Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.
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PMID:Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment. 1501 Aug 36

Despite advances in surgical treatment and chemotherapy, gastric cancer remains a major global health burden. The most recent estimates show that it is the fourth most common cancer and the second most common cause of cancer deaths worldwide. Various etiologic factors have been linked with the disease. It is widely accepted that Helicobacter pylori infection and high salt intake are positively associated with this neoplastic process. Controversial associations have been found with smoking or drinking habits. In contrast, there is convincing evidence that the adequate consumption of fresh fruits and vegetables reduces the risk of gastric cancer. Prevention intervention trials involving antioxidant supplements and anti- H. pylori treatment have shown beneficial effects in preventing the progression of pathologic changes in the gastric mucosa. On the other hand, recent advances related to differences in the genotypes of the bacteria and in human cytokine polymorphisms would allow the design and implementation of large-scale screening programs to identify subjects at the highest risk of gastric cancer. Curing the infection in such subjects and supplying adequate amounts of antioxidants should prevent a neoplastic outcome, and this intervention should be monitored by endoscopic surveillance.
Gastric Cancer 2004
PMID:The future of gastric cancer prevention. 1505 34

This case control study presents data on the concentrations of nitrite and nitrate and a variety of pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta), interleukin-2R (IL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor TNF-alpha in gastric fluid and serum. Patients with gastritis, gastric ulcer and gastric cancer are studied and grouped according to infection by Helicobacter pylori. The 208 patients who underwent upper gastrointestinal endoscopic examination were classified as follows; H. pylori-positive gastritis (n = 32), H. pylori-negative gastritis (n = 32), H. pylori-positive ulcers (n = 34), H. pylori-negative ulcers (n = 34), 43 patients with H. pylori-positive gastric cancer in addition to 33 H. pylori-negative healthy control individuals. Gastric fluids and blood samples were taken concomitantly. Cytokines and nitrite and nitrate determinations were attempted as soon as possible after collection of the samples. Nitrite and nitrate levels of serum and gastric fluids of H. pylori-positive gastritis and ulcers were higher than H. pylori-negative gastritis and ulcers. The concentrations of total nitrite and nitrate and cytokines (TNF-alpha, IL-2R, IL-6, and IL-8) in gastric fluids and sera of H. pylori-positive gastric cancer patients were higher than H. pylori-negative control groups. IL-1 beta level was significantly elevated in gastric fluid of infected cancer patients but not in serum. Taken together, the results suggest that an increase in cytokine-NO combination in gastric mucosa previously reported by many studies is not restricted to local infected gastric tissue but also detected in gastric fluid and sera of H. pylori-positive subjects and may have an important role in the pathogenesis and development of common gastric diseases.
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PMID:Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori. 1516 24

In 1984, Reg protein was shown to be stimulated during the regeneration of pancreatic islets. Since then, many Reg-related proteins have been identified in humans and other animals. These Reg-related proteins are classified into four subfamilies according to their amino-acid sequences, but they share a similar structure and physiological function. The role of Reg in gastric tissue was investigated, and Reg I was found to be expressed mainly in gastric fundic enterochromaffin-like (ECL) cells. Reg I production in ECL cells is stimulated by gastrin, as well as by the proinflammatory cytokine, cytokine-induced neutrophil chemoattractant (CINC)-2Beta. In patients with chronic hypergastrinemia, Reg production is stimulated, with the increased proliferation of gastric mucosal cells. Patients with Helicobacter pylori infection also showed increased Reg production in the gastric mucosa, partly via increased plasma gastrin concentration and partly via increased proinflammatory cytokine production. Thus, Reg protein induced by H. pylori infection may be partly responsible for the increased proliferation of gastric epithelial cells in H. pylori-infected patients. Reg protein is also produced in many gastric cancer cells, especially in poorly differentiated and advanced cancers. Reg protein stimulates the proliferation of several gastric cancer cell types, and gastric cancers with Reg protein expression tend to show a poorer clinical outcome. In summary, Reg protein may be a growth factor that regulates the proliferation and differentiation of normal and neoplastic gastric epithelial cells.
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PMID:Reg protein is a unique growth factor of gastric mucosal cells. 1523 66

