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1.  Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer 
Current Oncology  2013;20(5):e388-e395.
Recent studies have suggested a controversial role of Helicobacter pylori infection in gastric cancer prognosis. The aim of the present study was to investigate the potential impact of H. pylori status on the prognosis of patients with gastric cancer in a Chinese prospective cohort.
Between 2007 and 2009, 261 patients with curatively resected gastric cancer were enrolled in the study. H. pylori status was defined by means of immunohistochemical staining in tumour and non-neoplastic tissues. Treatment prognosis was measured in terms of cancer-specific survival and disease-free survival (dfs). Univariate and multivariate Cox regression models were used to assess the association between H. pylori status and patient prognosis.
Positivity for H. pylori infection was observed in 188 of the 261 patients (72.0%). In patients positive for H. pylori, mean cancer-specific survival was 55.2 months [95% confidence interval (ci): 53.4 to 56.9 months] and mean dfs was 53.9 months (95% ci: 51.8 to 56.0 months); the same survivals were, respectively, 45.1 months (95% ci: 42.2 to 47.9 months) and 43.7 months (95% ci: 40.4 to 47.0 months) in patients negative for H. pylori. In univariate analysis, positive H. pylori status was associated with better cancer-specific survival [hazard ratio (hr): 0.486; 95% ci: 0.271 to 0.870; p = 0.015] and dfs (hr: 0.540; 95% ci: 0.307 to 0.950; p = 0.033). In multivariate analysis, H. pylori was an independent prognostic factor for cancer-specific survival (hr: 0.485; 95% ci: 0.265 to 0.889; p = 0.019).
Our study demonstrates that positive H. pylori status is a beneficial prognostic indicator in patients with gastric cancer and might suggest possible therapeutic approaches for gastric cancer. Further research is required to better understand inflammation mechanisms and cancer progression.
PMCID: PMC3805408  PMID: 24155636
Helicobacter pylori; gastric cancer; survival; relapse
2.  Contribution of H. pylori and Smoking Trends to US Incidence of Intestinal-Type Noncardia Gastric Adenocarcinoma: A Microsimulation Model 
PLoS Medicine  2013;10(5):e1001451.
Jennifer Yeh and colleagues examine the contribution of IHelicobacter pyloriI and smoking trends to the incidence of past and future intestinal-type noncardia gastric adenocarcinoma.
Please see later in the article for the Editors' Summary
Although gastric cancer has declined dramatically in the US, the disease remains the second leading cause of cancer mortality worldwide. A better understanding of reasons for the decline can provide important insights into effective preventive strategies. We sought to estimate the contribution of risk factor trends on past and future intestinal-type noncardia gastric adenocarcinoma (NCGA) incidence.
Methods and Findings
We developed a population-based microsimulation model of intestinal-type NCGA and calibrated it to US epidemiologic data on precancerous lesions and cancer. The model explicitly incorporated the impact of Helicobacter pylori and smoking on disease natural history, for which birth cohort-specific trends were derived from the National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS). Between 1978 and 2008, the model estimated that intestinal-type NCGA incidence declined 60% from 11.0 to 4.4 per 100,000 men, <3% discrepancy from national statistics. H. pylori and smoking trends combined accounted for 47% (range = 30%–58%) of the observed decline. With no tobacco control, incidence would have declined only 56%, suggesting that lower smoking initiation and higher cessation rates observed after the 1960s accelerated the relative decline in cancer incidence by 7% (range = 0%–21%). With continued risk factor trends, incidence is projected to decline an additional 47% between 2008 and 2040, the majority of which will be attributable to H. pylori and smoking (81%; range = 61%–100%). Limitations include assuming all other risk factors influenced gastric carcinogenesis as one factor and restricting the analysis to men.
Trends in modifiable risk factors explain a significant proportion of the decline of intestinal-type NCGA incidence in the US, and are projected to continue. Although past tobacco control efforts have hastened the decline, full benefits will take decades to be realized, and further discouragement of smoking and reduction of H. pylori should be priorities for gastric cancer control efforts.
Please see later in the article for the Editors' Summary
Editors' Summary
Cancer of the stomach (gastric cancer) is responsible for a tenth of all cancer deaths world-wide, with an estimated 700,000 people dying from this malignancy every year, making it the second most common cause of global cancer-related deaths after lung cancer. Unfortunately, the projected global burden of this disease estimate that deaths from gastric cancer will double by 2030. Gastric cancer has a poor prognosis with only a quarter of people with this type of cancer surviving more than five years. In order to reduce deaths, it is therefore of utmost importance to identify and reduce the modifiable risk factors associated with gastric cancer. Smoking and chronic gastric infection with the bacteria Helicobacter pylori (H. pylori), are known to be two common modifiable risk factors for gastric cancer, particularly for a type of gastric cancer called intestinal-type noncardia gastric adenocarcinoma (NCGA), which occurs at the distal end of the stomach and accounts for more than half of all cases of gastric cancer in US men.
Why Was This Study Done?
H. pylori initiates a precancerous process, and so infection with this bacteria can increase intestinal-type NCGA risk by as much as 6-fold while smoking doubles cancer risk by advancing increasing progression of existing lesions. Changes in these two risk factors over the past century (especially following the US Surgeon General's Report on Smoking and Health in 1964) have led to a dramatic decline in the rates of gastric cancer in US men. Understanding the combined effects of underlying risk factor trends on health outcomes for intestinal-type NCGA at the population level can help to predict future cancer trends and burden in the US. So in this study, the researchers used a mathematical model to estimate the contribution of H. pylori and smoking trends on the decline in intestinal-type NCGA incidence in US men.
What Did the Researchers Do and Find?
The researchers used birth cohorts derived from data in two national databases, the National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS) to develop a population-based model of intestinal-type NCGA. To ensure model predictions were consistent with epidemiologic data, the researchers calibrated the model to data on cancer and precancerous lesions and using the model, projected population outcomes between 1978 and 2040 for a base-case scenario (in which all risk factor trends were allowed to vary over time). The researchers then evaluated alternative risk factors scenarios to provide insights on the potential benefit of past and future efforts to control gastric cancer.
Using these methods, the researchers estimated that the incidence of intestinal-type NCGA (standardized by age) fell from 11.0 to 4.4 per 100,000 men between 1978 and 2008, a drop of 60%. When the researchers incorporated only H. pylori prevalence and smoking trends into the model (both of which fell dramatically over the time period) they found that intestinal-type NCGA incidence fell by only 28% (from 12.7 to 9.2 per 100,000 men), suggesting that H. pylori and smoking trends are responsible for 47% of the observed decline. The researchers found that H. pylori trends alone were responsible for 43% of the decrease in cancer but smoking trends were responsible for only a 3% drop. The researchers also found evidence that after the 1960s, observed trends in lower smoking initiation and higher cessation accelerated the decline in intestinal-type NCGA incidence by 7%. Finally, the researchers found that intestinal-type NCGA incidence is projected to decline an additional 47% between 2008 and 2040 (4.4 to 2.3 per 100,000 men) with H. pylori and smoking trends accounting for more than 80% of the observed fall.
What Do These Findings Mean?
