Biomedical subjects

Kazue Imai

Publications and source records attributed to Kazue Imai.

17 recordsLinked to original sources

PubMed2007

Short-term culture and gammaH2AX flow cytometry determine differences in individual radiosensitivity in human peripheral T lymphocytes.

Histone H2AX, a subfamily of histone H2A, is phosphorylated and forms proteinaceous repair foci at the sites of DNA double-strand breaks in response to genotoxic insults, such as ionizing radiation. This process is believed to play a key role in the repair of DNA damage. In this study, we established a flow cytometry (FCM) system for measuring radiation-induced phosphorylated histone H2AX (gammaH2AX) in cultured human T lymphocytes to evaluate individual radiation sensitivity in vitro. Irradiation of short-term ( approximately 7 days) cultured T lymphocytes exhibited significant interindividual, but not interexperimental, differences in the cellular content of gammaH2AX 6 hr after 4 Gy of X-irradiation in three independent experiments using peripheral blood lymphocytes from six healthy donors. However, these differences were not as marked in uncultured lymphocytes, or lymphocytes that were cultured for a prolonged period ( approximately 13 days). The variation of gammaH2AX focus formation in lymphocytes of individuals was reproducible, with differences reaching about 1.5-fold following 7 days of culture. Therefore, the FCM-based gammaH2AX measurement appeared to reflect both the temporal course and the amount of DNA damage within the irradiated lymphocytes. Further, we confirmed that the differences in residual lymphocyte subsets were not involved in individual radiosensitivity. These results suggest that the FCM-based gammaH2AX assay using cultured T lymphocytes might be useful for the rapid and reliable assessment of individual radiation sensitivity involved in DNA damage repair.

Adult↗

PubMed2006

Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance.

We have previously shown that natural cytotoxic activity of peripheral blood lymphocytes was inversely related to cancer development based on a prospective cohort study. The genetic fraction of cytotoxic activity needs to be clarified, identifying individuals immunogenetically susceptible to cancer. A case-control study within the cohort members was designed: 102 cancer cases with peripheral lymphocyte DNA available and three control groups, each of which consisted of 204 subjects with each tertile level of cytotoxic activity. We first compared two control groups with high and low cytotoxic activity in terms of the single nucleotide polymorphisms in the natural killer complex gene region on chromosome 12p, identifying the haplotype alleles that were associated with the activity. Next, cancer risks were assessed for these haplotypes. We found two haplotype blocks, each of which generated two major haplotype alleles: low-activity-related LNK1 (frequency 0.478 and 0.615 in groups with high and low activity, respectively; P < 0.00008) and high-activity-related HNK1 (0.480 and 0.348; P < 0.0001), LNK2 (0.711 and 0.821; P < 0.0002), and HNK2 (0.272 and 0.174; P < 0.0008). These NKG2D haplotype alleles showed a significant difference between cases (0.632 for LNK1 and 0.333 for HNK1) and controls (0.554 for LNK1 and 0.406 for HNK1). The haplotype HNK1/HNK1 revealed a decreased risk of cancer (odds ratio, 0.471; 95% confidence interval, 0.233-0.952) compared with LNK1/LNK1. Individuals who are genetically predisposed to have low or high natural cytotoxic activity can in part be determined by NKG2D haplotyping, which in turn reveals an increased or decreased risk of cancer development.

Adult↗

PubMed2006

Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population.

The AXIN2 gene, a negative regulator gene of Wnt/beta-catenin signaling, is a putative tumor suppressor gene on human chromosome 17q24. In the genomic locus on which the AXIN2 gene is located, allelic loss and rearrangement were frequently detected in many cancers. An association between human cancer risk and a single nucleotide polymorphism (SNP) at codon 50 of the AXIN2 gene, encoding either proline (CCT) or serine (TCT), remains undefined. We, therefore, investigated the distribution of the SNP at codon 50 in 110 healthy controls and 160 patients with non-small-cell lung cancer, 113 patients with colorectal cancer, and 63 patients with head and neck cancer. We found that the frequency of the homozygous T/T (Ser/Ser) genotype was significantly less in lung cancer patients (5.0%) than in healthy controls (13.6%) (p=0.005). As compared with the C/C (Pro/Pro) genotype of the controls, lung cancer patients with the T/T genotype showed reduced risk of cancer; the adjusted odds ratio (OR) for patients with the homozygous T/T (Ser/Ser) genotype was 0.31 (95% confidence interval (CI), 0.12-0.79). The association was particularly strong in lung cancer patients with lung adenocarcinoma (LAD) (adjusted OR, 0.24; 95% CI, 0.07-0.81), with well-differentiated grade cancer (adjusted OR, 0.12; 95% CI, 0.01-0.99) and with moderately-differentiated grade cancer (adjusted OR, 0.18; 95% CI, 0.04-0.85). These results suggest that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed. This is the first report to show an association between the AXIN2 SNP and lung cancer risk.

