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Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

The coronavirus disease 2019 (COVID-19) pandemic has reduced the ability to prevent or control chronic disease due to the concerns about safety in accessing health care. Inflammatory bowel disease (IBD) is a chronic condition requiring long- term sustained treatment, which is difficult in the current panedemic situation. The Korean Association for the Study of Intestinal Diseases (KASID) has developed an expert consensus statement on the clinical practice management of adult inflammatory bowel disease during the COVID-19 pandemic. This expert consensus statement is based on guidelines and clinical reports from several countries around the world. It provides recommendations to deal with the risk of COVID-19 and medication use in IBD patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and emphasizes the importance of right treatment approach to avoid worsening of the disease condition in IBD patients.

With the advent of checkpoint inhibitors, it has opened up opportunities for numerous cancer patients. However, as is the case with every treatment, complications need to be weighed. Gastrointestinal adverse effects, such as diarrhea and colitis are well-known complications for checkpoint inhibitors. In severe cases, colitis-induced colonic perforation may occur with an estimation of 1.0% to 1.5% in anti-CTLA-4 antibodies. However, only a handful of cases of such devastating complications have been reported in anti-PD-1 antibodies such as pembrolizumab and nivolumab. We here report a case of intestinal perforation in a patient treated with nivolumab.

Background and Objectives: There is currently no consensus on the criteria for admitting older adults to the intensive care unit. Methods: This single-center retrospective study evaluated the baseline and clinical characteristics of older adults admitted to the intensive care unit between January 2017 and June 2017; patients were analyzed according to their age group. Factors associated with in-hospital mortality were specifically determined using logistic regression analysis. Results: Among 582 patients included in the present study, 34.2%, 46.6%, and 19.2% were aged 65–74, 75–84, and over 84 years, respectively. In terms of clinical outcomes, although there were no significant differences in the length of intensive care unit and hospital stay and intensive care unit mortality, significant differences were observed in terms of in-hospital mortality, hospital discharge disposition, and neurologic outcomes at discharge ( p = 0.039, p = 0.005, and p = 0.032, respectively). Predictive factors for in-hospital mortality were age (⩾85 years), initial mental status (stupor to coma), a Korean Triage and Acuity Scale level of 1, underlying diagnosis of cancer, abdominal pain or discomfort, apnea, and a chief compliant of dyspnea. Conclusion: Compared to those aged 65–84 years, in-hospital mortality was 1.96-fold higher in those aged over 84 years. However, the overall mortality in our cohort was not considerably different from that of the younger population. Intensive care unit admission should be considered in selected older adults after evaluating the risk factors for mortality.

Cancer is a catabolic inflammatory disease that causes patients to often experience weight loss, or even cachexia in severe cases. Undernourishment in patients with cancer impairs the quality of life and therapeutic response, further leading to poor prognosis. Active and frequent nutritional screening and assessment using valid tools are important for fast and appropriate nutritional intervention. Additionally, a suitable individualized nutritional intervention strategy should be established based on the nutritional assessment result. In general, nutritional intervention begins with nutritional counseling of patients diagnosed with cancer, and a well-planned nutritional counseling improves the treatment adherence and nutritional status. When planning nutritional supplementation for cancer patients, specific nutrients, including amino acids and fatty acids, should be considered. However, there has been no consistent result showing that any particular nutrient significantly improves the prognosis of cancer patients. Hence, continuous attention from clinical physicians is needed to plan nutritional improvement in patients with cancer.

Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, is threatening global health worldwide with unprecedented contagiousness and severity. The best strategy to overcome COVID-19 is a vaccine. Various vaccines are currently being developed, and mass vaccination is in progress. Despite the very encouraging clinical trial results of these vaccines, there is insufficient information on the safety and efficacy of vaccines for inflammatory bowel disease (IBD) patients facing various issues. After reviewing current evidence and international guidelines, the Korean Association for the Study of Intestinal Diseases (KASID) developed an expert consensus statement on COVID-19 vaccination issues for Korean IBD patients. This expert consensus statement emphasizes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination be strongly recommended for IBD patients, and it is safe for IBD patients receiving immunomodulatory therapy.

TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 (AMPK&alpha, 1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPK&alpha, 1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPK&alpha, 1-knockout (AMPK&alpha, 1KO) HEK293T or AMPK&alpha, 1-knockdown (AMPK&alpha, 1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPK&alpha, 1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPK&alpha, 1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPK&alpha, l levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs (n = 5) with high AMPK&alpha, l levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPK&alpha, 1KO MDA-MB-231 and AMPK&alpha, 1KO MCF-7 human breast cancer cells. These results suggest that AMPK&alpha, 1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.

