bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP71 Efficacy of once-daily, orally administered obefazimod in patients with moderately to severely active UC at weeks 8, 48, and 96 broken down by induction treatment dose
Authors: Vermeire S , Danese S , Peyrin-Biroulet L , Dubinsky M , Dulai P , Tilg H , Siegmund B , Sloan S , Gineste P , Rabbat C , Sands B E 
Published: January 2024

Abstract

Background
Obefazimod (obe) is an investigational, oral, once-daily, small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obe demonstrated efficacy in patients with UC at week-8 in a phase 2b, double-blind, placebo-controlled, dose ranging, induction trial and in the subsequent open-label maintenance (OLM) study [2].

Methods
During the induction Phase 2b trial, patients received placebo or obe 25mg, 50mg or 100mg once daily (od). Irrespective of their clinical response, patients could enter the optional 96-week OLM study with obe 50mg od. Of the 222 eligible patients, 217 continued treatment in the OLM. We examine the efficacy outcomes at weeks 8, 48, and 96, for patients enrolled in the OLM according to their induction dose group.

Results
Among the 58 patients who initially received obe 25 mg during the induction period, 28% (16/58) achieved clinical remission at week 8. After switching to 50 mg in the OLM, the rate of clinical remission increased to 60% (35/58) at weeks 48 and 96. Similar trends were observed for clinical response (66% (38/58) at week 8, 85% (49/58) at week 48, and 74% (43/58) at week 96), endoscopic improvement (36% (21/58) at week 8, 60% (35/58) at week 48, and 66% (38/58) at week 96), and endoscopic remission (7% (4/58) at week 8, 28% (16/58) at week 48, and 47% (27/58) at week 96).
In the group of patients who received obe 50 mg in the induction period (n= 51), 20% (10/51) achieved clinical remission at week 8. After switching to 50 mg in the OLM, the rate of clinical remission increased to 49% (25/51) at week 48 and 96. Similar trends were observed for clinical response and endoscopic improvement (Table 1).
Among the 53 patients who received obe 100 mg in the induction period, 28% (15/53) achieved clinical remission at week 8. After switching to 50 mg in the OLM, the rate of clinical remission increased to 55% (29/53) at week 48 and week 96. Similar trends were observed for clinical response and endoscopic improvement (Table 1).
Among the 55 patients who received placebo in the induction period, 15% (8/55) achieved clinical remission at week 8. After switching to 50 mg in the OLM, the rate of clinical remission increased to 55% (30/55) at week 48, and 45% (25/55) at week 96. Similar trends were observed for clinical response and endoscopic improvement (Table 1).

Conclusion
These findings suggest that patients with UC treated with obefazimod 50mg od after the week 8 induction period maintained efficacy and continued to improve, irrespective of their induction dose, as evidenced by higher percentages of patients reaching clinical endpoints at weeks 48 and 96 relative to week 8.
DOP78 Efficacy of ozanimod by patient response trajectory subgroups identified using group-based trajectory modelling: a post hoc analysis of the phase 3 True North study
Authors: Schreiber S W , Feagan B G , Sands B E , Rieder F , Torres J , Liu Z , Jain A , Poehler A M , Wu H , Osterman M T , Abreu M T , Dulai P S 
Published: January 2024

Abstract

Background
Ozanimod (OZA) is approved for the treatment of adults with moderately to severely active ulcerative colitis (UC). A previous post hoc analysis of the phase 3 True North (TN) trial identified 5 discrete groups of patient (pt)-response trajectories to OZA using group-based trajectory modelling (GBTM). The current analysis further evaluated symptomatic, clinical, and mucosal outcomes in these groups.

Methods
Five trajectory groups were previously identified by GBTM using change from baseline (BL) in partial Mayo score in pts on continuous OZA treatment until W52 (OZA/OZA; N=229): super-response (Group 1; n=38), sustained improvement (Group 2; n=85), partial improvement (Group 3; n=60), fast rebound (Group 4; n=25), and slow rebound (Group 5; n=21) (Schreiber et al. Am J Gastroenterol. 2023;118:S671–2). In each of these groups, symptomatic remission and response were evaluated through W52, and results were compared with placebo (PBO). Clinical and mucosal EPs were evaluated at W10 and/or W52 using nonresponder imputation analysis.

