bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMPROVEMENT IN BOWEL URGENCY IS ASSOCIATED WITH STOOL FREQUENCY AND RECTAL BLEEDING REMISSION AT 12 AND 52 WEEKS IN PATIENTS WITH MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS
Authors: Long Millie , Gisbert Javier , McGinnis Kim , Ferrante Marc , Rogler Gerhard , Sapin Christophe , Hunter Theresa , Milata Joe , Navabi Seyedehsan 
Published: January 2023

Abstract

INTRODUCTION
Mirikizumab, an anti-IL23p19 antibody, has demonstrated safety and efficacy versus placebo across clinical remission, symptomatic remission, and endoscopic and histologic endpoints in patients with moderately-to-severely active ulcerative colitis (UC) in a Phase 3, double-blind, 12-week induction study (LUCENT-1/NCT03518086) and 40-week maintenance study (LUCENT-2/NCT03524092). Here, we examine the relationship between bowel urgency (BU) clinically meaningful improvement (CMI) and BU remission with rectal bleeding (RB) remission and stool frequency (SF) remission (Table 1 for definitions).

METHODS
Patients in LUCENT-1 (N=1281) were randomly assigned 3:1 to receive intravenous mirikizumab 300mg or placebo every four weeks (Q4W) for a total of 12 weeks. Patients who achieved clinical response to mirikizumab by Week 12 of LUCENT-1 (N=544) were re-randomized 2:1 to subcutaneous mirikizumab 200mg or placebo Q4W for 40 weeks in LUCENT-2 (maintenance study). Patients recorded their BU severity in the previous 24 hours using an 11-point Urgency Numeric Rating Scale (UNRS; 0=no urgency to 10=worst possible urgency) in an electronic daily diary. Weekly scores were averaged for patients with at least 4 of 7 days of complete diary data. BU remission was defined as UNRS score of 0 or 1, and BU CMI was defined as ≥3-point decrease in UNRS score compared to baseline. For patients who achieved clinical response at the end of induction, analyses were repeated for the end of maintenance at Week 40 (for 52 weeks of continuous treatment). Patients with UNRS&lt;3 at baseline were not included in this analysis.

RESULTS
A total of 1087 patients reported a baseline UNRS score ≥3. Patients achieving BU CMI had significantly higher rates of RB remission and SF remission at both Week 12 and Week 40 compared with patients not achieving these outcomes (all p&lt;0.001, Table 1, Figure 1). Similarly, at Week 12 and Week 40, patients achieving BU remission had significantly higher rates of achieving RB remission and SF remission compared to those who did not achieve BU remission (all p&lt;0.001, Table 1, Figure 1).

CONCLUSION
A higher proportion of patients enrolled in LUCENT-1 and -2 who achieved BU CMI and BU remission achieved RB remission and SF remission. These results support that the symptom of bowel urgency is an important marker of UC disease activity that is related to and distinct from other commonly accepted symptoms of active UC.
LONGITUDINAL MONITORING OF INFLAMMATORY BOWEL DISEASE ACTIVITY USING WEARABLE DEVICES THROUGH INFLAMMATORY MARKERS IN SWEAT
Authors: Hirten Robert , Lin Kai-chun , Whang Jessica , Shahub Sarah , Sardesai Abha , Helmus Drew , Muthukumar Sriram , Sands Bruce , Prasad Shalini 
Published: January 2023

Abstract

BACKGROUND
Current methods to monitor inflammatory bowel disease (IBD) activity, such as colonoscopy, blood and stool markers, or imaging, are suboptimal and rely on single timepoint assessments that are inconvenient, expensive, or invasive. Wearable devices are a highly scalable mobile health technology that can non-invasively, continuously, and accurately monitor several physiological parameters that have been linked to flare in IBD. We performed a pilot feasibility study in subjects with IBD of a wearable device to monitor sweat-based inflammatory markers.

METHODS
Eligible participants were aged ≥ 18 years, diagnosed with IBD, admitted to the Mount Sinai Hospital for an IBD-related admission and had an elevated CRP (&gt;5 mg/L). The sweat sensing device was worn by subjects to continuously measure the inflammatory markers C-reactive protein (CRP), tumor necrosis factor (TNF)α, and interleukin-6 (IL-6). The immunoassay on the sweat sensor was developed by immobilizing a specific capture probe antibody to capture CRP, TNFα and IL-6 in sweat. Data were transmitted from the device via Bluetooth to the cloud server. Sensor response was measured using impedance spectroscopy. Serum samples were collected daily. To evaluate the relationship between inflammatory markers in the sweat and serum, the Pearson correlation coefficient was calculated between longitudinal sweat measurements and serum CRP, TNFα and IL-6 levels. This was calculated for each subject with 2 or more consecutive serum values. The coefficient of variation was then calculated for each inflammatory marker.