Biological response modifiers (BRMs) augment the cytotoxic activity of various effector cells by the induction of multiple cytokines and suppression of immunosuppressive factors. BRMs are used extensively in adjuvant therapy for gastric cancer in Japan. In dendritic cell (DC)-based vaccine therapy, the quality of DCs is important in inducing strong antitumor immunity. A good manufacturing practice (GMP) grade agent for DCs maturation is desirable for safety. Here we report the effects of two BRMs, OK432 and PSK, which are GMP grade agents for the functional maturation of DCs. OK432 and PSK were examined in vitro, and compared with lipopolysaccharide (LPS) and a cytokine cocktail (IL-1beta, TNF-alpha, IL-6 and PGE2). In the immunophenotypical analysis, the expression of CD80 and CD83 of DCs stimulated with OK-432 increased significantly compared with PSK and medium, and this up-regulation was the same as levels of DCs stimulated with cytokine cocktail. DCs stimulated with OK-432 showed significantly higher production of IL-12 and Th1-type cytokines (IL-2 and IFN-gamma) compared with DCs stimulated with LPS or cytokine cocktail. OK-432 stimulated DCs could induce the significantly high level of cytotoxic T cell activity compared with PSK-stimulated or unstimulated DCs. These results suggest that OK432 is a GMP-grade reagent that promotes functional maturation of DCs and could be applied in DC-based vaccinations.
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PMID:Usefulness of immunomodulators for maturation of dendritic cells. 1525 44

The tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha (LTA) are proinflammatory cytokines with immunoregulatory effects. TNF is also known to inhibit gastric acid secretion. Previously we have shown that the known proinflammatory genotypes, IL-1B -31C/+ and IL-1RN *2/*2, were not associated with increased risks for gastric cancer/duodenal ulcer in the Korean population. In this study, we tested the association between the polymorphisms of another candidate cytokine TNF/LTA and 341 gastric cancers, 133 duodenal ulcers, and 261 healthy controls. Five TNF promoter polymorphisms (-1031, -863, -857, -308, and -238) and two LTA polymorphisms (intron 1 and Thr26Asn) were analyzed. Individual polymorphisms were not associated with the gastric cancer and/or duodenal ulcer risk. When a haplotype analysis was performed with seven polymorphisms, differences in haplotype profile between the controls and gastric cancer and/or duodenal ulcer were not statistically significant. However, the frequencies of individual haplotypes C and D, which had opposite alleles at -1031, -863, and -857, showed statistically significant differences between the gastric cancer and duodenal ulcer (P=0.005 and P=0.02, respectively), suggesting that the TNF/LTA genotypes might play an opposite role in the pathogenesis of gastric cancer and duodenal ulcer.
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PMID:TNF/LTA polymorphisms and risk for gastric cancer/duodenal ulcer in the Korean population. 1538 Nov 84

The proinflammatory cytokine interleukin-1 has been implicated in host susceptibility to Helicobacter pylori-associated disease. Recent studies suggest that this susceptibility may be under genetic control. It remains to be determined whether the relationship between IL-1 gene polymorphism and gastrointestinal disease in patients with H. pylori infection is due to the role of IL-1 in determining susceptibility to H. pylori infection per se or to the development of distinct pathological lesions. The aim of this study was to prospectively investigate the relationship between selected polymorphisms in three of the major IL-1 gene family members, seeking associations with H. pylori infection and/or gastric cancer. A total of 559 individuals were studied: 191 patients attending for gastroscopy, 98 with current or previous H. pylori, an additional 79 patients with gastric cancer, and 289 healthy controls. The major novel finding of the study was a marked difference in the genotype frequencies for the IL1R1 Hinfl SNP in those with current or previous evidence of H. pylori compared to those without. (GG, 53 vs 75%; GA, 40 vs 19%; AA, 7 vs 6%; P = 0.0079). The association indicates an increased risk of H. pylori infection or persistence in those with the IL1R1 Hinfl A allele (0.27 vs 0.156; P = 0.009; OR = 2.01). Our results suggest that the relationship among IL-1 gene polymorphism, H. pylori, and disease is more complex than initially proposed. More detailed studies of the IL-1 gene cluster are needed.
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PMID:A functional polymorphism in the interleukin-1 receptor-1 gene is associated with increased risk of Helicobacter pylori infection but not with gastric cancer. 1548 35

