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G Leclercq

Publications and source records attributed to G Leclercq.

At least 19 recordsLinked to original sources
PubMed2006

T-, B- and NK-lymphoid, but not myeloid cells arise from human CD34(+)CD38(-)CD7(+) common lymphoid progenitors expressing lymphoid-specific genes.

Hematopoietic stem cells in the bone marrow (BM) give rise to all blood cells. According to the classic model of hematopoiesis, the differentiation paths leading to the myeloid and lymphoid lineages segregate early. A candidate 'common lymphoid progenitor' (CLP) has been isolated from CD34(+)CD38(-) human cord blood cells based on CD7 expression. Here, we confirm the B- and NK-differentiation potential of CD34(+)CD38(-)CD7(+) cells and show in addition that this population has strong capacity to differentiate into T cells. As CD34(+)CD38(-)CD7(+) cells are virtually devoid of myeloid differentiation potential, these cells represent true CLPs. To unravel the molecular mechanisms underlying lymphoid commitment, we performed genome-wide gene expression profiling on sorted CD34(+)CD38(-)CD7(+) and CD34(+)CD38(-)CD7(-) cells. Interestingly, lymphoid-affiliated genes were mainly upregulated in the CD7(+) population, while myeloid-specific genes were downregulated. This supports the hypothesis that lineage commitment is accompanied by the shutdown of inappropriate gene expression and the upregulation of lineage-specific genes. In addition, we identified several highly expressed genes that have not been described in hematopoiesis before.

ADP-ribosyl Cyclase 1↗
PubMed2005

[Emphysematous pyelonephritis with favourable outcome after conservative treatment].

Emphysematous pyelonephritis is a necrotizing renal infection characterized by bacterial gas production in the renal and perirenal area. It is a rare infection diagnosed in diabetic patients in most cases. Emphysematous pyelonephritis is responsible for a high mortality rate. We report the case of a woman, unknown diabetic, who presented with emphysematous pyelonephritis. Early diagnosis performed by CT-scan allowed effective and conservative surgical treatment and final positive outcome.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2005

Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells.

PURPOSE: Estrogen receptor alpha (ERalpha) plays a major role in breast cancer development. It acts as ligand-inducible transcription factor which determines growth, survival and differentiation of breast cancer cells. The aim of this study is to evaluate the potential interference between radiotherapy and estrogen receptor responsiveness. Materials and methods. The effect of ionizing radiation was assessed on the estrogen receptor alpha status, growth (proliferation and apoptosis) and sensitivity of MCF-7 breast cancer cells to estrogenic (17beta-estradiol (E2)), selective estrogen receptor modulator (SERM) and anti-estrogenic compounds. Results. We have observed a ligand-independent decrease in ERalpha expression after radiation, resulting from a specific reduction in mRNA level and protein synthesis. This ERalpha disappearance occurred 72 h post-irradiation at 8 Gy and decreased the transcriptional activity in ERalpha of these cells. On the other hand, E2 impedes the growth inhibitory effects (essentially on proliferation) of ionizing radiation in MCF-7 cells, which potentially decreases radiosensitivity of these cells. This effect was totally blocked by SERM and anti-estrogenic treatments. Moreover, this growth effect of concurrent anti-estrogenic drugs and ionizing radiation appeared to be strongly synergistic. CONCLUSIONS: This study may increase general comprehension of ERalpha modulation by radiotherapy and improve adjuvant therapeutic approaches based on co-administration of radiation and endocrine therapy.

Analysis of Variance↗
PubMed2004

Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.

