幽门螺杆菌感染与胃癌中p21和p27表达的关系

探讨胃癌中p21~(WAF1)和p27~(KIP1)的表达及其临床意义,并分析幽门螺杆菌(Hp)感染和p21~(WAF1)、p27~(KIP1)表达的关系。采用免疫组化法检测了89例胃癌组织中p21~(WAF1)和p27~(KIP1)表达水平,并采用快速尿素酶试验和组织病理学检测两种方法检查这些胃癌病例的Hp感染情况。实验结果显示,胃癌组织p21~(WAF1)的表达水平在不同病例组织中有所差异。结合临床病理学指数分析显示,降低的p21~(WAF1)表达与较深的肿瘤侵袭密切相关(P<0.05)。免疫组织化学结果显示,p27~(KIP1)无论在细胞浆中还是细胞核内都有表达,p27~(KIP1)核表达水平与胃癌的组织病理学分型密切相关(P<0.05)。此外,还发现Hp阳性病例的p27~(KIP1)阳性表达率明显低于Hp阴性者(P<0.05),而p21~(WAF1)表达阳性率在Hp阳性和阴性胃癌病例中无显著差异(P>0.05)。结果提示,胃癌的进展与细胞周期调节蛋白p21~(WAF1)和p27~(KIP1)的表达下调有关,Hp感染的致癌过程中可能有p27~(KIP1)参与。     

幽门螺旋杆菌感染与胃癌中Shh和C-myc表达的关系

为了探讨胃癌中幽门螺旋杆菌(Hp)感染和Sonic Hedgehog(Shh)、C-myc表达,它们之间的相关性以及胃癌发生的可能机制,采用免疫组化法检测89例胃癌组织及20例正常胃上皮组织中Shh及C-myc的表达。并采用快速尿素酶试验,组织病理学检测两种方法检查Hp。实验结果显示,胃癌组织Shh的表达要明显高于正常上皮组织,二者之间有显著差异(P<0.05);胃癌组织C-myc的表达水平也高于正常胃上皮组织,二者之间有显著差异(P<0.05);Hp阳性的C-myc阳性表达率明显高于Hp阴性,二者之间有显著差异(P<0.05);Shh表达阳性率在Hp阳性和阴性胃癌中无显著差异(P>0.05)。结果提示,胃癌的发生与癌基因Shh及C-myc的过度表达有关,Hp感染的致癌机制中可能有癌基因C-myc参与。     

Polymorphisms of the DNA Methyltransferase 1 Associated with Reduced Risks of Helicobacter pylori Infection and Increased Risks of Gastric Atrophy

Introduction

DNA methyltransferase-1(DNMT1) is an important enzyme in determining genomic methylation patterns in mammalian cells. We investigated the associations between SNPs in the DNMT1 gene and risks of developing H. pylori seropositivity, gastric atrophy and gastric cancer in the Chinese population.

Methods

The study consisted of 447 patients with gastric cancer; 111 patients with gastric atrophy; and 961 healthy controls. Five SNPs, rs10420321, rs16999593, rs8101866, rs8111085 and rs2288349 of the DNMT1 gene were genotyped. Anti-H.pylori IgG was detected by ELISA. Gastric atrophy was screened by the level of serum pepsinogen Ιand II and then confirmed by endoscopy and histopatholgical examinations.

Results

The age- and sex-adjusted OR of H. pylori seropositivity was 0.67 (95%CI: 0.51–0.87) for rs8111085 TC/CC genotypes, significantly lower than the TT genotype in healthy controls. The adjusted OR of H.pylori seropositivity was 0.68 (95%CI: 0.52–0.89) for rs10420321 AG/GG genotypes. In addition, patients carrying rs2228349 AA genotype have a significantly increased risk for H.pylori seropositivity (OR = 1.67; 95%CI: 1.02–2.75). Further haplotype analyses also showed that the ATTTG and ATCTA are significantly associated with increased risks in H.pylori infection compared to the GTCCG haplotype (OR = 1.38, 95%CI: 1.08–1.77; OR = 1.40, 95% CI: 1.09–1.80). The adjusted ORs of gastric atrophy were 1.66 (95%CI: 1.06–2.61) for rs10420321 GG genotype, and 1.67 (95%CI 1.06–2.63, P = 0.03) for rs8111085 CC genotype, but no association was found between SNPs in the DNMT1 gene and risk of developing gastric cancer.

Conclusions

Individuals with rs10420321 GG and rs8111085 CC genotype of the DNMT1 gene were associated with reduced risks for H.pylori infection. On the other hand, higher risks of gastric atrophy were found in the carriers with these two genotypes compared to other genotypes. Our results suggested that SNPs of DNMT1 could be used as genotypic markers for predicting genetic susceptibilities to H.pylori infection and risks in gastric atrophy.     

