Kei Nakachi

Publications (97)277.11 Total impact

• Article: Development of Lymphoproliferative Diseases by Hypoxia Inducible Factor-1alpha Is Associated with Prolonged Lymphocyte Survival.

  Eisaburo Sueoka, Naoko Sueoka-Aragane, Akemi Sato, Masaru Ide, Hideaki Nakamura, Yusuke Sotomaru, Choji Taya, Hiromichi Yonekawa, Tomoyuki Kitagawa, Yasushi Kubota, Shinya Kimura, Kei Nakachi, Keiji Tanimoto
  [show abstract] [hide abstract]
  ABSTRACT: Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.
  PLoS ONE 01/2013; 8(4):e57833. · 4.09 Impact Factor
• Article: Improved PCR amplification for molecular analysis using DNA from long-term preserved formalin-fixed, paraffin-embedded lung cancer tissue specimens.

  Masataka Taga, Hidetaka Eguchi, Tomoko Shinohara, Keiko Takahashi, Reiko Ito, Wataru Yasui, Kei Nakachi, Yoichiro Kusunoki, Kiyohiro Hamatani
  [show abstract] [hide abstract]
  ABSTRACT: Archival tissue specimens are valuable resources of materials for molecular biological analyses in retrospective studies, especially for rare diseases or those associated with exposure to uncommon environmental events. Although successful amplification with PCR is essential for analysis of DNA extracted from archival formalin-fixed, paraffin-embedded (FFPE) tissue specimens, we have often encountered problems with poor PCR amplification of target fragments. To overcome this, we examined whether heat treatment in alkaline solution could efficiently restore the PCR template activity of DNA that had already been extracted from FFPE lung cancer tissue specimens. The effect of the heat treatment was assessed by PCR for the TP53 gene and other lung cancer-related gene loci. The heat treatment of DNA samples in borate buffer resulted in successful PCR amplification of DNA fragments ranging from 91 to 152 bp. This technique for restoration of template activity of DNA for PCR amplification is very simple and economical, and requires no special apparatus, so it may be applicable for molecular analysis of DNA samples from FFPE tissue specimens at various laboratories.
  International journal of clinical and experimental pathology 01/2013; 6(1):76-9. · 1.89 Impact Factor
• Article: Rearranged Anaplastic Lymphoma Kinase (ALK ) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors.

  Kiyohiro Hamatani, Mayumi Mukai, Keiko Takahashi, Yuzo Hayashi, Kei Nakachi, Yoichiro Kusunoki
  [show abstract] [hide abstract]
  ABSTRACT: Background: We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAF(V600E)) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. Methods: The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription-polymerase chain reaction and 5' rapid amplification of cDNA ends (5' RACE). Results: We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Conclusion: Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC.
  Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 Impact Factor
• Article: Compromised hematopoiesis and increased DNA damage following non-lethal ionizing radiation of a human hematopoietic system reconstituted in immunodeficient mice.

  Changshan Wang, Shunsuke Nakamura, Motohiko Oshima, Makiko Mochizuki-Kashio, Yaeko Nakajima-Takagi, Mitsujiro Osawa, Yoichiro Kusunoki, Seishi Kyoizumi, Kazue Imai, Kei Nakachi, Atsushi Iwama
  [show abstract] [hide abstract]
  ABSTRACT: Purpose: Precise understanding of radiation effects is critical to development of new modalities for the prevention and treatment of radiation-induced damage. In this study, we evaluated the effects of non-lethal doses of X-ray irradiation on human hematopoietic stem and progenitor cells (HSPC) reconstituted in NOD/Shi-scid, IL2Rγ(null) (NOG) immunodeficient mice. Materials and methods: We transplanted cord blood CD34(+) HSPC into NOG mice irradiated with 2.0 Gy via tail veins. At the 12th week after transplantation, the NOG mice were irradiated with 0, 0.5, 1.0, 2.0, or 4.0 Gy, and the radiation effects on human HSPC in vivo were evaluated. Results: Although a majority of the mice irradiated with 2.0 Gy or more died in 12 weeks after irradiation, the mice that were exposed to 0.5 or 1.0 Gy of irradiation survived and were subjected to analysis. The chimerism of human CD45(+) hematopoietic cells in peripheral blood and bone marrow (BM) of the recipient mice was reduced in an X-ray dose-dependent manner after irradiation. Percentages of human CD34(+) HSPC as well as human (CD34+CD38-) HSC in BM similarly declined. (CD34+CD38-) HSC purified from the humanized mice at the 12th week after irradiation showed significantly increased numbers of phosphorylated H2AX (γH2AX) foci, a marker of DNA breaks, in an X-ray dose- dependent manner. Expression of p16INK4A, a hallmark of aging of HSC, was also detected only in HSPC from irradiated mice. Conclusions: With further refinement, the humanized mouse model might be effectively used to study the biological effects of non-lethal radiation in vivo.
  International Journal of Radiation Biology 10/2012; · 2.28 Impact Factor
• Article: Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects.

