bluuebunny/crossref_metadata_2025_split huggingface dataset:
P016 SZN-1326, a Wnt signal activator, is more efficacious than cyclosporine A in an acute DSS model
Authors: Xie L , Baribault H , Lu C , Handa P , Newman M , Le L , Liu A , Mutha D , Deshmukh S , Shah D , Tun C , Le T , Fletcher R , Chen H , Ye J , Tibbitts J , Srinivasan U , Li Y , Vanhove G , Yeh W C 
Published: May 2021

Abstract

Background
Current Inflammatory bowel disease (IBD) treatments focus on inhibition of excessive inflammation, and clinical remission rates have reached a plateau. There is a clear unmet need for agents that directly repair and regenerate the intestinal epithelial barrier as mucosal healing has been associated with reduced hospitalizations and long-term remission. Wnt/β-catenin signaling promotes intestinal stem cell renewal and is crucial for intestinal epithelial homeostasis and regeneration. Fzd5, a Wnt receptor, is highly expressed in intestinal epithelium. We have engineered a FZD5,8 and LRP6 bi-specific IgG1 antibody, SZN-1326, which potently induced Wnt signaling in a Super Top Flash (STF) Luciferase reporter assay, stimulated intestinal organoid growth, increased Wnt target gene Axin2 expression in the colon tissue and ameliorated Dextran Sulfate Sodium (DSS)-induced colitis in mice. The objective of the current studies was to compare the efficacy of SZN-1326, a Wnt signal activator, to Cyclosporine A, which has been shown to have activity in an acute DSS-induced colitis mouse model.

Methods
To induce acute colitis, 7- to 8-week-old female C57BL/6 mice were given drinking water containing 4.0% (w/v) DSS for 7 days followed by 1.0% DSS for 3 days. Groups of mice were treated either with an isotype control antibody (anti-GFP), one intraperitoneal (IP) injection of SZN-1326 at 2, 6, 20 mg/kg on day 4 or two injections of SZN-1326 at 1, 3, 10 mg/kg on days 4 and 7, or treated daily with Cyclosporine A by oral gavage at 80 mg/kg on days 0–9, and the mice were taken down on day 10.

Results
Mice subjected to DSS developed severe colitis characterized by profound and sustained weight loss and bloody diarrhea, resulting in the increase of disease activity index (DAI). SZN-1326 treatments improved body weight, decreased fecal score, and reduced DAI much more effectively than Cyclosporine A. Histological evaluation showed SZN-1326 treatments repaired the damaged colon epithelium, decreased colon histology scores of inflammation, mucosal erosion, and goblet cell loss, at doses as low as 1 mg/kg dosed twice or a single dose of 2 mg/kg. In addition, SZN-1326 treatments significantly decreased serum levels of inflammatory cytokines, Lipocalin-2, IL-6 and IL-8, while Cyclosporine A treatment led only to a reduction of Lipocalin-2.

Conclusion
In an acute mouse IBD model, SZN-1326 at various dosing regimen stimulated intestinal epithelial regeneration, induced mucosal healing and restored the epithelial barrier resulting in reduced inflammation, improved body weight and reduced disease activity. In contrast, Cyclosporine A showed only a mild effect on reducing DAI and lipocalin-2.
P028 The Apa I polymorphism in the Vitamin D receptor gene is associated with a stricturing behaviour in Crohn′s disease patients
Authors: Gisbert-Ferrandiz L , Llau J , Cosin-Roger J , Coll S , Bauset C , Ortiz-Masia D , Hinojosa J , Calatayud S , Barrachina M D 
Published: May 2021

Abstract

Background
Vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors that plays an immunomodulatory role in the gastrointestinal tract through binding Vitamin D. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been related to inflammatory bowel disease. Indeed, Crohn′s disease (CD) patients carrying the Taq I polymorphism in VDR gene run a higher risk of developing a penetrating behaviour. We analyse here the association between the VDR SNPs Taq I, Bsm I, Apa I and Fok I and the clinical characteristics of CD.

Methods
DNA was extracted from blood samples from 80 patients diagnosed with CD from the Hospital of Manises (Valencia). Four polymorphisms identified in the VDR gene (Bsm I, Fok I, Apa I and Taq I) were genotyped using PCR-RFLP. Clinical data for each patient, including the Montreal classification was collected. Statistical significance was done using contingency tables and measured by Chi-squared or Fisher test.

Results
Results reveal a strong linkage disequilibrium between Apa I, Bsm I and Taq I polymorphisms. Apa I appears next to Bsm I and it is negatively associated with Taq I. The presence of at least a risk allele for Apa I is significantly associated with a stricturing behaviour in CD patients (P=0.014, Table 1), while the ancestral genotype (WT) of Apa I was significantly associated with a penetrating behaviour (P=0.062, Table 2). Finally, the presence of the risk genotype of Apa I is associated with a non-colonic location of the disease (P=0.059, Table 3). Fok I was not significantly associated with any of the parameters analysed.