The impact of adherence to follow-up examination after a fecal occult blood test (FOBT) remains ill-defined.To evaluate the impact of adherence to the follow-up examination on clinical outcomes in individuals with positive FOBT results.This was a retrospective cohort study involving Korean individuals aged 50 years or older who participated in the National Cancer Screening Program for CRC from 2009 to 2010. Individuals who underwent a confirmative examination within a year after positive FOBT results were included in compliant group, and those who did not were included in non-compliant group. The incidence and stage of CRC, and 5-year survival were compared between two groups.5,914 were diagnosed with CRC in the compliant group and 2,973 in the non-compliant group. The proportion of advanced-stage CRC was significantly higher in the non-compliant group (localized CRC 44.6% vs. 36.7% and distant CRC 8.7% vs. 12.5%, p0.0001). The survival probability within 5 years was 71.0% in the non-compliant group and 85.9% in the compliant group (hazard ratio 1.70, 95% CI, 1.52-1.90, p0.001).Individuals who underwent follow-up examination 1 year or more after positive FOBT had a lower survival rate compared with that in those who underwent examination within 1 year.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

This study aimed to understand whether the effect of non-metastatic cells 1 (NME1) on recurrence-free survival (RFS) in early stage non-small cell lung cancer (NSCLC) can be modified by &beta, catenin overexpression and cisplatin-based adjuvant chemotherapy. Expression levels of NME1 and &beta, catenin were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 425 early stage NSCLC patients. Reduced NME1 expression was found in 39% of samples. The median duration of follow-up was 56 months, and recurrence was found in 186 (44%) of 425 patients. The negative effect of reduced NME1 expression on RFS was worsened by cisplatin-based adjuvant chemotherapy (adjusted hazard ratio = 3.26, 95% CI = 1.16&ndash, 9.17, p = 0.03). &beta, catenin overexpression exacerbated the effect of reduced NME1 expression on RFS and the negative effect was greater when receiving cisplatin-based adjuvant chemotherapy: among patients treated with cisplatin-based adjuvant chemotherapy, hazard ratios of patients with reduced NME1 expression increased from 5.59 (95% confidence interval (CI) = 0.62&ndash, 50.91, p = 0.13) to 15.52 (95% CI = 2.94&ndash, 82.38, p = 0.001) by &beta, catenin overexpression, after adjusting for confounding factors. In conclusion, the present study suggests that cisplatin-based adjuvant chemotherapy needs to be carefully applied to early stage NSCLC patients with overexpressed &beta, catenin in combination with reduced NME1 expression.

This study aimed to understand the clinicopathological significance of runt-related transcription factor 1 (RUNX1) in non-small cell lung cancer (NSCLC). The methylation and mRNA levels of RUNX1 in NSCLC were determined using the Infinium HumanMethylation450 BeadChip and the HumanHT-12 expression BeadChip. RUNX1 protein levels were analyzed using immunohistochemistry of formalin-fixed paraffin-embedded tissues from 409 NSCLC patients. Three CpGs (cg04228935, cg11498607, and cg05000748) in the CpG island of RUNX1 showed significantly different methylation levels (Bonferroni corrected p &lt, 0.05) between tumor and matched normal tissues obtained from 42 NSCLC patients. Methylation levels of the CpGs in the tumor tissues were inversely related to mRNA levels of RUNX1. A logistic regression model based on cg04228935 showed the best performance in predicting NSCLCs in a test dataset (N = 28) with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.96 (95% confidence interval (CI) = 0.81&ndash, 0.99). The expression of RUNX1 was reduced in 125 (31%) of 409 patients. Adenocarcinoma patients with reduced RUNX1 expression showed 1.97-fold (95% confidence interval = 1.16&ndash, 3.44, p = 0.01) higher hazard ratio for death than those without. In conclusion, the present study suggests that abnormal methylation of RUNX1 may be a valuable biomarker for detection of NSCLC regardless of race. And, reduced RUNX1 expression may be a prognostic indicator of poor overall survival in lung adenocarcinoma.

Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.

Cancer cachexia is a syndrome accompanying weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer. Since interleukin-6 (IL-6) is one of core mediators causing cancer cachexia and kimchi can modulate IL-6 response, we hypothesized dietary intake of kimchi can ameliorate cancer cachexia. In this study, we studied preemptive administration of kimchi can ameliorate mouse colon carcinoma cells colon (C26) adenocarcinoma-induced cancer cachexia and explored anti-cachexic mechanisms of kimchi focused on the changes of muscle atrophy, cachexic inflammation, and catabolic catastrophe. As results, dietary intake of kimchi significantly attenuated the development of cancer cachexia, presented with lesser weight loss, higher muscle preservation as well as higher survival from cancer cachexia in mice. Starting from significant inhibition of IL-6 and its signaling, kimchi afforded significant inhibition of muscle specific ubiquitin-proteasome system including inhibition of atrogin-1 and muscle ring finger protein-1 (MuRF-1) with other muscle related genes including mitofusin-2 (Mfn-2) and PGC-1α. Significant inhibition of lipolysis gene such as adipose triglyceride lipase (ATGL) and hormone-sensitive ligase (HSL) accompanied with significant induction of fatty acid synthase (FAS) and sterol response element binding protein 1 (SREBP1) was achieved with kimchi. As gene regulation, IL-6 and their receptor as well as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were significantly attenuated with kimchi. In conclusion, dietary intake of cancer preventive kimchi can be an anticipating option to ameliorate cancer cachexia via suppressive action of IL-6 accompanied with decreased muscle atrophy and lipolysis.

