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See detailA hybrid human-computer approach for large-scale image-based measurements using web services and machine learning
Marée, Raphaël ULg; Rollus, Loïc ULg; Stevens, Benjamin ULg et al

in Proceedings IEEE International Symposium on Biomedical Imaging (2014, May)

We present a novel methodology combining web-based software development practices, machine learning, and spatial databases for computer-aided quantification of regions of interest (ROIs) in large-scale ... [more ▼]

We present a novel methodology combining web-based software development practices, machine learning, and spatial databases for computer-aided quantification of regions of interest (ROIs) in large-scale imaging data. We describe our main methodological choices, and then illustrate the benefits of the approach (workload reduction, improved precision, scalability, and traceability) on hundreds of whole-slide images of biological tissue slices in cancer research. [less ▲]

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See detailMethod for increasing the bioavailability of inhaled compounds
Vanbever, Rita; Koussoroplis, Salomé; Cataldo, Didier ULg et al

Patent (2014)

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See detailPEGylation of antibody fragments greatly increases their local residence time following delivery to the respiratory tract.
Koussoroplis, Salome Juliette; Paulissen, Geneviève ULg; Tyteca, Donatienne et al

in Journal of Controlled Release (2014), sous presse

Inhalation aerosols offer a targeted therapy for respiratory diseases. However, the therapeutic efficacy of inhaled biopharmaceuticals is limited by the rapid clearance of macromolecules in the lungs. The ... [more ▼]

Inhalation aerosols offer a targeted therapy for respiratory diseases. However, the therapeutic efficacy of inhaled biopharmaceuticals is limited by the rapid clearance of macromolecules in the lungs. The aim of this research was to study the effects of the PEGylation of antibody fragments on their local residence time after administration to the respiratory tract. We demonstrate that the conjugation of a two-armed 40-kDa polyethylene glycol (PEG) chain to anti-interleukin-17A (IL-17A) F(ab')2 and anti-IL-13 Fab' greatly prolonged the presence of these fragments within the lungs of mice. The content of PEGylated antibody fragments within the lungs plateaued up to 4hours post-delivery, whereas clearance of unconjugated proteins started immediately after administration. Forty-eight hours post-delivery, F(ab')2 and Fab' content in the lungs had decreased to 10 and 14 % of the dose initially deposited, respectively. However, this value was 40 % for both PEG40-F(ab')2 and PEG40-Fab'. The prolonged pulmonary residency of the anti-IL-17A PEG40-F(ab')2 translated into an improved efficacy in reducing lung inflammation in a murine model of house dust mite-induced lung inflammation. We demonstrate that PEGylated proteins were principally retained within the lung lumen rather than the nasal cavities or lung parenchyma. In addition, we report that PEG increased pulmonary retention of antibody fragments through mucoadhesion and escape from alveolar macrophages rather than increased hydrodynamic size or improved enzymatic stability. The PEGylation of proteins might find broad application in the local delivery of therapeutic proteins to diseased airways. [less ▲]

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See detailA rich internet application for remote visualization and collaborative annotation of digital slide images in histology and cytology
Marée, Raphaël ULg; Stevens, Benjamin ULg; Rollus, Loïc ULg et al

in Diagnostic Pathology (2013), 8(S1), 26

This work proposes a new web-based tool to ease collaborative projects in digital histology and cytology.

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See detailResident lung CD11b+Ly6C- dendritic cells are responsible for allergic airway sensitization to house dust mite in mice
Mesnil, Claire ULg; Sabatel, Catherine ULg; Marichal, Thomas ULg et al

in Proceeding of International Congress of Immunology 2013 (2013)

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See detailOxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis.
Pichavant, M.; Remy, G.; Bekaert, Sandrine ULg et al

in Mucosal Immunology (2013)

Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have ... [more ▼]

Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation. In the current study, we investigate the role of iNKT cells in COPD pathogenesis. The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls. In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis. The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17. CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferongamma and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein. In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD. Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level.Mucosal Immunology advance online publication, 30 October 2013; doi:10.1038/mi.2013.75. [less ▲]

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See detailMyeloid Hif1alpha counteracts allergic airway sensitization in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Abstract book of Keystone Symposium "Myeloid Cells: Regulation and Inflammation" (2013)

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. In contrast, we observed that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to the experimental allergen ovalbumin as well as to house dust mite antigens. Following allergen exposure, these mice indeed developed enhanced allergen-specific T cell responses due to augmented activation of lung dendritic cells. Further analyses supported the idea that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine Interleukin (IL)-10 by lung interstitial macrophages. Interstitial macrophage-derived IL-10 in turn counteracts allergen-induced lung dendritic cell activation, consequently preventing the development of allergen-specific T cell responses. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailAspects biologiques de l'angiogenèse dans le myélome multiple
Otjacques, Eléonore ULg; Binsfeld, Marilène ULg; Beguin, Yves ULg et al

in Oncohématologie (2013), 7(2), 6-12

Le myélome multiple (MM) est une maladie hématologique caractérisée par la prolifération excessive de plasmocytes cancéreux au sein de la moelle osseuse. Une des caractéristiques principales de cette ... [more ▼]

