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See detailTreatment algorithm and prognostic factors for patients with stage I–III carcinoma of the anal canal: a 20-year multicenter study
Bruyère, Diane ULiege; Monnien, Franck; Colpart, Prudence et al

in Modern Pathology (in press)

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See detailTGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma
Staumont, Bernard ULiege; Jamakhani, Majeed ULiege; Costa, Chrisostome et al

in Cancers (2020), 12(6), 1484

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline ... [more ▼]

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy. [less ▲]

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See detailIncreased Endoplasmic Reticulum stress specific chaperones characterise CD fibrosis epithelium tissues and participates to in vitro induction of intestinal fibroblasts differentiation
Vieujean, Sophie ULiege; Hu, Shurong; Bequet, Emeline ULiege et al

Poster (2020, March 05)

Background: Intestinal fibrosis is a complication of Crohn’s disease (CD) characterized by myofibroblasts and extracellular matrix accumulation within the submucosa and smooth muscles, leading to bowel ... [more ▼]

Background: Intestinal fibrosis is a complication of Crohn’s disease (CD) characterized by myofibroblasts and extracellular matrix accumulation within the submucosa and smooth muscles, leading to bowel strictures. No medical treatment exists to treat or reverse intestinal fibrosis leading often to surgical resection. The potential role of intestinal epithelium in the fibrotic process remains poorly defined. Methods: We performed a pilot study on ileal fibrostricturing CD surgical samples (n=5), comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones. Confirmation of the specific protein increases was obtained by immunohistochemistry in colonic and ileal samples of CD (n=44) compared to healthy subjects (n=40), as well as in intestinal epithelial cell line under induced Endoplasmic Reticulum (ER) stress. A model of fibroblast to myofibroblast differentiation induction was also challenged using preconditioned media of intestinal epithelial cells after a pulsed ER stress. Results: Label free proteomics revealed high ER stress in the epithelium surrounding fibrotic bowel wall, involving Anterior gradient protein 2 homolog (AGR2) and 78kDA glucose regulated protein (BiP). Confirmation of both proteins increase was obtained by immunohistochemistry. ER stress induction in intestinal epithelial cells was associated with an intracellular increase of AGR2, BiP and ER stress markers as sXPB1 and CHOP. AGR2 was also detected in the culture medium of these epithelial cells and myofibroblast differentiation was obtained using this culture medium. Conclusions: The increase of ER stress proteins observed in fibrostenosing tissues together with These preliminary evidences of fibroblast to myofibrobast differentiation obtained by paracrine action of intestinal epithelial cell preconditioned to ER stress induction, suggest a role of epithelial ER stress in Crohn’s disease intestinal fibrosis. [less ▲]

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See detailSLC12A2 as a potential histological marker of ulcerative colitis associated colorectal dysplasia
Merli, Angela-Maria ULiege; Vieujean, Sophie ULiege; Massot, Charlotte et al

Conference (2020, March 04)

Introduction: Patients suffering from ulcerative colitis (UC) are at increased risk of developing dysplasia (DAI) and colorectal cancer (CAC). Differentiating DAI from inflammation remains difficult for ... [more ▼]

