Transforming growth factor beta 1 (TGF-ß1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer.

BACKGROUND: Transforming growth factor-beta 1 (TGF-ß1), a multifunctional cytokine, acts as a key factor for Epstein-Barr virus (EBV) reactivation. We investigated the role of TGF-ß1 in latent and lytic stages of EBV in relation to Helicobacter pylori infection among patients with gastric cancer (GC) and peptic ulcer disease (PUD). METHOD: Gastric mucosal TGF-ß1 expression was determined in 95 EBV positive patients with gastroduodenal pathology [GC 40, PUD 19 and non-ulcer dyspepsia (NUD) 36] by quantitative real time PCR. Presence of H. pylori infection was diagnosed when either culture or any two of three tests (RUT, histopathology and specific ureA PCR) were positive. Serum level of TGF-ß1 was detected among 60 patients using ELISA. RESULTS: Mucosal TGF-ß1 mRNA expression was detected in 85 of 95 EBV positive patients and it was significantly higher in patients with GC (p=0.042). TGF-ß1 expression tended to be higher among H. pylori non-infected than infected patients (3.80±6.24 vs. 2.07±2.50, p=0.085). Both mRNA and serum level had significant association with lytic stage of EBV in absence of H. pylori infection when compared with its presence (5.21±4.00 vs. 2.29±2.89, p=0.040 and 842.00 [669.55] vs. 662.63 [628.76], p=0.049; respectively). CONCLUSION: TGF-ß1 expression was significantly associated with GC. TGF-ß1 was higher both at expression and translational levels in lytic EBV infection without H. pylori suggests that H. pylori infection might play important role in preventing EBV reactivation through attenuated TGF-ß1 expression. This might be a "wise host defense against EBV reactivation".

Epstein-Barr virus association with peptic ulcer disease.

Background. Helicobacter pylori (HP) infection and nonsteroidal anti-inflammatory drugs (NSAID) use are considered the main risk to develop peptic ulcer disease (PUD). However, PUD also occurs in the absence of HP infection and/or NSAID use. Recently, we have found evidence that Epstein-Barr virus (EBV) reactivation increases the risk to develop premalignant and malignant gastric lesions. Objective. To study a possible association between EBV and PUD. Methods. Antibodies against an EBV reactivation antigen, HP, and the HP virulence factor CagA were measured in sera from 207 Mexican subjects, controls (healthy individuals, n = 129), and PUD patients (n = 78, 58 duodenal and 20 gastric ulcers). Statistical associations were estimated. Results. Duodenal PUD was significantly associated with high anti-EBV IgG titers (p = 0.022, OR = 2.5), while anti-EBV IgA was positively associated with gastric PUD (p = 0.002, OR = 10.1). Conclusions. Our study suggests that EBV reactivation in gastric and duodenal epithelium increases the risk to develop PUD.

Serum 8 Hydroxydeoxyguanosine and Cytotoxin Associated Gene A as Markers for Helicobacter pylori Infection.

BACKGROUND: Helicobacter pylori (H.pylori) is associated with chronic gastritis, peptic ulcers, gastric adenocarcinomas and mucosa associated tissue lymphomas. Cytotoxin associated gene A (CagA) is one of the virulence factors of H.pylori. It is hypothesized that reactive oxygen species (ROS) play roles in H.pylori associated disease especially in development of gastric adenocarcinoma. Individuals infected with H.pylori bearing CagA produce more ROS than others. 8-hydroxydeoxyguanosine (8OHdG) is an in vitro marker of DNA damage and oxidative stress. The aim of this study was to investigate the relationship between 8OHdG level, H.pylori infection and CagA and alterations of serum 8OHdG level after H.pylori eradication. MATERIALS AND METHODS: Patients admitted with dyspeptic complaints and upper gastrointestinal endoscopy were assessed. H.pylori was determined from histopathology of specimens. Serum 8OHdG levels of three groups (H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive) were compared. Patients with H.pylori infection received eradication therapy. Serum 8OHdG levels pretreatment and posttreatment were also compared. RESULTS: In total, 129 patients (M/F, 57/72) were enrolled in the study. Serum 8OHdG level of H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive groups were significantly different (5.77±1.35 ng/ml, 5.43±1.14 ng/ml and 7.57±1.25 ng/ml respectively, p=0.05). Furthermore, eradication therapy reduced serum 8OHdG level (6.10±1.54 ng/ml vs 5.55±1.23 ng/ml, p=0.05). CONCLUSIONS: Individuals infected with H.pylori bearing CagA strains have the highest serum 8OHdG level and eradication therapy decreases the serum 8OHdG level. To the best of our knowledge this is the first study that evaluated the effect of CagA virulence factor on serum 8OHdG level and the effect of eradication therapy on serum 8OHdG levels together. Eradication of CagA bearing H.pylori may prevent gastric adenocarcinoma by decreasing ROS. 8OHdG level may thus be a good marker for prevention from gastric adenocarcinoma.

