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World J Gastroenterol. 2010 October 7; 16(37): 4738–4746.
Published online 2010 October 7. doi:  10.3748/wjg.v16.i37.4738
PMCID: PMC2951527

Mn-SOD and CuZn-SOD polymorphisms and interactions with risk factors in gastric cancer

Abstract

AIM: To investigate the effects of superoxide dismutase (SOD) polymorphisms (rs4998557, rs4880), Helicobacter pylori (H. pylori) infection and environmental factors in gastric cancer (GC) and malignant potential of gastric precancerous lesions (GPL).

METHODS: Copper-zinc superoxide dismutase (SOD1, CuZn-SOD)-G7958A (rs4998557) and manganese superoxide dismutase (SOD2, Mn-SOD)-Val16Ala (rs4880) polymorphisms were genotyped by SNaPshot multiplex polymerase chain reaction (PCR) in 145 patients with GPL (87 cases of gastric ulcer, 33 cases of gastric polyps and 25 cases of atrophic gastritis), 140 patients with GC and 147 healthy controls. H. pylori infection was detected by immunoblotting analysis.

RESULTS: The SOD1-7958A allele was associated with a higher risk of gastric cancer [odds ratio (OR) = 3.01, 95% confidence intervals (95% CI): 1.83-4.95]. SOD2-16Ala/Val genotype was a risk factor for malignant potential of GPL (OR = 2.04, 95% CI: 1.19-3.49). SOD2-16Ala/- genotype increased the risk of gastric cancer (OR = 2.85, 95% CI: 1.66-4.89). SOD1-7958A/- genotype, SOD2-16Ala/- genotype, alcohol drinking, positive family history and type I H. pylori infection were associated with risk of gastric cancer, and there were additive interactions between the two genotypes and the other three risk factors. SOD2-16Ala/Val genotype and positive family history were associated with malignant potential of GPL and jointly contributed to a higher risk for malignant potential of GPL (OR = 7.71, 95% CI: 2.10-28.22). SOD1-7958A/- genotype and SOD2-16Ala/- genotype jointly contributed to a higher risk for gastric cancer (OR = 6.43, 95% CI: 3.20-12.91).

CONCLUSION: SOD1-7958A/- and SOD2-16Ala/-genotypes increase the risk of gastric cancer in Chinese Han population. SOD2-16Ala/-genotype is associated with malignant potential of GPL.

Keywords: Copper-zinc superoxide dismutase, Manganese superoxide dismutase, Gastric cancer, Gastric precancerous lesions, Gene polymorphisms, Interaction

INTRODUCTION

Gastric cancer (GC) is the second most common malignancy worldwide and 42% of the cases occur in China[1]. Gastric carcinogenesis is a complex multi-factor and multi-step process involving various environmental carcinogens, Helicobacter pylori (H. pylori) infection and genetic variants. The involvement of reactive oxygen species (ROS) in the pathogenesis of gastric malignancies is well known[2,3]. ROS are molecules or ions formed by the incomplete one-electron reduction of oxygen, including singlet oxygen, superoxides, peroxides, hydroxyl radical, and hypochlorous acid, which contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, induce oxidative damage to nucleic acids, proteins and lipids, and affect membrane fluidity by altering the amounts of unsaturated fatty acids and proteins in the cell membrane[4]. ROS participates simultaneously in Ras-Raf-MEK1/2-ERK1/2 and the p38 mitogen-activated protein kinases (MAPK) signaling pathway that have inverse functions in tumorigenesis[4]. In addition, with aging, humans tend to have an increased affectability of lipid peroxides caused by ROS[5]. A recent research has indicated that ROS also plays a critical role in the energy dysfunction of mitochondria caused by ethanol induced gastric mucosal injury[6].

Superoxide dismutase (SOD) is a major antioxidant enzyme, which plays a vital role in clearance of ROS. Among the isoforms of SOD, copper-zinc superoxide dismutase (SOD1, CuZn-SOD) with copper (Cu) and zinc (Zn) in its catalytic center is localized in the intracellular cytoplasmic compartments, and manganese superoxide dismutase (SOD2, Mn-SOD) plays an important role as a primary mitochondria antioxidant enzyme[7]. In addition, many researches have shown that the activity and expression of SOD changed significantly in gastric cancer patients[2,8,9], which can either promote or suppress tumor formation in human gastric mucosa[10].