Polymorphisms in Toll-Like Receptor 4 Underlie Susceptibility to Tumor Induction by the Mouse Polyomavirus

PERA/Ei (PE) mice are susceptible to tumor induction by polyomavirus (Py), while C57BR/cdJ (BR) mice are resistant. Antigen-presenting cells from BR mice respond to the virus with interleukin-12 (IL-12) and those from PE mice with IL-10. These polarized cytokine responses underlie the development of effective antitumor immunity in BR mice and the lack thereof in PE mice. An ex vivo cytokine production assay using spleen cells from infected [PE × BR] F2 mice together with a genome-wide SNP (single-nucleotide polymorphism)-based QTL (quantitative trait locus) analysis was used to map the determinant of cytokine production to a region of chromosome 4 carrying the Toll-like receptor 4 (TLR4) gene. Genotyping of infected F2 mice showed concordance of TLR4 allele-specific DNA sequences with the cytokine profile. Cytokine responses elicited by Py are MyD88 dependent. Bacterial lipopolysaccharide (LPS), a known TLR4 ligand, induced the same polarized responses as the virus in these host strains. Spleen cells from C3H/HeJ and C57BL/10ScNJ LPS-nonresponsive mice challenged in vitro with Py showed an impaired IL-12 response but were unaffected in IL-10 production. TLR4s of strains PE and BR differ by 3 amino acid substitutions, 2 in the extracellular domain and 1 in the intracellular domain. cDNAs encoding the TLR4s signaled equally to an NF-κB reporter in 293 cells in a ligand-independent manner. When introduced into TLR2/TLR4 double-knockout macrophages, the TLR4 cDNA from BR mice conferred a robust IL-12 response to Py and no IL-10 response. The TLR4 cDNA from PE mice failed to confer a response with either cytokine. These results establish TLR4 as a key mediator of the cytokine response governing susceptibility to tumor induction by Py.     

Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women

Background

Although behavioral risk factors are strongly associated with urinary tract infection (UTI) risk, the role of genetics in acquiring this disease is poorly understood.

Methodology/Principal Findings

To test the hypothesis that polymorphisms in Toll-like receptor (TLR) pathway genes are associated with susceptibility to UTIs, we conducted a population-based case-control study of women ages 18–49 years. We examined DNA variants in 9 TLR pathway genes in 431 recurrent cystitis (rUTI) cases, 400 pyelonephritis cases, and 430 controls with no history of UTIs. In the Caucasian subgroup of 987 women, polymorphism TLR4_A896G was associated with protection from rUTI, but not pyelonephritis, with an odds ratio (OR) of 0.54 and a 95% confidence interval (CI) of 0.31 to 0.96. Polymorphism TLR5_C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of rUTI (OR(95%CI): 1.81 (1.00–3.08)), but not pyelonephritis. Polymorphism TLR1_G1805T was associated with protection from pyelonephritis (OR(95%CI): 0.53 (0.29–0.96)).

Conclusions

These results provide the first evidence of associations of TLR5 and TLR1 variants with altered risks of acquiring rUTI and pyelonephritis, respectively. Although these data suggest that TLR polymorphisms are associated with adult susceptibility to UTIs, the statistical significance was modest and will require further study including validation with independent cohorts.     

Genetic Variation in MDM2 and p14 ARF and Susceptibility to Salivary Gland Carcinoma

Background

The p14^ARF/MDM2/p53 pathway plays an important role in modulation of DNA damage and oxidative stress responses. The aim of this study was to determine whether genetic variants in MDM2 and p14^ARF are associated with risk of salivary gland carcinoma (SGC).

Methods

Four single nucleotide polymorphisms (SNPs) in MDM2 and p14^ARF (MDM2-rs2279744, MDM2-rs937283, p14^ARF-rs3731217, and p14^ARF-rs3088440) were genotyped in 156 patients with SGC and 511 cancer-free controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results

MDM2-rs2279744 was significantly associated with a moderately increased risk of SGC (OR, 1.5, 95% CI, 1.1–2.2). There was a trend toward significantly increased SGC risk with increasing number of risk genotypes of the four polymorphisms (P _trend = 0.004). Individuals carrying 3–4 risk genotypes in MDM2 and p14^ARF were at increased SGC risk (OR, 2.0, 95% CI, 1.1–2.7) compared with individuals carrying 0–2 risk genotypes. Moreover, the combined effect of risk genotypes of MDM2 and p14^ARF was more pronounced among young subjects (≤45 years), female subjects, subjects with race/ethnicity other than non-Hispanic white, ever-smokers, and ever-drinkers.

Conclusion

Our results support the involvement of SNPs of MDM2 and p14^ARF, either alone or more likely in combination, in susceptibility to SGC. Larger studies are needed to validate our findings.     

Esophageal Squamous Cell Carcinoma and Gastric Cardia Adenocarcinoma Shared Susceptibility Locus in PLCE1: A Meta-Analysis

Background And Objective

Two recent genome-wide association studies have identified a shared susceptibility variation PLCE1 rs2274223 for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). Subsequent case-control studies have reported this association in other populations. However, the findings were controversial and the effect remains undetermined. Our aim is to provide a precise quantification of the association between PLCE1 rs2274223 variation and the risk of ESCC and GCA.