Conclusion
Our results in CD patients reveal that the presence of the risk allele of Apa I in the VDR genotype is associated with a stricturing behaviour and tends towards a non-colonic location of the disease. This suggests that the analysis of this polymorphism may be useful for clinicians as a prognostic factor.
P039 New molecular markers of the development of ulcerative colitis
Authors: Iakovlev A A , Volkov A , Tarasova G , Zubova A 
Published: May 2021

Abstract

Background
The mechanisms of ulcerative colitis (UC) progression require detailed study. Modern achievements of proteomic methods of analysis are ideal for research that is free from hypotheses and allows us to define molecular characteristics of inflammation in colon mucosa of UC patients.

Methods
The study was comparative cohort with parallel design and included 88 patients (range from 22 to 35 years, 37 men and 51 women): 53 (60.2%) pancolitis and 35 (39.8%) left-sided UC, mild and moderate activity. The control group included 30 healthy individuals. Biosamples of colon mucosa in patients with UC in the active stage and in healthy persons were received by ileocolonoscopy with colon mucosa biopsy. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database.

Results
We identified following functional groups of peptides and proteins in molecular patterns of colon mucosa in UC patients: SMAD family member 2 (SMAD2) activates the transcription of TFG1β, that leads to specific regulation of the CCN2 gene in cells and the development of fibrosis in colon submucosa in UC patients; the stimulation of the expression of apoС-III in affected colon mucosa in UC is associated with the activation of the FOXO1 signaling pathway that supports inflammatory processes in colon mucosa; the second small heat shock protein (HSP2) controls the apoptosis of colonocytes, is also responsible for the mucosa resistance to therapeutic strategies; caspase 8 protects colonocytes from TNFα-induced cell death through a necroptosis mechanism via the blockade of the RIP3 expression; the expression of prohibitin maintains optimal activity of the electronic transport chain through the activity of transcription factor STAT3 and the decrease in the TNFα expression; significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes the activity of immune and inflamation processes in colon mucosa and a significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa.

Conclusion
Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. This information may provide new avenues for the development of novel diagnostic tests for UC.
P068 The combination of JAK1 and TPL2 or IRAK4 inhibitors is more effective than single agents in reducing TLR-mediated cytokine responses in human monocyte populations
Authors: Hornsby E , Yadon A N , Clarke A , Grant E , Lindsay J O , Stagg A J 
Published: May 2021

Abstract

Background
Dysregulated Toll-like receptor (TLR)-mediated responses in intestinal monocyte-derived cells contribute to pathology in inflammatory bowel disease (IBD). JAK inhibitors regulate the production of inflammatory mediators and are an emerging therapy in IBD. Recent data suggest that combination therapies may be more effective than single agents, and therapies targeting aspects of TLR signalling pathways are being developed. We assessed the impact of inhibitors of IRAK4, TPL2 and JAK1 (IRAK4i, TPL2i and JAK1i, respectively) either alone or in combination on TLR-mediated cytokine responses and associated signalling pathways in classical (CD14+CD16-), intermediate (CD14+CD16+) and non-classical (CD14lowCD16+) human blood monocyte subsets.

Methods
Peripheral Blood Mononuclear Cells (PBMCs) or CD14+ monocytes from healthy volunteers were pre-incubated with TPL2i, IRAK4i or JAK1i individually or with JAK1i in combination with TPL2i or IRAK4i for 1 hour at 37°C. Cells were then stimulated at 37°C with agonists of TLR4 (E.coli lipopolysaccharide; LPS) or TLR2 (Pam3CYSK4). Intra-cellular staining and flow cytometry were used to measure phosphorylation of signalling molecules (NF-kappaB p65, p38 MAPK and ERK) or cytokines (TNF-alpha and IL-1-beta) in the three monocyte subsets after stimulation for 15 minutes or 3 hours respectively.

Results
Pre-incubation of PBMCs or CD14+ monocytes with IRAK4i, TPL2i or JAK1i individually led to a significant dose-dependent reduction in TLR-stimulated cytokine production (the frequency of TNF-alpha+ cells and the per cell level of IL-1-beta) within the classical, intermediate and non-classical monocyte subsets. The combination of JAK1i with IRAK4i or TPL2i had an additive effect. TPL2i reduced LPS-stimulated ERK phosphorylation, but p65 and p38 phosphorylation in response to LPS was not affected by any of the inhibitors.

