Background and Aim
Nuclear factor kappa B (NF‐κB) activation and endoplasmic reticulum (ER) stress signaling play significant roles in the pathogenesis of inflammatory bowel disease (IBD). Thus, we ...evaluated whether new therapeutic probiotics have anti‐colitic effects, and we investigated their mechanisms related to NF‐κB and ER‐stress pathways.
Methods
Luciferase, nitric oxide, and cytokine assays using HT‐29 or RAW264.7 cells were conducted. Mouse colitis was induced using dextran sulfate sodium and confirmed by disease activity index and histology. Macrophages and T‐cell subsets in isolated peritoneal cavity cells and splenocytes were analyzed by flow cytometry. Gene and cytokine expression profiles were determined using reverse‐transcription polymerase chain reaction.
Results
Lactobacillus acidophilus (LA1) and Pediococcus pentosaceus inhibited nitric oxide production in RAW264.7 cells, but only LA1 inhibited Tnfa and induced Il10 expression. LA1 increased the lifespan of dextran sulfate sodium‐treated mice and attenuated the severity of colitis by inducing M2 macrophages in peritoneal cavity cells and Th2 and Treg cells in splenocytes. The restoration of goblet cells in the colon was accompanied by the induction of Il10 expression and the suppression of pro‐inflammatory cytokines. Additionally, we found that LA1 exerts an anti‐colitic effect by improving ER stress in HT‐29 cells as well as in vivo.
Conclusions
We showed that LA1 significantly interferes with ER stress and suppresses NF‐κB activation. Our findings suggest that LA1 can be used as a potent immunomodulator in IBD treatment, and the regulation of ER stress may have significant implications in treating IBD.
Previous studies have investigated the relationship between visceral obesity and the risk of colorectal tumors. Visceral obesity may affect the outcome of colorectal cancer (CRC), including survival ...and metastasis. We investigated the associations between visceral adipose tissue and oncologic outcomes in stage III CRC.
Four hundred seventy-two patients with stage III CRC were identified. Subcutaneous and visceral adipose tissue areas were measured volumetrically via computed tomography for each patient at different levels of the lumbar spine. After adjusting for age, sex, and other clinical factors, the effects of visceral adipose tissue area on mortality and recurrence were assessed using Cox proportional hazard regression.
In univariate and multivariate analyses, a higher visceral adipose tissue to total adipose tissue (VT) ratio (hazard ratio HR, 1.041; 95% CI, 1.008 to 1.075; p=0.015) and higher visceral adipose tissue to subcutaneous adipose tissue (VS) ratio (HR, 1.016; 95% CI, 1.005 to 1.028; p=0.006) were both associated with poor CRC-specific survival. Interestingly, in the evaluation of each site of recurrence, a higher VT ratio (HR, 1.069; 95% CI, 1.010 to 1.131; p=0.020) and higher VS ratio (HR, 1.024; 95% CI, 1.003 to 1.045; p=0.023) were both related to a higher risk of peritoneal seeding and tumor recurrence. The VT ratio at the L3-L4 level was significantly associated with a higher risk of peritoneal seeding and tumor recurrence (HR, 4.969; 95% CI, 1.303 to 18.949; p=0.019), while other levels showed no such relationship.
Visceral obesity is closely related to increased risks of CRC-specific mortality and peritoneal seeding metastasis in stage III CRC patients.
Prior studies have demonstrated the utility of microRNA assays for predicting some cancer tissue origins, but these assays need to be further optimized for predicting the tissue origins of ...adenocarcinomas of the liver. We performed microRNA profiling on 195 frozen primary tumor samples using 14 types of tumors that were either adenocarcinomas or differentiated from adenocarcinomas. The 1-nearest neighbor method predicted tissue-of-origin in 33 samples of a test set, with an accuracy of 93.9% at feature selection p values ranging from 10-4 to 10-10. According to binary decision tree analyses, the overexpression of miR-30a and the underexpression of miR-200 family members (miR-200c and miR-141) differentiated intrahepatic cholangiocarcinomas from extrahepatic adenocarcinomas. When binary decision tree analyses were performed using the test set, the prediction accuracy was 84.8%. The overexpression of miR-30a and the reduced expressions of miR-200c, miR-141, and miR-425 could distinguish intrahepatic cholangiocarcinomas from liver metastases from the gastrointestinal tract.
