bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nature, severity, and impact of chronic oropharyngeal dysphagia following curative resection for esophageal cancer: a cross-sectional study
Authors: Gillman Anna , Kenny Ciaran , Hayes Michelle , Walshe Margaret , Reynolds John V , Regan Julie 
Published: January 2024

Summary
Chronic oropharyngeal dysphagia (COD) and aspiration after esophageal cancer surgery may have clinical significance; however, it is a rarely studied topic. In a prospective cross-sectional observational study we comprehensively evaluated the nature, severity, and impact of COD, its predictors, and the impact of the surgical approach and site of anastomosis. Forty participants were recruited via purposive sampling from the (Irish) National Center between November 2021 and August 2022. Swallow evaluations included videofluoroscopy [Dynamic Imaging Grade of Swallowing Toxicity v2 (DIGESTv2), MBS Impairment Profile, Penetration-Aspiration Scale)]. Functional Oral Intake Scale (FOIS) identified oral intake status. The patient reported outcome measures of swallowing, and Quality of Life (QL) included EAT-10 and MD Anderson Dysphagia Inventory (MDADI). Fourteen (35%) participants presented with COD on DIGESTv2 and 10% had uncleared penetration/aspiration. Avoidance or modification of diet on FOIS was observed in 17 (42.5%). FOIS was associated with pharyngeal dysphagia (OR = 4.05, P = 0.046). Median (range) EAT-10 and MDADI Composite results were 3(0–30) and 77.9(60–92.6), respectively. Aspiration rates significantly differed across surgical groups (P = 0.029); only patients undergoing transhiatal surgery aspirated. Survivors of esophageal cancer surgery may have COD that is undiagnosed, potentially impacting swallow-related QL. Given the small number of aspirators, further research is required to determine whether aspiration risk is associated with surgical approach. A FOIS score below 7 may be a clinically useful prompt for the MDT to refer for evaluation of COD following curative intent surgery. These data present findings that may guide preventive and rehabilitative strategies toward optimizing survivorship.
OP24 SPP1 in colitis-associated colon cancer
Authors: Manna S , Cardoso da Silva D , Sehn M , Wiese J , Heldt C , Plumbom I , Conrad T , Schallenberg S , Dony V , Farahani S K , Weiss F , Branchi F , Elezkurtaj S , Siegmund B , Weixler B , Hummel M , Gröne J , Schumann M 
Published: January 2024

Abstract

Background
Patients with ulcerative colitis (UC) and Crohn’s disease (CD) face a lifelong risk of developing colitis-associated carcinoma (CAC). Current insights into CAC development originate from murine CAC models, while human CAC studies primarily focus on mutational analyses. Although the mutational landscape reveals distinct patterns and frequencies compared to colorectal cancer, it falls short in elucidating the inflammatory mechanisms of CAC development. Consequently, we adopted a multi-omics approach to unravel CAC carcinogenesis, utilizing human samples from patients with CD, CD-associated CAC (CD-CAC), UC, and UC-associated CAC (UC-CAC). Findings were further validated in vitro using human colon organoids.

Methods
A Nanostring Immunology v2 panel was employed on RNA (archival FFPE sections) from 40 patients suffering from either IBD or CAC, alongside inflammation-free healthy controls (n=10 per group). Our data revealed a robust upregulation of the SPP1 (Secreted Phosphoprotein 1) gene encoding osteopontin (OPN) in CAC patients. Prospectively, we extended our methodology to an unbiased imaging-based spatial RNA in situ sequencing (ISS) approach (477 genes, Xenium, 10X Genomics) using FFPE sections from CAC and UC patients (n=3 per group). This provided insights into the spatial expression of SPP1 and its target receptors at a subcellular resolution. Findings were validated using whole FFPE section confocal microscopy. In addition, in vitro models, including human UC organoids, were analyzed by bulk RNA-Seq, RT-qPCR, and downstream functional assays.

