Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.

Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.

No evidence of thyroid consequences in seven nuclear workers at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Plant accident: 10-year follow-up results of thyroid status.

Seven emergency nuclear workers, who had internal exposure due to an intake of radionuclides, mainly I-131, during the emergency response operation in March 2011, after the accident at the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi Nuclear Power Plant (FDNPP), visited the National Institute of Radiological Sciences (NIRS) outpatient clinic for medical evaluation. They were followed up after their first visit for 10 years. The estimated committed equivalent doses to the thyroid were distributed between 3.2 to 1.2 × 10 Sv. This group thought to be received highest exposure at the accident. None of the workers had symptoms related to abnormal thyroid function. The examinations, including thyroid function tests and ultrasound, detected no abnormalities related to radiation exposure. However, there is a need for continuous monitoring of their thyroid status for longer periods in the future.

Anti-CENP-C Antibody-Based Immunofluorescence Dicentric Assay: Radiation Dose-Response, Validation Studies, and Radiation Dose-Dependency on Sister Centromere Fluorescence.

Dicentric chromosome assay (DCA) is the most accepted cytological technique for the purpose of biological dosimetry in radiological and nuclear accidents, however, it is not always easy to evaluate dicentric chromosomes because of the technical difficulty in identifying dicentric chromosomes on Giemsa-stained metaphase chromosome samples. Here, we applied an antibody recognizing centromere protein (CENP) C, CENP-C, whose antigenicity is resistant to the fixation with Carnoy's solution. Normal human diploid cells were irradiated with various doses of 137Cs γ rays at 1 Gy/ min, treated with hypotonic solution, fixed with Carnoy's fixative, and metaphase chromosome spreads were stained with anti-CENP-C antibody. Dose-dependent induction of dicentric chromosomes was confirmed between 1 and 10 Gy of γ rays, and the results were compatible with those obtained by the conventional Giemsa-stained chromosome samples. The CENP-C assay also uncovered the difference in the fluorescence from the sister centromeres on the same chromosome, which was more pronounced after radiation exposure. Although the underlying mechanism is still to be determined, the result suggests a novel effect of radiation on centromeres. The innovative protocol for CENP-C-based DCA, which enables ideal visualization of centromeres, is simple, effective and reliable. It does not require skilled examiners, so that it may be an alternative method, avoiding uneasiness of the current DCA using Giemsa-stained metaphase chromosome samples.

Characteristics and immune checkpoint status of radioiodine-refractory recurrent papillary thyroid carcinomas from Ukrainian Chornobyl Tissue Bank donors.

Introduction: The radioiodine-refractory (RAI-R) recurrent papillary thyroid carcinomas (PTCs) are more frequent in elderly patients and have an unfavorable prognosis. Data on the prevalence and characteristics of RAI-R recurrent PTCs in patients of young and middle age with or without a history of radiation exposure in childhood are poorly described. The aim of the current study was: i) to determine the frequency of RAI-R recurrent PTCs among donors of the Chornobyl Tissue Bank (CTB) and analyze the clinicopathological features of primary tumors (PTs), primary metastases (PMTSs), recurrent metastases (RMTSs) and risk factors for RMTS, and ii) to determine the immune checkpoint status (ICS) of the RAI-R recurrent PTCs and to assess the factors associated with ICS positivity. Methods: Sixty RAI-R recurrent PTCs (46 exposed to radiation and 14 non-exposed, 2.5% of all cases registered with the CTB) from the Ukrainian patients aged up to 48 years were identified. Results: The clinicopathological characteristics of the PTs moderately to weakly resembled those of the PMTS and RMTS from the same patients while the metastatic tissues were highly similar. The multivariate model of RMTS included the dominant solid-trabecular growth pattern of the PT, cystic changes, N1b metastases, and the probability of a causation (POC) of PTC by radiation as risk factors. Among these factors, the lateral PMTS (N1b) had the strongest effect. The longer period of latency (a POC component) was the second statistically significant characteristic. ICS percent agreement between the PT and RAI-R RMTS was 91.5%; 23.7% of PTs and 28.8% of RMTSs had positive ICS (positive PD-L1 tumor epithelial cells (TECs) and positive PD-L1/PD1 tumor-associated immune cells). ICS positivity of PTs was associated with pronounced oncocytic changes and high density of the p16INK4A-positive TECs in the invasive areas of PTs. In RMTSs, ICS positivity was associated with pronounced oncocytic changes and Ki-67 labeling index ≥ 4.5% of PTs, and the dominant solid-trabecular growth pattern, Ki-67 labeling index ≥ 7.6% and p16INK4A-positivity of RMTS. Discussion: The findings are of clinical relevance and may be useful for developing individual treatment approaches for patients with RAI-R recurrent PTCs possibly involving immunotherapy.

The high degree of similarity in histopathological and clinical characteristics between radiogenic and sporadic papillary thyroid microcarcinomas in young patients.