Background/Aims: The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) ...and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function. Methods: Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanate-dextran permeability assay. Results: Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharide-triggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner. Conclusions: The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a small-molecule therapeutic option for IBD.
Although colonic perforation is a dreadful adverse event associated with stent placement, data on this topic are sparse. We aimed to investigate the clinical outcomes of colonic perforation and ...factors related to its occurrence in patients who received self-expandable metal stents (SEMSs) for malignant colorectal obstruction.
We retrospectively reviewed the data of 474 patients with malignant colorectal obstruction who received endoscopic SEMS insertion from April 2004 to May 2011 in Severance Hospital and Gangnam Severance Hospital. Early perforation, defined as perforation occurring within 2 weeks, was assessed in bridge-to-surgery (n = 164) and palliative stent placement patient groups (n = 310). Delayed perforation was analyzed using data from the palliative stent placement group alone.
The technical and clinical success rates were 90.5% and 81.0%, respectively. Early and delayed perforations occurred in 2.7% (13/474) and 2.7% (8/301) of patients, respectively. Among 21 patients with perforation, 14 (66.7%) received emergency surgery and 5 (23.8%) died within 30 days after perforation. Regarding the perforation-related factors, age ≥70 years (odds ratio, 3.276; 95% confidence interval CI, 1.041-10.309) and sigmoid colonic location (odds ratio, 7.706; 95% CI, 1.681-35.317) were independently associated with occurrence of early perforation. Stent location in the flexure (hazard ratio, 17.573; 95% CI, 2.004-154.093) and absence of peritoneal carcinomatosis (hazard ratio, 6.139; 95% CI, 1.150-32.776) were significantly associated with delayed perforation.
The perforation-related 30-day mortality rate was 23.8%. Older age and sigmoid colonic location were significantly associated with occurrence of early perforation, whereas flexure location and absence of peritoneal carcinomatosis were related to delayed perforation.
Metformin use has been associated with decreased cancer risk and mortality. However, the effects of metformin on clinical outcomes of colorectal cancer (CRC) are not defined. This study aimed to ...evaluate the association between metformin use and mortality of CRC in diabetic patients. We identified 595 patients who were diagnosed both CRC and diabetes mellitus. Patients were compared by two groups; 258 diabetic patients taking metformin and 337 diabetic patients not taking metformin. Patient's demographics, clinical characteristics, overall mortality and CRC‐specific mortality were analyzed. After a median follow‐up of 41 months, there were 71 total deaths (27.5%) and 55 CRC‐specific deaths (21.3%) among 258 patients who used metformin, compared with 136 total deaths (40.4%) and 104 CRC‐specific deaths (30.9%) among 337 patients who did not use metformin. Metformin use was associated with decreased overall mortality (p = 0.018) and CRC‐specific mortality (p = 0.042) by univariate analysis. After adjustment for clinically relevant factors, metformin use showed lower risk of overall mortality (HR, 0.66; 95% CI 0.476–0.923; p = 0.015) and CRC‐specific mortality (HR, 0.66; 95% CI 0.45–0.975; p = 0.037) in CRC patients with diabetes. Metformin use in CRC patients with diabetes is associated with lower risk of CRC‐specific and overall mortality.
Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with ...lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.
Patients with inflammatory bowel disease (IBD) and intestinal Behçet's disease (BD) are vulnerable to micronutrient deficiencies due to diarrhea-related gastrointestinal loss and poor dietary intake ...caused by disease-related anorexia. However, few studies have investigated the incidence and risk factors for micronutrient deficiency.
