bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia
Authors: Ishida Yamato , Kobayashi Takuya , Chiba Shuhei , Katoh Yohei , Nakayama Kazuhisa 
Published: January 2021

Abstract
Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140 and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.
STOCHASTIC INTERINDIVIDUAL MICROBIOME VARIATION MAY GUIDE PROTECTIVE PERINATAL PROBIOTIC DEVELOPMENT AGAINST IBD
Authors: Krishna Mahesh , Engevik Melinda , Queliza Karen , Britto Savini , Shah Rajesh , Ruan Wenly , Wang Hangtao , Versalovic James , Kellermayer Richard 
Published: January 2021

Abstract
The purpose of our experiment was to explore how stochastic inter-individual variation in the mammalian gut microbiome may link to inflammatory bowel disease (IBD) susceptibility, and guide the development of a perinatal preventative probiotic.
Dextran sodium sulfate (DSS) was introduced to C57BL/6J mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach towards stochastic DSS susceptibility. Lactobacilli (two different cocktails of L. reuteri and L. johnsonii strains) or control media were supplemented by mouth to dams prior to delivery and during lactation (i.e. perinatal probiotic). The pups were evaluated for DSS susceptibility at young adulthood.
Fecal Lactobacillus was increased in the DSS-resistant mice in both the discovery and validation cohorts. Maternal supplementation of female offspring with an L. reuteri cocktail (strains 6798-1, 6798-jm, and 6798-cm) induced progressive microbiome separation and protection against colitis by young adulthood.
Maternal supplementation of L. reuteri could confer protection against DSS colitis in young adult female mice. This work is the first to exploit stochastic mammalian microbiome variation to guide microbial therapeutic identification. Our findings underscore neonatal microbiome plasticity and set the stage for the potential development of perinatally deliverable protective probiotics against human IBD.
EFFECT OF OZANIMOD ON FECAL CALPROTECTIN AND FECAL LACTOFERRIN, BIOMARKERS OF INTESTINAL INFLAMMATION, IN THE PHASE 2 TOUCHSTONE STUDY OF PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS
Authors: Sandborn William , Feagan Brian , Wolf Douglas , D’Haens Geert , Vermeire Séverine , Hanauer Stephen , Ghosh Subrata , Southworth Harry , Harris Sarah 
Published: January 2021

Abstract

Introduction
Efficacy and safety of ozanimod, an oral sphingosine-1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, was previously demonstrated in the double-blind phase 2 TOUCHSTONE study (NCT01647516) in patients with moderate-to-severe ulcerative colitis. Here we report the effect of ozanimod on levels of fecal calprotectin (FCP) and fecal lactoferrin (FLF), two markers of intestinal inflammation.

Methods
Patients in TOUCHSTONE were randomized 1:1:1 to once daily oral ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg), ozanimod HCl 1.0 mg (equivalent to ozanimod 0.92 mg), or placebo for 8 weeks; responders at week 8 (based upon Mayo score) entered a maintenance phase through week 32. Stool collection occurred at baseline and weeks 8 and 32 to measure levels of FCP and FLF.

Results
A total of 197 patients were randomized and received treatment (n=65, placebo; n=65, ozanimod 0.5 mg; n=67, ozanimod 1 mg). Median baseline levels of FCP were 1272, 1477, and 1238 μg/g, respectively; baseline FCP levels were not associated with baseline Mayo score. Median baseline levels of FLF were 29.0, 30.6, and 29.9 μg/g, respectively; baseline FLF was related to week 8 Mayo score even after adjusting for baseline Mayo score. At week 8, FCP levels declined across treatment groups (median percent change from baseline, -53.4, -68.7, and -70.0 in placebo, ozanimod 0.5 mg and 1 mg groups, respectively); declines in FCP were maintained at week 32 (median percent change from baseline, -42.3, -72.6, and -80.6, respectively). At week 8, declines in FCP were greater in patients achieving clinical response (based on Mayo score) than in non-responders on ozanimod 1 mg. Declines in FCP at week 8 were also greater in patients achieving clinical remission than in those who did not, with greater declines with ozanimod 1 mg relative to 0.5 mg. FLF levels declined at weeks 8 and 32 across treatment groups, with greater changes in the ozanimod 1 mg group vs placebo (median percent change from baseline, week 8: -35.7, -61.0, and -84.7, respectively; week 32: -60.2, -62.5, -85.3, respectively, for placebo, ozanimod 0.5 mg, and ozanimod 1 mg). Reductions in FLF at week 8 were greater for treatment responders vs non-responders and for those achieving vs not achieving clinical remission in the ozanimod 1 mg group.

