scholarly journals Identification of Pharmacological Autophagy Regulators of Active Ulcerative Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Peishan Qiu ◽  
Lan Liu ◽  
Jun Fang ◽  
Meng Zhang ◽  
Haizhou Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Intestinal Mucosa ◽  
Immune Cell ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Unknown Etiology ◽  
Healthy Controls ◽  
Aminosalicylic Acid ◽  
Activated T Cells ◽  
Increased Risk

Background: Ulcerative colitis (UC) is a chronic recurrent disease of unknown etiology. Recently, it has been reported that autophagy-related gene polymorphism is closely associated with increased risk of UC, and the therapeutic effect of some UC drugs is mediated by regulating autophagy pathways. This study aims to identify pivotal autophagy-related regulators in UC pathogenesis and provide novel molecular targets for the treatment of active UC.Methods: Gene expression profiles and clinical information of active UC patients were obtained from GEO databases. CIBERSORT was adopted to evaluate the immune cell infiltration. We used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify the pivotal modules and genes associated with active UC. Subsequently, we conducted validation in the validation set and explored its relationship with commonly used UC therapeutics.Results: 36 healthy controls and 46 active UC patients have been obtained from the training set of GSE53306, GSE87466, and GSE134025. There were 423 differentially expressed genes (DEGs) found, which dramatically enriched in autophagy-related pathways. And more infiltration of mast cells, activated T cells, dendritic cells, and M1 macrophages were observed in the intestinal mucosa of active UC, while more infiltration of resting immune cells and M2 macrophages in healthy controls. WGCNA indicated that the turquoise and blue modules were the critical modules. CASP1, SERPINA1, and CCL2 have been identified as the hub autophagy-related genes of active UC, after combining DEGs and 232 autophagy-related genes from HADb with the genes of turquoise and blue modules, respectively. We further verified that CASP1, SERPINA1, and CCL2 were positively associated with active UC and served as an autophagy-related biomarker for active UC. Moreover, increased SERPINA1 in the involved intestinal mucosa was reduced in patients with active UC who responded to golimumab or glucocorticoid therapy. But, neither CASP1, SERPINA1, and CCL2 were changed by treatment of 5-aminosalicylic acid (5-ASA) and azathioprine.Conclusion: CASP1, SERPINA1, and CCL2 are autophagy-related hub genes of active UC. And SERPINA1 may serve as a new pharmacological autophagy regulator of UC, which provides a new target for the use of small molecules targeting autophagy in the treatment of active UC.

scholarly journals Innate Immunity Modulation by the IL-33/ST2 System in Intestinal Mucosa

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Marina García-Miguel ◽  
M. Julieta González ◽  
Rodrigo Quera ◽  
Marcela A. Hermoso
Keyword(s):  
Ulcerative Colitis ◽  
Innate Immunity ◽  
Intestinal Mucosa ◽  
Inflammatory Bowel Diseases ◽  
The Body ◽  
Unknown Etiology ◽  
Adequate Food ◽  
Bowel Diseases ◽  
Surface Contact Area ◽  
Inflammatory Bowel

Innate immunity prevents pathogens from entering and spreading within the body. This function is especially important in the gastrointestinal tract and skin, as these organs have a large surface contact area with the outside environment. In the intestine, luminal commensal bacteria are necessary for adequate food digestion and play a crucial role in tolerance to benign antigens. Immune system damage can create an intestinal inflammatory response, leading to chronic disease including inflammatory bowel diseases (IBD). Ulcerative colitis (UC) is an IBD of unknown etiology with increasing worldwide prevalence. In the intestinal mucosa of UC patients, there is an imbalance in the IL-33/ST2 axis, an important modulator of the innate immune response. This paper reviews the role of the IL-33/ST2 system in innate immunity of the intestinal mucosa and its importance in inflammatory bowel diseases, especially ulcerative colitis.

