Gen Suzuki

Spectrum of Znfn1a1 (Ikaros) Inactivation and its Association with Loss of Heterozygosity in Radiogenic T-Cell Lymphomas in Susceptible B6C3F1 Mice

Abstract Kakinuma, S., Nishimura, M., Sasanuma, S-I., Mita, K., Suzuki, G., Katsura, Y., Sado, T. and Shimada, Y. Spectrum of Znfn1a1 (Ikaros) Inactivation and its Association with Loss of Heterozygosity in Radiogenic T-Cell Lymphomas in Susceptible B6C3F1 Mice. Radiat. Res. 157, 331u200a–u200a340 (2002). Ikaros (now known as Znfn1a1), a Krüppel-type zinc-finger transcription factor that plays a critical role in both lineage commitment and differentiation of lymphoid cells, has recently been shown to function as a tumor suppressor gene. We have previously reported a high frequency of LOH (∼50u200a%) at the Znfn1a1 locus in radiation-induced T-cell lymphoma in susceptible B6C3F1 mice. The aim of the present study was to delineate the types of Znfn1a1 inactivation, with special reference to the LOH status, and to determine the relative contribution of each type of Znfn1a1 inactivation in radiation-induced T-cell lymphomas in B6C3F1 mice. We demonstrated that Znfn1a1 was frequently altered (in ∼50u200a% of T-cell lymphomas), and that its inactivation was caused by a variety of mechanisms, which came under one of the following four categories: (1) null expression (14u200a%); (2) expression of unusual dominant-negative isoforms (11u200a%); (3) amino acid substitutions in the N-terminal zinc-finger domain for DNA binding caused by point mutations (22u200a%); (4) lack of the Znfn1a1 isoform 1 due to the creation of a stop codon by insertion of a dinucleotide in exon 3 (3u200a%). The null expression, amino acid substitutions, and dinucleotide insertion inactivation types were well correlated with LOH at the Znfn1a1 allele (86u200a%) and were consistent with Knudsons two-hit theory. On the other hand, T-cell lymphomas expressing dominant-negative Znfn1a1 isoforms retained both alleles. These results indicate that Znfn1a1 inactivation takes place by a variety of mechanisms in radiation-induced murine T-cell lymphomas and is frequently associated with LOH, this association depending on the type of inactivation.

Longitudinal trends of hemoglobin levels in a Japanese population – RERF's Adult Health Study subjects

Abstract: Conflicting results have been reported on the long‐term relationship between hemoglobin (Hb) level and age. We analyzed that relationship over a 40‐yr period in a Japanese population, adjusting for the effects of sex, birth cohort, smoking, and anemia‐associated diseases. We used Hb levels measured biennially between 1958 and 1998 for 4858 Adult Health Study subjects of the Radiation Effects Research Foundation. Using the mixed‐effects model, we showed that the aging Hb profile varied by sex (Pu2003<u20030.001) and birth cohort (Pu2003<u20030.001). Male Hb levels peaked in the third and fourth decades and then decreased while female Hb levels dipped slightly in the third decade, peaked in the sixth and seventh, and then decreased. Levels were higher in younger cohorts. The rate of Hb decline after the sixth decade of life was greater for subjects with anemia‐associated diseases (Pu2003=u20030.002). The annual rate of decline between 70 and 80 yr of age for disease‐free men ranged from 0.083 to 0.042u2003g/dL and for disease‐free women from 0.049 to 0.036u2003g/dL. Levels were higher for ever‐smokers (Pu2003<u20030.001), more so for women than men. A decreasing trend in Hb concentration with advancing age was detected for elderly men and women after controlling for anemia‐associated diseases, suggesting that anemia in the elderly is due not only to disease but also to aging. Cohort and smoking effects on Hb levels were also observed.