Conclusion
Small molecule inhibitors of TPL2, IRAK4 and JAK1 dampen TLR4- and TLR2- mediated inflammatory responses in human monocyte subsets, by affecting pathways independent of p65 or p38. This is due to a cell intrinsic effect on CD14+ monocytes. TPL2 inhibition may in part act to dampen cytokine production in monocytes through the reduction of ERK phosphorylation. Combining JAK1i with IRAK4i or TPL2i may be more effective in reducing inflammatory responses than single agents. Further work is required to elucidate the mechanisms by which IRAK4i and JAK1i dampen TLR-mediated inflammation in monocyte subsets.
P163 The impact of the COVID-19 pandemic on Health-Related Quality of Life of Patients with Inflammatory Bowel Disease in The Netherlands
Authors: Paulides E , Pasma A , Erler N S , van Eijk R L A , de Vries A C , van der Woude C J 
Published: May 2021

Abstract

Background
To learn from the current crisis caused by the COVID-19 pandemic and be prepared for future pandemics, it is important to investigate the impact of this extraordinary period on the wellbeing of patients with inflammatory bowel disease (IBD). Therefore, the aim of this research was to describe the self-reported Health-Related Quality of Life (HRQoL) and disease control of patients with IBD from the start of the COVID-19 pandemic and measures in The Netherlands.

Methods
This was a prospective study initiated on March 17, 2020 until July 1st, 2020. All patients aged 18 years and older with IBD that visited the Erasmus MC (Rotterdam, The Netherlands) outpatient clinic between March 2019 to February 2020 received up to date information on COVID-19. Patients were invited to complete online questionnaires at week 0, 2, 6 and 12. The Inflammatory Bowel Disease Questionnaire (IBDQ), the Inflammatory Bowel Disease control-8 (IBD-control-8 and the Numeric Rating Scale (NRS) on fatigue were used. The evolution of the different outcomes over time was measured using mixed models.

Results
Of 1151 invited patients, 851 participants (67% had CD and 33% UC or IBD-U) completed one or more questionnaires (response rate 74%). Median age of the participants was 41 years, with 57% being female. No relevant changes in total scores were found over time for the IBDQ (effect estimate 0.006, 95% CI [-0.003–0.015]) and IBD-control-8 (effect estimate 0.004, 95% CI [0.998–1.011]). There was a slight, increasing trend in fatigue scores over time (effect estimate 0.011, 95% CI [0.004, 0.019]).

Conclusion
This first lock down due to the COVID-19 pandemic in The Netherlands did not impact on the HRQoL and disease control of patients with IBD. Up to date information may have contributed to a stable HRQoL in IBD patients even in an extreme period with restrictions and insecurities.
P168 Depression and fatigue dependent variation of gut microbiome in patients with active Inflammatory Bowel Disease
Authors: Reindl W , Wuestenberg T , Knoedler L , Ebert M , Wirbel J , Zeller G , Thomann A 
Published: May 2021

Abstract

Background
Fatigue and depression are highly prevalent extraintestinal symptoms in IBD, especially during active disease. The underlying mechanisms are still poorly understood, but an involvement of the microbiota-gut-brain-axis seems likely. The aim of this study was to examine associations between the gut microbiota and symptoms of fatigue and depression in patients with active IBD.

Methods
We included 62 patients with active IBD. Blood and stool samples were collected before a change of therapy and patients completed questionnaires regarding fatigue (WEIMuS) and depression (HADS). Fecal microbiota were analyzed by means of shotgun metagenomic sequencing.
Based on taxonomical and functional metagenomic annotations of gut microbiome, we investigated the correlation between functional modules and psychometric scores as well as the nature of co-occurrence networks on the genus level using Bayesian statistical methods and analyzed modulating effects of fatigue and depression on genera co-occurrence. CRP levels as well as age, gender, diagnosis and medication were included as nuisance variables.

Results
Half of the patients (n=31) were fatigued (WEIMuS &gt;/= 32P.), and 18 patients reported symptoms of at least mild to moderate depression (HADS D &gt;/=10P.). Co-occurrence of genera that is influenced by depression or fatigue in this active IBD-sample with is displayed in Figure 1 (Log10(BF10) ≥ 1.0, strong evidence for H1).

Evidence for an influence of depression severity was found for 10 genera combinations, with the strongest effects on the Dorea-Butyrococcus-association (Log10(BF10) = 1.41, increase of association strength with higher depression score) and the association between an unknown genus of the Coriobacteriaceae family with Arabia (Log10(BF10) = 1.00, decrease of association strength with higher depression score). Modulatory effects of fatigue severity was present in 10 genera combinations, most pronounced for the Azospirillum-Akkermansia- (Log10(BF10) =2.39, increase of association strength with higher fatigue-score) and Odoribacter-Actinomyces-association (Log10(BF10) =1.58, decrease of association strength with higher fatigue-score) (Figure 2).