Aged↗

PubMed2005

Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk.

The RASSF1 gene, a putative tumor suppressor gene located on human chromosome 3p21, garners much attention for the frequent allelic loss and gene silencing via promoter hypermethylation in a variety of human malignancies. An association between a single nucleotide polymorphism (SNP) at codon 133 of the RASSF1 gene, encoding either alanine (GCT) or serine (TCT), and human cancer risk remains undefined. We therefore, investigated the distribution of the Ala133Ser SNP in 101 patients with lung cancer, 63 with head and neck cancer, 72 with colorectal cancer, 56 with esophageal cancer and 110 healthy controls by polymerase chain reaction and restriction enzyme-digestion assay. The heterozygous Ala/Ser genotype was significantly more frequent in lung cancer patients than in healthy controls (P=0.028). The adjusted odds ratio (OR) for the patients with heterozygous Ala/Ser genotype as compared with the controls with the Ala/Ala genotype was 2.59 (95% confidence interval (CI); 1.11-6.04). The increased risk of the Ala/Ser genotype was found in lung cancer patients but not in other cancer patients we examined. The association was particularly strong in those lung cancer patients of male (adjusted OR; 3.33, 95% CI; 1.37-8.12), with adenocarcinoma (adjusted OR; 3.33, 95% CI; 1.36-8.15), early stages (adjusted OR; 3.42, 95% CI; 1.33-8.75) and with smoking habit (adjusted OR; 2.70, 95% CI; 1.06-6.83). These results suggest that the RASSF1 Ala133Ser SNP is associated with development of lung cancer, especially of lung adenocarcinoma. The increased risk of the heterozygous genotype is intriguing, implying a close relation with the dimerization feature of RASSF1 proteins.

Adenocarcinoma↗

PubMed2005

A single nucleotide polymorphism in the 5' untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer.

OBJECTIVE: Epidermal growth factor (EGF) has many biological functions and plays an important role in the progression of various tumors including gastric cancer. An A-G single nucleotide polymorphism (SNP) at position 61 in the 5'-untranslated region (UTR) of the EGF gene has recently been reported to be associated with different levels of EGF production. We examined whether this polymorphism is correlated with the development and malignant phenotypes of gastric cancer. METHODS: The study population included 200 gastric cancer patients and 230 healthy control subjects. The SNP in the 5'-UTR of the EGF gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The A allele was significantly less frequent in patients than in controls (p = 0.01). Individuals with the A/A or A/G genotype showed a significantly lower risk of gastric cancer than those with the G/G genotype [adjusted odds ratio (OR) = 0.56], whereas the same genotypes were associated with malignant progression of this cancer, e.g. deeper tumor invasion, increased lymph node metastasis and advanced clinical stage, and histological classification in gastric cancer patients (adjusted OR = 1.80, 1.98, 2.26 and 1.89, respectively). CONCLUSIONS: Our findings suggest that the A-G polymorphism of EGF is involved not only in the occurrence but also in the malignant progression of gastric cancer.

5' Flanking Region↗

PubMed2005

Stability of frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor binding protein-3, transforming growth factor beta, soluble Fas, and superoxide dismutase activity for the JACC study.

BACKGROUND: Subjects of the Japan Collaborate Cohort Study (JACC Study) gave peripheral blood samples collected between 1988 and 1990. We conducted to investigate whether levels of serum components measured after 9 years of frozen storage are stable or not. METHODS: To assess the degradation of frozen serum components in the JACC Study, we compared levels of various components (IGF-I, IGF-II, IGFBP-3, TGF-beta 1, sFas, and total SOD activity) between fresh and stored sera collected from other inhabitants. Serum levels of constituents were measured by immunoradiometric assay (IGF-I, IGF-II and IGFBP-3), quantitative enzyme immunoassay (TGF-beta1), enzyme-linked immuno-adsorbent assay (sFas), and an improved nitrite method (SOD activity). RESULTS: The coefficients of variation for intra- and inter-assay precisions of the measurements were less than 9%. Levels of IGF-I, IGF-II, IGFBP-3, TGF-beta 1 and sFas in sera after storage for 9 years at--80 degrees C were similar to those of fresh sera newly collected from inhabitants. The distributions of serum IGF-I, IGF-II, IGFBP-3, TGF-beta 1, sFas and SOD activity for specimens collected from different individuals tended to be similar to those of serum levels for frozen specimens collected from different individuals and stored for 9 years. CONCLUSIONS: There was no statistically significant difference in distribution of measured values of IGF-I, IGF-II, IGFBP-3, TGF-beta 1, and sFas between newly collected sera and frozen specimens stored for 9 years. Thus, measurements of these serum constituents of specimens stored for the JACC Study can be reliably used in nested case-control study.

