Application of clinical decision support tools for predicting outcomes with vedolizumab therapy in patients with inflammatory bowel disease: A KASID multicentre study.

BACKGROUND/AIM: We aimed to validate clinical decision support tools (CDSTs) to predict real-life effectiveness of vedolizumab (VDZ) in patients with inflammatory bowel disease. METHODS: We retrospectively enrolled patients with Crohn's disease (CD) or ulcerative colitis (UC) treated with VDZ at 10 tertiary referral centres in Korea between January 2017 and November 2021. We assessed clinical remission (CREM) and response (CRES), corticosteroid-free clinical remission (CSF-CREM) and response (CSF-CRES), biochemical response based on C-reactive protein (BioRES[CRP]) and faecal calprotectin (BioRES[FC]), endoscopic healing (EH), and the need to optimise or switch drugs based on CDST-defined response groups. Additionally, the area under the receiver operating characteristics curve (AUC) for the CDSTs was calculated. RESULTS: We included 143 patients with CD and 219 with UC. We observed incremental trends on CSF-CRES at week 14 (W14) (ptrend = 0.004) and decreasing trends for the need to optimise or switch drugs (ptrend = 0.016) in CD from the low to high probability groups. Except for CSF-CREM at W54, we noticed incremental trends for all clinical responses at W14, W26 and W54 (ptrend <0.001) in UC. W26 and W54 BioRES[CRP] and W14 EH also showed increasing trends (ptrend <0.05) in UC. With increasing probabilities of response, drug optimisation or switching was less frequently required in UC (ptrend = 0.013). With 26 points cut-off, CDSTs effectively identified W14 CSF-CRES, W26 BioRES[CRP], BioRES[FC] and W54 BioRES[CRP] in UC, all with AUCs >0.600, whereas CDSTs showed poor accuracy in CD. CONCLUSIONS: CDSTs for VDZ had acceptable accuracy in predicting effectiveness outcomes including clinical and biochemical outcomes in UC. However, their utility in CD was limited.

Human umbilical cord/placenta mesenchymal stem cell conditioned medium attenuates intestinal fibrosis in vivo and in vitro.

BACKGROUND: A significant unmet need in inflammatory bowel disease is the lack of anti-fibrotic agents targeting intestinal fibrosis. This study aimed to investigate the anti-fibrogenic properties and mechanisms of the conditioned medium (CM) from human umbilical cord/placenta-derived mesenchymal stem cells (UC/PL-MSC-CM) in a murine intestinal fibrosis model and human primary intestinal myofibroblasts (HIMFs). METHODS: UC/PL-MSC-CM was concentrated 15-fold using a 3 kDa cut-off filter. C57BL/6 mice aged 7 weeks old were randomly assigned to one of four groups: (1) control, (2) dextran sulfate sodium (DSS), (3) DSS + CM (late-phase treatment), and (4) DSS + CM (early-phase treatment). Chronic DSS colitis and intestinal fibrosis was induced by three cycles of DSS administration. One DSS cycle consisted of 7 days of oral DSS administration (1.75%, 2%, and 2.5% DSS), followed by 14 days of drinking water. UC/PL-MSC-CM was intraperitoneally administered in the late phase (from day 50, 10 times) or early phase (from day 29, 10 times) of DSS cycles. HIMFs were treated with TGF-ß1 and co-treated with UC/PL-MSC-CM (10% of culture media) in the cellular model. RESULTS: In the animal study, UC/PL-MSC-CM reduced submucosa/muscularis propria thickness and collagen deposition, which improved intestinal fibrosis in chronic DSS colitis. The UC/PL-MSC-CM significantly reduced the expressions of procollagen1A1 and α-smooth muscle actin, which DSS significantly elevated. The anti-fibrogenic effect was more apparent in the UC-MSC-CM or early-phase treatment model. The UC/PL-MSC-CM reduced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs in the cellular model. The UC/PL-MSC-CM downregulated fibrogenesis by suppressing RhoA, MRTF-A, and SRF expression. CONCLUSIONS: Human UC/PL-MSC-CM inhibits TGF-ß1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and chronic DSS colitis-induced intestinal fibrosis. Thus, it may be regarded as a novel candidate for stem cell-based therapy of intestinal fibrosis.

Obesity and novel management of inflammatory bowel disease.

Obesity is prevalent within the inflammatory bowel disease (IBD) population, particularly in newly developed countries. Several epidemiological studies have suggested that 15%-40% of IBD patients are obese, and there is a potential role of obesity in the pathogenesis of IBD. The dysfunction of mesenteric fat worsens the inflammatory course of Crohn's disease and may induce formation of strictures or fistulas. Furthermore, obesity may affect the disease course or treatment response of IBD. Given the increasing data supporting the pathophysiologic and epidemiologic relationship between obesity and IBD, obesity control is being suggested as a novel management for IBD. Therefore, this review aimed to describe the influence of obesity on the outcomes of IBD treatment and to present the current status of pharmacologic or surgical anti-obesity treatments in IBD patients.