Results
Nanostring Immunology v2 gene expression data revealed upregulation of the SPP1 gene encoding OPN (Fig 1A) and EMT transcription factors FN1 and ZEB1 in CAC patients. Xenium RNA in situ sequencing (ISS) unveiled the spatial heterogeneity of SPP1 expression in CAC (Fig 1B). Unsupervised graph-based clustering identified an SPP1+CD68+ macrophage cluster exclusively in CAC (Fig 1C), validated through OPN/CD68 immunostainings (Fig 1D). In vitro OPN stimulation across multiple human and mice colon organoid models excluded OPN as the trigger of EMT. Interestingly, Xenium ISS and immunostainings revealed a mutually exclusive spatial location of SPP1/OPN+ macrophages and CD8+ T cells (Fig 1E, F and G).

Conclusion
SPP1 is significantly upregulated in CAC (RNA and protein), expressed by CD68+ macrophages. In vitro OPN stimulation demonstrated no direct effect on intestinal epithelial organoids. The mutually exclusive spatial locations of SPP1/OPN+ macrophages and CD8+ T cells suggests a crucial role of SPP1/OPN in modulating the immunosurveillance of CAC cells by CD8+ tumour lymphocytes.
OP27 Oxalyl-CoA decarboxylase is a major and specific virulence factor for Adherent Invasive Escherichia coli
Authors: Toumi E , Orianne G , Reisacher C , Rolhion N , Sokol H , Skurnik D 
Published: January 2024

Abstract

Background
Adherent Invasive E. coli (AIEC) strains are found in one-third of patients with ileal Crohn’s disease (CD). To date, the bacterial genes involved in AIEC survival in the inflammatory environment are still unclear. Here, we systematically identify the genes of AIEC required for gut colonization and survival under the inflammatory conditions present in a mouse model of IBD.

Methods
We performed a transposon sequencing (TnSeq) approach using the laboratory strain E. coli K12 MG1655 and the AIEC strain LF82. We created two saturated Tn mutant libraries (3x105 mutant per bank) and gavaged them to mice with and without dextran-sodium sulfate (DSS)-induced colitis. We screened for essential genes for each bacterium in both conditions in the Cecum, Colon, Ileum and Jejunum.

Results
After High-throughput sequencing, we identified oxc gene, encoding for the oxalyl-CoA decarboxylase enzyme, as crucial for the survival of LF82 but not MG1655 in the whole gastrointestinal tract in colitis setting. To confirm our TnSeq results, the effect of oxc isogenic mutant (∆oxc) and complemented strains of LF82 and MG1655 was tested.
The inflammation severity was exacerbated in mice colonized with LF82WT or the complemented strain compared to LF82∆oxc. LF82∆oxc strain load decreased after colitis induction while the LF82WT and the complemented strain persisted. In a competition between LF82 WT and ∆oxc, the WT strain was able to outcompete the ∆oxc strain. This altered ability of LF82∆oxc to colonize the gut was associated with decreased bacterial motility and flagella expression.
In vitro, we found a decreased resistance of different AIEC strains to oxidative stress and acidic pH compared to a collection of commensal E. coli strains. This difference was abolished in all the ∆oxc AIEC strains we built and tested, demonstrating a crucial role for this gene in the tolerance to oxidative and acidic stress. Finally, lack of oxc also caused a reduction in survival into RAW264.7 macrophages, and an altered pro-inflammatory response of the macrophage, with a significant reduction of TNF-α levels.

Conclusion
oxc plays a major role in vitro and in vivo for AIEC strains but not for laboratory or commensal strains. Further studies to (i) fully explore this role and (ii) evaluate Oxc as a therapeutic target are currently under investigation.
OP40 Transcriptomic signature of response to vedolizumab in patients with moderate-to-severe ulcerative colitis: Results from an international, multicentre, retrospective cohort study
Authors: Linggi B , Salas A , Veny M , Borowski K , Silverberg M S , Milgrom R , Stempak J , Boland B , Eckmann L , Smith M I , Parker C E , Jairath V , Teft W , Vande Casteele N 
Published: January 2024

Abstract

Background
Transcriptomic analysis has the potential to facilitate drug development and clinical decision making in inflammatory bowel disease. Current understanding of pharmacodynamic response to vedolizumab is limited by a lack of publicly available mucosal biopsy RNA samples/sequencing data and corresponding clinical information. We aimed to identify gene signatures associated with response to vedolizumab in ulcerative colitis (UC) patients by pooling data from 3 international sites.

