References of "Hubert, Pascale"
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See detailThérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie
Costa, Chrisostome ULg; Vandermeers, Fabian ULg; Reddy, NS Sathyanarayana ULg et al

Diverse speeche and writing (2011)

Thérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie. Chrisostome Costa 1, Fabian Vandermeers 2, Sathyanarayana Reddy 2, Céline Mascaux 3, Pascale Hubert 2 ... [more ▼]

Thérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie. Chrisostome Costa 1, Fabian Vandermeers 2, Sathyanarayana Reddy 2, Céline Mascaux 3, Pascale Hubert 2, Philippe Delvenne 2, Luc Willems 1,2 1 Laboratoire de biologie cellulaire et moléculaire, ULg, Gemboux Agro Bio-Tech, 13 av. Maréchal Juin, 5030 Gembloux ; Tél. : 32-(0)-81-622157 ; Fax : 32-(0)-81-6138 88 ; Courriel: ccosta@doct.ulg.ac.be 2 GIGA, ULg, Liège 3 Institut Bordet, ULB, Bruxelles - Introduction : Le mésothéliome pleural malin (MPM) est un cancer de la plèvre causé principalement par l’inhalation de fibres d’amiante. Nous avons montré précédemment que les inhibiteurs d’histones deacetylases (tel que le valproate, VPA) augmentent significativement l’efficacité des composés utilisés en chimiothérapie (pemetrexed et cisplatin) et prolonge la survie des patients atteints de MPM. Malheureusement, une proportion importante des patients développe une résistance au traitement de seconde ligne avec la doxorubicine et le VPA. - But du projet : L’objectif du travail est de disséquer les mécanismes qui régissent la réponse au traitement de seconde ligne du MPM. - Méthodes et résultats : Nous avons tout d’abord comparé deux types de lignées cellulaires présentant soit une sensibilité (cellules M14K) soit une résistance (cellules H28) au traitement combiné VPA+doxorubicine. En utilisant des microdamiers (Agilent), nous avons analysé le profil d’expression génique de cellules M14K et H28 traitées avec le VPA et la doxorubicine. Après quantification des fluorescences, une analyse statistique (Genespring GX) et une modélisation bioinformatique (Ingenuity) ont permis d’identifier les gènes candidats les plus relevants. En fonction de la p-value et du fold change, un nombre limité de gènes ont été sélectionnés et validés par la technique de qRT-PCR. Parmi ceux-ci, nous avons identifié le gène TGFA dont l’expression corrèle avec la résistance au traitement. En effet, nous avons observé que le niveau d’expression basale du gène TGFA est beaucoup plus important dans la lignée résistante H28 que dans la lignée sensible M14K. Dans le but de valider son implication dans la réponse à la thérapie, nous avons diminué (par interférence ARN) ou augmenté (par transfection d’un vecteur d’expression) l’expression de TGFA respectivement dans les lignées H28 ou M14K. Nous avons ensuite déterminé les taux d’apoptose en évaluant la fragmentation de l’ADN en présence de doxorubicine et de VPA. Les résultats montrent que la diminution de l’expression de TGFA permet une augmentation sensible de l’apoptose induite par le traitement combiné doxorubicine et VPA dans la lignée résistante H28 (de 9% à 36%). A l’inverse, la surexpression de TGFA est associée avec une diminution d’apoptose dans la lignée sensible M14K (de 28% à 18%). Ces observations ont été confirmées par une analyse de l’activité des caspases 3 et 7. En accord avec la propriété de la protéine TGFAd’induire la prolifération cellulaire via le récepteur à l’EGF, des inhibiteurs de l’activité tyrosine kinase (l’Iressa et le Tarceva) augmentent l’apoptose induite par la doxorubicine et le VPA dans la lignée résistante H28 (de 16% à 40%). L’efficacité du traitement combiné VPA+doxorubicine+Iressa/Tarceva est actuellement évaluée en modèle murin (souris SCID). - Conclusions : Nous avons identifié un gène, le TGFA, dont l’expression corrèle avec la résistance à l’apoptose induite par la doxorubicine et le VPA. L’utilisation d’inhibiteurs du récepteur EGF pourrait donc améliorer le traitement de seconde ligne du MPM. [less ▲]

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See detailLiposome surface charge influence on skin penetration behaviour
Gillet, Aline ULg; Compère, Philippe ULg; Lecomte, Frédéric ULg et al

in International Journal of Pharmaceutics (2011), 411(1-2), 223-231

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See detailFrom the Clinics to the Bench and back to the Clinics: design of a medical treatment for Cervical Intraepithelial Neoplasia (CIN)
Jost, Maud; Frankenne, Francis; Maillard, Catherine ULg et al

Conference (2011, May 20)

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See detailMucosal junctions: open doors to HPV and HIV infections?
Herfs, Michael ULg; Hubert, Pascale ULg; Moutschen, Michel ULg et al

in Trends in microbiology (2011), 19(3), 114-120

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at ... [more ▼]

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies. [less ▲]

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See detailSkin penetration behaviour of liposomes as a function of their composition
Gillet, Aline ULg; Lecomte, Frédéric ULg; Hubert, Pascale ULg et al

in European Journal of Pharmaceutics & Biopharmaceutics (2011), 79

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See detailInterest of vesicular systems in dermal drug delivery
Gillet, Aline ULg; Lecomte, Frédéric ULg; Hubert, Pascale ULg et al

