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See detailPotential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homolog in Crohn’s Disease Fibrosis
VIEUJEAN, Sophie ULiege; Hu, Shurong; Bequet, Emeline ULiege et al

in Journal of Crohn's and Colitis (2021)

Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive ... [more ▼]

Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). Proteins of interests were validated by immunohistochemistry (IHC) in ileal and colonic samples of stricturing CD (n=44), pure inflammatory CD (n=29) and control (n=40) subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2) and Binding-immunoglobulin protein (BiP). This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation. Conclusions: The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2. [less ▲]

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See detailPotential Role of Epithelial Protein Disulphide Isomerases in Crohn’s Disease Fibrosis
Vieujean, Sophie ULiege; Hu, Shurong; Bequet, Emeline ULiege et al

in Acta Gastro-Enterologica Belgica (2021, March 03)

Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD) characterized by an accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive ... [more ▼]

Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD) characterized by an accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. In in-vitro experiments, this myofibroblastic differentiation is elicited by a whole series of factors among which transforming growth factor β1 (TGF-β1) seems to play a key role. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser-capture microdissection in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). The pro-fibrotic role of selected epithelial proteins was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2), Protein disulphide isomerase A6 (PDIA6) and Endoplasmic reticulum resident protein 44 (ERP44) which are 3 protein disulphide isomerases. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2, PDIA6, ERP44 as well as TGF β1 intracellular expression and their secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin (Tm), led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. The application of blocking agents for AGR2, PDIA6, ERP44 or TGF β1 in the supernatant of these Tm pre conditioned HT-29 cells, attenuated the myofibroblastic differentiation induced by this supernatant, suggesting a pro-fibrotic role of these secreted epithelial proteins. Conclusions: The development of CD fibrotic strictures may involve ER stress in epithelial cells, releasing a whole set of proteins into their environment, including AGR2, PDIA6, ERP44 as well as TGF-β1, which could exercise a pro-fibrotic role through a paracrine action. [less ▲]

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See detailMagnetic resonance enterography perfusion parameters reveal complex changes in affected and unaffected segments in Crohn's disease
VIEUJEAN, Sophie ULiege; COIBION, Caroline; SEIDEL, Laurence ULiege et al

in Scandinavian Journal of Gastroenterology (2020)

Objectives: To compare dynamic contrast-enhanced (DCE)-MRI parameters in affected and unaffected segments of CD patients with those of a control group, and to assess the correlation between DCE-MRI ... [more ▼]

Objectives: To compare dynamic contrast-enhanced (DCE)-MRI parameters in affected and unaffected segments of CD patients with those of a control group, and to assess the correlation between DCE-MRI parameters and clinical index of activity (HBI) as well as biomarkers (CRP and faecal calprotectin). Methods: We performed a single-center prospective study of CD patients and control subjects who underwent DCE-MRI. Regions of interest were drawn in segments and the program (Olea Medical - Canon) provided values for transfer constant (Ktrans), fractional volume of extravascular-extracellular space (Ve), slope of enhancement (SoE), time to maximum enhancement (TME), maximum enhancement (ME) and enhancement ratio (ER) which were determined and compared. Results: Fifteen CD patients (mean age 42 years; 10 women) and 7 healthy subjects (mean age 40.4 years; 6 women) were included. Paired comparisons of affected and unaffected segments in CD showed a significant increase of all parameters in affected segments, except for ER and TME. When comparing to controls, the affected segments did not show any significant difference, while a significant decrease in most of the parameters (except for ER and TME) was observed when comparing unaffected segments of CD patients to controls. In CD, significant correlations between DCE-MRI parameters and biomarkers (CRP, faecal calprotectin) were more frequent in unaffected segments than in affected segments. Conclusions: Significant differences in perfusion parameters were observed between affected and unaffected segments of CD patients and between unaffected segments and those of control subjects. This suggests complex perfusion changes in both unaffected and affected intestinal segments in CD. [less ▲]

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See detailMacrophage-derived exosomes attenuate fibrosis in airway epithelial cells through delivery of antifibrotic miR-142-3p
GUIOT, Julien ULiege; Cambier, Maureen ULiege; Boeckx, Amandine ULiege et al

in Thorax (2020), 75(10), 870-881

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs ... [more ▼]