Adult↗

PubMed2005

A single nucleotide polymorphism in the extracellular domain of TRAIL receptor DR4 at nucleotide 626 in gastric cancer patients in Japan.

Death receptor 4 (DR4) is a member of the tumor necrosis factor-related apoptosis-inducing ligand receptor genes. A single nucleotide polymorphism (Thr or Arg, C or G) in the extracellular domain was reported to be associated with a risk of lung cancer, head and neck cancer, and bladder cancer. In this study, we examined the association between the DR4 polymorphism and gastric cancer. The Thr/Thr, Thr/Arg and Arg/Arg genotypes were found in 250 (91.2%), 23 (8.4%) and 1 (0.4%) of 274 gastric cancer patients and in 317 (92.2%), 21 (6.1%) and 6 (1.7%) of 344 control subjects, respectively. The OR of Thr/Arg or Arg/Arg genotype did not reveal a significantly enhanced risk of 1.13 (95% CI, 0.63-2.00) compared to Thr/Thr genotype, suggesting that the DR4 polymorphism did not modify the risk of gastric cancer. In patients, no association between the genotype and clinicopathological characteristics (depth of invasion, lymph node metastasis, distant metastasis, stage and grade of differentiation) of gastric carcinoma was found. DR4 was constantly expressed in gastric carcinoma, but not in non-neoplastic gastric epithelium in immunohistochemistry. In conclusion, a Thr to Arg single nucleotide polymorphism in the extracellular domain of DR4 could not be associated with the development and progression of gastric cancer.

Adenocarcinoma↗

PubMed2004

Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients.

Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including in the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important in affecting gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. The CDX2 homeobox transcription factor plays a key role in intestinal development, but CDX2 is also expressed in most of the intestinal metaplasia and part of the carcinomas of the stomach. We analyzed the methylation status of the CDX2 5' CpG island in gastric cancer cell lines by methylation-specific PCR (MSP), and then CDX2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. We further examined the methylation status of CDX2 in primary gastric carcinomas by MSP and compared it with the past lifestyle of the patients, including dietary habits. Methylation of CDX2 was found in 20 (34.5%) of the 58 male patients and one (6.7%) of the 15 female patients. Since the methylation frequency was low in the female patients, the analysis was performed only on the male cases. CDX2 methylation was correlated with the decreased intake of green tea and cruciferous vegetables, and also with full or overeating habits. These findings are consistent with epidemiological observations on gastric cancer. We also analyzed the methylation status of p16/INK4a and hMLH1, but their frequencies were not associated with dietary factors or other lifestyle factors. Thus, diet could be an important factor determining the methylation status of genes such as CDX2 and the resultant aberrant expression of genes involved in carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2004

A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer.

PURPOSE: Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position -1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the -1562 C/T polymorphism and the development and progression of gastric cancer. METHODS: The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied. RESULTS: Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each). CONCLUSIONS: Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.

Aged↗

PubMed2004

A single nucleotide polymorphism in the MMP-1 promoter is correlated with histological differentiation of gastric cancer.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) plays a key role in cancer invasion and metastasis by degradation of extracellular matrix (ECM) and basement membrane barriers. The 1G/2G single nucleotide polymorphism (SNP) in the MMP-1 promoter at position -1607 bp has been reported to affect the transcriptional activity. In the light of these findings, we investigated whether this SNP in the MMP-1 promoter is associated with the development, differentiation, and progression of gastric cancer. METHODS: The 215 gastric cancer patients and 166 controls were used in this study. The SNP of the MMP-1 promoter was analyzed by PCR-RFLP and sequencing. The genotype frequency was compared between cases and controls, and the association with clinicopathological parameters among cases was studied. RESULTS: The frequency of 1G/2G genotypes in gastric cancer patients was similar to those in controls (p=0.57). The degree of tumor invasion, the presence of lymph node metastasis, and clinical stage showed no significant association with the SNP. On the other hand, we found a significant association with histological differentiation and gender among gastric cancer patients (p<0.05, respectively). CONCLUSIONS: The presence of 2G allele in the MMP-1 promoter did not enhance the risk of gastric cancer; however, it may be involved in differentiation of gastric cancer.