  Tomonori Hayashi, Yukari Morishita, Ravindra Khattree, Munechika Misumi, Keiko Sasaki, Ikue Hayashi, Kengo Yoshida, Junko Kajimura, Seishi Kyoizumi, Kazue Imai, Yoichiro Kusunoki, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Past exposure to atomic bomb (A-bomb) radiation has exerted various long-lasting deleterious effects on the health of survivors. Some of these effects are seen even after >60 yr. In this study, we evaluated the subclinical inflammatory status of 442 A-bomb survivors, in terms of 8 inflammation-related cytokines or markers, comprised of plasma levels of reactive oxygen species (ROS), interleukin (IL)-6, tumor necrosis factor α (TNF-α), C-reactive protein (CRP), IL-4, IL-10, and immunoglobulins, and erythrocyte sedimentation rate (ESR). The effects of past radiation exposure and natural aging on these markers were individually assessed and compared. Next, to assess the biologically significant relationship between inflammation and radiation exposure or aging, which was masked by the interrelationship of those cytokines/markers, we used multivariate statistical analyses and evaluated the systemic markers of inflammation as scores being calculated by linear combinations of selected cytokines and markers. Our results indicate that a linear combination of ROS, IL-6, CRP, and ESR generated a score that was the most indicative of inflammation and revealed clear dependences on radiation dose and aging that were found to be statistically significant. The results suggest that collectively, radiation exposure, in conjunction with natural aging, may enhance the persistent inflammatory status of A-bomb survivors.-Hayashi, T., Morishita, Y., Khattree, R., Misumi, M., Sasaki, K., Hayashi, I., Yoshida, K., Kajimura, J., Kyoizumi, S., Imai, K., Kusunoki, Y., Nakachi, K. Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects.
  The FASEB Journal 08/2012; · 5.71 Impact Factor
• Article: Conventional case-cohort design and analysis for studies of interaction.

  John Cologne, Dale L Preston, Kazue Imai, Munechika Misumi, Kengo Yoshida, Tomonori Hayashi, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: The case-cohort study design has received significant methodological attention in the statistical and epidemiological literature but has not been used as widely as other cohort-based sampling designs, such as the nested case-control design. Despite its efficiency and practicality for a wide range of epidemiological study purposes, researchers may not yet be aware of the fact that the design can be analysed using standard software with only minor adjustments. Furthermore, although the large number of options for design and analysis of case-cohort studies may be daunting, they can be reduced to a few simple recommendations. We review conventional methods for the design and analysis of case-cohort studies and describe empirical comparisons based on a study of radiation, gene polymorphisms and cancer in the Japanese atomic bomb survivor cohort. Stratified, as opposed to simple, random subcohort selection is recommended, especially for studies of gene-environment interaction, which are notorious for lacking statistical power. Methods based on the score-unbiased exact pseudo-likelihood (or its analogue with stratified case-cohort data) are recommended for use in conjunction with the asymptotic variance estimator. We present an example of how to implement case-cohort analysis methods using SPSS, a popular statistical package that lacks some of the features necessary to directly adapt and implement published methods based on other software platforms. We also illustrate case-control analysis using Epicure, which provides greater risk-modelling flexibility than other software. Our conclusions and recommendations should help investigators to better understand and apply the case-cohort design in epidemiological research.
  International Journal of Epidemiology 07/2012; 41(4):1174-86. · 6.41 Impact Factor
• Article: Challenging the effectiveness of green tea in primary and tertiary cancer prevention.