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown. Methods: Two independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from 19 patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription–PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung fibroblasts. Results: Exosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p<0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor β receptor 1 (TGFβ-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGFβ-R1 by miR-142-3p transfer in target cells. Discussion: Our results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142–3 p to alveolar epithelial cells and lung fibroblasts. [less ▲]

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See detailSpecificity of metabolic colorectal cancer biomarkers in serum through effect size
Di Giovanni, Nicolas ULiege; MEUWIS, Marie-Alice ULiege; LOUIS, Edouard ULiege et al

in Metabolomics (2020), 16(8),

Introduction: Colorectal cancer is one of the most diagnosed cancers, leading to numerous deaths. In addition to existing screening methods, metabolic profiling could help both to diagnose and to ... [more ▼]

Introduction: Colorectal cancer is one of the most diagnosed cancers, leading to numerous deaths. In addition to existing screening methods, metabolic profiling could help both to diagnose and to understand the various states of the disease. Objectives: Find specific candidate biomarkers (CB) in serum of patients with colorectal cancer (CRC), in comparison to the situation after remission (R-CRC), evaluated on distinct patients. Methods: All serum samples were analyzed using comprehensive two-dimensional gas chromatography (GC × GC) coupled to high resolution time of flight mass spectrometry (TOF-MS) through an optimized and validated untargeted analytical method regulated by a quality control (QC) system. First, we used a specific multi-approaches data (pre)processing workflow to highlight, annotate and assess the performances of the most altered metabolites between CRC patients (n = 18) and healthy control samples (HC, n = 19) specifically matched for age and gender, two of the most influential confounding factors. On the contrary, due to the difficulty to control for all clinical and demographic traits when sampling small cohorts, the samples from patients in remission (n = 17) were not matched. Because of the consequent risk of bias, the usual null hypothesis significance tests (NHST) could not be applied reliably. Therefore, we compared the R-CRC samples to another specifically matched group of healthy controls (R-HC, n = 17), and used this comparison to indirectly address the difference between patients with colorectal cancer and patients in remission through a measure called effect size (ES) whose methodological aspects were investigated. Results: 24 candidate biomarkers were found significantly altered and able to discriminate the CRC and HC samples efficiently (Receiver Operating Characteristic (ROC) area under the curve (AUC) of 0.86, sensitivity and specificity of 0.72 and 0.78). 10 of those were found to have signals close to healthy levels in the R-CRC samples and were therefore specific to colorectal cancer. In the point-biserial case studied here, r-like (strength of association) and d-like (standardized mean difference) ES were directly convertible and only linear and rank-based ES were different. We therefore used and recommend Hedges' g, Spearman's rho and Kendall's tau, along with an unstandardized ES. The confidence intervals, that quantify the uncertainty of the measure, were well represented through scatterplots and distribution curves. Conclusion: The candidate biomarkers found, along with their specificity, could help for the detection of colorectal cancer, the diagnosis of remission, and for the understanding of its pathophysiology, after proper validation on independent cohorts. The effect size, here applied on a MS global profiling data set, is an ideal complement to NHST and a useful tool to compare and combine distinct cohorts, within a study as well as between studies (meta-analysis). [less ▲]

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See detailExosomal Long Non-Coding RNAs in Lung Diseases
Poulet, Christophe ULiege; NJOCK, Makon-Sébastien ULiege; MOERMANS, Catherine ULiege et al

in International Journal of Molecular Sciences (2020), 21(10), 3580

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung ... [more ▼]

