Radiation research includes three disciplines. Mechanistic studies of radiation effects try to correlate the primary radio-physical processes to the final biological outcome. Medical applications of the knowledge of basic radiation biology are another expanding field in the era of ever increasing medical use of radiations. Risk evaluation of low dose and low dose rate radiation is the major concern of the society where radiation use is widespread in our modern life and this is a field where basic radiobiology can again of great importance. Thus, radiation research is a field where basic science is combined with applied science. Furthermore, the field can extend even into social science. Historically, radiation research started around 1950 when researchers tried to understand biological effect of radiation through the knowledge of basic physical processes of radiation action. The field then moved into the kinetical studies of tissue culture cells and thereafter expanded to the analyses of radiation effects on whole body systems. Among many of these studies, research on DNA repair expanded rapidly with the extensive use of molecular technologies and now the resulting damage response field is now integral to the basic life science. For these expansions of the field, reverse genetics played a significant role. At the same time, it is becoming clearer that the forward genetics approach can plays an important role in radiation research. For example, in order to solve one of the fundamental issues of low dose and low dose rate radiation risk, one has to know how mutation is induced in the cells in tissues and what could be the fate of the mutant cells. Advanced technology of embryo manipulation enables us to construct sophisticated systems which are expected to give exact answers to previously unsolved questions. In my lecture, I would like to discuss how we can make radiation research as science for the future.

View full abstract

In my presentation I will briefly touch upon such subjects including "about ICRP and UNSCEAR", "Sources of radiation exposure", "health effects attributable to radiation exposure" and "framework of radiation protection" based on my experiences as a member of main commission of ICRP and chairman of UNSCEAR.
With the increasing recognition of hazardous effects of radiation ICRP was established in 1928 as a committee of the ICR. Its field of work has widened from protection in medical radiology to all aspects of protection against ionizing radiation. The latest general recommendation was issued in 1990 as publication 60. The commission is now preparing the new recommendation to be completed probably in 2007. In the latest ICRP general meeting held Sept. 9-16, 2005, a new committee 5 was started in order to discuss and report on radiation protection of environment or non-human biota.
UNSCEAR was founded in 1955, having been urged by increasing concerns worldwide about the effects of fallout from atmospheric nuclear testing. UNSCEAR is the UN body with a mandate to provide estimates on the levels and effects of radiation exposures. It collects information, reviews and validates scientific soundness of the information.
On these scientific basis ICRP provides guidance on the fundamental principles on which appropriate radiological protection can be based. UNSCEAR's estimates, together with the ICRP recommendations, are used by the IAEA in discharging its statutory responsibilities of establishing BSS and providing for their application.

View full abstract

From 1968 to 1972,a survey was carried out to find miraculously survived persons who had been exposed to Atomic Bomb within 500 meters from the hypocenter, by Hiroshima University, NHK Hiroshima and Hiroshima City. After the confirmation of 78 survivors, Hiroshima University started a project called "Comprehensive Study on Heavily Exposed Survivors" in 1972. In this presentation, sociological, psychological and physiological damages among those 78 persons will be reported, as well as some evidences on biological effects caused by the high dose of radiation. Sociological damages: destruction of family unit by loss of more than two members at time of the bombing, orphans resulted from the A-bomb disaster; disturbance of family construction due to divorces. Psychological damages: psychological burdens due to spontaneous abortion in the female survivors; shift to neurosis or dysautonomia from normal condition after 50 - 60 years of the exposure, revealed by Cornel Medical Index method. Physiological damages: 55 deaths, of which 29 due to cancers(38%) including four persons with double or triple cancers, 20(36 %) due to cerebro-cardiovascular diseases and 6( 10 %) others. Exposed radiation doses estimated by chromosome aberration of the peripheral lymphocytes distributed from 1.1 to 5.1 Sv. Evidences of biological effects: chromosome aberration rate of the bone marrow cells in 40 years after the exposure was two third of that of the peripheral lymphocyte; presence of abnormal clones in the bone marrow and the exchanges by newly produced ones; a high value of EB(Epstein-Barr) virus antibody; presence of chromosome aberration-inducible serum factor(s)(bystander effects); RAS gene mutations in the bone marrow cells which might lead to the leukemia or solid tumor developments of the survivors; activation of intrinsic retrovirus; high incidences of meningioma and multiple cancers among the survivors.

View full abstract

Translesion DNA synthesis is a cellular response to the DNA damage. This biological function is essential for the maintenance of chromosomal integrity as well as the DNA repair function. It has been suggested that functions of the REV genes are required for error-prone post-replication repair, essential for induction of mutations and prevention of cell death caused by ionizing radiation. REV1 is the deoxycytidyl transferase and a member of the Y-family DNA polymerase. The activity is capable of extending a primer terminus by insertion of dCMP opposite a variety of damaged bases. REV3 and REV7 encode an error-prone DNA polymerase, pol ζ. Genetic data suggest that those proteins form specialized machinery for translesion DNA synthesis.
To elucidate molecular mechanisms of the induced mutagenesis in humans, we have purified the recombinant proteins and demonstrated that the REV1 is the deoxycytidyl transferase and forms a stable heterodimer with REV7. Recently, it has been found that the REV1 interacts with all of the Y-family DNA polymerases, pol η, pol ι, pol κ, suggesting the central role of REV1 in the translesion DNA synthesis. In this symposium, we present the biochemical property of the REV1 protein and discuss the molecular roles in the translesion DNA replication.

View full abstract

Higher eukaryotes cell nucleus has a compartmentalized structure built up by chromosome territories (CTs) and an interchromatin compartment (IC). The IC expands both between neighboring CTs and into the interior of indivisual CTs and is lined by the surfaces of smaller and larger chromatin domains. However, little is known about the dynamic organization of higher order nuclear architectures including chromatin and non-chromatin nuclear domains after induction of DNA damage. To examine the dynamic organization of higher order nuclear architecture for DNA repair, we have developed a system for local irradiation of cell nuclei using a focused UV-laser (laser-UV-microirradiation). Furthermore, we have studied the dynamics of DNA repair proteins in living cells by the combination of the laser-UVA-microirradiation sysytem with Fluorescence Recovery after Photobleaching (FRAP) technique. Using these techniques, we have revealed that DNA repair proteins accumulated at site of containing DNA damage at various times after induction of DNA damage, and that chromatin structure showed dynamic change from just after induction of DNA damage. Now to examine the topological and chronological relationships between several non-chromatin nuclear domains associated with DNA repair in a single cell, we are developing a multicolor immunofluorescence staining method.Dynamic organization of higher order nuclear architecture for DNA repair will be discussed.

View full abstract

Mutation has been assumed to play a central role in carcinogenesis for a long time. However, the incidence of mutation in human cancers is not so high. Even if cancer-associated genes are not mutated, chromosomal aberrations are likely to lead to cancer. Among a variety of chromosomal aberrations, we focus on aneuploidy, a numeral chromosome aberration. Aneuploidy is so frequently observed in cancer that researchers have not paid much attention to the molecular mechanism of the origin of aneuploidy. However, it is of great importance to investigate the biological significance of aneuploidy in carcinogenesis, because we cannot explain cancer development only by mutation and aberrant methylation. To understand the mechanism of the formation of aneuploidy, we have investigated the role of DNA double-strand break repair genes in chromosome instability. Although aneuploidy is frequently observed in human cancer cells deficient in double-strand break repair, the molecular mechanism of this phenotype varies. We will discuss how DNA double-strand breaks lead to aneuploidy.

