References of "Hubert, Pascale"
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See detailProinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers: Implications for chronic obstructive pulmonary disease therapy.
Herfs, Michael ULg; Hubert, Pascale ULg; POIRRIER, Anne-Lise ULg et al

in American Journal of Respiratory Cell and Molecular Biology (2012), 47(1), 67-79

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this ... [more ▼]

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia is still unclear. In the present study, we investigated the implication of cigarette smoke-mediated pro-inflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. By using immunohistological techniques, we showed a higher epithelial expression of TNFalpha, IL-1beta and IL-6 as well as an activation of NF-kappaB and AP-1/MAPK signalling pathways in the respiratory tract of smoking patients compared to the normal ciliated epithelium of non-smoking patients. In addition, we demonstrated that these signalling pathways strongly influence the proliferation and the differentiation state of in vitro generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks and demonstrated that anti-TNFalpha (etanercept), anti-IL-1beta (anakinra) and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and squamous metaplasia development. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, administration of pro-inflammatory cytokine antagonists may have clinical application in the management of COPD patients. [less ▲]

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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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