Radiation and Thyroid Diseases : Experiences in Nagasaki and around Chernobyl

The needs of a society are closely related to medical progress and its contribution. For instance, research on AIDS and cancer is carried out to meet the demand of contemporary society. Thyroid disease caused by iodine deficiency is one such challenge, and "radiation and thyroid" is another major research theme. Clinical investigation and basic research on radiation-induced thyroid diseases through molecular epidemiology have received much attention from scientists in Nagasaki because of our historical background of atomic bomb exposure and accumulated data of radiationinduced human diseases. We, therefore, introduce the experiences of thyroid examination in Nagasaki and Chernobyl and epidemiological analysis of the effect of radiation on thyroid diseases

Cyclooxygenase-2 is Involved in the Progression of Thyroid Cancer

Although the inducible form of cyclooxygenase (COX), COX-2, is highly expressed in various cancers and it is also involved in cancer progression, its role in thyroid cancer is not fully understood. We assessed in the situ cyclooxygenase expression in normal thyroids (n=6), Graves\u27 thyroids (n=6), thyroid adenomas (n=12), thyroid follicular (n=15) and papillary carcinomas (n=30). In comparison to the constitutive expression of COX-1, COX-2 was highly expressed in thyroid cancers (90.0% of thyroid papillary carcinomas and 73.3% of thyroid follicular carcinomas) and moderately in thyroid adenomas (25.5%), but barely expressed in normal and Graves\u27 thyroid tissues. This quantitative assessment employed immunohistochemical methods. Thereafter we compared the effect of COX-2 inhibition on a human follicular thyroid carcinoma cell line (WRO), and a human papillary carcinoma cell line (NPA), using selective COX-2 inhibitor(NS-398). The treatment with 50 μM NS-398 suppressed the growth of the COX-2 expressing cells, NPA cells (37.7%;p<0.01) and WRO cells (10.1%;p<0.05). Moreover, at concentrations ? 100 μM, NS-398 induced cell death a mitochondrial dysfunction. In addition, 50 μM of NS-398 inhibited the activation of extracellular signal-regulated kinase in NPA cells after the stimulation with fetal bovine serum. Our results indicate that COX-2 is involved in the progression of thyroid cancer

Risk for Progression to Overt Hypothyroidism in an Elderly Japanese Population with Subclinical Hypothyroidism

Background: Few population-based studies report the changes with time in thyroid function tests in patients with subclinical hypothyroidism. We compared the risk for developing overt hypothyroidism in patients with subclinical hypothyroidism and euthyroid controls from the same population of elderly Japanese. We also sought associations of selected parameters with the development of overt hypothyroidism in the subclinical hypothyroid and euthyroid groups. Methods: We measured thyrotropin (TSH) and free thyroxine (T4) levels at baseline examinations performed from 2000 to 2003 in the cohort of Japanese atomic-bomb survivors and identified 71 patients with spontaneous subclinical hypothyroidism (normal free T4 and TSH >4.5 mIU/L without a history of thyroid treatment, mean age 70 year) and 562 euthyroid controls. We re-examined TSH and free T4 levels an average of 4.2 years later (range, 1.9-6.9). Results: The risk for progression to overt hypothyroidism was significantly increased in subclinical hypothyroid patients (7.0%) compared with control subjects (1.6%) after adjusting for age and sex (odds ratio, 4.56; p=0.009). Higher baseline TSH levels were associated with progression from subclinical to overt hypothyroidism (p=0.02) in the multivariate analysis, including age, sex, antithyroid peroxidase antibody, and ultrasonography (US) findings. The analysis using binary TSH data suggested that a TSH level >8 mIU/L was a predictive value for development of overt hypothyroidism (p=0.005). On the other hand, serum TSH levels spontaneously normalized in 38 (53.5%) of the patients with subclinical hypothyroidism. In the multivariate analysis, normalization of TSH levels was associated with lower baseline TSH levels (p=0.004) and normal and homogenous thyroid US findings (p=0.04). Atomic-bomb radiation dose was not associated with subclinical hypothyroidism or its course. Conclusions: Subclinical hypothyroidism was four times more likely to be associated with development of overt hypothyroidism than euthyroid controls in the sample population of Japanese elderly. TSH levels in half of the patients normalized spontaneously when assessed after an average follow-up period of 4.2 years. Baseline TSH level and thyroid US findings are potential predictors of future thyroid function in subclinical hypothyroidism

Relationship between thyroid tumor radiosensitivity and nuclear localization of DNA-dependent protein kinase catalytic subunit

Thyroid tumors are the most common types of endocrine malignancies and are commonly treated with radioactive iodine (RAI) to destroy remaining cancer cells following surgical intervention. We previously reported that the expression levels of double-stranded DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which plays a key role in non-homologous end joining, are correlated with the radiosensitivity of cancer cells. Specifically, cells expressing high levels of DNA-PKcs exhibited radiation resistance, whereas cells expressing low levels were sensitive to radiation treatment. In this study, we observed full-length native DNA-PKcs (460 kDa) in radiation-resistant FRO and KTC-2 cells through western blot analysis using an antibody against the C-terminus of DNA-PKcs. In contrast, cleaved DNA-PKcs (175 kDa) were observed in radiation-sensitive TPC-1 and KTC-1 cells. Almost equal amounts of DNA-PKcs were observed in moderately radiation-sensitive WRO cells. We also describe a simple method for the prediction of radiation therapy efficacy in individual cases of thyroid cancers based on staining for DNA-PKcs in human cancer cell lines. Immunofluorescent staining showed that native DNA-PKcs was localized largely in the cytoplasm and only rarely localized in the nuclei of radiation-resistant thyroid cancer cells, whereas in radiation-sensitive cancer cells a 175-kDa cleaved C-terminal fragment of DNA-PKcs was localized mainly inside the nuclei. Therefore, DNA-PKcs moved to the nucleus after γ-ray irradiation. Our results suggest a new method for classifying human thyroid tumors based on their cellular distribution patterns of DNA-PKcs in combination with their radiosensitivity