View full abstract

Bloom syndrome (BS) is a rare genetic disorder associated with cancer predisposition and genomic instability. BS cells show high frequency of recombination between homologous recombination as well as sister chormtids, resulting in mitotic recombination and sister chromatid exchange (SCE), respectively. We focused on this characteristic of BS and applied it as a novel genetic tool.
Forward genetic screen is a powerful strategy to identify genes corresponding to the phenotype of interest. But this has been hampered in mammalian systems because of the difficulty to introduce null mutation to both alleles and to construct a comprehensive mutant library that covers all genes. To overcome this limitation, we focused on the high frequency of mitotic recombination of BS, which converts introduced heterozygous mutations to homozygous, thus enabling us to construct a random mutant library.
We introduced a tet-off cassette into the Blm locus to regulate recombination. In targeted homozygous ES cells, Blm protein disappears quickly and shows elevated level of SCEs upon administration of doxycycline. The rate of mitotic recombination was elevated 27 folds. Combining with ENU mutagenesis, we made a mutant library and screened mutants, lacking GPI-anchor biosynthesis. Mutants corresponding to half of 23 known genes and 2 novel mutants were obtained from the library, indicating the effective generation of bi-allelic mutant library. Our new method for comprehensive isolation of bi-allelic mutants should have a major impact for annotating genes with functional information.

View full abstract

In nucleus, DNA is packaged in chromatin. The fundamental subunit of chromatin is the nucleosome, which consists of approximately 165 base pairs of DNA wrapped in two superhelical turns around an histone octamer. Chromatin structure restricts the access of proteins to DNA binding sites. How the DNA repair machinery detects a DNA lesion and fixes it in chromatin has been an intriguing question. To investigate the relationship between chromatin dynamics and nucleotide excision repair (NER), we have examined the effect of chromatin structure on the formation of two major classes of UV-induced DNA lesions. Furthermore, we established a model chromatin-NER system using reconstituted 5S dinucleosomes and purified human NER factors. We found that although the chromatin structure of DNA does not inhibit its formation of UV-induced lesions, excision of this damage with six NER factors are severely inhibited by this structure. Interestingly, NER dual incision is facilitated by an ATP-dependent chromatin remodeling factor. Furthermore, we developed a chromatin assembly system with nucleosome assembly protein-1 (NAP-1) as a linker histone chaperone. This assay system revealed that somatic histoen H1 prevents ATP-dependent chromatin remodeling, whereas maternal histone B4 allows chromatin to be remodeled by it. The repressive effects of somatic H1 on ATP-dependent chromatin remodeling were abrogated by addition of free linker histone chaperone. These results illuminate molecular pathway of damage repair in chromatin.

View full abstract

Eukaryotic chromosomes consist of chromatin, which is locally remodeled by the action of histone-modifying enzymes, ATP-dependent chromatin remodeling factors, and sequence-specific DNA binding proteins such as transcription factors. Recently, it has been demonstrated that acetylation and phosphorylation of histones play pivotal roles in the regulation of repair of DNA double strand breaks (DSBs), recruiting some other DNA repair proteins and factors related to cell cycle checkpoint systems.
We have been involved in the study on regulation of meiotic homologous recombination in yeast as a model system. We found that a subclass of meiotic homologous recombination is positively regulated in a site-dependent manner by the histone acetylation and remodeling mediated by histone acetylases (HATs) and ATP-dependent chromatin remodeling (ADCR) factors. Similar regulation of homologous recombination by histone acetylation can be found in the gene conversion (a type of homologous recombination) occurring in the cultured chicken B-cell line DT40. From these results, together with some data by others, I would like to discuss about the roles of histone modification and chromatin remodeling in the regulation of homologous recombination.

View full abstract

Through the passage of replication fork, parental nucleosomes are transiently disassembled and transferred to the newly synthesized DNA (parental nucleosome segregation), and the nascent histones H3-H4 tetramers are also deposited onto newly replicated DNA behind the replication fork (de novo nucleosome assembly), followed by loading of H2A-H2B dimers to complete nucleosome formation.CAF-1, composed of p150, p60, and p48 subunits, was purified from human cell nuclear extract as an activity to promote nucleosome assembly of replicating DNA in SV40 replication system. CAF-1 is recruited in replication foci with nascent histones H3-H4 in human cells, via interaction with DNA polymerase sliding clump, PCNA (Shibahara and Stillman, 1999, Cell). Therefore, CAF-1 is a prime candidate for the factor involved in, at least, the de novo nucleosome assembly. CAF-1 also mediates nucleosome assembly during NER following UV irradiation. Null mutations of CAF-1 homologue in Arabidopsis displayed unstable propagation of gene expression through plant growth and mild sensitivity to various DNA damaging agents including MMS and IR (Kaya et al., Cell, 2004; submitted). Recently, we analyzed conditional knockout chicken DT40 cells in which CAF-1 can be depleted by addition of tetracycline. CAF-1 depletion led to delayed S-phase progression with retarded DNA synthesis and defects in a rapid nucleosome formation of newly replicated DNA. Furthermore, we obtained some evidence suggesting that CAF-1 is involved in the activation of replication checkpoint via Chk1 (Takami et al., submitted).

View full abstract

Eukaryotic genome is the tightly packed into the chromatin, a hierarchically organized complex of DNA and histone and nonhistone proteins. This packing represents a common obstacle for most of the DNA functions. We have already shown that TIP60 histone acetylase complex involved in DNA repair and apoptosis. However, it remains unknown how TIP60 complex involve in DNA repair. To better understand the mechanism of TIP60 complex in DNA repair, TIP60 complex purifies from chromatin soluble fraction after DNA damage. As a result, the TIP60 complex is associated with g-H2AX after DNA damage. Histone H2AX, histone H2A variant, is phosphorylated at the site of DNA double-strand breaks (DSBs). Furthermore, it has been revealed that H2AX is highly mobile upon DSBs in the nucleus in the experiment of the Photo-bleaching with micro-irradiation. Interestingly, in mutated TIP60 (which is lack of histone acetylase activity) expressing human fibroblast cells, the dynamics of H2AX is inhibited upon DSBs relative to parental human fibroblast cells. Thus TIP60 complex regulates the dynamics of H2AX after induction of DNA damage. These results indicate that dynamics of H2AX might have important implications for initial DNA repair process.