Effects of Mesenchymal Stem Cells Treatment on Radiation-Induced Proctitis in Rats.

PURPOSE: There are no effective treatment methods with which to control complications of radiation proctitis with fistula or recurrent bleeding following radiation treatment for prostate, cervical, or rectal cancer. Mesenchymal stem cells (MSCs) can induce immune modification, resulting in tissue repair and regeneration. Therefore, we used a rat model of radiation-induced proctitis and observed the effects of using human placenta-derived (PD) and adipose tissue-derived (AD) MSCs. MATERIALS AND METHODS: Female Sprague Dawley rats were irradiated at the pelvic area with 25 Gy. We injected 1×106 cells of human PD-MSCs, human AD-MSCs, human foreskin fibroblasts, and control media into the rectal submucosa following irradiation. We sacrificed rats for pathologic evaluation. RESULTS: Fibrosis on the rectum was reduced in both MSC groups, compared to the control group. Mucosal Ki-67 indices of both MSC injected groups were higher than those in the control group. Although caspase-3 positive cells in the mucosa gradually increased and decreased in the control group, those in both MSC injected groups increased rapidly and decreased thereafter. CONCLUSION: We demonstrated the effects of regional MSC injection treatment for radiation-induced proctitis in rats. MSC injection reduced fibrosis and increased proliferation in rat mucosa. Human AD-MSCs and PD-MSCs had similar effectiveness.

Fibrostenotic strictures in Crohn's disease.

The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn's disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.

Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A.

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-ß1 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-ß1-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-ß1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-ß1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-ß1 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-ß1-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.

Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases.

The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn's disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.

Periodontitis is associated with an increased risk for proximal colorectal neoplasms.

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 < 0.001). Independent risk factors for proximal CRNs in the multivariate analysis were periodontitis, smoking, age, waist circumference, and triglycerides, and those for proximal advanced CRNs were periodontitis, age, and family history of CRC. However, periodontitis was not a risk factor for overall CRNs and advanced CRNs. Periodontitis was associated with an increased risk of proximal CRNs (odds ratio [OR], 1.525; 95% confidence intervals [95% CI], 1.071-2.172) and proximal advanced CRNs (OR, 2.671; 95% CI, 1.088-6.560). Periodontitis might be associated with proximal CRNs and proximal advanced CRNs.

Author Correction: Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts.

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-ß1 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-ß1 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-ß1-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-ß1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-ß1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-ß1 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-ß1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective.

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- ß1 (TGF-ß1) 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-ß1. TGF-ß1 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-ß1 stimulated intestinal organoids. TNF-α and TGF-ß1 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-ß synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.

Overview of gastrointestinal cancer prevention in Asia.

"War on cancer" was declared through the National Cancer Act by President Richard Nixon in 1971, but cancer statistics from the American Cancer Society and other sources indicated the failure of this war, suggesting instead focus on the message that a "prevention strategy" might be much more effective than cancer treatment. While cancer statistics notoriously showed sharp increases in incidence as well as in mortality concurrent with economic growth in Asia, fortunately Asian countries benefit from plentiful resources of natural compounds, which can prevent cancer. Just like cancer chemotherapeutics targeted to kill cancer cells in Western countries, natural agents activating molecular mechanisms for cancer prevention, reversion of premalignant tumors, and even ablation of cancer stem cells, are very abundant in Asia. Currently, these natural agents are under very active investigations targeting the hallmarks of cancer prevention, including selective induction of apoptosis in cancer cells, suppression of growth factors or their signaling, suppression of cell proliferation and of cancer-promoting angiogenesis, induction of mesenchymal-epithelial transition, and disruption of the tumor microenvironment, developing promising cancer preventive agents. However, Asia is the most populous continent in the world and some Asian countries do not have the resources to implement cancer screening programs for early detection or treatment. In addition, despite the excellent cancer preventive screening strategies in some Asian countries, well-designed clinical trials for cancer prevention are somewhat delayed compared to Western countries. In this review article, several phytochemicals/phytoceuticals produced and studied in different Asian countries will be introduced, including Korean red ginseng (pride of Korea), curcumin (Indian spice for life), black or green tea (popular in Japan/Sri Lanka), genistein from tofu (famous Chinese food), diallylsulfide or S-allylcysteine (garlic, popularly consumed as a food ingredient in many Asian countries), capsaicin, 6-gingerol, flavopiridol, and silymarin (abundant in various Asian foods). Whereas in Western countries cancer chemotherapeutics involve strategies not only to block the growth of the primary tumor, but also to inhibit its progression to metastatic disease, the endless pursuit of effective agents for cancer prevention may be a unique and featured strategy in Asia. More active efforts for clinical application of these principles should be supported.