These findings suggest that, combined with a fall in smoking rates, almost half of the observed fall in rates of intestinal-type NCGA cancer in US men between 1978 and 2008 was attributable to the decline in infection rates of H. pylori. Rates for this cancer are projected to continue to fall by 2040, with trends for both H. pylori infection and smoking accounting for more than 80% of the observed fall, highlighting the importance of the relationship between risk factors changes over time and achieving long-term reduction in cancer rates. This study is limited by the assumptions made in the model and in that it only examined one type of gastric cancer and excluded women. Nevertheless, this modeling study highlights that continued efforts to reduce rates of smoking and H. pylori infection will help to reduce rates of gastric cancer.
Additional Information
Please access these Web sites via the online version of this summary at
The National Cancer Institute gives detailed information about gastric cancer
The Gastric Cancer Foundation has information on gastric cancer for patients and professionals
Cancer Research UK explains types of gastric cancer
PMCID: PMC3660292  PMID: 23700390
3.  Early-Life Family Structure and Microbially Induced Cancer Risk 
PLoS Medicine  2007;4(1):e7.
Cancer may follow exposure to an environmental agent after many decades. The bacterium Helicobacter pylori, known to be acquired early in life, increases risk for gastric adenocarcinoma, but other factors are also important. In this study, we considered whether early-life family structure affects the risk of later developing gastric cancer among H. pylori+ men.
Methods and Findings
We examined a long-term cohort of Japanese-American men followed for 28 y, and performed a nested case-control study among those carrying H. pylori or the subset carrying the most virulent cagA+ H. pylori strains to address whether family structure predicted cancer development. We found that among the men who were H. pylori+ and/or cagA+ (it is possible to be cagA+ and H. pylori− if the H. pylori test is falsely negative), belonging to a large sibship or higher birth order was associated with a significantly increased risk of developing gastric adenocarcinoma late in life. For those with cagA+ strains, the risk of developing gastric cancer was more than twice as high (odds ratio 2.2; 95% confidence interval 1.2–4.0) among those in a sibship of seven or more individuals than in a sibship of between one and three persons.
These results provide evidence that early-life social environment plays a significant role in risk of microbially induced malignancies expressing five to eight decades later, and these findings lead to new models to explain these interactions.
This study suggests that early-life social environment has a significant role in risk of microbially induced malignancies such as gastric adenocarcinoma occuring five to eight decades later.
Editors' Summary
Although the theory that certain cancers might be caused by infectious agents (such as bacteria and viruses) has been around for some time, concrete evidence linking specific cancers and infections is only recently beginning to emerge. There is now very good evidence that stomach cancer, once one of the frequent types worldwide but now less common, is strongly associated with a particular infection of the stomach lining. This specific bacterium colonizing the stomach, Helicobacter pylori (or H. pylori), often infects people early in childhood through close contact with other people, and tends to stay in the body throughout life. However, most people do not suffer any symptoms as a result of being colonized with H. pylori. Researchers are interested in the relationship between stomach cancer and aspects of someone's upbringing, for example whether an individual has a large number of sisters and brothers and whether they are the youngest or oldest in a large group of siblings. One reason for being interested in this topic is that if H. pylori is mainly spread from one child to another in the home, we might expect children from large sibling groups, and the youngest children in a group, to be at greater risk of being infected, and then more likely to get stomach cancer later in life. Furthermore—and this was the primary reason for the study—the researchers wished to determine whether, among H. pylori+ people, the structure of the family affects the risk of developing stomach cancer much later in life. With all study participants being H. pylori+, the essential comparison was between people of high and low birth order.
Why Was This Study Done?
This group of researchers had already done a previous study that had shown that people who carry H. pylori in their stomachs are more likely to get stomach cancer, and also that younger children in a sibling group are more likely to get stomach cancer. In the period following that study, the examined population has become older and more of the people concerned have developed stomach cancer. This meant that the researchers could go back and extend their previous work to see, more reliably, whether stomach cancer was linked to family structure. It also meant that the researchers could look at the effects of each factor not only in isolation, but also the combined effect of all the different factors. The researchers also stratified for the most virulent strains (those that were cagA+).
What Did the Researchers Do and Find?
In this study, the researchers started out with a pool of 7,429 Japanese-American men living in Hawaii, USA, who had donated blood samples between 1967 and 1975. Of these men, 261 eventually developed stomach cancer. Each of the 261 men was then matched with a similarly aged man from the original pool of 7,429 men who did not have stomach cancer. The researchers then went back to the original blood samples taken many years before and tested the samples to see if the men were infected with H. pylori at the time the sample was taken and, if so, whether a particular strain of the bacterium, cagA, was present. The researchers then looked at whether the risk of getting stomach cancer was associated with the number of siblings a man had and whether he was older or younger than the other siblings.
Similar to the prior study, they found that men who had stomach cancer were three times more likely to carry H. pylori compared to men who did not develop stomach cancer. In men who had H. pylori, those with large numbers of siblings were more likely to get stomach cancer, and this was especially true for men who had the cagA strain of H. pylori. In the whole group of men with cancer, the order of birth (whether a man was older or younger in his sibling group) did not seem to be particularly linked to development of stomach cancer. However, in men who had the cagA strain of H. pylori, those from the largest sibships were at highest risk of developing gastric cancer; in this group, one particular type of cancer (the most common type—intestinal-type gastric cancer) was also associated with later birth order.
What Do These Findings Mean?
The researchers initially thought that men with H. pylori would be at a higher risk of getting stomach cancer if they had a large number of sisters and brothers, and especially if they were a younger sibling in a large group. This idea was supported by their data. These findings support the idea that people often get H. pylori from their older sisters and brothers, but there is not conclusive proof of this. There might be some other factor that explains the association between large family size and stomach cancer, for example that people from large families might be poorer and more at risk from stomach cancer for some other reason. Currently, most doctors do not recommend routinely testing people without any symptoms to see if they have H. pylori, but people with pain or discomfort in the upper abdomen would generally be screened for H. pylori and then treated to eliminate the infection if it is found. The main novel idea is that those people who are born in a large sibship, and/or are of higher birth order, are more likely to acquire their H. pylori from a genetically related person (a sibling) than from an unrelated person (friend/classmate). This “family-structure effect” could be the explanation as to why there is a higher risk of stomach cancer developing later—the strain from a genetically related person already is “preadapted” to the new host, and has a “head-start” on immunity, compared to a strain from an unrelated person. The researchers hypothesize that it is the nature of that initial interaction with the host that sets the stage for the kind of events that lead to cancers decades later.
Additional Information.
Please access these Web sites via the online version of this summary at
A Perspective article by Dimitrios Trichopoulos and Pagona Lagiou discusses these findings further
MedLine Plus encyclopedia entry on stomach cancer
Wikipedia entry on Helicobacter pylori (Wikipedia is an internet encyclopedia that anyone can edit)
The US National Cancer Institute publishes information about stomach cancer
PMCID: PMC1769414  PMID: 17227131
4.  Comparison of Helicobacter pylori infection and gastric mucosal histological features of gastric ulcer patients with chronic gastritis patients 
AIM: To compare Helicobacter pylori infection and gastric mucosal histological features of gastric ulcer patients with chronic gastritis patients in different age groups and from different biopsy sites.
