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Hiroshi Ikeda,1 Kazuya Ishiguro,1 Tetsuyuki Igarashi,1 Yuka Aoki,1 Toshiaki Hayashi,1 Tadao Ishida,1 Yasushi Sasaki,1,2 Takashi Tokino,2 Yasuhisa Shinomura1 1Department of Gastroenterology, Rheumatology and Clinical Immunology, 2Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan Abstract: A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Keywords: multiple myeloma, drug resistance, genome-wide sequencing, semiconductor sequencer, target therapy

Background: We previously reported that gastrin induces expression of CXC chemokines through activation of nuclear factor κB (NFκB) in gastric epithelial cells that express gastrin receptor. Aims: To clarify gastrin [...]

Background: Diffuse proliferation of interstitial cells of Cajal (ICCs) in the myenteric plexus layer of the intestine has been described in patients with familial and multiple gastrointestinal stromal tumours (GISTs). [...]

Background and study aims: Growing evidence suggests that esophageal stricture frequently develops after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) in early esophageal cancer patients, with an incidence proportional to the greater extent of mucosal defects resulting from improved EMR/ESD techniques. There seems to be a potential risk of perforation during bougienage in such patients. Patients and methods: 648 stricture dilations for 78 lesions in 76 patients were consecutively included. The outcomes after combined use of Maloney and Savary wire-guided bougienage for esophageal strictures after EMR/ESD were analyzed in a single-institute retrospective case series study. The perforation rate was determined and risk factors for perforation were identified. Results: Patients underwent a median of 5.0 dilation procedures performed over a median 3.0 months for post-EMR/ESD strictures. Initial dilation was done a median 14 days following endoscopic resection. Perforations developed in seven patients (7/648 dilation procedures, 1.1 %), all in the lower esophagus, and bleeding occurred in one patient (0.1 % dilations). Two independent risk factors for development of perforation during dilation therapy for post-EMR/ESD stricture were identified: multiple dilations (odds ratio [OR] 1.2; P = 0.012), and lower site of stricture (OR 12.8; P = 0.043). Dysphagia was ameliorated by the dilations, and no patient required surgery. Conclusions: A specific emerging risk of perforation in dilation therapy for post-EMR/ESD strictures was identified. Carefully planned treatment is necessary in patients with severe post-EMR/ESD strictures especially strictures requiring multiple dilations or located in the lower esophagus. [ABSTRACT FROM AUTHOR]

Antioxidant molecules reduce oxidative stress and protect cells from reactive oxygen species (ROS)-mediated cellular damage and probably the development of cancer. We have investigated the contribution of X-box-binding protein (XBP1), a major endoplasmic reticulum stress-linked transcriptional factor, to cellular resistance to oxidative stress. After exposure to hydrogen peroxide (H2O2) or a strong ROS inducer parthenolide, loss of mitochondrial membrane potential (MMP) and subsequent cell death occurred more extensively in XBP1-deficient cells than wild-type mouse embryonic fibroblast cells, whereas two other anticancer agents induced death similarly in both cells. In XBP1-deficient cells, H2O2 exposure induced more extensive ROS generation and prolonged p38 phosphorylation, and expression of several antioxidant molecules including catalase was lower. Knockdown of XBP1 decreased catalase expression, enhanced ROS generation and MMP loss after H2O2 exposure, but extrinsic catalase supply rescued them. Overexpression of XBP1 recovered catalase expression in XBP1-deficient cells and diminished ROS generation after H2O2 exposure. Mutation analysis of the catalase promoter region suggests a pivotal role of CCAAT boxes, NF-Y-binding sites, for the XBP1-mediated enhancing effect. Taken together, these results indicate a protective role of XBP1 against oxidative stress, and its positive regulation of catalase expression may at least in part account for this function.Cell Death and Differentiation (2009) 16, 847–857; doi:10.1038/cdd.2009.14; published online 27 February 2009 [ABSTRACT FROM AUTHOR]

Although mutation of APC or CTNNB1 (beta-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a beta-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. [ABSTRACT FROM AUTHOR]

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1beta (HNF1beta), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2'deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4alpha, a transcriptional target of HNF1beta, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment. [ABSTRACT FROM AUTHOR]