Introduction: Patients suffering from ulcerative colitis (UC) are at increased risk of developing dysplasia (DAI) and colorectal cancer (CAC). Differentiating DAI from inflammation remains difficult for both endoscopists and anatomopathologists due to macro and microscopic features shared by these lesions. Aim: The aim of our work was to confirm, by histological evaluation, a potential proteomic biomarker discriminating early DAI lesions from chronic inflamed and normal tissues in UC. Methods: We included 15 paired tissues from UC patients (n=5) presenting low-grade DAI. Epithelial cells were isolated by laser capture microdissection and analyzed by label-free proteomics. We selected one protein differentially distributed between DAI, inflamed (I) and normal (N) tissues for confirmation by immunochemistry (IHC). IHC characterization was performed using both the staining intensity score (0 to 4) and the staining pattern: “gradient” (staining intensity increasing from the epithelium lumen to the bottom of the crypts) or “no gradient” (homogenous staining). UC patients with DAI (n=28), dysplastic lesion in non-inflammatory colon (DSp) (n=9), CAC (n=14) and at high risk of CAC (>10 years of UC duration) but free of dysplasia or cancer (n=23) were included. We further studied this potential marker tissue distribution in the mouse model of CAC (AOM/DSS treated mice) to trace its presentation at different evolution stages and assessed low (n=51), high-grade DAI (n=35) and CAC (n=38), as well as relevant paired control tissues. This potential tissue marker was finally evaluated in sporadic precancerous colorectal lesions of UC-free patients with low (n=19) and highgrade (n=16) adenomas and cancerous lesions (CRC): pT1 to pT4 (n=82) and compared to paired normal tissues when available. Results: Proteomics identified 1070 proteins among which 19 showed a differential distribution between DAI and I or N. The sodium chloride co-transporter SLC12A2 was only identified in DAI. SLC12A2 IHC “no gradient” staining pattern was associated to DAI and DSp compared to I or N (with p <0.0001 and 0.0002 respectively). The IHC score was also higher for DAI, DSp and CAC compared to paired I and N (p<0.0001 and 0.0084 respectively). These results were confirmed from low-grade dysplasia to more advanced lesions in the AOM/DSS mice model. The “no gradient” pattern was also significantly associated to low and high-grade adenomas, and CRC of UC-free patients compared to normal control tissues. The sensitivity and specificity of SLC12A2 histological pattern reached 89% and 95% for DAI versusI; 90% and 93% for CAC and/or DAI versus I. In addition, the sensitivity and specificity reached 99% and 87% for all precancerous and cancerous lesions (DAI, DSp, CAC and CRC) versus N and I (including also non-progressing UC patients). Conclusions: A specific histological pattern for SLC12A2 is associated to precancerous and cancerous colorectal lesions, and is able to be discriminate these lesions from inflammation and normal tissue in UC. The continuous upregulation of SLC12A2 in advanced colorectal lesionsin the CAC mice model also suggests a role of this protein in the pathophysiology of inflammation-associated colon neoplasia. [less ▲]

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See detailIncreased Endoplasmic Reticulum stress specific chaperones characterise CD fibrosis epithelium tissues and participate to in vitro induction of intestinal fibroblasts differentiation
Vieujean, Sophie ULiege; Hu, Shurong; Bequet, Emeline et al

Poster (2020, February 14)

Background: Intestinal fibrosis is a complication of Crohn’s disease (CD) characterized by myofibroblasts and extracellular matrix accumulation within the submucosa and smooth muscles, leading to bowel ... [more ▼]

Background: Intestinal fibrosis is a complication of Crohn’s disease (CD) characterized by myofibroblasts and extracellular matrix accumulation within the submucosa and smooth muscles, leading to bowel strictures. No medical treatment exists to treat or reverse intestinal fibrosis leading often to surgical resection. The potential role of intestinal epithelium in the fibrotic process remains poorly defined. Methods: We performed a pilot study on ileal fibrostricturing CD surgical samples (n=5), comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones. Confirmation of the specific protein increases was obtained by immunohistochemistry in colonic and ileal samples of CD (n=44) compared to healthy subjects (n=40), as well as in intestinal epithelial cell line under induced Endoplasmic Reticulum (ER) stress. A model of fibroblast to myofibroblast differentiation induction was also challenged using preconditioned media of intestinal epithelial cells after a pulsed ER stress. Results: Label free proteomics revealed high ER stress in the epithelium surrounding fibrotic bowel wall, involving Anterior gradient protein 2 homolog (AGR2) and 78kDA glucose regulated protein (BiP). Confirmation of both proteins increase was obtained by immunohistochemistry. ER stress induction in intestinal epithelial cells was associated with an intracellular increase of AGR2, BiP and ER stress markers as sXPB1 and CHOP. AGR2 was also detected in the culture medium of these epithelial cells and myofibroblast differentiation was obtained using this culture medium. Conclusions: The increase of ER stress proteins observed in fibrostenosing tissues together with These preliminary evidences of fibroblast to myofibrobast differentiation obtained by paracrine action of intestinal epithelial cell preconditioned to ER stress induction, suggest a role of epithelial ER stress in Crohn’s disease intestinal fibrosis. [less ▲]

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See detailP2X1 ion channel deficiency causes massive bleeding in inflamed intestine and increases thrombosis
Wéra, Odile ULiege; LECUT, Christelle ULiege; Servais, Laurence ULiege et al

in Journal of Thrombosis and Haemostasis (2019), 18(1), 44-56

Background: Intestinal inflammation is associated with bleeding and thrombosis, two processes that may involve both platelets and neutrophils. However, the mechanisms and the respective contribution of ... [more ▼]