A target molecule responsible for cell cycle arrest by metformin was discovered using a gene chip array in lung cancer cells and the effect of metformin on E2F8 was assessed. The siRNA-mediated knockdown of E2F8 significantly suppressed G1-S progression while ectopic expression of E2F8 relieved metformin-induced G1 arrest. The mRNA levels of p21 were found to be inversely related to those of E2F8 in lung cancer cells while siRNA-mediated knockdown of p21 partly rescued siE2F8-induced arrest of the cell cycle. Metformin had no effect on degradation of E2F8 mRNA. Activation and inhibition of AMPK by AICAR and Dorsomorphin, respectively, did not affect E2F8 suppression by metformin. The clinical significance of E2F8 was analyzed in The Cancer Genome Atlas (TCGA) data. One hundred six (13%) of 848 TCGA lung cancers overexpressed E2F8 mRNA. The overexpression of E2F8 was associated with poor overall survival (adjusted hazard ratio = 1.58, 95% confidence interval = 1.13–2.22; P = 0.008). The present study suggests that metformin may induce cell cycle arrest at the G1 phase by suppressing E2F8 expression in lung cancer cells. In addition, E2F8 may be associated with poor overall survival in lung cancer patients irrespective of histology.

To generate accurate next-generation sequencing (NGS) data, the amount and quality of DNA extracted is critical. We analyzed 1564 tissue samples from patients with metastatic or recurrent solid tumor submitted for NGS according to their sample size, acquisition method, organ, and fixation to propose appropriate tissue requirements. Of the 1564 tissue samples, 481 (30.8%) consisted of fresh-frozen (FF) tissue, and 1,083 (69.2%) consisted of formalin-fixed paraffin-embedded (FFPE) tissue. We obtained successful NGS results in 95.9% of cases. Out of 481 FF biopsies, 262 tissue samples were from lung, and the mean fragment size was 2.4 mm. Compared to lung, GI tract tumor fragments showed a significantly lower DNA extraction failure rate (2.1 % versus 6.1%, p = 0.04). For FFPE biopsy samples, the size of biopsy tissue was similar regardless of tumor type with a mean of 0.8 × 0.3 cm, and the mean DNA yield per one unstained slide was 114 ng. We obtained highest amount of DNA from the colorectum (2353 ng) and the lowest amount from the hepatobiliary tract (760.3 ng) likely due to a relatively smaller biopsy size, extensive hemorrhage and necrosis, and lower tumor volume. On one unstained slide from FFPE operation specimens, the mean size of the specimen was 2.0 × 1.0 cm, and the mean DNA yield per one unstained slide was 1800 ng. In conclusions, we present our experiences on tissue requirements for appropriate NGS workflow: > 1 mm2 for FF biopsy, > 5 unstained slides for FFPE biopsy, and > 1 unstained slide for FFPE operation specimens for successful test results in 95.9% of cases.

Background: The compliance with the follow-up examination after a positive fecal occult blood test (FOBT) is lower than expected. We aimed to evaluate the adherence rate to the follow-up examination in patients with a positive FOBT and to identify the clinical factors associated with this adherence. Methods: The study population comprised adults aged &ge, 50 years who participated in the National Cancer Screening Program for colorectal cancer (CRC) in 2013. Compliance was defined as undergoing follow-up examination within 1 year of a positive FOBT. Results: From 214,131 individuals with a positive FOBT, 120,911 (56.5%) were in the compliance group and 93,220 (43.5%) were in the non-compliance group. On multivariate analysis, good compliance was associated with men (odds ratio (OR) = 1.12, 95% confidence interval (CI) (1.09&ndash, 1.15)), younger ages (70&ndash, 79 years, OR = 2.19 (2.09&ndash, 2.31), 60&ndash, 69 years, OR = 3.29 (3.13&ndash, 3.46), 50&ndash, 59 years, OR = 3.57 (3.39&ndash, 3.75) vs. &gt, 80 years), previous experience of CRC screening (a negative FOBT, OR = 1.18 (1.15&ndash, 1.21), a positive FOBT, OR = 2.42 (2.31&ndash, 2.54)), absent previous experience of colonoscopy or barium enema (OR = 2.06 (1.99&ndash, 2.13)), higher economic income (quartile, 75%, OR = 1.14 (1.11&ndash, 1.17), 100%, OR = 1.22 (1.19&ndash, 1.25)), current smokers (OR = 1.12 (1.09&ndash, 1.15)), alcohol intake (OR = 1.03 (1.01&ndash, 1.05)), active physical activity (&ge, 3 times/week, OR = 1.13 (1.11&ndash, 1.15)), depression (OR = 1.11 (1.08&ndash, 1.14)), and present comorbidities (Charlson Comorbidity Index, &ge, 1). Conclusion: This study identified clinical factors, namely, male, younger ages, prior experience of fecal test, absent history of colonoscopy or double-contrast barium enema (DCBE) within 5 years, and high socioeconomic status to be associated with good adherence to the follow-up examination after a positive FOBT.

