Screening of alternative drugs to the tumor suppressor miR-375 in esophageal squamous cell carcinoma using the connectivity map.

OBJECTIVE: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). METHODS: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. RESULTS: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. CONCLUSION: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.

Gastric secretory and hormonal patterns in end-stage chagasic achalasia.

Achalasia surgical treatment alters the esophagogastric junction anatomy (cardiomyotomy plus fundoplication or esophagectomy and gastric pull-up), thus favoring a certain degree of gastroesophageal reflux. Gastric secretory and hormonal functioning is not completely known in chagasic patients. The aim of this study was to evaluate the gastric secretory and hormonal response in patients with end-stage chagasic achalasia compared with normal subjects. Gastric secretion and hormonal response were assessed by estimation of gastric acid secretion (GAS) in basal condition and after pentagastrin stimulation, basal serum gastrin, and serum pepsinogen (SP) in basal condition and after betazole hydrochloride (Histalog; Eli Lilly and Company, Indianapolis, IN, USA) stimulation in 27 patients with chagasic achalasia. The results were then compared with those of 24 normal subjects. In the chagasic group, the mean basal and stimulated GAS were significantly lower than in the control group (basal: 1.277 vs. 3.13, P = 0.002; stimulated: 15.9 vs. 35.8, P = 0.0001). Chagasic patients' SG levels showed a significantly higher basal value than the control group (83.3 vs. 36.8, P = 0.0001). There was a significant increase of SP after stimulation compared with the basal levels in both chagasic and control groups. Although the chagasic patients' SP values were higher than the controls, this difference was not statistically significant, either in basal and stimulated conditions (basal: 122.0 vs. 108.9, stimulated 120 min: 177.1 vs. 158.9). In patients with chronic Chagas' disease (ChD), although autonomic denervation does not suppress the strength of the gastric mucosal cells' secretory response to stimulation, it reduces GAS (parietal cell) without, however, affecting SP production (chief cells). On the other hand, the gastrin-producing cells have continuously been stimulated by low GAS.

A Case of Primary Cutaneous Mucinous Adenocarcinoma / 대한피부과학회지

We report a case of primary cutaneous mucinous adenocarcinotna in a 64-year-old female. The tumor was about 2cm in size, forminga round dome-shaped alopecic scalp mass which had gradually increased in size over about 5 years, Histalogic examination revealed that the tumor was divided into numerous compartments by strands of fibrous tissue. In each compartment, abundant amounts of pale-staining mucin surrounded nests or cords of moderately anaplastic epithelial cells. We couldn't find any evidence of internal neoplasms as a source of metastasis. We resected the tumor with approximately a 1 cm margin and then performed a split thickness skin graft.

Site of peptic ulcer. comparison of hydrochloric acid output, pepsinogen and gastrin serum levels.

BACKGROUND/AIMS: Basal (BAO) and maximum (PAO) hydrochloric acid output after Histalog stimulation, basal pepsinogen (SPL-B), at 60 (SPL-60) and at 90 minutes (SPL-90), and basal gastrin (BG) levels were measured and compared in different gastric (GU) and duodenal (DU) ulcer sites. MATERIAL AND METHODS: Fifty nine patients with peptic ulcer were grouped according to Johnson's classification for gastric ulcers: type I (15), type II (16) type III (12) GU and (16) DU. Fifteen normal subjects were studied as controls. RESULTS: The BAO was greater in the DU than in the control or GU groups. No significant difference was noted in the production of hydrochloric acid after stimulation with Histalog. The SPL-B, at 60 and at 90 minutes was higher in type II GU than in the DU group and controls. The SPL-60 was higher in type II GU patients than in type III GU. Basal gastrin was higher in group DU and types II and III GU compared to the type I GU patients and controls. CONCLUSION: The topographic criteria for differentiating peptic ulcers has low discrimination capacity based on comparison of mean values of HCl acid production, pepsinogen and gastrin serum levels both basal and after stimulation with Histalog due to heterogeneity of these variables in group studies. In these studies, peptic ulcers from different sites should not be grouped as distinct entities except for type II gastric ulcers.