RESULTS
A total of 16 subjects were enrolled. The sweat sensor device demonstrated the ability to measure in sweat CRP in the range of 525 to 1175.38 pg/ml, IL-6 in the range of 0.45 to 3.14 pg/ml, and TNFα in the range of 10.22 to 11.32 pg/ml. These measurements were correlated to their serum levels which were in the range of 2,200,000 to 12,7800,000 ug/ml for CRP, 0.68 to 31.66 pg/ml for IL-6, and 0.15 to 15.01 pg/ml for TNFα. The Pearson correlation coefficients between sweat and serum readings for CRP, IL-6 and TNFα are presented in Table 1. The coefficient of variation for CRP is 16.2% (mean 33,6863.14; standard deviation [std] 54,654.71), IL-6 is 19.5% (mean 33.23; std 7.06), and TNFα is 16.3% (mean 2.37; std 0.39). Figure 1 demonstrates temporal serum and sweat trends in a participant.

CONCLUSION
Longitudinally collected sweat CRP, IL-6 and TNFα, measured using a wearable device, correlate with serum measurements. This work is the first demonstration of continuous, non-invasive methods to longitudinally monitor inflammatory markers in sweat, and suggests the feasibility of using a non-invasive sweat-sensing wearable device to monitor IBD disease activity.
ANALYSIS OF THE GENETIC EXPRESSION OF COLON CANCER GENETIC BIOMARKERS ON INFLAMMATORY BOWEL DISEASE ON BLOOD AND BIOPSY SAMPLES
Authors: Martinez Evelyn Calderon , Zevallos-Delgado Christian , Joseph Maria 
Published: January 2023

Abstract

INTRODUCTION
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition of the gastrointestinal tract. Its incidence rose steadily in the last century and the estimated incidence is approximately 2.5 million in Europe and 1.5 million in North America [1]. This condition can be associated with an increased risk of cardiovascular diseases, infections, and cancer [2] The risk of colorectal cancer (CRC) is approximately 2- to 3-fold higher for IBD patients than in the general population. [2] Malignancies are the second most common cause of mortality after cardiovascular disease in patients with IBD. [3] Several genetic biomarkers have been studied as prognostic factors, such as BRAF, CEACAM5, SMAD4, APC, MLH1 (part of the Microsatellite instability prognosis factors), and KRAS.

OBJECTIVE
The aim of this study was to determine the gene expression of CRC genetic biomarkers in IBD patients' peripheral blood and biopsy samples.

METHODOLOGY
The gene expression data was retrieved from the Gene Expression Omnibus (peripheral blood: GSE186507 and colon biopsies: GSE193677). This data was submitted by Argmann et al, a study that included healthy control patients (n=243), UC (n=421), and CD (n=243). The biopsy samples were obtained from the ileum, colon, and rectum. Several CRC biomarkers were retrieved from the literature. We compared the expression of these biomarkers between the groups in both, blood samples and the different sites of biopsies using T-test (UC vs control, CD vs control, and UC vs CD).

RESULTS
The analysis showed a significant difference in some CRC gene biomarkers between IBD patients and the control group in peripheral blood and the different locations where the biopsies were obtained. MLH1 was more expressed in IBD patients compared with healthy patients in the cecum (CD vs control p=8e-06; CD vs UC p= 0.00046), left colon (CD vs UC p= 0.02), right colon (UC vs control p=0.022; CD vs UC p=0.0053), sigmoid colon (UC vs control p=0.037; CD vs UC p=0.028), and rectum (CD vs control p=5e-10, CD vs UC p= 1.2e-13). In the case of the blood samples, the gene expression of SMAD4 (p = 0.03) CEACAM5 (p= 0.02), KRAS (p= 0.0005), and MLH1 (p= 0.0002) was significantly higher in IBD patients compared with control group.
THE EFFECTS OF BIOLOGIC AND SMALL MOLECULE INHIBITOR THERAPY ON THE MUCOSAL IMMUNE SYSTEM IN ULCERATIVE COLITIS
Authors: Briggs Kristi , Tam Ada , Housseau Franck , Melia Joanna , Pardoll Drew 
Published: January 2023