  Hirota Fujiki, Kazue Imai, Kei Nakachi, Masahito Shimizu, Hisataka Moriwaki, Masami Suganuma
  [show abstract] [hide abstract]
  ABSTRACT: Drinking green tea daily is part of Japanese culture, and various studies have revealed that green tea is a cancer preventive. We here review our progress in cancer prevention with green tea on 12 main topics, from basic to clinical level. TOPICS AND METHODS: Biochemical and biological studies of green tea catechins, a prospective cohort study, preclinical safety trials with tablets of green tea extract, double-blind randomized clinical phase II prevention trial for recurrence of colorectal adenomas, and synergistically enhanced inhibition by the combination of green tea catechins and anticancer drugs. All results were significant, including human studies with informed consent. Drinking 10 Japanese-size cups of green tea per day delayed the cancer onset of humans 7 years for females. For tertiary cancer prevention, consuming 10 cups of green tea per day fortified by green tea tablets, 50 %, significantly prevented the recurrence of colorectal adenomas. A minimum effective amount of green tea catechins for cancer prevention was found in humans. In addition, the combination of green tea catechins and anticancer drugs engendered a new cancer therapeutic strategy. The consumption of 10 Japanese-size cups of green tea per day is a significant factor in primary cancer prevention for the general population, and the preventive effect on recurrence of colorectal adenomas in patients is vital evidence in tertiary cancer prevention.
  Journal of Cancer Research and Clinical Oncology 06/2012; 138(8):1259-70. · 2.56 Impact Factor
• Article: Effects of NKG2D haplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomic-bomb survivors.

  Kazue Imai, Tomonori Hayashi, Mika Yamaoka, Junko Kajimura, Kengo Yoshida, Yoichiro Kusunoki, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: NKG2D is a primary activating receptor that triggers cell-mediated cytotoxicity in NK cells against tumor and virus-infected cells. We previously identified the NKG2D haplotypes in the natural killer gene complex region on chromosome 12p. Two major haplotype alleles, LNK1 and HNK1, were closely related to low and high natural cytotoxic activity phenotypes, respectively. Furthermore, the haplotype of HNK1/HNK1 has revealed a decreased risk of cancer compared with LNK1/LNK1. In the present study, using flow cytometry, we evaluated the functional effects of NKG2D haplotypes and five htSNPs in terms of the cell-surface expression of NKG2D protein on NK and CD8 T cells of peripheral blood among 732 atomic-bomb survivors. NKG2D expression on NK cells showed significant increases, in the order of LNK1/LNK1, LNK1/HNK1 and HNK1/HNK1 haplotypes (p for trend=0.003), or with major homozygous, heterozygous, and minor homozygous genotypes for individual htSNPs (p for trend=0.02-0.003). The same trend was observed for NKG2D expression on CD8 T cells. Our findings indicate that the NKG2D haplotypes are associated with the expression levels of NKG2D protein on NK and CD8 T cells, resulting in inter-individual variations in human cytotoxic response.
  Human immunology 04/2012; 73(6):686-91. · 2.55 Impact Factor
• Article: Body iron stores and breast cancer risk in female atomic bomb survivors.

  Richard G Stevens, John B Cologne, Kei Nakachi, Eric J Grant, Kazuo Neriishi
  [show abstract] [hide abstract]
  ABSTRACT: Iron can be a potent pro-oxidant and, on this basis, elevated body iron may increase the risk of cancer. Although epidemiological evidence is mixed, there is overall support for this possibility. In addition, because of this same oxidative capacity, body iron levels may alter radiation sensitivity. In the present study, a nested case-control study of breast cancer was conducted in Japanese atomic bomb survivors. Stored serum samples from the Adult Health Study cohort were assayed for ferritin levels and joint statistical analyses were conducted of ferritin and radiation dose on the risk of breast cancer. Serum ferritin is the best feasible indicator of body iron levels in otherwise healthy people. A total of 107 cases and 212 controls were available for analysis. The relative risk (RR) of breast cancer for a 1 log unit increase in ferritin was 1.4 (95% confidence interval 1.1-1.8). This translates to an RR of 1.64 comparing high and low values of the interquartile range among controls (58 and 13.2 ng/mL, respectively). The results support the hypothesis that elevated body iron stores increase the risk of breast cancer. However, the study was inconclusive regarding the question of whether body iron alters radiation-induced breast cancer risk.
  Cancer Science 08/2011; 102(12):2236-40. · 3.33 Impact Factor
• Article: Associations of ionizing radiation and breast cancer-related serum hormone and growth factor levels in cancer-free female A-bomb survivors.