Poster (2010, October)

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See detailImplication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia
Demoulin, Stéphanie ULg; Herfs, Michael ULg; Somja, Joan ULg et al

Poster (2010, September)

The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process. Interestingly, a ... [more ▼]

The cervical transformation zone is a dynamic area of a few millimeters in which a glandular epithelium has been replaced by a squamous epithelium through a metaplastic process. Interestingly, a substantial majority (87%) of cervical (pre)cancerous lesions develops within this peculiar microenvironment. Our previous studies reported that intrinsic immune features altered in the metaplastic epithelium could contribute to cancer development by preventing efficient antitumor/antiviral immune response. Plasmacytoid dendritic cells (pDC) are key effectors in host innate immunity and orchestrate adaptive immune responses. Recently, infiltration by these subtypes of dendritic cells has been shown in different cancers. However their implication in antitumor response is largely debated. The present study was performed to determine the implication of pDC in the cervical “metaplasia-dysplasia-cancer” sequence. We demonstrated that the density of pDC increases in the epithelium of metaplastic and (pre)cancerous cervical tissues as well as in underlying stroma as compared with normal exocervical epithelium. This could be partially explained by the increased expression of chemerin, their chemotactic peptide, observed in those areas. We developed a method to efficiently generate pDC cells exhibiting morphological and immunohistochemical features of blood pDC from a limited number of CD34+ cord blood progenitors. Using these in vitro generated pDC, we demonstrated that medium conditioned by transformed keratinocytes modified the activation status of pDC, by inducing a decreased expression of costimulatory molecules such as CD86 and HLA-DR. Moreover, malignant keratinocytes diminished the ability of pDC to produce IFNα in response to an oligonucleotide containing CpG motifs, a defined microbial stimulus for pDC. These results suggest that pDC could be educated within the metaplastic and/or (pre)cancerous microenvironment to acquire a tolerogenic phenotype that could promote carcinogenesis. In agreement with those results, we observed that both metaplastic areas and (pre)cancerous lesions of the cervix are infiltrated by T regulatory cells. [less ▲]

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See detailImmune suppression in head and neck cancers: a review.
Duray, Annaëlle; Demoulin, Stéphanie ULg; Hubert, Pascale ULg et al

in Clinical & Developmental Immunology (2010), 2010

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer in the world. Despite significant advances in the treatment modalities involving surgery, radiotherapy, and concomitant ... [more ▼]

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer in the world. Despite significant advances in the treatment modalities involving surgery, radiotherapy, and concomitant chemoradiotherapy, the 5-year survival rate remained below 50% for the past 30 years. The worse prognosis of these cancers must certainly be link to the fact that HNSCCs strongly influence the host immune system. We present a critical review of our understanding of the HNSCC escape to the antitumor immune response such as a downregulation of HLA class I and/or components of APM. Antitumor responses of HNSCC patients are compromised in the presence of functional defects or apoptosis of T-cells, both circulating and tumor-infiltrating. Langerhans cells are increased in the first steps of the carcinogenesis but decreased in invasive carcinomas. The accumulation of macrophages in the peritumoral areas seems to play a protumoral role by secreting VEGF and stimulating the neoangiogenesis. [less ▲]

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See detailRegulation of p63 Isoforms by Snail and Slug Transcription Factors in Human Squamous Cell Carcinoma.
Herfs, Michael ULg; Hubert, Pascale ULg; Suarez-Carmona, Meggy ULg et al

in American Journal of Pathology (2010), 176(4), 1941-1949

TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the ... [more ▼]

TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of DeltaN and TAp63 isoforms were, respectively, down- and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of DeltaNp63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that DeltaNp63 silencing reduced cell-cell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness. [less ▲]

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See detailLocal applications of GM-CSF induce the recruitment of immune cells in cervical low-grade squamous intraepithelial lesions.
Hubert, Pascale ULg; Doyen, Jean ULg; Capelle, Xavier ULg et al

in American Journal of Reproductive Immunology (2010), 64(2), 126-136

Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished ... [more ▼]

Abstract Problem Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished capacity to capture viral antigens and to induce a protective immune response. Method of study To test if a cervical application of GM-CSF could restore an immune response against HPV in women with cervical low-grade squamous intraepithelial lesions (LSIL). We performed two clinical trials with11 healthy women and 15 patients with LSIL. Results GM-CSF applications were well tolerated in all enrolled women and no difference in toxicity between the treated and placebo groups was observed during the follow up (until 30 months). Interestingly, in the GM-CSF treated group, a significant increased APC and cytotoxic T lymphocyte infiltration was observed in the cervical biopsies with no change in regulatory T cell numbers. All the HPV16+ patients exhibited an immune response against HPV16 after GM-CSF applications, as shown by NK and/or T cells producing IFN-γ whereas no cellular immune response was observed before the treatment. Moreover, the anti-VLP antibody titers also increased after the treatment. Conclusion These encouraging results obtained from a limited number of subjects justify further study on the therapeutic effect of APC in cervical (pre)neoplastic lesions. [less ▲]

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See detailThe L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context.
Herman, Ludivine ULg; Hubert, Pascale ULg; Herfs, Michael ULg et al

in European Journal of Immunology (2010), 40(11), 3075-84

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately ... [more ▼]

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-kappaB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells. [less ▲]

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