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In micro- and nanofluidic devices, liquid flows are often influenced by ionic currents generated by electric fields in narrow channels, which is an electrokinetic phenomenon. Various technologies have been developed that are analogous to semiconductor devices, such as diodes and field effect transistors. On the other hand, measurement techniques for local electric fields in such narrow channels have not yet been established. In the present study, electric fields in liquids are locally measured using glass micro-electrodes with 1-μm diameter tips, which are constructed by pulling a glass tube. By scanning a liquid poured into a channel by glass micro-electrodes, the potential difference in a liquid can be determined with a spatial resolution of the size of the glass tip. As a result, the electrical conductivity of sample solutions can be quantitatively evaluated. Furthermore, combining two glass capillaries filled with buffer solutions of different concentrations, an ionic diode that rectifies the proton conduction direction is constructed, and the possibility of pH measurement is also demonstrated. Under constant-current conditions, pH values ranging from 1.68 to 9.18 can be determined more quickly and stably than with conventional methods that depend on the proton selectivity of glass electrodes under equilibrium conditions.

BackgroundDelayed bleeding is the major adverse event in upper gastrointestinal endoscopic treatment (UGET). We aimed to investigate the efficacy of vonoprazan, which is the novel strong antisecretory agent, to reduce the risk for delayed bleeding in comparison with proton pump inhibitors (PPIs) in UGET.MethodsThis retrospective population-based cohort study used the Diagnosis Procedure Combination database in Japan. We included patients on vonoprazan or PPI in UGET between 2014 and 2019. The primary outcome was delayed bleeding. We conducted propensity score matching to balance the comparison groups, and logistic regression analyses to compare the bleeding outcomes.ResultsWe enrolled 124,422 patients, in which 34,822 and 89,600 were prescribed with vonoprazan and PPI, respectively. After propensity score matching, the risk for delayed bleeding was lower in vonoprazan than in PPI (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.71–0.80), consistent with sensitivity analysis results. In the subgroup analyses of seven UGET procedures, vonoprazan was significantly advantageous in esophageal endoscopic submucosal dissection (E-ESD) (OR, 0.71; 95% CI, 0.54–0.94) and gastroduodenal endoscopic submucosal dissection (GD-ESD) (OR, 0.70; 95% CI, 0.65–0.75), although correction for multiple testing of the outcome data removed the significance in E-ESD. These results were also consistent with sensitivity analysis results. In the five other procedures, no significant advantage was found.ConclusionsThis nationwide study found that, compared with PPI, vonoprazan can reduce delayed bleeding with approximately 30% in GD-ESD. Vonoprazan has the possibility to become a new treatment method for preventing delayed bleeding in this procedure.

BackgroundRecent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease.AimsWe aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development.MethodsTo evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis.ResultsIn the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-β-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-β-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, β-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with β-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration.ConclusionsLocal exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-β-catenin-signaling in GC.

According to the European and Japanese guidelines, additional treatment is recommended for cases of superficial esophageal squamous cell carcinoma (ESCC) and early gastric cancer (EGC) that do not meet the curability criteria for endoscopic resection (ER), i.e., non-curative ER, owing to the risk of lymph node metastasis (LNM). However, the rates of LNM in such cases were relatively low (e.g., 8% for EGC). Several recent advances have been made in this field. First, pathological risk stratification for metastatic recurrence following non-curative ER without additional treatment was developed for both superficial ESCC and EGC. Second, the pattern of metastatic recurrence and prognosis after recurrence following non-curative ER without additional treatment was found to be considerably different between superficial ESCC and EGC. Third, a combination of ER and selective chemoradiotherapy was developed as a minimally invasive treatment method for clinical T1b-SM ESCC. These findings may help clinicians decide the treatment strategy for patients following non-curative ER; however, for optimal therapeutic decision-making in such patients, it is also important to predict the prognosis other than SESCC or EGC and impaired quality of life. Thus, a novel algorithm that considers these factors, as well as metastatic recurrence, should be developed.

