Thermally activated delayed fluorescence of a Zr-based metal-organic framework.

The first metal-organic framework exhibiting thermally activated delayed fluorescence (TADF) was developed. The zirconium-based framework (UiO-68-dpa) uses a newly designed linker composed of a terphenyl backbone, an electron-accepting carboxyl group, and an electron-donating diphenylamine and exhibits green TADF emission with a photoluminescence quantum yield of 30% and high thermal stability.

The clinical significance of cysteine dioxygenase type 1 methylation in Barrett esophagus adenocarcinoma.

Methylation of cysteine dioxygenase type 1 (CDO1) gene, a tumor suppressor gene, has been studied in various cancers; however, there is no information regarding Barrett esophagus cancer. In this study, the clinical significance of CDO1 methylation in Barrett esophagus adenocarcinoma (BEA) was clarified. CDO1 gene promoter methylation was analyzed for DNA from the patient's specimens using quantitative methylation-specific polymerase chain reaction. Thirty-eight BEA patients who underwent resection were identified between 2000 and 2014. Hypermethylation of CDO1 gene was demonstrated to be frequently recognized even at early stage in BEA by quantitative methylation-specific polymerase chain reaction. In BEA, there is a robust prognostic difference between stage I and stage II/III/IV with regard to 5-year relapse-free survival (P = 0.0016) and 5-year overall survival (P = 0.0024), and the tumor size separated by 7 cm was also a prognostic factor. There was significant difference in CDO1 gene methylation according to the tumor size (P = 0.036). BEA patients with CDO1 gene methylation were shown marginally significantly poorer prognosis (P = 0.054) than otherwise patients. In conclusion, higher CDO1 gene methylation was seen in BEA at earlier stage than in squamous cell carcinoma, and it may account for aggressive phenotype of BEA.

Reduced preoperative serum albumin and absence of peritoneal dissemination may be predictive factors for long-term survival with advanced gastric cancer with positive cytology test.

BACKGROUND: Peritoneal lavage cytology cancer-positive (CY1) is a critical prognostic factor and is taken as representing stage IV in gastric cancer. There is no consensus treatment strategy for CY1-gastric cancer, and the detailed clinicopathological features remain obscure. PATIENTS AND METHODS: Among 790 gastric cancer patients between 2005 and 2009, 52 cases of CY1 were identified (6.6%). A multivariate prognostic model was applied to the univariate prognostic factors to identify independent prognostic factors and factors associated with long-term survival in CY1-gastric cancer. RESULTS: (1) Five-year overall survival (OS) was 17.6% in CY1-gastric cancer as compared with 93.9% in CYX and 77.7% in CY0 (77.7%), where tumors with pT2 or beyond were included in 11% of CYX, 73% of CY0, and 98% of CY1 cases. (2) On univariate analysis, factors associated with a negative prognosis were the presence of peritoneal dissemination (p = 0.029) and high preoperative serum albumin (p = 0.011) in CY1-gastric cancer. The multivariate Cox proportional hazards and logistic regression model using propensity score identified preoperative albumin as a critical independent prognostic indicator. (3) Long-term survivors were identified and, were often characterized by long-term postoperative adjuvant treatment. CONCLUSION: Reduced preoperative serum albumin and absence of peritoneal dissemination may be predictive factors for long-term survival in patients with advanced gastric cancer with positive cytology test. Long-term postoperative adjuvant therapy might improve survival of patients with CY1.

Acid-suppressive effects of generic omeprazole: comparison of three brands of generic omeprazole with original omeprazole.

