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In the mouse intestinal epithelium, Lgr5Transcriptional heterogeneity among colonic epithelial cells was analyzed by means of single-cell RNA sequencing analysis of human and mouse colonic epithelial cells. To trace the fate of human colonic stem or differentiated cells, we generated LGR5-tdTomato, LGR5-iCasase9-tdTomato, LGR5-split-Cre, and KRT20-ERCreER knock-in human colon organoids via genome engineering. p27Single-cell RNA sequencing analysis illuminated the presence of nondividing LGR5Our results highlight the quiescent nature of human LGR5

Question: A previously healthy 39-year-old man presented to our hospital with a 1-week history of epigastric pain, nausea, and vomiting. He had no concomitant medical condition. His past medical history was unremarkable. He had no previous surgery or thoracoabdominal trauma history. The routine work-up on admission was normal. An immediate chest radiograph demonstrated the air–fluid level that projected above the diaphragm, to the far left of the midline (Figure A). The upper gastrointestinal (GI) series showed the esophagogastric unction was in the normal position, but the contrast medium would not pass through the mid-stomach (Figure B). The contour and orientation of the stomach by upper GI series and endoscopy suggested a mesenteroaxial gastric volvulus with herniation of the gastric body into the thorax (Figure C). Subsequent computed tomography of the chest and abdomen showed a diaphragmatic hernia containing he transverse colon as well as a significant portion of the posterior gastric body (Figure D). He elected to undergo a laparoscopic operation. he intraoperative finding is shown in Figure E (1, lower esophagus; 2, left paraesophageal space; 3, intervening muscle band; 4, left iaphragmatic crus; 5, lower lobe of the left lung through the defect). What is the diagnosis? Look on page 1623 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information n submitting your favorite image to Clinical Challenges and Images in GI.

Background & Aims: We have previously reported a 75-kilodalton autoantigen specific to X-linked autoimmune enteropathy (AIE) associated with tubulonephropathy. The aim of this study was to identify the autoantigen. Methods: Complementary DNA (cDNA) clones were isolated by immunoscreening a human duodenal cDNA-expression library with serum from a patient with AIE. Results: cDNA encoding the 75-kilodalton antigen (AIE-75) was identified. The composite nucleotide sequence of the cDNA for AIE-75 was 2214 base pairs long and encoded 552 amino acids. The genomic sequence of AIE-75 was found in Sequence DataBank, which consisted of 21 exons and was located on the chromosome 11p14.3. Recombinant AIE-75 specifically reacted with sera from 3 of 4 unrelated patients with AIE but not with 58 control sera. AIE-75 was predominantly distributed in the epithelial cells of the luminal surface and the upper half of the crypts of the intestine and in the proximal renal tubulus. Similarity searches revealed that the AIE-75 cDNA sequence was an authentic form of several colon cancer–related cDNAs of unknown function. The deduced amino acid sequence contained 3 conserved PSD-95/Dlg/ZO-1 (PDZ) domains. Conclusions: AIE-75 is a PDZ domain–containing protein expressed in the differentiated epithelial cells of the intestine and kidney and may be involved in protein-protein interaction. The identification of the autoantigen may prove useful in the approach to the pathogenesis of this poorly understood disease. GASTROENTEROLOGY 1999;117:823-830

Background & Aims: The molecular alterations that underlie carcinoid tumor pathogenesis remain poorly defined. The homeobox gene HOXC6 was highly up-regulated in human gastrointestinal carcinoid tumors, and we sought to define its pathogenic role. Methods: The functional and physical properties of Hoxc6 were investigated by establishing carcinoid cells that stably overexpressed Hoxc6 or were deficient in Hoxc6. Cellular proliferation assays, luciferase reporter assays, Western blotting, immunoprecipitation, DNA affinity precipitation, and DNA microarray studies were performed. Results: Expression of Hoxc6 in cultured human BON1 carcinoid cells enhanced their proliferation, and knock-down of Hoxc6 inhibited their growth. Hoxc6 activated the oncogenic activator protein-1 signaling pathway through a physical interaction with JunD. Mutations in the homeodomain of Hoxc6 blocked this interaction and inhibited proliferation of carcinoid cells. Of note, Hoxc6 induced the expression of genes that characteristically are up-regulated in carcinoid tumors, including neurotensin and connective tissue growth factor. Conclusions: A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis.

