33 research outputs found

    Expression of C-terminal deleted p53 isoforms in neuroblastoma

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    The tumor suppressor gene, p53, is rarely mutated in neuroblastomas (NB) at the time of diagnosis, but its dysfunction could result from a nonfunctional conformation or cytoplasmic sequestration of the wild-type p53 protein. However, p53 mutation, when it occurs, is found in NB tumors with drug resistance acquired over the course of chemotherapy. As yet, no study has been devoted to the function of the specific p53 mutants identified in NB cells. This study includes characterization and functional analysis of p53 expressed in eight cell lines: three wild-type cell lines and five cell lines harboring mutations. We identified two transcription-inactive p53 variants truncated in the C-terminus, one of which corresponded to the p53β isoform recently identified in normal tissue by Bourdon et al. [J. C. Bourdon, K. Fernandes, F. Murray-Zmijewski, G. Liu, A. Diot, D. P. Xirodimas, M. K. Saville and D. P. Lane (2005) Genes Dev., 19, 2122–2137]. Our results show, for the first time, that the p53β isoform is the only p53 species to be endogenously expressed in the human NB cell line SK-N-AS, suggesting that the C-terminus truncated p53 isoforms may play an important role in NB tumor development

    Spatially extended PAHs in circumstellar disks around T Tauri and Herbig Ae stars

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    Our aim is to determine the presence and location of the emission from polycyclic aromatic hydrocarbons (PAHs) towards low and intermediate mass young stars with disks using large aperture telescopes. VLT-VISIR N-band spectra and VLT-ISAAC and VLT-NACO L-band spectra of 29 sources are presented, spectrally resolving the 3.3, 8.6, 11.2, and 12.6 micron PAH features. Spatial-extent profiles of the features and the continuum emission are derived and used to associate the PAH emission with the disks. The results are discussed in the context of recent PAH-emission disk models. The 3.3, 8.6, and 11.2 micron PAH features are detected toward a small fraction of the T Tauri stars, with typical upper limits between 1E-15 and 5E-17 W/m^2. All 11.2 micron detections from a previous Spitzer survey are confirmed with (tentative) 3.3 micron detections, and both the 8.6 and the 11.2 micron features are detected in all PAH sources. For 6 detections, the spatial extent of the PAH features is confined to scales typically smaller than 0.12-0.34'', consistent with the radii of 12-60 AU disks at their distances (typically 150 pc). For 3 additional sources, WL 16, HD 100546, and TY CrA, one or more of the PAH features are more extended than the hot dust continuum of the disk, whereas for Oph IRS 48, the size of the resolved PAH emission is confirmed as smaller than for the large grains. For HD 100546, the 3.3 micron emission is confined to a small radial extent of 12 +- 3 AU, most likely associated with the outer rim of the gap in this disk. Gaps with radii out to 10-30 AU may also affect the observed PAH extent for other sources. For both Herbig Ae and T Tauri stars, the small measured extents of the 8.6 and 11.2 micron features are consistent with larger (>= 100 carbon atoms) PAHs.Comment: 14 pages, 17 figures, accepted for publication in A&

    ISO spectroscopy of disks around Herbig Ae/Be stars

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    We have investigated the infrared spectra of all 46 Herbig Ae/Be stars for which spectroscopic data is available in the ISO data archive. Our quantitative analysis of these spectra focusses on the emission bands linked to polycyclic aromatic hydrocarbons (PAHs), the amorphous 10 micron silicate band and the crystalline silicate band at 11.3 micron. We have detected PAH emission in 57% of the Herbig stars in our sample. Clear examples of differences in the PAH spectra are present within our sample, indicating differences in PAH size, chemistry and/or ionization. Amorphous silicate emission was detected in the spectra of 52% of the sample stars, amorphous silicate absorption in 13%. We have detected crystalline silicate emission in 11 stars (24% of our sample), of which four (9%) also display strong PAH emission. We have classified the sample sources according to the strength of their mid-IR energy distribution. The systems with stronger mid-infared (20-100 um) excesses relative to their near-infrared (1-5 um) excess display significantly more PAH emission than those with weaker mid-infrared excesses. This provides strong observational support for the disk models by Dullemond (2002), in which systems with a flaring disk geometry display a strong mid-infrared excess, whereas those with disks that are strongly shadowed by the puffed-up inner rim of the disk only display modest amounts of mid-infrared emission. The PAH emission is expected to be produced mainly in the part of the disk atmosphere that is directly exposed to radiation from the central star. In this model, self-shadowed disks should display weaker PAH emission than flared disks, consistent with our observations.Comment: 27 pages, 26 figures, A&A accepted (22/06/2004

    Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow.