Conclusion
In TOUCHSTONE, treatment with ozanimod was associated with declines in FCP levels in treatment responders (for the 1 mg dose group) or those who achieved clinical remission (both doses). Ozanimod 1 mg was also associated with declines in FLF for treatment responders and those achieving remission.
ROLE OF MAGNETIC RESONANCE ENTEROGRAPHY IN THE DIAGNOSTICS OF ACTIVE CROHN’S DISEASE IN CHILDREN
Authors: Siejka Karolina , Kuczynska Maryla , Grzegorczyk Magdalena , Nowakowska Malgorzata , Piekarska Monika , Zbroja Monika , Cyranka Weronika , Brodzisz Agnieszka , Wozniak Magdalena Maria 
Published: January 2021

Abstract

Background
Crohn’s disease (CD) is an idiopathic inflammatory bowel disease of the gastrointestinal tract. It is more common in the developed and industrialized countries, particularly in the Western Europe and North America. Up to 20–30% of patients present first symptoms during childhood or adolescence. Traditionally it is diagnosed by clinical indicates, endoscopy and histological findings. Assessment of the disease activity and location along the gastrointestinal tract are of crucial importance for diagnosis and implementation of the proper treatment. Active inflammation can manifest as mural thickening, edema, ulcerations, abscesses or fistulas. Magnetic resonance enterography (MRE) is the most modern radiological method in depicting all of these manifestations of CD.

Objective
The aim of the study was to assess the value of MRE in evaluation of Crohn’s disease in pediatric patients.

Materials and Methods
18 children (8 boys, 10 girls) with confirmed diagnosis of Crohn’s disease, were included in the study. Each patient underwent MR enterography with intravenous administration of a contrast agent. All studies were performed using a 1.5T scanner according to a local study protocol.

Results
All MRE findings were associated with small bowel inflammation. All patients showed asymmetric ileal wall thickening and edema. Edematous ileocecal valve was visible in 8 patients. In 7 cases reactive lymphadenopathy was detected (lymph nodes ≥ 10 mm in short axis). In 4 patients small intestine fistulas were found, whereas abscess was observed in another 4 patients. In contrast-enhanced images, a vivid enhancement of the affected bowel section was revealed in all patients and in 10 children inflammatory infiltration of periintestinal fat was depicted.

Conclusion
MRE is a reliable tool in diagnosis, evaluation of the disease activity and assessment of potential complications of Crohn’s disease. Due to the lack of ionizing radiation MRE exhibits beneficial safety profile and can be offered to patients who repeatedly require follow-up examinations, especially in pediatric patients.
COLORECTAL ADENOCARCINOMA DEVELOPING IN A YOUNG FEMALE WITH OVERLAP SYNDROME AND VERY EARLY ONSET-INFLAMMATORY BOWEL DISEASE: A CASE REPORT
Authors: Kandavel Prashanthi , Shakhin Victoria , Chavannes Mallory , Gayer Christopher , Naon Hillel , Larry Wang , Yanni George 
Published: January 2021