Background: Intestinal inflammation is associated with bleeding and thrombosis, two processes that may involve both platelets and neutrophils. However, the mechanisms and the respective contribution of these cells to intestinal bleeding and extra-intestinal thrombosis remain largely unknown. Objective: Our study aimed at investigating the mechanisms underlying the maintenance of vascular integrity and thrombosis in intestinal inflammation. Methods: We used a mouse model of acute colitis induced by oral administration of dextran sodium sulfate (DSS) for 7 days. Bleeding was assessed after depletion of platelets, neutrophils, or glycoprotein VI (GPVI); treatment with aspirin or clopidogrel; or in P2X1-deficient mice. Extra-intestinal thrombosis was analyzed using a laser-induced injury model of thrombosis in cremaster muscle arterioles. Results: Platelet depletion or P2X1 deficiency led to macrocytic regenerative anemia due to intestinal hemorrhage. In contrast, GPVI, P2Y12, and thromboxane A2 were dispensable. Platelet P-selectin expression and regulated on activation, normal T-cell expressed and secreted (RANTES) plasma levels were lower in DSS-treated P2X1-deficient mice as compared to wild-type mice, indicative of a platelet secretion defect. Circulating neutrophils had a more activated phenotype, and neutrophil infiltration in the colon was increased. P2X1-deficient mice also had elevated plasma granulocyte-colony stimulating factor (G-CSF) levels. Neutrophil depletion limited blood loss in these mice, whereas exogenous administration of G-CSF in colitic wild-type mice caused macrocytic anemia. Anemic colitic P2X1-deficient mice formed atypical neutrophil- and fibrin-rich, and platelet-poor thrombi upon arteriolar endothelial injury. Conclusions: Platelets and P2X1 ion channels are mandatory to preserve vascular integrity in inflamed intestine. Upon P2X1 deficiency, neutrophils contribute to bleeding and they may also be responsible for enhanced thrombosis. © 2019 International Society on Thrombosis and Haemostasis [less ▲]

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See detailComprehensive Approach for Monitoring Human Tissue Degradation
Dubois, Lena ULiege; Stefanuto, Pierre-Hugues ULiege; Perrault, Katelynn ULiege et al

in Chromatographia (2019), 82(5), 857-871

In recent years, comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC–TOFMS) has been reported as a suitable tool for the determination of volatile organic ... [more ▼]

In recent years, comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC–TOFMS) has been reported as a suitable tool for the determination of volatile organic compounds (VOCs) emitted during the process of cadaveric decomposition. The main aim of the present study was to investigate temporal changes in VOC patterns during the decomposition process of various human tissues. The focus of previous research was mainly on the analysis of VOCs produced by whole cadavers. However, this study aimed to identify whether the VOCs produced during decomposition differ between specific organs, and further, to determine the extent of the variation between cadavers. The sampling process developed for this project allowed inter- and intra-cadaveric comparison. The headspace of heart, lung, liver, kidney and blood was monitored during the decomposition process. Tissue samples from five different cadavers were sampled regularly by dynamic pumping onto sorbent tubes that were further thermally desorbed onto a GC × GC–TOFMS system. A large amount of data (n = 774) was obtained, leading to challenges in the integration, interpretation and representation of the results. Eventually, multivariate statistical methods, such as principal components analysis (PCA) and hierarchical cluster analysis (HCA) were applied to the dataset to evaluate trends and differences in subgroups. It was demonstrated that there were subtle differences between the sets of compounds produced from each organ due to the different functions they carry out within the body. However, VOC profiles were more similar among organs from the same cadaver than when comparing samples from different cadavers. Various reasons may cause the differences between the analyzed cadavers, ranging from the individual diet and lifestyle to the time since death. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. [less ▲]

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See detailTGFBI, an ECM interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration
Costanza, Brunella ULiege; Rademaker, Gilles ULiege; Tiamiou, Assia ULiege et al

in International Journal of Cancer (2019)

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC ... [more ▼]

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high TGFBI expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates FAK signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic ECM interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies. [less ▲]

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See detailUnveiling of a new role for DPF3 protein in cancer biology
Verrillo, Giulia ULiege; Hanache, Sarah ULiege; Duchemin, Amandine ULiege et al

Poster (2019, February)

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See detailProteomics highlights common and distinct pathophysiological processes associated with ileal and colonic ulcers in Crohn's disease.
Pierre, Nicolas ULiege; Salee, Catherine ULiege; MASSOT, Charlotte ULiege et al

in Journal of Crohn's & colitis (2019)

BACKGROUND AND AIMS: Based on genetics and natural history, Crohn's disease can be separated in two entities, an ileal and a colonic disease. Protein based-approaches are needed to elucidate whether such ... [more ▼]

