An elevated expression of serum exosomal microRNA-191, - 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker.

BACKGROUND: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. METHODS: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. RESULTS: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5-20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). CONCLUSIONS: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).

Vonoprazan-based triple therapy is non-inferior to susceptibility-guided proton pump inhibitor-based triple therapy for Helicobacter pylori eradication.

BACKGROUND: All Helicobacter pylori-infected patients are recommended for eradication with an appropriate regimen in each geographic area. The choice of the therapy is somewhat dependent on the antimicrobial susceptibility. The rate of clarithromycin resistance has been increasing and is associated with failure; thus, susceptibility testing is recommended before triple therapy with clarithromycin. However, antimicrobial susceptibility testing is not yet clinically available and an alternative newly developed acid inhibitor vonoprazan is used for triple therapy in Japan. The aim of this study was to determine whether vonoprazan-based triple therapy is plausible treatment in H. pylori eradication. METHODS: A retrospective observational study of H. pylori eradication was conducted in a single institute. The patients who requested antimicrobial susceptibility testing were treated with susceptibility-guided proton pump inhibitor-based triple therapy in International University of Health and Welfare Hospital from 2013 to 2016. Other patients were treated with empirical treatment with a proton pump inhibitor. From 2015 to 2016, vonoprazan-based triple treatment (vonoprazan, 20 mg; amoxicillin, 750 mg; and clarithromycin, 200 or 400 mg, b.i.d.) was conducted, and its effectiveness was compared with susceptibility-guided proton pump inhibitor-based triple therapy. We also investigated the improvement in eradication rate when antimicrobial susceptibility testing was performed, and compared the outcomes of vonoprazan-based and proton pump inhibitor-based empirical therapy. RESULTS: A total of 1355 patients who received first-line eradication treatment were enrolled in the present study. The eradication rates of the empirical proton pump inhibitor-based therapy and the vonoprazan-based therapy group in a per-protocol analysis were 86.3% (95% CI 83.8-88.8) and 97.4% (95% CI 95.7-99.1), respectively. In 212 patients who received antimicrobial susceptibility testing, the rate of clarithromycin resistant was 23.5% and the eradication rate in susceptibility-guided treatment was 95.7% (95% CI 92.9-98.4). The difference between susceptibility-guided and vonoprazan-based therapy was - 1.7% (95% CI - 4.9 to 1.5%), and the non-inferiority of vonoprazan-based triple therapy was confirmed. CONCLUSIONS: Vonoprazan-based triple therapy was effective as susceptibility-guided triple therapy for H. pylori eradication. An empirical triple therapy with vonoprazan is preferable even in area with high rates of clarithromycin-resistance. Trial registration The study was retrospectively registered in University Hospital Medical Information Network (UMIN000032351).

Efficacy of Vonoprazan-Based Triple Therapy for Helicobacter pylori Eradication: A Multicenter Study and a Review of the Literature.

BACKGROUND: Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment. MATERIALS AND METHODS: Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature. RESULTS: The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies. CONCLUSIONS: Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APCmin/+ Mouse Models of Experimental Colon Cancer.

Chemopreventative properties of traditional medicines and underlying mechanisms of action are incompletely investigated. This study demonstrates that dietary daikenchuto (TU-100), comprised of ginger, ginseng, and Japanese pepper effectively suppresses intestinal tumor development and progression in the azoxymethane (AOM) and APCmin/+ mouse models. For the AOM model, TU-100 was provided after the first of six biweekly AOM injections. Mice were sacrificed at 30 weeks. APCmin/+ mice were fed diet without or with TU-100 starting at 6 weeks, and sacrificed at 24 weeks. In both models, dietary TU-100 decreased tumor size. In APC min/+ mice, the number of small intestinal tumors was significantly decreased. In the AOM model, both TU-100 and Japanese ginseng decreased colon tumor numbers. Decreased Ki-67 and ß-catenin immunostaining and activation of numerous transduction pathways involved in tumor initiation and progression were observed. EGF receptor expression and stimulation/phosphorylation in vitro were investigated in C2BBe1 cells. TU-100, ginger, and 6-gingerol suppressed EGF receptor induced Akt activation. TU-100 and ginseng and to a lesser extent ginger or 6-gingerol inhibited EGF ERK1/2 activation. TU-100 and some of its components and metabolites of these components inhibit tumor progression in two mouse models of colon cancer by blocking downstream pathways of EGF receptor activation. Copyright © 2016 John Wiley & Sons, Ltd.