  Eric J Grant, Kazuo Neriishi, John Cologne, Hidetaka Eguchi, Tomonori Hayashi, Susan Geyer, Shizue Izumi, Nobuo Nishi, Charles Land, Richard G Stevens, Gerald B Sharp, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Levels of exposure to ionizing radiation are increasing for women worldwide due to the widespread use of CT and other radiologic diagnostic modalities. Exposure to ionizing radiation as well as increased levels of estradiol and other sex hormones are acknowledged breast cancer risk factors, but the effects of whole-body radiation on serum hormone levels in cancer-free women are unknown. This study examined whether ionizing radiation exposure is associated with levels of serum hormones and other markers that may mediate radiation-associated breast cancer risk. Serum samples were measured from cancer-free women who attended biennial health examinations with a wide range of past radiation exposure levels (N  =  412, ages 26-79). The women were selected as controls for separate case-control studies from a cohort of A-bomb survivors. Outcome measures included serum levels of total estradiol, bioavailable estradiol, testosterone, progesterone, prolactin, insulin-like growth factor-1 (IGF1), insulin-like growth factor-binding protein 3 (IGFBP-3), and ferritin. Relationships were assessed using repeated-measures regression models fitted with generalized estimating equations. Geometric mean serum levels of total estradiol and bioavailable estradiol increased with 1 Gy of radiation dose among samples collected from postmenopausal women (17%(1Gy), 95% CI: 1%-36% and 21%(1Gy), 95% CI: 4%-40%, respectively), while they decreased in samples collected from premenopausal women (-11%(1Gy), 95% CI: -20%-1% and -12%(1Gy), 95% CI: -20%- -2%, respectively). Interactions by menopausal status were significant (P  =  0.003 and P < 0.001, respectively). Testosterone levels increased with radiation dose in postmenopausal samples (30.0%(1Gy), 95% CI: 13%-49%) while they marginally decreased in premenopausal samples (-10%(1Gy), 95% CI: -19%-0%) and the interaction by menopausal status was significant (P < 0.001). Serum levels of IGF1 increased linearly with radiation dose (11%(1Gy), 95% CI: 2%-18%) and there was a significant interaction by menopausal status (P  =  0.014). Radiation-associated changes in serum levels of estradiol, bioavailable estradiol, testosterone and IGF1 were modified by menopausal status at the time of collection. No associations with radiation were observed in serum levels of progesterone, prolactin, IGFBP-3 or ferritin.
  Radiation Research 06/2011; 176(5):678-87. · 2.68 Impact Factor
• Article: Lymphocyte subset characterization associated with persistent hepatitis C virus infection and subsequent progression of liver fibrosis.

  Kengo Yoshida, Waka Ohishi, Eiji Nakashima, Saeko Fujiwara, Masazumi Akahoshi, Fumiyoshi Kasagi, Kazuaki Chayama, Masayuki Hakoda, Seishi Kyoizumi, Kei Nakachi, Tomonori Hayashi, Yoichiro Kusunoki
  [show abstract] [hide abstract]
  ABSTRACT: This study aims to deepen the understanding of lymphocyte phenotypes related to the course of hepatitis C virus (HCV) infection and progression of liver fibrosis in a cohort of atomic bomb survivors. The study subjects comprise 3 groups: 162 HCV persistently infected, 145 spontaneously cleared, and 3,511 uninfected individuals. We observed increased percentages of peripheral blood T(H)1 and total CD8 T cells and decreased percentages of natural killer (NK) cells in the HCV persistence group compared with the other 2 groups after adjustment for age, gender, and radiation exposure dose. Subsequently, we determined that increased T(H)1 cell percentages in the HCV persistence group were significantly associated with an accelerated time-course reduction in platelet counts-accelerated progression of liver fibrosis-whereas T(C)1 and NK cell percentages were inversely associated with progression. This study suggests that T(H)1 immunity is enhanced by persistent HCV infection and that percentages of peripheral T(H)1, T(C)1, and NK cells may help predict progression of liver fibrosis.
  Human immunology 06/2011; 72(10):821-6. · 2.55 Impact Factor
• Article: TP53 codon 72 polymorphism is associated with pancreatic cancer risk in males, smokers and drinkers.