The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor. In the present study, we investigated the role of met expression on the modulation of apoptosis in colorectal tumours. The gene expressions of c-met and the anti-apoptotic bcl-2 family, including bcl-2, bcl-x[SUBL] and bcl-w, were analysed in human colorectal adenomas and adenocarcinomas by using a quantitative polymerase chain-reaction combined with reverse transcription. In seven of 12 adenomas and seven of 11 carcinomas, the c-met gene was overexpressed. The bcl-w, bcl-2 and bcl-x[SUBL] genes were over-expressed in nine, five and six of 12 adenomas and in five, two and seven of 11 carcinomas, respectively. The c-met mRNA level in human colorectal adenomas and carcinomas was correlated with bcl-w but not with bcl-2 or with bcl-x[SUBL] mRNA level. The administration of c-met-antisense oligonucleotides decreased Met protein levels in the LoVo human colon cancer cell line. In the case of c-met-antisense-treated cells, apoptotic cell death induced by serum deprivation was more prominent, compared to control or c-met-nonsense-treated cells. Treatment with c-met-antisense oligonucleotides inhibits the gene expression of bcl-w in LoVo cells. On the other hand, the gene expression of bcl-2 or bcl-x[SUBL] was not affected by treatment with c-met-antisense oligonucleotides. These findings suggest that Met expression modulates apoptosis through bcl-w expression in colorectal tumours. [ABSTRACT FROM AUTHOR]

The physiological relevance of cholecystokinin (CCK) in gastric pepsin secretion is unclear, although CCK has been reported to stimulate pepsin secretion in intact animals and in dispersed chief cell. To clarify the physiological role played by this peptide in pepsin secretion, we determined the effects of intravenous infusions of CCK on gastric pepsin release, and investigated the effect of endogenous CCK released by small amounts of trypsin inhibitor on pepsin secretion in conscious rats. The infusion of CCK-8 at 1 nmol/kg per h resulted in a plasma CCK concentration of 204 pM and a 2.5-fold increase in pepsin secretion compared to the baseline rate. The infusion of CCK-8 at 0.3 nmol/kg per h resulted in a plasma CCK concentration of 41.8 pM and also caused a significant increase in pepsin secretion compared to the baseline rate. However, the infusion of CCK-8 at 0.1 nmol/kg per h (plasma CCK level, 19.9 pM), which is still far beyond the physiological plasma levels of CCK, did not significantly affect pepsin secretion. In addition, the intraduodenal infusion of soybean trypsin inhibitor increased the plasma CCK concentration to 4.4 pM, a value comparable to that observed after feeding (3.3 pM), but again, this had no effect on gastric pepsin secretion. We conclude that CCK is not a physiological regulator of gastric pepsin secretion in rats. [ABSTRACT FROM AUTHOR]

This study examined the effects of eradication of Helicobacter pylori (H pylori) infection on gastric mucosal morphology and acid secretion. Sixteen H pylori positive patients with enlarged gastric body folds were divided into two groups: (a) patients with moderate enlargement (fold width: 6 to 10 mm, n = 8) and (b) patients with severe enlargement (> 10 mm, n = 8). After successful treatment, gastric body fold width was reduced in both groups (p < 0.01) with an associated decrease in inflammatory infiltrates in the body mucosa (p < 0.01 and p < 0.05). Basal acid output and tetragastrin stimulated maximal acid output (mean (SEM)) in all 16 patients significantly increased from 1.1 (0.5) to 2.9 (0.9) mmol/h (p < 0.05) and from 5.4 (1.3) to 18.7 (2.3) mmol/h (p < 0.01), respectively, with a significant decrease in fasting serum gastrin concentrations, from 127.1 (16.1) to 59.6 (3.8) pg/ml (p < 0.01). The increase in acid secretion after eradication of H pylori was more noticeable in the severe group, who had shown lower acid secretion and higher serum gastrin concentrations (p < 0.05) before eradication, than the increase seen in the moderate group. The decreases in ammonia nitrogen content seen after eradication were significant in basal (from 0.91 (0.17) to 0.37 (0.08) mmol/h, p < 0.05) and stimulated gastric secretions (from 1.57 (0.19) to 0.37 (0.13) mmol/h, p < 0.01), although these changes were too small to explain the increases in basal acid output and maximal acid output. These results suggest that inflammation of the gastric body mucosa caused by H pylori infection is associated with enlarged gastric body folds and inhibition of acid secretion in H pylori positive patients with enlarged gastric body folds. [ABSTRACT FROM PUBLISHER]

