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See detailDUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Amand, Mathieu ULg; Erpicum, Charlotte ULg; BAJOU, Khalid ULg et al

Poster (2014, January 27)

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See detailX-ray microtomography: A new tool to follow soft material shrinkage during convective drying
Léonard, Angélique ULg; Blacher, Silvia ULg; Marchot, Pierre ULg et al

in 2nd World Congress on Industrial Process Tomography : Hannover, Germany 29-31 août 2001 (2014)

X-ray microtomography is proposed as a new tool to investigate the shrinkage of soft material which occurs during convective drying. Reliable shrinkage curves are obtained with samples of wastewater ... [more ▼]

X-ray microtomography is proposed as a new tool to investigate the shrinkage of soft material which occurs during convective drying. Reliable shrinkage curves are obtained with samples of wastewater treatment sludge. We develop a four zones model to describe the drying kinetics based of the experimental data provided by X-ray microtomography. The observation of the drying and shrinkage curves allows us to determine 3 critical water content values, which define different drying zones where extragranular, intragranular or mixed limitations prevail. When drying is externally controlled, the decrease of the drying rate observed during experiments can be related to the reduction of the external area of the sample. © 2014 International Society for Industrial Process Tomography. [less ▲]

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See detailDUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase
Amand, Mathieu ULg; Erpicum, Charlotte ULg; BAJOU, Khalid ULg et al

in Molecular Cancer (2014)

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies ... [more ▼]

Background DUSP3 phosphatase, also known as Vaccinia-H1 Related (VHR) phosphatase, encoded by DUSP3/Dusp3 gene, is a relatively small member of the dual-specificity protein phosphatases. In vitro studies showed that DUSP3 is a negative regulator of ERK and JNK pathways in several cell lines. On the other hand, DUSP3 is implicated in human cancer. It has been alternatively described as having tumor suppressive and oncogenic properties. Thus, the available data suggest that DUSP3 plays complex and contradictory roles in tumorigenesis that could be cell type-dependent. Since most of these studies were performed using recombinant proteins or in cell-transfection based assays, the physiological function of DUSP3 has remained elusive. Results Using immunohistochemistry on human cervical sections, we observed a strong expression of DUSP3 in endothelial cells (EC) suggesting a contribution for this phosphatase to EC functions. DUSP3 downregulation, using RNA interference, in human EC reduced significantly in vitro tube formation on Matrigel and spheroid angiogenic sprouting. However, this defect was not associated with an altered phosphorylation of the documented in vitro DUSP3 substrates, ERK1/2, JNK1/2 and EGFR but was associated with an increased PKC phosphorylation. To investigate the physiological function of DUSP3, we generated Dusp3-deficient mice by homologous recombination. The obtained DUSP3-/- mice were healthy, fertile, with no spontaneous phenotype and no vascular defect. However, DUSP3 deficiency prevented neo-vascularization of transplanted b-FGF containing Matrigel and LLC xenograft tumors as evidenced by hemoglobin (Hb) and FITC-dextran quantifications. Furthermore, we found that DUSP3 is required for b-FGF-induced microvessel outgrowth in the aortic ring assay. Conclusions All together, our data identify DUSP3 as a new important player in angiogenesis. [less ▲]

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See detailBone marrow-derived mesenchymal stem cells drive lymphangiogenesis.
Maertens, Ludovic ULg; Erpicum, Charlotte ULg; Detry, Benoît ULg et al

in PLoS ONE (2014), 9(9), 106976

It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during ... [more ▼]

It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during the lymphangiogenic process is poorly described. Using BM-MSC isolated from mice of two different backgrounds, we demonstrate a paracrine lymphangiogenic action of BM-MSC both in vivo and in vitro. Co-injection of BM-MSC and tumor cells in mice increased the in vivo tumor growth and intratumoral lymphatic vessel density. In addition, BM-MSC or their conditioned medium stimulated the recruitment of lymphatic vessels in vivo in an ear sponge assay, and ex vivo in the lymphatic ring assay (LRA). In vitro, MSC conditioned medium also increased the proliferation rate and the migration of both primary lymphatic endothelial cells (LEC) and an immortalized lymphatic endothelial cell line. Mechanistically, these pro-lymphangiogenic effects relied on the secretion of Vascular Endothelial Growth Factor (VEGF)-A by BM-MSC that activates VEGF Receptor (VEGFR)-2 pathway on LEC. Indeed, the trapping of VEGF-A in MSC conditioned medium by soluble VEGF Receptors (sVEGFR)-1, -2 or the inhibition of VEGFR-2 activity by a specific inhibitor (ZM 323881) both decreased LEC proliferation, migration and the phosphorylation of their main downstream target ERK1/2. This study provides direct unprecedented evidence for a paracrine lymphangiogenic action of BM-MSC via the production of VEGF-A which acts on LEC VEGFR-2. [less ▲]