[Helicobacter pylori -- 2014]. / Helicobacter pylori -- 2014.

The author reviews the main achievements in Helicobacter pylori research in the past 2 years. Of the more than 1000 microRNAs described thus far, sets of over- and underexpressed samples were identified that are associated with either gastric cancer or precancerous lesions, and some of them could be either markers or therapeutic targets in the near future. Meta-analyses involved 95 new publications: the association between infection and oesophageal, colorectal, pancreatic and liver carcinomas is supported by the increased odds ratios, but the results do not reach the strength seen in gastric carcinoma. Epstein-Barr virus is an emerging pathogen: 10% of gastric cancers are virus-associated; the prevalence of the virus in normal mucosa, chronic gastritis and peptic ulcer are currently being studied. Current Helicobacter pylori eradication regimens frequently achieve suboptimal results: a few optimisation methods are presented, although not all are supported by the meta-analyses. In 2013, the European Helicobacter Study Group proposed the development of a pan-European registry; data from 5792 patients registered so far indicated that many therapeutic regimens resulted in a low eradication rate. In 2013, the Healthy Stomach Initiative was started with the aim of supporting and disseminating research performed in the field of healthy and diseased stomachs.

Genetic polymorphism of cytochrome P450 (CYP) 1A1, CYP1A2, and CYP2E1 genes modulate susceptibility to gastric cancer in patients with Helicobacter pylori infection.

BACKGROUND: Activity of cytochrome P450 (CYP), a polymorphic carcinogen-activating enzyme, is exaggerated following Helicobacter pylori infection. We studied the role of CYP2E1, CYP1A2 (rs762551), and CYP1A1 (rs4646903) polymorphisms in association with H. pylori infection in gastric carcinogenesis. METHODS: Genotyping of CYP2E1 (96-bp insertion), CYP1A2 (164A to C), and CYP1A1 (3801C to T) was carried out in 88, 76, 53, and 170 patients with gastric cancer (GC), functional dyspepsia (FD), peptic ulcer (PU), and healthy controls (HC), respectively. Serum IgG antibody (all subjects), rapid urease test, and histology (GC, FD, and PU patients) were used to test for H. pylori. RESULTS: CYP2E1 gene polymorphism was more common among patients with GC than HC and PU [48/88 (54.5 %) vs. 67/170 (39.4 %); OR 1.9, 95 % CI 1.1-3.2, p = 0.016) and [PU 18/53 (34 %); OR 2.3 (1-4.7), p = 0.02]. CYP1A2 CC or CT genotypes was lower among patients with GC than HC [50/88 (56.8 %) vs. 120/170 (70.6 %); OR 0.54 (0.31-0.92), p = 0.023]. CYP1A1 polymorphism and CYP1A1-CYP1A2 haplotypes were comparable among different groups. CYP2E1 was also more common in patients with GC than HC and PU in the absence of H. pylori [33/60 (55 %) vs. 19/52 (36.5 %); OR 4 (1.5-11.4), p = 0.007 and PU 7/22 (31.8 %); OR 3.4 (1-11.6), p = 0.05]. CYP1A1 (CT + TT) was more common in patients with GC than PU in presence of H. pylori [17/26 (65.4 %) vs. 11/29 (38 %); OR 3.0 (1.03-9.3), p = 0.045]. CONCLUSIONS: The presence of CYP2E1 (96-bp insertion) is associated with increased risk of GC even in absence of H. pylori. CYP1A2 CC or CT is associated with reduced risk of GC.