The immunochemical protein content of group II phospholipase A2 (PLA2) and PLA2 enzymatic activity were measured for colonic mucosal biopsy samples obtained from patients with either Crohn's disease of the colon or ulcerative colitis, and control patients without inflammatory bowel disease. Immunoreactive group II PLA2 (IR-PLA2 II) content and PLA2 activity in actively inflamed colonic mucosa of Crohn's disease patients were significantly higher than those in inactively inflamed mucosa of Crohn's disease patients and the colonic mucosa of controls. IR-PLA2 II content and PLA2 activity in severely inflamed mucosa of ulcerative colitis patients were significantly higher than those in the colonic mucosa of the controls. Mucosal PLA2 enzymatic activity was closely correlated with mucosal IR-PLA2 II content in patients with Crohn's disease and ulcerative colitis. These results suggest that an increase in PLA2 enzymatic activity in inflamed colonic mucosa of Crohn's disease and ulcerative colitis was mainly attributed to increased protein content of group II PLA2, and that an increase in mucosal group II PLA2 may be involved in the pathogenesis of intestinal inflammation of Crohn's disease and ulcerative colitis. [ABSTRACT FROM PUBLISHER]

Calcium dependent phospholipase A2 activity in the mixed micelles of 1-palmitoyl-2-oleoyl-phosphatidylglycerol and cholate was measured in sera of 39 patients with Crohn's disease, 40 patients with ulcerative colitis, and 40 healthy controls. The phospholipase A2 activity was significantly raised in those sera of the patients with active Crohn's disease and those with moderate and severe ulcerative colitis. The major phospholipase A2 activity derived from the sera was separated into two peaks by reverse phase high performance liquid chromatography. The phospholipase A2 active fractions were immunochemically characterised using specific antibody directed against human group II phospholipase A2 purified from rheumatoid synovial fluid. The results suggest that raised serum phospholipase A2 activity in patients with Crohn's disease and ulcerative colitis was mainly attributed to the two forms of phospholipase A2 immunochemically related to group II enzyme. In patients with Crohn's disease, serum phospholipase A2 activity decreased in parallel with clinical improvement, and correlated with serum C-reactive protein and erythrocyte sedimentation rate. The results suggest that serum phospholipase A2 activity may serve as an additional indicator of disease activity. Serum phospholipase A2 activity in patients with ulcerative colitis tends to increase in relation with endoscopic severity, and may be a more sensitive laboratory index than serum C-reactive protein and erythrocyte sedimentation rate to evaluate disease activity. [ABSTRACT FROM PUBLISHER]

The article presents a case study of a 61-year-old man who was taken to the hospital because of melena and progressive anemia requiring transfusion. His colonoscopy and upper gastrointestinal endoscopy were all normal. He was performed with laparoscopy because both anterograde and retrograde single-balloon enteroscopy failed to reach the tumor. The article discusses pyogenic granuloma, a disease of the gastrointestinal tract which arises on the oral mucosa and extremities.

The article presents a case study of a 45-year-old man who was diagnosed with fibrovascular polyps (FVPs) of the esophagus. It mentions that the patient underwent laryngoscopy and esophagogastroduodenoscopy and was treated through transoral resection under general anesthesia. It discusses FVPs of the esophagus which were typically pedunculated and big that arises from the cervical esophagus.

A letter to the editor is presented in response to gastric antral vascular ectasia associated with systemic sclerosis.

A letter to the editor on Mikulicz's disease in the 2006 issue is presented.

Editorial. Argues on the effectiveness of pirenzipine in the suppression of undesirable effects of a proton pump inhibitor on enterochromaffin-like (ECL) cells. Role of ECL cells in the regulation of acid technology; Diseases caused by the administration of proton pump inhibitor; Use of experimental hypergastrinemia on the number of ECL cells of an experimental rat.

Abstract Background Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. Methods DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. Results DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8–18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8–50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and suppression of p44/42 MAP kinase and AKT activity. Conclusion Our study highlights the utility of DGS for identification of copy-number alterations. Using DGS, we identified KRAS as a gene that is amplified in human gastric cancer. We demonstrated that gene amplification likely forms the molecular basis of overactivation of KRAS in gastric cancer. Additional studies using a larger cohort of gastric cancer specimens are required to determine the diagnostic and therapeutic implications of KRAS amplification and overexpression.