  Takayuki Sonoyama, Akiko Sakai, Yuichiro Mita, Yukiko Yasuda, Hirofumi Kawamoto, Takahito Yagi, Masao Yoshioka, Tetsushige Mimura, Kei Nakachi, Mamoru Ouchida, Kazuhide Yamamoto, Kenji Shimizu
  [show abstract] [hide abstract]
  ABSTRACT: Tumor protein p53 (TP53) is the best-known tumor suppressor gene and plays a crucial role in carcinogenesis. The TP53 Arg 72 Pro polymorphism has been reported to be a risk factor for several types of cancer, but its association with pancreatic cancer has not been fully evaluated. Therefore, we investigated the effects of this polymorphism on pancreatic cancer in relation to smoking and drinking habits by examining the distribution of the SNP genotypes in 226 pancreatic cancer patients and 448 healthy controls. The frequencies of Arg/Arg, Arg/Pro and Pro/Pro were found to be 37, 49 and 15% in the pancreatic cancer cases and 44, 46 and 10% in the controls, respectively. Compared to the controls with the Arg/Arg genotype, cases with Pro/Pro homozygosity exhibited a significantly increased risk [adjusted odds ratio (OR)=1.70; 95% confidence interval (CI) 1.01-2.88]. In stratified studies, the association was particularly strong in males (OR=2.62; 95% CI 1.32-5.23), particularly in those smoking in excess of 20 pack-years and drinking in excess of 23 g ethanol/day (OR=5.02; 95% CI 1.12-22.51). We found that the TP53 Pro/Pro genotype compared to the Arg/Arg genotype had a profound effect on pancreatic cancer risk among males, particularly among heavy smokers and excessive alcohol drinkers.
  Molecular Medicine Reports 05/2011; 4(3):489-95. · 0.42 Impact Factor
• Source

  Available from: Saeko Fujiwara

  Article: Biomarkers of radiosensitivity in a-bomb survivors pregnant at the time of bombings in hiroshima and nagasaki.

  Edward F Miles, Yoshimi Tatsukawa, Sachiyo Funamoto, Naoko Kamada, Eiji Nakashima, Yoshiaki Kodama, Thomas Seed, Yoichiro Kusonoki, Kei Nakachi, Saeko Fujiwara, Masazumi Akahoshi, Kazuo Neriishi
  [show abstract] [hide abstract]
  ABSTRACT: Purpose. There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods. We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results/Conclusions. Data on approximately 250 women were available to assess dose-response rates for serum cholesterol, white blood cell count, erythrocyte sedimentation rate, and serum hemoglobin, and on approximately 85 women for stable chromosome aberrations, glycophorin A locus mutations, and naïve CD4 T-cell counts. Although there is no statistically significant evidence of increased radiosensitivity in pregnant women, the increased slope of the linear trend line in the third trimester with respect to stable chromosome aberrations is suggestive of an increased radiosensitivity.
  ISRN obstetrics and gynecology 01/2011; 2011:264978.
• Source

  Available from: rerf.or.jp

  Article: T-cell immunosenescence and inflammatory response in atomic bomb survivors.

  Yoichiro Kusunoki, Mika Yamaoka, Yoshiko Kubo, Tomonori Hayashi, Fumiyoshi Kasagi, Evan B Douple, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors. All these effects of radiation on T-cell immunity resemble effects of aging on the immune system, suggesting that ionizing radiation might direct the T-cell system toward a compromised phenotype and thereby might contribute to an enhanced immunosenescence. Furthermore, there are inverse, significant associations between plasma levels of inflammatory cytokines and the relative number of naïve CD4 T cells, also suggesting that the elevated levels of inflammatory markers found in A-bomb survivors can be ascribed in part to T-cell immunosenescence. We suggest that radiation-induced T-cell immunosenescence may result in activation of inflammatory responses and may be partly involved in the development of aging-associated and inflammation-related diseases frequently observed in A-bomb survivors.
  Radiation Research 12/2010; 174(6):870-6. · 2.68 Impact Factor
• Article: Increased DNA damage in hematopoietic cells of mice with graft-versus-host disease.