Results
Significantly more pts in Group 1 vs PBO achieved early symptomatic response on Day (D) 5 (34.2% vs 11.1%; P=0.0002) and remission on D6 (10.5% vs 2.8%; P=0.0264). Symptomatic EPs were sustained for 52 wk in Groups 1–3, whereas Groups 4 and 5 started losing symptomatic efficacy by W18 (Figure 1). The highest proportions of symptomatic remission at W10 were achieved by pts in Groups 1 and 2 (97.4% and 75.3%) and were sustained until W52 (73.7% and 64.7%) (Figure 1A); similarly ~100% of pts in Groups 1 and 2 achieved symptomatic response by W10 and it was sustained in &gt;80% of pts until W52 (Figure 1B). Generally, Groups 1&gt;2&gt;3 had sustained or increased rates of clinical and mucosal EPs from W10 to W52, whereas Groups 4 and 5 had decreased rates of clinical and mucosal EPs at W52 (Table). Corticosteroid (CS)-free remission at W52 was greatest in Groups 1&gt;2&gt;3. Analysis of BL parameters showed that Group 1 had the least prior CS (60.5%), immunomodulator (26.3%), and anti–tumor necrosis factor (TNF) use (23.7%).

Conclusion
This analysis shows 3 distinctly different OZA populations within the responders, with the super-response Group 1 achieving symptomatic response as early as D5. Early response was related to long-term benefits, with Group 1 (and to a lesser extent with Groups 2 and 3) being more likely to achieve disease control at W52 with OZA. These findings demonstrate the utility of personalized medicine to direct therapeutic choice but need to be confirmed in future prospective cohorts.
DOP84 Colonic CD4+ T cell senescence is implicated in the progression of experimental colitis in aged mice
Authors: Zhang Y , Xu J , Zhang Y , Ke Z , Fang X , Lin Y , Liu Y 
Published: January 2024

Abstract

Background
Evidence from recent epidemiological data suggests that the burden of IBD in the elderly is increasing globally. However, the mechanisms underlying the age-related IBD susceptibility remain elusive. Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to autoimmune disease. Herein, we sought to determine the role of immunosenescence in age-dependent colitis and to explore the underlying mechanisms.

Methods
Young (2-3 months), middle-aged (10-12 months), and aged (20-24 months) mice were established models of colitis by 2% dextran sulfate sodium salt (DSS) treatment. Weight loss, colon length, disease activity indexes (DAI) and histological scores were evaluated to assess the severity of colitis. Using a second-generation fluorogenic substrate for β-galactosidase and multi-parameter flow cytometry, we detected the senescence-associated β-galactosidase (SA-βGal) activity in lymphocytes isolated from colon, including CD4+ T cells, CD8+ T cells, B cells, natural killer cells, microphages, neutrophils and dendritic cells. Based on the immunocytes that exhibit greatest age-related increases in SA-βGal activity, inflammatory cytokines such as TNF-α、IFN-γ、IL-17 were evaluated in senescent immunocytes through flow cytometry. Single-cell and bulk RNA-seq of colonic immune cells in mice with different ages were performed to further investigate the precise molecular mechanisms.

Results
Ageing increased the severity of DSS-induced colitis wherein aged mice exhibited worsened weight loss, shortened colon length, higher DAI and histological scores compared to young mice. The greatest age-associated increases of SA-βGal activity were observed in colonic CD4+ T cell populations. Additionally, aging resulted in systemic activation of CD4+ T cells, exhibiting an expansion of CD4+ effector memory T (TEM) cells in colon, as well as in spleen. Aged colonic CD4+ T cells generate higher levels of IFN-γ and IL-17 comparing to young colonic CD4+ T cells, especially in status of colitis. Moreover, the accumulated CD4+ TEM cells in the aged colon were the main source of IL-17 production. Single-cell analysis revealed that aging increased colonic CD4+ TEM cells, which were associated with T cell-mediated cytotoxicity and cytokine-mediated signaling pathway. Splenic CD4+ TEM cells isolated from aged colitis mice were confirmed to involve in cellular senescence, Th17 differentiation and inflammatory signaling pathway through bulk RNA-seq.