In recent years, host genetic factors are emerging as determinants of increasing risk for many cancers including GC[11,12]. Therefore, SOD genes are good candidates to evaluate the genetic susceptibility to gastric cancer. The gene polymorphism SOD2-Val16Ala (rs4880) has been evaluated widely for its association with various cancers including GC[13-18]. Moreover, Val16Ala significantly reduced SOD2 catalytic activity in hepatocytes[19]. However, there have been few studies on the correlations between SOD1 polymorphisms and cancer, and SOD1 polymorphisms have not been evaluated for its association with risk of gastric cancer.

Epidemiologic evidence has shown that gastric cancer is associated with H. pylori colonization[1,20]. H. pylori, which infects 50% of the world’s population, is a major factor in both the induction of atrophic gastritis and histological progression to gastric cancer. Bacterial virulence factors such as cytotoxin-associated protein (CagA), vacuolating cytotoxin (VacA), and others have been associated with higher risks for gastric cancer development[21,22]. H. pylori vacuolating cytotoxin VacA can induce cellular vacuolation in epithelial cells and efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest[23], and CagA protein can promote signal transduction of oncogene and cell division[24]. H. pylori is also associated with ROS and SOD. It has been shown that H. pylori induced the production of intracellular ROS in gastric cells[25], resulting in changes in the activity and content of SOD[26,27]. H. pylori infection can also cause DNA oxidative damage by its main virulence CagA and VacA, which further implied the role of bacteria in tumorogenesis[28,29].

Gastric cancer is a multifactorial disease. Besides genetic susceptibility and H. pylori infection, gastric cancer is also associated with dietary and environmental factors[30]. It has been indicated that long-term massive alcoholic consumption could induce gastric mucosal injury such as hyperemia, edema and erosion, and promote bacterial multiplication and the synthesis of carcinogenic nitrosamines[31]. Smoking has also been found as a risk factor of gastric cancer[32]. In this study, we investigated the association between gastric cancer and the polymorphisms of SOD1-G7958A (rs4998557) and SOD2-Val16Ala (rs4880), and evaluated the relationship between gastric cancer and the epidemiological factors including age, sex, smoking, alcohol drinking, family history of gastric cancer and different types of H. pylori infection.

MATERIALS AND METHODS

Study population

From June 2007 to June 2009, 145 patients with gastric precancerous lesions (GPL) (87 cases of gastric ulcer, 33 cases of gastric polypus and 25 cases of atrophic gastritis), 140 patients with gastric cancer and 147 healthy controls were recruited from 3A grade hospitals in Hexi Region, Gansu Province of China. The recruiting criteria of cases include newly diagnosed, histopathologically confirmed and previously untreated patients in the oncology, gastroenterology and general surgery departments. Healthy controls were composed of 147 individuals who visited the outpatient department for physical examination, without tumors and gastrointestinal diseases. Subjects were informed of the detailed study protocol, and signed consent forms, and the study was approved by local ethics committees. A questionnaire given to each patient collected information on (1) demographic factors, such as age and sex; (2) smoking (at least one cigarette per day for 6 mo or longer) and alcohol drinking history (at least twice a week for 6 mo or longer and at least 100 g each time); and (3) family history of gastric cancer (first-degree relatives with gastric cancer including parents, brothers and sisters). Each subject was donated 3 mL peripheral vein blood in EDTA-K2 anticoagulative tube for DNA extraction and 2 mL serum for H. pylori infection test, and all specimens were kept frozen at -80°C.

Extraction of genomic DNA

Genomic DNA was extracted from the whole blood using Blood Genome DNA Extraction Kit (TaKaRa Bio, Dalian, China) according to the manufacturer’s instructions. Concentration and purity of DNA were determined by SP-721 spectrophotometer (Eppendorf, Hamburg, Geman) at A260 nm and A280 nm. Integrity of DNA was confirmed by 1% agarose electrophoresis. The DNA samples were diluted to 5-10 ng/μL for genotyping. DNA was stored at -80°C until use.