Development of gastric acid secretion in pigs from birth to thirty six days of age: the response to pentagastrin.

The development of the gastric acid secretory response to pentagastrin was studied using 56 Large White x Landrace pigs, 0-36 days of age, 1.1-13.3 kg body-weight, obtained from 12 litters. Gastric acid secretory capacity was measured using a gastric perfusion technique and intravenous infusion of pentagastrin at dose rates of 2, 4 and 8 micrograms/h per kg. Significant positive linear correlations were found between stomach weight and age, and between stomach weight and body-weight during the 36 day period. The stomach weight to body-weight ratio increased for the first 3 days of age and then decreased during the following 33 days. Basal acid secretion was detected in all unsuckled pigs (n = 9), 2- to 8-h old. Maximal acid outputs in response to pentagastrin in these pigs were 0.16 +/- 0.02 mmol/kg body-weight and 0.034 +/- 0.001 mmol/g stomach weight. For the 56 pigs, significant linear correlations were found between maximal acid output and age, maximal acid output and body-weight, and maximal acid output and stomach weight. There was a significant linear increase in maximal acid output per unit stomach weight during the first 7 days of age, but during the subsequent 29 days the pattern of increase in gastric secretory capacity was slower and curvilinear. In the oldest nine pigs, 24-36 days of age, maximal acid outputs were 0.974 +/- 0.058 mmol/kg body-weight and 0.234 +/- 0.016 mmol/g stomach weight which represents a six to seven-fold increase compared with those determined in pigs at birth. Comparison of gastric acid secretory capacity determined under anaesthesia with that in conscious pigs showed that anaesthesia appeared to suppress basal output but had no effect on pentagastrin stimulated output. Comparison of response to histalog (betazole HCl) and pentagastrin indicated that newborn pigs were more sensitive to histalog but in pigs 9-38 days of age, there were no significant differences in responsiveness to the two secretagogues. These results show that gastric sensitivity to pentagastrin increases rapidly in the first week of life, that the stomach of the newborn pig is more sensitive to histalog than pentagastrin and that studies of the effect of pentagastrin on acid secretion, done under anaesthesia, are comparable to those in the conscious pig.

Serum pepsinogen in gastric and duodenal ulcer patients before and after proximal gastric vagotomy

O pepsinogenio serico em situacao basal e sob o estimulo betazolico foi avaliado em 69 pacientes: 14 normais, nove ulcerosos duodenais nao operados, 36 apos vagotomia gastrica proximal devido a ulcera duodenal e dez ulcerosos gastricos, antes e apos serem submetidos a vagotomia gastrica proximal. O seguimento medico foi de 38.7 meses para os pacientes operados por ulcera duodenal e de um ano para os dez ulcerosos gastricos. Dos 36 operados por ulcera duodenal, 22 nao apresentavam recidiva ulcerosa, enquanto 14 a apresentava. Tanto os niveis de pepsinogenio serico basal como estimulado foram estatisticamente elevados nos ulcerosos duodenais nao operados, quando comparados aos controles e aos pacientes submetidos a vagotomia gastrica proximal. O pepsinogenio serico nao mostrou sensibilidade para diferenciar os ulcerosos gastricos do grupo controle. O pepsinogenio serico diferenciou pacientes com e sem recidiva ulcerosa apos vagotomia gastrica proximal devido a ulcera duodenal, tanto em situacao basal, como apos estimulo betazolico. O pepsinogenio serico discrimina pacientes ulcerosos duodenais dos individuos normais e reduz-se significantemente apos vagotomia gastrica proximal, apesar de nao ser indicador sensivel de ulcera gastrica ou recidiva ulcerosa apos vagotomia gastrica proximal.

