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Biomedical subjects

O Delattre

Publications and source records attributed to O Delattre.

At least 19 recordsLinked to original sources
PubMed2002

[Developmental lumbar stenosis in eleven French Antilles patients].

PURPOSE OF THE STUDY: Developmental lumbar stenosis is a rare entity, exceptionally described in the literature. No study has been directly devoted to this condition. The purpose of the present study was to examine specific features, particularly clinical and anatomic expression, observed in a series of operated patients. MATERIAL AND METHODS: Eleven patients from the French Antilles were treated for developmental lumbar stenosis between 1996 and 2000. The Verbiest criteria were used to define canal narrowness. Signs of degeneration and presence of discal herniation were exclusion criteria. Epidemiological and clinical data were collected for the 11 patients. The degree of sagittal stenosis (fixed diameter at the bone level and mobile diameter at the discal level) was measured on computed tomography images. Transverse stenosis was determined by measuring the interpedicular and interapophyseal distances. Lateral stenosis was determined by measuring the depth of the recessus. RESULTS: These patients were young (mean age 42.4 years). Most of the clinical signs were monoradicular. Discal level stenosis predominated, generally at level L4-L5. It was generally central and lateral, sagittal and transverse. The interpedicular distance was the only diameter that remained within normal limits. Soft tissues (yellow ligaments and joint capsules) played an important role in the stenosis. DISCUSSION: The rare reports of developmental lumbar stenosis describe decompensated stenosis due to discal herniation in the adolescent. Developmental lumbar stenosis is considered to be a genetic disease and its particular high frequency in the French Antilles favors this hypothesis. The stenosis results from bony (short pedicles, hypertrophic lateral masses) and ligament (hypertrophy of the yellow ligament and joint capsules) structures. CONCLUSION: Developmental lumbar stenosis produces a global (sagittal, transverse, central, lateral) narrowing of the lumbar canal where soft tissue structures apparently play a greater role than usually thought. A prospective study examining the impact of ethnic origin is required to analyze the genetic hypothesis.

Adult↗
PubMed2001

CGH analysis of secondary genetic changes in Ewing tumors: correlation with metastatic disease in a series of 43 cases.

The occurrence of secondary chromosome changes is frequent in Ewing tumors, in particular trisomies for chromosomes 8 and 12, and unbalanced (1;16) translocations leading to gains of 1q and losses of 16q. The prognostic value of these secondary aberrations has not been statistically demonstrated. We report here a CGH analysis of a series of 43 primary tumors corresponding to 21 localized and 22 metastatic tumors. For five of them, a sufficient amount of DNA for the CGH analysis was available from the frozen samples. For 19 samples, a preliminary step of DOP-PCR amplification of the DNA was necessary. For the last 19 tumors, DNA was obtained after DOP-PCR amplification of small amount of DNA contaminating the RNA. As a whole, the main chromosome imbalances previously described, such as trisomies for 1q, 8, and 12, were observed. It is noteworthy that the mean number of imbalances was more frequent in localized versus metastatic tumors. Gain of 1q was more frequent in metastatic than in localized tumors. Nevertheless, these two results do not reach statistical significance. Conversely, a statistically significant excess of copy number of chromosome 2 was observed in non-metastatic tumors, suggesting that this imbalance, which has never been previously reported, could be associated with more favorable tumor behavior.

Chromosome Aberrations↗
PubMed2001

Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2and c-Myc expression.

Ewing tumour is characterized by specific chromosome translocations which fuse EWS to a subset of genes encoding ETS transcription factors, most frequently FLI-1. We report the analysis of the expression of various cell cycle regulators both in Ewing tumour derived cell lines and in different cellular models with either inducible or constitutive EWS-FLI-1 cDNA expression. In Ewing cell lines, cyclin D1, CDK4, Rb, p27KIP1 and c-Myc were consistently highly expressed whereas p57KIP2, p15INK4B and p14ARF demonstrated undetectable or low expression levels. The amount of p16INK4A, p21CIP1, p18INKAC and CDK6 was variable from one cell line to the other. The inducible expression of EWS-FLI-1 led to a strong upregulation of c-Myc and a considerable downregulation of p57KIP2. Other proteins did not show evident modification. High c-Myc and very low p57KIP2 expression levels were also observed in neuroblastoma NGP cells constitutively expressing EWS-FLI-1 as compared to parental cells. Analysis of the p57KIP2 promoter indicated that EWS-FLI-1 downregulates, possibly through an indirect mechanism, the transcription of this gene. Finally, we show that ectopic expression of p57KIP2 in Ewing cells blocks proliferation through a complete G1 arrest. These results suggest that the modulation of p57(KIP2) expression by EWS-FLI-1 is a fundamental step in Ewing tumorigenesis.