Methods
Patients receiving vedolizumab for the treatment of moderate-to-severe UC at Hospital Clínic de Barcelona (IDIBAPS), Mount Sinai Hospital (MSH), and University of California, San Diego (UCSD) with baseline and post-treatment (week 14 [± 4 weeks]) mucosal biopsy RNA-sequencing data and Mayo Clinic endoscopic subscores (MCES) were eligible for inclusion. Endoscopic response was defined as an MCES &lt;1. Demographic and clinical data were collected. Differential expressed genes (DEGs) between baseline and week 14 were identified using linear mixed models with a &gt;1.5 or &lt;-1.5-fold change (adjusted P-value &lt;.05). Enrichment was performed using Reactome pathway analysis and a previously published UC gene signature (adjusted P-value &lt;.05).1 Analyses were performed using R version 4.3.0.

Results
Twenty-three patients were included (IDIBAPS: n=12; MSH: n=8; UCSD: n=3). Site-specific differences in sex, surgical history, and corticosteroid use were observed (Table). Analysing data by site yielded a relatively small number of DEGs between baseline and week 14 (IDIBAPS=57 [27 up-regulated, 30 down-regulated]; MSH=0; UCSD=0) among endoscopic responders (IDIBAPS: n=5; MSH: n=7; UCSD: n=2). Combining data from the 3 sites increased the number of DEGs among endoscopic responders at week 14 (n=14) to 1162 (662 up-regulated and 500 down-regulated). The down-regulated DEGs were enriched for genes involved in 37 of 103 up-regulated Reactome pathways in UC, including neutrophil degranulation, interleukin-4 and interleukin-13 signalling, interleukin-10 signalling, and integrin cell surface interactions. The up-regulated DEGs were enriched for genes involved in 1 of 39 down-regulated Reactome pathways in UC (Drug ADME).

Conclusion
We defined a pharmacodynamic signature using mucosal biopsies from UC patients who had endoscopic response to vedolizumab at week 14. The signature was enriched for several, but not all, pathways involved in UC. In addition to providing insight into vedolizumab’s mechanism of action, we underscored the utility of multi-site collaboration to access data, increase statistical power, and enhance the generalizability of research findings. Reference: 1. Linggi et al. Sci Rep 2021;11:18243.
DOP12 Efficacy and safety of obefazimod in UC patients at weeks 48 and 96 of an open-label maintenance study among clinical responders at week 8 of the Phase 2b induction trial
Authors: Vermeire S , Peyrin-Biroulet L , Danese S , Dubinsky M , Dulai P , Tilg H , Siegmund B , Gineste P , Sloan S , Rabbat C , Sands B E 
Published: January 2024

Abstract

Background
Obefazimod 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]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we report efficacy and safety at weeks 48 and 96 among patients who achieved clinical response at week 8 of the double-blind induction trial and compared efficacy to the overall study population.

Methods
Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the Phase 2b, induction trial and, irrespective of their clinical response, could enter the optional 96-week OLM study with obefazimod 50mg od. Patients were followed monthly for safety and efficacy. This analysis focuses on efficacy and safety among patients who reached clinical response (decrease from baseline in the Modified Mayo score (MMS) ≥ 2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score (RBS) ≥ 1 or an absolute RBS ≤ 1) at week 8 of double-blind induction and continued treatment in the OLM.

Results
Among the 217 patients who participated in the OLM, 57% (124/217) achieved clinical response at week 8 of the induction trial. Within this subgroup, 66% (82/124) and 60% (74/124) achieved clinical remission at weeks 48 and 96, respectively. Clinical response was achieved by 86% (107/124) and 77% (95/124), endoscopic improvement was achieved by 70% (87/124) and 64% (79/124), and endoscopic remission was achieved by 38% (47/124) and 42% (52/124) at weeks 48 and 96, respectively. The proportions of patients achieving these efficacy endpoints in this subpopulation were numerically higher than those observed in the overall study population (Table 1). No new safety findings were observed in this sub-population during the OLM.