Tamoxifen is the standard first-line endocrine therapy for breast cancer, but recent data indicate that it is likely to be replaced by the effective aromatase inhibitors (AIs), in both the metastatic and adjuvant settings. Aromatase inhibitors induce complete oestrogen deprivation that leads to clinically significant bone loss. Several ongoing or planned trials combine AIs with bisphosphonates, even more so that recent data reveal that clodronate may reduce the incidence of bone metastases and prolong survival in the adjuvant setting. Bisphosphonates can inhibit breast cancer cell growth in vitro, but they have never been studied in steroid-free medium (SFM), an in vitro environment that mimics the effects of AIs in vivo. Quite surprisingly, in SFM, clodronate stimulated MCF-7 cell growth in a time- and dose-dependent manner by up to two-fold (crystal violet staining assay), whereas it had no mitogenic activity in complete medium. The bisphosphonate similarly increased the proliferation of IBEP-2 cells, which also express a functional oestrogen receptor (ER), while it weakly inhibited the growth of the ER-negative MDA-MB-231 cells. Expectedly, 17beta-oestradiol stimulated the growth of MCF-7 and IBEP-2 cells cultured in SFM, and had no effect on MDA-MB-231 cells. Moreover, partial (4-OH-tamoxifen) and pure antioestrogens (fulvestrant, ICI 182,780), in combination with clodronate, completely suppressed the mitogenic effect of the bisphosphonate, suggesting that it was mediated by an activation of ER. In accordance with this view, clodronate induced ER downregulation, weakly increased progesterone receptor expression, and stimulated the transcription of an oestrogen-responsive reporter gene. In conclusion, we report a previously unknown stimulatory effect of clodronate on MCF-7 cells grown in SFM, in vitro conditions that are potentially relevant to the use of AIs for breast cancer. Moreover, our data suggest that ER is involved in these effects of clodronate on cancer cell growth.

Antimetabolites↗
PubMed2004

About GATA3, HNF3A, and XBP1, three genes co-expressed with the oestrogen receptor-alpha gene (ESR1) in breast cancer.

In breast tumours and breast cancer cell (BCC) lines, microarray analyses have revealed that a series of genes are expressed in close association with the oestrogen receptor-alpha (ER-alpha) gene, ESR1. Three of them, GATA3, HNF3A (also known as FOXA1), and XBP1 encode transcription factors. Here, we present these factors and we discuss their potential involvement in the ER-alpha-mediated actions in BCC. We notably show the relations that exist, or that might exist, between these factors and the oestrogen-inducible trefoil factor TFF1.

Base Sequence↗
PubMed2004

[Impact of the law of the 4 March 2002 relative to patients' rights on request for medical information received in a medical dispatching center and mobile intensive care unit (Samu 93)].

INTRODUCTION: Law of the 4 March 2002 allowed patient's access to his medical record. This law could increase the number of requests in medical dispatching centers and prehospital intensive care units. OBJECTIVE: The aim of this study was to evaluate the impact of this law on the number of requests for medical information received in our unit. METHODS: Since the promulgation of the law, from March to December 2002, medical requests were prospectively collected and classified in categories including request for transmission of medical record. Requests received before the law, from January 2000 to February 2002 were classified according to the same items. Number of requests received during the two periods were compared according to the total number of medical record managed in our medical dispatching center and prehospital intensive care unit. RESULTS: The total number of requests for medical information significantly increased since the law of March 2002 (results are expressed as cases per month per 10 000 record: 4.8 +/- 2.5 vs. 8.0 +/- 4.5; p = 0.04). Specific request for transmissions of medical record significantly increased since the law (1.3 +/- 1.6 vs. 3.0 +/- 3.0; P = 0.046). This increase was progressive and constant since March 2002. DISCUSSION: Physicians and patients should take in consideration consequences of this law. Physician should be vigilant with the quality of their medical dossiers. Interpretation of this law and its ethics consequences will probably be discussed again as one should not exclude perverse impact of this law. In effect, insurances and mutual insurances companies could find in this law a way to obtain medical information, such as circumstances of death, previously unavailable. CONCLUSION: The law of 4 March 2002 relative to patients' rights significantly increased number of requests for medical information received in our dispatching center and prehospital intensive care unit.

Access to Information↗
PubMed2004

Extracellular calcium downregulates estrogen receptor alpha and increases its transcriptional activity through calcium-sensing receptor in breast cancer cells.