METHODS: The biopsy specimens were taken from the antrum, corpus and upper angulus of gastric ulcer and chronic gastritis patients. Giemsa staining, improved Toluidine-blue staining and H pylori-specific antibody immune staining were performed as appropriate for the histological diagnosis of H pylori infection. Hematoxylin-eosin staining was used for the histological diagnosis of activity of H pylori infection, mucosal inflammation, glandular atrophy and intestinal metaplasia and scored into four grades according to the Updated Sydney System.
RESULTS: Total rate of H pylori infection, mucosal inflammation, activity of H pylori infection, glandular atrophy and intestinal metaplasia in 3839 gastric ulcer patients (78.5%, 97.4%, 82.1%, 61.1% and 64.2%, respectively) were significantly higher than those in 4102 chronic gastritis patients (55.0%, 90.3%, 56.2%, 36.8%, and 37.0%, respectively, P<0.05). The rate of H pylori colonization of chronic gastritis in <30 years, 31-40 years, 41-50 years, 51-60 years, 61-70 years and >70 years age groups in antrum was 33.3%, 41.7%, 53.6%, 57.3%, 50.7%, 43.5%, respectively; in corpus, it was 32.6%, 41.9%, 53.8%, 60.2%, 58.0%, 54.8%, respectively; in angulus, it was 32.4%, 42.1%, 51.6%, 54.5%, 49.7%, 43.5%, respectively. The rate of H pylori colonization of gastric ulcer in <30 years, 31-40 years, 41-50 years, 51-60 years, 61-70 years and >70 years age groups in antrum was 60.5%, 79.9%, 80.9%, 66.8%, 59.6%, 45.6%, respectively; in corpus, it was 59.7%, 79.6%, 83.6%, 80.1%, 70.6%, 59.1%, respectively; in angulus, it was 61.3%, 77.8%, 75.3%, 68.8%, 59.7%, 45.8%, respectively. The rate of H pylori colonization at antrum was similar to corpus and angulus in patients, below 50 years, with chronic gastritis and in patients, below 40 years, with gastric ulcer. In the other age- groups, the rate of H pylori colonization was highest in corpus, lower in antrum and lowest in angulus (all P<0.05). The rates of glandular atrophy and intestinal metaplasia were higher and earlier in H pylori-positive patients than those without H pylori infection (both P<0.01). In comparison of gastric ulcer patients with chronic gastritis patients, the rate of glandular atrophy and intestinal metaplasia was higher in H pylori-positive patients with gastric ulcer than in H pylori-positive patients with chronic gastritis (both P<0.01); the rate of glandular atrophy and intestinal metaplasia were also higher in H pylori-negative patients with gastric ulcer than in H pylori-negative patients with chronic gastritis (both P<0.01). Both glandular atrophy and intestinal metaplasia were much more commonly identified in the angulus than in the antrum, lowest in corpus (all P<0.01).
CONCLUSION: Rate of H pylori infection, glandular atrophy and intestinal metaplasia in gastric ulcer were higher than in chronic gastritis in all-different age -groups. Distribution of H pylori colonization is pangastric in the younger patients. It is highest in corpus, lower in antrum and lowest in angulus in the older age groups. Progression of glandular atrophy and intestinal metaplasia seem to have a key role in the distribution of H pylori colonization. H pylori appears to be the most important risk factor for the development of glandular atrophy and intestinal metaplasia, but it is not the only risk.
PMCID: PMC4250788  PMID: 15742399
Helicobacter pylori infection; Gastric ulcer; Glandular atrophy; Intestinal metaplasia
5.  Interleukin 10 in Helicobacter pylori associated gastritis: immunohistochemical localisation and in vitro effects on cytokine secretion 
Journal of Clinical Pathology  2001;54(4):285-292.
Background/Aims—Interleukin 10 (IL-10) is a counterinflammatory peptide implicated in the downregulation of human intestinal immune responses. Enhanced secretion of IL-10 has been documented in gastric biopsy organ culture in Helicobacter pylori infection. This study aimed to define the cellular origins of IL-10 in H pylori associated gastritis, and to determine the effects of endogenous IL-10 on proinflammatory cytokine secretion in vitro.
Methods—Endoscopic biopsies were obtained from the gastric antrum at endoscopy from patients with dyspepsia. Two pairs of antral biopsies were cultured in vitro for 24 hours, one pair in the presence of neutralising anti-IL-10 monoclonal antibody, the other pair as controls. The cytokine content of culture supernatants (tumour necrosis factor α (TNF-α), IL-6, and IL-8) was determined by enzyme linked immunosorbent assay and corrected for biopsy weight. Helicobacter pylori status was established by histology and biopsy urease test, and histopathology graded by the Sydney system. In a subgroup of patients, western blotting was used to establish CagA serological status. Immunohistochemistry for IL-10 was performed on formalin fixed tissues using a combination of microwave antigen retrieval and the indirect avidin–biotin technique. Immunoreactivity was scored semiquantitatively.
Results—In vitro culture was performed in 41 patients: 31 with H pylori positive chronic gastritis and 10 H pylori negative. In vitro secretion of TNF-α, IL-6, and IL-8 for "control" biopsies was significantly higher in H pylori positive versus negative samples, with values of TNF-α and IL-6 correlating with the degree of active and chronic inflammation and being higher in CagA seropositive cases. No evidence for enhanced cytokine secretion was seen in biopsies cocultured in the presence of anti-IL-10 monoclonal antibody. Immunohistochemistry was performed in 29 patients, of whom 13 were H pylori positive. IL-10 immunoreactivity was observed in the surface epithelium in all H pylori positive cases and in 13 of 16 negative cases, especially in areas of surface epithelial degeneration. Lamina propria mononuclear cells (LPMNCs) were positively stained in all H pylori positive cases and in 12 of 16 negative cases, with a significantly greater proportion of positive LPMNCs in the positive group.
Conclusions—This study localised IL-10 protein to the gastric epithelium and LPMNCs. In vitro proinflammatory cytokine secretion was increased in H pylori infection (especially CagA positive infection), but blocking endogenous IL-10 secretion did not significantly increase cytokine secretion. IL-10 is implicated in H pylori infection and might "damp down" local inflammation. The role of gastric IL-10 secretion in determining the clinicopathological outcome of infection merits further study.
Key Words: Helicobacter pylori infection • interleukin 10 • gastritis • immunohistochemistry
PMCID: PMC1731395  PMID: 11304845
6.  Involvement of Aquaporin 3 in Helicobacter pylori-Related Gastric Diseases 
PLoS ONE  2012;7(11):e49104.
Gastric cancer is one of the most common and lethal malignant cancers worldwide, and numerous epidemiological studies have demonstrated that Helicobacter pylori (H. pylori) infection plays a key role in the development of gastric carcinomas. Our previous studies showed that aquaporin 3 (AQP3) is overexpressed in gastric carcinoma and promotes the migration and proliferation of human gastric carcinoma cells, suggesting that AQP3 may be a potentially important determinant of gastric carcinoma. However, the role of AQP3 in H. pylori carcinogenesis is unknown.
The AQP3 protein and H. pylori were detected in human gastric tissues by immunohistochemistry and modified Giemsa staining respectively. AQP3 knockdown was obtained by small interfering (si) RNA. Western blot assays and RT-PCR were used to evaluate the change of AQP3 in the human gastric cancer AGS and SGC7901 cell lines after co-culture with H. pylori. Sprague Dawley rats were orally inoculated with H. pylori to establish a rat model colonized by H. pylori.