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See detailImproved computer-assisted analysis of the global lymphatic network in human cervical tissues.
Balsat, Cédric ULg; Signolle, Nicolas; GOFFIN, Frédéric ULg et al

in Modern Pathology : An Official Journal of the United States & Canadian Academy of Pathology, Inc (2014), 27(6), 887-98

Lymphatic dissemination is a key event in cervical cancer progression and related tumor lymphatic markers are viewed as promising prognostic factor of nodal extension. However, validating such parameters ... [more ▼]

Lymphatic dissemination is a key event in cervical cancer progression and related tumor lymphatic markers are viewed as promising prognostic factor of nodal extension. However, validating such parameters requires an objective characterization of the lymphatic vasculature. Here, we performed a global analysis of the lymphatic network using a new computerized method applied on whole uterine cervical digital images. Sixty-eight cases of cervical neoplasia (12 CIN3, 10 FIGO stage 1A and 46 stage IB1) and 10 cases of normal cervical tissue were reacted with antibodies raised against D2-40, D2-40/p16 and D2-40/Ki67. Immunostained structures were automatically detected on whole slides. The lymphatic vessel density (D2-40), proliferating lymphatic vessel density (D2-40/ki67) and spatial lymphatic distribution in respect to the adjacent epithelium were assessed from normal cervix to early cervical cancer and correlated with lymphovascular space invasion and lymph node status. Prominent lymphatic vessel density and proliferating lymphatic vessel density are detected under the transformation zone of benign cervix and no further increase is noted during cancer progression. Notably, a shift of lymphatic vessel distribution toward the neoplastic edges is detected. In IB1 cervical cancer, although intra- and peritumoral lymphatic vessel density are neither correlated with lymphovascular space invasion nor with lymph node metastasis, a specific spatial distribution with more lymphatic vessels in the vicinity of tumor edges is predictive of lymphatic dissemination. Herein, we provide a new computerized method suitable for an innovative detailed analysis of the lymphatic network. We show that the transformation zone of the benign cervix acts as a baseline lymphangiogenic niche before the initiation of neoplastic process. During cancer progression, this specific microenvironment is maintained with lymphatic vessels even in closer vicinity to tumor cells.Modern Pathology advance online publication, 6 December 2013; doi:10.1038/modpathol.2013.195. [less ▲]

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See detailBlocking lipid synthesis overcomes tumor re-growth and metastasis after anti-angiogenic therapy withdrawal.
Sounni, Nor Eddine ULg; Cimino, Jonathan ULg; BLACHER, Silvia ULg et al

in Cell Metabolism (2014), 20(2), 280-94

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches ... [more ▼]

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. [less ▲]

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See detailCell invasion in the spheroid sprouting assay: a spatial organisation analysis adaptable to cell behaviour.
Blacher, Silvia ULg; Erpicum, Charlotte ULg; Lenoir, Benedicte et al

in PLoS ONE (2014), 9(5), 97019

The endothelial cell spheroid assay provides a suitable in vitro model to study (lymph) angiogenesis and test pro- and anti-(lymph) angiogenic factors or drugs. Usually, the extent of cell invasion ... [more ▼]

The endothelial cell spheroid assay provides a suitable in vitro model to study (lymph) angiogenesis and test pro- and anti-(lymph) angiogenic factors or drugs. Usually, the extent of cell invasion, observed through optical microscopy, is measured. The present study proposes the spatial distribution of migrated cells as a new descriptor of the (lymph) angiogenic response. The utility of this novel method rests with its capacity to locally characterise spheroid structure, allowing not only the investigation of single and collective cell invasion but also the evolution of the spheroid core itself. Moreover, the proposed method can be applied to 2D-projected spheroid images obtained by optical microscopy, as well as to 3D images acquired by confocal microscopy. To validate the proposed methodology, endothelial cell invasion was evaluated under different experimental conditions. The results were compared with widely used global parameters. The comparison shows that our method prevents local spheroid modifications from being overlooked and leading to the possible misinterpretation of results. [less ▲]