Base Sequence↗
PubMed2001

Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification.

We have studied the occurrence and association of 11q deletions with other chromosomal imbalances in Stage 4 neuroblastomas. To this purpose we have performed comparative genomic hybridization (CGH) analysis on 50 Stage 4 neuroblastomas and these data were analyzed together with those from 33 previously published cases. We observed a high incidence of 11q deletion in Stage 4 neuroblastoma without MYCN amplification (59%) whereas 11q loss was only observed in 15% of neuroblastomas with MYCN-amplification (p = 0.0002) or 11% of cases with 1p deletion detected by CGH (p = 0.0001). In addition, 11q loss showed significant positive correlation with 3p loss (p = 0.0002). Event-free survival was poor and not significantly different for patients with or without 11q deletion. Our study provides further evidence that Stage 4 neuroblastomas with 11q deletions represent a distinct genetic subgroup that typically shows no MYCN-amplification nor 1p deletion. Moreover, it shows that neuroblastomas with 11q deletion also often present 3p deletion. This genetic subgroup shows a similar poor prognosis as MYCN amplified 4 neuroblastomas.

Adolescent↗
PubMed2001

Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: how many genetic subgroups are there?

PROCEDURE: Analysis of comparative genomic hybridization (CGH) data of 120 tumors from four different studies, and data of 84 previously unpublishied tumors, allowed delineation of at least six different genetic subsets of neuroblastomas. RESULTS AND CONCLUSIONS: A small number of tumors show no detectable imballances. A second group of tumors presents with gains and losses of whole chromosomes and is found predominantly in prognostically favorable stage 1 and 2 tumors. The remaining groups are characterized by the presence of partial chromosome imbalances, and are found mostly in stage 3, 4, and 4S tumors. The third group shows 17q gain without 11q loss, 1p loss, or MYCN amplification (MNA). The fourth group has 1p deletion or MNA, and finally, a fifth group shows 11q loss without 1p deletion or MNA, and is found mainly in stage 4 tumors. The latter group is significantly associated with losses of 3p, 4p, and 14q.

Chromosome Aberrations↗
PubMed2001

Intracranial Ewing sarcoma/'peripheral' primitive neuroectodermal tumor of dural origin with molecular genetic confirmation.

Ewing sarcoma/'peripheral' primitive neuroectodermal tumor (ES/pPNET) is the designation given to a family of small cell neoplasms that typically arise in bone or soft tissue and are unified by their common expression of the MIC2 antigen and specific translocations involving a gene on chromosome 22q12 [the most common being t(11;22)(q24;q12)]. ES/pPNET of intracranial origin is extraordinary. We report the case of a 6-year-old boy with a large left frontal region mass that adhered to dura and was extracerebral at surgery. Histologic study revealed a high-grade, undifferentiated-appearing neoplasm of small cell type that was negative on immunostudy for glial fibrillary acidic protein, synaptophysin, desmin, leukocyte common antigen, smooth muscle actin and epithelial membrane antigen, but positive for vimentin and neuron-specific enolase and diffusely labeled by antibody O13 (which recognizes the MIC2 gene product). RNA-based polymerase chain reaction assay confirmed the diagnosis of ES/pPNET by demonstrating fusion transcripts indicative of t(11;22) translocation. Bone scan, computerized tomography of the chest and bone marrow examination revealed no systemic tumor. The limited observations published to date suggest that primary intracranial ES/pPNET is most likely to present in childhood as a circumscribed, contrast-enhancing and dural-based extracerebral mass. It must be distinguished from a variety of small cell neoplasms, particularly PNETs of central neuroepithelial origin.

Brain Neoplasms↗
PubMed2001

Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1.

Integase interactor 1 (INI1), also known as hSNF5, is a protein that interacts with HIV-1 integrase. We report here that a cytoplasmically localized fragment of INI1 (S6; aa183-294) containing the minimal integrase-interaction domain potently inhibits HIV-1 particle production and replication. Mutations in S6 or integrase that disrupt integrase-INI1 interaction abrogated the inhibitory effect. An integrase-deficient HIV-1 transcomplemented with integrase fused to Vpr was not affected by S6. INI1 was specifically incorporated into virions and was required for efficient HIV-1 particle production. These results indicate that INI1 is required for late events in the viral life cycle, and that ectopic expression of S6 inhibits HIV-1 replication in a transdominant manner via its specific interaction with integrase within the context of Gag-Pol, providing a novel strategy to control HIV-1 replication.