Liquid biopsy (LB) is an essential tool for obtaining tumor‐derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell‐free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor‐derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers. A multigene panel for plasma liquid biopsy (LB) can also be applied to bile cell‐free DNA to identify mutations in biliary duct cancers. A machine learning approach was successfully applied to classify possible tumor‐derived variants among the prefiltered variant calls of a multigene panel. Bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.

Although endoscopic submucosal dissection (ESD) is a minimally invasive treatment method for upper gastrointestinal (GI) tumors, patients undergoing upper GI ESD sometimes fall into a serious condition from complications. Thus, it is important to fully understand how to prevent complications when performing upper GI ESD. One of the major complications in esophageal and gastric ESD is intraoperative perforation. To prevent this complication, blind dissection should be avoided. Traction‐assisted ESD is a useful technique for maintaining good endoscopic view. This method was proven to reduce the incidence of intraoperative perforation, which would become a standard technique in esophageal and gastric ESD. In gastric ESD, delayed bleeding is the most common complication. Recently, a novel prediction model (BEST‐J score) consisting of 10 factors with four risk categories for delayed bleeding in gastric ESD was established, and a free mobile application is now available. For reducing delayed bleeding in gastric ESD, vonoprazan ≥20 mg/day is the sole reliable method in the current status. Duodenal ESD is still challenging with a much higher frequency of complications, such as perforation and delayed bleeding, than ESD in other organs. However, with the development of improved devices and techniques, the frequency of complications in duodenal ESD has been decreasing. To prevent intraoperative perforation, some ESD techniques, such as using the distal tips of the Clutch Cutter, were developed. An endoscopic mucosal defect closure technique would be mandatory for preventing delayed complications. However, several unresolved issues, including standardization of duodenal ESD, remain and further studies are demanded.

Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta‐6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere‐forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2‐knockdown cells. The oxygen consumption ratio was also decreased in FADS2‐depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy. We screened a novel gene required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta‐6 desaturase. Depletion of FADS2 attenuated cancer cell malignancy, reduced lipid content, including triglyceride and cholesterol esters, and decreased oxygen consumption ratio, which reflects beta‐oxidation of fatty acids. We found a novel function of FADS2 as a tumor‐promoting factor in cholangiocarcinoma.

Background and Objective: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients’ mucosal integrity of the proximal esophagus. Methods: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis. Results: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1β mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules. Conclusions: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.

A 69‐year‐old woman, a long‐term survivor of subtotal stomach‐preserving pancreatoduodenectomy with the splenic vein resection for pancreatic cancer, visited our hospital with a chief complaint of bloody stools. Previously, she was diagnosed with varices in the ascending colon due to left‐sided portal hypertension after pancreatoduodenectomy by computed tomography and colonoscopy. After emergency hospitalization, she went into shock, and blood tests showed acute progression of severe anemia. Computed tomography showed a mosaic‐like fluid accumulation from the ascending colon to the rectum. She was diagnosed with ruptured varices in the ascending colon. Emergency colonoscopy was performed, and treatment with endoscopic injection sclerotherapy using N‐butyl‐2‐cyanoacrylate was successful. Ectopic varices occur at any location other than the esophagus and stomach, and colonic varices are rare among them. They are mostly caused by portal hypertension due to liver cirrhosis. However, with the trend of improving the prognosis for patients with pancreatic cancer, we should occasionally pay attention to the development of ectopic varices including colonic varices in patients who have undergone pancreatoduodenectomy with superior mesenteric and splenic veins resection. Treatment methods for colonic varices varied from case to case, including conservative therapy, interventional radiology, and endoscopic procedure. In this case, endoscopic injection sclerotherapy was successfully performed without any complications. To the best of our knowledge, this is the first study to report successful treatment with endoscopic injection sclerotherapy for varices in the ascending colon caused by left‐sided portal hypertension after pancreatoduodenectomy. Colonic varices should be considered in patients with obscure gastrointestinal bleeding after pancreatoduodenectomy.