Serum zinc status and Helicobacter pylori infection in gastric disease patients.

The role of Helicobacter pylori status and serum zinc value in gastric disease patients and healthy controls were investigated. Cases used in this work were 45 gastric cancer patients, 44 with peptic ulcers, 52 suffering gastritis and 64 healthy controls, all diagnosed histologically with the controls undergoing medical checkups. Helicobacter pylori status and serum levels of Zn were determined by 13C-urea breath test and flame atomic absorption spectrophotometer, respectively. Our study showed that Helicobacter pylori infection has no change in gastritis, peptic ulcer and gastric cancer group, on the contrast, serum levels of Zn were significantly reduced in gastritis, peptic ulcer and gastric cancer group, compared with healthy controls, and the higher the Zn levels are, the more increased risk of gastric cancer. Helicobacter pylori infection is a cause of gastritis, peptic ulcers and even gastric cancer, while serum zinc level is an indicator of protection of gastric membranes against damage.

Expression profile of latent and lytic transcripts of epstein-barr virus in patients with gastroduodenal diseases: a study from northern India.

Epstein-Barr virus (EBV) has been shown to be associated with gastric cancer. However, inconsistent findings have been reported regarding the EBV reactivation in gastric cancer and non-carcinomatous gastric epithelium. Therefore, the aim of the study was to investigate the effect of clinicopathological findings on the expression of different transcripts of EBV in patients with gastric cancer, peptic ulcer, and dyspepsia. A total of 200 adult patients (dyspepsia [120], peptic ulcer [30], gastric cancer [50]) undergoing upper gastrointestinal endoscopy were enrolled. EBV infection was diagnosed with non-polymorphic Epstein-Barr nuclear antigen1 (EBNA1) gene based PCR and confirmed by real-time PCR. The transcripts of EBV were detected by real-time RT-PCR. In patients with gastric cancer and peptic ulcer, EBV DNA was detected more often than in those with dyspepsia (P < 0.05). EBNA1 transcript was detected in all EBV positive cases and its expression was neither associated with disease nor with histopathological findings. The expression of BZLF1 was significantly associated with gastric cancer and peptic ulcer compared to dyspepsia (P < 0.01). BZLF1 expression was also found to be higher in Helicobacter pylori infected patients (P = 0.058). Expression of BARF1 and BcLF1 were significantly higher in gastric epithelium of patients having severe grade chronic inflammation (P = 0.05) and gastric atrophy (P = 0.02), respectively. In conclusion, increased expression of lytic transcripts in patients with gastric cancer, peptic ulcer, gastric atrophy, chronic inflammation and H. pylori infection suggests the association of these factors with EBV reactivation.

Involvement of Ras and AP-1 in Helicobacter pylori-induced expression of COX-2 and iNOS in gastric epithelial AGS cells.

Helicobacter pylori (H. pylori) is an important risk factor for chronic gastritis, peptic ulcer, and gastric cancer. The genetic differences of H. pylori isolates play a role in the clinical outcome of the infection. Inflammatory genes including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are involved in H. pylori gastritis. Transcription factor AP-1 is composed of c-Fos and c-Jun and mediates inflammation and carcinogenesis. Ras acts as a regulator for AP-1 activation in various cells. We investigated whether H. pylori in a Korean isolate (HP99), a cagA ( + ), vacA ( + ) strain, induces the expression of c-Fos and c-Jun for AP-1 activation to induce COX-2 and iNOS and whether HP99-induced expressions of COX-2 and iNOS are mediated by Ras and AP-1, determined by the expressions of c-Fos and c-Jun, in gastric epithelial AGS cells, using transfection with mutant genes for Ras (ras N-17) and c-Jun (TAM-67). As a result, HP99 induced the expression of c-Fos and c-Jun and the expressions of COX-2 and iNOS in AGS cells. Transfection with mutant genes for Ras or c-Jun suppressed HP99-induced expressions of COX-2 and iNOS in AGS cells. In conclusion, H. pylori in a Korean isolate induces the expression of COX-2 and iNOS via AP-1 activation, which may be mediated by Ras and the expression of c-Fos and c-Jun in gastric epithelial cells.