Conclusion
A substantial proportion of patients who reached clinical response at week 8 of the induction study achieved clinical efficacy endpoints at week 48 and 96 of the open-label maintenance study. Among these patients, nearly 8 out of 10 maintained clinical response, and 6 of 10 achieved durable clinical remission for up to 96 weeks of treatment with 50 mg of once-daily obefazimod.
References
1. Vermeire S, et al. J Crohns Colitis. 2023; doi: 10.1093/ecco-jcc/jjad067;
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022.
DOP14 Proctocolectomy is associated with improved transplant-free survival in patients with primary sclerosing cholangitis: results from a pooled collaborative international study
Authors: Mol B , van Nieuwamerongen M , Färkkilä M , Folseraas T , Boberg K , Vesterhus M , Bergquist A , Bogaards H , Ponsioen C 
Published: January 2024

Abstract

Background
It is hypothesized that the gut-liver axis plays a pivotal role in the aetiology of primary sclerosing cholangitis (PSC). Colectomy before liver transplantation is associated with decreased rates of recurrent PSC.1 We previously observed that proctocolectomy with permanent ileostomy is associated with better transplant-free survival in a population-based Dutch cohort.2 The aim of the present study is to confirm the effect of colectomy on PSC disease course in an international context.

Methods
We conducted a retrospective analysis on the International PSC Registry (IPSCR), comprising patients from Finland, Norway, Sweden, and the Netherlands. Endpoints were defined as liver transplantation (LT) and PSC-related death (excluding colorectal carcinoma) and were censored in the first year after colectomy to allow for a delayed protective effect. Cox proportional hazards regression was performed, with correction for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, and inflammatory bowel disease (IBD) status (i.e. ulcerative colitis, Crohn’s disease or IBD unspecified). IBD status and colectomy status were included as time-dependent exposure variables, the latter stratified for extent and indication for colectomy.

Results
A total of 2595 patients were included, of which 1341 from the Netherlands, 560 from Finland, 528 from Norway, and 166 from Sweden. Of all patients 1900(73%) were diagnosed with IBD and 346(15%) had undergone a colectomy; 34(9%) hemi-, 91(26%) subtotal, and 172(50%) proctocolectomy with pouch and 65(19%) with ileostomy. During a total follow-up of 28,282 patient years, 848(33%) patients reached the endpoint LT or PSC-related death.
Hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy (0.70(0.52-0.93)) compared to patients without colectomy with variation per country (Netherlands 0.82(0.56-1.19), Finland 0.52(0.24-1.13), Norway 0.59(0.31-1.03), Sweden 0.28(0.06-1.24)). This effect was less pronounced in case of a hemi- or subtotal colectomy (HR 0.84(059-1.20)). The effect was most pronounced in the proctocolectomy with permanent ileostomy group (HR 0.55(0.30-0.99)). Of the known risk factors only a concurrent IBD diagnosis had no significant effect on transplant-free survival.

Conclusion
Our extended data confirm that colectomy is associated with a decreased risk of liver transplantation and PSC-related death. An incremental effect was seen with the extent of the colectomy, with the most pronounced effect in the proctocolectomy group with permanent ileostomy. Our data support the putative role of the gut-liver axis in the disease course of PSC.
DOP57 Cystic fibrosis risk variants confer a protective effect against Inflammatory Bowel Disease in large-scale exome sequencing analysis
Authors: Yu M 
Published: January 2024

Abstract

Background
Genetic mutations that produce defective Cystic fibrosis transmembrane regulator (CFTR) proteins are known to cause cystic fibrosis (CF), a lethal autosomal recessive Mendelian disorder. Existing studies have debated the roles of CFTR mutations in Inflammatory Bowel Disease (IBD), with inconclusive evidence supporting both risk and protective effects.

Methods
We generated the largest IBD exome sequencing callset with 38,744 cases and 69,570 controls of European ancestries from the International Inflammatory Bowel Disease Genetics Consortium. After rigorous quality control analyses, we performed association testing using a logistic mixed-model implemented in REGENIE v.2.2.4. A set of LD-pruned high-confidence variants (MAF &gt; 1% and call rate &gt; 99%) was used for polygenic effect parameter estimation, which was included as covariates. To control for residual population structure and sequencing heterogeneity, we included as covariates a binary variable representing the sample sequencing platform and the top five principal components calculated from LD-prune well-genotyped common SNPs. Sex as a biological variable was also included as a covariate. Firth correction was applied to association tests with P &lt; 0.05 to control for case-control imbalance.