View full abstract

The dosimetry system for the atomic bomb survivors in Hiroshima and Nagasaki has been changed many times and recently the new dosimetry system 2002 (DS02) was determined. The individual dose was obtained as the Tentative 1965 dose (T65D) and used to determine the radiation risks joining with the epidemiology study in Radiation Effects Research Foundation. After this, US scientists found some contradiction between T65D and the newly obtained doses by super computers. In 1981 reevaluation study of T65D was begun. In 1987 the Dosimetry System 1986 (DS86) was determined and used again for the risk estimation of the radiation. The change from T65D to DS86 was not small, for example neutron dose in Hiroshima decreased to 1/5 to 1/9, and became negligible as that of Nagasaki. However even in the newly obtained DS02, contradiction between the data and calculation was found. Therefore again reevaluation study was began.
In the study of DS02 and DS86 Japanese side mainly collected exposed samples such as concrete, iron and granite samples for the measurements of neutron induced activities (Co-60, Cl-36 and Eu-152) and tiles, roof tiles and bricks for the measurements of gamma ray, and measured these samples to obtain neutron and gamma-ray doses. US side measured Cl-36 activity and made very extensive calculation such as the process of explosion, transport of neutrons and gamma rays, house shielding effects and organ doses.
Finally the problems existed in Hiroshima were solved. Height of burst was elevated 20 m to decrease neutrons of DS86 at short distances. The inter-comparison study was performed between Eu-152 and Cl-36 using already collected samples, of which data became close to DS02. The results of the individual organ doses will be used to calculate radiation risks.

View full abstract

The Radiation Effects Research Foundation has conducted a mortality study since 1950 and a cancer incidence study since 1958 on a fixed population (LSS cohort) of about 120,000 subjects including atomic-bomb survivors and their controls to determine health effects of atomic-bomb radiation. Clinical examinations have also been conducted biennially for about 20% of the LSS cohort since 1958.
The most important late effect observed among atomic-bomb survivors is an increase of cancer risk. In contrast to the leukemia risk, the risk of solid cancers (stomach, lung, etc.) started increasing only after the exposed reached the cancer-prone age, and now continues to increase in proportion to the increase of the background cancer risk.
We have studied whether radiation risk on solid cancers varies depending on the site, radiation dose, sex, age, or the state of exposure to other carcinogens, including cigarettes. In summary, although no statistically significant increase in cancer risk has been observed for some sites, including the rectum and pancreas, an effect from radiation has been observed for the cancers of many sites, including the lung, stomach, and colon. The dose-response relationship for these sites shows a linear increase with radiation dose. The younger was the age at exposure, the higher the relative risk. The effect of radiation does not vary significantly by other carcinogenic factors, including smoking.
With the elapse of 60 years after the atomic bombings, the proportion of living subjects of the LSS cohort has decreased to 50% or under. About 80% of those exposed before age 20 are still alive. The mortality and cancer incidence studies for the LSS cohort will continue to provide important information.

View full abstract

The elevated risk of leukemia that appeared a few years later has been considered declined to background level by early 1960. However, recent studies in either Hiroshima or Nagasaki suggest that myelodysplastic syndromes (MDS), so called preleukemic states, appear to increase in incidence among proximally exposed population. If this is true, leukemia-related neoplasia seems to become evident along with aging of the Atomic Bomb survivors. This might be compatible with the trend for persistence of elevated risks for solid neoplasia along with aging. Thus it is extremely important to establish dose response relationship for MDS to prove persistence or re-emergence of myeloid neoplasia along with aging.
Multiple myeloma (MM) is a major lymphoid neoplasia that was once considered induced by the atomic bomb radiation. However, summary analysis by RERF in late 1980ies disclosed negative result. Since MM is a rather indolent neoplasia that is not easy to detect among the survivor, we are now conducting in Nagasaki a large scale detection program for Monoclonal Gammopathy of Unknown Significance (MGUS), so called pre-MM state, and progression to full MM. Recent preliminary analysis suggests that, similar to MDS, risk for MGUS is also elevated among proximally exposed survivors. It is still early to calculate progression rate to full MM according to distance.
In this paper I would like to summarize epidemiological studies on Blood Cell Neoplasia among survivors during the past 60 years and try to provide perspectives for future studies to know why single high dose total body irradiation by the Atomic Bombs continue to induce excessive neoplasia over whole lives of survivors. The answer, if provided in future, is extremely important to understand human cancer induction by radiation.

View full abstract

Human leukemia frequently involves recurrent translocations. Since radiation is a well-known inducer of both leukemia and chromosomal translocations, it has long been suspected that radiation might cause leukemia by inducing specific translocations. However, recent studies clearly indicate that spontaneous translocations specific to acute lymphocytic leukemia (ALL) actually occur much more frequently than do leukemia cases with the same translocations. Moreover, the ALL-associated translocation-bearing cells are often found to have clonally expanded in individuals who do not develop ALL. Since radiation-induced DNA damage is generated essentially randomly in the genome, it does not seem likely that radiation could ever be responsible for the induction of identical translocations of relevance to ALL in multiple cells of an individual and hence be the primary cause of radiation-related leukemia. An alternative hypothesis described here is that the radiation-related ALL risk to a population is almost entirely attributable to a small number of predisposed individuals in whom relatively large number of translocation-carrying pre-ALL cells have accumulated. This preleukemic clone hypothesis explains various known characteristics of radiation-related ALL, and implies that people who do not have substantial numbers of preleukemic cells (i.e. the great majority) are likely at low risk of developing leukemia. The hypothesis can also be applied to chronic myelogenous leukemia, and to young-at-exposure cases of acute myelogenous leukemia.

View full abstract

The necessity to investigate the HLNRA in Karunagappally in Kerala, India was emphasized by the WHO as early as 1959. BARC since 1960, started studies on the detrimental effects of HLNR on biological systems. Studies of Grunberg et al (1966) on rats and those of Gopal Aiyyengar (1972) on human were not suggestive of any positive genetic effect. Cytogenetic studies on Flora from these areas have indicated significant positive correlations between cytological damage, external radiation levels and internal radionuclide content in plants (George et al, 1991). Monitoring of newborns at birth for malformations and a comprehensive Health Audit Survey by the BARC team indicated that HNLR in Kerala has no heritable effect on humans (Thampi et al, 2004).
RCC, Trivandrum in 1990 initiated a baseline socio-demographic lifestyle survey, radiation level measurements (dosimetry) and Cancer Registry in this area. Analysis of 181 soil samples in this area indicated ²³²Th to be the main radiation contributing source. Radiation levels between and within the panchayaths showed large variations and a radiation cohort has been identified (RRK Nair et al, 2004). Since 1990, NBRR of RCC, has been studying the cancer causing potential of HLNR. At the end of ten years of study, NBRR was in a position to assert that there is no alarming increase in cancer due to HLNR (Gangadharan et al, 2004; jayalekshmi et al, 2004). RCC has already initiated studies to calculate the cumulative dose after measuring the individual exposure rate and to evaluate the cytogenetic effects of the same.