The present study found that AQP3 expression correlated with H. pylori infection status in gastric cancer tissues and corresponding normal mucosa, and H. pylori co-culture upregulated AQP3 expression in human gastric adenocarcinoma cells in vitro via the extracellular signal-regulated kinase signaling pathway. H. pylori infection also increased AQP3 expression in gastric mucosa colonized by H. pylori in a Sprague Dawley rat model.
These findings provide further information to understand the mechanism of H. pylori carcinogenesis and a potential strategy for the treatment of H. pylori-associated gastric carcinoma.
PMCID: PMC3494660  PMID: 23152856
7.  CpG island methylator phenotype and Helicobacter pylori infection associated with gastric cancer 
AIM: To investigate the association between the CpG island methylator phenotype (CIMP) and serum Helicobacter pylori (H. pylori) levels for clinical prediction of gastric cancer (GC) progression.
METHODS: We analyzed the serum CIMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infection in serum was assayed with an anti-H. pylori immunoglobulin G antibody test and a rapid urease test.
RESULTS: The frequencies of high-level methylation in GC tissues for the seven genes were: 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad. The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP+ (defined as ≥ 3 methylated genes) was associated with 47 (62.67%) GC tissue samples and 44 (58.67%) GC serum samples. CIMP+ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 (68%) were H. pylori+, and 24 (32%) were H. pylori-. Of the 51 H. pylori+ cases, 36 were CIMP+ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP+, and 13 were CIMP-. The difference was significant between the H. pylori+ and H. pylori- groups (χ2 = 4.27, P < 0.05). Of the 51 H. pylori+ GC patients, 34 were CIMP+ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP+ and 14 were CIMP-. The difference was significant between the H. pylori+ and H. pylori- groups (χ2 = 4.21, P < 0.05). A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori+/CIMP+ cases and the H. pylori+/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum (P < 0.05). However, there were no significant differences in survival rates between the two groups.
CONCLUSION: H. pylori+/CIMP+ cases are associated with higher rates of metastasis and recurrence than H. pylori+/CIMP- cases. Serum may be useful for examining CIMP status.
PMCID: PMC3460343  PMID: 23049225
CpG island methylator phenotype; Helicobacter pylori; Serum; Prognosis; Gastric cancer
8.  Gastric pathology in patients with common variable immunodeficiency 
Gut  1999;45(1):77-81.
BACKGROUND/AIMS—Common variable immunodeficiency (CVID) is an immunological disorder characterised by defective antibody production. Patients with CVID have a high risk of gastric cancer. It has been suggested that gastric cancer results from an interaction between environmental factors and a genetic predisposition. The role of Helicobacter pylori as an environmental factor in gastric carcinogenesis is of current interest. Moreover, p53 gene mutations have been reported in gastric cancer. This study focuses on the gastric pathology of patients with CVID and correlation with H pylori infection.
METHODS—Thirty four consecutive dyspeptic patients with CVID (mean age 49.6 years, range 14-72; 17 men) were included in the study. An upper gastrointestinal endoscopy was performed and biopsy specimens were taken from the antrum, incisura angularis, and gastric body. Biopsies were used for histological assessment, to identify the presence of H pylori, and to evaluate p53 overexpression.
RESULTS—H pylori infection was detected in 14/34 (41%) patients. Chronic active gastritis involving both antrum and body was observed more frequently in H pylori positive (79%) than H pylori negative (20%) patients (p = 0.001). Similarly, a histological feature of multifocal atrophic gastritis was found more frequently in infected (50%) than uninfected patients (10%) (p = 0.012). In addition, one case of gastric adenocarcinoma and another of notable dysplasia were observed in the H pylori positive group. Overexpression of p53 was found in six (18%) patients, including one with normal gastric mucosa.
CONCLUSIONS—It can be hypothesised that both H pylori and p53 alterations play a role in the gastric carcinogenesis of patients with CVID.

Keywords: common variable immunodeficiency; Helicobacter pylori; p53; pathology; carcinogenesis; gastritis
PMCID: PMC1727591  PMID: 10369708
9.  Correlation of Epstein-Barr virus and its encoded proteins with Helicobacter pylori and expression of c-met and c-myc in gastric carcinoma 
AIM: To investigate the interrelationship of Epstein-Barr virus (EBV) and EBV- encoded proteins with Helicobacter pylori (H pylori) infection and the expression of c-met and c-myc oncogene proteins in gastric carcinoma, and to explore their role in gastric carcinogenesis.
METHODS: One hundred and eighty-five gastric carcinoma tissues were detected by polymerase chain reaction (PCR)-Southern blot for EBV genome and in situ hybridization (ISH) for EBV-encoded small RNA 1 (EBER1). Gastric carcinoma with positive EBER1 signals was confirmed EBV-associated gastric carcinoma (EBVaGC). The status of H pylori infection in 185 gastric carcinomas was assessed by rapid urease test and PCR. The samples with positive PCR and urease test were defined as H pylori infection. The expression of c-met and c-myc oncogene proteins in tissues of EBVaGC and matched EBV-negative gastric carcinoma (EBVnGC) were examined by immunohistochemistry. RT-PCR and Southern hybridization were used to detect the expression of nuclear antigens (EBNAs) 1 and 2, latent membrane protein (LMP) 1, early genes BARF1 and BHRF1 in EBVaGC cases.
RESULTS: The positive rate of H pylori and EBV in 185 gastric carcinomas was 59.45% (110/185) and 7.03% (13/185) respectively. No difference was found in sex, age, pathological differentiation, clinical stages and lymph node metastasis between H pylori-positive and H pylori-negative gastric carcinomas. However, the positive rate of H pylori infection in the antrum gastric carcinomas was higher than that of cardia and body gastric carcinomas. In our series, age, pathological differentiation, clinical stages, lymph node metastasis and location of cancer were not different between EBVnGC and EBVaGC, while the positive rate of EBV in male patients was significantly higher than that of female patients. The positivity of H pylori in EBV-associated and EBV-negative gastric carcinomas was 46.15% (6/13) and 81.40%(104/172) respectively. There was no significant correlation between EBV and H pylori infection. The c-met overexpression was significantly higher in the EBVaGC group than in the EBVnGC group. However, c-met and c-myc expression did not show significant difference between the two groups. Transcripts of EBNA1 were detected in all 13 EBVaGCs, while both EBNA2 and LMP1 mRNA were not detected. Six of the 13 cases exhibited BARF1 transcripts and 2 exhibited BHRF1 transcripts.
CONCLUSION: The positivity of H pylori in EBVnGCs is higher than that of EBVaGCs, but no significant correlation is found between EBV infection and H pylori infection. H pylori-positive gastric carcinoma is predominant in antrum location, while EBVaGC has a tendency of predominance in cardia/body location. EBV infection is associated with c-met abnormal expression but not with c-myc protein in EBVaGC. c-met overexpression is not induced by LMP1. BARF1 and BHRF1 may play important roles in the tumorigenesis of EBVaGC through different pathways.