Abstract
Ulcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD) that causes relapsing and remitting inflammation in the colon and rectum. Numerous treatment options are available for patients with UC including biologics and small molecule inhibitors that target the immune system. Although these therapies have dramatically improved options for patients with IBD, there remains a modest ceiling for their overall efficacy. Currently there are no biomarkers that can guide treatment decisions in patients with UC. Some studies have reported certain molecules or immune populations that are associated with treatment resistance or as predictors of treatment response. However, their clinical utility have yet to be fully determined because there is a paucity of longitudinal studies examining the direct effects of current biologics and small molecule inhibitors approved for UC on the immune biology of the colon mucosa. In this study, we perform longitudinal immune phenotyping using flow cytometry in patients with UC before and after therapy. Colon biopsy tissue was taken prior to treatment from 10 UC patients who were then followed and repeat biopsies were obtained from the same patients after 6-12 months of treatment. Tissue was analyzed using high dimensional flow cytometry with a panel of 24 markers of both lymphoid and myeloid lineages. Pre-treatment samples with inflammation correlated with higher populations of CD4+ T cells and CD4+ FOXP3 regulatory T cells also positive for TIGIT and GITR. Inflammation also corresponded with the presence of a CD33+ HLA-DR- population classically known as myeloid-derived suppressor cells (MDSC). Overall, therapy significantly decreased immune cell infiltration in the colon, most notably in B and T cell populations. However, certain treatments increased the MDSC population along with the stromal compartment of non-immune cells. A comprehensive analysis of the populations present during active inflammation and the treatment-induced changes in mucosal immunity will help identify biomarkers to predict response to therapy. In addition, examining the interplay between immune cells and the surrounding stroma can may lead to important findings that improve our understanding of each drug’s mechanism and efficacy. Future experiments with single cell RNA and T cell receptor sequencing on the same patients will identify effects of biologic therapy on the T cell repertoire and interactions between immune, epithelial, and stromal cells in the colonic mucosa. With the advent of novel sequencing and immune profiling assays, we now have the ability to harness the power of precision medicine to make more informed therapeutic decisions for IBD patients that improve clinical outcomes.
A NEW MODEL TO STUDY INTESTINAL FIBROSIS USING IPSC-DERIVED HUMAN EPITHELIAL AND MESENCHYMAL CELLS FROM CROHN’S DISEASE PATIENTS
Authors: Valencia Christian Wong , Patel Shachi , Bay Olivia , Estrada Hannah , Casero David , Targan Stephan , Barrett Robert 
Published: January 2023

Abstract

INTRODUCTION
Intestinal fibrosis is a serious complication of Crohn's disease (CD) and is caused by the excess deposition of extracellular matrix protein. There are no therapies to prevent or treat this and surgical intervention remains the only treatment option. Numerous cell types, including intestinal epithelial and mesenchymal cells, are implicated in this but research efforts are impaired by a lack of in vitro models. Human intestinal organoids (HIOs), derived from induced pluripotent stem cells (iPSCs), are comprised of both of these cell types; therefore iPSC-derived HIOs represent an approach in which an unlimited number of patient specific cells could be generated for such models. Our goal was to confirm the feasibility of using iPSC-derived epithelial and mesenchymal cells from CD patients to model intestinal fibrosis

METHODS
iPSCs from CD patients with and without fibrotic complications were directed to form HIOs. As iPSC-derived HIOs contain epithelial and mesenchymal cells, the organoids were dissociated to generate purified cultures of epithelial-only HIOs (eHIOs) and mesenchymal cells. Both cell types were cultured with TNFα and TGFβ, and responses were assayed after 8, 24 and 48 hrs. Further assessment on the transcriptomic profile of the cultures was conducted using the Nanostring nCounter Fibrosis Panel.