Hepatic nerve growth factor induced by iron overload triggers defenestration in liver sinusoidal endothelial cells.

The fenestrations of liver sinusoidal endothelial cells (LSECs) play important roles in the exchange of macromolecules, solutes, and fluid between blood and surrounding liver tissues in response to hepatotoxic drugs, toxins, and oxidative stress. As excess iron is a hepatotoxin, LSECs may be affected by excess iron. In this study, we found a novel link between LSEC defenestration and hepatic nerve growth factor (NGF) in iron-overloaded mice. By Western blotting, NGF was highly expressed, whereas VEGF and HGF were not, and hepatic NGF mRNA levels were increased according to digital PCR. Immunohistochemically, NGF staining was localized in hepatocytes, while TrkA, an NGF receptor, was localized in LSECs. Scanning electron microscopy revealed LSEC defenestration in mice overloaded with iron as well as mice treated with recombinant NGF. Treatment with conditioned medium from iron-overloaded primary hepatocytes reduced primary LSEC fenestrations, while treatment with an anti-NGF neutralizing antibody or TrkA inhibitor, K252a, reversed this effect. However, iron-loaded medium itself did not reduce fenestration. In conclusion, iron accumulation induces NGF expression in hepatocytes, which in turn leads to LSEC defenestration via TrkA. This novel link between iron and NGF may aid our understanding of the development of chronic liver disease.

Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress.

Bifidobacterium breve and other Gram-positive gut commensal microbes protect the gastrointestinal epithelium against inflammation-induced stress. However, the mechanisms whereby these bacteria accomplish this protection are poorly understood. In this study, we examined soluble factors derived from Bifidobacterium breve and their impact on the two major protein degradation systems within intestinal epithelial cells, proteasomes and autophagy. Conditioned media from gastrointestinal Gram-positive, but not Gram-negative, bacteria activated autophagy and increased expression of the autophagy proteins Atg5 and Atg7 along with the stress response protein heat shock protein 27. Specific examination of media conditioned by the Gram-positive bacterium Bifidobacterium breve (Bb-CM) showed that this microbe produces small molecules (<3 kDa) that increase expression of the autophagy proteins Atg5 and Atg7, activate autophagy, and inhibit proteasomal enzyme activity. Upregulation of autophagy by Bb-CM was mediated through MAP kinase signaling. In vitro studies using C2BBe1 cells silenced for Atg7 and in vivo studies using mice conditionally deficient in intestinal epithelial cell Atg7 showed that Bb-CM-induced cytoprotection is dependent on autophagy. Therefore, this work demonstrates that Gram-positive bacteria modify protein degradation programs within intestinal epithelial cells to promote their survival during stress. It also reveals the therapeutic potential of soluble molecules produced by these microbes for prevention and treatment of gastrointestinal disease.

A selective splicing variant of hepcidin mRNA in hepatocellular carcinoma cell lines.

Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells.

Perspectives of Japanese oncologists on the health economics of innovative cancer treatments.

BACKGROUND: Few reports have thus far discussed the influence of economic factors on treatment decision-making by patients. The objective of the present study was to clarify the awareness among oncologists of health economics in cancer treatment. METHODS: The present study was based on the questionnaire regarding health economics in cancer treatment carried out by the Japan Society of Clinical Oncology (JSCO) in July 2013. The subjects were trustees registered with JSCO. The survey investigated the influence of medical expenses on patient access to and selection of medical treatment in order to clarify the primary attributes of the respondents and their awareness of economics. The study also investigated the maximum allowable public medical expenses to prolong the life expectancy of a cancer patient by 1 year and the factors that can influence treatment selection. RESULTS: The 172 respondents had completed a mean of 30.3 ± 6.2 postgraduate years, and the mean number of patients they treated annually was 1323 ± 1963. The degree of treatment accessibility among patients was perceived positively by 112 (71.3 %) and negatively by 49 (28.7 %) of the respondents, irrespective of medical expenses. Of the 172 respondents, 66 (41.0 %) believed that the maximum allowable medical expenses for cancer treatment should be ≤4 million yen/LY, with 62 (39.8 %) reporting a value of 4.01-8 million yen/LY. CONCLUSION: The findings of this study suggest that a certain range of medical expenses has come to be regarded as the standard range of medical expenses for cancer treatment among oncologists, with answers based on the premise that patients should have access to effective medical treatment.