Abstract
We present a 4-year-old female diagnosed with very-early onset inflammatory bowel disease (VEO-IBD), ulcerative colitis type, and overlap syndrome based on clinical presentation, blood and stool studies, diagnostic endoscopies and liver biopsy. Her clinical course was complicated by pervasive psychological stressors, non-compliance with medical therapy, and frequent provider changes. Initial treatment included Prednisone, 6-mercaptopurine and Ursodiol. Treatment was escalated to include multiple biological agents which were stopped prematurely due to non-adherence. She developed weight loss and growth stunting, necessitating exclusive enteral nutrition and then parenteral nutrition. Due to medically refractory disease, she underwent a total colectomy with end ileostomy at the age of 13. Pathology revealed stage III colorectal adenocarcinoma (CRC) with lymph node involvement and transmural inflammation diagnostic of Crohn’s disease (CD). Genetic testing of the resected colon noted a missense mutation of TP53. Our patient completed 6 cycles of extensive and targeted chemotherapy with no evidence of disease reccurrence. She recently underwent ileal pouch-anal anastomosis and creation of a diverting ileostomy.
CRC is exceedingly rare in pediatric IBD (PIBD) patients, with less than 30 reported cases in the available literature1. Most cases occurred in males and patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC), where the risk of developing CRC is four times greater2. The risk of CRC increases with disease duration, with most PIBD patients developing CRC at 25 years of age1. Interestingly, mutations in TP53, a tumour suppressor gene, have been found to occur more frequently in patients with IBD-CRC compared to those with sporadic-CRC or IBD without dysplasia3. Mutations in TP53 may not only increase a patients general susceptibility to CRC but may also accelerate its development by contributing to excessive inflammation4.
Our patient’s treatment refractory clinical course and transition in IBD diagnosis from UC to CD highlights the complexity of VEO-IBD management. While rare in pediatric patients, the development of CRC is a life-threatening risk and it should be considered in patients with prolonged and severely refractory IBD with concomitant autoimmune liver disease. Our patient’s young age at the time of CRC diagnosis emphasizes the need for vigilant yearly endoscopic screening and development of pediatric guidelines for dysplasia monitoring in this high risk population. Further research is needed to evaluate the role of genetic variant screening in CRC risk stratification.
References:
1. Aardoom MA, et al. Inflamm Bowel Dis. 2018;24(4):732–741.
2. Soetikno RM, et al. Gastrointest Endosc. 2002;56(1):48–54.
3. Yaeger R, et al. Gastroenterology. 2016;151(2):278–287.
4. Cooks T, et al. Cancer Cell. 2013;23(5):634–46.
OUTCOMES FOR PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND IBD: ULCERATIVE COLITIS VERSUS CROHN’S DISEASE- AN ANALYSIS OF THE NATIONAL INPATIENT SAMPLE 2015–2017
Authors: Dasu Neethi , Khalid Yaser , Joo Lucy , Blair Brian 
Published: January 2021

Abstract

Introduction
There is a scarcity of data on the influence of sex, race, insurance status on mortality, hospital length of stay (LOS), and total hospital charges for patients with ulcerative colitis (UC) and acute myocardial infarction (AMI) versus patients with Crohn’s disease and AMI. Previous studies have identified that patients with inflammatory bowel disease (IBD) have a lower incidence of AMI compared to the general population, but Ulcerative Colitis has not been compared to Crohn’s Disease for AMI. The aim of this study was to identify risk factors in a national population cohort (in the USA) admitted to hospital between 2015 and 2017.

Methods
All patients aged 18 years with AMI and UC and AMI and Crohn’s disease,who had been admitted to hospital between 2015 and 2017, were identified from the US Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database in the USA. Multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics.

Results
Our study identified approximately 200,000 patients who had been discharged with either UC or Crohn’s disease from 2015 to 2017. Of these patients, 208 were admitted with UC and AMI versus 258 with Crohn’s disease and AMI. The analysis revealed that mortality was decreased (OR -1.19, p &lt;0.237), length of stay (LOS) was increased (OR 2.08, p &lt;0.038), and total hospital charges were increased (OR 3.54, p &lt;0.0001) for patients with UC and AMI compared to patients with Crohn’s disease and AMI. Independent positive predictors of mortality were age, black race, and Medicaid insurance. Independent positive predictors of increased hospital LOS were age and Hispanic ethnicity. Independent positive predictors of increased total hospital charges were Hispanic ethnicity and Medicare insurance.

Conclusions
Patients with UC and AMI have increased LOS and total hospital charges compared to patients with Crohn’s disease and AMI. We identified key drivers for these outcomes. Previous studies showed that patients with IBD had a lower incidence of AMI compared to the general population, but newer studies demonstrate that patients with IBD may be at higher risk. This could possibly be related to the underlying shared pathophysiology of inflammation. In the future, more randomized clinical trials are required to compare patients with UC to patients with Crohn’s disease, especially the impact of therapeutic interventions on the incidence of AMI for this patient population.
RISK OF ANAL CANCER IN INFLAMMATORY BOWEL DISEASE PATIENTS IN THE US: A POPULATION-BASED STUDY 2008–2018
Authors: Suk Ryan , Sonawane Kalyani , Bauer Cici , Lairson David , Deshmukh Ashish 
Published: January 2021

Abstract

Background
Patients with inflammatory bowel disease (IBD) are at elevated risk of developing anal cancer. However, it remains unclear whether the increased risk manifests from immunosuppressant use or location of the disease (inflammation). We aimed to examine whether the risk of anal cancer in IBD patients is attributable to immunosuppression or the disease’s location by comparing IBD patients with rheumatoid arthritis (RA) and diverticulitis patients, respectively.