Background The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). Methods The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. Results UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. Conclusions UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis.

Interval colorectal cancers detected after colonoscopy are known to be highly associated with proximal colorectal neoplasms (CRNs). This cross-sectional study investigated whether periodontitis could be a risk factor for proximal CRNs in healthy individuals. A total of 2504 subjects who received a colonoscopy and dental exam were enrolled in this study. We divided the subjects into the periodontitis group (n = 216) and the control group (n = 2288). The periodontitis group was defined as subjects who had one or more teeth with a probing pocket depth (PPD) ≥4 mm. The prevalence of proximal CRNs was significantly higher in the periodontitis group (25.0%) than in the control group (12.3%) (P

Background and Aim The diagnostic and prognostic values of fecal calprotectin (FC) levels in patients with inflammatory bowel diseases have been proven. However, little is known about the usefulness of FC measurement in predicting intestinal involvement of Behcet's disease (BD). Methods Forty-four consecutive patients with systemic BD who underwent colonoscopy for the evaluation of gastrointestinal symptoms were prospectively enrolled between November 2012 and March 2014 in a single tertiary medical center. Fecal specimens from the patients were obtained the day before bowel cleansing and 3 months after colonoscopy. Results Twenty-five patients showed intestinal ulcerations on colonoscopy (12 [48.0%] typical and 13 [52.0%] atypical ulcerations). The median FC level in the intestinal BD group was significantly higher than that in the non-diagnostic group (112.53 [6.86–1604.39] vs 31.64 [5.46–347.60] µg/g, respectively, P = 0.003). Moreover, the typical ulceration group showed a significantly higher median FC level than the atypical ulceration group in patients with intestinal BD (435.995 [75.65–1604.39] vs 71.42 [6.86–476.94] µg/g, respectively, P = 0.033). Multivariate analysis revealed higher FC as an independent predictor of intestinal BD (OR = 38.776; 95% CI = 2.306–652.021; P = 0.011). The cut-off level of FC for predicting intestinal BD was 68.89 µg/g (76% sensitivity and 79% specificity). The absolute changes between fecal calprotectin levels and the disease activity index of intestinal BD from initial diagnosis of intestinal BD to 3 months after diagnosis were significantly correlated (Pearson's correlation coefficient = 0.470, P = 0.027). Conclusion The FC level might serve as a non-invasive surrogate marker of intestinal involvement of BD.

Introduction This study was aimed at understanding the effect of β-catenin and cyclin D1 on overall survival in patients with early-stage NSCLC and at evaluating if the prognostic effect can be modified by adjuvant chemotherapy. Methods We retrospectively analyzed the expression of β-catenin and cyclin D1 using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 576 patients with early-stage NSCLC. Results The median duration of follow-up was 5.1 years. Overexpression of β-catenin and cyclin D1 was found in 56% and 50% of 576 cases, respectively. Overexpression of β-catenin and cyclin D1 was significantly associated with poor overall survival ( p = 0.003 and p = 0.0009, respectively; log rank test) in squamous cell carcinomas, not in adenocarcinomas. The prognostic significance of each protein in the squamous cell carcinomas was limited to stages IA, IB, and IIA. In addition, simultaneous overexpression of β-catenin and cyclin D1 in the squamous cell carcinomas synergistically increased hazard ratios (HRs) 15.79 (95% confidence interval [CI] = 1.09–51.23; p =0.04) for stage IA, 10.30 (95% CI = 2.29–46.41; p = 0.002) for stage 1B, and 3.55 (95% CI = 1.22–10.36; p = 0.02) times for stage 2A compared to those without overexpression of the two proteins, after adjusting for confounding factors. In addition, the effect was not dependent on adjuvant chemotherapy. Conclusions The present study suggests that simultaneous overexpression of β-catenin and cyclin D1 may be associated with poor overall survival irrespective of platinum-based adjuvant chemotherapy in stage IA–IIA squamous cell carcinoma of the lung.

Recently reported genome-wide association studies have identified more than 20 common low-penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR=1.44, 95% CI=1.04-1.98, P=.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR=2.14, 95% CI 1.39-3.30, P=5.8x10-4). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR=2.29, 95% CI 1.29-4.05, P=.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR=5.24, 95% CI 2.36-11.64, P= 4.8x10-5). Moreover, we found that PKD1L2 variation in obese patients (BMI>=25) was associated with poor survival rate (P=.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival. This article is protected by copyright. All rights reserved.