RESULTS
Mesenchymal cells treated with TNFα for 48 hrs showed a significant increase in MMP9 expression, whereas TGFβ elicited an upregulation in COL1A1 and COL5A1. Further analysis via Nanostring identified the upregulation of numerous other fibrosis-related genes in response to TNFα stimulation, mainly: CCL2, IL6, MMP7, and MMP9. In eHIO cultures, after 24 hrs of cytokine exposure, we detected a significant upregulation in EMT (NCAD, VIM, and SNAI2) and fibrosis genes (COL1A1, COL5A1, and MMP9), mainly in response to TGFβ and the combination TNFα/TGFβ. Nanostring further identified a total of 121 differentially expressed genes, mostly in response to these treatments, particularly: CCL2, IL11, MMP9, MMP10. Overall, Nanostring analysis found an upregulation in pathways associated with ECM production and remodeling, immunomodulation, and ligands associated with EMT and cell migration.

CONCLUSION
We have successfully generated a system to assay intestinal fibrosis in a patient-specific manner using iPSC-derived epithelial and mesenchymal cells from CD patients. Our model elicited a reliable and reproducible response to inflammatory and fibrogenic stimuli, measured by the differential expression of key fibrosis-associated genes. Future studies will focus on a broader analysis of these data via RNA-seq to investigate a potential fibrogenic phenotype and to identify novel genes/pathways that may play in role in the pathophysiology of intestinal fibrosis in CD.
CREATINE KINASE EXPRESSION IS PROTECTIVE IN A MOUSE COLITIS MODEL
Authors: Hall Caroline , Lanis Jordi , Dowdell Alexander , Murphy Emily , Colgan Sean 
Published: January 2023

Abstract

BACKGROUND
We have previously identified a loss of expression of creatine pathway proteins in mucosal tissue samples from inflammatory bowel disease patients. This is important as creatine is vital to ATP buffering in energetically active cells. The goal of this study was to determine the impact of decreased creatine kinase (CK) expression on mucosal inflammation by utilizing a whole body CK Brain and CK Mitochondrial knockout mouse (CKB/MitKO) in the dextran sulfate sodium (DSS) model of acute colitis.

METHODS
CKB/MitKO and matched controls were administered 1.5% DSS in drinking water for 5 days and assessed by body weight loss, disease activity index, mucosal permeability, histology and inflammatory cytokine production by Mesoscale analysis. In subsequent experiments, interferon-γ (IFN-γ) was given by intraperitoneal injection during the DSS experiment. We also analyzed transcriptional differences between CKB/MitKO and controls using a transcription factor array and western blot. Finally, we evaluated the impact of CK on the regulation of IFN-γ and transcriptional regulation of IFN-γ production in immune cells by flow cytometry.

RESULTS
Loss of CKB/Mit did not result in detectable baseline inflammation or barrier dysfunction in CKB/MitKO mice as compared to controls. However, in the setting of the chemical irritant DSS, CKB/MitKO mice had significantly increased weight loss, disease activity, intestinal permeability, histologic inflammation and decreased colon length. While control mice treated with DSS had significant increases in mucosal IFN-γ, the CKB/MitKO mice had strikingly absent mucosal protein concentrations of IFN-γ. Although IFN-γ is commonly considered a pro-inflammatory cytokine, it has also been shown to help promote inflammatory resolution. Therefore, we proceeded to add back IFN-γ in DSS experiments and we identified significant protection from weight loss and histologic damage with the addition of IFN-γ. We went on to identify transcription factor differences between CKB/MitKO and control splenocytes that revealed a &gt;40-fold increase in the hypoxia responsive factor, HIF-1a, in CKB/MitKO splenocytes. We confirmed a causative relationship between HIF-1 expression and IFN-γ by treating mouse splenocytes with a HIF stabilizer and identified that HIF stabilization results in a reduction of IFN-γ production by CD4+ and CD8+ T cells.

CONCLUSIONS
CK is an essential energetic regulator. Using CK knockout mice we have identified an important role for CK in regulating IFN-γ production, mediated at least in part by HIF stabilization. These findings support a novel role for CK in tissue protection by immune regulation during acute colitis. Better understanding the role of energetics and the creatine pathway in particular may provide novel therapeutic options in inflammatory bowel disease.
EXCESS DIETARY SUGAR ALTERS COLONOCYTE METABOLISM AND IMPAIRS THE EARLY PROLIFERATIVE RESPONSE TO DAMAGE
Authors: Burr Ansen , Ji Junyi , Ozler Kadir , Mentrup Heather , Eskiocak Onur , Cumberland Rachel , Menk Ashley , Zhang Xiaoyi , Overacre-Delgoffe Abigail , Rittenhouse Natalie , Marshall Chris , Cooper Vaughn , Poholek Amanda , Delgoffe Greg , Beyaz Semir , Hand Timothy 
Published: January 2023