Aged↗

PubMed2004

Excess concordance of cancer incidence and lifestyles in married couples (Japan): survival analysis of paired rate data.

OBJECTIVE: A population-based cohort study was conducted to examine concordance of cancer incidence and lifestyle in married couples. METHODS: Cancer incidence from 1 September 1986 to 30 June 2000 was followed for a baseline cohort of 2601 community-living married couples aged 40-84 years who were cancer-free and had completed an epidemiologic questionnaire in 1986 in Saitama, Japan. We computed age-adjusted cross-ratios: spouse-with/spouse-without rate ratios as a measure of association for paired rate data, using a bivariate survival analysis method. RESULTS: Concordance of lifestyles for couples was high for dietary habits, and low for smoking and alcohol habits. During the 14 year follow-up, 464 cancer cases occurred (husbands only: 279, wives only: 119, both: 33 couples). Wives whose husbands developed cancer were at an increased risk of developing cancer themselves, compared with those whose husbands had not had cancer (CR: 1.70, 95% CI: 1.12-2.58). Mean age at diagnosis was 68.2 years for husbands and 66.0 years for wives. And correlation of cancer incidence was further seen among couples who shared habits of smoking and/or drinking. CONCLUSIONS: Our data suggest that shared lifestyles including smoking and drinking habits are associated with an excess concordance of cancer incidence among married couples.

Adult↗

PubMed2004

Perspectives on cancer immuno-epidemiology.

Estimating human cancer risk based on host-environment interaction is one task of epidemiology, and it has provided indispensable knowledge for prevention of cancer. The recent develop-ment of gene-engineered mice has also provided solid evidence about the relationship between cancer development and immunity. The aim of this review is to discuss the possible contribution of epidemiology to understanding the role of immunity in host defense against cancer, and also to assess the involvement of inflammation in the occurrence of selected cancers. Here we look at the concepts of cancer immunosurveillance and infection-inflammation-cancer, and include a brief introduction to recent studies in humans and experimental animal models. It has been postulated for many years that the immune system has the ability to recognize and eliminate nascent transformed cells in the body (so-called cancer immunosurveillance hypothesis), and this idea has recently obtained strong support from animal experiments. In humans, follow-up studies among immunosuppressed transplant recipients revealed a remarkably increased risk of not only selected malignancies, but also cancers with no known viral etiology. On the other hand, a prospective cohort study among the general population revealed that individuals with low natural cytotoxic activity of peripheral blood lymphocytes had an increased risk of cancer development. More studies are warranted to allow the construction of a model for the interaction between host immunity, aging, and the environment. The host immune system is also involved in inflammatory responses to pathogen infection: insufficient immune function of the host, or repeated infection, may result in persistent inflammation, where growth/survival factors continuously act on initiated cells. The combined use of biomarkers will be necessary to define low-grade persistent inflammation in future cohort studies; and, in addition to these phenotype marker-based cohort studies, one plausible future direction will be a genomic approach that can be undertaken within cohort studies, looking at the genetic background underlying individual variations in phenotype markers.

Animals↗

PubMed2003

A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer.

Alterations of the HER-2 (erbB-2/neu) proto-oncogene have been associated with carcinogenesis and poor prognosis of certain cancers. A single nucleotide polymorphism (Ile/Val, A/G) in the transmembrane domain was reported to be associated with a risk of breast cancer. In our study, we examined the association between the HER-2 polymorphism and gastric carcinoma. The Ile/Ile, Ile/Val and Val/Val genotypes were found in 146 (68.9%), 56 (26.4%) and 10 (4.7%) of 212 gastric cancer patients and in 234 (81.5%), 48 (16.7%) and 5 (1.8%) of 287 control subjects, respectively. The Ile/Val or Val/Val genotype was significantly more frequent in patients than in controls (p = 0.005 and 0.033, respectively). The OR of Val/Val genotype then revealed a significantly enhanced risk of 3.25 (95% CI 1.09-9.70) compared to Ile/Ile genotype; heterozygous Ile/Val genotype showed an intermediate risk of 1.97 (1.27-3.06). In patients, carcinomas of advanced stage were significantly more frequent in patients with Ile/Val or Val/Val genotype than those with Ile/Ile genotype (p < 0.001). The logistic regression analysis for tumor invasion, lymph node metastasis and distant metastasis revealed that lymph node metastasis was most closely associated with the HER-2 genotype. These results suggest that this nucleotide polymorphism in the transmembrane domain-coding region of HER-2 could be associated with development of gastric carcinoma and may serve as a predictor of risk for a malignant phenotype of gastric cancer. The association of HER-2 genotype with clinicopathologic characteristics of gastric cancer was also suggested, which has to be confirmed with a larger sample size.