Background & Aims: The surgical indications for multiple hepatocellular carcinomas (HCCs) and for HCC with portal hypertension (PHT) remain controversial. Methods: We reviewed 434 patients who had undergone an initial resection for HCC and divided them into a multiple (n = 126) or single (n = 308) group according to the number of tumors. We also classified 386 of the patients into a PHT group (n = 136) and a no-PHT (n = 250) group according to whether they had PHT (defined by the presence of esophageal varices or a platelet count of Results: Among Child–Pugh class A patients, the overall survival rates in the multiple group were 58% at 5 years, and 56% in the PHT group, which were lower than those in the single group (68%, P = .035) and the no-PHT group (71%, P = .008). Among Child–Pugh class B patients with multiple HCCs, the 5-year overall survival rate was 19%. Multivariate analyses revealed that the presence of multiple tumors was an independent risk factor for postoperative recurrence (relative risk, 1.64; 95% confidence interval, 1.23–2.18; P = .001). A second resection resulted in satisfactory overall survival after the diagnosis of recurrence in the multiple (73% at 3 years) or PHT (73%) groups, as well as in the single (79%) or no PHT (81%) groups. Conclusions: Resection can provide survival benefits even for patients with multiple tumors in a background of Child–Pugh class A cirrhosis, as well as in those with PHT.

Background & Aims: The early embryonic pancreas gives rise to exocrine (ducts and acini) and endocrine lineages. Control of exocrine differentiation is poorly understood, but may be a critical avenue through which to manipulate pancreatic ductal carcinoma. Retinoids have been shown to change the character of pancreatic ductal cancer cells to a less malignant phenotype. We have shown that 9- cis retinoic acid (9cRA) inhibits acinar differentiation in the developing pancreas, in favor of ducts, and we wanted to determine the role of retinoids in duct versus acinar differentiation. Methods: We used multiple culture systems for the 11-day embryonic mouse pancreas. Results: Retinoic acid receptor (RAR)-selective agonists mimicked the acinar suppressive effect of 9cRA, suggesting that RAR-RXR heterodimers were critical to ductal differentiation. RARα was only expressed in mesenchyme, whereas RXRα was expressed in epithelium and mesenchyme. Retinaldehyde dehydrogenase 2, a critical enzyme in retinoid synthesis, was expressed only in pancreatic epithelium. 9cRA did not induce ductal differentiation in the absence of mesenchyme, implicating a requirement for mesenchyme in 9cRA effects. Mesenchymal laminin is necessary for duct differentiation, and retinoids are known to enhance laminin expression. In 9cRA-treated pancreas, immunohistochemistry for laminin showed a strong band of staining around ducts, and blockage of laminin signaling blocked all 9cRA effects. Western blot and RT-PCR of pancreatic mesenchyme showed laminin-β1 protein and mRNA induction by 9cRA. Conclusions: Retinoids regulate exocrine lineage selection through epithelial–mesenchymal interactions, mediated through up-regulation of mesenchymal laminin-1. GASTROENTEROLOGY 2002;123:1331-1340

Background: Eradication therapy for Helicobacter pylori-related chronic gastritis was approved for coverage by the Japanese national insurance in February 2013. Therefore, the use of eradication therapy has rapidly increased in Japan. The primary eradication rate of H. pylori using the 7-day triple therapy has gradually decreased in recent years. Drug resistance to clarithromycin (CAM), poor treatment compliance, and smoking are factors associated with eradication failure. A recent study showed that combination of eradication agents is useful for increasing eradication success, because combination treatments are prepared using daily dosages on one sheet. In our study, we prospectively compared the eradication rate in patients receiving conventional therapy with three drugs to that in patients receiving combination therapy. Patients and methods: Between July 2012 and September 2013, we included 276 patients (147 men and 129 women; mean age, 62.2 years) with H. pylori-positive peptic ulcers and gastritis. Combination therapy (Lansap®; lansoprazole 30 mg plus amoxicillin 750 mg plus CAM 200 mg) was administered to 54 patients twice a day for 7 days, and conventional therapy (omeprazole 20 mg or esomeprazole 20 mg or rabeprazole 20 mg plus amoxicillin 750 mg plus CAM 200 mg) was administered to 221 patients as individual drugs twice a day for 7 days. The 13C-urea breath test was used to confirm the eradication of H. pylori at least 6 weeks after the completion of eradication therapy. Patients who had undergone H. pylori eradication therapy in the past and patients who used proton pump inhibitors and antibiotics within 4 weeks were excluded. Results: No significant difference was observed in the background criteria of patients between the combination group and conventional group. The eradication rate (per protocol analysis) in the combination group was 90.3% (47/52), which was significantly different from that in the conventional group (74.9%; 161/215; p< 0.01). In addition, the eradication rate in intention-to-treat (ITT) analysis was significantly higher in the combination group (85.4%, 47/55) than in the conventional group (72.8%, 161/221; p< 0.01). No significant difference was observed in the incidence of adverse drug reactions (such as diarrhea, dysgeusia, and eruption) between the two groups (combination group 4.1%; conventional group 4.7%). Conclusions: Our study suggested that combination therapy with eradication agents is more useful for successful eradication of H. pylori than conventional therapy, although the primary eradication rate has decreased in Japan in the recent years. The underlying reason for the decrease in the primary eradication rate might be greater compliance to combination therapy.