Abstract
The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. An important regulator of ISC and TA cell function is dietary metabolites which can affect their proliferative capacity. Over the last 150 years, the diet of high-income countries contains increasing amounts of simple sugars, such as sucrose, but whether excess sugar affects the function of ISCs and TA cells directly is unknown. We used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (DSS colitis) to demonstrate the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. We demonstrate that high sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative and key stem cell gene signatures. Further, high-glucose conditions led to the accumulation of glycolytic metabolite pyruvate in colonoids, with a concomitant decrease in ATP, suggesting impaired glycolytic fuel metabolism. Treatment of colonoids with DCA, which forces pyruvate into the TCA cycle, restored their growth, ATP levels, and the expression of proliferation and stem cell gene signatures. Similarly, DSS treatment of mice fed a high sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Metabolic analyses of crypt cells from high-sucrose-fed mice revealed increased glycolytic potential without a commensurate increase in aerobic respiration. Rather, epithelium from high-sucrose-fed mice has increased mitochondrial content, without increased levels of ATP, further demonstrating impaired oxidative phosphorylation and fuel metabolism. Finally, we demonstrated impaired proliferative potential of ISCs and reduced number of TA direct daughter cells in high-sucrose-fed mice with DSS damage. Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury, as is seen in patients with an acute flare of Ulcerative Colitis.
STRUCTURAL MODIFICATIONS OF BUTYRATE REVEAL TEMPLATES FOR INTESTINAL EPITHELIAL HIF STABILIZERS
Authors: Ornelas Alfredo , Wang Ruth , Countess Jake , Colgan Sean 
Published: January 2023

Abstract
Microbiota-derived short chain fatty acids, particularly butyrate (BA), show multiple beneficial influences on health. In the colon, BA ranges from 10-20 mM and up to 99% is utilized as a metabolic fuel by the mucosa. BA plays a key role in epithelial barrier regulation, reduces inflammation, and regulates cell growth and differentiation. There are multiple mechanisms by which BA contributes to gut health, many due to its regulatory capacity for gene expression. Our group reported (PMID: 34190032) a direct influence of BA on the stabilization of the transcription factor hypoxia-inducible factor (HIF). It is known that HIF stabilization is essential for appropriate mucosal barrier regulation and the coordination of regenerative capacity in the intestine. However, BA is constantly metabolized limiting its HIF stabilization effect. This observation led to the design and investigation of BA-mimicking compounds that stabilize HIF, but may not be involved in metabolism. We hypothesize that structural modifications of BA yield analogues that stabilize HIF with better efficacy and a longer biological half-life. A library of BA derivatives was screened in search of a non-endogenous analogue with higher potency and/or longer half-life for HIF stabilization. In vitro screenings at physiologically-relevant concentrations (5 mM) were performed using intestinal epithelial cell lines (T84 and CaCO2) in normoxia to determine HIF-1a protein abundance. Various analogues stabilized HIF, with 4-mercapto-butyrate (MBA) being the most promising candidate. The best analogues were validated through the induction of classic HIF gene targets, including BNIP3 and CAIX by q-PCR. MBA exhibited higher induction of these targets compared to BA. Time-course studies revealed that MBA exhibits significantly longer half-life as observed in the stabilization of HIF and induction of gene targets for up to 72 h compared to BA (24 h). Loss of gene induction was observed in MBA treated cells expressing lentiviral shRNA against HIF1b (HIF1b KD), supporting a HIF-dependent transcription. Furthermore, it’s been widely reported that BA enhances epithelial barrier, primarily through HIF coordinated barrier protection. Among several other BA derivatives, MBA enhanced and prolonged epithelial barrier function in intestinal epithelial cells. In vivo studies in C57BL/6 mice explored the induction of HIF targets in tissue and specifically erythropoietin (EPO) in circulation following administration of BA and MBA at similar doses. These studies revealed that induction of EPO with a single dose of MBA exceeded that of native BA. In colonic and kidney tissue, GLUT1 and BNIP3 were moderately induced in vivo. Thus, a non-endogenous BA derivative (MBA) stabilizes HIF at higher potency and longer half-life than native BA and will be used as a template for the development of HIF stabilizing agents.