Detection of H. pylori infection

Presence and type of H. pylori infection were tested with H. pylori antibody Immunoblotting Kit (Blot Biotech, Shenzhen, China) following the manufacturer’s instructions. Type I H. pylori infection was defined when either CagA or VacA was positive, or both were positive. Type II H. pylori infection was defined if ureases (UreA/UreB) were positive. Patients were defined as H. pylori negative if CagA, VacA and ureases were negative.

Genotyping of SOD polymorphisms

SOD1 G7958A and SOD2 Val16Ala (T201C) polymorphisms were determined by multiplex SNaPshot technology. PCR and single-base extension primers were designed using Primer3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi) (Table (Table1).1). Multiplex PCR was performed in a 20 μL reaction mixture containing 2 μL 10 × Buffer I, 1 U HotStarTaq polymerase (Qiagen, Dusseldorf, Geman), 0.3 mM dNTP, 3.0 mM MgCl2 (Qiagen), 2 μL each PCR primer, and 5 ng template DNA in a thermal cycler (Applied Biosystems, Foster City, USA). PCR conditions were 95°C for 15 min denaturation; 11 cycles at 94°C for 20 s, 65-0.5°C /cycle for 40 s, and 72°C for 100 s; 24 cycles at 94°C for 20 s, 59°C for 30 s, 72°C for 1.5 min; and 72°C for 2 min. PCR product was stored at 4°C. One U SAP (Promega, Madison, USA) and 1 U Exonuclease I (Epicentre, San Diego, USA) were added into 10 μL PCR product for purification at 37°C for 60 min, and 75°C for 15 min. SNaPshot analysis was performed in a volume of 10 μL containing 5 μL SNaPshot Multiplex Kit (Applied Biosystems), 2 μL multiplex PCR product, 1 μL single-base extension primer mix and 2 μL ddH2O. Extension reactions were performed in a thermal cycler (Applied Biosystems) at 96°C for 1min; 28 cycles at 96°C for 10 s, 50°C for 5 s, 60 °C for 30 s; and 60°C for 1 min. Extension product was stored at 4°C. One U SAP (Promega) was added into 2 μL extension product for purification at 37°C for 60 min, and 75°C for 15 min. Single-base extension products after purification were mixed with deionized formamide containing GeneScan 120 LIZ Size Standard, denatured at 95°C for 5 min and analyzed on an ABI Prism 3130XL genetic analyzer using GeneMapper 4.0 (Applied Biosystems).

Table 1
Primers used for genotyping

For quality control, positive and negative controls and blinded duplicate samples were run. Alternative genotyping approaches were used as required to verify technical reliability and accuracy. Blinded repeat samples were run in 10% of the samples. A second scientist checked all laboratory interpretations independently.

Statistical analysis

Statistical analysis was performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA). Differences of measurement data and numeration data were assessed by single factor analysis of variance and Pearson χ2 test, respectively. Goodness-of-fit χ2 test was used to verify whether the distribution of SOD genotypes was in accordance with Hardy-Weinberg equilibrium. Non-conditional logistic regression analysis was performed to analyze the association of risk factors and genotypes of SOD with gastric cancer. According to the interaction model proposed by Khoury et al[33] and Ottman et al[34], we set up dummy variables in accordance with different genes-environmental exposure and analyzed genes-environment interaction in gastric cancer development by logistic regression. We determined the presence or absence of interactions by interaction coefficients (γ, γ = βeg/βe) (β, regressive coefficient; βeg, regressive coefficient when genetic and environmental factors coexist; βe, regressive coefficient when environmental factors exist alone) and judged the types of interaction by quantitative relationship of OReg (OR, odds ratio; OReg, OR when genetic and environmental factors coexist), ORe (ORe, OR when environmental factors exist alone) and ORg (ORg, OR when genes exist alone)[35-37]. Age and sex corrected odds ratios (ORs) with corresponding 95% confidence intervals (95% CI) and regressive coefficient (β) were calculated by logistic regression analysis. A P value of less than 0.05 was considered statistically significant.

RESULTS

Subject characteristics and analysis of risk factors for GC and malignant potential of GPL

The demographic characteristics and frequency distributions of smokers, alcohol drinkers and different types of H. pylori are shown in Table Table2.2. There was no statistically significant difference among the three groups in terms of age, sex and smoking histories (P > 0.05). Alcohol drinking, positive family history and type I H. pylori infection were associated with an increased risk for GC development (OR = 3.29, 95% CI: 2.03-5.34; OR = 4.66, 95% CI: 2.33-9.32; OR = 4.86, 95% CI: 2.83-8.35, respectively). A positive family history was associated with an increased risk for malignant potential of GPL (OR = 1.99, 95% CI: 1.13-3.49).