Skeleton is the most common organ targeted by breast cancer cells, especially from estrogen receptor alpha (ER)-positive neoplasms. Metastatic cells can stimulate directly or indirectly osteoclast-mediated bone resorption. Tumor-induced osteolysis is often extensive and leads to the release of large quantities of calcium. Metastatic cancer cells can be thus exposed to high calcium concentrations (40 mM has been reported at the resorption site). However, the effects of Ca2+ on breast cancer cells have been minimally examined. We showed that 20-mM extracellular Ca2+ induced a downregulation of ER protein in MCF-7 cells and caused ER-mediated transactivation of a reporter gene by 55 +/- 10% (mean +/- SD) in MVLN cells (MCF-7 cells stably transfected with ERE and luciferase reporter gene). Moreover, 3 mM Ca2+ increased progesterone receptor (PgR) expression by 45 +/- 8%. Mg2+ tested at up to 20 mM did not exert any effects, while 17beta-estradiol downregulated ER, transactivated the reporter gene, and enhanced PgR expression. The pure antiestrogen ICI 182,780 was able to abrogate the transactivation of the reporter gene and the increase in PgR levels induced by Ca2+, indicating that Ca2+ may exert a weak and specific estrogenic effect in MCF-7 cells. Ca2+ effects on ER probably start at the cell membrane level since a large Ca2+ influx caused by the ionophore A23187 failed to activate ER. We have thus studied the involvement of the membrane calcium-sensing receptor (CaR) that is known to be expressed notably in MCF-7 cells. We first tested the effects of a specific activator of CaR. Exposure to 10(-4) M calcimimetic NPS R-467 mirrored the changes observed with extracellular Ca2+ by inducing a marked decrease in ER protein levels, increasing the transcriptional activity of ER (67 +/- 12%) and stimulating PgR expression (41 +/- 4%). As expected, the NPS S-467 isomer was less effective. Furthermore, a highly selective CaR antagonist partly suppressed the downregulation of ER as well as transactivation of the reporter gene induced by Ca(2+). Our results suggest that the effects of extracellular Ca2+ on ER expression and activity are mediated, at least in part, by the CaR. In summary, calcium released during the process of metastatic bone destruction could modulate the functions of the estrogen receptor, a key receptor involved in breast cancer cells growth and function, and thus participate in the pathogenesis of tumor-induced osteolysis.

Breast Neoplasms↗
PubMed2004

Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics.

It is widely believed that ductal breast cancer dissemination involves a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Such changes have frequently been attributed to the sequential acquisition of various alterations in a single cell followed by clonal selection and expansion, thus leading to intra-tumor diversity. According to this multi-step view, extensive genotype and phenotype (marker expression, grade) shift may occur in the same tumor during progression; this may lead to the co-existence of molecularly and/or pathologically different areas within the same lesion. An increasing amount of data of various natures now appear to challenge this concept: only a few distinct 'portraits', in relation to estrogen receptor (ER) status and grade, may be found among tumors. Moreover, although undergoing increasing genetic alteration, most individual lesions largely maintain their phenotype when they evolve from in situ to the metastatic state. While many of the data presented here are related to ductal tumors, lobular cancer is also discussed.

Breast Neoplasms↗
PubMed2004

The first organometallic selective estrogen receptor modulators (SERMs) and their relevance to breast cancer.

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.

Antineoplastic Agents, Hormonal↗
PubMed2004

Gene regulation by phorbol 12-myristate 13-acetate in MCF-7 and MDA-MB-231, two breast cancer cell lines exhibiting highly different phenotypes.

We have examined the effects of the protein kinase C (PKC)-activator phorbol 12-myristate 13-acetate (PMA) on gene expression in two breast cancer cell (BCC) lines exhibiting highly different phenotypes. These are the estrogen receptor alpha (ERalpha)-positive, weakly invasive, luminal epithelial-like MCF-7 and the ERalpha-negative, highly invasive, fibroblast-like MDA-MB-231. They express constitutively low and high PKC activities, respectively. After a 24-h exposition to 100 nM PMA, the number of genes showing an altered expression at the 2-fold change level was much higher in MCF-7 (n=435) than in MDA-MB-231 (n=18) BCC. Four of these genes, namely CDC2, CENPA, NR4A1 and MMP10, were altered in the same way in both cell lines. Two genes were regulated in an opposite way: ID1 and EVA1. Many of the genes down-regulated in MCF-7 BCC appeared to be preferentially expressed in the G1, S, and/or G2 phases of the cell cycle. The ERalpha gene, ESR1, and other genes associated to the ERalpha-positive, luminal epithelial-like BCC phenotype were down-regulated, while a series of genes related to a more aggressive, fibroblast-like BCC phenotype were up-regulated. Other altered genes were notably linked to cell architecture, supporting profound effects of PMA on cell morphology and motility, as well as on the interactions between BCC and their neighboring proteins. Of note, all the modulated genes involved in proteolysis and its control were up-regulated. In summary, PMA effects suggest that PKC activation may induce, to some extent, a more fibroblast-like phenotype in the ERalpha-positive, luminal epithelial-like MCF-7 BCC, and significantly modulate the interactions of these cells with their environment.