PMCID: PMC4087508  PMID: 16609989
Epstein-Barr virus; Helicobacter pylori; Gastric carcinoma; c-met; c-myc
10.  Association between TNF-α promoter polymorphism and Helicobacter pylori cagA subtype infection 
Yea, S | Yang, Y | Jang, W | Lee, Y | Bae, H | Paik, K
Journal of Clinical Pathology  2001;54(9):703-706.
Aims—To assess the importance of tumour necrosis factor α (TNF-α) promoter polymorphism in relation to infection with the cytotoxin associated gene A (cagA) subtype of Helicobacter pylori within a dyspeptic Korean population.
Methods—Eighty three patients with gastric disease and 113 healthy controls were studied. The DNA from gastric biopsy specimens was analysed by H pylori specific and cagA specific polymerase chain reaction (PCR). To characterise TNF-α polymorphism at positions -308 and -238, PCR based restriction fragment length polymorphism analysis was performed.
Results—Helicobacter pylori infection was closely correlated with G to A transition at position -308 of the TNF-α promoter when compared with healthy controls (odds ratio (OR), 2.912; 95% confidence interval (CI), 1.082 to 7.836; p = 0.034). Although TNF-α -308 polymorphism in patients with H pylori was not significantly different from that in patients without H pylori, the -308A polymorphism was strongly associated with H pylori cagA subtype infection when compared with the polymorphism in cagA negative H pylori infection (OR, 8.757; 95% CI, 1.413 to 54.262; p = 0.019) and healthy controls (OR, 3.683; 95% CI, 1.343 to 10.101; p = 0.011). G to A genetic change at position -238 of the TNF-α gene was not significantly associated with H pylori cagA subtype infection. In addition, genetic polymorphisms at both sites of the TNF-α promoter in patients with H pylori infection did not correlate with the severity of disease.
Conclusion—TNF-α -308A polymorphism was significantly related to infection with the H pylori cagA subtype in Korean patients with gastric disease.
Key Words: Helicobacter pylori • cagA • tumour necrosis factor α • polymorphism
PMCID: PMC1731516  PMID: 11533078
11.  Detection and location of Helicobacter pylori in human gastric carcinomas 
AIM: To define the infection status of Helicobacter pylori in 109 patients with gastric cancers and H pylori localization in gastric carcinoma tissues in South China.
METHODS: The incidence of H pylori infection in gastric carcinomas was estimated by polymerase chain reaction (PCR), simultaneously; both morphological features and the localization of H pylori in gastric carcinomas were demonstrated by Warthin-Starry (WS) staining. The relationships between H pylori infection and the clinical-pathologic factors of gastric carcinomas were analyzed by software SPSS10.0.
RESULTS: H pylori was found in 42 (39.03%) and 58 (53.21%) cases of 109 patients with gastric carcinomas by PCR and WS, respectively. H pylori infection rate detected in gastric carcinomas by WS was higher than that by PCR (χ2 = 9.735, P<0.005<0.01). WS stain showed that H pylori existed in the gastric antrum mucus, mucosal gland of normal tissues adjacent to gastric carcinomas and the gland, mucus pool of cancer tissues. The positive rate of H pylori in normal tissues adjacent to carcinomas was higher than that in cancer tissues (χ2 = 15.750, P<0.005<0.01). No significant differences in age, sex, site, histological types and lymph node metastasis were found between H pylori-positive gastric carcinomas and H pylori-negative cases by both methods, but there were statistically significant differences of H pylori positive rate between early and advanced stage of gastric carcinomas (χ2 = 4.548 or 5.922, P = 0.033 or 0.015<0.05).
CONCLUSION: These results suggested that H pylori infection might play a certain role in the early stage of carcinogenesis of human gastric mucosa epithelia.
PMCID: PMC4250691  PMID: 15761982
Gastric carcinoma; H pylori; Polymerase chain reaction; Warthin-Starry staining
12.  Serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis. 
Mediators of Inflammation  2004;13(1):25-28.
INTRODUCTION: Helicobacter pylori (H. pylori) is a non-invasive microorganism causing intense gastric mucosal inflammatory and immune reaction. H. pylori-induced gastric mucosal cytokine overproduction has been clearly documented previously. The stomach has a large surface area and continuous spill-over of locally produced cytokines into the blood stream is a possibility. There are few and conflicting data on circulatory proinflammatory cytokine levels in patients with H. pylori infection. MATERIALS AND METHODS: Forty-two dyspeptic patients were enrolled into the study. The presence of H. pylori infection was diagnosed with antral histopathologic examination. After overnight fasting; serum samples were obtained from each patient to determine circulating interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) levels. RESULTS: H. pylori was shown in 30 cases using Giemsa stain in antral histopathologic evaluation. Twelve cases were negative for H. pylori staining. Both the age and sex distribution had an insignificant difference in both H pylori-positive and H. pylori-negative groups. The mean circulatory levels of IL-6, IL-8 and TNF-a in both groups were not different. The situation was same in respect to the serum levels of these cytokines and the degree of inflammation, H. pylori density and activation scores according to Sydney classification. CONCLUSION: We could not show elevated circulatory levels of IL-6, IL-8 and TNF-alpha in H. pylori-infected cases. We believe that H. pylori-related cytokine activation become concentrated on gastric mucosa and this pathogen-induced local inflammatory cascade does not cause changes in circulatory levels of these cytokines. Moreover, there is no correlation between the levels of serum cytokines and Sydney parameters.
PMCID: PMC1781536  PMID: 15203561
13.  Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users. Response to omeprazole dual therapy. 
Gut  1996;39(1):22-26.
BACKGROUND: The relation between Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers remains unclear; in particular, it is not known whether H pylori plays a part in the healing and recurrence of these ulcers. AIMS: To evaluate prospectively in a consecutive series of arthritis patients receiving longterm NSAID treatment the prevalence of peptic ulcer as well as the effect of H pylori eradication on the healing and recurrence of gastric and duodenal ulcer found. PATIENTS: Some 278 consecutive patients underwent gastroscopy with multiple biopsies of the gastric antrum and corpus for histological examination and rapid urease test. One hundred peptic ulcers (59 gastric ulcers, 39 duodenal ulcers, and two gastric ulcers concomitant with a duodenal ulcer) were found. Seventy per cent of these ulcers were H pylori positive. METHODS: According to their H pylori status, ulcer patients were randomised to one of the following treatments: H pylori negative ulcers received omeprazole 20 mg twice daily for four to eight weeks, whereas H pylori positive lesions were treated with omeprazole 20 mg twice daily plus amoxycillin 1 g twice daily (the second of these for the first two weeks) or omeprazole alone for four to eight weeks while continuing NSAID therapy. Patients with healed ulcers were endoscopically followed up for six months after stopping antiulcer therapy while continuing NSAIDs. RESULTS: Endoscopic healing rates for gastric and duodenal ulcers in the three different groups were similar both at four and eight weeks. H pylori eradication did not influence healing, which occurred in 14 of 20 (70%) of patients in whom H pylori was eradicated, compared with 14 of 17 (82%) of patients with persistent infection. Cumulative recurrence rates at six months did not statistically differ among the three different groups (27% in H pylori negative, 46% in H pylori positive, and 31% in those where H pylori was eradicated during the healing phase), although a numerical trend in favour of a higher recurrence rate in infected patients was evident. CONCLUSIONS: H pylori eradication does not confer any significant advantage on the healing of gastric and duodenal ulcers associated with longterm NSAID use. It remains to be established with certainty whether eradication may be helpful in the reduction of recurrence in a specific subset of NSAID associated ulcer.