BACKGROUND: Generic omeprazole contains the same active ingredient as original omeprazole and require verification of the bioequivalence with original omeprazole. However, very few clinical studies have been reported. AIMS: A prospective, randomised, open-label, crossover study to compare acid-suppressive effect of generic omeprazole with that of original omeprazole. SUBJECTS: Seven healthy Helicobacter pylori-negative subjects of CYP2C19 extensive metaboliser. METHODS: Intragastric pH was measured for 24 h without medications (placebo) and on day 7 of repeated administration of 10 mg once daily after breakfast of original omeprazole, Omeprazon, or three brands of generic omeprazole, Omeprazole-Towa, Ovulanze or Omerap. RESULTS: Median values of intragastric pH and percentages of time with pH>4 for 24 h were significantly higher with administration of any omeprazole formulation compared with placebo (P<0.05, Wilcoxon signed-rank test). Whereas, during the night-time period (20:00-08:00 h), percentages of time with pH>4 with Omeprazole-Towa and Omerap were not significantly higher than placebo. Compared with Omeprazon, these two parameters for 24 h showed significantly greater inter-subject variations with Omeprazole-Towa (P<0.05 and P<0.01, F-test) and Ovulanze (P<0.05). CONCLUSIONS: Acid-suppressive effects of some brands of generic omeprazole are not the same as original omeprazole. These differences might be reflected in clinical outcomes.

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist.

BACKGROUND: Omeprazole 10 mg is used as maintenance therapy for gastro-oesophageal reflux disease, but previous reports have not mentioned the potency of its acid suppression. AIM: To evaluate the potency of acid suppression with omeprazole 10 mg, in relation to CYP2C19 genotypes. METHODS: Eighteen healthy subjects without Helicobacter pylori participated. After a 7-day regimen of omeprazole 10 mg, 20 mg, lafutidine 20 mg (a novel H2-receptor antagonist) or water only (baseline data), intragastric pH was measured for 24 h. RESULTS: With omeprazole 10 mg, greater differences were observed than 20 mg in median pH values and pH > 4 holding time ratios between poor metabolizers (PMs, n = 6) and the others [homozygous extensive metabolizers (homo-EMs, n = 6) and heterozygous extensive metabolizers (hetero-EMs, n = 6)]. With lafutidine 20 mg, these parameters were not influenced by the genotype. The potency of acid suppression was: omeprazole 20 mg approximately lafutidine 20 mg > omeprazole 10 mg in homo-EMs, omeprazole 20 mg > omeprazole 10 mg approximately lafutidine 20 mg in hetero-EMs, and omeprazole 20 mg approximately omeprazole 10 mg > lafutidine 20 mg in PMs. CONCLUSIONS: Omeprazole 10 mg strongly suppresses acid secretion, but depending on the CYP2C19 genotypes shows greater interindividual variations in suppression than 20 mg.

Improvement in gastric histology following Helicobacter pylori eradication therapy in Japanese peptic ulcer patients.

We aimed to determine if successful or failed eradication of Helicobacter pylori with triple therapy causes any difference in gastric mucosal histology. Japanese H. pylori-positive patients with a healed peptic ulcer received high (n = 112) or low (n = 113) doses of triple therapy (omeprazole, amoxicillin and clarithromycin) for 1 week. Biopsies from the greater curvature of the central antrum and upper corpus were taken 6 weeks and 30 weeks after treatment completion, and gastric mucosal histology compared between successful (n = 171) and failed (n = 34) eradication groups. Morphological variables of gastritis were graded according to the updated Sydney System. Successful eradication therapy was defined as improvement in inflammation, neutrophil activity and atrophy; failed eradication therapy as improvement in inflammation and neutrophil activity only. Gastric mucosal atrophy gradually improved (in addition to improvements in inflammation and neutrophil activity) with successful eradication of H. pylori infection.

Nonselective cation channel as a Ca(2+) influx pathway in pepsinogen-secreting cells of bullfrog esophagus.

In pepsinogen-secreting cells of bullfrog (Rana catesbeiana), recent evidence suggests that Ca(2+) release from internal stores followed by Ca(2+) influx across the plasma membrane elicits pepsinogen secretion. Such a Ca(2+) influx could be carried by a background current, potentiated by bombesin, that was found in these cells using the whole cell patch-clamp technique. The permeability ratio of Cs(+)-Rb(+)-K(+)-Na(+)-Li(+)-N-methyl-D-glucamine(+)-Ca(2+) was 1.01:1:1:0.86:0.72:0.54:0.34. The current was almost totally blocked by the nonselective cation channel blockers La(3+) (0.1 mM) and Gd(3+) (0.1 mM) and was activated by intracellular Ca(2+). These properties demonstrated that the current, which was activated by bombesin, was a nonselective cation current. At the same time, Gd(3+) suppressed pepsinogen secretion by 29 +/- 5.6% in isolated pepsinogen-secreting glands. These results are in accord with the idea that a nonselective cation channel in pepsinogen-secreting cells plays a role as a Ca(2+) influx pathway leading to secretion of pepsinogen in bullfrog esophageal mucosa.