Studies suggest that IL-1beta (encoded by IL-1B gene) is a pro-inflammatory cytokine and potent inhibitor of gastric acid secretion, which is proposed as a key determinant in gastric carcinogenesis. Two potentially functional polymorphisms (C-31T and T-511C) in the IL-1B promoter were suggested to be correlated with alteration of Helicobacter pylori infection and IL-1beta expression and therefore may be associated with risk of gastric cancer. To test the hypothesis that these two polymorphisms are associated with gastric cancer risk, we performed a case-control study of 280 histologically confirmed gastric cancer patients and 258 age, sex frequency-matched cancer-free controls in a Chinese population. Multivariate logistic regression analyses revealed that the risks (adjusted odds ratio [OR] and 95% confidence interval [CI]) associated with the IL-1B variant genotypes were 1.64 (95% CI, 1.01-2.66) for -31TT and 1.52 (95% CI, 0.91-2.54) for -511CC, respectively, compared with their wild-type homozygotes. The risks were significantly more evident in individuals with H. pylori infection (adjusted OR, 2.14; 95% CI, 1.13-4.06 for -31TT; adjusted OR, 2.00; 95% CI, 1.02-3.89 for -511CC), which was consistent with the biological effects of IL-1beta. When we used the haplotype analyses and assumed the IL-1B -31T and -511C as risk alleles, no synergistic effect was found between these two loci. These findings indicate that these two IL-1B promoter variants may contribute to the risk of developing gastric cancer in the Chinese population, especially in individuals with H. pylori infection.
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PMID:Interleukin-1B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population. 1629 15

Several cytokine gene polymorphisms have been associated with increased risk of distal gastric cancer (GC) and its precursor histological markers in Caucasian, Asian and Portuguese populations although little is known about their role in other ethnic groups. Our study investigates the role of the IL-1B-31, IL-1RN and TNF-A-308 gene polymorphisms as risk factors for the development of GC in a Mexican population. We studied 278 patients who were enrolled at the Hospital Universitario Dr. Jose Eleuterio Gonzalez, Universidad Autonoma de Nuevo Leon. The subjects were divided into 2 groups. Sixty-three patients with histologically confirmed distal GC (mean age = 58.8 years, range = 22-84, F:M = 0.56), and 215 patients with no evidence of distal or proximal GC (mean age = 56.1 years, range = 18-92, F:M = 1.17). The IL-1B-31 and the TNF-A-308 polymorphisms were determined by PCR-RFLP and pyrosequencing, respectively, in all cases and controls. The VNTR polymorphism in intron 2 of the 1L-1RN gene was typed by PCR in 25 cases and 201 controls. The H. pylori status was determined by histology, rapid urease test, culture and serology for non-cancer controls and by histology for the GC cases. The carriage of the proinflammatory IL-1B-31*C allele was associated with increased risk of distal GC (odds ratio [OR] = 7.63, 95% confidence interval [CI] = 1.73-46.94, p = 0.003). When cases and controls were matched by age and gender, the OR value was higher (OR = 8.05, 95% CI = 1.8-50.22, p = 0.001). When only H. pylori GC cases and controls were compared, the OR value was 7.8 (95% CI = 1.05-161.8, p = 0.04). No association was found between any of the other polymorphisms studied and distal GC. In this Mexican population, the IL-1B proinflammatory genotype increases the risk of distal GC. These findings are similar to previous reports in Caucasian populations and underscore the importance of cytokine gene polymorphisms in the development of distal GC.
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PMID:Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. 1554 Feb 24

Helicobacter pylori is a highly successful bacterial pathogen of humans, infecting the stomach of more than half of the world's population. The H. pylori infection results in chronic gastritis, eventually followed by peptic ulceration and, more rarely, gastric cancer. H. pylori has developed a unique set of virulence factors, actively supporting its survival in the special ecological niche of the human stomach. Vacuolating cytotoxin (VacA) and cytotoxin-associated antigen A (CagA) are two major bacterial virulence factors involved in host cell modulation. VacA, so far mainly regarded as a cytotoxin of the gastric epithelial cell layer, now turns out to be a potent immunomodulatory toxin, targeting the adapted immune system. Thus, in addition to the well-known vacuolating activity, VacA has been reported to induce apoptosis in epithelial cells, to affect B lymphocyte antigen presentation, to inhibit the activation and proliferation of T lymphocytes, and to modulate the T cell-mediated cytokine response.
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PMID:The Helicobacter pylori vacuolating cytotoxin: from cellular vacuolation to immunosuppressive activities. 1554 7


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