Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.

(1) Mature miRNAs, ranging from 18 to 25 nucleotides in length, processed by two-step cleavage involving Drosha and Dicer are thought to negatively regulate messenger RNA (mRNA). The mature miRNA binds to target mRNA and induces its cleavage or translational repression depending on the degree of complementarity.(2) Although hundreds of miRNAs have been already cloned, only a small number of them have been characterized.Recently, several miRNAs have been reported to be involved in cell proliferation or apoptosis in various types of cancers. (3,4) MiR-15a and miR-16 induce apoptosis by targeting BCL2, and these miRNAs are frequently deleted or underexpressed in chronic lymphocytic leukemia.(5) Let-7 expression is reduced in lung cancer with poor prognosis, (6) and inversely correlates with expression of RAS protein, suggesting a possible mechanism for cancer cell proliferation.(7) Compared to these underexpressed miRNAs, miR-21 has an antiapoptotic function and is overexpressed in glioblastoma. Knockdown of miR-21 in glioblastoma cells induced caspase activation, resulting in apoptotic cell death.(8) Thus, miRNAs can act as both tumor suppressor and oncogene.The miR-17-92 cluster, composed of seven miRNAs (miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92-1) and located in intron 3 of the C13orf25 gene, is overexpressed in lung cancer and B-cell lymphoma.(9,10) Enforced expression of truncated clusters comprising miR-17-5p~19b (miR-17-19b), the vertebrate-specific portion of the miR-17-92 cluster, accelerated tumor development in a mouse B-cell lymphoma model, suggesting oncogenic function of miR-17-19b. On the other hand, O'Donnell et al. have reported that expression of oncogenic E2F1 is negatively regulated by miR-17-5p and miR-20a, members of the cluster, implying that they act as a tumor suppressors.(11) Thus, the function of the cluster is still controversial.In thyroid cancer, overexpression of several miRNAs has been reported. He et al. have reported that three miRNAs (miR-221, miR-222, and miR-146) are overexpressed in papillary thyroid carcinomas (PTC) and regulate KIT expression.(12) Another group has also shown that miR-221, miR-222 and miR-181b are overexpressed in PTC, and inhibition of miR-221 by antisense oligonucleotides led to attenuation of cell growth.(13) In follicular thyroid cancers (FTC), miR-197 and miR-346 are significantly overexpressed. (14) In vitro overexpression of either miRNA induced cell proliferation, whereas inhibition led to growth arrest. Very recently, Visone et al. have reported that significant decrease in miR-30d, miR-125b, miR-26a, and miR-30a-5p was detected in human anaplastic thyroid cancers (ACT). (15) ATC are highly aggressive and fatal tumors with less than 8 months of mean survival after diagnosis.(16) Various treatment patterns including radiation and chemotherapy have been tried in ATC, but they are mostly unsuccessful.(17) Therefore, the identification of miRNAs involved in proliferation or apoptosis in ATC cells has important therapeutic imp...

ObjectiveTo assess relationships between the perception of radiation risks and psychological distress among evacuees from the Fukushima nuclear power plant disaster.MethodsWe analysed cross-sectional data from a survey of evacuees conducted in 2012. Psychological distress was classified as present or absent based on the K6 scale. Respondents recorded their views about the health risks of exposure to ionizing radiation, including immediate, delayed and genetic (inherited) health effects, on a four-point Likert scale. We examined associations between psychological distress and risk perception in logistic regression models. Age, gender, educational attainment, history of mental illness and the consequences of the disaster for employment and living conditions were potential confounders.FindingsOut of the 180 604 people who received the questionnaire, we included 59 807 responses in our sample. There were 8717 respondents reporting psychological distress. Respondents who believed that radiation exposure was very likely to cause health effects were significantly more likely to be psychologically distressed than other respondents: odds ratio (OR) 1.64 (99.9% confidence interval, CI: 1.42–1.89) for immediate effects; OR: 1.48 (99.9% CI: 1.32–1.67) for delayed effects and OR: 2.17 (99.9% CI: 1.94–2.42) for genetic (inherited) effects. Similar results were obtained after controlling for individual characteristics and disaster-related stressors.ConclusionAmong evacuees of the Fukushima nuclear disaster, concern about radiation risks was associated with psychological distress.

There is increasing evidence that cancers contain their own stem-like cells called cancer stem cells (CSCs). A small subset of cells, termed side population (SP), has been identified using flow cytometric analysis. The SP cells have the ability to exclude the DNA binding dye, Hoechst33342, and are highly enriched for stem cells in many kinds of normal tissues. Because CSCs are thought to be drug resistant, SP cells in cancers might contain CSCs. We initially examined the presence of SP cells in several human thyroid cancer cell lines. A small percentage of SP cells were found in ARO (0.25%), FRO (0.1%), NPA (0.06%), and WRO (0.02%) cells but not TPC1 cells. After sorting, the SP cells generated both SP and non-SP cells in culture. The clonogenic ability of SP cells was significantly higher than that of non-SP cells. Moreover, the SP prevalence was dependent on cell density in culture, suggesting that SP cells preferentially survived at lower cell density. Microarray experiment revealed differential gene expression profile between SP and non-SP cells, and several genes related to stemness were up-regulated. However, non-SP population also contained cells that were tumorigenic in nude mice, and non-SP cells generated a small number of SP cells. These results suggest that cancer stem-like cells are partly, but not exclusively, enriched in SP population. Clarifying the key tumorigenic population might contribute to the establishment of a novel therapy for thyroid cancer.

437 nuclear power plants are in operation at present around the world to meet increasing energy demands. Unfortunately, five major nuclear accidents have occurred in the past--ie, at Kyshtym (Russia [then USSR], 1957), Windscale Piles (UK, 1957), Three Mile Island (USA, 1979), Chernobyl (Ukraine [then USSR], 1986), and Fukushima (Japan, 2011). The effects of these accidents on individuals and societies are diverse and enduring. Accumulated evidence about radiation health effects on atomic bomb survivors and other radiation-exposed people has formed the basis for national and international regulations about radiation protection. However, past experiences suggest that common issues were not necessarily physical health problems directly attributable to radiation exposure, but rather psychological and social effects. Additionally, evacuation and long-term displacement created severe health-care problems for the most vulnerable people, such as hospital inpatients and elderly people.

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A high prevalence of the activating BRAF mutation, BRAF(T1796A), is observed in adult papillary thyroid carcinomas (PTCs). The prognosis of childhood PTCs is generally fairly good despite the fact that distant metastases are often documented in these cases. To investigate the differences between the characteristics of childhood and adult PTCs, we analyzed both BRAF(T1796A) and RAS mutations in 31 Japanese and 48 post-Chernobyl Ukrainian thyroid carcinomas. In the 31 Japanese childhood cases, BRAF(T1796A) was found in only one instance (3.2%), and no RAS mutations were detected. In the Ukrainian subjects, of the 15 childhood and the 33 adolescent and young adult PTCs examined, the BRAF(T1796A) mutation was found in zero and eight cases, respectively, and RAS mutations were found in two of the young adult cases. In addition, 17 of the 48 Ukrainian cases showed expression of the RET tyrosine kinase region, indicating the existence of RET/PTC rearrangements. Unlike adult PTCs, we could detect no positive association between BRAF(T1796A) mutations and clinical parameters in the childhood carcinomas, suggesting that a low prevalence of BRAF(T1796A) is a common feature of PTCs in children regardless of radiation exposure levels. The differences in the prevalence of BRAF(T1796A) mutations between childhood and adult cases of PTC may well reflect inherent differences in the clinical features of these cancers between the two age groups.

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