We retrospectively analyzed 205 patients with IBD who underwent micronutrient examination, including folate, vitamin B12, 25-OH-vitamin D, and/or ferritin level quantification, with follow-up blood tests conducted 6 months later.
Eighty patients (39.0%), who were deficient in any of the four micronutrients, were classified as the deficiency group, and the remaining 125 (61.0%) were classified as the non-deficient group. Compared to those in the non-deficiency group, patients in the deficiency group were much younger, had more Crohn's disease (CD) patients, more patients with a history of bowel operation, and significantly less 5-amino salicylic acid usage. Multivariate analysis revealed that CD and bowel operation were significant independent factors associated with micronutrient deficiency.
The incidence of micronutrient deficiency was high (39.0%). Factors including CD, bowel operation, and younger ages were found to be associated with higher risks of deficiency. Therefore, patients with IBD, especially young patients with CD who have undergone bowel resection surgery, need more attention paid to micronutrition.
Background and Aims
Catheter‐based endobiliary radiofrequency ablation (RFA) is an endoscopic local treatment for patients with malignant biliary stricture (MBS). However, excessive heating of the ...bile duct by the current RFA system can induce serious complications. Recently, a new RFA system with automatic temperature control was developed. In the present study, we examined the safety of the new RFA system in patients undergoing endobiliary RFA for extrahepatic MBS.
Methods
This prospective, multicenter study enrolled patients with unresectable or inoperable extrahepatic (> 2 cm from the hilum) MBS. Endobiliary RFA was performed using a newly developed RFA catheter (ELRA™, STARmed, Goyang, Korea) at a setting of 7 or 10 W for 120 s and with a target temperature of 80°C. A self‐expandable metallic stent was inserted after endobiliary RFA. The rate of procedure‐related adverse events was assessed.
Results
The 30 patients were enrolled in this study. Cholangiocarcinoma was diagnosed in 19 patients, pancreatic cancer was found in 9, and gallbladder cancers were recorded in 2. The mean stricture length was 22.1 ± 6.6 mm. Post‐procedural adverse events occurred in three patients (10.0%; 2 mild pancreatitis and 1 cholangitis) without hemobilia and bile duct perforation. The pancreatitis and cholangitis resolved with conservative treatment. The cumulative duration of stent patency and survival were 236 and 383 days, respectively.
Conclusions
Automatic temperature‐controlled endobiliary RFA using a newly developed catheter was safely applied in patents with extrahepatic MBS. Further prospective studies are needed to confirm the efficacy of endobiliary RFA for MBS.
High heart rate is an independent predictor of total cancer incidence and all-cause mortality in patients with cancer. We aimed to evaluate the impact of resting heart rate on the recurrence of ...colorectal polyp, using long-term surveillance follow-up data of colorectal cancer survivors.
Three hundred patients were selected from the colorectal cancer survivor cohort of Severance Hospital, Seoul, Korea. Resting heart rate, physical activity, and body composition analysis at the time of 5-year survival, and clinical data including colonoscopy surveillance results were collected for mean follow-up duration of 8 years.
Patients with a high resting heart rate showed a significantly higher recurrence rate of advanced adenoma than those with a low resting heart rate (quartile 1, 45-66 beats per minute (b.p.m.); quartile 2, 67-73 b.p.m.; quartile 3, 74-80 b.p.m.; quartile 4, 81-120 b.p.m.; 3.8% vs. 7.9% vs. 10.0% vs. 14.7%, p for trend = 0.018). After adjustment for various risk factors, patients in the highest quartile of resting heart rate (≥ 81 b.p.m.) had a significantly higher risk of advanced adenoma recurrence (hazard ratio HR: 6.183, 95% confidence interval CI: 1.181-32.373, p = 0.031), compared to those in the lowest quartile (≤ 66 b.p.m.). In subgroup analysis, the association of resting heart rate with advanced adenoma recurrence appeared to be stronger among patients who had more than normal body fat mass or sedentary life style.
Elevated resting heart rate was independently associated with a higher rate of advanced adenoma recurrence in colorectal cancer survivors.
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