Association between cetuximab response and differential immunologic gene expression signatures in colorectal cancer metastases.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 558-558 ◽  
Author(s):  
Michael Sangmin Lee ◽  
Benjamin Garrett Vincent ◽  
Autumn Jackson McRee ◽  
Hanna Kelly Sanoff
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Activated T Cells ◽  
Gene Sets

558 Background: Different immune cell infiltrates into colorectal cancer (CRC) tumors are associated with different prognoses. Tumor-associated macrophages contribute to immune evasion and accelerated tumor progression. Conversely, tumor infiltrating lymphocytes at the invasive margin of CRC liver metastases are associated with improved outcomes with chemotherapy. Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cellular cytotoxicity (ADCC) in vitro. However, it is unclear in humans if response to cetuximab is modulated by the immune response. We hypothesized that different immune patterns detected in gene expression profiles of CRC metastases are associated with different responses to cetuximab. Methods: We retrieved gene expression data from biopsies of metastases from 80 refractory CRC patients treated with cetuximab monotherapy (GEO GSE5851). Samples were dichotomized by cetuximab response as having either disease control (DC) or progressive disease (PD). We performed gene set enrichment analysis (GSEA) with GenePattern 3.9.4 using gene sets of immunologic signatures obtained from the Molecular Signatures Database v5.0. Results: Among the 68 patients with response annotated, 25 had DC and 43 had PD. In the PD cohort, 59/1910 immunologic gene sets had false discovery rate (FDR) < 0.1. Notably, multiple gene sets upregulated in monocyte signatures were associated with PD. Also, gene sets consistent with PD1-ligated T cells compared to control activated T cells (FDR = 0.052) or IL4-treated CD4 T cells compared to controls (FDR = 0.087) were associated with PD. Conclusions: Cetuximab-resistant patients tended to have baseline increased expression of gene signatures reflective of monocytic infiltrates, consistent with also having increased expression of the IL4-treated T-cell signature. Cetuximab resistance was also associated with increased expression of the PD1-ligated T cell signature. These preliminary findings support further evaluation of the effect of differential immune infiltrates in prognosis of metastatic CRC treated with cetuximab.

scholarly journals P223 Degree of Histological Activity is not Associated with Vedolizumab Therapy Outcome in Ulcerative Colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S276-S276
Author(s):  
J Doherty ◽  
S Brennan ◽  
K Dinneen ◽  
C Muldoon ◽  
S Mc Kiernan ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Primary Endpoint ◽  
Immune Cell ◽  
Demographic Data ◽  
Therapy Outcome ◽  
Cell Trafficking ◽  
Therapy Assessment ◽  
Additional Information ◽  
Increased Risk ◽  
Histological Activity

Abstract Background Histological inflammation is known to be associated with increased risk of disease relapse in patients with ulcerative colitis (UC). Vedolizumab (VDZ) is a gut selective anti-integrin which inhibits intestinal immune cell-trafficking. Whether the degree of histological activity at the time of VDZ therapy initiation is associated with therapy outcome is not known. We aimed to determine if there is an association between histological activity at the time of VDZ initiation and outcome of therapy. Methods A retrospective review was performed to identify UC patients treated with VDZ who had undergone an endoscopic assessment prior to therapy commencement. Baseline demographic data, information on therapy outcome and Mayo endoscopic sub score (MES) was collected for all patients. Endoscopic biopsies were retrieved and were scored for histological activity using the Geboes Score (GS). For Kaplan Meir analyses of primary endpoint, the cohort was dichotomised around a GS grade of 5. Primary endpoint was VDZ therapy outcome defined as persistence on VDZ therapy over time. Secondary endpoints included association between GS and MES and the association between a combined endoscopic and histological endpoint (MES = 3 & GS grade 5) and VDZ therapy outcome. Results 33 patients were included [median age 44.3 years (range 17.2 -84.3); 36% male gender]. 24%, 43% and 33% of the cohort had proctitis, left-sided colitis and extensive colitis respectively. 67% of subjects had prior anti-TNF exposure. Median time from endoscopy to commencement of VDZ was 9 weeks. Median study follow-up was 68 weeks (range 6.1 – 228.7). 3%, 21%, 42% and 33% had MES of 0, 1, 2 and 3 respectively. GS grade was significantly associated with MES (p = 0.04) (Figure 1). GS grade was not associated with time to discontinuation of VDZ (p=0.64) (Figure 2). Combined endoscopic and histological endpoint was not associated with time to discontinuation of VDZ (p=0.43) (Figure 3). The presence of lamina propria eosinophils was not associated with time to discontinuation of VDZ (p=0.92). Conclusion GS grade is associated significantly with MES which has been demonstrated previously. Neither histological activity alone nor in combination endoscopic activity were associated with outcome of VDZ therapy. Assessment of histological activity does not appear to provide additional information when selecting patients for VDZ therapy.