Base Sequence↗
PubMed2001

A multiplex real-time pcr assay for the detection of gene fusions observed in solid tumors.

SUMMARY: Specific gene fusions observed in solid tumors are extremely useful diagnostic markers. We report the development of a method based on real-time PCR which enables the detection upon identical PCR conditions of the different fusions specifically observed in Ewing tumors (ET), alveolar rhabdomyosarcoma (ARMS), synovial sarcoma (SS), small round cell desmoplastic tumors (SRCDT), extraskeletal myxoid chondrosarcoma, malignant melanoma of soft parts, congenital fibrosarcoma, and anaplastic large cell lymphoma. A simple assay, based on multiplexing of primers and probes, is described for the routine genetic diagnosis of small round cell tumors of children. It enables the detection of the five EWS-ETS, the two PAX-FKHR, the three SYT-SSX, and the EWS-WT1 fusions of ET, ARMS, SS, and SRCDT, respectively. The sensitivity of this test is high enough to detect all fusions, including the large EWS-FLI-1 transcripts, with the equivalent of 100 tumor cells as a starting material. This multiplex fluorescent analysis of chromosome translocations (MFACT) was validated in comparison with conventional RT-PCR on a series of 79 tumors. A major advantage of this method is that it completely abolishes the manipulation of PCR-products. It, therefore, considerably lowers the risk of cross-contamination linked to carry-over of RT-PCR products. It also constitutes an important step toward the complete automation of the detection of cancer-specific gene fusions.

Artificial Gene Fusion↗
PubMed2001

Characterization of a new brain-specific isoform of the EWS oncoprotein.

EWS and related TAFII68 and TLS/FUS genes are fused with different genes encoding transcription factors in various human cancers. The products of these genes have the ability to bind RNA and have been shown to be part of splicing and transcription complexes. We show that the EWS, TAFII68 and TLS/FUS proteins are expressed to various levels in all adult murine tissues. We characterize a new isoform of EWS that is specifically expressed in the central nervous system, in both mice and humans. It is shown to be related to a splice variant which includes a new 18-bp exon, termed 4', between exon 4 and 5. The detection of this isoform in spontaneously differentiating SH-SY5Y neuroblastoma cells and in nerve growth factor-induced PC12 cells further links this isoform to neural differentiation. RT-PCR experiments indicate that the level of expression of the brain-specific EWS isoform is stable during brain development whereas that of the ubiquitous EWS isoform decreases during this period. The two isoforms show a parallel decrease in expression after birth. The 4' exon is not detected in tumour-specific EWS fusion transcripts, suggesting that its presence may impair their oncogenic properties. Interestingly, sequences of the 4' exon and flanking regions show remarkable similarities to that of the neural-specific c-src exon, suggesting common mechanisms for the alternative splicing of these exons. The phylogenetic conservation and relationship to neural differentiation strongly suggests an important functional role for this exon.

Amino Acid Sequence↗
PubMed2001

INI1 mutations in meningiomas at a potential hotspot in exon 9.

Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.

Alleles↗
PubMed2001

[Detection of micrometastases and circulating tumour cells using molecular biology technics in solid tumours].

The extension of a cancer is a major prognostic factor which determines the therapeutic strategy. The occurrence of metastatic relapses in patients with initially localized tumours, despite a good local control, gives evidence for the possibility of spreading of occult tumour cells. The recent improvements of immunohistochemistry and molecular biology methods enable to detect tumour cells in various sites such as lymph nodes, bone marrow and blood with a considerably increased sensitivity as compared to conventional approaches. The markers used to detect tumour cells by PCR or RT-PCR can be either "tissue-specific" or "tumour specific". The drawback of the first group of markers is linked to the observation that tissue-specificity is frequently a relative concept leading to a high rate of false positives. Tumour-specific markers include gene fusions observed in various sarcomas, point mutations and presence of viral genomes in tumour cells. They are available and can be easily monitored in only a limited set of cancers. This review focuses on the molecular biology approaches which are used to detect occult tumour cells and on their clinical applications. The large number of studies which have been published in that field show that such a detection can be performed in a variety of target sites. However, results of studies performed on larger series of patients together with a better standardization of technics are necessary before they can be used for individual staging of patients.

