Eun Soo Kim

Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease

Background and Aims To identify the associations of genetic and epigenetic variations in IL-23R and IL-17A with inflammatory bowel diseases (IBD). Methods The promoter and exon regions of IL-23R and IL-17A were analysed in 727 subjects (201 Crohns disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, IL-17A mRNA expression and methylation of the IL-17A promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. Results A case–control analysis showed that development of Crohns disease is associated with the IL-23R variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and IL-17A variants −737C>T (OR 1.50, 95% CI 1.06 to 2.13), −197G>A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G>C (OR 8.93, 95% CI 1.12 to 70.99). The −877G, −737T and −444A risk alleles of IL-17A displayed higher binding affinities with the transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and IL-17A mRNA level. Finally, Jurkat cells recovered IL-17A mRNA expression after exposure to demethylating agent. Conclusions The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis.

Development and Validation of Novel Diagnostic Criteria for Intestinal Behçet's Disease in Korean Patients With Ileocolonic Ulcers

OBJECTIVES:It is difficult to diagnose intestinal Behçets disease (BD) due to various extraintestinal manifestations emerging at different time points in the disease course and a lack of reliable diagnostic criteria. We conducted this study to develop and validate novel diagnostic criteria for intestinal BD.METHODS:Experts from three universities generated the preliminary diagnostic criteria for intestinal BD, and a consensus was reached using a modified Delphi method with 13 gastroenterologists participating. To validate the criteria, we recruited 12,850 consecutive patients who underwent colonoscopic examinations between January 2000 and December 2006 at Severance Hospital, Yonsei University, Seoul, Korea.RESULTS:The novel diagnostic criteria were developed on the basis of two aspects: colonoscopic findings and extraintestinal manifestations. Of the 12,850 patients, 280 with ileocolonic ulcers were enrolled for validation. At the time of initial colonoscopic examinations, patients were categorized for BD status into 4 groups: definite (84 patients), probable (67), suspected (15), and nondiagnostic (114). At the end of the follow-up period (mean, 50.9±25.7 months), intestinal BD was confirmed in 145 patients (51.8%)—84 (100%) from the definite group, 49 (73.1%) from the probable group, 10 (66.7%) from the suspected group, and 2 (1.8%) from the nondiagnostic group. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the diagnosis probability of these criteria were 98.6, 83.0, 86.1, 98.2, and 91.1%, respectively.CONCLUSIONS:These newly proposed, simple criteria might be useful in diagnosing intestinal BD, especially in patients with ileocolonic ulcers who do not fully satisfy the diagnostic criteria of systemic BD.

Inflammatory Bowel Disease in Korea: Epidemiological, Genomic, Clinical, and Therapeutic Characteristics

Inflammatory bowel disease (IBD) describes chronic inflammatory disease of the intestines and has a variable course; Crohns disease and ulcerative colitis comprise the two main forms of the condition. Although IBD occurs worldwide, its epidemiologic and clinical characteristics vary depending upon the geographic location and the ethnicity of the population. Identifying the characteristic features of IBD in populations living in different geographical locations and with different ethnicities may provide significant clues about its etiology and pathophysiology, which in turn may be helpful in the development of more appropriate treatment strategies for IBD for these different populations. Therefore, it is important for each country and region to evaluate critically the epidemiology, genomics, and clinical characteristics of IBD among its own population. We have performed a critical review of the recent data in Korea, and describe herein the current epidemiologic and genotypic status, as well as the clinical manifestations and therapeutic responses of IBD that are unique to Korean patients.

Utility of impulse oscillometry in young children with asthma.

Impulse Oscillometry (IOS) was developed as a tool to measure lung function, and as it only requires passive cooperation, it has been successfully used in younger children. The aim of this study was to assess the utility of IOS compared to conventional spirometry for lung function measures in asthmatic Korean children aged 3 to 6 yrs. Total serum IgE levels, total eosinophil counts, and specific IgE levels were measured in 77 children with asthma and 55 control subjects. IOS and spirometry were performed in the children before and after bronchodilator administration. Asthmatic children significantly differed from control subjects in baseline resistance at 10 Hz and in their IOS‐assessed bronchodilator responses through a Δresistance at 5 Hz (mean, −27.4% vs. −13.1%; p = 0.002), 10 Hz (mean, −20.4% vs. −11.5%; p = 0.012), 20 Hz (mean, −16.4% vs. −9.4%; p = 0.016), and 35 Hz (mean, −17.2% vs. −10.2%; p = 0.020). Conventional spirometry did not show statistically significant findings. Asthmatic children significantly differed from control subjects in IOS‐assessed bronchodilator response through a Δresistance at 5 Hz, both in atopic children and in non‐atopic children. For atopic children, atopic asthmatic children (n = 58) also significantly differed from atopic controls (n = 30) in baseline resistance at 10 Hz, 20 Hz, 35 Hz and impedance and in IOS‐assessed bronchodilator responses through a Δ resistance at 10 Hz and 35 Hz. There were some significant correlations between bronchodilator responses of spirometric parameters and IOS parameters. IOS is useful diagnostic tool in early asthma development and might be a helpful objective outcome measure of early interventions.