Partially covered versus uncovered self-expandable nitinol stents with anti-migration properties for the palliation of malignant distal biliary obstruction: A randomized controlled trial.

OBJECTIVE: Covered self-expandable metal stents (SEMSs) are increasingly used as alternatives to uncovered SEMSs for the palliation of inoperable malignant distal biliary obstruction to counteract tumor ingrowth. We aimed to compare the outcomes of partially covered and uncovered SEMSs with identical mesh structures and anti-migration properties, such as low axial force and flared ends. MATERIALS AND METHODS: One hundred and three patients who were diagnosed with inoperable malignant distal biliary obstruction between January 2006 and August 2013 were randomly assigned to either the partially covered (n = 51) or uncovered (n = 52) SEMS group. RESULTS: There were no significant differences in the cumulative stent patency, overall patient survival, stent dysfunction-free survival and overall adverse events, including pancreatitis and cholecystitis, between the two groups. Compared to the uncovered group, stent migration (5.9% vs. 0%, p = 0.118) and tumor overgrowth (7.8% vs. 1.9%, p = 0.205) were non-significantly more frequent in the partially covered group, whereas tumor ingrowth showed a significantly higher incidence in the uncovered group (5.9% vs. 19.2%, p = 0.041). Stent migration in the partially covered group occurred only in patients with short stenosis of the utmost distal bile duct (two in ampullary cancer, one in bile duct cancer), and did not occur in any patients with pancreatic cancer. CONCLUSIONS: For the palliation of malignant distal biliary obstruction, endoscopic placement of partially covered SEMSs with anti-migration designs and identical mesh structures to uncovered SEMSs failed to prolong cumulative stent patency or reduce stent migration.

Dietary, non-microbial intervention to prevent Helicobacter pylori-associated gastric diseases.

Since the discovery of Helicobacter pylori (H. pylori) infection as the major cause of gastroduodenal disorders including acute and chronic gastritis, gastroduodenal ulcer, chronic atrophic gastritis, and gastric cancer almost three decades ago, the possibility of preventing these clinical diseases through eradicating H. pylori has been the focus of active research, but soon debate in the scientific community, though eradication opens the feasibility of cancer prevention and the removal of bacteria significantly prevents development or recurrence of peptic ulcer diseases and some clinical diseases, was proposed due to uncertainty in either achievement of complete eradication or inefficacy in cancer prevention with eradication alone. Still its linkage to gastric cancer is incontestable. Since the multiple combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer is intervened, simple eradication deemed the feasibility of cancer prevention. Therefore, our group open strong hypothesis that non-microbial, dietary approach might be the alternate, for which several interventions of nutritional components can highlight rejuvenation of chronic atrophic gastritis as well as amelioration of H. pylori-associated procarcinogenic inflammation. In this review article, the experience and outcome regarding nutritional application to rejuvenate gastric atrophy will be introduced, using Korean red ginseng, garlic extracts, cancer preventive Korea kimchi, n-3 polyunsaturated fatty acids (PUFA), special form of licorice, and probiotics. The detailed influence of dietary intervention and bacterial eradication therapy on disease progression and reversibility of premalignant lesions are discussed.

Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis.

BACKGROUND AND AIMS: Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL-37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts. METHODS: C57BL/6J mice (n=6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6-7 weeks) colitis with fibrosis. mCRAMP peptide (5 mg/kg every 3 day, week 5-7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp expressing lentivirus (107 infectious units day 11) was administered intravenously. RESULTS: TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice, compared to vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-beta1 (TGF-beta1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, that was reduced by LL-37 (3-5 µM) through a MAP kinase-dependent mechanism. CONCLUSION: Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.

Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts.

BACKGROUND: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. METHODS: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial-mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. RESULTS: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. CONCLUSION: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation.

Effect of acute auditory stress on gastric motor responses to a meal in healthy volunteers.