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung diseases. We present here a compilation of the current knowledge on lncRNAs commonly found in Chronic Obstructive Pulmonary Disease (COPD), asthma, Idiopathic Pulmonary Fibrosis (IPF), or lung cancers. We built interaction networks describing the mechanisms of action for COPD, asthma, and IPF, as well as private networks for H19, MALAT1, MEG3, FENDRR, CDKN2B-AS1, TUG1, HOTAIR, and GAS5 lncRNAs in lung cancers. We identified five signaling pathways targeted by these eight lncRNAs over the lung diseases mentioned above. These lncRNAs were involved in ten treatment resistances in lung cancers, with HOTAIR being itself described in seven resistances. Besides, five of them were previously described as promising biomarkers for the diagnosis and prognosis of asthma, COPD, and lung cancers. Additionally, we describe the exosomal-based studies on H19, MALAT1, HOTAIR, GAS5, UCA1, lnc-MMP2-2, GAPLINC, TBILA, AGAP2-AS1, and SOX2-OT. This review concludes on the need for additional studies describing the lncRNA mechanisms of action and confirming their potential as biomarkers, as well as their involvement in resistance to treatment, especially in non-cancerous lung diseases. [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 ULiege 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 ULiege 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 detailColorectal Cancer : Biomarkers and Effect Size
Di Giovanni, Nicolas ULiege; Meuwis, Marie-Alice ULiege; Louis, Edouard ULiege et al

Poster (2020, January 22)

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See detailRisk of Late Postoperative Recurrence of Crohn's Disease in Patients in Endoscopic Remission After Ileocecal Resection, Over 10 Years at Multiple Centers.
Pouillon, Lieven; Remen, Thomas; AMICONE, Caroline ULiege et al

in Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2020)

BACKGROUND & AIMS: The risk of recurrence of Crohn's disease (CD) from 1 to 10 years after surgery despite initial endoscopic remission (late post-operative recurrence) is not clear. METHODS: We performed ... [more ▼]

BACKGROUND & AIMS: The risk of recurrence of Crohn's disease (CD) from 1 to 10 years after surgery despite initial endoscopic remission (late post-operative recurrence) is not clear. METHODS: We performed a retrospective study, at 3 inflammatory bowel disease (IBD) centers in France and Belgium, of all patients with CD (n = 86) undergoing an ileocecal resection with curative intent from 2006 through 2016 who did not have endoscopic evidence for recurrence (Rutgeerts score less than i2) at their baseline assessment. Post-operative recurrence after baseline endoscopy was defined as a composite endpoint of at least 1 of the following: clinical recurrence, IBD-related hospitalization, occurrence of bowel damage, need for endoscopic balloon dilatation of the anastomosis, and need to repeat the surgery. Risk of mucosal disease progression was studied as a secondary outcome. RESULTS: The median time between surgery and baseline endoscopy was 7 months (IQR, 5.7-9.5 months); 40 patients (46.5%) received medical prophylaxis in this period. The median follow-up time was 3.5 years (IQR, 1.6-5.3 years). Thirty-five patients (40.7%) had a late post-operative recurrence of CD, with a median time to disease recurrence after baseline endoscopy of 14.2 months (IQR, 6.3-26.1 months). Recurrence status did not differ significantly between patients with Rutgeerts scores of i0 (20/55) or i1 (15/31) at baseline (P = .28) and was independent of medical prophylaxis (16/40 with prophylactic therapy vs 19/46 without prophylactic therapy; P = .90). Mucosal disease progressed in 29 of the 71 patients (40.8%) with available data. We did not identify risk factors for late post-operative recurrence of CD or mucosal disease progression. CONCLUSIONS: Among patients with CD treated by ileocecal resection, 40% of patients had a late recurrence, despite initial endoscopic remission, after a median follow-up time of 3.5 years. Tight monitoring of these patients is recommended beyond 18 months. [less ▲]

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See detailUstekinumab in bio-naïve and bio-failure Crohn's disease patients: Results from a « real-life » monocentric cohort.
Monin, Lucie ULiege; Dubois, Simon ULiege; REENAERS, Catherine ULiege et al

in Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (2020)

BACKGROUND: The pivotal clinical trials have largely demonstrated the efficacy and safety of ustekinumab in Crohn's disease. Real-life cohorts published so far only include very few bio-naïve patients ... [more ▼]