Little is known about predictable clinical factors associated with the occurrence of malignant large bowel obstruction (MLBO) in incurable stage IV colorectal cancer (CRC) patients undergoing medical treatment. This study investigates the clinical characteristics associated with MLBO that occurred while patients with stage IV CRC were receiving chemotherapy. A total of 216 patients who were diagnosed with stage IV CRC without bowel obstruction and who received chemotherapy between May 2005 and June 2012 were retrospectively included in this study. Patients were divided into an “obstruction group” and a “non-obstruction group” based on whether they did or did not develop MLBO during chemotherapy or follow-up, respectively. The initial endoscopic findings and clinical information were retrospectively reviewed and compared between the two groups. Forty-six patients (21.3 %) developed MLBO during the treatment or follow-up periods. The mean duration between diagnosis and MLBO was 9.8 ± 9.3 months. After adjusting for clinically relevant factors, MLBO development was independently associated with the following factors: higher initial tumor-occupying circumference (HR 1.030 [95 % CI, 1.012–1.049], P = 0.001), longer initial horizontal tumor width (HR 1.035 [95 % CI, 1.011–1.059], P = 0.004), primary tumor location at a turning point in the colon (HR 2.404 [95 % CI, 1.185–4.877], P = 0.015), and the presence of primary tumor ulceration at presentation (HR 3.767 [95 % CI, 1.882–7.538], P

This study examined the impact of two single-nucleotide polymorphisms (SNPs) in the telomerase-associated protein 1 (TEP1) gene on the risk of breast, colorectal, hepatocellular, lung and stomach cancer. A significantly increased stomach cancer risk associated with the GG genotype at rs1760893 (odds ratio (OR)=1.64, 95% confidence interval (CI)=1.23-2.20, P=0.004) or CC genotype at rs1713423 (OR=2.40, 95% CI=1.88-3.07, P0.0001) was observed, compared with their wild-type counterpart. The GG genotype at rs1760893 was also associated with enhanced hepatocellular cancer susceptibility (OR=1.46, 95% CI=1.05-2.03, P=0.02). In classification and regression tree analysis, individuals carrying the CC genotype at rs1713423 had 2.69-fold increased risk of stomach cancer (95% CI=2.18-3.32, P0.0001) compared with the TT and TC genotypes. The current results suggested that genetic variants at TEP1 SNPs rs1760893 and rs1713423 may be associated significantly with increased risk of stomach cancer.

This study aimed at understanding the effect of metformin on histone H3 methylation, DNA methylation, and chromatin accessibility in lung cancer cells. Metformin significantly reduced H3K4me3 level at the promoters of positive cell cycle regulatory genes such as CCNB2, CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. Metformin suppressed the expression of H3K4 methyltransferases MLL1, MLL2, and WDR82. The siRNA-mediated knockdown of MLL2 significantly downregulated global H3K4me3 level and inhibited lung cancer cell proliferation. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, and a Cox proportional hazards analysis showed that recurrence-free survival of lung adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08–4.72, p = 0.02) times poorer than in those without it. Metformin showed little effect on DNA methylation and chromatin accessibility at the promoter regions of cell cycle regulatory genes. The present study suggests that metformin reduces H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. Additionally, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.

In-depth molecular pathogenesis of ground-glass nodular lung adenocarcinoma has not been well understood. The objectives of this study were to identify genomic alterations in ground-glass nodular lung adenocarcinomas and to investigate whether viral transcripts were detected in these tumors. Nine patients with pure (n = 4) and part-solid (n = 5) ground-glass nodular adenocarcinomas were included. Six were females with a median age of 58 years. We performed targeted exon sequencing and RNA sequencing. EGFR (n = 10), IDH2 (n = 2), TP53 (n = 1), PTEN (n = 1), EPHB4 (n = 1), and BRAF (n = 1) were identified as driver mutations by targeted exon sequencing. Vasculogenesis-associated genes including NOTCH4 and TGFBR3 expression were significantly downregulated in adenocarcinoma tissue versus normal tissue (adjusted P values

// Ji Yun Lee 1, * , Kyunghee Park 2, * , Sung Hee Lim 1 , Hae Su Kim 1 , Kwai Han Yoo 1 , Ki Sun Jung 1 , Haa-Na Song 1 , Mineui Hong 3 , In-Gu Do 3 , TaeJin Ahn 2 , Se Kyung Lee 4 , Soo Youn Bae 4 , Seok Won Kim 4 , Jeong Eon Lee 4 , Seok Jin Nam 4 , Duk-Hwan Kim 5 , Hae Hyun Jung 6 , Ji-Yeon Kim 1 , Jin Seok Ahn 1 , Young-Hyuck Im 1 , Yeon Hee Park 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Samsung Genomic Institute, Samsung Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Center of Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea 6 Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Yeon Hee Park, e-mail: yhparkhmo@skku.edu Keywords: breast cancer, brain metastasis, gene, mutation, mechanism Received: August 27, 2015 Accepted: October 06, 2015 Published: October 20, 2015 ABSTRACT Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0–7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

