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Biomedical subjects

F Gilles

Publications and source records attributed to F Gilles.

At least 19 recordsLinked to original sources
PubMed2004

Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma.

Using a cDNA microarray, we found that suppressor of cytokine signaling 3 (SOCS3) is highly expressed in anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) cell lines. As SOCS3 is induced by activated signal transducer and activator of transcription 3 (STAT3), and ALK activates STAT3, we hypothesized that SOCS3 may play a role in ALK+ ALCL pathogenesis via the Janus kinase 3 (JAK3)-STAT3 pathway. Using ALCL cell lines, we show by coimmunoprecipitation experiments that SOCS3 physically binds with JAK3 in vitro, and that JAK3 inhibition by WHI-P154 downregulates SOCS3 expression. Western blot analysis confirmed expression of SOCS3 and also showed coexpression of phosphorylated (activated) STAT3 (pSTAT3). Direct sequencing of the SOCS3 gene showed no mutations or alternative splicing. In ALCL tumors that were assessed by immunohistochemistry, nine of 12 (75%) ALK+ tumors were SOCS3 positive and eight (67%) coexpressed pSTAT3. In comparison, 18 of 25 (72%) ALK-- tumors were SOCS3 positive and seven (28%) coexpressed pSTAT3. These results show that SOCS3 is overexpressed in ALCL, attributable to JAK3-STAT3 activation and likely related to ALK in ALK+ tumors. However, SOCS3 is also expressed in tumors that lack STAT3 and ALK suggesting alternative mechanisms of upregulation.

Alternative Splicing↗
PubMed2001

Gp120 activates children's brain endothelial cells via CD4.

Encephalopathy represents a common and serious manifestation of HIV-1 infection in children, but its pathogenesis is unclear. We demonstrated that gp120 activated human brain microvascular endothelial cells (HBMEC) derived from children in up-regulating ICAM-1 and VCAM-1 expression, IL-6 secretion and increased monocyte transmigration across monolayers. Another novel observation was our demonstration of CD4 in isolated HBMEC and on microvessels of children's brain cryosections. Gp120-induced monocyte migration was inhibited by anti-gp120 and anti-CD4 antibodies. This is the first demonstration that gp120 activates HBMEC via CD4, which may contribute to the development of HIV-1 encephalopathy in children.

AIDS Dementia Complex↗
PubMed2001

Establishment of a human cell line (SKI-DLCL-1) with a t(1;14)(q21;q32) translocation from the ascites of a patient with diffuse large cell lymphoma.

Cytogenetic abnormalities at chromosome 1q21 are among the most common second genetic events observed in Non-Hodgkin's Lymphomas and have prognostic significance. Recently, BCL9 has been cloned from a pre-B-cell lymphoblastic leukemia cell line, which carried a t(1:14)(q21;q32). However, among a panel of 39 B-cell malignancies with 1q21 translocation, only two cases showed rearrangement for the BCL9 gene. We report the establishment of a new lymphoma cell line from a patient with relapsed diffuse large cell lymphoma. This cell line SKI-DLCL-1 showed cell surface antigens identical to the original tumor and demonstrated the profile of a mature B-cell phenotype: CD19 and CD20 positive, CD5 and C10 negative. It carried a t(1;14)(q21;q32) translocation identical to the original tumor. Although the clinical presentation was an isolated effusion lymphoma, studies for HIV-1, HHV8 and EBV were all negative. Southern blot analysis demonstrated that BCL9 was not rearranged in the SKI-DLCL-1 cell line. In addition, the BCL9 gene was not over-expressed in SKI-DLCL-1 cell line. The identification of a new locus at 1q21 will help clarify the pathogenesis of B-cell malignancies with a translocation involving this locus.

Aged↗
PubMed2000

Cloning and characterization of a Golgin-related gene from the large-scale polymorphism linked to the PML gene.