BACKGROUND: The pivotal clinical trials have largely demonstrated the efficacy and safety of ustekinumab in Crohn's disease. Real-life cohorts published so far only include very few bio-naïve patients. This study assesses effectiveness and safety of ustekinumab in bio-naïve and bio-failure patients treated with ustekinumab in routine practice and look for predictors of response. METHODS: We performed a retrospective monocentric study. Initial response was assessed by maintenance therapy beyond week 16. Sustained response was assessed by the continuation or cessation of therapy over time for another reason than stopping in sustained remission. Treatment persistence was assessed by Kaplan Meier curves and predictors of treatment persistence were studied by univariate and multivariate Cox model. RESULTS: Out of 156 recorded patients, three patients were still in their induction phase at time of analysis and 5 patients were lost to follow-up, leaving 148 patients for clinical effectiveness analyses, including 35 bio-naïve when starting ustekinumab. A maintenance therapy was initiated in 79.7%. At one year, the probability to be still treated with ustekinumab was 73.8%. Treatment cessation increased with smoking in multivariate analysis. Previous biologic failure (as a whole), CRP and fecal calprotectin baseline levels did not influence initial response and treatment persistence. CONCLUSION: A large proportion of CD patients initially respond to ustekinumab and continue this treatment beyond one year. Treatment persistence is as high in bio-failure as in bio-naïve patients. [less ▲]

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See detailAbcès hépatique : rapport de cas et revue de la littérature.
ZEEVAERT, Jean-Baptiste ULiege; Wain, E.; Louis, Edouard ULiege et al

in Revue medicale de Liege (2020), 75(11), 731-737

Liver abscess is a rare condition. There are multiple etiologies and mortality linked to the infections or local complications is high. The rapid diagnosis and the implementation of an adequate and ... [more ▼]

Liver abscess is a rare condition. There are multiple etiologies and mortality linked to the infections or local complications is high. The rapid diagnosis and the implementation of an adequate and effective treatment are essential to allow healing without sequels. We report the case of a monofocal bacterial hepatic abscess in a 61-year-old patient with an iatrogenic origin. A review of the literature is proposed in order to address the incidence, the different microorganisms, the different etiologies and the different possibilities of treatment. It should be noted that mycotic abscess, which is extremely rare outside the immunocompromised patient, will not be discussed in this article. [less ▲]

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See detailGlycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases.
Klarić, Lucija; Tsepilov, Yakov A.; Stanton, Chloe M. et al

in Science Advances (2020), 6(8), 0301

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many ... [more ▼]

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases. [less ▲]

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See detailDiet as an environmental trigger in inflammatory bowel disease: A retrospective comparative study in two European cohorts
Preda, C.; Manuc, T.; Chifulescu, A. E. et al

in Revista Espanola de Enfermedades Digestivas (2020), 112(6), 440-447

Background and aims: inflammatory bowel disease development has been associated with several environmental factors, among which, diet can play a key role, probably due to a westernized lifestyle. However ... [more ▼]

Background and aims: inflammatory bowel disease development has been associated with several environmental factors, among which, diet can play a key role, probably due to a westernized lifestyle. However, its involvement in the pathogenesis of inflammatory bowel disease (IBD) is difficult to demonstrate. The aim of this study was to analyze dietary composition in a Romanian and Belgian population with IBD. Methods: An observational retrospective comparative study was performed using two European cohorts (Romanian and Belgian). The IBD group included 76 Romanian and 53 Belgian patients with an IBD diagnosis, while the control group included a total of 56 healthy people (35 Romanians and 21 Belgians). All subjects were interviewed and asked to fill in a questionnaire regarding diet. Results: in the entire IBD cohort (Romanian + Belgian), a significantly increased consumption of sweets (OR 3.36 [95 % CI 1.6,7]), processed and high fat meat (OR 2.5 [95 % CI 1.4, 4.7], fried food (OR 9.5 [3.8, 23.6]), salt (OR 2.8 [1.5, 5.3]), ice cream (OR 3.25 [1.1, 9.8]), mayonnaise (OR 3.49 [1.1, 10.3]), margarine (OR 5.63 [1.64, 19.33]) and chips/nachos/other snacks (OR 2.3 [0.97, 5.73]) were found compared to the healthy control group. The intake of seeds, nuts (OR 0.26 [0.14, 0.52]) and yoghurt consumption (OR 0.44 [0.23, 0.83]) was lower in the IBD group compared to the control group. Conclusion: A westernized diet with increased consumption of sweets, processed food, high fat meat, fried food, salt, margarine, snacks, ice cream and mayonnaise seems to be a risk factor for IBD in Romanian and Belgian IBD patients. Intake of seeds, nuts and yoghurt may be a protective factor. © 2020. SEPD y © ARÁN EDICIONES, S.L. [less ▲]