The clinical importance of "bamboo joint-like appearance" on upper gastrointestinal endoscopy for the diagnosis of Crohn's disease.

Upper gastrointestinal (GI) lesions are frequently reported in Crohn's disease, in which the entire GI tract is affected. In these cases, erosive fissures regularly transversing folds that are longitudinally aligned along the lesser curvature of the gastric body and cardia are described as having a "bamboo joint-like appearance". We designed a blinded experiment in which upper GI imaging without a final diagnosis was checked by three observers to determine the usefulness of the bamboo joint-like appearance in the diagnosis of Crohn's disease. For the three observers, sensitivities of appearance were 30.5%, 56.9%, and 51.4%, while specificities were 99.6%, 98.5%, and 99.3%. Thus, the bamboo joint-like appearance was not useful for the identification of Crohn's disease patients. Nevertheless, patients exhibiting the bamboo joint-like appearance in upper GI imaging should undergo further examination due to the high probability of Crohn's disease.

Host-microbe interactions via membrane transport systems.

Living organisms take in essential molecules and get rid of wastes effectively through the selective transport of materials. Especially in the digestive tract, advanced transport systems are indispensable for the absorption of nutrients and elimination of waste products. These transport pathways control physiological functions by modulating the ionic environment inside and outside the cells. Moreover, recent studies have shown the importance of the expression of trafficking-related molecules and the population of gut microbiota. We found that the molecules secreted from microorganisms are imported into the cells via transporters or endocytosis and that they activate cell survival pathways of intestinal epithelial cells. These findings indicate that the interactions between the gut microbiota and host cells are mediated, at least partly, by the membrane transport systems. In addition, it is well known that the breakdown of transport systems induces various diseases. This review highlights the significance of the transport systems as the pathogenic molecules and therapeutic targets in gastrointestinal disorders. For example, abnormal expression of the genes encoding membrane transport-related molecules is frequently involved in digestive diseases, such as colorectal cancer and inflammatory bowel disease. We herein review the significance of these molecules as pathogenic and therapeutic targets for digestive diseases.

microRNA-26a and -584 inhibit the colorectal cancer progression through inhibition of the binding of hnRNP A1-CDK6 mRNA.

While the progress of chemotherapy and molecular targeted therapy has improved the outcome of colorectal cancer patients, the mortality of colon cancer remains high, indicating the need to develop novel therapeutic targets for improving the outcome of colon cancer. Heterogeneous ribonucleoprotein A1 (hnRNP A1) is highly expressed in colorectal cancer and its expression correlates with malignant transformation. In this study, we performed a microarray analysis with the RNA immunoprecipitation (RNA-IP) method and identified hnRNP A1-interacting miRs, including miR-26a and -584, in a colorectal cancer cell line, SW620. A SRB assay revealed the tumor suppressive effect of miR-26a and -584, and the tumor suppressive effect of these miRs was diminished by the downregulation of hnRNP A1. The combined method of a transcriptome analysis and RNA-IP revealed hnRNP A1-interacting mRNAs, including cyclin dependent kinase 6 (CDK6). A Western blot analysis revealed the downregulation of CDK6 in miR-26a and -584 overexpression cells, as well as hnRNP A1 knockdown cells. The binding assay indicated that the binding of hnRNP A1-CDK6 mRNA was reduced by transfection of miR-26a and -584. The expression of cleaved caspase-3 was induced in miR-26a and -584 overexpression cells. These data indicate that miR-26a and -584 inhibit the binding of hnRNP A1-CDK6 mRNA and induce colorectal cancer cell apoptosis.

Probiotic-derived polyphosphate improves the intestinal barrier function through the caveolin-dependent endocytic pathway.

Probiotics exhibit beneficial functions for host homeostasis maintenance. We herein investigated the mechanism by which Lactobacillus brevis-derived poly P exhibited a beneficial function. Immunostaining indicated that poly P was captured in the plasma membrane via integrin ß1 in Caco2/bbe cells. The uptake of poly P was reduced by the inhibition of integrin ß1 as well as caveolin-1, a major component of lipid rafts. The function of poly P, including the induction of HSP27 and enhancement of the intestinal barrier function, was suppressed by the inhibition of caveolin-1, illustrating that the function of poly P was mediated by the endocytic pathway. High-throughput sequencing revealed that poly P induced tumor necrosis factor alpha-induced protein 3, which contributes to cytoprotection, including upregulation of the intestinal barrier function. The present study demonstrates a novel host-probiotic interaction through the uptake of bacterial substance into host cells, which is distinct from pattern recognition receptor pathways.