Methods

Studies were identified by a literature search in MEDLINE and EMBASE databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association in allele, dominant, recessive, homozygous, and heterozygous models.

Results

Ten articles were identified, including 22156 ESCC cases and 28803 controls, 5197 GCA cases and 17613 controls. Overall, PLCE1 rs2274223 G allele (G vs. A: OR=1.26, 95% CI: 1.15-1.39 for ESCC; OR=1.51, 95% CI: 1.35–1.69 for GCA) and its carrier (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49 for ESCC; OR =1.62; 95% CI =1.15-2.29 for GCA) were significantly associated with the risk of ESCC and GCA. In stratified analysis by ethnicity, significant association of PLCE1 rs2274223 G allele and the risk of ESCC (OR=1.33, 95% CI 1.21–1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) was observed in Chinese population.

Conclusions

Our meta-analysis results indicated that PLCE1 rs2274223 G allele significantly contributed to the risk of ESCC and GCA, especially in Chinese population.     

霉菌、幽门螺杆菌及双菌种感染在胃溃疡、胃癌中检出的意义

探讨霉菌、幽门螺杆菌(Hp)单菌种感染和霉菌、Hp(双菌种)同时感染在胃癌及胃溃疡中的组织病理学变化、发病情况及意义。采用常规石蜡切片,HE染色和PAS、Giemsa特殊染色、免疫组织化学染色及PCR方法,对223例慢性浅表性胃炎、111例慢性萎缩性胃炎、116例胃溃疡、121例胃癌纤维胃镜活检标本进行回顾性研究。结果显示,慢性浅表性胃炎、慢性萎缩性胃炎未检出双菌种感染。胃溃疡双菌种感染11例,检出率9.5%;胃癌双菌种感染21例,检出率17.4%。双菌种感染在胃癌及胃溃疡中的发现,表明双菌种感染可能是导致胃溃疡、胃癌发生的又一致病因素。     

Toll-Like Receptor 4 +3725 G/C Polymorphism, Helicobacter pylori Seropositivity, and the Risk of Gastric Atrophy and Gastric Cancer in Japanese

Background:  Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms were reported to be a risk factor of gastric carcinoma or its precursors in Caucasian and Indian population, but these polymorphisms are absent in Japanese. We investigated the associations of TLR4 +3725 G/C polymorphism, another functional polymorphism of TLR4 , with risk of gastric cancer and gastric atrophy in Japanese.
Materials and Methods:  Study subjects were 583 histologically diagnosed gastric cancer patients and age- and sex-matched 1592 control outpatients, who visited Aichi Cancer Center Hospital from 2001 to 2005. Serum anti- H. pylori IgG antibody and pepsinogens were measured to evaluate H. pylori infection and gastric atrophy, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a logistic model.
Results:  Among the seropositive subjects, the age- and sex-adjusted OR of gastric atrophy was 1.17 (95%CI: 0.91–1.50) for G/C , 1.20 (95%CI: 0.76–1.89) for C/C , and 1.18 (95%CI: 0.93–1.49) for G/C + C/C relative to G/G genotype. The age- and sex-adjusted OR of severe gastric atrophy among H. pylori seropositive subjects was 1.43 (95%CI: 0.99–2.06) for G/C , 1.47 (95%CI: 0.76–2.88) for C/C , and 1.43 (95%CI: 1.01–2.04) for G/C + C/C . The OR of gastric cancer compared with gastric atrophy controls was not statistically significant.
Conclusion:  Our study found that TLR4 +3725 G/C polymorphism was a risk factor of severe gastric atrophy in H. pylori seropositive Japanese. Our results underscored the significance of the variations in host innate immunity due to TLR4 polymorphism as genetic predispositions to gastric precancerous lesions in Eastern Asian populations with the same backgrounds.     

Susceptibility in vitro of Helicobacter pylori to cetylpyridinium chloride

The antimicrobial agent cetylpyridinium chloride (CPC) which is used in therapy of oro-pharyngeal infections and for antiseptic treatment of the oral cavity is active against different bacterial species. Determination of the minimal inhibitory concentration (MIC) using the agar dilution technique revealed that the gastric pathogen Helicobacter pylori in vitro is highly susceptible to CPC as indicated by an MIC of 10 microM (3.4 microg ml(-1)) which was significantly lower than the MIC of CPC against other bacterial species, which were analyzed in comparison to H. pylori. Bacteria of the genus Campylobacter, various Streptococcus spp., Staphylococcus aureus and Escherichia coli showed higher MICs ranging from 100 microM to 2 mM. In summary, this finding renders CPC-containing drugs candidates possibly useful for eradication or for the prevention of transmission of the gastric pathogen.