View full abstract

The Talesh Mahalleh area in Ramsar has the highest terrestrial radiation potential effective public dose levels in Iran. The high background radiation of this area is mainly due to hot springs with high concentrations of radium-226 and its decay products, which flow into the surrounding areas causing a high potential for public exposure. To identify the dose-dependent increase of dicentrics and ring chromosomes in lymphocytes of the residents in the high background radiation area (HBRA) of Ramsar, personal dose monitoring and cytogenetic investigation were performed for 15 elderly housekeeping women living in Talesh Mahalleh and 10 matched elderly women in the nearby control area (CA) of Katalom where lifestyle and living circumstances of the residents are similar to those of the HBRA. All the subjects in our study are nonsmokers. The age ranges were 50-63 (average of 55.6 ± 4.4) years in HBRA and 50-62 (average of 53.3 ± 4.9) years in the CA. To obtain accurate data in quantifying dicentric and ring chromosomes, we carried out a cytogenetic study using advanced techniques with improved recovery of metaphase. Dicentric and ring chromosomes were scored for more than 2000 cells per individual under a microscope equipped with an automated stage. The exposed radiation dose of each individual in the HBRA and the CA was estimated from the dose measured by an electronic pocket dosimeter (EPDTM) and a Luxel badge. The results of the analysis of unstable chromosome aberrations found in the residents in the HBRA and the control areas will be presented.

View full abstract

Chromosome translocation is a stable type aberration that accumulates in the body by being exposed to environmental mutagens. In order to compare the biological effect of low dose radiation with those of other environmental mutagens, we investigated the frequency of chromosome translocations in peripheral lymphocytes in 28 healthy and elderly residents of a high-background radiation area (HBRA) in southern China, and in 24 matched residents of a control area (CA). The mean ages of those residents were 63.0 in the HBRA and 63.1 in the CA. The radiation they received in the HBRA was 3 to 5 times higher than that in the CA. The total numbers of cells analyzed were 123,065 in the HBRA and 93,117 in the CA. The mean frequencies of translocations per 1,000 cells in the HBRA and CA were 12.4 ± 5.3 and 10.0 ± 3.8, respectively. No significant difference in frequency was found between the HBRA and CA (P>0.05, Mann-Whitney U test). When those individuals were classified into smokers and nonsmokers, a significant difference was found in the frequencies between smokers and nonsmokers in the CA (P<0.05, Mann-Whitney U test). Furthermore a tendency toward difference (T-value near 0.05) was found in a comparison of smokers in the HBRA vs. nonsmokers in the CA. The present results indicate that the elevated level of natural radiation in the HBRA plays a less significant role than smoking in the induction of stable-type aberrations in those areas.
We also examined age-matched smokers living in Beijing more than 40 years to investigate the effect of air pollution. The frequencies of translocations in these subjects showed a larger individual variation than those in the rural areas.

View full abstract

Theoretically translocations and dicentrics should be induced by radiation equally. However, most papers have reported that translocations are observed slightly more often than dicentrics after exposure to radiation.In order to learn the reason why translocations are induced more than dicentrics, induction rates of dicentrics and translocations involving chromosomes 2 and 4 in peripheral lymphocytes irradiated with X-rays at a dose of 3 Gy were examined using conventional Giemsa staining method and painting method.A total of 228 reciprocal exchanges detected in 982 metaphases were classified into three groups according to the break points of the original chromosomes. The incidence of both acentric fragments being larger than half of the original chromosome was only seven (3%), and did not contribute significantly to induction rates. When the broken acentric fragments of two affected chromosomes were smaller than half of the original chromosomes, which was found in 175 (77 %) of the rearrangements, the induction rates of dicentrics and translocations were about the same (86:89). But if the sizes of the broken segments were unequal in both chromosomes (one with a larger acentric part and the other with a smaller acentric part), the yield of dicentrics was significantly lower than that of translocations (16:30).It was found that preferential reduction of dicentrics in reciprocal exchanges originated from the heteromorphic size of broken chromosomes in the last combination. The mechanism of this preferential reduction is unknown.

View full abstract

Cytogenetic and hematological analyses were performed on the peripheral blood lymphocytes (PBLs) obtained from Korean native goats bred on farms in two nuclear power plants (Wolsong and Uljin) and in a control area. The frequencies of gamma-ray-induced micronuclei (MN) in the cytokinesis-blocked (CB) lymphocytes were measured at several doses in three Korean native goats. The measurements performed after irradiation showed dose-related increases in the MN frequency in each of the donors. The results were analyzed using a linear-quadratic model with a line of best fit of y = 0.0093+ 0.1019D + 0.0045D^2 (y = number of MN/CB cells and D = irradiation dose in Gy). The MN rates in the goats from the Wolsong and Uljin nuclear power plants, and the control area were 9.60 ± 2.88, 6.83 ± 1.47 and 9.88 ± 4.32 per 1,000 CB lymphocytes, respectively. The apparent difference is not statistically significant. The MN frequencies of PBLs from goats bred in three areas means that the values are within the background variation in this experiment. The MN frequencies and hematological values were similar regardless of whether or not the goats were bred in a nuclear power plant.

View full abstract

Residents in Ramsar are exposed to levels of natural radiation as high as 60-200 times higher than the average natural dose rate. Radon levels in some regions of Ramsar are up to 3700 Bq-m^-3. To study the adaptive response in residents in high levels of natural radiation areas in Ramsar, the lung cacer patients recorded over the past two years in eight district of Ramsar with different levels of radon were studied. Data from the Ramsar Health Network show that both crude lung cancer rate and adjusted lung cancer rate in one district with the highest recorded levels of external radiation and radon concentration are lower than those of the other seven districts. It may be concluded that lung cancer rate may show a negative correlation with natural radon concentration. To make a solid conclusion more research is needed

View full abstract

Radiation-induced adaptive response is a complicated phenomenon in radiobiology. Its study provides an important scientific basis for radiation risk estimates. As with previous research on cultured cells and in adult animals, an adaptive response in fetal mice could be induced only when application of irradiation and animal factors met a set of strict conditions. As the characterization of essential conditions offers significant insight into the novel biological defense mechanisms involved in radiation protection, a series of experimental trials on these conditions was performed. The findings were that there was a specific interval (one day) between the priming dose and the challenging dose, reduced digital defects were correlated to the suppression of apoptosis, there was one efficient priming dose for ICR mice (0.3 Gy) and two for C57BL/6J mice (0.05 and 0.3 Gy), both Trp53 alleles were essential, and there were two differential dose-rate ranges (0.18-0.98 Gy/min, 3.5-4.6 Gy/min) efficient for the same priming dose in ICR mice. These findings suggest the existence of multiple pathways of signal transduction activated by the priming irradiation, and multiple cell populations with various susceptibilities to radiation may be involved. The decrease in radiation-induced apoptosis implies the involvement of an anti-apoptotic pathway, and thus further study on apoptosis-related genes is probably warranted. These findings imply that there is no consistent pattern for successful induction in regard to the complex interplay between the inducting system and biological subjects.