Adenocarcinoma complicating Barrett's esophagus: an analysis of cell proliferation.

In Japan, cases of Barrett's esophagus with concurrent adenocarcinoma are relatively rare. We report herein a case of long-segment Barrett's esophagus-associated adenocarcinoma in a 72-year-old Japanese man. The surgical specimen showed that an ulcerating tumor, measuring 5.5 x 3.9 cm, was present in the lower esophagus adjacent to the esophagogastric junction, the background lower esophagus having an erythematous appearance. Histologically, the ulcerating tumor was a well-to-moderately differentiated tubular adenocarcinoma, with a small area of signet ring cell carcinoma invading the adventitia. In addition, the esophageal epithelium was replaced by columnar epithelium (9.5 cm in length) with multifocal dysplastic changes. Immunohistochemically, the number of Ki-67-positive cells gradually increased, moving from the normal gastric mucosa (mean Ki-67 labeling index [mKLI], 2.6%) through Barrett's epithelium (mKLI, 12.9%), low-grade dysplasia (mKLI, 16.9%), and high-grade dysplasia (mKLI. 23.7%) to invasive carcinoma, in that order, with labeling higher in the invasive tubular adenocarcinoma elements (mKLI, 40.5%) than in areas of signet ring cell carcinoma (mKLI, 20.4%). Findings in our patient suggest that increased cellular proliferation plays an integral part, in the progression of Barrett's metaplasia to adenocarcinoma. The collection of further cases for analysis will be necessary to confirm this hypothesis.

Recent results in the surgical treatment of gastric cancer according to the Japanese and TNM classification.

BACKGROUND: Recent outcomes based on surgical long-term follow-up of patients with gastric cancer using current staging systems have not been fully evaluated. MATERIALS AND METHODS: A total of 1357 patients with primary gastric carcinoma (911 males and 446 females, ranging in age from 20 to 87 years; average 59.1 years) who had undergone gastric resection between 1986 and 1996 were examined with respect to their clinicopathological features, surgical procedures and patient survival according to Japanese and UICC-TNM classifications. RESULTS: The 5-year survival rate was 95.3% for stage Ia, 85.5% for stage Ib, 73.8% for stage II, 45.7% for stage IIIa, 20.9% for stage IIIb, 17.3% for stage IVa and 5.8% for stage IVb (8.8% for IVa and IVb) on the Japanese classification. By way of contrast, the 5-year survival rate was 95.6% for stage Ia, 85.0% for stage Ib, 72.1% for stage II, 49.3% for stage IIIa, 30.2% for stage IIIb and 12.0% for stage IV on the TNM classification. CONCLUSION: Although minor problems are associated with both the Japanese and TNM classification systems, both appear to be clinically significant and appropriate independent predictors of prognosis. The findings of the present study provide important information for comparing results among different institutes and for introducing new clinical trials for gastric cancer at the beginning of the new century.

Gastrointestinal motility in patients with irritable bowel syndrome studied by using radiopaque markers.

BACKGROUND: Irritable bowel syndrome (IBS) has been identified as a physiologic abnormality, but no test has been established as a diagnostic standard for gastrointestinal dyskinesia in IBS patients. The aim of this study was to investigate gastrointestinal motility in patients with IBS by using radiopaque markers. METHODS: Gastrointestinal motility was studied in IBS patients (n = 72), constipation patients (n = 19), diarrhoea patients (n = 9), and healthy controls (n = 23). Using three types of radiopaque markers, analysis was performed to establish the transit time and a new indicator, the 'scattering index'. RESULTS: Transit times were not characteristic in IBS. The patients with IBS had significantly higher scattering indexes in the colon and total gut than the healthy controls and the patients with constipation and diarrhoea. The transit time and scattering index of the colon were linearly correlated in the healthy controls and the constipation and diarrhoea patients but were not correlated in the IBS patients. Using transit time and scattering index was a reliable means of evaluating gastrointestinal motility in IBS patients, with a sensitivity of 65% and a specificity of 96%. CONCLUSION: Three days' use of the radiopaque marker method was useful for providing an objective means of detecting gastrointestinal dysmotility in IBS patients.