Prevalence of Hepatitis B Virus Infection among Atomic Bomb Survivors

Abstract Fujiwara, S., Sharp, G. B., Cologne, J. B., Kusumi, S., Akahoshi, M., Kodama, K., Suzuki, G. and Yoshizawa, H. Prevalence of Hepatitis B Virus Infection among Atomic Bomb Survivors. Radiat. Res. 159, 780–786 (2003). The aim of this study was to determine whether the prevalence of hepatitis B virus (HBV) carriers increased with atomic bomb radiation dose, and whether radiation decreased the ability to clear HBV among the atomic bomb survivors. The study subjects were 6,121 participants in the Adult Health Study of atomic bomb survivors in Hiroshima and Nagasaki. After adjustment for age, sex, city and potential confounders, the rates of seropositivity for hepatitis B surface antigen (HBsAg), indicating current HBV infections, and anti-hepatitis B core antibody, indicating either cured or current infections, increased with radiation dose. However, no relationship was observed between radiation and anti-hepatitis B surface antibody (indicating cured infection). The proportion of persons who were unable to clear the virus, as the proportion of HBsAg-positive persons among those ever infected by HBV (positive for HBsAg or surface or core hepatitis B antibody), increased significantly with radiation dose among those receiving blood transfusions. This proportion was not related to dose among those who reported no such transfusions. The findings may suggest a lower likelihood of clearance after HBV infection among those who were more likely to have been infected with HBV as adults after atomic bomb irradiation rather than as infants or adults prior to irradiation.

Monoclonal gammopathy of undetermined significance in atomic bomb survivors: incidence and transformation to multiple myeloma.

Summary. Among 6737 atomic bomb survivors who did not have monoclonal gammopathy at the first examination, 112 developed monoclonal gammopathy of undetermined significance (MGUS) between 1985 and 2001. The crude incidence rate was 164 per 100u2003000 person‐years in the overall study population, with a sharp increase in incidence after age 60u2003years. The incidence was not significantly associated with radiation dose (Pu2003=u20030·91), although the incidence at less than 80u2003years of age showed a marginally significant association (Pu2003=u20030·05). Among 75 patients with MGUS detected in 1985, 50 patients (67%) had died by 2001, 16 (21%) of these deaths were due to multiple myeloma (MM). MM mortality among MGUS patients was 2284 per 100u2003000 person‐years while the rate in the total population was 14·6 per 100u2003000 person‐years. The risk of MM mortality was greater in the older generation. The transformation from MGUS to MM was faster in exposed persons than in non‐exposed persons, but this was not statistically significant.

Elevated interleukin-9 receptor expression and response to interleukins-9 and -7 in thymocytes during radiation-induced T-cell lymphomagenesis in B6C3F1 mice.

Dysregulation of cytokine receptor expression and responsiveness to cytokines is hypothesized to play an important role in the development and expansion of preneoplastic cells or progression of neoplastic cells during the early and late stages of leukemogenesis. To determine the crucial changes in initiated cells that confer significant growth during the early stage of radiation‐induced lymphomagenesis, we examined both the expression of receptors for thymus‐derived cytokines and thymocyte response to cytokines before the onset of T cell lymphomas in B6C3F1 mice after split‐dose irradiation. After irradiation, thymic T cell subsets underwent delayed regeneration consisting of two phases as determined by receptor expression. The first phase occurred within 1 week post‐irradiation and was accompanied by transient expansion of T cell subsets strongly expressing receptor genes for IL‐1, IL‐2, IL‐6, IL‐7, IL‐15, and TNFα. The second phase occurred 12 weeks after irradiation and was characterized by increased expression of IL‐9Rα. Thymocytes from non‐irradiated control mice were unresponsive to IL‐9. However, IL‐9 acted synergistically with IL‐7 and PHA to stimulate the proliferation of irradiated cells during the second post‐irradiation phase. Moreover, these cells showed hyper‐responsiveness to IL‐7 or PHA alone compared to age‐matched non‐irradiated control thymocytes. These results suggest that the unusual expression of IL‐9 receptors and/or increased responsiveness of thymocytes to cytokines are key processes in the development of radiation‐induced T cell lymphomas. J. Cell. Physiol. 198: 82–90, 2004.