Adenocarcinoma↗

PubMed2003

Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance.

Hypoxia-inducible factor-1 (HIF-1) is a pivotal factor that regulates cellular responses to hypoxia and is presumably linked to regulation of angiogenesis and tumor growth. We assessed the difference in transcription activity of two HIF-1alpha polymorphic variants (P582S and A588T), along with molecular epidemiological study among head and neck squamous cell carcinoma (HNSCC) patients. Both HIF-1alpha variants revealed significantly higher transcription activity than wild-type (WT) did, under normoxic and hypoxic conditions (P < 0.02). Furthermore, tumors from HNSCC patients with heterozygous alleles having P582S or A588T had significantly increased numbers of microvessels compared with those with homozygous WT (P = 0.02). In addition, all patients with tumors of T1 (below 2 cm diameter) were WT, while 14 of 47 patients with tumors of > or =T2 were heterozygous. The elevated transactivation capacity of variant forms of HIF-1alpha implies a role of HIF-1alpha polymorphisms in generating individually different tumor progression.

Amino Acid Sequence↗

PubMed2003

Can teatime increase one's lifetime?

Lifestyle-related diseases, including cancer and cardiovascular disease, are also characterized as aging-related diseases, where aging may be the most potent causal factor. In light of this, prevention of lifestyle-related diseases will depend on slowing the aging process and avoiding the clinical appearance of the diseases. Green tea is now accepted as a cancer preventive on the basis of numerous in vitro, in vivo and epidemiological studies. In addition, green tea has also been reported to reduce the risk of cardiovascular disease. We found an apparent delay of cancer onset/death and all cause deaths associated with increased consumption of green tea, specifically in ages before 79 in a prospective cohort study of a Japanese population with 13-year follow-up data. This is consistent with analyses of age-specific cancer death rate and cumulative survival, indicating a significant slowing of the increase in cancer death and all cause death with aging. These results indicate that daily consumption of green tea in sufficient amounts will help to prolong life by avoiding pre-mature death, particularly death caused by cancer.

Aged↗

PubMed2002

Green tea: cancer preventive beverage and/or drug.

Green tea and (-)-epigallocatechin gallate (EGCG) are now acknowledged cancer preventives in Japan and has made it possible for us to establish the concept of a cancer preventive beverage. For the general population, we recommend 10 cups of green tea daily supplemented with green tea tablets. For cancer patients following treatment, we here present new evidence that green tea and a cancer preventive drug, sulindac, have synergistic preventive effects. An approach to develop green tea capsules as a cancer preventive drug in the US is discussed, aiming at taking full advantage of this cancer preventive beverage.

Antineoplastic Agents↗

PubMed2002

Involvement of TNF-alpha changes in human cancer development, prevention and palliative care.

Cancer development and ageing are complex sciences. From the study on the process of rodent carcinogenesis, we identified tumor necrosis factor-alpha (TNF-alpha) as an important mediator of cancer development. This paper presents three clinical examples of TNF-alpha up-regulation: by cord factors of Mycobacterium tuberculosis, such as trehalose 6-monomycolate, as an activator of protein kinase C and by a cord factor like fraction of Microsporum canis obtained in the air inside houses in Thailand, both of which are risk factors in human lung cancer development, and by Helicobacter pylori gene product, H. pylori membrane protein 1 (HP-MP1) in relation to human stomach cancer. The second part of this paper deals with down-regulation of TNF-alpha by a wide variety of cancer preventive agents. Among the various agents, (-)-epigallocatechin gallate (EGCG) and green tea polyphenols inhibited TNF-alpha gene expression in the cells induced by tumor promoter, mediated through inhibition of NF-kappaB activation. Studying growth inhibition of human cancer cell lines by morphine, we found that morphine and the new morphine derivatives KT-90 and KT-87 have anticancer activity mediated through induction of apoptosis, in addition to analgesic action. We conclude that environmental and endogenous factors induce NF-kappaB activation mediated through expression of inflammatory cytokine genes, such as TNF-alpha, and that the expression pattern of the genes operates similarly in the aging process.

Humans↗