Efficacy and adverse events of EMR and endoscopic submucosal dissection for the treatment of colon neoplasms: a meta-analysis of studies comparing EMR and endoscopic submucosal dissection.

BACKGROUND: EMR and endoscopic submucosal dissection (ESD) are used frequently to remove colon neoplasms. However, the predominance of these procedures has not yet been thoroughly explored. OBJECTIVE: To compare the efficacy and adverse events related to EMR with those related to ESD for colon neoplasms. DESIGN: A meta-analysis of 8 studies published between 2005 and 2013. SETTING: Multicenter review. PATIENTS: Patients from 8 studies yielding 2299 lesions. INTERVENTIONS: EMR or ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection, curative resection, recurrence, and adverse events. RESULTS: The pooled odds ratios (OR) (OR [95% confidence interval]) for the tumor size, length of the procedure, en bloc resection, curative resection, recurrence, additional surgery, delayed bleeding, and perforation by ESD versus EMR were 7.38 (6.42-8.34), 58.07 (36.27-79.88), 6.84 (3.30-14.18), 4.26 (3.77-6.57), 0.08 (0.04-0.17), 2.16 (1.16-4.03), 0.85 (0.45-1.60), and 4.96 (2.79-8.85), respectively. LIMITATIONS: This analysis included only nonrandomized studies. CONCLUSION: The size of the tumor and rate of en bloc resection and curative resection were higher, and the rate of recurrence was lower in the ESD group versus the EMR group. However, in the ESD group, the procedure was longer, and the rate of additional surgery and perforation was higher, suggesting that the indications for ESD should therefore be rigorously determined in order to avoid such problems.

Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias.

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10­40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was ­10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and ­13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

Quantification of autofluorescence imaging can accurately and objectively assess the severity of ulcerative colitis.

BACKGROUND AND AIMS: No endoscopic examination has been able to evaluate severity of ulcerative colitis (UC) by quantification. This prospective study investigated the efficacy of quantifying autofluorescence imaging (AFI) to assess the severity of UC, which captures the fluorescence emitted from intestinal tissue and then quantifies the intensity using an image-analytical software program. MATERIALS AND METHODS: Eleven endoscopists separately evaluated 135 images of conventional endoscopy (CE) and AFI from a same lesion. A CE image corresponding to Mayo endoscopic subscore 0 or 1 was defined as being inactive. The fluorescence intensities of AFI were quantified using an image-analytical software program (F index; FI). Active inflammation was defined when Matts' histological grade was 2 or more. A cut-off value of the FI for active inflammation was determined using a receiver operating characteristic (ROC) analysis. The inter-observer consistency was calculated by unweighted kappa statistics. RESULTS: The correlation coefficient for the FI was inversely related to the histological severity (r = -0.558, p < 0.0001). The ROC analysis showed that the optimal cut-off value for the FI for active inflammation was 0.906. The average diagnostic accuracy of the FI was significantly higher than those of the CE (84.7 vs 78.5 %, p < 0.01). The kappa values for the inter-observer consistency of CE and the FI were 0.60 and 0.95 in all participants, 0.53 and 0.97 in the less-experienced endoscopists group and 0.67 and 0.93 in the expert group, respectively. CONCLUSIONS: The quantified AFI is considered to be an accurate and objective indicator that can be used to assess the activity of ulcerative colitis, particularly for less-experienced endoscopists.

Current therapeutic strategies for multiple myeloma.

The introduction of novel molecular targeting agents against multiple myeloma has dramatically and rapidly changed the therapeutic strategies for this incurable hematologic disease. Novel agents such as thalidomide, bortezomib and lenalidomide have significantly improved the response rate, progression-free survival, and overall survival compared with conventional chemotherapies, and made it easy to control the disease for longer periods of time. Initial therapies for newly diagnosed myeloma patients depend on the individual's clinical condition. Induction therapy with novel agents and high-dose chemotherapy followed by autologous stem cell transplantation is a standard therapy for newly diagnosed younger myeloma patients. On the other hand, several combinations of novel agents and other drugs (melphalan, prednisone, dexamethasone, etc.) are widely used as initial therapy for transplantation-ineligible myeloma patients. Although the clinical advantage of maintenance therapy after induction therapy has been reported, it is not recommend in routine practice. Maintenance therapy would be an option for some patients. Despite the significant improvements with the use of novel agents, the majority of patients eventually relapse. A number of treatment options including novel agents, which demonstrated marked clinical effects, are reported in the setting of salvage therapy. The choice of appropriate therapy for relapsed or refractory patients must take the disease status or patient status in consideration. Furthermore, a new generation of novel agents such as pomalidomide, carfilzomib or panobinostat has recently become available for relapsed or refractory myeloma. It is necessary to determine the optimal combination of drugs, administration timing and patients to be treated in future clinical trials.