Table 2
Demographic characteristics and risk factors for gastric cancer and malignant potential of gastric precancerous lesion

Distribution of SOD1 and SOD2 polymorphisms

All genotypes in the healthy controls were in Hardy-Weinberg equilibrium (P > 0.05). The frequencies of AG and AA genotypes in SOD1 were significantly higher in patients with GC than in healthy controls (P < 0.05), and the risk of gastric cancer in carriers with SOD1 A/- genotype was 3.01 folds higher (95% CI: 1.83-4.95) than in carriers with GG genotype. The frequencies of Val/Ala and Ala/Ala genotypes in SOD2 were significantly higher in patients with GC than in healthy controls (P < 0.05), and the risk of gastric cancer in carriers with SOD2 Ala/- genotype was 2.85 folds higher (95% CI: 1.66-4.89) than in carriers with Val/Val genotype. The malignant potential of GPL in carriers with SOD2 16Ala/Val and 16Ala/- genotypes was 2.04 folds (95% CI: 1.19-3.49) and 2.19 folds (95% CI: 1.30-3.68) higher than in those with Val/Val genotype, respectively (Table (Table33).

Table 3
Distribution of SOD1 G7958A and SOD2 Val16Ala polymorphisms

Interaction of SOD2 Val16Ala and positive family history for malignant potential of GPL

A positive family history combined with SOD2 Ala/- genotype resulted in an increased risk for malignant potential of GPL (OR = 7.71, 95% CI: 2.10-28.22) (Table (Table4).4). The interaction coefficients (γ) was 2.96. SOD2 Ala/- genotype could generate the amplification effect on a positive family history, and the interaction accorded with the super-multiplication model.

Table 4
Interaction of family history and SOD2 Val16Ala for malignant potential of gastric precancerous lesion

Interaction of SOD1 G7958A and environmental factors for gastric cancer development

Interaction 1: Alcohol drinking coexisted with SOD1 A/- genotype resulted in an increased risk for gastric cancer development (OR = 16.50, 95% CI: 6.67-40.86). The γ value was 1.20. SOD1 A/- genotype could generate the amplification effect on alcohol drinking.

Interaction 2: A positive family history coexisted with SOD1 A/- genotype resulted in an increased risk for gastric cancer development (OR = 15.56, 95% CI: 5.57-43.50). The γ value was 1.35. SOD1 A/- genotype could generate the amplification effect on a positive family history.

Interaction 3: Type I H. pylori infection coexisted with SOD1 A/- genotype resulted in an increased risk for gastric cancer development (OR = 10.71, 95% CI: 4.92-23.33). The γ value was 1.27. SOD1 A/- genotype could generate the amplification effect on type I H. pylori infection. All the interactions accorded with the additive model (Table (Table55).

Table 5
Interaction of SOD1 G7958A and environmental factors for gastric cancer development

Interaction of SOD2 Val16Ala and environmental factors for gastric cancer development

Interaction 1: Alcohol drinking coexisted with SOD2 Ala/- genotype resulted in an increased risk for gastric cancer (OR = 9.46, 95% CI: 4.08-21.94). The γ value was 1.36. SOD2 Ala/- genotype could generate the amplification effect on alcohol drinking.

Interaction 2: A positive family history coexisted with SOD2 Ala/- genotype resulted in an increased risk for gastric cancer (OR = 12.86, 95% CI: 3.36-49.25). The γ value was 1.38. SOD2 Ala/- genotype could generate the amplification effect on a positive family history.

Interaction 3: Type I H. pylori infection coexisted with SOD1 A/- genotype SOD2 Ala/- genotype resulted in an increased risk for gastric cancer (OR, 9.07, 95% CI: 4.36-18.86). The γ value was 1.53. SOD1 A/- genotype could generate the amplification effect on type I H. pylori infection. All these interactions accorded with the additive model (Table (Table66).