View full abstract

An image-guided radiation therapy is the delivery of very focused, precise, and biologically potent radiation dose to tumors in the chest, abdomen, and pelvis. This therapy constitutes the culmination and implementation of a variety of modern radiation delivery technologies. It facilitates implementation of very powerful radiobiological dose fractionation schedules known to be very effective against tumor but previously thought to be too toxic. In this aspect, our radiosurgical system, CyberKnife, provides the advantages of spatial accuracy, high conformality, and an accelerated dose regimen that is noninvasive. Korea Cancer Center Hospital installed a CyberKnife system in June, 2002. As of June, 2005, we have treated more than 1,000 patients by this system, and have had a very prospective and promising results. To reduce the tumor motion a special device, which was developed at my department, could reduce the diaphragmatic movement to an average 45% of its initial range. For stereotactic radiosurgery of body tumors excluding brain and head & neck tumors, we inserted 6 fiducials, as reference markers, into spines adjacent to tumors treated. The number of fractionation is one to 4. Most of metastatic tumors have been treated with single fraction, while the other body tumors treated with 3 fractions. In this symposium, based upon my clinical experience, I would like to present the data on treatment results for metastasis to para-aortic lymph nodes from colo-rectal and gynecologic cancers.

View full abstract

Purpose: To reduce uncertainty due to setup error and organ motion during radiotherapy of tumors in or near the lung, by means of real-time tumor tracking system and gating of a linear accelerator for intercepting radiotherapy .Methods and Materials: The real-time tumor-tracking system consists of two sets of diagnostic X-ray television systems, an image processor unit, a gating control unit, and an image display unit. The system recognizes the position of a 1.5-mm gold marker in the human body 30 times per second using two X-ray television systems. The marker is inserted in or near the tumor using image guided implantation. The linear accelerator is gated to irradiate the tumor only when the marker is within 1 - 2 mm from its planned coordinates relative to the isocenter. Results: The phantom experiment demonstrated that the geometric accuracy of the tumor-tracking system is better than 1.5 mm for moving targets up to a speed of 100 mm/s. The dose due to the diagnostic X-ray monitoring ranged from 0.01% to 1% of the target dose for a 2.0-Gy irradiation of a chest phantom. In 16 patients with Stage IA non-small celllung cancer, the 4-year survival was 95% by givign 48 Gy in fractions in 4-6 days.Conclusion: We successfully implemented and applied a tumor-tracking system for gated radiotherapy. The system significantly improves the accuracy of irradiation of targets in motion at the expense of an acceptable amount of diagnostic X-ray exposure.

View full abstract

Carbon ion is one of high LET particles and carbon ion radiotherapy is a promising modality for photon resistant tumor because of its high biological effectiveness. Additionally carbon ion has a Bragg peak with superior dose distribution in radiotherapy avoiding unexpected doses for the surrounding important normal tissues. In 1994, clinical trials for many clinical sites were initiated in the National Institute of Radiological Sciences (NIRS). Till the end of February 2005, a total of 2,192 patients were treated by carbon ions. The results of clinical trials show good tumor control, especially for non-squamous cell carcinoma in the head and neck, prostate cancer, bone and soft tissue tumors, rectal cancer( post operative relapse) and adenocarcinoma of the uterine. For the lung and the liver cancer, small fractionation method within 1 or 2 days was applied. Also clinical trials for malignant gliomas and pancreas cancer are undergoing. Carbon ion radiotherapy was permitted as highly advanced medical technology on November 2003 and 342 patients were treated till the February of 2005.To assess the genetic alterations and identify the genes induced by carbon ion irradiation in cell lines, a genome expression study was conducted. The list of differentially expressed genes includes ones that are involved in cell cycle, adhesion, proliferation and apoptosis. IPA showed that THBS1 and UPP1 were activated by linked genes associated with apoptosis, including p53 and RUNX1.

View full abstract

We report on preclinical study and clinical pilot study for applying boron neutron capture therapy (BNCT) to malignant liver tumors. In the preclinical study, rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. Borocaptate sodium (BSH) (75 mg/kg)/lipiodol (0.3 ml/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of 10B in the liver tumors. In the pilot study, we applied BSH-lipiodol BNCT to two cases of liver tumors, a 63-year-old man with multiple hepatocellular carcinomas (HCCs) and a 60-year-old man with chorangiocellular carcinoma. Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6 and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images. In the clinical study, no acute side effect was observed in two cases treated with BNCT. In the case of HCCs, the multiple tumors in the right lobe treated with BNCT showed no growth in one month after the treatment. Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of 10B selectively to the liver tumors. The feasibility of our protocol for treating multiple liver tumors with BNCT was confirmed.

View full abstract

Purpose The aim of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases.Patients and Methods One hundred and five patients with stage IE and IIE nasal NK/T cell lymphoma were reviewed. There were 83 stage IE and 22 stage IIE. Stage IE was subdivided into limited stage IE confined to the nasal cavity (37 patients), or extensive stage IE with an extension beyond the nasal cavity (46 patients). All except 3 patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT) (CMT). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT and 3 with CT alone.Results Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. The 5-year OS and PFS were 82% and 80% for limited stage IE versus 75% and 45% for extensive stage IE, respectively. Complete response (CR) was achieved in 91 (87%) patients after RT and/or CT. Initial RT resulted in a superior CR as compared to initial CT, with 54 of 65 (83%) patients achieving CR with initial RT, versus only 8 of 40 (20%) after initial CT. For 102 patients who received RT with or without CT, the outcome of primary treatment with RT alone was compared to that of CMT. Five-year OS and PFS was 66% and 61% for RT alone and 76% and 61%% for CMT.Conclusion RT is a primary therapy in early stage nasal NK/T cell lymphoma.

View full abstract

Purpose: The comprehensive analysis of gene expressions using microarray is useful for clarifying the signal transduction of response to radiation in tumors and predicting the prognosis after radiotherapy. In this study, gene expression profiles of cervical cancers treated by either radiotherapy or chemoradiotherapy were compared to identify genes induced by each type of treatment. Materials and Methods: The subjects were 24 patients with cervical cancer, who had received definitive radiation therapy (X-ray alone (XR); 11 cases and chemoradiotherapy (CRT); 13 cases). All samples were obtained before radiotherapy and 1 week after the start of the treatment. mRNA was extracted from the tissues and oligonucletide microarray (CodeLink Bioarray Perfect System) was used for assessment of gene expressions. Results: By unsupervised analysis, outlier arrays were detected and these arrays were excluded from further analysis. Statistical analysis with ANOVA found approximately 400 genes, in which their expression values were significantly different between XR and CRT. Genes related with immunological response, such as interleukin and chemokine, or genes related with apoptosis were included. The 91 genes could divide the patients into each treatment group, individually. Conclusion: To investigate gene expressions by the microarray is useful to explore peculiar signal transduction pathway for each radiotherapy modality. These results have possibility of producing a new approach by radiation therapy combined with molecular target therapy for cervical cancer.

