where m is in AMU and q is in unit charges) are observed to be spherically symmetric in velocity space, indicating strong pitch angle scattering. The discontinuity known as the magnetic pile-up boundary (MPB) is apparent only in proton, alpha, and magnetometer data, indicating that it is a tangential discontinuity of solar wind origin. HERS observations show no significant change in the properties of the heavy ions across the MPB. A comparison of the observations to an MHD model is made. The plasma flow directions at all distances greater than 30,000 km from the nucleus are in agreement with MHD calculations. However, despite the agreement in flow direction, within 200,000 km of the nucleus the magnitude of the velocity is lower than predicted by the MHD model and the density is much larger (a factor of 4). Within 30,000 km of the nucleus there are large theoretical differences between the MHD model flow calculations for the plane containing the magnetic field and for the plane perpendicular to the magnetic field. The observations agreed much better with the pattern calculated for the plane perpendicular to the magnetic field. The data obtained by the High Energy Range Spectrometer (HERS) of the IMS that are published herein were provided to the International Halley Watch archive

Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection

Absence probable de la translocation robertsonienne 1/29 en race bovine Blanc Bleu Belge

International audienc

Bovine leukaemia virus and enzootic bovine leukosis

Infection of bovines with bovine leukaemia virus (BLV) manifests itself in either of two ways: 30-70% of carriers develop persistent lymphocytosis (PL), with the viral genome integrated at a large number of different sites in the DNA of the affected B-lymphocytes, without causing any chromosomal abnormalities. Only 0,1-10 % of carriers develop lymphoid tumours, which also consist of B-lymphocytes. In contrast to PL, however, they are of mono- or oligoclonal origin in terms of the integration site, which is characteristic for each tumour. All cells contain one or more copies of the viral genome, chromosomal aberrations are common and if deletions are present they are invariably found in the 5' -half of the virus DNA sequence. In both types of affected cells transcription is repressed in vivo, but transient virus production can be induced in vitro and detected by means of syncytia induction or haemagglutination. In vivo production of virus in some unknown cell is suggested by the presence of high antibody titres in infected animals, especially against the envelope glycoprotein gp51 . This can be detected by various techniques such as immunodiffusion, radioimmune assay or ELISA. Monoclonal antibodies against gp51 have revealed 8 epitopes, 3 of which are recognized by neutralizing antibodies and one by a cytolytic antibody. The BLV genome, about 9 kb in size, have been cloned, and some of the information obtained on its molecular structure and function is discussed. It codes for at least 4 non-glycosylated and 2 glycoproteins. Of special interest is the recently discovered serological relationship between some of the non-glycosylated proteins and those of the human T-cell leukaemia virus. The functional role of BLV in leukaemogenesis is largely unknown. The presence of the viral genome seems to be necessary for the maintenance of the transformed state, but not its continuous expression nor an LTR- mediated promotion of transcription of cellular genes. No oncogene is carried by the virus. Although bovine leukosis is not of major economic importance, its eradication is desirable and feasible in countries with a relatively low incidence, by means of testing and elimination. For endemic situations vaccination would be preferable, and distinct possibilities exist for the development of gp51 based vaccinesThe articles have been scanned in colour with a HP Scanjet 5590; 600dpi. Adobe Acrobat XI Pro was used to OCR the text and also for the merging and conversion to the final presentation PDF-format

Methodology and software to detect viral integration site hot-spots

<p>Abstract</p> <p>Background</p> <p>Modern gene therapy methods have limited control over where a therapeutic viral vector inserts into the host genome. Vector integration can activate local gene expression, which can cause cancer if the vector inserts near an oncogene. Viral integration hot-spots or 'common insertion sites' (CIS) are scrutinized to evaluate and predict patient safety. CIS are typically defined by a minimum density of insertions (such as 2-4 within a 30-100 kb region), which unfortunately depends on the total number of observed VIS. This is problematic for comparing hot-spot distributions across data sets and patients, where the VIS numbers may vary.</p> <p>Results</p> <p>We develop two new methods for defining hot-spots that are relatively independent of data set size. Both methods operate on distributions of VIS across consecutive 1 Mb 'bins' of the genome. The first method 'z-threshold' tallies the number of VIS per bin, converts these counts to z-scores, and applies a threshold to define high density bins. The second method 'BCP' applies a Bayesian change-point model to the z-scores to define hot-spots. The novel hot-spot methods are compared with a conventional CIS method using simulated data sets and data sets from five published human studies, including the X-linked ALD (adrenoleukodystrophy), CGD (chronic granulomatous disease) and SCID-X1 (X-linked severe combined immunodeficiency) trials. The BCP analysis of the human X-linked ALD data for two patients separately (774 and 1627 VIS) and combined (2401 VIS) resulted in 5-6 hot-spots covering 0.17-0.251% of the genome and containing 5.56-7.74% of the total VIS. In comparison, the CIS analysis resulted in 12-110 hot-spots covering 0.018-0.246% of the genome and containing 5.81-22.7% of the VIS, corresponding to a greater number of hot-spots as the data set size increased. Our hot-spot methods enable one to evaluate the extent of VIS clustering, and formally compare data sets in terms of hot-spot overlap. Finally, we show that the BCP hot-spots from the repopulating samples coincide with greater gene and CpG island density than the median genome density.</p> <p>Conclusions</p> <p>The z-threshold and BCP methods are useful for comparing hot-spot patterns across data sets of disparate sizes. The methodology and software provided here should enable one to study hot-spot conservation across a variety of VIS data sets and evaluate vector safety for gene therapy trials.</p