Serum pepsinogen before and after proximal gastric vagotomy in duodenal ulcer treatment.

Serum pepsinogen (SP) behavior was evaluated under basal conditions and under betazole stimulation in 59 patients: 14 controls, nine unoperated duodenal ulcers (DU) and 36 DU after proximal gastric vagotomy (PGV), 14 with and 22 without recurrent ulcer. The mean follow-up of the 36 patients who underwent PGV was 38.7 months. SP was higher in unoperated DU than in the control group (p less than 0.05). After PGV in DU, there is a significant decrease of SP for both the patients with and without recurrent ulcer (p less than 0.05), being statistically similar to the control group. No difference of SP was observed between DU with and without recurrent ulcer after PGV. We concluded that SP can differentiate normal subjects from DU patients, although it is not a sensitive indicator of recurrent ulcer after PGV.

[Influences of respiratory frequency on breathing mechanics during artificial ventilation in man and animal].

Effects of respiratory frequency on breathing mechanics were examined on 11 surgical patients during artificial ventilation with inhalation of nitrous oxide, oxygen and halothane (GOF). When the respiratory frequency was increased stepwise from 10 to 30/min, the total compliance was significantly reduced stepwise (from 55.42 +/- 9.55 ml/cmH2O to 47.38 +/- 9.31, p less than 0.01). In animal experiment, the respiratory frequency was similarly increased from 10 to 30/min in 11 mongrel dogs under sodium thiamylal anesthesia with air breathing. The total pulmonary compliance decreased significantly from a control level of 13.62 +/- 5.04 ml/cmH2O to a value of 10.96 +/- 3.00 ml/cmH2O which was obtained under the administration of synthetic histamine (betazole hydrochloride) (p less than 0.01). However, the decreases in compliance with histamine were parallel with the control values without the drug treatment. From these results it was assumed that the reduction of the total pulmonary compliance under increased respiratory frequency was due not to changes in small airway but to those in large airway.

2-substituted derivatives of benzimidazole inhibiting gastric acid secretion in rats.

Benzimidazole and its 2-derivatives with amino, carbamonitrile, urea, and guanidine groups have been tested for their activity on gastric secretory process. The carbamonitrile-, urea-, and guanidine compounds decrease gastric acid secretion, basal and stimulated with histamine or betazole, in Shay-rats and depress the guinea pig auricle activity stimulated by betazole. The results suggest that the studied 2-substituted benzimidazole compounds exhibit anti H2-histamine activity.

[Changes in gastric mucosal blood flow after selective proximal vagotomy; an experimental study in rats].

The effect of selective proximal vagotomy (SPV) on gastric mucosal blood flow (MBF) was studied in rats using hydrogen gas clearance technique. The following results were obtained. 1) Resting MBF of the corpus decreased significantly from 106.3 +/- 9.8 ml/min/100g to 74.5 +/- 15.5 ml/min/100g at 12 weeks after SPV (p less than 0.01). Resting MBF of the antrum did not decrease. 2) Tetragastrin, betazol-HCl and 2-deoxy-d-glucose (2DG)-stimulated acid outputs were reduced following SPV for more than 12 weeks after operation. 3) The increase of corporal MBF after tetragastrin, betazol-HCl and 2DG stimulation was less significant with accompanying reduction of acid output. 4) The increase of antral MBF after tetragastrin or betazol-HCl stimulation was less significant after SPV. But, the increase after 2DG stimulation was as much as after SPV.

Inhibitory activity of 2-benzimidazolylurea on gastric acid secretion in rats.