BACKGROUND AND AIM: Stress is believed to play a role in the pathogenesis of functional gastrointestinal disorders. The aim of the present study was to investigate the effect of acute auditory stress on gastric motor responses to a meal in healthy subjects. METHODS: A total of eight healthy volunteers (seven men and one woman; median age, 33.4 years [30-35 years]) who had no recurrent gastrointestinal symptoms participated in the prospective, randomized, crossover study. Gastric half-emptying time and meal-induced proximal gastric accommodation were measured using gastric scintigraphy under the auditory stress and control conditions in a randomized crossover design. RESULTS: The gastric half-emptying time under the stress condition was significantly longer than that under the control condition (130.8 ± 16.6 vs. 105.0 ± 13.1 min; P = 0.005 by paired t-test). Under the stress and control conditions, the proximal gastric volume significantly increased after a meal (P < 0.001 by repeated measures analysis of variance). The degree of the postprandial increase in proximal gastric volume did not significantly differ between both conditions (P = 0.598 by tests of between-subjects effects using repeated measures analysis of variance). The severity scores of postprandial epigastric discomfort and fullness were significantly higher under the stress condition than under the control condition (P = 0.001 and P = 0.039, respectively, by paired t-test). CONCLUSIONS: Acute auditory stress delays gastric emptying and increases the severity of postprandial symptoms in the healthy subjects, suggesting the relevance of psychological stress to the pathophysiological mechanism of functional dyspepsia.

Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes.

Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI. Recent studies indicated that human monoclonal antibodies (MAbs) against toxins A and B reduce their cytotoxic and secretory activities and prevent CDI in hamsters. Moreover, anti-toxin A and anti-toxin B MAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these MAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocyte cells (PBMCs) has never been examined. We used fresh human colonic biopsy specimens and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling, and histologic damage. Incubation of anti-toxin A (MK3415) or anti-toxin B (MK6072) MAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) expression. MK3415 and MK6072 also diminished toxin A- and toxin B-mediated NF-κB p65 phosphorylation in human monocytes, respectively, and significantly reduced toxin A- and B-induced TNF-α and IL-1ß expression as well as histologic damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B-mediated inflammatory responses and histologic damage.

Preoperative colonoscopy for detection of synchronous neoplasms after insertion of self-expandable metal stents in occlusive colorectal cancer: comparison of covered and uncovered stents.

BACKGROUND/AIMS: In patients with occlusive colorectal cancers, a complete preoperative evaluation of the colon proximal to the obstruction is often impossible. We aimed to evaluate the feasibility of preoperative colonoscopy after stent placement and to determine whether the success rate of colonoscopy differs between covered and uncovered stents. METHODS: Seventy-three patients with malignant colorectal obstruction were enrolled prospectively. In patients with a resectable cancer, a preoperative colonoscopy was performed after insertion of a self-expandable metal stent (SEMS). The success rate of complete preoperative colonoscopy was compared between covered and uncovered stents. RESULTS: Forty-five of 73 patients who underwent stent placement had a resectable cancer (61.6%). A complete preoperative colonoscopy was possible in 40 of 45 patients (88.9%). The success rate of complete preoperative colonoscopy was significantly lower in the covered-stent group when the obstructing mass lesion was located in the sigmoid colon (p=0.024). Synchronous cancer was detected in one patient (2.2%). Stent migration was observed in four patients with a covered stent. CONCLUSIONS: A preoperative complete colonoscopy after SEMS placement was feasible and safe in most patients with malignant colorectal obstruction. Uncovered stents seem to have more advantages than covered stents in preoperative colonoscopy proximal to the obstruction.

How can we predict the presence of missed synchronous lesions after endoscopic submucosal dissection for early gastric cancers or gastric adenomas?

GOALS: To identify predictive factors associated with the presence of missed synchronous lesions after endoscopic submucosal dissection (ESD) for gastric adenoma or early gastric cancer (EGC). BACKGROUND: Secondary gastric neoplasms that develop during follow-up period after ESD for gastric adenoma or EGC are divided into metachronous lesions and missed synchronous lesions. METHODS: ESD was performed in 250 patients with EGC or gastric adenoma. The patients with endoscopic follow-ups of <1 year, patients without curative resection, and patients with additional surgery were excluded from the study. Missed synchronous lesions were defined as secondary gastric neoplasms detected within one year of ESD but initially missed. We compared clinicopathologic factors between patients with missed synchronous lesions and patients without missed synchronous lesions. RESULTS: Missed synchronous lesions were found in 11.6% of the patients (29/250). The occurrence of missed synchronous lesions had significant correlation with tumor number at the time of ESD and age in the univariate analysis. Tumor number at the time of ESD and age were significant independent predictive factors for presence of missed synchronous lesions by multivariate logistic regression analysis (odds ratio 5.302, P = 0.006; odds ratio 2.315, P = 0.040, respectively). Missed synchronous lesions tended to be smaller, often located in the same third of the stomach as the main lesions. CONCLUSIONS: Tumor number at the time of ESD and age could be predictive factors for the presence of missed synchronous lesions after ESD. Careful endoscopic surveillance should be performed after ESD for multiple lesions or for elderly patients.