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    Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr-/- cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34+ cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation

    Searching for a link between the magnetic nature and other observed properties of Herbig Ae/Be stars and stars with debris disks

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    Among the 21 Herbig Ae/Be stars studied, new detections of a magnetic field were achieved in six stars. For three Herbig Ae/Be stars, we confirm previous magnetic field detections. The largest longitudinal magnetic field, = -454+-42G, was detected in the Herbig Ae/Be star HD101412 using hydrogen lines. No field detection at a significance level of 3sigma was achieved in stars with debris disks. Our study does not indicate any correlation of the strength of the longitudinal magnetic field with disk orientation, disk geometry, or the presence of a companion. We also do not see any simple dependence on the mass-accretion rate. However, it is likely that the range of observed field values qualitatively supports the expectations from magnetospheric accretion models giving support for dipole-like field geometries. Both the magnetic field strength and the X-ray emission show hints for a decline with age in the range of ~2-14Myrs probed by our sample supporting a dynamo mechanism that decays with age. However, our study of rotation does not show any obvious trend of the strength of the longitudinal magnetic field with rotation period. Furthermore, the stars seem to obey the universal power-law relation between magnetic flux and X-ray luminosity established for the Sun and main-sequence active dwarf stars.Comment: 21 pages, 16 figures, 7 tables, accepted for publication in A&

    Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma

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    International audienceChronic hepatitis B virus (HBV) infection is etiologically related to human hepatocellular carcinoma (HCC). Most HCCs contain integrated HBV DNA in the liver cellular DNA, suggesting that the integration may be involved in carcinogenesis. From a comparison of a single HBV integration site present in a hepatoma with the corresponding unoccupied site in the non-tumourous tissue of the same liver, we have shown that HBV DNA inserted in a putative cellular exon with striking similarity to the DNA-binding domain of the thyroid/steroid hormone receptors. The corresponding cDNA has been isolated (hap gene) and shown to encode the retinoic acid receptor. In the original patient, integration took place so that the first codons of the viral surface protein gene became fused in frame with most of the hap gene. Because retinoic acid is known to regulate the transcription of target genes crucial for cellular growth and differentiation, it is most probable that consequent to the HBV insertion, hap, usually transcribed at a very low level in normal hepatocytes, became inappropriately expressed as an altered chimaeric retinoic acid receptor, thus contributing to the cell transformation. These results strongly support the possibility that HBV may play a direct role in liver carcinogenesis by insertional mutagenesis

    A PML/retinoic acid receptor alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia

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    International audienceThe t(15;17) translocation is specifically observed in patients with promyelocytic leukemia (AML3). The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha (RAR alpha) and PML genes, resulting in PML/RAR alpha fusion transcripts. Our previous studies have shown that a polymerase chain reaction (PCR) amplification product could be obtained from the cDNA of the NB4 promyelocytic cell line from which the chimaeric PML/RAR alpha was cloned. We report here that in all 14 AML3 patients tested, reverse transcriptase-PCR (RT-PCR) allows the detection of three specific fusion products. In eight patients, one amplification product was detected corresponding to the previously described abnormal fusion. Five patients displayed a different amplified fragment corresponding to a different fusion point. One other patient always showed a third different-sized product. The different types of fusion transcripts amplified were correlated to the size of the abnormal RAR alpha transcripts detected in these patients by Northern analysis, but did not prove determinant for either the phenotypic features or the retinoic acid responsiveness in AML3 cells in this group of patients. The consistent identification by RT-PCR of the fusion of the PML and RAR alpha genes in AML3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients
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