An Association between Oxidative Stress and Radiation-Induced Lymphomagenesis

Abstract Suzuki, G., Shimada, Y., Hayashi, T., Akashi, M., Hirama, T. and Kusunoki, Y. An Association between Oxidative Stress and Radiation-Induced Lymphomagenesis. Radiat. Res. 161, 642–647 (2004). It is generally thought that reactive oxygen species (ROS) play an important role in carcinogenesis. However, direct evidence supporting this idea is still lacking. In the present study, we measured ROS in thymocytes at the thymic prelymphoma stage in C57BL/6 mice. Mice (n = 20) were irradiated at 1.6 Gy/week for 4 consecutive weeks and the levels of ROS were measured 8 to 11 weeks later by dehydrorhodamine 123, which accumulated in mitochondria and became fluorescent dye upon oxidation. Unirradiated littermates (n = 17) served as controls. Thymic prelymphoma cells were diagnosed by the aberrant CD4/CD8 staining profile and monoclonal or oligoclonal T-cell receptor gene rearrangement. A significant fraction of mice (11/13) bearing thymic prelymphoma cells exhibited elevated levels of ROS in thymocytes (P < 0.001). The result is consistent with the hypothesis that ROS may play an important role in radiation carcinogenesis.

HLA haplotype is associated with diabetes among atomic bomb survivors

We examined radiation effects on the relationship between diabetes development and genetic background in atomic-bomb (A-bomb) survivors. Our main aim in this study was to shed light on the role of genetic background in diabetes onset among A-bomb survivors by studying possible relationships between human leukocyte antigen (HLA) genotypes and the diabetes in patients and controls. We examined the effects of different HLA haplotypes on type 2 diabetes development by determining the DQA1 and DRB1 alleles of Hiroshima A-bomb survivors (111 diabetic patients and 774 controls) using the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. We noted an increased risk of diabetes in the higher dose group among these patients (trend p = 0.001). The risk of the most heavily exposed group was significantly higher than that of the unexposed group or the low-dose group especially in survivors with the DQA1*03-DRB1*09 or DQA1*0401-DRB1*08 haplotypes (trend p = 0.002 or p = 0.05, respectively). By contrast, in people with other haplotypes, the risk did not increase significantly with increasing dose. These results suggest that individuals with specific HLA haplotypes may have an increased risk of diabetes with increased-dose categories.

Radiological findings of accidental radiation injury of the fingers : A case report

This case report describes the medical follow-up of a 46-y-old (at the time of exposure) man who in 1971 accidentally exposed the fingers of his right hand to gamma-ray radiation from an iridium source that was used for nondestructive testing [estimated radiation dose: 26 Gy to 90 Gy (2,600 rad to 9,000 rad)]. No prominent acute injury was detected except for leukocytopenia (800 mm(-3)) and thrombocytopenia (15,000 mm(-3)). Three years later, the first, second, and third fingers presented repeated infection and started to develop contracture. Twenty-two years after exposure, he underwent amputation of the first and second fingers, and a toe graft was done. Radiological examinations prior to and following the operation revealed atrophic change of the finger bones and arterial injuries. Angiographic findings coincided with the region and extent of radiation injury of the fingers, which indicates that arterial damage is involved in the development of this chronic disorder.

Body Surface Contamination Levels of Residents under Different Evacuation Scenarios after the Fukushima Daiichi Nuclear Power Plant Accident

Abstract Body surface contamination levels should be correlated with inhaled actual thyroid doses during evacuation following the Fukushima Daiichi nuclear power plant (FDNPP) accident. Evacuees and residents were screened for body surface contamination using a Geiger-Mueller survey meter. The authors obtained 7,539 individual screening data sheets as well as gamma-spectrometry data from measurements made on clothing of two subjects by using a germanium spectrometer. Body surface contamination levels were analyzed in four residential groups during two different periods: 12–14 and 15–17 March 2011. Contamination levels during 12–14 March in the Tomioka/Okuma/Futaba/Naraha group were very low, indicating that residents evacuated before the radioactive plume reached their towns on 12 March. In contrast, levels in the Namie and Minamisoma groups were higher than those in the other groups in both periods, indicating that these residents were exposed to plumes twice on 12 and 15–16 March. The plume on 12 March was enriched with short-lived radionuclides: averaged proportions of radioactivity (relative to 131I) from 132Te, 133I, and 137Cs measured in clothing from two subjects were 2.3, 1.1, and 0.1, respectively, after correction for physical decay by 12:00 on 12 March. These proportions are similar to those (relative to 131I) from 132Te and 137Cs in dust sampled by a high-volume air sampler in the zone 20 km from the FDNPP on 12 March: 1.9 and 0.1, respectively. These data indicate that the relative contribution to inhaled thyroid dose of short-lived radionuclides in radioactive plumes released on 12 March could be as much as 37.5% in 1‐y-old children.