View full abstract

Combined radiation therapy with molecular targeting, which targets a specific molecule involved in tumor cell survival after irradiation, is one of promising approaches for improvement of tumor control. Because of tumor heterogeneity and the existence of multiple tumor radio-resistance pathways, an extension of this approach being investigated at the pre-clinical level is to use Hsp90 chaperone complex inhibitors as a means of reducing the levels of multiple radioresponse regulatory proteins. Hsp90 binds to multiple molecules that play an important role in malignant potential or determination of radiosensitivity of cancer cells, and stable binding between Hsp90 and these molecules (client proteins) is needed to maintain stability and function of client proteins. We have been investigating the effect of Hsp90 chaperone complex inhibition on radiosensitivity of several cancer cells, and confirmed synergistic enhancement of radiation-induced cell killing. In underlining mechanism for potentiation of radiation-induced cell killing, modification of several radioresponse regulatory proteins such as EGFR or Akt caused by Hsp90 chaperone complex inhibition was involved. In prostate cancer cells, Hsp90 inhibitor induced degradation of androgen receptor and downlegulation of prostate specific protein. Combined Hsp90 inhibitor with radiation caused synergistic enhancement effect of radiosensitivity of prostate cancer cells. In this conference, we report and discuss our results regarding the effect of Hsp90 chaperone complex inhibition on radiation-induced cell killing in cancer cells.

View full abstract

Radiation therapy plays a critical role in the management of a majority of patients diagnosed with cancer. Identification factors that help predict which patients are at risk for relapse within the irradiated field remains an active area of investigation. Although conventional clinical and pathological factors have been helpful in identifying risk and guiding clinical decision-making for both local and systemic management, there is clearly a need to identify additional prognostic markers, which can aid in refining our treatment strategies and improving outcomes. A substantial amount of research efforts have been devoted to identifying molecular markers fro prognostic and therapeutic strategies. Heat shock proteins (HSP) are a large family of proteins with different molecular weights and different intracellular localizations and HSP25/HSP27 belongs to the small heat shock proteins. Recently HSP25/27 reported that it acts as emerging anti-apoptotic molecules. In the present study, we described molecular signaling of HSP27/25 in predictor of radiation sensitivity, especially focused on inhibition of PKCdelta-mediated apoptosis.

View full abstract

Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-kappaB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-kappaB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IkappaB (MCF-7/ErbB2/mIkappaB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-kappaB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-kappaB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-kappaB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were downregulated by inhibition of NF-kappaB in MCF-7/ErbB2/mIkappaB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-kappaB response to IR, and that a specific prosurvival network downstream

View full abstract

One of the critical determinants of cellular response to exogenous stimuli is the cellular redox status. Intracellular generation of reactive oxygen species (ROS) is tightly regulated by the intrinsic anti-oxidant defense systems. Despite the conventional dogma that ROS are harmful to the cell, experimental evidence over the last decade that ROS also play an important role as signaling molecules in diverse physiological processes. Indeed, low levels of intracellular ROS have been linked to cellular proliferation and cell cycle progression, which provides an explanation for the pro-oxidant state invariably associated with the transformed phenotype. Contrary to that are recent observations implicating increase of intracellular ROS level in tumor cells promoting cell death signals delivered upon exposure to radiation or chemotherapeutic drugs. These studies provide convincing evidence to support a direct or indirect role for intracellular superoxide anion in creating an intracellular milieu permissive for cell death execution. Thus a novel approach to enhancing tumor cell sensitivity to radiation-induced cell death would be to favourably tailor the cytosolic milieu to allow efficient apoptotic execution. Here we present our recent data on the role of ROS in cell transformation and in the modulation of ionizing radiation-induced cell death signaling.

View full abstract

Radiation is one of the major treatment modes for cancer therapy. However, exposure of tumor cells to radiation as well as anticancer drugs, both of which are DNA-damaging agents, leads to cellular responses to repair DNA. The DNA repair has a critical role for tumors to cope with DNA damage and to survive genotoxic stress. When DNA is broken, two-pathways are effective for the double-strand break repair. One is non-homologous endjoining at the G0 and G1 phases of the cell cycle and another is homologous recombination at the S phase of the cell cycle. We focused on the latter mechanism, where Rad51 plays a critical role for homology search and strand exchange. We investigated the effect of RNAi of Rad51 gene in cancer cells to their radiosensitivity. The double stranded short RNA (small interfering RNA) of Rad51 were synthesized and transfected by use of lipofectamine to mouse teratocarcinoma F9 cells and HeLa cells. The Western blot showed that the amount of RAD51 protein in cells transfected withRad51 siRNA was greatly reduced to about 16 % to that of cells transfected with control or scrabled siRNAs. In addition, the F9 teratocarcinoma cells transfected with Rad51 siRNA became much more sensitive to X-irradiation at 6 Gy. The Rad51 siRNA transfected F9 cells also became more sensitive to cisplatin. This method can be applied to cancer radiotherapy and chemotherapy to minimize the doses of radiation or anticancer drugs, which usually are thought to exert their effects by breaking double-stranded DNA.

View full abstract

Insulin-like growth factor I receptor (IGF-IR) plays a pivotal role in cell growth, transformation, and cell survival. We found that cellular radioresistance is obtained when human wild-type IGF-IR is expressed in IGF-IR-knockout mouse embryo fibroblasts (R-). Mutational analysis revealed that the tyrosine at residue 950 (Y950) of IGF-IR, as well as the C-terminal domain, are required for radioresistance and that both domains must be mutated to abrogate the phenotype. Furthermore, the contribution of downstream pathways was analyzed by combining the use of wild-type or Y950 and C-terminal mutants with specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) or mitogen-activated protein extracellular signal-regulated kinase (ERK) kinase (MEK). Radioresistance could be induced by IGF-IR as long as the ability of the receptor to stimulate the MEK/ERK pathway was retained. This was confirmed by the expression of constitutively active MEK in R- cells. The ability to stimulate the PI3-K pathway alone was not sufficient, but PI3-K activation coupled with MEK/ERK pathway-independent signals from the C-terminus was able to induce radioresistance. Collectively, these results indicate that the IGF-IR-mediated radioresistant signaling mechanism progresses through redundant downstream pathways. The redundancy of the survival signals related to the development of cellular radioresistance revealed by this study may have clinical implications regarding the use of molecular targeting in radiotherapy.

View full abstract

It is well known that the gene status of tumor suppressor p53 can determine the cell's fate. In fact, wild-type (wt) p53 cells were more sensitive to low-linear energy transfer (LET) radiation such as X-rays than mutated (m) p53 cells due to p53-dependent apoptosis. However, there is little information available on p53-dependent and -independent apoptosis following exposure to high-LET radiation from different types of heavy-ion beams. Therefore, we examined radiation-induced apoptosis in response to high-LET radiation in a human lung cancer cell line. The wtp53 or mp53 gene was transfected to the p53-null parental cells. The cells were exposed to X-rays or high-LET radiation using different nuclei ion-beams (C-beams, 13 KeV/µm; Ne-beams, 35 KeV/µm; Si-beams, 55 KeV/µm; Ar-beams, 85 KeV/µm; Fe-beams, 200 KeV/µm). We found that (i) there was no significant difference in cellular sensitivity to high-LET radiations (> 85 KeV/µm) among these cells, although the sensitivity of wtp53 cells to X-rays was higher than that of mp53 or p53-null cells; (ii) X-ray-induced apoptosis at higher frequencies in wtp53 cells when compared to mp53 and p53-null cells; (iii) Fe-beams induced efficiently apoptosis in a p53-independent manner. The present results indicate that high-LET radiation induces apoptosis in a p53-independent manner, and suggest that this radiation is useful to any types of p53-pacients in cancer therapy.