BACKGROUND AND AIMS: Based on genetics and natural history, Crohn's disease can be separated in two entities, an ileal and a colonic disease. Protein based-approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. METHODS: The proteome of ulcer edge was compared to the one of paired control tissue (n=32 biopsies) by differential proteomics in the ileum and the colon of Crohn's disease patients (n=16). The results were analysed though a hypothesis-driven (based on literature) and a hypothesis-free approach (pathway enrichment analysis). To confirm one of the key pathway highlighted by proteomics, two proteins were also studied by immunochemistry in tissue biopsies. RESULTS: In the ileum and the colon, 4428 and 5204 proteins, respectively, were identified and quantified. Ileal and colonic ulcer edge differed by a distinct distribution of proteins of epithelial-mesenchymal transition, neutrophil degranulation and ribosome. Ileal and colonic ulcer edge were similarly characterised by an increase of the proteins implicated in the pathway of protein processing in endoplasmic reticulum and a decrease of mitochondrial proteins. Immunochemistry confirmed the presence of endoplasmic reticulum stress in the mucosa of ileal and colonic ulcer edge. CONCLUSION: This study provides protein-based evidences showing partly distinct pathophysiological processes associated to ileal and colonic ulcer edge in Crohn's disease patients. This could constitute a first step toward the development of gut segment-specific diagnostic markers and therapeutics. [less ▲]

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See detailFacteurs anatomo-cliniques influançant la collecte ganglionnaire dans les pièces de résection chirurgicale pour cancer colorectal
LEDUC, G; BAWIN, Maxime; KESTEMAN, M et al

in Revue Médicale de Liège (2019), 74:10

Dans la stadification de l’adénocarcinome colorectal, le statut ganglionnaire anatomopathologique constitue une information capitale pour le clinicien et doit être défini avec un maximum d’exactitude ... [more ▼]

Dans la stadification de l’adénocarcinome colorectal, le statut ganglionnaire anatomopathologique constitue une information capitale pour le clinicien et doit être défini avec un maximum d’exactitude. L’analyse de la pièce de résection chirurgicale requiert la collecte au sein du méso du plus grand nombre possible de ganglions lymphatiques. Dans cette étude, nous avons analysé une série de facteurs anatomo-cliniques pouvant influencer la collecte ganglionnaire. Un total de 239 patients a été inclus dans notre étude. Les facteurs avec une influence statistiquement significative sur la collecte ganglionnaire (p < 0,05) ont été l’âge et le sexe du patient, la taille de la tumeur primitive, la taille de la pièce d’exérèse, le degré d’activité du chirurgien et le laboratoire d’anatomie pathologique. La présence ou non d’une radiochimiothérapie néoadjuvante n’a pas eu d’impact sur le nombre de ganglions prélevés. Cette étude souligne l’importance de la collecte ganglionnaire au sein des pièces de résection chirurgicale d’un cancer colo-rectal. [less ▲]

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See detailHuman colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis.
Rademaker, Gilles ULiege; Costanza, Brunella ULiege; Bellier, Justine ULiege et al

in Oncogenesis (2019)

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use ... [more ▼]

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour-promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anti-cancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer. [less ▲]

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See detailUne sarcoïdose dans le décours d'une tuberculose. Existe-t-il un lien étiologique entre ces deux maladies granulomateuses ?
Maalioune, Sonia ULiege; Corhay, Jean-Louis ULiege; Delvenne, Philippe ULiege et al

in Revue medicale de Liege (2019), 74(7-8), 394-400

We report the case of a 38-year old non-smoking female who initially presented to the hospital with frequent cough and sputum for several weeks. The investigations confirmed the diagnosis of tuberculosis ... [more ▼]

We report the case of a 38-year old non-smoking female who initially presented to the hospital with frequent cough and sputum for several weeks. The investigations confirmed the diagnosis of tuberculosis and a triple therapy was introduced with clinical improvement. Two years later, the patient reported recurrence of respiratory symptoms. The new investigations concluded initially to a recurrence of tuberculosis and a quadriple therapy was introduced. The treatment was poorly tolerated and rapidly stopped. It was then decided to perform a biopsy through mediastinoscopy in the hilar ganglia, which confirmed the diagnosis of sarcoidosis. The etiology of sarcoidosis is not yet clearly established, one of the hypothesis would be the direct involvement of an infectious agent that would induce an excessive immune response. The clinical case below supports a possible role of Mycobacterium tuberculosis in the pathogenesis of sarcoidosis. [less ▲]

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