scholarly journals Non-invasive diagnostic tool for Parkinson’s disease by sebum RNA profile with machine learning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuya Uehara ◽  
Shin-Ichi Ueno ◽  
Haruka Amano-Takeshige ◽  
Shuji Suzuki ◽  
Yoko Imamichi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differentially Expressed Genes ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Alpha Synuclein ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Non Invasive

AbstractParkinson's disease (PD) is a progressive neurodegenerative disease presenting with motor and non-motor symptoms, including skin disorders (seborrheic dermatitis, bullous pemphigoid, and rosacea), skin pathological changes (decreased nerve endings and alpha-synuclein deposition), and metabolic changes of sebum. Recently, a transcriptome method using RNA in skin surface lipids (SSL-RNAs) which can be obtained non-invasively with an oil-blotting film was reported as a novel analytic method of sebum. Here we report transcriptome analyses using SSL-RNAs and the potential of these expression profiles with machine learning as diagnostic biomarkers for PD in double cohorts (PD [n = 15, 50], controls [n = 15, 50]). Differential expression analysis between the patients with PD and healthy controls identified more than 100 differentially expressed genes in the two cohorts. In each cohort, several genes related to oxidative phosphorylation were upregulated, and gene ontology analysis using differentially expressed genes revealed functional processes associated with PD. Furthermore, machine learning using the expression information obtained from the SSL-RNAs was able to efficiently discriminate patients with PD from healthy controls, with an area under the receiver operating characteristic curve of 0.806. This non-invasive gene expression profile of SSL-RNAs may contribute to early PD diagnosis based on the neurodegeneration background.

scholarly journals Transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis

2020 ◽  
Author(s):  
Reza Yarani ◽  
Oana Palasca ◽  
Nadezhda T. Doncheva ◽  
Christian Anthon ◽  
Bartosz Pilecki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Mouse Model ◽  
High Throughput ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Unknown Etiology ◽  
Small Rna Sequencing ◽  
Complex Nature

1.AbstractBACKGROUND & AIMSUlcerative colitis (UC) is an inflammatory bowel disorder with unknown etiology. Given its complex nature, in vivo studies to investigate its pathophysiology is vital. Animal models play an important role in molecular profiling necessary to pinpoint mechanisms that contribute to human disease. Thus, we aim to identify common conserved gene expression signatures and differentially regulated pathways between human UC and a mouse model hereof, which can be used to identify UC patients from healthy individuals and to suggest novel treatment targets and biomarker candidates.METHODSTherefore, we performed high-throughput total and small RNA sequencing to comprehensively characterize the transcriptome landscape of the most widely used UC mouse model, the dextran sodium sulfate (DSS) model. We used this data in conjunction with publicly available human UC transcriptome data to compare gene expression profiles and pathways.RESULTSWe identified differentially regulated protein-coding genes, long non-coding RNAs and microRNAs from colon and blood of UC mice and further characterized the involved pathways and biological processes through which these genes may contribute to disease development and progression. By integrating human and mouse UC datasets, we suggest a set of 51 differentially regulated genes in UC colon and blood that may improve molecular phenotyping, aid in treatment decisions, drug discovery and the design of clinical trials.CONCLUSIONGlobal transcriptome analysis of the DSS-UC mouse model supports its use as an efficient high-throughput tool to discover new targets for therapeutic and diagnostic applications in human UC through identifying relationships between gene expression and disease phenotype.

scholarly journals Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn’s Disease and Ulcerative Colitis

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Maria Dobre ◽  
Elena Milanesi ◽  
Teodora Ecaterina Mănuc ◽  
Dorel Eugen Arsene ◽  
Cristian George Ţieranu ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Differential Diagnosis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Mucosa ◽  
Expression Profiles ◽  
Genetic Research ◽  
Gene Expression Profiles ◽  
Normal Mucosa ◽  
Transcript Levels