Conclusion
These results provide a significant insight into the contribution of senescent CD4+ T cells to age-dependent colitis and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly IBD patients.
P001 MicroRNA-155-5p contributes to the development of Ulcerative Colitis by regulating T lymphocyte proliferation and functions
Authors: Sumiyoshi N , Toyonaga T , Shumway A , Nakagawa F , Tanaka M , Saeki C , Furey T , Sheikh S , Sethupathy P , Saruta M 
Published: January 2024

Abstract

Background
MicroRNA (miRNA) is a small non-coding RNA which regulate a variety of cell functions by suppressing target mRNAs in a post-transcriptional manner. Recent works have identified an increased expression of miR-155-5p in the colonic mucosa of UC patients. However, the role of miR-155-5p in the pathophysiology of UC remains understudied. This study aims to clarify the role of miR-155-5p in development of colitis in UC patients.

Methods
MiRNA and mRNA expression profiles in colon were compared between 15 UC and 5 healthy controls by running small RNA-sequencing (smRNA-Seq) and RNA-Seq on the matched colon tissue. Candidate target genes of miR-155-5p were identified by analyzing sequencing data sets using a statistical simulation method (miRhub). MiR-155-5p expressing cells were identified by in situ hybridization in combination with immunohistochemistry on inflamed colon tissue of UC patients. The impact of miR-155-5p on colonic inflammation was tested in the dextran sulfate sodium (DSS) -induced colitis model using miR-155 deficient mice.

Results
MiR-155-5p expression was significantly higher in the inflamed colonic tissue of UC patients than in healthy controls with more pronounced up-regulation in the treatment refractory UC patients compared to the treatment naïve UC patients (UC vs. healthy controls, log2FC = 0.83, adjusted p-value = 0.014). MiRhub analysis identified 10 candidate target genes of miR-155-5p including SHANK2, MYO1D, ADD3, AHCYL2, NR3C2, MIER3, TRIM2, GPD1L, SEMA5A, and SATB2 most of which were involved in cell proliferation and immune response (NR3C2, MIER3, TRIM2, GPD1L, SEMA5A, and SATB2). In situ hybridization identified a group of CD3 positive T lymphocytes with increased miR-155-5p expression in the inflamed colonic mucosa. MiR-155 deficient mice showed attenuated DSS-induced inflammation in colon compared to the control wild type mice (colon weight/length ratio, miR-155 deficient mice vs. controls, 27.2 vs. 44.6, p&lt;0.01).

Conclusion
MiR-155-5p may contribute to the development of colitis in UC by regulating T lymphocyte proliferation and functions.
P008 Machine learning derived histological features of epithelial injury and repair in Ulcerative Colitis biopsies correlate with disease severity
Authors: Griffin M , Zhang Y , Shah C , Shamshoian J , Mountain V , Sucipto K , Jayson C , Najdawi F 
Published: January 2024

Abstract

Background
Ulcerative colitis (UC) is an incurable chronic and debilitating disease. Frequent relapse is common despite available therapeutics. Endoscopically and histologically confirmed mucosal healing is the gold standard for long term remission, but a better understanding of disease pathology is needed for all patients to achieve inflammation reduction plus epithelial repair and wound healings. Here, we describe machine learning (ML) models that exhaustively quantify the inflammatory and epithelial histologic morphology of the colonic mucosa. Model-derived features are associated with Geboes Score (GS).

Methods
ML models (IBDExploreTM, PathAI, Boston) previously trained to quantify tissue features (e.g. epithelium) and cells (e.g. lymphocytes) were deployed on 447 whole slide images (WSI) of hematoxylin and eosin (H&E)-stained UC colonic mucosa from clinical and commercial sources.
Model predictions yielded &gt;900 quantitative human interpretable features (HIFs). To identify histological features of epithelial injury and repair, further analyses focused on 212 relevant HIFs that describe the epithelial layer that were divided into 10 Feature Categories (FCs, Table 1) based on whether they describe loss of integrity, surface or crypt injury and repair.
Slide-level GS (Grade Level and Subgrade 3) were assigned to each WSI based on a median consensus scores of three expert gastrointestinal pathologists. Absolute Spearman rank correlations between individual HIFs and GS were calculated and associations between HIFs and GS were assessed at the FC level.