Methods
We conducted a retrospective cohort study using the US Optum® commercial claims database (2008–2018). We estimated the risk of anal cancer in the IBD cohort compared to the RA cohort (to examine risk attributable to immunosuppressant use) and the diverticulitis cohort (to examine risk attributable to similar disease location). Disease cohorts and index dates were identified using a combination of ICD diagnosis codes and prescription drug use. Patients 18 years and older and with a minimum of 12 months of continuous insurance enrollment were included. All three cohorts were mutually exclusive; we excluded persons with HIV/AIDS or organ transplant. We estimated hazard ratios (HRs) using Cox proportional regression, adjusting for age at diagnosis, comorbidity, risk factors for HPV infection (smoking, obesity, genital wart, substance abuse, alcoholism), and prescription drug use. Analyses were stratified by sex.

Results
The study included 70,314 patients with IBD, 164,991 with RA, and 129,558 with diverticulitis. In men, the adjusted hazard ratio (aHR) of developing anal cancer was 6.78 (95% CI, 3.40–13.55) comparing IBD to RA, and was 2.68 (95% CI, 0.99–7.30) comparing IBD to diverticulitis. Among women, the risk of developing anal cancer was significantly higher in IBD compared to RA (aHR 2.70; 95% CI, 1.36–5.35), but not different compared to diverticulitis (aHR 0.70; 95% CI, 0.20–2.44). The factors associated with a higher risk of anal cancer in both men and women were age at diagnosis, history of genital wart, corticosteroid use, and immunosuppressant use.

Conclusion
We found a significantly elevated risk of anal cancer in IBD patients than RA patients. However, anal cancer risk was not significantly different when comparing IBD patients to diverticulitis patients. These results indicate that the location of the disease is more strongly associated with anal cancer incidence than the treatment of autoimmune disease.
INFLAMMATORY CYTOKINES AND MICROBIAL LIGANDS AND METABOLITES INTERACT TO MODULATE DUOX2 EXPRESSION AND ACTIVITY
Authors: Hazime Hajar , Fritsch Julia , Santander Ana , Brito Nivis , Fernandez Irina , Pignac-Kobinger Judith , Conner Gregory , Abreu Maria , Burgueno Juan 
Published: January 2021

Abstract

Background
The pathogenesis of inflammatory bowel diseases (IBD) is characterized by a dysregulated crosstalk between the host and the microbiome that leads to the development of inflammation and dysbiosis. Dysbiosis in IBD involves an expansion of Proteobacteria and a reduction of Firmicutes, particularly of butyrate-producing species such as Faecalibacterium prausnitzii. The epithelial NADPH oxidase dual oxidase 2 (DUOX2), which prevents bacterial colonization of the mucosa through the production of hydrogen peroxide (H2O2), is the only gene consistently altered in IBD patients before the onset of disease. However, the involvement of DUOX2 in IBD is not well understood. We aimed to define how inflammation and the microbiota regulate DUOX2 activity.

Methods
C57BI/6J males raised in specific-pathogen free (SPF) and germ-free (GF) conditions underwent a model of dextran sulfate sodium (DSS)-induced colitis for 6 days. We obtained colon specimens for histopathology and isolation of colon epithelial cells (CEC). We stimulated colonoids from wild-type (WT), toll-like receptor 4-KO (Tlr4-KO), and Duox2-KO mice with IFNγ, heat-killed adherent invasive Escherichia coli (AIEC) strain LF82, and heat-killed F. prausnitzii strain A2-165 and determined expression of Duox2, Duoxa2, and production of H2O2. We also treated colonoids with butyrate, a microbial metabolite with anti-inflammatory properties. Extracellular H2O2 production was analyzed by means of the Amplex Red assay, whereas gene expression was determined by qPCR.