// Su Jin Hwang 1, * , Hye Won Lee 2, * , Hye Ree Kim 1 , Hye Jin Song 4 , Dong Heon Lee 3 , Hong Lee 1 , Chang Hoon Shin 1 , Je-Gun Joung 5 , Duk-Hwan Kim 4, 6 , Kyeung Min Joo 1, 4 , Hyeon Ho Kim 1, 7 1 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea 2 Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Neurosurgery, Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea 5 Translational Bioinformatics Laboratory, Samsung Genome Institute, Samsung Medical Center, Seoul, Korea 6 Center for Genome Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Hyeon Ho Kim, e-mail: hyeonhkim@skku.edu Kyeung Min Joo, e-mail: kmjoo@skku.edu Keywords: microRNA-95-3p, brain metastasis, cyclin D1, lung adenocarcinoma Received: January 18, 2015 Accepted: April 25, 2015 Published: May 07, 2015 ABSTRACT Despite great efforts to improve survival rates, the prognosis of lung cancer patients is still very poor, mainly due to high invasiveness. We developed brain metastatic PC14PE6/LvBr4 cells through intracardiac injection of lung adenocarcinoma PC14PE6 cells. Western blot and RT-qPCR analyses revealed that PC14PE6/LvBr4 cells had mesenchymal characteristics and higher invasiveness than PC14PE6 cells. We found that cyclin D1 was upregulated, miR-95-3p was inversely downregulated, and pri-miR-95 and its host gene, ABLIM2 , were consistently decreased in PC14PE6/LvBr4 cells. MiR-95-3p suppressed cyclin D1 expression through direct binding to the 3′ UTR of cyclin D1 mRNA and suppressed invasiveness, proliferation, and clonogenicity of PC14PE6/LvBr4 cells. Ectopic cyclin D1 reversed miR-95-3p-mediated inhibition of invasiveness and clonogenicity, demonstrating cyclin D1 downregulation is involved in function of miR-95-3p. Using bioluminescence imaging, we found that miR-95-3p suppressed orthotopic tumorigenicity and brain metastasis in vivo and increased overall survival and brain metastasis-free survival. Consistent with in vitro metastatic cells, the levels of miR-95-3p, pri-miR-95, and ABLIM2 mRNA were decreased in brain metastatic tissues compared with lung cancer tissues and higher cyclin D1 expression was involved in poor prognosis. Taken together, our results demonstrate that miR-95-3p is a potential therapeutic target for brain metastasis of lung adenocarcinoma cells.

Background and Aim Considering the significant racial and ethnic diversity in genetic variation, it is unclear whether the genome-wide association studies-identified colorectal cancer (CRC)-susceptibility single-nucleotide polymorphisms (SNPs) discovered in European populations are also relevant to the Korean population. However, studies on CRC-susceptibility SNPs in Koreans are limited. Methods To investigate the racial and ethnic diversity of CRC-susceptibility genetic variants, we genotyped for the established European CRC-susceptibility SNPs in 198 CRC cases and 329 controls in Korea. To identify novel genetic variants using genome-wide screening in Korea, Illumina HumanHap 370K/610K BeadChips were performed on 105 CRC patients, and candidate CRC-susceptibility SNPs were selected. Subsequently, genotyping for replication was done in 189 CRC cases and 190 controls. Results Among the European CRC-susceptibility SNPs, rs4939827 in SMAD7 was associated with a significant decreased risk of Korean CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 0.67 [95% CI, 0.47–0.95]; dominant model, 0.59 [95% CI, 0.39–0.91]). rs4779584 and rs10795668 were associated with CRC risk in females and males, respectively. Among candidate CRC-susceptibility SNPs selected from genome-wide screening, novel SNP, rs17051076, was found to be associated with a significantly increased risk of microsatellite instability-high CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 4.25 [95% CI, 1.51–11.98]; dominant model, 3.52 [95% CI, 1.13–10.94]) in the replication study. Conclusions rs4939827, rs4779584, and rs10795668 may contribute to the risk of CRC in the Korean population as well as in European populations. Novel rs17051076 could be associated with microsatellite instability-high CRC in Koreans. These associations support the ethnic diversity of CRC-susceptibility SNPs and should be taken into account in large-scale studies.

The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice. IEOs were treated with transforming growth factor- β1 (TGF-β1) or Tumor necrosis factor-α (TNF-α) to evaluate their phenotypic change. Raw 264.7 cells (macrophage) stimulated with lipopolysaccharide were co-cultured with IEOs in growth media with or without TGF-β1. TGF-β1 alone slightly induced epithelial to mesenchymal transition (EMT) in the IEOs but mainly disrupted them. Macrophage released cytokines synergistically induced mesenchymal phenotypic changes in TGF-β1 stimulated intestinal organoids. TNF-α and TGF-β1 synergistically induced proliferation of mesenchymal cells as well as EMT in the IEOs. We generated a novel OEMT model based on our finding that TNF-α and TGF-β synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.