Focal adhesion kinase regulates intestinal epithelial barrier function via redistribution of tight junction.

Disruption of epithelial barrier function was identified as one of the pathologic mechanisms in inflammatory bowel diseases (IBD). Epithelial barrier consists of various intercellular junctions, in which the tight junction (TJ) is an important component. However, the regulatory mechanism of tight junction is still not clear. Here we examined the role of focal adhesion kinase (FAK) in the epithelial barrier function on Caco-2 monolayers using a specific FAK inhibitor, PF-573, 228 (PF-228). We found that the decrease of transepithelial resistance and the increase of paracellular permeability were accompanied with the inhibition of autophosphorylation of FAK by PF-228 treatment. In addition, PF-228 inhibited the FAK phosphorylation at Y576/577 on activation loop by Src, suggesting Src-dependent regulation of FAK in Caco-2 monolayers. In an ethanol-induced barrier injury model, PF-228 treatment also inhibited the recovery of transepithelial resistance as well as these phosphorylations of FAK. In a sucrose gradient ultracentrifugation, FAK co-localized with claudin-1, an element of the TJ complex, and they co-migrate after ethanol-induced barrier injury. Immunofluorescence imaging analysis revealed that PF-228 inhibited the FAK redistribution to the cell border and reassembly of TJ proteins in the recovery after ethanol-induced barrier injury. Finally, knockdown of FAK by siRNA resulted in the decrease of transepithelial resistance. These findings reveal that activation of FAK is necessary for maintaining and repairing epithelial barrier in Caco-2 cell monolayer via regulating TJ redistribution.

Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis.

BACKGROUND & AIMS: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. METHODS: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. RESULTS: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models. CONCLUSIONS: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis.

Decreased numbers of vascular networks and irregular vessels on narrow-band imaging are useful findings for distinguishing intestinal lymphoma from lymphoid hyperplasia.

BACKGROUND: No method for sufficiently making the differential diagnosis of intestinal lymphoma resembling lymphoid hyperplasia (LH) on endoscopy has yet been established. OBJECTIVE: The aim of this study was to evaluate the usefulness of narrow-band imaging (NBI) in diagnosing intestinal lymphoma. DESIGN: Prospective study. SETTING: Single-center study. PATIENTS: Sixty-one patients with primary or systemic lymphoma were enrolled in this study. INTERVENTIONS: The terminal ileum and entire colon were observed by using conventional endoscopy. NBI was subsequently performed when small polypoid lesions were detected. A decrease in the number of vascular networks (DVNs) and the presence of irregular vessels on the surface of the epithelia were defined as characteristic findings of intestinal lymphoma. The diagnostic accuracy of these 2 findings in distinguishing intestinal lymphoma from LH was examined. MAIN OUTCOME MEASUREMENTS: The ability to use NBI to distinguish intestinal lymphoma from LH. RESULTS: Two hundred ninety-four small polypoid lesions, including 59 lymphomas and 235 LH lesions, were detected. The rates of detecting DVNs and the presence of irregular vessels were significantly higher in the lymphoma samples (81.4% and 62.7%) than in the LH samples (25.5% and 4.7%). Based on these findings, the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values for differentiating intestinal lymphoma from LH were 88.8%, 62.7%, 95.3%, 77.1%, and 91.1%, respectively, which are significantly higher than those of conventional endoscopy. LIMITATIONS: Single-center study. CONCLUSION: DVNs and the presence of irregular vessels on NBI are thus considered to be useful findings for differentiating intestinal lymphoma from benign LH.

Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice.

AIM: There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD. METHODS: Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1ß, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated. RESULTS: The expression of inflammatory cytokines such as TNF, IL-1ß, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA. CONCLUSION: In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.