Megabase-scale mapping of the PML gene locus revealed the presence of a large-scale insertion-deletion polymorphism located 25 kb downstream of the PML gene. The polymorphism is organized as a head-to-tail tandem 25-kb repeat containing one to five units. Characterization of the first repeat unit downstream of PML revealed the presence of a gene with strong homology to a family of Golgin-related proteins. The gene, designated GLP (for Golgin linked to PML), is strongly expressed as a 6-kb transcript in normal human testis. In situ hybridization of normal human testis demonstrated that the expression of GLP was restricted to late meiotic germ cells. There was weak expression in late pachytene spermatocytes and strong expression in spermatids. GLP is 50% homologous to other Golgin-related proteins including the vesicle docking protein GM130. Southern blot hybridization of genomic DNA with a GLP probe demonstrated numerous homologous bands outside the PML locus. Three of these loci have been mapped by fluorescence in situ hybridization to chromosome loci 9q34.1, 15q11-q13, and 15q22-q24. Hybridization of a GLP cDNA probe to a zoo blot demonstrated multiple signals in nonhuman primates but not in other species and suggested the duplication of an ancestral locus around 20 million years ago.

Amino Acid Sequence↗
PubMed2000

MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma.

Cytogenetic abnormalities at chromosome 1q21 are among the most common lesions in diffuse large-cell lymphoma and have been associated with a poor prognosis. A novel cell line, SKI-DLCL-1, was established from ascitic fluid that carries a t(1;14)(q21;q32) chromosomal translocation. Using pulsed-field gel electrophoresis, the breakpoint on the IgH locus mapped to a gamma locus between Calpha(1) and Calpha(2). A cosmid library was prepared from SKI-DLCL-1, and Cgamma-positive clones spanning the breakpoint were identified by screening with fluorescence in situ hybridization. The breakpoint occurs 860 bp downstream of the 3' UTR of the MUC1 gene. The break appears to be a staggered double-strand break consistent with an error in immunoglobulin class switching. The MUC1 gene is highly transcribed and translated, and the protein is highly glycosylated. It is postulated that MUC1 expression is brought under the control of the 3'Ealpha enhancer. MUC1 lies in a region of chromosome 1 characterized by an unusually high density of genes, with 7 known genes in a region of approximately 85 kb. To determine whether there was a pleiotropic effect of the expression of genes in the region as a consequence of the translocation, the expression of 6 additional genes was assessed. None of the other genes in this region (CLK2, propin, COTE1, GBA, metaxin, and thrombospondin 3) are overexpressed in SKI-DLCL-1. Thus, the translocation t(1;14)(q21;q32) seen in both the primary tumor and the derived cell line results in the marked overexpression of MUC1 without affecting the expression of other genes in the region. (Blood. 2000;95:2930-2936)

Ascites↗
PubMed2000

A novel gene STORP (STOmatin-Related Protein) is localized 2 kb upstream of the promyelocytic gene on chromosome 15q22.

We generated a 100-kb map of the region 5' of the PML (promyelocytic leukemia) gene on human chromosome 15q22 and identified a new gene provisionally named STORP for stomatin-related protein. The STORP gene is positioned 2 kb upstream of the PML gene in a head-to-head configuration, and contains 7 exons spanning a genomic region of about 11 kb. There is an open reading frame of 398 amino acids, which would encode a protein of 45 kD. Northern blot analysis demonstrated that the STORP gene has a ubiquitous pattern of expression similar to that of the PML gene. Hybridization of STORP cDNA probe to genomic DNA from other species demonstrated that the STORP gene is conserved among mammalian vertebrates and that the physical linkage with PML is conserved in mice. Unlike PML, the STORP gene is not induced by interferon alpha (IFNalpha), and thus can be distinctly regulated from the PML gene. STORP is homologous to the EPB72 gene coding for the erythrocyte band 7 integral membrane protein or stomatin, which is deficient in a certain form of hereditary stomatocytosis. The function of STORP is unknown. Further study will focus on studying its potential role in red cell function and disorders.

Amino Acid Sequence↗
PubMed2000

Physical linkage of the lysyl oxidase-like (LOXL1) gene to the PML gene on human chromosome 15q22.