2-Benzimidazolylurea (BIU) decreases gastric acid secretion. The antisecretive activity appears to be associated with antihistaminic and antimuscarinic effects. The antihistaminic activity of BIU appears from its inhibitory effects on betazole stimulated gastric acid secretion and from its inhibitory activity on the isolated guinea pig auricle stimulated by betazole. The antimuscarinic activity of BIU appears from several experiments: this molecule decreases gastric acid secretion stimulated by carbachol in rats, depresses the neostigmine-stimulated motility of duodenum in the anaesthetized cat, lessens the hypertonus of isolated guinea pig trachea caused by pilocarpine and also inhibits guinea pig ileum activity stimulated by acetylcholine. BIU probably depresses gastric acid secretion by interfering with both histamine and acetylcholine receptors.

Effect of nizatidine and cimetidine on betazole-stimulated gastric secretion of normal subjects: comparison of effects on acid, water, and pepsin.

The effect of nizatidine, a new histamine H2 receptor antagonist, on gastric secretory function of eight normal subjects stimulated with betazole, was compared with that of cimetidine. Single oral doses of 75 mg, 150 mg, and 300 mg nizatidine, 300 mg cimetidine, and a placebo were administered on separate occasions 1 h before betazole stimulation. Gastric secretions were recovered in 15-min fractions for the ensuing 2 h, and the pH, H+ concentration and output, volume, and pepsin concentration and output were determined. Doses of 150 mg and 300 mg nizatidine depressed the secretory response significantly more than did cimetidine. The antisecretory effects of 75 mg nizatidine was no different than that of 300 mg cimetidine. Nizatidine 300 mg inhibited pepsin output significantly more than volume. Although pepsin concentration was reduced more than volume, the difference was not significant. These observations, in contrast to results of previous studies, suggest a direct inhibition of pepsin secretion, although to a lesser extent than that of acid.

Histamine H2-receptor of human and rabbit parietal cells.

The histamine H2-receptor on the human parietal cell has been characterized by using dose-response curves and the negative logarithm of the molar concentration of an antagonist (pA2) analyses of cimetidine antagonism of betazole, histamine, and impromidine stimulation in isolated human and rabbit gastric glands. To evaluate the in vitro results, betazole-stimulated gastric acid secretion with and without cimetidine was also studied in healthy subjects. In the in vivo model, individual dose-response curves were shifted to the right with increasing cimetidine concentrations, but this was counteracted by increasing betazole doses, indicating competitive, reversible antagonism. The pA2 values ranged from 6.1 to 6.3. In isolated human gastric glands, impromidine was shown to be eight times more potent than histamine, indicating higher receptor affinity, but the maximally stimulated aminopyrine accumulation was the same as for histamine, and the pA2 values for cimetidine antagonism did not differ significantly, i.e., 5.7 (histamine) and 6.1 (impromidine). In isolated rabbit gastric glands, cimetidine inhibited the histamine- and impromidine-stimulated response with pA2 values of 6.0 and 7.3, respectively. Impromidine was shown to be approximately 100 times more potent than in human gastric glands, whereas histamine had the same potency. This confirms the role of the histamine H2-receptor and suggests a difference between the species concerning receptor affinity.

Comparison of noninvasive breath hydrogen test for gastric acid secretion to standard intubation test in adults.

We have developed a noninvasive test for gastric acid secretion based on the reaction of ingested magnesium metal with gastric acid to produce hydrogen gas, which is excreted in exhaled air and belches. This test was compared to the standard intubation test by performing both, on different days, in 36 adult Peruvian outpatients referred for gastric analysis; the correlation coefficient for this comparison was 0.71. The new test was repeated in nine subjects, and the resulting test-retest correlation coefficient was 0.83. The new test thus compares favorably with the standard intubation test. Because it is also noninvasive and should therefore be more acceptable to subjects, this new test may be useful for clinical evaluation and research studies on subjects in whom intubation would be difficult or unacceptable.

Comparison of noninvasive breath hydrogen test for gastric acid secretion to standard intubation test in infants and young children.