Results
Here, we report two lines of evidence establishing a protective role of CF-causing variants against IBD. First, we found delF508, the known CF-causing variant that accounts for 70% of all CFTR mutations observed in CF patients, is significantly associated with IBD (P=1.7E-10) with a protective effect (BETA=-0.30, SE=0.048). The conclusion remained unchanged if we excluded individuals carrying two copies of delF508. Second, we conducted an unweighted gene burden test of CFTR restricted to all variants (excluding delF508) annotated as CF-causing in the Clinical and Functional Translation of CFTR (CFTR2) database. This burden test indicates a significant association between CF-causing variants and IBD (P=1.1E-6) with a slightly smaller protective effect (BETA=-0.23, SE=0.047). As a negative control, another burden test was performed on CFTR using all rare (MAF&lt;0.001) nonsynonymous non-CF-causing variants. This test showed no significant association (P=0.42).

Conclusion
Leveraging a large-scale IBD exome sequencing dataset, we report two lines of evidence that convincingly suggest CF-causing variants confer a protective effect against IBD. Follow-up experimental studies are warranted to investigate the cellular pathways that CF-causing mutations disrupt to exert such an anti-inflammatory effect, which may provide insights for novel therapeutic interventions for IBD.
DOP59 Integration of in silico analysis and in vitro functional analysis reveals Tissue Factor Pathway Inhibitor 2 (TFPI2) as a master transcriptional regulator and potential target to impede Infliximab resistance in adult UC patients
Authors: Genua F , Lawal O , Kel A , Tosetto M , Stack R , Sheahan K , Yochum G , Doherty G , Das S 
Published: January 2024

Abstract

Background
Standard biological therapy for moderate-severe cases of UC consists in the use of Infliximab (IFX), an anti-tumour necrosis factor α (anti-TNF-α) targeting agent. However, approximately 40% of the patients do not respond to IFX. While transcriptional alterations have been widely associated with non-response to IFX, the precise factors that regulates this altered gene expression remains poorly understood. The aim of this study was perform a robust in silico analysis to identify master transcriptional regulators (MTRs) which regulate gene expression changes in IFX non-responsive UC patients, followed by perturbation in vitro to establish their functional role in UC pathogenesis.

Methods
Differentially expressed genes (DEGs) identified from four independent public datasets were applied to the GeneXplain platform to identify transcription factors (TFs) enriched for the DEG’s. This was followed by an upstream analysis to identify MTR’s which regulate expression of these genes through the TFs. We next explored the role of these MTRs in driving UC-associated phenotype, using siRNA-mediated knock-down in a novel IBD-like in vitro system comprising of normal rectal epithelial cells treated with TNFa.

Results
Over 200 TFs were identified in both upregulated and downregulated genes in IFX non-responders across all data sets. RELA, NANOG, FOSJUN were the top 3 TF’ enriched for upregulated genes in three out of the four datasets. Using the TF data, the upstream analysis identified CXCL8, SELE, PTGS2, FCGR3, TFPI2 as the top five MTRs. Next, we showed that of the 5 MTRs, only TFPI2 (tissue factor pathway inhibitor 2) were significantly upregulated in an IBD-like in vitro model (normal rectal epithelial cell line: CRL1831 +TNFa). siRNA-mediated knock-down of TFPI2 in this model resulted in a significant decrease in genes including TNFAIP6, TNFAIP3, FCGR3B, BIRC3 and CXCL5, all of which were predicted in silico to be upregulated by TFPI2 during the upstream analysis. Intriguingly, we showed that downregulation of TFPI2 resulted in significant amelioration of pro-inflammatory cytokines including IL1β, IFNγ, IL10, IL13, IL6 and IL8.

Conclusion
Our study for the first time identifies key MTRs such TFPI2 which acts as a master regulator of genes whose upregulation drives poor response to IFX. Therefore, these results warrant further in vitro/ex vivo investigation to rationalise their role of TFPI2 as a potential therapeutic target, whose perturbation in UC patient would likely result in improved response to IFX.