Background: Eradication therapy for Helicobacter pylori-related chronic gastritis was approved for coverage by the Japanese national insurance in February 2013. Therefore, the use of eradication therapy has rapidly increased in Japan. The primary eradication rate of H. pylori using the 7-day triple therapy has gradually decreased in recent years. Drug resistance to clarithromycin (CAM), poor treatment compliance, and smoking are factors associated with eradication failure. A recent study showed that combination of eradication agents is useful for increasing eradication success, because combination treatments are prepared using daily dosages on one sheet. In our study, we prospectively compared the eradication rate in patients receiving conventional therapy with three drugs to that in patients receiving combination therapy. Patients and methods: Between July 2012 and September 2013, we included 276 patients (147 men and 129 women; mean age, 62.2 years) with H. pylori-positive peptic ulcers and gastritis. Combination therapy (Lansap®; lansoprazole 30 mg plus amoxicillin 750 mg plus CAM 200 mg) was administered to 54 patients twice a day for 7 days, and conventional therapy (omeprazole 20 mg or esomeprazole 20 mg or rabeprazole 20 mg plus amoxicillin 750 mg plus CAM 200 mg) was administered to 221 patients as individual drugs twice a day for 7 days. The 13C-urea breath test was used to confirm the eradication of H. pylori at least 6 weeks after the completion of eradication therapy. Patients who had undergone H. pylori eradication therapy in the past and patients who used proton pump inhibitors and antibiotics within 4 weeks were excluded. Results: No significant difference was observed in the background criteria of patients between the combination group and conventional group. The eradication rate (per protocol analysis) in the combination group was 90.3% (47/52), which was significantly different from that in the conventional group (74.9%; 161/215; p< 0.01). In addition, the eradication rate in intention-to-treat (ITT) analysis was significantly higher in the combination group (85.4%, 47/55) than in the conventional group (72.8%, 161/221; p< 0.01). No significant difference was observed in the incidence of adverse drug reactions (such as diarrhea, dysgeusia, and eruption) between the two groups (combination group 4.1%; conventional group 4.7%). Conclusions: Our study suggested that combination therapy with eradication agents is more useful for successful eradication of H. pylori than conventional therapy, although the primary eradication rate has decreased in Japan in the recent years. The underlying reason for the decrease in the primary eradication rate might be greater compliance to combination therapy.

Recently, several retrospective studies have shown an inverse association between appendectomy and development of ulcerative colitis. We describe a 21-year-old man with distal ulcerative colitis and appendiceal involvement. The patient passed bloody stools continually during the 3 years before admission. Macroscopic and microscopic findings showed chronic moderate inflammation of the appendix and rectum. The ratio of CD4 to CD8 lymphocytes isolated from rectal and appendiceal mucosa was increased (4.3 and 3.8, respectively) compared with controls (n = 11; 1.0 in the rectum and 1.4 in the appendix). Clinical symptoms and colonoscopic and microscopic findings improved significantly after appendectomy. In addition, the amount of interferon gamma secreted from rectal lymphocytes was reduced to 89 pg/mL after surgery (before appendectomy, 254 pg/mL). However, interleukin 4 production was below detectable levels both before and after appendectomy. These findings suggest that appendectomy resulted in altered T-helper (Th)1/Th2 balance in this patient. In the 3 years since surgery, the patient has been in good condition without recurrence of symptoms. This is the first report demonstrating therapeutic benefit of appendectomy in a patient with ulcerative colitis and potential mechanistic relationship.