Lung cancer is the leading cause of cancer-related deaths in the world. Despite significant advances in the early detection and treatment of the disease, the prognosis remains poor, with an overall 5-year survival rate ranging from 15% to 20%. This poor prognosis results largely from early micrometastatic spread of cancer cells to nearby lymph nodes or tissues and partially from early recurrence after curative surgical resection. Recently, precision medicines that target potential oncogenic driver mutations have been approved to treat lung cancer. However, some lung cancer patients do not have targetable mutations, and many patients develop resistance to targeted therapy. Tumor heterogeneity and mutational density are also challenges in treating lung cancer, which underscores the need for developing alternative therapeutic strategies for treating lung cancer. Epigenetic therapy may circumvent the problems of tumor heterogeneity and drug resistance by affecting the expression of several hundred target genes. This review highlights precision medicine using an innovative approach of epigenetic priming prior to conventional standard therapy or targeted cancer therapy in lung cancer.

A previous genome-wide methylation array for colorectal cancer (CRC) identified aberrant promoter methylation of eyes absent 4 (EYA4). However, the correlations between EYA4 methylation and gene expression, the role played by EYA4 protein in colorectal carcinogenesis, and results of the gene-enrichment and functional annotation analysis have not yet been established. We analyzed the EYA4 methylation status and found EYA4 promoter methylation in CRC cell lines (100%), CRC tissues (93.5%) and advanced adenoma tissues (50.7%), compared with normal mucosa (32.6%). There was a significant inverse correlation between EYA4 methylation and expression. EYA4 transfection led to inhibition of cell proliferation in colony assays and xenograft studies. On performing the gene-enrichment and functional annotation analysis, we observed that the differentially expressed genes have been associated with the Wnt and MAPK signaling pathways. Our results demonstrate that EYA4 is under epigenetic regulation in CRC. It is a candidate tumor suppressor gene that acts by inducing up-regulation of DKK1 and inhibiting the Wnt signaling pathway. In addition, EYA4 methylation may be identified in stool samples and it serves as a potential stool biomarker for detection of advanced adenoma and CRC. © 2015 Wiley Periodicals, Inc.

Background This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results Four thousand seven hundred and twenty-six CpGs (P 0.05, Wilcoxon rank-sum test). However, their methylation levels were significantly different between paired bronchial biopsy and washing (P

Background Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs). Methods HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-β1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-β1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent. Results Both PPAR-γ agonists reduced the TGF-β1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-β1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-β1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-β1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent. Conclusions Troglitazone and rosiglitazone suppress TGF-β1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s12876-017-0627-4) contains supplementary material, which is available to authorized users.

Background/Aims In patients with corticosteroid-refractory ulcerative colitis (UC), cyclosporine or infliximab may be added to the treatment regimen to induce remission. Here, we aimed to compare the efficacy of cyclosporine and infliximab. Methods Between January 1995 and May 2012, the medical records of 43 patients with corticosteroid-refractory UC who received either infliximab or cyclosporine as a rescue therapy at a tertiary care hospital in Korea were reviewed. Results Among the 43 patients, 10 underwent rescue therapy with cyclosporine and the remaining 33 patients received infliximab. A follow-up of 12 months was completed for all patients. The colectomy rate at 12 months was 30% and 3% in the cyclosporine and the infliximab groups, respectively (p=0.034). However, the Cox proportional hazard model indicated that the treatment of rescue therapy was not an independent associate factor for preventing colectomy (p=0.164). In the subgroup analysis, infliximab with azathioprine was superior to cyclosporine for preventing colectomy (hazard ratio of infliximab with azathioprine compared with cyclosporine only, 0.073; 95% confidence interval, 0.008 to 0.629). Conclusions No difference between infliximab and cyclosporine with respect to preventing colectomy was noted. However, infliximab with azathioprine may be more effective than cyclosporine alone for preventing colectomy.

The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD. We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn’s disease (CD), and 83 with intestinal Behcet’s disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count

Little is known about the role of follow-up endoscopy in patients with inflammatory bowel disease (IBD). The present study aimed to evaluate whether repeated endoscopies would be beneficial in improving outcomes of patients with IBD. Patients who had been initially confirmed to have IBD at two tertiary hospitals in Korea were regularly followed and included in this study. The clinical impact as assessed by the presence or absence of a change in management after endoscopy and cumulative hospitalization rate was compared between two groups classified according to the presence or absence of indications. A total of 188 patients with IBD were enrolled [69 patients with Crohn’s disease (CD) and 119 with ulcerative colitis (UC)]. Of these patients, 130 underwent follow-up endoscopy (48 with CD and 82 with UC). The rate of management change was significantly higher in the group with indications for follow-up endoscopy (p = 0.001 in CD and