Results
HIFs were assessed at the FC level to identify broad trends associated with GS. Goblet cell HIFs in all epithelium and in crypt epithelium had the strongest associations, and were negatively correlated with Grade Level GS; positive correlations were found with enterocytes and loss of epithelial integrity HIFs (Figure 1A). Subgrade 3 GS was most strongly, and positively, correlated with epithelial injury and repair in the crypts, and negatively correlated with goblet cells in crypt epithelium and crypt epithelium goblet cell mucin (Figure 1B). Within FCs, the HIF driving the correlation trend was identified (Table 1). Model overlay outputs allow direct visualisation of histological features (Figure 1 C,D) illustrating disparities in the composition of GS0 and GS5 epithelium, and this is supported by the computed HIF values from each WSI.

Conclusion
Quantitative HIFs describing mucosa epithelial injury and repair strongly correlate with GS. Our models produce a granular, measurable blueprint of the epithelium that can be leveraged to inform hypotheses for therapeutic target selection, mechanism of action, and disease progression and remission.
P026 Differential effects of tofacitinib on macrophage activation may contribute to lack of response in ulcerative colitis patients
Authors: Melón-Ardanaz E , Veny M , Corraliza A M , Garrido-Trigo A , Gudiño V , Moro M , Sanzo-Machuca Á , Esteller M , Masamunt M C , Caballol B , Ordás I , Fernández-Clotet A , Ricart E , Panés J , Salas A 
Published: January 2024

Abstract

Background
We previously showed that ulcerative colitis (UC) patients refractory to tofacitinib present an increase in the activation and the pro-inflammatory profile of intestinal macrophages1. However, the mechanism by which tofacitinib promotes further activation of macrophages in these group of patients remains unknown.

Methods
Blood monocytes from healthy individuals were cultured in the presence of M-CSF as previously described2. The differentiated macrophages were treated with LPS (10ng/ml), TNF (20ng/ml) or IFNγ (5ng/ml) in the presence or absence of tofacitinib (300nM). The effect of tofacitinib on gene expression and protein production in response to each stimulus was measured by qPCR and ELISA, respectively. Single-cell RNAseq (scRNAseq) data generated in a cohort of UC patients treated with tofacitinib1 was compared to the bulk transcriptome of monocyte-derived macrophages stimulated with LPS +/- anti-IL-10 mAb3.

Results
Monocyte-derived macrophages treated with tofacitinib significantly reduced the expression of activation markers downstream from IFNγ or TNFα. In contrast, the response to LPS was either maintained or intensified by tofacitinib as seen by the increase in expression of inflammatory marker genes including chemokines and cytokines CXCL1, CXCL5, IL1B, TNFA and IL6, and M1-like markers INHBA and CLEC5A (Figure 1A). Protein analysis of cell supernatants confirmed these observations. Compared to IFNγ and TNF, LPS drives the production of high concentrations of the anti-inflammatory IL-10 (Figure 1B) which can act on macrophages through a JAK-dependent signaling pathway. We hypothesized that by inhibiting IL-10 autocrine signaling on LPS-activated macrophages tofacitinib would promote their hyperactivation. Indeed, the transcriptional profile of LPS-stimulated macrophages treated with a blocking anti-IL-10 antibody3 highly overlapped with those genes that were upregulated in macrophages from patients refractory to tofacitinib, including IL1B, IL6, INHBA and IDO1 (Figure 1C). This overlap was not observed in responder patients.

Conclusion
Based on the combination of biopsy scRNAseq from tofacitinib-treated patients and in vitro macrophage cultures, we suggest that lack of response to tofacitinib is driven by its effect on IL-10 signaling. While IL-10 is essential to control macrophage activation when stimulated with the pathogen molecular pattern LPS, it plays no significant role when macrophages are activated with IFNγ or TNF. Hence, we hypothesize that LPS-dependent inflammation may predispose to lack of response to tofacitinib.
P037 Modelling gut complexity and disease: development of a next-generation adult stem cell based tubular gut-on-a-chip model
Authors: Kosim K , Bokkers M , Oudshoorn J , van Heusden T , Morelli M , Kurek D , van den Broek L , Joore J , Vulto P 
Published: January 2024

Abstract

Background
Developing effective therapies for Inflammatory Bowel Disease (IBD) necessitates advanced in vitro models that faithfully replicate the intricacies of the gut. The current challenge is to create models that encompass the 3D morphology, heterogeneity, and boundary characteristics of intestinal tissue while also being amenable to high-throughput screening. Microfluidic techniques are emerging as vital tools to introduce physiologically relevant cues into conventional cell cultures.