Biomarkers, Tumor↗
PubMed2003

Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development.

Class I homeobox (HOX) genes comprise a large family of transcription factors that have been implicated in normal and malignant hematopoiesis. However, data on their expression or function during T-cell development is limited. Using degenerated RT-PCR and Affymetrix microarray analysis, we analyzed the expression pattern of this gene family in human multipotent stem cells from fetal liver (FL) and adult bone marrow (ABM), and in T-cell progenitors from child thymus. We show that FL and ABM stem cells are similar in terms of HOX gene expression, but significant differences were observed between these two cell types and child thymocytes. As the most immature thymocytes are derived from immigrated FL and ABM stem cells, this indicates a drastic change in HOX gene expression upon entry into the thymus. Further analysis of HOX-A7, HOX-A9, HOX-A10, and HOX-A11 expression with specific RT-PCR in all thymocyte differentiation stages showed a sequential loss of 3' region HOX-A cluster genes during intrathymic T-cell development and an unexpected expression of HOX-A11, previously not recognized to play a role in hematopoiesis. Also HOX-B3 and HOX-C4 were expressed throughout thymocyte development. Overall, these data provide novel evidence for an important role of certain HOX genes in human T-cell development.

Adult↗
PubMed2003

Recent advances in the development of phytoestrogens and derivatives: an update of the promising perspectives in the prevention of postmenopausal diseases.

Phytoestrogens constitute a promising alternative in the treatment of diseases associated with menopause. Nevertheless, the lack of data concerning their pharmacology and their toxicology requires use precautions. After reminding the pharmacology of estrogen receptors, this review outlines the estrogenicity and the therapeutic potentialities of phytoestrogens according to their structure.

Humans↗
PubMed2002

Tula hantavirus in Belgium.

European common voles (Microtus arvalis), captured in Belgium in 1999, were proven by molecular as well as by serological techniques to be infected with Tula hantavirus (TULV). This is the first evidence for the presence of TULV in this country. No indication of spill-over infections of Puumala virus, known to be highly endemic among bank voles (Clethrionomys glareolus) within the same geographical regions as the trapped TULV-infected common voles, was observed. Together with previous reports on the circulation of TULV in eastern/central Europe, this finding suggests a more wide-spread circulation of this hantavirus serotype throughout the continent.

Animals↗
PubMed2002

Induction of IL-15 by TCR/CD3 aggregation depends on IFN-gamma and protects against apoptosis of immature thymocytes in vivo.

TCR/CD3 aggregation by injection of anti-CD3 Ab produces T cell activation, release of cytokines such as IFN-gamma, and apoptosis in the cortical region of the thymus. We show that anti-CD3 Ab induces IL-15 mRNA in spleens of wild-type but not IFN-gamma receptor-knock-out (IFN-gammaR KO) mice. The loss of IL-15 mRNA induction in IFN-gammaR KO mice was associated with increased thymocyte apoptosis. Pretreatment of wild-type mice with neutralizing anti-IL-15 Ab increased the anti-CD3-triggered thymocyte apoptosis, thus mimicking the sensitive phenotype of IFN-gammaR KO mice. Inversely, anti-CD3-induced apoptosis in IFN-gammaR KO mice was suppressed by administration of recombinant IL-15. In IFN-gammaR KO mice and in wild-type mice that were treated with anti-IL-15, augmented apoptosis affected mainly CD4+CD8+ immature thymocytes. IL-15 as well as IL-15Ralpha mRNA expression in thymocytes was not increased by anti-CD3. These data demonstrate that systemic IL-15 exerts anti-apoptotic activity on immature T cells and establish a regulatory mechanism whereby TCR/CD3 engagement induces IL-15 expression via an IFN-gamma-dependent pathway. The self-amplifying nature of this IFN-gamma/IL-15 connection may constitute a regulatory pathway in central tolerance to self.