Conclusion
This study is the first to address the relationship between extraintestinal symptoms like fatigue and depression and microbiota parameters in patients with active IBD by means of network analysis with Bayesian methods. Our results show strong associations between these symptoms and co-occurring genera in a sample-specific network, indicating a role of the microbiota-gut-brain-axis in the development of fatigue and depression during active disease.
P260 An analysis of non-melanoma skin cancer rates in the tofacitinib Ulcerative Colitis clinical programme
Authors: Sands B E , Cohen R D , Ha C , Reinisch W , Salese L , Mundayat R , Lawendy N , Panés J 
Published: May 2021

Abstract

Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020).

Methods
NMSC events were evaluated from 3 randomised, placebo (PBO)-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612), as 3 cohorts: Induction (P3 induction studies [patients (pts) receiving tofacitinib 10 mg twice daily (BID) or PBO]); Maintenance (P3 maintenance study [pts receiving tofacitinib 5 or 10 mg BID or PBO]); Overall (pts receiving tofacitinib 5 or 10 mg BID in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &lt;15 or ≥15 mg, respectively (82% of pts received PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis.

Results
1124 pts were evaluated for NMSC (2809.4 pt-years of tofacitinib exposure; up to 7.8 years of treatment; median duration 685.5 days). NMSC events in Induction and Maintenance were previously reported (Table 1).1 In Overall, NMSC occurred in 21 pts (IR 0.73 [95% confidence interval (CI) 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (0.44, 1.25) (Table 1); 2 new cases since May 2019.1 Eleven pts had squamous cell carcinoma and 15 pts had basal cell carcinoma; 5 pts had both. No NMSC was metastatic or led to discontinuation. IRs by time interval and subgroup are reported (Table 2). Prior NMSC (hazard ratio [HR] 12.08 [95% CI 4.20, 34.76]) and age (per 10-year increase, HR 2.01 [1.38, 2.93]) were significant risk factors for NMSC in the multivariable analysis. Prior immunosuppressant use was not a significant risk factor in either the multivariable or univariate analyses.

Conclusion
In this analysis, NMSC IRs for tofacitinib were similar to those in pts with UC treated with biologics2 and those previously reported in the tofacitinib UC clinical programme.1 NMSC events were more likely to occur in pts with recognised NMSC risk factors: prior NMSC and increasing age.3 Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs remained stable over time, up to 7.8 years of exposure.

References
P269 Real-world impact of biological therapies on work impairment and quality of life in Inflammatory Bowel Disease patients
Authors: Thomas P , Den Broeder N , West R , Russel M , Jansen J , Römkens T , Hoentjen F 
Published: May 2021

Abstract

Background
Randomised controlled trials have reported improvement of work productivity and activity impairment (WPAI) as well as quality of life in biological-treated inflammatory bowel disease (IBD) patients. However, data beyond clinical trials are limited.

Methods
This multicentre prospective cohort study evaluated the effect of initiating biological or small molecule therapy on work impairment in IBD patients. Subjects completed the WPAI questionnaire and Short IBD questionnaire (SIBDQ) at biological therapy initiation and at week 26. Clinical disease activity was assessed using the Harvey Bradshaw Index and Simple Clinical Colitis Activity Index. Biochemical disease activity was assessed using C-reactive protein and faecal calprotectin. Data are presented as mean ± standard deviation.

Results
In total, 156 IBD patients were included for analysis (median age 40 years, 55% male, 55% Crohn’s disease). Of these patients, 28% started infliximab, 33% adalimumab, 19% vedolizumab, 18% ustekinumab, 1% tofacitinib and 1% golimumab. Concomitant medication use at baseline included 28% prednisone, 12% budesonide, 34% mesalamine, and 46% immunomodulator. At baseline, 58% had clinical disease activity and 58% had biochemical disease activity. In our cohort, 111 (71%) were employed and 17 (11%) patients reported partial or full occupational disability. The mean total work impairment at baseline was 52% ± 36%. During follow-up, 7 patients lost their job and 8 patients started employment. For the entire cohort, improvements in all WPAI domains were observed: mean 11%-points decrease in missed working hours, 4%-points decrease in impairment while working, 15%-points decrease in total work impairment and 15%-points decrease in total activity impairment. Parallel improvements were seen in SIBDQ scores (mean improvement 7.6 ± 11.3). At week 26, 66 (42%) patients achieved the minimal clinical important difference in total work impairment (improvement ≥7%-points). Patients with clinical disease activity at baseline and clinical response to the biological (n=32) showed a larger improvement in total work impairment compared with other subjects (n=86) (mean difference 29%-points versus 10%-points; p=0.036 (T-test)). Similarly, these patients showed greater improvement in SIBDQ scores compared to other subjects (mean 13.8 versus 5.4, respectively; p&lt;0.001 (T-test)).

Conclusion
IBD patients experienced substantial work impairment prior to initiating biological treatment. Improved work impairment scores were seen after initiation of biological therapy and patients with clinical response showed even greater improvements. These results underline the importance of IBD disease control to improve work productivity and participation.