Association of Helicobacter pylori and Epstein-Barr virus with gastric cancer and peptic ulcer disease.

OBJECTIVE: Helicobacter pylori and Epstein-Barr virus (EBV) infections are common world-wide. Though H. pylori infection is a major factor in gastroduodenal diseases, its role in association with EBV infection is unknown. We prospectively studied the association of H. pylori and EBV in patients with gastric cancer (GC) and peptic ulcer disease (PUD). MATERIAL AND METHODS: A total of 348 adult patients (non-ulcer dyspepsia (NUD) 241, PUD 45, GC 62) undergoing upper gastrointestinal endoscopy between September 2003 and May 2007 were enrolled in the study. H. pylori infection was diagnosed by rapid urease test, culture, histopathology and polymerase chain reaction (PCR). EBV DNA was detected by non-polymorphic Epstein-Barr nuclear antigen-1 (EBNA-1) gene-based PCR and sequence analysis. RESULTS: The rate of H. pylori infection was higher in patients with PUD than in those with GC (80% versus 56.5%, p=0.01) and NUD (80% versus 55.2%, p=0.002). In patients with GC and PUD, EBV DNA was detected more often than in those with NUD (GC versus NUD - 82.3% versus 37.3%, p<0.001; PUD versus NUD - 75.5% versus 37.3%, p<0.001). H. pylori infection and EBV DNA detected in different groups of patients was as follows: 62.2% in PUD, 46.8% in GC and 29.5% in NUD. PUD and GC were significantly associated (p<0.001 and <0.05, respectively) with the presence of H. pylori infection and EBV DNA as compared with NUD. CONCLUSIONS: EBV DNA either alone or in combination with H. pylori infection was significantly associated with GC and PUD, suggesting that EBV might play an important role in gastroduodenal pathology.

Herpes simplex virus type 1 in peptic ulcer disease: an inverse association with Helicobacter pylori.

AIM: To assess the frequency of herpes simplex virus type I in upper gastrointestinal tract ulcers and normal mucosa with the modern and better assays and also with a larger number of well characterized patients and controls and its relationship to Helicobacter pylori(H pylori). METHODS: Biopsy specimens from 90 patients (34 with gastric ulcer of the prepyloric area and 56 with duodenal ulcer) were evaluated. Biopsies from 50 patients with endoscopically healthy mucosa were considered as the control group. The method used to identify herpes simplex virus-1 (HSV-1) was polymerase chain reaction. H pylori was detected by the CLO-test and by histological method. RESULTS: Herpes simplex virus-1 was detected in 28 of 90 patients with peptic ulcer (31%) [11 of 34 patients with gastric ulcer (32.4%) and 17 of 56 with duodenal ulcer (30.4%)] exclusively close to the ulcerous lesion. All control group samples were negative for HSV-1. The likelihood of H pylori negativity among peptic ulcer patients was significantly higher in HSV-1 positive cases than in HSV-1 negative cases (P = 0.009). Gastric ulcer patients with HSV-1 positivity were strongly associated with an increased possibility of Helicobacter pylori negativity compared to duodenal ulcer patients (P = 0.010). CONCLUSION: HSV-1 is frequent in upper gastro-intestinal tract ulcers but not in normal gastric and duodenal mucosa. There is an inverse association between HSV-1 and H pylori infection.

Detection of Epstein-Barr virus in gastrectomy specimens.