A contig was constructed centered on the PML (promyelocytic leukemia) gene. Using an exon-trapping approach to identify potential genes from a pool of cosmids located 5' of the PML gene, four exons were identified that showed 100% sequence homology with the previously cloned lysyl oxidase-like (LOXL1) gene. An exon probe identified a single transcript of 2.4 kb on a multitissue Northern blot with a pattern identical to the one reported for the LOXL1 gene. Pulsed-field gel electrophoresis showed comigrating bands for both the PML cDNA and LOXL1 probes, demonstrating a physical linkage between these two genes. These data provide physical mapping information to complement the previous cytogenetic localization of LOXL1.

Blotting, Southern↗
PubMed1997

Selective expression of adhesion molecules on human brain microvascular endothelial cells.

Human microvascular endothelial cells were isolated from children's brain and examined for their morphological characteristics and upregulation of cell adhesion molecules in response to TNF alpha. Our human brain microvascular endothelial cells (HBMEC) were positive for factor VIII-Rag, carbonic anhydrase IV, Ulex Europeus Agglutinin I, took up fluorescently labeled acetylated low density lipoprotein and expressed gamma glutamyl transpeptidase, demonstrating their brain endothelial cell characteristics. Upon treatment with TNF alpha. VCAM and ICAM but little ELAM was expressed on HBMEC, while VCAM, ICAM and ELAM were clearly evident on HUVEC. This selective expression of cell adhesion molecules was also demonstrated by in situ stimulation of brain tissues. In conclusion, microvascular endothelial cells from childrens brains display selective expression of cell adhesion molecules, which differ from macrovascular endothelial cells. This may have consequences for leukocyte trafficking into the central nervous system.

Brain↗
PubMed1996

The c-ets-1 proto-oncogene is a new early-response gene differentially regulated by cytokines and growth factors in human fibroblasts.

In various invasive human tumors, c-ets-1 mRNA was found to be selectively expressed in stromal fibroblasts. We have now investigated the possibility that soluble factors could regulate c-ets-1 expression in cultured human fibroblasts. We show that both conditioned media from tumor cell lines and a number of characterized cytokines and growth factors were able to induce c-ets-1 expression. TNF alpha and IL-1 alpha were the most potent c-ets-1 stimulators, inducing rapid (within 1 h) and long-lasting (19 h) increases of c-ets-1 mRNA and protein expression. In contrast, bFGF, EGF, and PDGF were mainly delayed stimulators, with maximal stimulation being detected by 19 h. In addition, these growth factors potentiated the rapid induction of c-ets-1 by TNF alpha. While all these factors were able to stimulate c-ets-1 expression, TGF beta was found to be ineffective. Using inhibitors of transcription and translation, we also found that increase of c-ets-1 mRNA by TNF alpha resulted from new transcription rather than from stabilization and did not require new protein synthesis. These results demonstrated that c-ets-1 is a new nuclear target for several factors and behaves as an early-response gene for TNF alpha.

Cells, Cultured↗
PubMed1996

Ventriculomegaly, delayed myelination, white matter hypoplasia, and "periventricular" leukomalacia: how are they related?

Preterm infants, including some who have sustained intracranial hemorrhage, appear to be at increased risk of lateral ventricular enlargement. Although some occurrences might be due to an impairment of cerebrospinal fluid flow or absorption, many instances of ventriculomegaly without accompanying macrocephaly reflect diffuse white matter damage resulting in diminished (i.e., hypoplastic) white matter or an inadequate density of axons. Perinatally acquired widespread white matter damage is sometimes associated with the focal white matter necrosis. We hypothesize that in some infants both ventriculomegaly and delayed myelination are consequences of disturbances to myelinogenesis that result from an impairment of cells destined to become oligodendroglia or of disturbances to rapidly growing axons. The vulnerability of developing white matter in preterm newborns might, in part, reflect the diminished availability of growth/ survival factors, or a vulnerability to toxins or physiologic perturbations. Awareness that some ventriculomegaly reflects widely distributed white matter damage should prevent overtreatment of what might appear to be hydrocephalus, but is not due to impaired cerebrospinal fluid dynamics. Increased understanding of the phenomena leading to ventriculomegaly related to paucity of white matter should lead to successful efforts to prevent white matter damage in preterm newborns.