View full abstract

Heat shock proteins (HSPs) are induced by various physical, chemical and biological stresses. HSPs are known to function as molecular chaperones and they not only regulate various processes of protein biogenesis but also function as lifeguards against proteotoxic stresses. Since it is very useful to discover nontoxic chaperone-inducing compounds, we searched for them in herbal medicines. Some herbal medicines had positive effects on the induction of HSPs (Hsp70, Hsp40, Hsp27) in cultured mammalian cells. We next examined two major constituents of these herbal medicines, glycyrrhizin and paeoniflorin. Glycyrrhizin had an enhancing effect on the HSP induction by heat shock but could not induce HSPs by itself. In contrast, paeoniflorin had not only an enhancing effect but also an inducing effect by itself on HSPs expression. Thus, paeoniflorin might be termed a chaperone inducer and glycyrrhizin a chaperone co-inducer. Treatment of cells with paeoniflorin resulted in enhanced phosphorylation and acquisition of DNA binding ability of heat shock factor 1 (HSF1), as well as the formation of characteristic HSF1 granules in the nucleus, suggesting that the induction of HSPs by paeoniflorin is mediated by the activation of HSF1. Also, thermotolerance was induced by the treatment with paeoniflorin. In our preliminary study, paeoniflorin could prevent HCl-induced stomach ulcers, extend life span of nematoda, and suppress the growth of tumor cells.

View full abstract

To understand how therapeutic ultrasound works, understanding its biological effects is deemed necessary. Here, the molecular aspect, particularly on apoptosis induction, gene expression, and gene transfection were investigated. Apoptosis induction was assayed by flow cytometry and by other methods targeting indicators of apoptosis. Gene expressions were evaluated using western blotting, real-time PCR, and micro-array analyses. And gene transfection was investigated using luciferase assay and other methods. The results showed that low intensity ultrasound can induce apoptosis in cancer cell lines and that it can be optimized using pulsed ultrasound. Ultrasound resulted to down-regulation or up-regulation of some genes. Of particular interest is the striking up-regulation of heme oxygenase-1 gene, a gene usually associated with oxidative stress. Introducing gene using ultrasound also showed promising results. We have shown that gene introduction is cavitation related such that it is enhanced by echo contrast agents and other factors cited above. Membrane damage is pivotal to the bioeffects that modifying the cell membranes either promotes or inhibits the desired effects. Although, ultrasound can enhanced liposome-mediated gene transfection, at optimized condition ultrasound alone can deliver gene more efficiently than liposome-mediated gene transfection. In summary, we conclude that ultrasound can be useful in therapy that requires apoptosis induction or gene introduction to cells. Further studies is however necessary to investigate the value of gene induction by ultrasound.

View full abstract

Ionizing radiation stimulates auto-phosphorylation of ATM protein at serine 1981, and phosphorylated ATM forms discrete foci. We found, in normal human diploid cells, that the initial phosphorylated ATM foci grew rapidly concurrently with DNA repair, and the foci were colocalized with the foci of phosphorylated histone H2AX, 53BP1 and NBS1. While most of the initial foci disappeared gradually after X-irradiation, there were persistent foci, whose size reached approximately 1 micron. To know biological significance of the grown foci we treated exposed cells with wortmannin, and found that number of the initial and residual phosphorylated ATM foci decreased similarly. Moreover, the effect was suppressed by calyculin A, which is a well known inhibitor of the protein phosphatase 1 and 2A. This suggests that altered chromatin structure persists if DNA broken ends are rejoined. Therefore, we next examined phosphorylated ATM foci on metaphase chromosomes isolated from X-irradiated CHO cells. We found that more than 60% of the foci were on chromosomes without detectable breaks. These results indicate that growing and persistent phosphorylated ATM foci were colocalized with damaged chromatin domains when the broken ends are rejoined, and they could mediate amplification of DNA damage checkpoint signals.

View full abstract

The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status. Template-based clustering analyses of gene expression profiles among these three cell lines revealed distinct patterns. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2 and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.

View full abstract

NBS1, mutated in Nijmegen breakage syndrome, is involved in checkpoints and DNA repair after exposure to radiation. NBS1 forms foci at sites of radiation-induced double strand breaks and interacts with BRCA1/SMCI, which is crucial for S-checkpoint through SMC1 phosphorylation by ATM. Therefore, NBS1 modulate the ATM-dependent checkpoint possibly by binding to ATM at the extreme C-terminus of NBS1. On the other hands, NBS1 regulates homologous recombination repair through MRE11 nuclease, since HR-regulating ability of NBS1 is completely abolished by deletion of the MRE11-binding domain. In contrast, HR frequencies are only slightly affected both by mutations in the serine residues, which are phosphorylated by ATM kinase, and by deletion of the extreme C-terminus. This was also confirmed by findings that ATM defects did not reduce the HR repair frequency of an induced DSB. These results demonstrate that NBS1 is the key regulator for ATM-dependent checkpoint and that the function of NBS1 in HR repair of an induced DSB is independent of ATM.

View full abstract

High LET heavy ion radiation has been successfully used for radiation cancer therapy and the biological effect is known to be more significant than low LET radiation such as X-rays. Despite its biological significance, the mechanism behind the high LET effect is not fully understood. In this presentation, the reason for the severe biological effects with high LET radiation is discussed in the context of DNA double strand break (DSB) repair, specifically non homologous end joining DSB repair pathway.We found LET dependent chromosome rejoining kinetics in normal human cells irradiated with 70 keV/um carbon and 200 keV/um iron ions. Furthermore, the iron ions seem to induce non-repairable DSB/chromosome damage. Using DSB repair deficient 180BR cells (DNA ligase IV mutant), a slow chromosome repair component (after 6h post-irradiation) was uncovered by comparing the iron and carbon rejoining kinetics. The experiment with phosphospecific antibody for DNA-PKcs also showed a significant delay in the phosphorylation process of this protein in cells exposed to high LET radiation when compared to X-rays. These results indicate that high LET heavy ion radiation induces DNA damage which is much more difficult to be repaired. The usefulness of high LET radiation to uncover the new mechanistic aspect of DNA DSB repair is also evident.

View full abstract

Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for safeguarding the human population from arsenic exposure. As Poly (ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, PARP-1 was evaluated in arsenic induced cytotoxic and genotoxic effects Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1-/- MEFs (mouse embryonic fibroblasts) (40%) as compared to PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite induced DNA lesions in PARP-1-/- MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite treated PARP-1-/- MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes of which a large fraction them have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Data obtained from other DNA repair deficient cells (such as cells lacking p53, DNA-PK, XPA) as well as telomerase negative mouse cells will be discussed.