Methods
We present an innovative in vitro model employing human adult stem cell-derived colon organoids cultivated as perfused epithelial tubules within the MIMETAS OrganoPlate®. This microfluidic platform facilitates the simultaneous culture of up to 64 independent gut tubules on an extracellular matrix, offering continuous media perfusion without artificial membrane interference. The barrier function of the epithelial tubules is assessed in real-time through transepithelial electrical resistance (TEER) measurements. Immunostaining and 3D reconstruction of confocal images evaluate the expression of relevant epithelial markers.

Results
The tubular epithelial model of the intestinal tract demonstrated rapid cell polarization, expression of cell-specific markers, tight junction formation, and the presence of functional transporters. TEER measurements indicated functional and reproducible barrier integrity across tubules generated from different organoid donors for at least 10 days. Incorporation of additional cell types, such as patient-derived immune cells and endothelium, marks a groundbreaking advancement in understanding disease pathogenesis. The plug-and-play modularity of these models allows for flexibility in incorporating specific cell types based on the biological pathway of interest.

Conclusion
Our next-generation gut-on-a-chip model faithfully mimics the IBD phenotype and facilitates screening for potential drug targets. Combining adult human stem cell-derived intestinal organoids with microfluidic technology provides a robust platform to study physiology and disease mechanisms in patient-specific gut models. The inclusion of IBD patient-derived cells promises further refinement, enabling a more profound exploration of disease phenotypes and treatment responsiveness. Moreover, organoids, as one of the most physiologically relevant cell sources, authentically represent patient biology, enhancing the translational potential of our findings.
P042 Significant correlation between intestinal ultrasound and magnetic resonance enterography for assessing disease activity and complications in Crohn’s disease
Authors: Bárbara A , Manso M , Bravo C , Reves J , Nascimento C , Gomes C , Torres J , Palmela C 
Published: January 2024

Abstract

Background
The advantages of intestinal ultrasound (IUS) over magnetic resonance enterography (MRE) include wide availability, low cost, and the possibility of being point-of-care. We here aimed to compare the performance of IUS with MRE for assessing disease activity and complications in Crohn’s disease (CD).

Methods
Prospective longitudinal study of CD patients starting anti-TNF therapy. IUS and MRE were performed at baseline (W0) and after 1 year of infliximab therapy (W54). Bowel wall thickness (BWT) of the most affected segment (MAS) was measured in both exams (average of 4 measurements) and compared. Transmural response (TR) was defined as a reduction in 25% of BWT. All MRE were centrally reviewed by a blinded radiologist.

Results
We included 48 CD patients (48% male; median age 31 years, IQR 26-44). Ileum was the most commonly affected segment in 63% of the patients. At baseline the agreement between the two methods to select the most affected segment was moderate (k=0.581, p&lt;0.001). At W54, 50% of patients had TR in IUS and 40% in MRE. After 1 year of therapy there was a significant decrease in median BWT in both methods (IUS: 4.88mm vs 3.22mm, MRE: 8.21mm vs 4.91mm, both p&lt;0.001). We found a significant association between the two methods in detecting intestinal complications (stricturing or penetrating disease) on both timepoints (W0: 31.25% vs 21.73%; p&lt;0.001; W54: 17.78% vs 20.83% ; p=0.004), and also a significant moderate to high correlation between BWT measured by IUS and MRE on both timepoints (W0:r=0.34, p=0.02; W54:r=0.58; p&lt;0.001). The correlation was higher when the MAS was the ileum (W0 and W54: r=0.65, p&lt;0.001).

Conclusion
We found a moderate to good agreement in the selection of MAS between IUS and MRE. There was also a moderate correlation between BWT measurements and detection of complications between the two methods, which increased when the MAS was the ileum. Our results suggest that IUS, a readily available and inexpensive tool, is accurate to evaluate disease activity and treatment response, particularly in patients with ileal disease.