Comparison of double-layered and covered Niti-S stents for palliation of malignant dysphagia

Background and Aim:  Covered metal stents have been accepted as the treatment of choice for malignant dysphagia caused by esophageal and gastric cardia cancer, but stent migration is a major shortcoming. A double‐layered Niti‐S stent was therefore introduced to obviate this problem. We aimed to compare double‐layered and covered Niti‐S stents regarding safety, efficacy, and feasibility in the treatment of malignant dysphagia.

Efficacy, safety, and predictors of response to infliximab therapy for ulcerative colitis: A Korean multicenter retrospective study

Infliximab is currently used for the treatment of moderate‐to‐severe ulcerative colitis (UC) with an inadequate response to conventional agents. The efficacy and safety of infliximab in Korean patients with UC were assessed.

Proteomic and cytokine plasma biomarkers for predicting progression from colorectal adenoma to carcinoma in human patients

In the present study, we screened proteomic and cytokine biomarkers between patients with adenomatous polyps and colorectal cancer (CRC) in order to improve our understanding of the molecular mechanisms behind turmorigenesis and tumor progression in CRC. To this end, we performed comparative proteomic analysis of plasma proteins using a combination of 2DE and MS as well as profiled differentially regulated cytokines and chemokines by multiplex bead analysis. Proteomic analysis identified 11 upregulated and 13 downregulated plasma proteins showing significantly different regulation patterns with diagnostic potential for predicting progression from adenoma to carcinoma. Some of these proteins have not previously been implicated in CRC, including upregulated leucine‐rich α‐2‐glycoprotein, hemoglobin subunit β, Ig α‐2 chain C region, and complement factor B as well as downregulated afamin, zinc‐α‐2‐glycoprotein, vitronectin, and α‐1‐antichymotrypsin. In addition, plasma levels of three cytokines/chemokines, including interleukin‐8, interferon gamma‐induced protein 10, and tumor necrosis factor α, were remarkably elevated in patients with CRC compared to those with adenomatous polyps. Although further clinical validation is required, these proteins and cytokines can be established as novel biomarkers for CRC and/or its progression from colon adenoma.

Guggulsterone induces apoptosis in colon cancer cells and inhibits tumor growth in murine colorectal cancer xenografts

The plant sterol guggulsterone has recently been shown to have anti-tumorigenic potential. This study was designed to investigate the anti-tumor efficacy of guggulsterone and to elucidate its molecular mechanisms in colon cancer. Guggulsterone significantly increased apoptosis in HT-29 cells by activating caspases-3 and -8. Furthermore, guggulsterone decreased cIAP-1, cIAP-2, and Bcl-2 levels and increased the levels of truncated Bid, Fas, p-JNK, and p-c-Jun. The size of HT-29 xenograft tumors in guggulsterone-treated mice was significantly smaller than of the size of tumors in control mice. The present study suggests a potential therapeutic use for this compound in the treatment of colorectal cancer.

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population.

AIMS Although polymorphisms in IL23R have recently been proposed to predispose to Behcets disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population. MAIN METHODS Single nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays. KEY FINDINGS Individual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12-3.92), p=0.021), and GG+GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03-3.57), p=0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13-4.34), p=0.021). Furthermore, statistically significant gene-gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development. SIGNIFICANCE Our results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.

Comparison of quality of life and worry of cancer recurrence between endoscopic and surgical treatment for early gastric cancer

BACKGROUND The quality of life (QOL) of patients who survive early gastric cancer (EGC) is an area of increasing interest. OBJECTIVE To compare the QOL and degree of worry of cancer recurrence in EGC patients who underwent endoscopic submucosal dissection (ESD) or surgery. DESIGN Cross-sectional study. SETTINGS A tertiary referral center. PATIENTS A total of 565 patients with EGC who received ESD or surgery. INTERVENTION Questionnaires. MAIN OUTCOME MEASUREMENTS QOL was evaluated using the Short-form Health Survey and the European Organization for Research and Treatment of Cancer QOL questionnaires (QLQ-C30 and EORTC-QLQ-STO22). Mood disorders and the worry of cancer recurrence were estimated using the Hospital Anxiety and Depression Scale (HADS) and Worry of Cancer Scale, respectively. RESULTS Questionnaires were completed by 55.7% of the ESD (137/246) and 58.9% of the surgery (188/319) patients. The surgery group had more QOL-related symptomatic and functional problems, including fatigue (P=.044), nausea/vomiting (P=.032), appetite loss (P=.023), diarrhea (P<.001), pain (P=.013), reflux symptoms (P=.005), eating restrictions (P<.001), anxiety (P=.015), taste impairment (P=.011), and poor body image (P<.001). The ESD group had significantly higher worry of cancer recurrence scores after adjusting for covariates, especially when visiting their physicians. The HADS results did not differ between the groups. LIMITATIONS Cross-sectional design. CONCLUSIONS Endoscopic treatment for EGC provides a better QOL, but stomach preservation might provoke cancer recurrence worries. Endoscopists should address this issue for relieving a patients concern of cancer recurrence during follow-up period after ESD. ( CLINICAL TRIAL REGISTRATION NUMBER WHO ICTRP KCT0000791.).