Genetic research has shaped the inflammatory bowel disease (IBD) landscape identifying nearly two hundred risk loci. Nonetheless, the identified variants rendered only a partial success in providing criteria for the differential diagnosis between ulcerative colitis (UC) and Crohn’s disease (CD). Transcript levels from affected intestinal mucosa may serve as tentative biomarkers for improving classification and diagnosis of IBD. The aim of our study was to identify gene expression profiles specific for UC and CD, in endoscopically affected and normal intestinal colonic mucosa from IBD patients. We evaluated a panel of 84 genes related to the IBD-inflammatory pathway on 21 UC and 22 CD paired inflamed and not inflamed mucosa and on age-matched normal mucosa from 21 non-IBD controls. Two genes in UC (CCL11 and MMP10) and two in CD (C4BPB and IL1RN) showed an upregulation trend in both noninflamed and inflamed mucosa compared to controls. Our results suggest that the transcript levels of CCL11, MMP10, C4BPB, and IL1RN are candidate biomarkers that could help in clinical practice for the differential diagnosis between UC and CD and could guide new research on future therapeutic targets.

scholarly journals P296 Stopping 5-aminosalicylic acid in patients with ulcerative colitis who are in clinical remission does not increase risks of flare

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S325-S326
Author(s):  
J W Y Mak ◽  
N T K Yuen ◽  
T C F Yip ◽  
R H M Lam ◽  
B K H Lam ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Remission ◽  
Cox Regression ◽  
Controlled Trial ◽  
Blood Parameters ◽  
Aminosalicylic Acid ◽  
Healthcare Database ◽  
Increased Risk ◽  
One Year

Abstract Background 5-aminosalicylic acid (ASA) has been the mainstay of treatment for ulcerative colitis (UC). However, it is unclear whether the medication can be stopped in patients with stable disease. We aimed to examine whether 5-ASA can be safely withdrawn in UC patients who have been in steroid-free clinical remission for at least 1 year. Methods This is a retrospective cohort study using a territory-wide healthcare database in Hong Kong. Primary outcome was development of UC flare defined as a composite of new corticosteroid use, UC-related hospitalization or surgery within 5 years after stopping-5ASA. UC patients who were on oral 5-ASA ≥ 2grams daily for at least 1 year, who had C-reactive protein &lt;1mg/dL and no escalation of 5-ASA dosage, no UC-related hospitalization and no use of corticosteroid in the past 1 year were included. UC patients who were on biologics were excluded. Patients were classified as stopping 5-ASA if 5-ASA had ever been withdrawn for at least 90 days within the follow-up period. We performed multivariable Cox regression models adjusting for demographics, blood parameters and immunosuppressants used. Adjusted hazard ratio (aHR) with 95% confidence interval (CI) was reported comparing groups stopping 5-ASA and those continuing 5-ASA. Results A total of 1408 patients with UC were included with a median follow-up duration of 41.8 months [Interquartile range (IQR): 17.2-60 months)]. Stopping 5-ASA was not associated with an increased risk of UC flare (aHR 0.99, 95% CI 0.76-1.30, p=0.722). Higher haemoglobin level at baseline was protective against flare (aHR 0.91, 95% CI 0.85-0.97, p=0.03), while higher CRP level at baseline was associated with an increased risk of flare (aHR 1.06, 95% CI 1.03-1.09, p&lt;0.001). Results were similar in sensitivity analysis investigating stopping 5-ASA for ≥ 180 days which showed no difference in risk of flare comparing groups continuing and stopping 5-ASA (aHR 1.02, 95%CI 0.71-1.48,p=0.912). There were no differences in the risk of requiring colectomy (HR: 2.23, 95% CI 0.67-7.49, p=0.193) or development of colorectal cancer (HR: 0.76, 95% CI 0.22-2.65, p=0.671) in patients who stopped 5-ASA and those who continued 5-ASA. Conclusion Stopping 5-ASA in patients with UC who have been in clinical remission for over one year was not associated with increased risk of flare. These results should be validated in prospective randomized controlled trial.

scholarly journals Identification of disease- and headache-specific mediators and pathways in migraine using blood transcriptomic and metabolomic analysis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Timea Aczél ◽  
Tamás Körtési ◽  
József Kun ◽  
Péter Urbán ◽  
Witold Bauer ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Immune Cell ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
White Blood Cells ◽  
Cell Activity ◽  
Gene Expression Profiles ◽  
Methionine Sulfoxide ◽  
Peripheral Blood Mononuclear ◽  
Plasma Metabolite

Abstract Background Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks. Methods Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit. Results We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks. Conclusions It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation.

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