Results
SPF mice undergoing DSS-induced colitis developed overt inflammation that was accompanied by upregulation of Duox2 and Duoxa2, as well as increased production of H2O2 in freshly isolated CECs. DSS-treated GF mice developed a mild inflammation that also caused increased H2O2 production and Duoxa2 upregulation. WT colonoid stimulation with IFNγ and the Crohn’s disease-associated pathobiont AIEC induced Duox2 and Duoxa2 expression, whereas heat-killed F. prausnitzii did not. Similarly, both IFNγ and AIEC promoted epithelial production of H2O2 in WT colonoids but not Duox2-KO colonoids, indicating that epithelial release of H2O2 in response to these stimuli is mediated by DUOX2. Response to AIEC additionally required functional TLR4. Although heat-killed F. prausnitzii did not alter H2O2 production, its metabolite butyrate caused a significant blockade in the release of H2O2 in response to both IFNγ and AIEC.

Conclusions
Our results show that both inflammation and pathobionts induce the expression and activity of DUOX2, which begets more inflammation. We posit that specific depletion of pathobionts or restitution with butyrate-producing bacteria such as F. prausnitzii may be beneficial in IBD.
DIFFERENTIALLY EXPRESSED GENE SIGNATURES OF ULCERATIVE COLITIS DETERMINE NOVEL REGULATORS AND PREDICT RESPONSE TO BIOLOGIC THERAPY
Authors: Penrose Harrison , Toraih Eman , Ruiz Emmanuelle , Iftikhar Rida , Collins Morgan , Kandil Emad , Savkovic Suzana 
Published: January 2021

Abstract
Disease heterogenicity among Ulcerative colitis (UC) patients and their variable responses to therapy is not well understood. Previously, using publicly available transcriptomes from colonic tissue of UC patients, we demonstrated the immune cell landscape and pathways that are common and distinct among patients and for non-responders to biologic therapy. Here, we AIM to determine differentially expressed gene signatures specific to inflamed UC tissue and for non-responders to biologic anti-TNFa and anti-a4b7 therapy in large patient cohorts. Methods: Transcriptomes from 210 UC patient samples from inflamed and matched uninflamed tissue (GSE4183, GSE14580, GSE38713, GSE107593) and from UC patients prior to and while receiving anti-TNFa (infliximab) and anti-a4b7 integrin (vedolizumab) (GSE12251, GSE73661) treatment were analyzed. Generating and analyzing differentially expressed genes (DEGs), transcriptional signatures, and hierarchical clustering were performed using the limma Bioconductor R package and Cluster3/JavaTree software. Disease/function analysis was performed by Ingenuity Pathway Analysis (IPA) and predicting outcomes to therapy by receiver operating characteristic (ROC) curve analysis and area under the curve (AUC). Transcripts were validated in primary UC tissue samples using qPCR. Results: In three UC cohorts, we identified a specific transcriptional signature of 100 DEGs (UC100) common among patients (Figure 1A-D). The UC100 signature was validated in an independent cohort, demonstrating the ability to distinctly separate inflamed from matched uninflamed transcriptomes (p=4.65e-08). The UC100 DEGs encode protein involved in inflammation, immunity, antimicrobial response, growth, cellular movement, metabolism (lipid, amino acid), and energy production. Among them are many DEGs with unexamined roles in UC, including PCK1, HMGCS2, ACAT1, HCAR3, LPCAT1, and LIPG. Their differential expression was further validated in primary UC tissue by qPCR. Moreover, we identified twenty DEGs in UC patients resistant to anti-TNFa and anti-a4b7 therapy (UCR20) (Figure 2A-C). The UC20R DEGs encode protein involved in inflammation, immune cell trafficking, antimicrobial responses, lipid metabolism, and mitochondrial dysfunction. Four of the top DEGs predicted resistance to both therapies with a sensitivity of 73.3% and specificity 85.7%; AUC for IGFBP5: 0.86±0.008, p=0.008; STC1: 0.83±0.09, p=0.015; VNN2: 0.81±0,10, p=0.022; and SELE: 0.77±0.11, p=0.045. Conclusion: This study demonstrates differentially expressed genes in UC common across cohorts and those with predictive power to biologic therapy outcome. This provides a platform for development of more precise diagnostic tools and personally tailored therapeutic regimens for UC patients.