PMCID: PMC1383224  PMID: 8881802
14.  Relationship between H.Pylori infection and clinicopathological features and prognosis of gastric cancer 
BMC Cancer  2010;10:374.
Aimed to assess the relationship between H.Pylori and the clinicopathological features and prognosis of gastric cancer by quantitative detection of H.Pylori.
157 patients were enrolled, all patients had a record of clinicopathological parameters. Specimens including the tumor and non-neoplastic were detected for H.Pylori by Real-Time PCR and analyzed clinical data retrospectively. Variables independently affecting prognosis were investigated by means of multivariate analysis using the Cox proportional hazards model.
H.Pylori infection was greater in non-neoplastic tissue than the tumor tissue (p < 0.05), H.Pylori infection and its copies were related to the tumor site and N staging (p < 0.05). Overall survival (OS) in all 157 patients has no correlation with the H.Pylori infection status (p = 0.715). As to the patients who underwent a curative surgery, relapse-free survival (RFS) has no correlation with the H.Pylori infection status (p = 0.639). Among the H.Pylori positive patients, OS and RFS of those with higher copies were longer than in patients with low copies, but there was no significant statistical difference.
H.Pylori infection status and its copies were related to N staging. The OS and RFS in patients with positive H.Pylori status has no significant difference from the patients with negative H.Pylori status.
PMCID: PMC2914705  PMID: 20637122
15.  CagA and VacA Helicobacter pylori antibodies in gastric cancer 
Infection with different genotypes of virulent Helicobacter pylori strains (cytotoxin-associated gene A [CagA]-and/or vacuolating cytotoxin A [VacA]-positive) can play a role in the development of atrophic gastritis, duodenal ulcer (DU) and gastric cancer (GC).
To determine whether patients with GC and H pylori-negative histological staining had previously been infected with H pylori CagA- and/or VacA-positive virulent strains.
Twenty-three GC patients with a mean (± SD) age of 68.14±9.8 years who tested H pylori-negative on histological staining took part in the study. Three control groups were included. The first group comprised 19 patients with past H pylori infection and DUs eradicated 10 years earlier, with a mean age of 58±18.2 years. H pylori-negative status for this group was determined every year with Giemsa staining, and follow-up testing occured 120±32 months (mean ± SD) after therapy. The subsequent control groups included 20 asymptomatic children, with a mean age of 7±4.47 years, and with H pylori-negative fecal tests; the final group contained 30 patients without clinical symptoms of H pylori infection, with a mean age of 68±11.6 years, who tested H pylori-negative by histological staining.
Prevalence of CagA and VacA seropositivity, respectively was 82.6% and 73.91% in GC patients; 84.2% and 84.2% in H pylori-negative DU patients; 25% and 5% in H pylori-negative children; and 36.6% and 16.6% in the patients without clinical symptoms on histological staining. CagA and VacA antibody positivity was not significantly different between GC patients and patients with DUs that had been eradicated 10 years earlier. Significant positivity was found between the children’s group and the H pylori-negative (with past DUs) group (P<0.001). A statistically significant difference was found in age between groups (P<0.03).
Patients with GC, even when H pylori-negative at the time of the present study, may have been infected by H pylori before the onset of the disease, as confirmed by CagA and VacA seropositivity. These data reinforce the hypothesis that H pylori may be a direct carcinogenic agent of GC.
PMCID: PMC2662200  PMID: 18354754
CagA; Gastric cancer; Helicobacter pylori; VacA
16.  Helicobacter pylori infection, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer and early gastric cancer 
AIM: To evaluate the histological features of gastric mucosa, including Helicobacter pylori infection in patients with early gastric cancer and endoscopically found superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer.
METHODS: The biopsy specimens were taken from the antrum, corpus and upper angulus of all the patients. Giemsa staining, improved toluidine-blue staining, and H pylori-specific antibody immune staining were performed as appropriate for the histological diagnosis of H pylori infection. Hematoxylin-eosin staining was used for the histological diagnosis of gastric mucosa inflammation, gastric glandular atrophy and intestinal metaplasia and scored into four grades according to the Updated Sydney System.
RESULTS: The overall prevalence of H pylori infection in superficial gastritis was 28.7%, in erosive gastritis 57.7%, in gastric erosion 63.3%, in gastric ulcer 80.8%, in early gastric cancer 52.4%. There was significant difference (P<0.05), except for the difference between early gastric cancer and erosive gastritis. H pylori infection rate in antrum, corpus, angulus of patients with superficial gastritis was 25.9%, 26.2%, 25.2%, respectively; in patients with erosive gastritis 46.9%, 53.5%, 49.0%, respectively; in patients with gastric erosion 52.4%, 61.5%, 52.4%, respectively; in patients with gastric ulcer 52.4%, 61.5%, 52.4%, respectively; in patients with early gastric cancer 35.0%, 50.7%, 34.6%, respectively. No significant difference was found among the different site biopsies in superficial gastritis, but in the other diseases the detected rates were higher in corpus biopsy (P<0.05). The grades of mononuclear cell infiltration and polymorphonuclear cell infiltration, in early gastric cancer patients, were significantly higher than that in superficial gastritis patients, lower than that in gastric erosion and gastric ulcer patients (P<0.01); however, there was no significant difference compared with erosive gastritis. The grades of mucosa glandular atrophy and intestinal metaplasia were significantly highest in early gastric cancer, lower in gastric ulcer, the next were erosive gastritis, gastric erosion, the lowest in superficial gastritis (P<0.01). Furthermore, 53.3% and 51.4% showed glandular atrophy and intestinal metaplasia in angular biopsy specimens, respectively; but only 40.3% and 39.9% were identified in antral biopsy, and 14.1% and 13.6% in corpus biopsy; therefore, the angulus was more reliable for the diagnosis of glandular atrophy and intestinal metaplasia compared with antrum and corpus (P<0.01). The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis with H pylori-positivity was 50.7%, 34.1%; of erosive gastritis 76.1%, 63.0%; of gastric erosion 84.8%, 87.8%; of gastric ulcer 80.6%, 90.9%; and of early gastric cancer 85.5%, 85.3%, respectively. The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis with H pylori-negativity was 9.9%, 6.9%; of erosive gastritis 42.5%, 42.1%; of gastric erosion 51.1%, 61.9%; of gastric ulcer 29.8%, 25.5%; and of early gastric cancer 84.0%, 86.0%, respectively. The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis, erosive gastritis, gastric erosion, and gastric ulcer patients with H pylori positivity was significantly higher than those with H pylori negativity (P<0.01); however, there was no significant difference in patients with early gastric cancer with or without H pylori infection.
CONCLUSION: The progression of the gastric pre-cancerous lesions, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis and gastric ulcer was strongly related to H pylori infection. In depth studies are needed to evaluate whether eradication of H pylori infection will really diminish the risk of gastric cancer.