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See detailChanges in elastin density in different locations of the vaginal wall in women with pelvic organ prolapse.
DE LANDSHEERE, Laurent ULg; Blacher, Silvia ULg; Munaut, Carine ULg et al

in International Urogynecology Journal & Pelvic Floor Dysfunction (2014)

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to analyze the histomorphometric properties of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: In 15 women undergoing ... [more ▼]

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to analyze the histomorphometric properties of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: In 15 women undergoing surgery for POP, full-thickness biopsies were collected at two different sites of location from the anterior and/or posterior vaginal wall. Properties of the precervical area (POP-Q point C/D) were compared with the most distal portion of the vaginal wall (POP-Q point Ba/Bp) using histological staining and immunohistochemistry. The densities of total collagen fibers, elastic fibers, smooth muscle cells, and blood vessels were determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. RESULTS: The mean elastin density was significantly decreased in the lamina propria and muscularis layer of the vaginal wall from the most distal portion of the prolapsed vaginal wall compared with the precervical area. This difference was statistically significant in the lamina propria for both anterior (8.4 +/- 1.2 and 12.1 +/- 2.0, p = 0.048) and posterior (6.8 +/- 0.5 and 10.1 +/- 1.4, p = 0.040) locations, and in the muscularis for the anterior (5.2 +/- 0.4 and 8.4 +/- 1.2, p = 0.009) vaginal wall. There were no statistically significant differences in the mean densities of collagen fibers, smooth muscle cells or blood vessels between the two locations. CONCLUSIONS: In this study, we observed changes in elastin density in two different locations of the vaginal wall from women with POP. The histomorphometric properties of the vaginal wall can be variable from one place to another in the same patient. This result supports the existence of most vulnerable locations within the vaginal wall and the potential benefit of site-specific prolapse surgery. [less ▲]

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See detailEffects of adenosine on lymphangiogenesis.
Lenoir, Bénédicte ULg; Wagner, Daniel R.; Blacher, Silvia ULg et al

in PloS one (2014), 9(3), 92715

BACKGROUND: The lymphatic system controls tissue homeostasis by draining protein-rich lymph to the vascular system. Lymphangiogenesis, the formation of lymphatic vessels, is a normal event in childhood ... [more ▼]

BACKGROUND: The lymphatic system controls tissue homeostasis by draining protein-rich lymph to the vascular system. Lymphangiogenesis, the formation of lymphatic vessels, is a normal event in childhood but promotes tumor spread and metastasis during adulthood. Blocking lymphangiogenesis may therefore be of therapeutic interest. Production of adenosine is enhanced in the tumor environment and contributes to tumor progression through stimulation of angiogenesis. In this study, we determined whether adenosine affects lymphangiogenesis. METHODS: Lymphatic endothelial cells (HMVEC-dLy) were cultured in presence of adenosine and their proliferation, migration and tube formation was assessed. Gelatin sponges embedded with the stable analogue of adenosine 2-chloro adenosine were implanted in mice ear and lymphangiogenesis was quantified. Mice were intravenously injected with adenoviruses containing expression vector for 5'-endonucleotidase, which plays a major role in the formation of adenosine. RESULTS: In vitro, we observed that adenosine decreased the proliferation of lymphatic endothelial cells, their migration and tube formation. However, in vivo, gelatin sponges containing 2-chloro adenosine and implanted in mice ear displayed an elevated level of lymphangiogenesis (2.5-fold, p<0.001). Adenovirus-mediated over-expression of cytosolic 5'-nucleotidase IA stimulated lymphangiogenesis and the recruitment of macrophages in mouse liver. Proliferation of lymphatic endothelial cells was enhanced (2-fold, p<0.001) when incubated in the presence of conditioned medium from murine macrophages. CONCLUSION: We have shown that adenosine stimulates lymphangiogenesis in vivo, presumably through a macrophage-mediated mechanism. This observation suggests that blockade of adenosine receptors may help in anti-cancer therapies. [less ▲]

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See detailMechanism of resistance to anti-angiogenic therapy.
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Debois, Delphine ULg et al

Poster (2013, May 17)

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See detailNew mechanism of resistance to anti-angiogenic therapy.
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Debois, Delphine ULg et al

Conference (2013, May 13)

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