  Yoichiro Kusunoki, Kanya Hamasaki, Kazuaki Koyama, Kazue Imai, Tomonori Hayashi, Paul J Martin, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Patients who received hematopoietic cell transplants have an increased risk for a new malignancy. In addition to genotoxic regimens such as radiotherapy and chemotherapy, graft-versus-host disease (GVHD) is a risk factor for development of new malignancies in long-term survivors. To understand mechanisms underlying this malignant transformation, we evaluated genomic damage in several murine models of GVHD by enumerating reticulocytes containing micronuclei (MN) in the blood after semi-allogeneic (parent-into-F1) hematopoietic cell transplantation. On day 40 after transplantation, MN frequencies were significantly increased in unirradiated (C57BL6 x DBA/2) F1 (BDF1) and (BALB/c x C57BL6) F1 (CBF1) mice that received cells from C57BL6 (B6) donors. MN frequencies were not significantly increased in F1 mice that received cells from DBA/2 or BALB/c donors. Serum levels of tumor necrosis factor-alpha (TNF-alpha) were higher after transplantation with B6 donors than with DBA/2 or BALB/c donors. The results indicate that GVHD, without irradiation, can induce genomic damage associated with inflammatory reactions manifested by increased TNF-alpha levels.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2010; 689(1-2):59-64. · 2.85 Impact Factor
• Article: Relationship between serum levels of insulin-like growth factors and subsequent risk of cancer mortality: findings from a nested case-control study within the Japan Collaborative Cohort Study.

  Truong-Minh Pham, Yoshihisa Fujino, Kei Nakachi, Koji Suzuki, Yoshinori Ito, Yoshiyuki Watanabe, Yutaka Inaba, Kazuo Tajima, Akiko Tamakoshi, Takesumi Yoshimura
  [show abstract] [hide abstract]
  ABSTRACT: We investigated the association between serum levels of IGF-I, IGF-II, and IGFBP-3 and the subsequent risk of cancer mortality. Our case-control study examined samples from 914 cancer deaths and their 2739 matched controls within the Japan Collaborative Cohort Study. Blood samples were obtained at the baseline and stored at -80 degrees C until analysis for IGF-I, IGF-II, and IGFBP-3 levels. The conditional logistic model was used to estimate odds ratios (ORs) for cancer mortality associated with these serum levels. The adjusted ORs for IGF-I quartiles ranged from 0.81 to 0.96 but were not significant. The adjusted ORs and 95% confidence interval (CI) for the second, third, and fourth IGF-II quartiles were 0.64 (95% CI: 0.52-0.79), 0.71 (95% CI: 0.58-0.88), and 0.73 (95% CI: 0.59-0.91), respectively, while those for the respective IGFBP-3 quartiles were 0.77 (95% CI: 0.63-0.96), 0.75 (95% CI: 0.60-0.94), and 0.71 (95% CI: 0.56-0.90). In the model of IGF-I, and IGF-II additionally adjusted for IGFBP-3, the associations of high IGFs levels were similar as observed in the above models, while the association of IGFBP-3 shifted into non-significance after adjusting for IGF-II. An increased level of IGF-II was significantly associated with decreased risk of cancer mortality, whereas the association between IGF-I and all cancer mortality was not significant. The inverse association of IGFBP-3 level with all cancer mortality was affected when adjusting for IGF-II levels, shifting from significant to non-significant. Confirmation of these results from further cohort studies may aid in identifying the potential association between these molecules and the risk of cancer among the general Japanese population.
  Cancer epidemiology. 06/2010; 34(3):279-84.
• Article: Relationship of sFas with metabolic risk factors and their clusters.

  Akiko Tamakoshi, Koji Suzuki, Yingsong Lin, Yoshinori Ito, Kiyoko Yagyu, Shogo Kikuchi, Yoshiyuki Watanabe, Yutaka Inaba, Kazuo Tajima, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Metabolic risk factors are known to cause atherosclerosis through inflammation. In the process of inflammation, soluble Fas (sFas) may interfere with the apoptotic pathway and contribute to dysregulated inflammation. Recent studies suggest sFas as a marker of inflammation in patients with cardiovascular diseases. However, whether a relationship exists between sFas levels and metabolic risk factors among healthy subjects remains unclear. We measured the serum sFas levels of 876 subjects selected as controls for a nested case-control study within the JACC Study. The adjusted means of the sFas levels were compared according to the presence of overweight/obesity, hypertension, hyperlipidaemia, diabetes and their clusters. sFas level was significantly associated with overweight/obesity (2.42 ng mL(-1) in overweight/obese men and 2.19 in others) and hyperlipidaemia (2.34 ng mL(-1) in men with hyperlipidaemia and 2.19 in others) among men, though not with hypertension or diabetes. Moreover, a clear association between sFas levels and the cluster number of metabolic risk factors was observed independently with age, smoking and drinking(2.39, 2.28, 2.24 and 2.11 ng dL(-1) in men with three to four, two, one and none of the four metabolic risk factors respectively). However, among women, clear associations were not observed between sFas levels and the four metabolic risk factors or their clustering. Serum sFas levels appear to be associated with overweight/obesity, hyperlipidaemia and clusters of metabolic risk factors among men, suggesting that sFas may elevate to down-regulate increased apoptosis in atherogenesis processes.
  European Journal of Clinical Investigation 06/2010; 40(6):527-33. · 3.02 Impact Factor
• Article: Memory CD4 T-cell subsets discriminated by CD43 expression level in A-bomb survivors.