Pepsinogen secretion: coupling of exocytosis visualized by video microscopy and [Ca2+]i in single cells.

Conventional in vitro studies of pepsinogen secretion have measured secretion into the bulk medium and have demonstrated the critical role of Ca2+ in the process. The present study was undertaken to obtain further details of the process of secretion and its relation to Ca2+ changes over very short time periods. The relation between Ca2+ mobilization and exocytosis in an isolated individual peptic cell of the bullfrog was investigated by a method to measure both intracellular Ca2+ ([Ca2+]i), using a fluorescent Ca2+ indicator, fura 2, and exocytosis from single cells using a video microscope analyzing system. Bombesin (3.2 x 10(-7) M) and bethanechol (3.2 x 10(-4) M) caused a rapid increase in [Ca2+]i (initial peak) and a corresponding high frequency of initial exocytosis. After the initial peak, [Ca2+]i was maintained at a somewhat elevated level over the baseline (sustained phase), with a corresponding low frequency of exocytosis. Both the sustained phase of elevated [Ca2+]i and the related exocytosis were eliminated by the depletion of extracellular Ca2+. Low concentrations of bombesin (3.2 x 10(-10) M) and bethanechol (3.2 x 10(-7) M) caused sustained low-amplitude Ca2+ oscillations with correspondingly low frequencies but also caused sustained exocytosis. These data show that 1) cellular response differs between high and low concentrations of stimulus, 2) there is a close relation between [Ca2+]i and exocytosis, 3) exocytosis follows elevation of [Ca2+]i by 14-45 s (n = 6), and 4) there is a significant positive correlation between the peak [Ca2+]i and the number of exocytoses.

Results of resection of gastric cancer with distant metastases.

BACKGROUND/AIMS: The present study was carried out in order to examine the outcome of resection in cases of gastric cancer with distant metastases. METHODOLOGY: The survival rates of two hundred and eighty-one patients who had undergone resection for primary carcinomas of the stomach, and who had distant metastases according to the TNM classification, were studied. RESULTS: The 5-year survival rates for patients with metastasis to the peritoneum or group 3 nodes were 8.9% and 15.3% respectively and were significantly higher than the survival rates for patients with metastasis to the liver (0%), to group 4 nodes (2.2%) or to more than one site among the liver, lymph nodes and peritoneum (3.5%). Moreover, the 5-year survival rates for patients with metastasis to the peritoneum and N3 nodes increased significantly to 29.4% and 24.2%, respectively, when curative surgery was performed. CONCLUSIONS: The findings of the present study suggests that metastases to the adjacent peritoneum or group 3 nodes have a greater chance of being cured using radical surgery, and that gastrectomy with extended lymphadenectomy (D2-D3) may be used for advanced gastric cancer if there is no gross evidence of metastasis to the distant peritoneum, liver or group 4 nodes.

Expression of bcl-2 protein in esophageal squamous cell carcinomas and its association with lymph node metastasis.

BACKGROUND: Recent studies on the role of bcl-2 in malignant tumors have suggested its prognostic significance. The goals of the current study were to determine any correlation between bcl-2 expression in esophageal squamous cell carcinoma and histopathology, lymph node metastasis, and clinical variables, and to assess its applicability as a parameter for prognosis. METHODS: Immunohistochemical staining for bcl-2 (clone 124) was performed on archival material from 105 esophageal squamous cell carcinomas. The results were compared among patient subgroups. RESULTS: bcl-2 was expressed in 58% of esophageal carcinomas, demonstrating positive correlations with a lack of keratinization and an early stage of disease. Lymph node metastasis was significantly less frequently observed in the subset of early stage carcinomas with bcl-2 staining. Univariate analysis revealed significantly longer disease free survival in patients with bcl-2 positive carcinomas than in those bcl-2 negative. bcl-2 expression did not have independent prognostic value in a multivariate survival analysis. CONCLUSIONS: bcl-2 is frequently expressed in esophageal carcinomas, and this expression is positively associated with nonkeratinization and an early stage, whereas it is negatively linked with lymph node metastasis and may indicate a favorable prognosis.