View full abstract

Epidemiological study on residential radon risk in ChinaQ SUN1, S Zhang1, S Tokonami2, W Zhuo2, H Yonehara2, S Akiba3, Y Yamada21 National Institute for Radiological Protection, China2 National Institute for Radiological Sciences, Japan3 Kagoshima University Faculty of Medicine, JapanWe recently measured indoor radon and thoron gas concentrations in selected areas of Gansu, Shanxi, Shannxi, Yunnan and Guandong provinces using a passive integrating radon-thoron discriminative detector. Concentrations of thoron decay products were estimated from measurements of their deposition rates. Among 304 dwellings in Gansu, Shanxi and Shannxi, indoor radon concentrations ranged from 17 to 300 Bq/m3 with a geometric mean (GM) of 63 Bq/m3, indoor thoron from 10-1381 Bq/m3 with GM of 178 Bq/m3, and indoor equilibrium equivalent thoron concentration from 0.3 to 6.1 Bq/m3 with GM of 1.8 Bq/m3. Some dwellings in Yunan and Guangdong are with high thoron concentrations. Our measurements revealed that the presence of thoron is not negligible for accurate radon measurements and a possible contamination of thoron exits in previous radon measurements in Gansu study. A New case-control study on indoor radon and thoron and lung cancer is to be conducted.

View full abstract

A nationwide survey on radon was conducted to estimate its annual average concentrations in Korea dwellings and to estimate the effective dose to the general public. Radon and thoron were measured with RadTrack (Landauer, USA) and RadoPot monitor (Hungary), respectively. During 1999 to 2004, radon concentration was measured at about 4000 dwellings, while thoron (²²⁰Rn) was measured at about 450 dwellings from 2002 to 2004. The annual mean radon and thoron concentration was estimated from 15 provinces in Korea over four quarters. The arithmetic mean and geometric mean of annual radon concentration in Korean dwellings were 58.6 ± 19.8 Bq/m³ and 45.2 ± 1.3 Bq/m³, respectively. The arithmetic mean and geometric mean of annual thoron concentration was 38.7 Bq/m³ and 7.3 Bq/m³. The radon and thoron concentrations in the traditional Korean-style houses were higher than those in other type houses. Seasonal variations of indoor radon and thoron concentrations were found to be highest in winter. Meanwhile, the average outdoor radon concentration measured at 10 Regional Environmental Radiation Monitoring Stations was 22 Bq/m³. By weighting the district population, the collective effective doses due to radon and thoron were calculated to be 58,967 man-Sv/y and 5,900 man-Sv/y, respectively, and hence the mean individual dose to be 1.41 mSv a year (radon; 1.27, thoron; 0.147), which corresponds to about 47% of the average annual effective dose (2.99 mSv/y) to Korean people from all natural radiation sources.

View full abstract

The variation of radon concentrations in different types of residences in the Philippines will be presented and the corresponding risks will be discussed.

View full abstract

Among various sources of natural radiation, the most important is radon gas exposure. UNSCEAR report 2000 has pointed out that radon exposure accounts for about half of natural radiation exposure among men. High-level radon exposure is well known to inclrease lung cancer risk as reported from studies among uranium miners and others. Recently, it has been strongly suspected that indoor exposure to radon levels as high as 100-200 Bq/m3 may also increase lung cancer risk among residents. WHO is now argueing that residential radon exposure is an important risk of lung cancer in addition to smoking, and has launched an international project on this problem, suspecting that such an exposure is an important Global Burden of Disease. At the First Meeting of the Expert Group for the WHO Project on Residential Radon Risk in last January, the results of two pooled analyses, one in North America and the other in Europe, were presented and their public health implications were discussed. In the present study, a brief summary of those studies will presented, problems regarding epidemiological studies on the relatiohship between radon expsoure and lung cancer risk will be discussed, and future direction of residential radon studies will be proposed.

View full abstract

TBD

View full abstract

Nuclear or radiological accident is an unintended or unexpected event occurring with a radiation source or during a practice involving ionizing radiation, which may result in significant human exposure and/or material damage. Recent events involving terrorist activities have focused attention on the radiological threats. So, medical preparedness and response to radiation emergency is very important.Radiation emergency system in China has been established for radiological emergency preparedness and response. National Coordination Committee of Radiation Emergency has been setup in 1994, which consist of 17 ministries. The Ministry is responsible for the medical assistance for radiation emergency. Chinese Center for Medical Response to Radiation Emergency (CCMRRE) was established in 1992, based on the National Institute for Radiological Protection, China CDC (NIRP, China CDC). The CCMRRE has been as one liaison institutes of WHO/REMPAN and functions as a national and professional institute for medical assistance in radiation accidents and terrorist events involving radioactive material.Under Provincial Committee of Radiation Emergency, there are local organizations of medical assistance in radiation emergency. The organizations carry out the first aid, regional clinic treatment, radiation protection and radiation monitory in nuclear accidents and radiological accidents.

View full abstract

The National Nuclear Accident Emergency Response Plan (NNAERP) by the responsible administrations, mainly the Atomic Energy Council (AEC), was instituted in 1981, while the Nuclear Accident Emergency Response Act (NAERA) was enacted in 2003 to further strengthen the framework and enhance the capacity and responsibilities of concerned parties. The NAERA is further reinforced recently at July, 2005. Under the Act, the functions of the National Nuclear Emergency Response Center (NNERC), the Radiation Monitoring and Dose Assessment Center, the Nuclear Emergency Support Center, and the Regional Nuclear Emergency Response Center are established, while a network including Nuclear Emergency Support Center and the Regional Nuclear Emergency Response Center are operated by the Military and local governments, respectively. On the other hand, a nation-wide medical emergency network was established, supported by the Ministry of Health since early 1990s, and was expanded to incorporate health resources in all 13 medical centers and more than 50 regional hospitals in Taiwan. This network is coordinated by one each medical center in southern and northern Taiwan, while regular training and rehearsal are implemented regularly. Further enforcement on steps of health care, including intensive health care units, exposure assessment, and medical treatment are undergoing now. The NNAERP now includes the network of radiation emergency plan and the health network to secure timely and sufficient support for radiation emergency in Taiwan.

View full abstract

Though a radiation accident in the nuclear power plants (NPP) is very rare, it can lead to a wide range of health problems to the public if happens. Thus, we need to be equipped with infrastructure and functional requirements for the radiation emergency. In this article, the recent development in Korea is introduced in terms of the preparedness for radiation emergency in NPPs. 'Law on the protection of nuclear facilities and the measures for radiological emergency' was established in 2004 to increase the radiation disaster preparedness in Korea, which is considered the most powerful tool in developing infrastructure. This law states necessary actions that need to be taken in case of radiation emergency. The representative medical infrastructure includes supports for hospitals in collaboration with RHRI, as well as coordination with other organizations. In terms of the functional aspect, RHRI has taken a leading role in increasing the radiation emergency preparedness of NPPs. Medical supports are comprised of radiation emergency equipments and special medical teams. Related activities include providing education/ training, culturing special radiation emergency medical teams, and operating 24 hours on call system etc. Also, RHRI conducts researchesrelated to the influence of an exposure to radiation on human health. It seems that emergency preparedness for the NPP accidents is well developed in Korea. However, feasible plans and methods in functionalrequirements need to be further developed for an effective intervention on radiation emergency.

View full abstract