This study was aimed at understanding the clinicopathological significance of HOXA9 hypermethylation in non-small cell lung cancer (NSCLC). HOXA9 hypermethylation was characterized in six lung cancer cell lines, and its clinicopathological significance was analyzed using methylation-specific PCR in 271 formalin-fixed paraffin-embedded tissues and 27 fresh-frozen tumor and matched normal tissues from 298 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA9 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2′-deoxycytidine (5-Aza-dC). Transient transfection of HOXA9 into H23 lung cancer cells resulted in the inhibition of cell migration but not proliferation. Conversely, sequence-specific siRNA-mediated knockdown of HOXA9 enhanced cell migration. The mRNA levels of HOXA9 in 27 fresh-frozen tumor tissues were significantly lower than in matched normal tissues (P

Integrins are cell surface receptors that mediate cell-cell/extracellular interactions and have shown an association with metastasis or transformation in several cancers. However, the correlation between the clinicopathological status of breast cancer and the altered integrin α4 status is not clear. In this study, we investigated DNA methylation of integrin α4 in breast cancer. We retrieved 351 cases of surgically resected breast cancer (290 invasive carcinoma and 61 intraductal carcinoma). Methylation-specific polymerase chain reaction was performed to determine integrin α4 methylation status. Integrin α4 methylation was frequently observed in breast cancer specimens (145/351 cases, 41.3 %). In addition, DNA methylation of integrin α4 showed statistical correlation with HER2 positivity and higher histologic grade (p = 0.001, 0.008 in ductal carcinoma in situ and 0.003 in invasive ductal carcinoma). However, other clinicopathological data such as estrogen receptor, progesterone receptor, metastasis, and TNM status showed no statistical correlation. Moreover, we found that the downregulated expression of integrin α4 in a heavily methylated breast cancer cell line (ZR-75) was restored by treatment with 5-aza-2'deoxycytidine, a DNA methyltransferase inhibitor, implying transcriptional silencing by DNA methylation. We observed that integrin α4 methylation is associated with the histologic grade of tumors and lymph node metastasis. Also, this data supports a previous study that suggested integrin α4 and HER2 are involved in the same signaling pathway. DNA methylation of integrin α4 may be a poor prognostic factor which affects undifferentiated histologic change of breast cancer.

// Jung-Ah Hwang 1 , Bo Bin Lee 2 , Yujin Kim 2 , Seong-Eun Park 2 , Kyun Heo 1 , Seung-Hyun Hong 1 , Young-Ho Kim 3 , Joungho Han 4 , Young Mog Shim 5 , Yeon-Su Lee 1 , and Duk-Hwan Kim 2 1 Cancer Genomics Branch, Research Institute, National Cancer Center, Goyang-si, Korea 2 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea 3 Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea Correspondence: Yeon-Su Lee, email: // Duk-Hwan Kim, email: // Keywords : HOXA11; Hypermethylation; Non-small cell lung cancer; Progression; Migration Received : October 3, 2013 Accepted : October 27, 2013 Published : October 28, 2013 Abstract This study was aimed at understanding the functional significance of HOXA11 hypermethylation in non-small cell lung cancer (NSCLC). HOXA11 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using formalin-fixed paraffin-embedded tissues from 317 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA11 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2’-deoxycytidine (5-Aza-dC). Transient transfection of HOXA11 into H23 lung cancer cells resulted in the inhibition of cell migration and proliferation. HOXA11 hypermethylation was found in 218 (69%) of 317 primary NSCLCs. HOXA11 hypermethylation was found at a higher prevalence in squamous cell carcinoma than in adenocarcinoma (74% vs. 63%, respectively). HOXA11 hypermethylation was associated with Ki-67 proliferation index ( P = 0.03) and pT stage ( P = 0.002), but not with patient survival. Patients with pT2 and pT3 stages were 1.85 times (95% confidence interval [CI] = 1.04-3.29; P = 0.04) and 5.47 times (95% CI = 1.18-25.50; P = 0.01), respectively, more likely to show HOXA11 hypermethylation than those with pT1 stage, after adjusting for age, sex, and histology. In conclusion, the present study suggests that HOXA11 hypermethylation may contribute to the progression of NSCLC by promoting cell proliferation or migration.

The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice. IEOs were treated with transforming growth factor- β1 (TGF-β1) or Tumor necrosis factor-α (TNF-α) to evaluate their phenotypic change. Raw 264.7 cells (macrophage) stimulated with lipopolysaccharide were co-cultured with IEOs in growth media with or without TGF-β1. TGF-β1 alone slightly induced epithelial to mesenchymal transition (EMT) in the IEOs but mainly disrupted them. Macrophage released cytokines synergistically induced mesenchymal phenotypic changes in TGF-β1 stimulated intestinal organoids. TNF-α and TGF-β1 synergistically induced proliferation of mesenchymal cells as well as EMT in the IEOs. We generated a novel OEMT model based on our finding that TNF-α and TGF-β synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.