  Seishi Kyoizumi, Mika Yamaoka, Yoshiko Kubo, Kanya Hamasaki, Tomonori Hayashi, Kei Nakachi, Fumiyoshi Kasagi, Yoichiro Kusunoki
  [show abstract] [hide abstract]
  ABSTRACT: Our previous study showed that radiation exposure reduced the diversity of repertoires of memory thymus-derived cells (T cells) with cluster of differentiation (CD)- 4 among atomic-bomb (A-bomb) survivors. To evaluate the maintenance of T-cell memory within A-bomb survivors 60 years after radiation exposure, we examined functionally distinct memory CD4 T-cell subsets in the peripheral blood lymphocytes of the survivors. Three functionally different subsets of memory CD4 T cells were identified by differential CD43 expression levels and measured using flow cytometry. These subsets consist of functionally mature memory cells, cells weakly responsive to antigenic stimulation, and those cells functionally anergic and prone to spontaneous apoptosis. The percentages of these subsets within the peripheral blood CD4 T-cell pool all significantly increased with age. Percentages of functionally weak and anergic subsets were also found to increase with radiation dose, fitting to a log linear model. Within the memory CD4 T-cell pool, however, there was an inverse association between radiation dose and the percentage of functionally mature memory cells. These results suggest that the steady state of T cell memory, which is regulated by cell activation and/or cell survival processes in subsets, may have been perturbed by prior radiation exposure among A-bomb survivors.
  International Journal of Radiation Biology 01/2010; 86(1):56-62. · 2.28 Impact Factor
• Article: Relationship of serum superoxide dismutase activity and lifestyle in healthy Japanese adults.

  Masanori Nojima, Fumio Sakauchi, Mitsuru Mori, Akiko Tamakoshi, Yoshinori Ito, Yoshiyuki Watanabe, Yutaka Inaba, Kazuo Tajima, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Superoxide dismutase (SOD) is an antioxidant enzyme that acts to degrade superoxide, a major causitive factor for oxidative stress associated with cancer, cardiovascular disease, and various other ailments. Here, to assess an association between antioxidants and lifestyle factors related to cancer risk, we analyzed serum SOD activity among the subjects within a large-scale cohort study in Japan. As results, significant differences in serum SOD activity were found between the sexes (lower in males), among female age groups (lower in younger individuals), and in males with the BMI (lower in those with a high BMI). Linear increase in serum SOD activity with aging and decrease with BMI were observed in females. Significantly low SOD activity was evident in male heavy smokers. In contrast, elevation was noted in female frequent drinkers. In conclusion, our findings do suggest associations between serum SOD activity and lifestyle factors. However, for further study, establishment of a standard measurement method for SOD activity should be a high priority.
  Asian Pacific journal of cancer prevention: APJCP 12/2009; 10 Suppl:37-40. · 0.66 Impact Factor
• Article: Relationship of soluble fas with body mass index in healthy Japanese adults.

  Akiko Tamakoshi, Koji Suzuki, Yingsong Lin, Yoshinori Ito, Kiyoko Yagyu, Shogo Kikuchi, Yoshiyuki Watanabe, Yutaka Inaba, Kazuo Tajima, Kei Nakachi
  [show abstract] [hide abstract]
  ABSTRACT: Recent studies have linked elevated serum sFas levels to atherosclerotic disease among patients. Confirming an association between obesity and serum sFas levels in healthy subjects would facilitate our understanding of obesity and its related disorders. We therefore analyzed serum sFas levels of 8,541 subjects selected as controls for a nested case-control study within the JACC Study. Body mass index (BMI) was calculated as the indicator of obesity based on self-reported height and weight. We found a statistically significant positive association between serum sFas levels and BMI among our apparently healthy subjects. Our result suggests that serum sFas rises to down-regulate increased apoptosis in atherogenesis processes caused by obesity.
  Asian Pacific journal of cancer prevention: APJCP 12/2009; 10 Suppl:41-4. · 0.66 Impact Factor