Le myélome multiple (MM) est une maladie hématologique caractérisée par la prolifération excessive de plasmocytes cancéreux au sein de la moelle osseuse. Une des caractéristiques principales de cette maladie est l’interaction entre les cellules myélomateuses et les cellules voisines situées dans la moelle. De par l’activation des cellules endothéliales, l’angiogenèse joue un rôle essentiel dans le développement du MM. Dans cet article, les processus permettant la progression du phénomène d’angiogenèse dans le MM seront abordés. Entre autres, nous identifierons les cellules interagissant avec les plasmocytes cancéreux, les cytokines influençant l’angiogenèse ou encore les protéases responsables de la dégradation de la matrice extracellulaire impliquées dans la pathologie. Finalement, l’influence du phénomène d’hypoxie (via l’expression de la protéine hypoxia-inducible factor-1) et le rôle de l’activation constitutive du Nuclear Factor-kB dans la néovascularisation seront mis en avant. [less ▲]

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See detailMyeloid hypoxia-inducible factor 1alpha prevents airway allergy in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Mucosal Immunology (2013), 6(3), 485-97

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1alpha-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailSunitinib inhibits inflammatory corneal lymphangiogenesis.
Detry, Benoît ULg; Blacher, Silvia ULg; Erpicum, Charlotte ULg et al

in Investigative Ophthalmology & Visual Science (2013), 54(5), 3082-93

PURPOSE: To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV). METHODS: Inflammatory corneal NV was induced by thermal ... [more ▼]

PURPOSE: To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV). METHODS: Inflammatory corneal NV was induced by thermal cauterization applied in the central cornea of mice, to which sunitinib malate was daily administered by gavage or not. At days 6, 11, or 17 post cauterization, lymphatic and blood vessels, as well as inflammatory cells were immunostained and quantified in whole-mounted corneas. RT-PCRs were performed to evidence VEGF-A, VEGF-C, VEGF-D, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor (VEGFR)-1 and -2 (sVEGFR-1, sVEGFR-2) expressions. Macrophages were isolated from mice peritoneal cavity following thioglycollate injection to produce conditioned medium. The effects of sunitinib were evaluated in vitro in the aortic and lymphatic ring assays in the presence or not of macrophage conditioned medium. RESULTS: Sunitinib treatment drastically reduced pathologic corneal lymphangiogenesis and angiogenesis. Reduced F4/80+ cell infiltration was evidenced in sunitinib-treated mice and was associated to decreased VEGF-A (by 50%, P < 0.01) and VEGF-C (by 35%, P < 0.01) expressions, while VEGF-D and sVEGFR-2 expressions were not affected. In vitro, sunitinib dose-dependently inhibited aortic ring outgrowth, but failed to affect lymphangiogenesis in the lymphatic ring assay. However, macrophage conditioned medium-enhanced angiogenesis and lymphangiogenesis were both strongly counteracted by sunitinib treatment. Mechanistically, sunitinib blocked VEGFR-2 phosphorylation induced by VEGF-A released by macrophages. CONCLUSIONS: Sunitinib exerts antihemangiogenic and antilymphangiogenic effects in vivo by reducing F4/80+ cell recruitment and interacting with their released factors. [less ▲]

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See detailMithramycin Exerts an Anti-Myeloma Effect and Displays Anti-Angiogenic Effects through Up-Regulation of Anti-Angiogenic Factors.
Otjacques, Eléonore ULg; Binsfeld, Marilène ULg; Rocks, Natacha ULg et al

in PLoS ONE (2013), 8(5), 62818

Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we ... [more ▼]

Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation. [less ▲]

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See detailMatrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.
Detry, Benoît ULg; Erpicum, Charlotte ULg; Paupert, Jenny ULg et al

in Blood (2012), 119(21), 5048-56

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to ... [more ▼]

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density and cross-linking). Transmission electron microscopy (TEM) and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LEC associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LEC negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis. [less ▲]

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See detail(18F)FPRGD2 PET/CT imaging of integrin αvβ3 in renal carcinomas : correlation with histopathology.
WITHOFS, Nadia ULg; SIGNOLLE, N.; NZARAMBA, EM. et al

in Journal of Nuclear Medicine (The) (2012), 53(SUPPL), 1647

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See detailResident CD11b(+)Ly6C(-) Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice.
Mesnil, Claire ULg; Sabatel, Catherine ULg; Marichal, Thomas ULg et al

in PLoS ONE (2012), 7(12), 53242

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway ... [more ▼]

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naive recipients. Transfer of lung CD11c(+)CD11b(+) DCs, but not CD11c(+)CD11b(-)CD103(+) DCs, was sufficient to prime airway allergy. The CD11c(+)CD11b(+) DC subpopulation was composed of CD11c(+)CD11b(+)Ly6C(+) inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c(+)CD11b(+)Ly6C(-) DCs, which remain stable. Counterintuitively, only CD11c(+)CD11b(+)Ly6C(-) DCs, and not CD11c(+)CD11b(+)Ly6C(+) DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c(+)CD11b(+)Ly6C(-) DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice. [less ▲]

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