Axons↗
PubMed1995

A novel L23-related gene 40 kb downstream of the imprinted H19 gene is biallelically expressed in mid-fetal and adult human tissues.

The closely linked IGF2 and H19 genes on human chromosome 11p15.5 are monoallelically expressed as a result of genomic imprinting and show altered expression in Wilms' tumors (WTs). To map regional imprinting we have sought to isolate additional human genes close to IGF2/H19 and to characterize their allelic expression patterns. Here we report a novel gene, provisionally named L23MRP [L23 (mitochondrial)-related protein], which is oriented 'tail-to-tail' with H19 and is transcribed to within 40 kb of the last H19 exon. L23MRP is expressed biallelically in many mid-fetal and adult human tissues. This gene is also expressed at normal levels in WTs which have lost expression of H19 either via loss of the maternal chromosome 11p15.5 or via an epigenetic pathway involving site-specific DNA hypermethylation. These data indicate that, at least in post-embryonic stages, L23MRP is functionally insulated from the IGF2/H19 imprinted domain.

Adult↗
PubMed1994

Stromal expression of c-Ets1 transcription factor correlates with tumor invasion.

The stroma reaction has an important role in tumor growth, invasion, and metastasis. In various invasive human carcinomas, as well as in a mouse model for tumor invasion, transcripts encoding the transcription factor c-Ets1 were detected within stromal fibroblasts, whereas they were absent in epithelial tumor cells. This expression of c-Ets1 was often increased in fibroblasts directly adjacent to neoplastic cells. Endothelial cells of stromal capillaries were also positive for c-Ets1 expression. In contrast, fibroblasts of corresponding noninvasive lesions and of normal tissues were consistently negative. In cultured human fibroblasts stimulated by basic fibroblast growth factor and tumor necrosis factor alpha, the expression of c-Ets1 correlated with the accumulation of transcripts for potential target genes, collagenase-1 and stromelysin-1. The same correlation was observed in some of the invasive carcinomas investigated. These results suggest that c-Ets1 participates in the regulation of tumor invasion in vivo.

Adult↗
PubMed1994

Use of texture parameters in the classification of soft tissue tumors.

Soft tissue tumors are a challenging group of tumors that presents wide morphologic variety. For pathologists, the degree of cellular differentiation, the cellular and nuclear polymorphism and the mitotic rate are major criteria for diagnosis. In image analysis, the architectural organization of such tumors shows local variations that can be understood as texture variations. This study introduced a method of measuring the architectural organization of soft tissue tumors from texture analysis of tissue sections at low magnification. We studied 40 cases of soft tissue tumors classified by pathologists into three groups according to their histologic patterns. Twelve texture parameters were calculated on subimages of 128 x 128 pixels. Our results show that tissue architecture evaluated by texture analysis provides good discrimination of myxoid, spindle cell and round cell tumors.

Cell Differentiation↗
PubMed1994

Grading of cystosarcoma phyllodes by texture analysis of tissue architecture.

Conventional histologic grading of cystosarcoma phyllodes of the breast has not been entirely successful in the prognosis of recurrence or metastasis. Our study first developed a tumor grade classification based on computerized texture features and then compared the classification to conventional grading of these tumors. Evaluation of the tissue architecture of histologic sections was obtained by measuring nine texture features on an image analysis system. Forty cases of cystosarcoma phyllodes were studied. Each parameter was calculated on subimages of 128 x 128 pixels. This size resulted from a preliminary study that confirmed that the difference between texture primitives depends on the area of subimages. We also compared our series to a panel of 20 extramammary sarcomas. The results show that tissue architecture evaluated by texture analysis allows good discrimination between benign, borderline and malignant cystosarcoma phyllodes. Furthermore, extramammary sarcomas and malignant cystosarcoma phyllodes were discriminated well in most cases.

Breast Neoplasms↗
PubMed1992

Evaluation of breast carcinoma chemosensitivity by flow cytometric DNA analysis and computer assisted image analysis.