Table 6
Interaction of SOD2 Val16Ala and environmental factors for gastric cancer development

Gene-gene interaction for gastric cancer development

The combination of SOD1 A/- genotype and SOD2 Ala/- genotype resulted in an increased risk for gastric cancer (OR = 6.43, 95% CI: 3.20-12.91). The interaction accorded with the additive model (Table (Table77).

Table 7
Interaction of SOD1 G7958A and SOD2 Val16Ala for gastric cancer development

DISCUSSION

Reactive oxygen species (ROS) can damage DNA in the form of mutations, deletions, gene amplification and rearrangements, which may cause programmed cell death, or activation of several proto-oncogenes and/or inactivation of some tumor suppressor genes[16]. SOD, as a major antioxidant enzyme, plays a vital role in clearance of ROS. Previous studies have shown that the expression and activity of SOD played a role in the promotion or suppression of tumor formation in human gastric mucosa[10], and SOD2-Val16Ala polymorphism has been evaluated widely for its association with various cancers including gastric cancer[13-18].

In our study, we found that SOD2-Val16Ala polymorphism was associated with gastric cancer susceptibility and malignant potential of GPL. SOD2-Ala/- genotype carriers had a nearly 3-fold and 2-fold increased risk for developing gastric cancer and malignant potential of GPL compared with Val/Val genotype carriers. The results were in agreement with other studies on tumors such as adult brain tumors[38], prostate cancer[7], breast cancer[39], lung cancer[40] and pancreatic cancer[41]. Contrary to our results, the polymorphism of SOD2-Val16Ala was not found to be associated with gastric cancer in a Polish case-control study[18]. It implies that the distribution of polymorphism varies among different regions and races. However, a further study with a larger sample size and geographic range is needed.

SOD1 polymorphisms have been rarely evaluated for its association with risk of cancer occurrence. They were not found to be associated with the risk of breast cancer[16] and prostate cancer[7]. We found for the first time that the SOD1-7958A/- genotype was a risk factor for gastric cancer development. Subjects carrying 7958A/- genotype had a 3-fold increased risk for developing gastric cancer compared with carriers with G/G genotype, but no association was found between the 7958A/- genotype and malignant potential of GPL. SOD1-G7958A polymorphism could be a susceptible biomarker for gastric cancer. Our results may provide a new target for gene-targeted therapy of gastric cancer.

Gastric carcinogenesis is a complex multi-factor and multi-step process involving interactions of various environmental carcinogens, bacterial and genetic variants. To our knowledge, there has been no study on the interactions between SOD1 and SOD2 polymorphisms and environmental factors, and gene-gene interactions of SOD1 and SOD2 in gastric cancer. In our study, we found that carriers with a positive family history of gastric cancer had a 2-fold increased risk for malignant potential of GPL. The combination of a positive family history and SOD2-16Ala/- genotype contributed to a higher risk for malignant potential of GPL. Meanwhile, we also found that alcohol drinking, a positive family history and type I H. pylori infection were significantly associated with gastric cancer, and there were additive interactions with SOD1-7958A/- genotype and SOD2-16Ala/- genotype for gastric carcinogenesis. H. pylori infection could result in changes in the activity and content of SOD[26,27] and DNA oxidative damage by its main virulence CagA and VacA[28,29]. Therefore, the interaction of H. pylori infection and the polymorphisms of SOD1 and SOD2 exists theoretically. Our results suggested that gastric carcinogenesis resulted from combined action of gene and environment but not the unitary effect of gene or environment. Similar to our previous researches, we found that CagA+ H. pylori infection was a definite risk factor for gastric cancer and that CagA+ H. pylori infection combined with 762Ala/Ala genotype in PARP-1 contributed to a higher risk for gastric cancer[42]. Therefore, the interaction of gene-environment has played a role in the gastric carcinogenesis. We also found that there was an interaction between SOD1-7958A/- genotype and SOD2-16Ala/- genotype in gastric carcinogenesis, which had a 6-fold increased risk for gastric cancer development. This discovery has practical implications for gene therapy, and confirms the importance of gene-gene interaction in targeted therapy for cancer.