Epstein Barr virus (EBV) has been reported to be present in a minority of gastric carcinomas and may be implicated in its pathogenesis. This study was aimed at determining the occurrence of EBV in 43 consecutive gastrectomy specimens with a variety of benign and malignant lesions. In situ hybridisation was used for detection of EBER RNA, the marker for latent EBV infection. Only 1/20 (5%) gastric cancers was EBER positive; a moderately differentiated adenocarcinoma with a heavy lymphocytic infiltration. The interstitial lymphocytic infiltrate was predominantly of B cell type, but the majority of lymphocytes overlying the tumour cells were CD8+ T cells. The other gastric lesions examined, which included 15 peptic ulcers, 6 stromal tumours and 2 lymphomas, were all EBER negative. Using a biotin detection system, scattered EBER positive cells were seen in adjacent normal gastric and/or duodenal mucosa in 9 sections from 8 cases (i.e., in 19% of all 43 cases examined). However, on using a digoxygenin detection system, no reactivity was found in these normal cells. An immunoperoxidase stain for chromogranin A showed that these apparently 'EBER positive' cells corresponded to normal chromogranin positive neuroendocrine cells within the gastric and duodenal mucosa. We conclude that EBV infection occurred only in the lymphoepithelioma type of gastric carcinoma and was absent from the other adenocarcinomas and from normal and benign tissues. The occasional EBER positive reaction encountered in normal cells was probably the result of a false signal arising from neuroendocrine cells as a consequence of the biotin-containing detection system.

Detection of genes of RNA viruses from freshly biopsied gastric mucosa by reverse transcription polymerase chain reaction.

The reverse transcription polymerase chain reaction (RT-PCR) was performed to detect genes of RNA viruses in the freshly biopsied gastric mucosa of seven patients with low gastric acidity. Although nucleoprotein genes of Sendai virus and hemmaglutinin genes of influenza virus A were not detected, nucleoprotein genes of influenza virus B were detected in samples from three of the seven patients. The first patient had had antrectomy and vagotomy for gastric ulcer, the second patient was receiving a histamine type 2 receptor blocker for gastritis, and the third patient was receiving a proton pump inhibitor for gastric ulcer. Virus isolation from gastric mucosa and from gargles was negative for all seven patients. These findings suggest that genes of influenza viruses may exist in the gastric mucosa of patients with low gastric acidity.

[Detection of human cytomegalovirus by PCR in patients with gastrointestinal disease].

Human cytomegalovirus (HCMV) genomes was detected by PCR in 51 patients' biopsy or operation specimens with gastrointestinal disease. The positive rate was 9.80%. At the same time, 41 patients' serum HCMV-IgM was detected by indirect immunofluorescence assay (IFA); the positive rate was 46.34%. Patients with cancer and colitis exhibited a higher HCMV infection rate than those without cancer and colitis. The results suggest that PCR is sensitive and specific in detection of gastrointestinal HCMV infection, and the examination of biopsy or surgical specimen is superior than that of IFA of serum HMCV-IgG.

To repair the fault or end the acid reign?

BACKGROUND: Despite the vast effort and expense devoted to the elucidation of the cause of esophagogastro-duodenal ulcer disease, relatively minimal progress has been made towards the understanding of causation. Since earliest times, it has been recognized that milk, chalk powder, or charcoal ameliorate the disease process and its symptoms. In addition, the avoidance of acidic or spicy foods provides some relief. Thus ulcer disease has been ascribed to acid or the consequences of hyperacidity. Reams of data and countless meetings have purported to confirm and support this viewpoint. Surprisingly, the co-secretion in the stomach of the powerful proteolytic enzyme pepsin has been virtually ignored as a pathogenetic agent. Marshalling distant antipodean resources, a novel bacteria, H. pylori, was identified as a significant causative agent in ulcer disease. To the amazement of nobody but gastroenterologists, it became apparent that there might be more than one cause for ulcer disease. Subsequently, both corporations and physicians seized the reins of multi-variant antibiotic therapy as a panacea for the third millennium treatment of peptic ulcer disease. Only a brave few have raised the issues of possible abnormalities in intrinsic mucosal function which might generate a locus minoris resistentiae. Defective mucosal repair mechanisms have barely been evaluated, since the regulation of normal mucosal healing is so poorly understood. Nevertheless, consideration of the therapeutic potential of mucosal protection has found support at both an intellectual and a clinical level. The more exciting recent possibility of the local delivery of growth factors which might promote healing has provided a unique opportunity for further therapeutic advance. CONCLUSIONS: Indeed in the future the exogenous regulation of mucosal repair may provide a milieu conductive to the resolution of an old but ill-understood problem. It is certainly apparent that processes beyond parietal cell proton secretion are critical and require both delineation and management. The acid reign may be in decline but the site of the fault and its repair remain to be defined.