Biomarkers, Tumor↗
PubMed2001

[Li-Fraumeni syndrome: update, new data and guidelines for clinical management].

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

Adult↗
PubMed2000

Presence of new alternative exons in human and mouse Fli-1 genes.

The mouse Fli-1 proto-oncogene is activated by proviral integration of four murine leukemia retroviruses and its human counterpart is translocated (11,22) in Ewing tumors. We have identified two alternative exons 1 by RACE analysis from a human neuroectodermal tumor. Exons 1a and 1b are located respectively 1.3 and 2.5 kb upstream from the published exon 1. Translation of these alternative messengers is predicted to generate very similar proteins. The sequence upstream from exon 1b showed functional promoter activity. Exon 1b was not conserved in the mouse but was detected in every analyzed human cell, whereas exon 1a was present only in a subset of them and also in various mouse cell lines. These results suggest that both mouse and human Fli-1 gene expression might be under the control of several independent promoter regions.

Alternative Splicing↗
PubMed2000

IFN-beta induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7.

Four human cell lines derived from Ewing's sarcoma, EW-7, EW-1, COH and ORS, were investigated to establish the effects of human recombinant interferon-alpha2a and human recombinant interferon-beta on cell proliferation and apoptosis. All four cell lines were much more sensitive to the antiproliferative effects of IFN-beta than of IFN-alpha. Analysis of the early signals triggered by IFN-alpha and IFN-beta demonstrated that the two IFNs were similarly effective in inducing tyrosine phosphorylation of the Jak-1 and Tyk-2 kinases and the transcription factors Stat-1 and Stat-2. Interestingly, an additional rapid phosphorylation of Stat-1 on serine was observed after IFN-beta treatment, with concomitant activation of p38 mitogen-activated protein kinase. In these cells, Stat-1 Ser727 phosphorylation in response to IFN-beta was found to be impaired by p38 MAPkinase inhibitor (SB203580). IFN-beta induced the formation of the Interferon Stimulated Gene Factor 3 complex more efficiently than IFN-alpha, as well as sustained induction of IRF-1, which may account for its greater induction of 2'5'oligo(A)synthetase and greater inhibition of cell proliferation. IFN-beta, but not IFN-alpha, induced apoptosis in wild-type p53 EW-7 and COH cell lines, but not in the mutated p53 EW-1 or ORS cell lines. The apoptosis induced by IFN-beta in EW-7 and COH cell lines appeared to be mediated by IRF-1 and involved the activation of caspase-7. Ectopic expression of IRF-1 induced apoptosis in all four cell lines which correlated with the activation of caspase-7 and with the downregulation of the Bcl-2 oncoprotein, as observed for IFN-beta-induced apoptosis in parental EW-7 and COH cell lines.

2',5'-Oligoadenylate Synthetase↗
PubMed2000

Induction of p21Waf1/Cip1 by TNFalpha requires NF-kappaB activity and antagonizes apoptosis in Ewing tumor cells.

The Ewing family of tumors is characterized by recurrent reciprocal translocations that generate chimeric proteins, either EWS - FLI-1 or EWS - ERG. These proteins are potent transcriptional activators and are responsible for maintaining the oncogenic properties of tumor cells. Since apoptosis appears to be the main mechanism whereby chemotherapy and radiation kill tumor cells, identification of events that can antagonize apoptosis in Ewing tumors is essential for improving their response to conventional therapies. Here, we report that the transcriptional factor NF-kappaB is a survival factor for Ewing tumor-derived cells. In fact, inhibition of NF-kappaB activation as a consequence of the overexpression of a degradation-resistant form of IkappaBalpha, IkappaBalpha (A32/36), sensitized these cells to TNFalpha-induced killing. Although treatment with TNFalpha did not modify the cellular expression of Bcl-2, c-IAP1, c-IAP2, p53 and EWS - FLI-1 proteins, it increased p21Waf1/Cip1 levels. This induction required NF-kappaB activation since it was not observed in the IkappaBalpha (A32/36) expressing cells. Moreover, overexpression of p21Waf1/Cip1 in these IkappaBalpha (A32/36)-expressing cells, in which NF-kappaB and consequently p21Waf1/Cip1 are no longer inducible by TNFalpha, decreased their susceptibility to TNFalpha-induced killing. Our results therefore identify p21Waf1/Cip1 as a mediator of the antiapoptotic effect of TNFalpha-induced NF-kappaB in Ewing tumor cells.

Antineoplastic Agents↗