Modulation of Ca2+-activated K+ channels by Mg2+ and ATP in frog oxyntic cells.

Ca2+-activated K+ channels in the basolateral plasma membrane of bullfrog oxynticopeptic cells are intimately involved in the regulation of acid secretion. Patch-clamp techniques were applied to study the regulating mechanism of these channels. In the excised inside-out configuration, intracellular Mg2+ decreased channel activity in a dose-dependent manner. In the absence of Mg2+, administration of adenosine 5'-trisphosphate (ATP) to the cytoplasmic side also inhibited channel activity. On the other hand, in the presence of Mg2+, addition of ATP markedly increased channel activity. At a fixed concentration of free Mg2+, the Mg-ATP complex caused channel activation and shifted the dose response relationship between channel activity and the intracellular Ca2+ concentration to the left. A nonhydrolysable ATP analogue, adenosine 5'-[beta,gamma-imido]triphosphate (AMP-PNP) adenylyl [beta,gamma-methylene]diphosphate (AMP-PCP), could not substitute for ATP in channel activation, but a hydrolysable ATP analogue, adenosine 5'-O-(3-thiotriphosphate) (ATP[gammaS]) could do so. Furthermore, application of alkaline phosphatase to the cytoplasmic side inhibited channel activity. These results demonstrate that Ca2+-activated K+ channels are regulated by Mg2+ and ATP, and suggest that a phosphorylation reaction may be involved in the regulation mechanism of these channels.

Modified treatment of early gastric cancer: evaluation of endoscopic treatment of early gastric cancers with respect to treatment indication groups.

The results of endoscopic treatment of early gastric cancers were evaluated. The lesions were divided into two groups: the group with an absolute indication (AI) and the other with a relative indication (RI) for endoscopic treatment. Endoscopic mucosal resection (EMR) was performed on 106 lesions in 104 patients. In addition, 108 patients were treated by laser irradiation (LI). The status of the patients were serially assessed during the postoperative period. The residual rate in AI patients who underwent EMR was 30.3%, whereas the rate in RI patients was 80%. The residual rate in 70 AI patients who underwent LI was 0%. Although the recurrence rate was 4.2%, the cumulative curative rate after additional treatments was 100%. The residual rate in RI patients who underwent LI was 17.4%, and the recurrence rate was 13.2%. The cumulative curative rate after additional treatments was 97.4%. In AI patients, the initial mode of treatment use was EMR. Patients who exhibited residual cancerous tissue after EMR or those in whom EMR was difficult to perform, either technically or otherwise, underwent LI. EMR was the first choice therapeutic technique because endoscopic specimens obtained could be subjected to histopathologic examination. In RI patients, the conventional operation was the therapeutic technique of first choice. The LI procedure was performed in those who either refused surgery or who could not undergo operative treatment for various reasons.

Intragastric pH in postlaparotomy patients--effects of cimetidine.

Intragastric pH was continuously monitored in 21 patients who underwent colorectal surgery. Monitoring was started before surgery, and was continued for two days after surgery. Intragastric pH tended to increase during surgery, compared with measurements obtained before and after surgery, but was not affected by the duration of anesthesia or of the surgical procedure, or surgical position. After surgery, patients were divided into two groups: the cimetidine group (10 patients) received intravenous cimetidine 200 mg 4 times a day, while the control group (11 patients) received no treatment. Postoperative intragastric pH was higher than 3.0 throughout the study in the cimetidine group, but was approximately 1.3 in the control group. Upper gastrointestinal bleeding occurred in 2 patients in the control group, with intragastric pH falling abruptly during the bleeding episode. To prevent post-operative upper gastrointestinal bleeding, in addition to the administration of H2-blockers or antacids, appropriate treatments in response to changes in intragastric pH are necessary. Continuous monitoring of intragastric pH in surgical patients is considered to be of clinical importance.