PMCID: PMC4250585  PMID: 15682469
Helicobacter pylori; Glandular atrophy; Intestinal metaplasia; Early gastric cancer
17.  Role of mucin Lewis status in resistance to Helicobacter pylori infection in pediatric patients 
Helicobacter  2010;15(4):251-258.
Helicobacter pylori causes gastritis, peptic ulcer and is a risk factor for adenocarcinoma and lymphoma of the stomach. Gastric mucins, carrying highly diverse carbohydrate structures, present functional binding sites for H. pylori and may play a role in pathogenesis. However, little information is available regarding gastric mucin in children with and without stomach diseases.
Material & Methods
Expression of mucins and glycosylation was studied by immunohistochemistry on gastric biopsies from 51 children with and without H. pylori infection and/or peptic ulcer disease.
In all children, MUC5AC was present in the surface epithelium and MUC6 in the glands. No MUC6 in the surface epithelium or MUC2 was detected in any section. The Leb and Lea blood-group antigens were present in the surface epithelium of 80% and 29% of children respectively. H. pylori load was higher in Leb negative children than in Leb positive individuals (means ± SEM 17.8±3.5 vs 10.8±1.5; p < 0.05), but there was no correlation between Lea or Leb status and gastritis, nodularity, and gastric or duodenal ulcer. Expression of sialyl-Lex was associated with H. pylori infection, and DU.
Mucin expression and glycosylation is similar in children and adults. However, in contrast to adults, pediatric H. pylori infection is not accompanied by aberrant expression of MUC6 or MUC2. Furthermore, the lower H. pylori density in Leb positive children indicates that H. pylori is suppressed in the presence of gastric mucins decorated with Leb, the binding site of the H. pylori BabA adhesin.
PMCID: PMC3209514  PMID: 20633185
Gastric Mucosa; Mucins; Helicobacter pylori; Carbohydrate Antigens; Pediatric; gastritis; peptic ulcer
18.  Expression of human β-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: antibacterial effect of hBD-2 against Helicobacter pylori 
Gut  2001;49(4):481-487.
BACKGROUND—Human β-defensin 2 (hBD-2) plays a role in the innate defence system at mucosal surfaces. Colonisation of Helicobacter pylori in the stomach is an important pathological factor in gastrointestinal illnesses, including gastritis, peptic ulcer, and gastric adenocarcinoma.
AIMS—To evaluate the antibacterial role of hBD-2 against H pylori infection in the gastric mucosa.
SUBJECTS—Biopsied gastric mucosa specimens from H pylori positive (n=6) and H pylori negative (n=6) individuals were used. H pylori was determined by the presence of urease activity and microscopic examination.
METHODS—The specimens were examined for hBD-2 expression by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and in situ hybridisation. The antibacterial effect of hBD-2 against H pylori was evaluated by the number of colony forming units of H pylori after incubation with 0, 10−9, 10−8, 10−7, 10−6, or 10−5 M of hBD-2 peptide.
RESULTS—All six H pylori positive specimens expressed a high level of hBD-2 mRNA while hBD-2 mRNA was not detected in the H pylori negative specimens by RT-PCR. Immunohistochemistry using anti-hBD-2 antiserum revealed that hBD-2 was expressed in the surface epithelium of H pylori infected specimens. In gastric specimens obtained after H pylori eradication, hBD-2 immunoreactivity had dramatically decreased. In situ hybridisation confirmed that hBD-2 transcripts were localised in the epithelium of H pylori infected gastric specimens. Incubation with hBD-2 reduced the growth rate of cultured H pylori in a dose dependent manner, and incubation with 10−5 M hBD-2 completely inhibited the proliferation of H pylori.
CONCLUSIONS—H pylori infection induces hBD-2 expression in the human gastric epithelium. hBD-2 inhibited the growth of H pylori in vitro, suggesting that hBD-2 plays an antibacterial role in H pylori induced gastritis.

Keywords: human β-defensin 2; Helicobacter pylori; gastritis; antimicrobial peptide
PMCID: PMC1728463  PMID: 11559643
19.  CCL28 Is Increased in Human Helicobacter pylori-Induced Gastritis and Mediates Recruitment of Gastric Immunoglobulin A-Secreting Cells▿  
Infection and Immunity  2008;76(7):3304-3311.
Human Helicobacter pylori infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only H. pylori-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosa-associated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in H. pylori-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from H. pylori-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA+ memory B cells from H. pylori-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from H. pylori-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1α). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in H. pylori-infected individuals.
PMCID: PMC2446710  PMID: 18426876
20.  Effect of Helicobacter pylori Eradication According to the IL-8-251 Polymorphism in Koreans 
Journal of Korean Medical Science  2012;27(10):1202-1207.
Previous studies suggested that polymorphisms of proinflammatory cytokine genes are important host genetic factors in Helicobacter pylori infection. The present study evaluated whether IL-8-251 polymorphism affected H. pylori eradication rate and to investigate the effect of H. pylori eradication on angiogenesis and the inflammatory process according to the IL-8-251 polymorphism. A total of 250 H. pylori-positive patients treated by endoscopic resection of the gastric neoplasm were classified into 3 groups (134 H. pylori-eradicated group, 19 H. pylori-eradication failure group, and 97 H. pylori-infected group). H. pylori status, histology, and angiogenic factor levels were evaluated at baseline, 6 months, and 18 months. H. pylori eradication rate was 92.9% in AA genotype, 85.7% in AT genotype and 88.4% in TT genotype (P value = 0.731). Elevated IL-8 and matrix metalloproteinase-9 concentrations in H. pylori-infected gastric mucosa were reversible by successful eradication of H. pylori, independent of the IL-8-251 polymorphism. It is suggested that elevated IL-8 and MMP-9 concentrations in H. pylori-infected gastric mucosa are altered significantly after successful eradication and these conditions continue for 18 months. However, IL-8-251 polymorphism does not affect H. pylori eradication rate and the sequential changes of related angiogenic factors after H. pylori eradication in Koreans.
PMCID: PMC3468757  PMID: 23091318
Helicobacter pylori; Interleukin-8; Polymorphism
21.  Novel action of gastric proton pump inhibitor on suppression of Helicobacter pylori induced angiogenesis 
Gut  2006;55(1):26-33.
Although activation of mitogen activated protein kinases (MAPKs) by Helicobacter pylori infection is associated with induction of host angiogenesis, which may contribute to H pylori associated gastric carcinogenesis, the strategy for its prevention has not been identified. As we previously reported a strong inhibitory action of gastric proton pump inhibitors (PPIs) on MAPK extracellular signal regulated kinase (ERK)1/2 phosphorylation, we investigated whether PPIs could suppress the H pylori induced angiogenesis via inhibition of MAPK ERK1/2.
To address the relationship between H pylori infection and angiogenesis, comparative analysis of density of CD34+ blood vessel was performed in tissues obtained from 20 H pylori positive gastritis and 18 H pylori negative gastritis patients. Expression of hypoxia inducible factor 1 (HIF‐1α) and vascular endothelial growth factor (VEGF) was tested by reverse transcription‐polymerase chain reaction and secretion of interleukin 8, and VEGF was measured by ELISA. To evaluate the direct effect of H pylori infection on the tubular formation of human umbilical vein endothelial cells (HUVEC), an in vitro angiogenesis assay was employed. Activation of MAPK and nuclear factor κB (NFκB) was detected by immunoblotting.