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See detailMarked Increased Production of Acute Phase Reactants by Skeletal Muscle during Cancer Cachexia.
Massart, Isabelle S.; PAULISSEN, Geneviève ULiege; Loumaye, Audrey et al

in Cancers (2020), 12(11),

Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a ... [more ▼]

Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. The changes in the muscle proteome of the C26 model were investigated by label-free proteomic analysis followed by a bioinformatic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins in the circulation. Our results revealed a marked increased muscular production of several acute phase reactants (APR: Haptoglobin, Serine protease inhibitor A3N, Complement C3, Serum amyloid A-1 protein) which are released in the circulation during C26 cancer cachexia. This was confirmed in other models of cancer cachexia as well as in cancer patients. Glucocorticoids and proinflammatory cytokines are responsible for an increased production of APR by muscle cells. Finally, their muscular expressions are strongly positively correlated with body weight loss as well as the muscular induction of atrogens. Our study demonstrates therefore a marked increased production of APR by the muscle in cancer cachexia. [less ▲]

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See detailA Qualitative Research for Defining Meaningful Attributes for the Treatment of Inflammatory Bowel Disease from the Patient Perspective
Louis, Edouard ULiege; Ramos-Goñi, J. M.; Cuervo, J. et al

in Patient (2020)

Introduction: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBD). Each class and type of medication available for the treatment of IBD has distinct ... [more ▼]

Introduction: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, inflammatory bowel diseases (IBD). Each class and type of medication available for the treatment of IBD has distinct characteristics and long-term effects that a patient may consider. We present the results of qualitative research that aimed to develop a descriptive framework that outlines the most relevant disease and/or treatment attributes for IBD treatment decisions and focuses on the patient perspective. Methods: This research employed a three-step approach: a literature review to identify a broad list of attributes, a focus group meeting including patients and clinicians to assess the relevance of the attributes, and two rounds of voting to name and define each attribute. The literature review was used to develop the initial list of attributes. Although the same attributes were defined for both UC and CD, the relative importance of each attribute to UC or CD was considered. The list of attributes was discussed and evaluated in the focus group meeting, which included eight patient representatives and nine gastroenterologists. Using feedback elicited from the focus group meeting, the research team developed a draft of the descriptive framework that grouped the attributes into domain subsets. All members of the focus group participated in two subsequent rounds of structured, online voting, which was used to refine the wording to name and define each attribute. Additionally, participants ranked all the attributes included in the descriptive framework to suggest which attributes were less relevant and could be omitted. Results: Among 574 publications retrieved from the databases and registries, we identified 32 eligible publications, and an initial list of attributes was developed. This list was refined during the focus group meeting, resulting in a draft descriptive framework of attributes within subsets of domains. The final descriptive framework was developed based on structured rounds of online voting to further refine attribute names and definitions. In the final descriptive framework, a total of ten attributes were identified: abdominal pain, other disease-related pain, bowel urgency, fatigue, risk of cancer and serious infections within the next 10 years, risk of mild to moderate complications, aesthetic complications related to treatment, emotional status, sexual life, and social life and relationships. These attributes were distributed across three domains: efficacy, complications and risk, and health-related quality of life. Conclusions: Through the identification of the ten most relevant attributes that influence patient decision making for IBD treatments, we developed a descriptive framework that should be considered by physicians when discussing IBD treatment options with their patients. The results of our qualitative research may also be helpful for the development of future IBD clinical studies and quantitative research. © 2020, The Author(s). [less ▲]

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See detailLooking for Innovative Digital Solutions to Optimize Patient Recruitment in Inflammatory Bowel Disease Trials.
Bouhnik, Yoram; Louis, Edouard ULiege; Peyrin-Biroulet, Laurent

in Gastroenterology (2020), 158(8), 2306-2307

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See detailSolute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis.
Merli, Angela-Maria ULiege; Vieujean, Sophie ULiege; MASSOT, Charlotte ULiege et al

in Journal of Crohn's & colitis (2020)

BACKGROUND AND AIMS: Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological ... [more ▼]

BACKGROUND AND AIMS: Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. METHODS: A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. RESULTS: Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed "loss of gradient" reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 - 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. CONCLUSIONS: We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients. [less ▲]

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