In summary, gastric carcinogenesis involves a variety of factors including genetic factors, environmental factors and gene-environment and gene-gene interactions. SOD1-7958A/- genotype, SOD2-16Ala/- genotype, alcohol drinking, a positive family history of gastric cancer, and type I H. pylori infection could be risk factors for gastric cancer in Chinese Han population, and there were positive gene-gene and gene-environment interactions. The effects of the interactions contributed to a higher risk for gastric cancer. Therefore, control of alcohol drinking and eradication of H. pylori infection may help lower the incidence of gastric cancer to a certain extent.

Because the sample size and risk factors investigated were limited in our study, and the genetic and environmental factors involved in carcinogenesis are numerous and complex, our conclusion remains to be further confirmed by studies of larger sample size on more risk factors among different races and regions so as to determine whether the SOD1-G7958A and SOD2-Val16Ala polymorphisms would be a susceptible biomarker for gastric cancer, and to evaluate whether there are interactions between gene and environment. In addition, Ala variant of SOD2 significantly reduced SOD2 catalytic activity in hepatocytes[19] and allows more efficient SOD2 to import into the mitochondrial matrix and generates more active SOD2 compared with the Val variant[43]. Thus, the Ala variant of SOD2 may increase the risk of gastric cancer by altering the activity or content of SOD2 to lower the ability of scavenging ROS. However, the carcinogenic mechanism of SOD1-7958A/- variant in gastric cancer is still unclear. As SOD1-G7958A is located in intron 1 of SOD1 gene, we imagine that the 7958A/- variant may cause gastric carcinogenesis by regulating the expression and alternative splicing of SOD1. This hypothesis remains to be further elucidated by detecting the expression levels of SOD1 and function analysis.

COMMENTS

Background

Gastric cancer (GC) is the second most common malignancy worldwide. Epidemiological evidences show that gastric carcinogenesis results from gene-environmental interactions. Superoxide dismutases (SOD) are major antioxidant enzymes, which play vital roles in clearance of reactive oxygen species (ROS) in vivo and can either promote or suppress tumor formation in human gastric mucosa. There have been few studies on the relationship between gene polymorphisms of SOD and GC in Chinese Han population and interactions between SOD polymorphisms and environmental factors in GC.

Research frontiers

In this study, the authors investigated the associations between gene polymorphisms of SOD and GC, evaluated the relationship between GC and the epidemiological factors including age, sex, smoking, alcohol drinking, family history of gastric cancer and different types of H. pylori infection, and analyzed gene-environmental and gene-gene interactions according to the interaction model.

Innovations and breakthroughs

This study showed that copper-zinc superoxide dismutase (SOD1)-7958A/- genotype and manganese superoxide dismutase (SOD2, Mn-SOD)-16Ala/- genotype, alcohol drinking, a positive family history of gastric cancer, and type I H. pylori infection were correlated with increased risk of GC in Chinese Han population. The gene-gene and gene-environment interactions contributed to a higher risk for GC.

Applications

This study showed that gene-environmental interactions play a great role in the gastric carcinogenesis, and control of alcohol drinking and eradication of H. pylori infection may contribute to a decreased incidence of GC to a certain extent.

Terminology

SODs are major antioxidant enzymes, which play vital roles in clearance of ROS. SOD1 with copper (Cu) and zinc (Zn) in their catalytic center are localized in intracellular cytoplasmic compartments. SOD2 plays an important role as a primary mitochondria antioxidant enzyme. The activity and expression of SOD change significantly in gastric cancer patients, which can either promote or suppress tumor formation in human gastric mucosa.

Peer review

The paper showed that SOD1 2809A/- genotype, SOD2 16Ala/- genotype, alcohol, positive family history and type I H. pylori infection were associated with risk of gastric cancer in Chinese Han population, and there were gene-gene and gene-environment interactions for gastric cancer development. SOD2 Ala/- genotype and a positive family history were risk factors for malignant potential of GPL, and there was a super-multiplication interaction. The described polymorphisms are novel with important scientific merit, but expanding the study with the mentioned aspects may improve the results.

Footnotes

Supported by National Natural Science Foundation of China, No. 30870364

Peer reviewers: Mitsuyoshi Urashima, MD, PhD, MPH, Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan; Ferenc Sipos, MD, PhD, Cell Analysis Laboratory, 2nd Department of Internal Medicine, Semmelweis University, Szentkirályi u. 46., Budapest 1088, Hungary

S- Editor Tian L L- Editor Ma JY E- Editor Ma WH

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