H pylori positive gastritis patients showed a higher density of CD34+ blood vessels (mean 40.9 (SEM 4.4)) than H pylori negative gastritis patients (7.2±0.8), which was well correlated with expression of HIF‐1α. Conditioned media from H pylori infected gastric epithelial cells directly induced tubular formation of HUVEC and the increase of in vitro angiogenesis was suppressed by PPI treatment. Infection of H pylori significantly upregulated expression of HIF‐1α and VEGF in gastric epithelial cells and expression of proangiogenic factors was mediated by MAPK activation and partially responsible for NFκB activation. PPIs effectively inhibited the phosphorylation of MAPK ERK1/2 that is a principal signal for H pylori induced angiogenesis.
The fact that PPIs could downregulate H pylori induced angiogenesis indicates that antiangiogenic treatment using a PPI could be a promising protective therapeutic approach for H pylori associated carcinogenesis.
PMCID: PMC1856363  PMID: 16127019
H+/K+‐ATPase; proton pump inhibitor;  Helicobacter pylori ; angiogenesis; MAPK ERK1/2
22.  Evaluation of the Association of Nine Helicobacter pylori Virulence Factors with Strains Involved in Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma  
Infection and Immunity  2004;72(2):880-888.
Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ “off” status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.
PMCID: PMC321584  PMID: 14742532
23.  Suppressed Gastric Mucosal TGF-β1 Increases Susceptibility to H. pylori-Induced Gastric Inflammation and Ulceration: A Stupid Host Defense Response 
Gut and Liver  2010;4(1):43-53.
Loss of transforming growth factor β1 (TGF-β1) exhibits a similar pathology to that seen in a subset of individuals infected with Helicobacter pylori, including propagated gastric inflammation, oxidative stress, and autoimmune features. We thus hypothesized that gastric mucosal TGF-β1 levels could be used to determine the outcome after H. pylori infection.
Northern blot for the TGF-β1 transcript, staining of TGF-β1 expression, luciferase reporter assay, and enzyme-linked immunosorbent assay for TGF-β1 levels were performed at different times after H. pylori infection.
The TGF-β1 level was markedly lower in patients with H. pylori-induced gastritis than in patients with a similar degree of gastritis induced by nonsteroidal anti-inflammatory drugs. There was a significant negative correlation between the severity of inflammation and gastric mucosal TGF-β1 levels. SNU-16 cells showing intact TGF-β signaling exhibited a marked decrease in TGF-β1 expression, whereas SNU-638 cells defective in TGF-β signaling exhibited no such decrease after H. pylori infection. The decreased expressions of TGF-β1 in SNU-16 cells recovered to normal after 24 hr of H. pylori infection, but lasted very spatial times, suggesting that attenuated expression of TGF-β1 is a host defense mechanism to avoid attachment of H. pylori.
H. pylori infection was associated with depressed gastric mucosal TGF-β1 for up to 24 hr, but this apparent strategy for rescuing cells from H. pylori attachment exacerbated the gastric inflammation.
PMCID: PMC2871604  PMID: 20479912
Helicobacter pylori; TGF-β; Inflammation; Ulcer; Host defense
24.  Concurrent Helicobacter bilis Infection in C57BL/6 Mice Attenuates Proinflammatory H. pylori-Induced Gastric Pathology▿  
Infection and Immunity  2009;77(5):2147-2158.
Because coinfections can alter helicobacter gastritis, we investigated whether enterohepatic Helicobacter bilis modulates Helicobacter pylori gastritis in C57BL/6 mice. Thirty mice per group were sham dosed, H. bilis or H. pylori infected, or H. bilis infected followed in 2 weeks by H. pylori and then evaluated at 6 and 11 months postinfection (mpi) for gastritis and premalignant lesions. Compared to H. pylori-infected mice, H. bilis/H. pylori-infected mice at 6 and 11 mpi had less severe gastritis, atrophy, mucous metaplasia and hyperplasia (P < 0.01) and, additionally, at 11 mpi, less severe intestinal metaplasia and dysplasia (P < 0.05). H. bilis/H. pylori-infected mice at 11 mpi exhibited less Ki67 labeling of proliferating epithelial cells, reduced numbers of FoxP3+ T-regulatory (TREG) cells, and lower FoxP3+ mRNA levels than did H. pylori-infected mice (P < 0.05). Proinflammatory interleukin-1β (IL-1β), gamma interferon, and tumor necrosis factor alpha mRNA levels were attenuated in H. bilis/H. pylori-infected mice at 6 and 11 mpi (P < 0.01), although anti-inflammatory IL-10, IL-13, and transforming growth factor β1 mRNA levels were not consistently impacted by H. bilis coinfection. Decreased pathology in H. bilis/H. pylori-infected mice correlated with higher gastric H. pylori colonization at 6 mpi (P < 0.001) and lower Th1-associated immunoglobulin G2c responses to H. pylori at 6 and 10 mpi (P < 0.05). We hypothesized that reduced pathology in H. bilis/H. pylori-infected mice was due to H. bilis-primed TREG cells in the lower bowel that migrated to the gastric compartment and inhibited Th1 responses to subsequent H. pylori infection. Thus, H. pylori-induced gastric lesions may vary in mouse models of unknown enteric helicobacter infection status and, importantly, variable sequelae to human H. pylori infection, particularly in developing countries, may occur where coinfection with lower bowel helicobacters and H. pylori may be common.
PMCID: PMC2681733  PMID: 19223483
25.  Levels of Interleukin-18 Are Markedly Increased in Helicobacter pylori–Infected Gastric Mucosa among Patients with Specific IL18 Genotypes 
The Journal of infectious diseases  2008;197(12):1752-1761.
The cellular immune response in gastric mucosa infected with Helicobacter pylori is proposed to be predominantly of the T helper cell type 1 type.
Interleukin (IL)–18, IL-12, and interferon (IFN)–γ levels were measured in gastric mucosal biopsy specimens by reverse-transcription polymerase chain reaction (PCR) and by enzyme-linked immunosorbent assay; IL18 polymorphisms were determined by PCR.
Biopsy specimens from 128 patients (56 with nonulcer dyspepsia, 28 with gastric ulcers, 28 with duodenal ulcers, and 16 with gastric cancer) were examined; 96 patients had H. pylori infection. IL-18 levels were markedly up-regulated in mucosa infected with H. pylori (P < .001), whereas IL-12 and IFN-γ levels were independent of H. pylori status. IL-18 levels correlated with IFN-γ levels only in infected patients (R = 0.31 to R = 0.51). IL-18 levels were the determining factor for monocyte infiltration in H. pylori–infected mucosa (P < .001). H. pylori–infected patients displaying IL18 –607C/C and –137G/G had higher IL-18 levels than did those with other genotypes and were more likely to experience treatment failure.
H. pylori infection induces IL-18 in the gastric mucosa. H. pylori–infected patients with IL18 –607C/C and –137G/G have higher IL-18 levels, which causes severe gastric inflammation. IL18 genotype might be a marker for predicting the effects of eradication therapy.
PMCID: PMC2833342  PMID: 18442334

Results 1-25 (1045991)