Animals↗
PubMed2002

Synthesis and cytotoxic activity of new 2,4-diaryl-4H,5H-pyrano[3,2-c]benzopyran-5-ones on MCF-7 cells.

A series of eight halogenated 2,4-diaryl-4H,5H-pyrano[3,2-c]benzopyran-5-ones have been synthesized, characterized and their stereochemistry determined. In a second stage of our work, the reported molecules were tested for their antiproliferative activity on MCF-7 breast carcinoma cells. Pharmacological results were compared with those of diethylstilbestrol (DES), an estrogen, as well as ICI 182,780, a pure antiestrogen. Then, these derivatives were evaluated for their capacity to activate the transcription of a reporter gene and for their affinity for human recombinant estrogen receptors alpha (hER alpha). These results were compared with those of coumestrol, a phytoestrogen structurally close to 2,4-diaryl-4H,5H-pyrano[3,2-c]benzopyran-5-ones, and with RU 58668, a pure antiestrogen. Although these derivatives exhibit a significant antiproliferative activity higher than that of ICI 182,780, neither of them displayed a significant estrogenicity or an affinity for hER alpha. Such results may suggest that their antiproliferative activity is not dependent of an antiestrogenic response.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Enforced expression of GATA-3 severely reduces human thymic cellularity.

Following bone marrow transplantation, patients often suffer from immune incompetence by reduced or late T cell development. Moreover, adult bone marrow stem cells have a lower capacity to generate T cells compared with fetal liver- and umbilical cord blood-derived progenitors. Therefore, enhancing thymic-dependent T cell generation might hold great therapeutic potential. GATA-3 is a transcription factor that is essential in T cell development. In this study we examined the therapeutic potential of GATA-3 to enhance T cell generation by overexpressing GATA-3 in T cell progenitors followed by fetal thymic organ culture (FTOC). We observed that early during FTOC, there was an enhanced differentiation toward the double positive stage of T cell development. From day 10 of FTOC, however, overexpression of GATA-3 induced a severe reduction in thymic cellularity, which probably correlates with the absence of a functional TCR-beta chain. We further show that the frequency of apoptosis was increased in GATA-3-transduced thymocytes. Despite the absence of a functional TCR-beta chain, GATA-3 transduced progenitors were able to differentiate into CD8beta(+) double positive thymocytes. This study shows that a strictly regulated expression of GATA-3 is essential for normal T cell development and this puts severe restrictions on the potential therapeutic use of continuously overexpressed GATA-3.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2001

Expression of Ly49E and CD94/NKG2 on fetal and adult NK cells.

Murine NK cells express inhibitory receptors belonging to the Ly49 and CD94/NKG2 family. Ly49E and CD94 are the only NK cell receptor transcripts detectable in fetal NK cells. Still unproved is the surface expression of Ly49E on NK cells. Here we generated two novel mAbs, a mAb recognizing Ly49E with cross-reactivity to Ly49C, and a mAb against NKG2A/C/E. Ly49E was immunoprecipitated as a disulfide-linked homodimer with 46-kDa subunits. Removal of N-linked carbohydrates revealed a 31-kDa protein backbone. NKG2A was immunoprecipitated as a 38-kDa protein. Although the frequency of fetal NK cells expressing Ly49E was higher than 25%, it decreased drastically from 2 wk after birth. Phenotypic analysis showed that approximately 90% of fetal NK cells and approximately 50% of adult NK cells express high levels of CD94/NKG2. The remaining 50% of adult NK cells expressed low surface levels of CD94/NKG2. Expression of Ly49E and CD94/NKG2 was not restricted to NK cells, but was also observed on NK T and memory T cells. Functional analysis showed that sorted Ly49E(+) and CD94/NKG2(+) fetal NK cells could discriminate between MHC class I-positive and MHC class I-negative tumor cells. We also demonstrated that Ly49E becomes phosphorylated following pervanadate stimulation of fetal NK cells. The expression levels of Ly49E and CD94/NKG2 were similar in wild-type compared with beta(2)-microglobulin(-/-) mice. In conclusion, generation of mAbs against Ly49E and NKG2 extended the phenotypic and functional characterization of NK cells.

Aging↗