We have developed a noninvasive test of gastric acid secretion for use in infants and young children. It is based on the reaction of ingested magnesium metal with gastric acid to produce hydrogen gas, which is excreted in exhaled air and belches. This test was compared to the standard intubation test by performing both, on different days, in 20 children (5-37 months of age) without known gastric disease. The results of the two tests compared well: correlation coefficients were 0.78, 0.75, or 0.72 when exhaled air was collected for a total of 56, 81, or 31 min, respectively. Because the test is noninvasive, it should be more acceptable to children and their parents than the intubation test and thus could be used to conduct studies which are currently impractical.

Perspective on the gastric antisecretory effects of misoprostol in man.

Misoprostol, a synthetic prostaglandin E1 analog, has been found to be safe and effective for the treatment of peptic ulcer disease. This brief overview summarizes the gastric antisecretory effects of misoprostol in healthy human subjects using randomized, double-blind, placebo-controlled studies. Misoprostol effectively and dose-dependently inhibited basal gastric acid secretion at single doses of 50, 100 and 200 mcg/subject. Furthermore, misoprostol effectively inhibited meal-, histamine-, coffee- and tetragastrin-stimulated gastric acid secretion. The inhibition of meal-stimulated gastric acid secretion was not a consequence of the reduction of serum gastrin. In addition, misoprostol inhibited nocturnal gastric acid secretion. In these studies, the titratable acidity, volume, acid output and pepsin activity were inhibited by misoprostol. The extent of the secretory inhibition achieved with the 200 mcg dose of misoprostol was comparable to that of cimetidine administered at a 300 mg dose. The duration of the gastric antisecretory actions was in the order of 3 to 5 hours. We conclude that misoprostol is a potent inhibitor of gastric acid secretion in man.

Inhibition of basal and betazole- and sham-feeding-induced acid secretion by omeprazole in man.

The effect of omeprazole, given as a buffered solution, on basal acid secretion and that induced by betazole and sham feeding in healthy subjects were studied. The three series of experiments showed a dose-dependent acid reduction during the 2nd to 4th h after administration of omeprazole in doses of 10-60 mg, with almost complete inhibition by the highest dose. The ED50 values were of the same magnitude for basal and stimulated acid secretion. This indicates that omeprazole is an equally potent inhibitor of both kinds of acid secretion irrespective of the manner in which the acid is activated.

Curva de gastrinemia: diferença de comportamento a estímulo alimentar entre portadores das formas hepatointestinal e hepatoesplênica da esquistossomose mansônica / Gastrinemia curve: difference of behavior to food stimulation in patients with hepatointestinal or hepatosplenic forms of schistosomiasis mansoni

Avaliamos em 28 indivíduos [9 controles, 10 portadores da forma hepatointestinal (EHI) e 9 da forma hepatoesplênica (EHE) da esquistossomose mansônica] tanto a secreçäo ácida gástrica (basal e após estímulo pelo Histalog) como a gastrinemia basal e após estímulo alimentar. A secreçäo ácida basal nos pacientes dos 2 grupos de esquistossomóticos foi normal mas o valor médio do grupo EHE foi significativamente inferior ao do grupo EHI; näo houve diferença significativa entre as médias da secreçäo ácida após estímulo dos 2 grupos de esquistossomóticos, mas a análise individual mostrou que em 7 pacientes do grupo EHE a secreçäo ácida após estímulo foi menor do que a que ocorreu na maioria dos pacientes do grupo EHI. Quanto à gastrinemia, verificamos ausência de resposta significativa desta ao estímulo alimentar em 7 dos 10 pacientes EHI (e em apenas 2 do grupo EHE e em 1 do grupo controle). Por outro lado, em 5 dos 9 pacientes do grupo EHE (e em apenas 2 dos 10 do grupo EHI) ocorreu resposta aumentada da gastrinemia ao estímulo alimentar. Esses achados mostram, em esquistossomóticos, diferença de comportamento de resposta da gastrinemia a estímulo alimentar, isto é, resposta deficiente no grupo EHI e aumentada no grupo EHE