Flow cytometric (FCM) DNA and S-Phase (S%) analyses were compared to computerized image analysis (SAMBA 2005) in 27 breast carcinomas (T3, N0-N1, M0) treated by 3 cycles of preoperative Adriamycin, vincristine, cyclophosphamide, methotrexate, 5-fluorouracil (AVCMF) chemotherapy (CT). Twelve carcinomas had shown objective regression and 15 no regression. Samples studied were obtained by sequential fine-needle cytopunctures. Comparing DNA profiles obtained by both methods before and after the first cycle, it appears that tumors can be divided into 3 groups. In the first group (10 cases), no changes were observed after the first cycle of CT. These tumors before treatment had either single DNA peak without cells in S% and G2M or a major peak with a small S% and G2M peak. The second group (9 cases) showed some changes in DNA profiles with an increased G2M peak but no additional values; these tumors before treatment had a small S% and a G2M peak. In the third group (8 cases), before treatment, all were non-diploid with high S% and high G2M. After the first cycle, all showed obvious changes in DNA profiles with a decrease of the G0/G1 peak and an increased S% and G2M with dispersed additional values along the scale in (G2M) x 2 and (G2M) x 4 regions. When changes were compared to tumor regression in the 1st and 2nd groups, 1/10 and 3/9 cases, respectively, were evaluated as objective regression. In the third group, all had objective regression (p less than 0.001). In most cases, a good correlation was observed with both methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Corpus callosotomy in the lithium-pilocarpine model of seizures and status epilepticus.

Section of the corpus callosum (SCC) is a useful surgical therapy in selected types of epilepsy, i.e., tonic, atonic, and intractable generalized convulsive seizures. Experimentally, the effects of SCC have been documented in animal models of focal seizures as well as generalized seizures. The object of this study was to determine the effect of SCC on behavioral and EEG symptomatology in the lithium-pilocarpine model of seizures and status epilepticus in the rat. SCC was well tolerated. Fifty-seven percent of SCC animals never developed status epilepticus, while all control animals developed status epilepticus. None of the SCC animals died after 24 h but 59% of control animals died within 24 h of status. Histology verified the extent of the SCC and demonstrated widespread brain damage in all animals who exhibited status epilepticus after 72 h. SCC was associated with a lesion of hippocampal commissure in 64% of animals in the SCC group. This protective effect was not related to lesion of the skull or the longitudinal sinus. The lesion of the hippocampal commissure may have contributed to the protective effect of SCC, since animals with an isolated lesion of the hippocampal commissure without SCC survived the status and showed an increased latency to seizure and status epilepticus. These data suggest that the lithium-pilocarpine model of status epilepticus may be useful in the study of the mechanism of efficacy of SCC in the treatment of epilepsy.

Animals↗
PubMed1986

Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions.

Immunohistochemical staining of 16 brains post mortem from patients with progressive multiple sclerosis and of two biopsy specimens from patients with acute demyelinating disease was performed using a panel of monoclonal antibodies reactive with T cells and T-cell subsets, B cells, and Ia (HLA-DR) antigens. Lymphocytic perivascular cuffs were most prominent at the edge of active plaques and were occasionally seen in areas with no evidence of demyelination or macrophage infiltration. Perivascular cuffs consisted predominantly of T cells and Ia+ cells, with many T8+ cells and variable numbers of T4+ cells. T8/T4 ratios in cuffs varied between 1:1 and 50:1. In normal-appearing white matter, cuffs were sparse and were predominantly T8+. The distribution of T cells in the parenchyma resembled that seen in perivascular cuffs, namely, predominantly T8+ cells and variable numbers of T4+ cells. Many Ia+ cells were present in active lesions, and the majority of these cells appeared, by histological criteria, to be macrophages. Tissue macrophages were also stained lightly by the anti-T4 antibody. No brain had more T4+ than T8+ cells, determined using both T4 and Leu3a monoclonal antibodies. B1+ cells were rare. These results suggest that the cellular infiltrate in multiple sclerosis consists predominantly of T cells and macrophages and that there is an overrepresentation of T8+ cells compared with T4+ cells.

Antibodies, Monoclonal↗