The potential overtreatment of patients with papillary thyroid microcarcinoma (MPTC) has been an important clinical problem in endocrine oncology over the past decade. At the same time, current clinical guidelines tend to consider prior radiation exposure as a contraindication to less extensive surgery, even for low-risk thyroid carcinomas, which primarily include microcarcinomas. This study aims to determine whether there are differences in the behavior of MPTC of two etiological forms (radiogenic and sporadic), including invasive properties, clinical data, and recurrence in patients aged up to 30 years. For this purpose, 136 radiogenic (from patients aged up to 18 years at the time of the Chornobyl accident) and 83 sporadic (from patients born after the Chornobyl accident) MPTCs were selected and compared using univariate and multivariate statistical methods in a whole group and in age and tumor size subgroups. No evidence of more aggressive clinical and histopathological behavior of radiogenic MPTCs as compared to sporadic tumors for basic structural, invasive characteristics, treatment options, and postoperative follow-up results was found. Moreover, radiogenic MPTCs were characterized by the lower frequencies of oncocytic changes (OR = 0.392, p = 0.004), nodal disease (OR = 0.509, p = 0.050), and more frequent complete remission (excellent response) after radioiodine therapy (OR = 9.174, p = 0.008). These results strongly suggest that internal irradiation does not affect tumor phenotype, does not associate with more pronounced invasive properties, and does not worsen prognosis in pediatric or young adult patients with MPTC, implying that radiation history may be not a pivotal factor for determining treatment strategy in such patients.

Clinicopathological Implications of the BRAF V600E Mutation in Papillary Thyroid Carcinoma of Ukrainian Patients Exposed to the Chernobyl Radiation in Childhood: A Study for 30 Years After the Accident.

With time after the Chernobyl accident, the number of papillary thyroid carcinomas (PTCs) driven by the BRAFV600E oncoprotein is growing in patients exposed to radiation at a young age. Clinicopathological associations of BRAFV600E in PTCs from patients with internal radiation history have not been sufficiently studied so far. This work analyzes the structural characteristics, proliferative activity, invasive features, clinical information, and dosimetric data in the BRAFV600E-positive and BRAFV600E-negative PTCs from the Ukrainian patients exposed to Chernobyl radiation and treated over 30 years after the accident. The study included 428 PTCs from patients aged 4-49 years at surgery who lived in the six northern regions of Ukraine most contaminated by 131I, were ≤18 years of age at the time of exposure, and were operated on from 1990 to 2017. Immunohistochemical staining for BRAFV600E was performed with the VE1 antibody. The probability of causation (POC) of a tumor due to radiation was determined using an interactive online NIH/NCI software. BRAFV600E was detected in 136/428 (31.8%) PTCs. In comparison with the BRAFV600E-negative PTCs, the BRAFV600E-positivity was associated with older patient age at the accident and at surgery, a longer period of latency, and lower POC. The BRAFV600E-positive PTCs were characterized by smaller tumor size, higher Ki67 labeling index, more frequent oncocytic changes, multifocality, and dominant papillary growth pattern. Tumor invasive features were less frequent in the BRAFV600E-positive PTCs and did not change with POC level. Despite a less aggressive tumor phenotype, BRAFV600E was a risk factor for recurrence, namely radioiodine-refractory (RAI-R) recurrent metastases. Multivariate models of RAI-R included BRAFV600E and/or histopathological parameters closely correlating with BRAFV600E such as tumor size, multifocality, dominant papillary growth pattern, or oncocytic changes. Thus, the BRAFV600E-positive PTCs from patients from a high-risk group for radiogenic thyroid cancer diagnosed in the 30 years after the Chernobyl accident did not display higher invasiveness regardless of POC level, but in view of the prognostic impact of this genetic alteration, knowledge of the BRAF status may be beneficial for middle-aged patients with radiogenic PTC considered for RAI therapy, and suggests more careful follow-up of patients with the BRAFV600E-positive tumors.

Intention to Return and Perception of the Health Risk Due to Radiation Exposure Among Residents in Tomioka Town, Fukushima Prefecture, Stratified by Gender and Generation.

OBJECTIVE: The aim of this study was to clarify residents' intentions to return (ITR) to Tomioka town, Fukushima Prefecture; and their risk perception of the health effects of radiation exposure as stratified by gender and generation. METHODS: Of almost 8000 residents who were 20 years of age or older and who had lived, prior to the accident, in the zones of Tomioka town where residents were permitted to return, 1860 were included in the analysis. For the analysis, the residents were divided into 4 groups which were stratified by gender and age: older males (over 50 years), young males (20-49 years), older females (over 50 years), and young females (20-49 years). RESULTS: ITR was found to be significantly lower in young males, young females, and older females than in older males. Conversely, young and older females had significantly higher levels of anxiety about drinking tap water and consuming food collected in Tomioka town. Young and older females also had greater concerns about adverse health effects on themselves and their offspring due to living in Tomioka town. CONCLUSION: Our results showed that special attention should be paid to younger residents, particularly to young females, with regard to recovery from a nuclear disaster.

The relationship of the clinicopathological characteristics and treatment results of post-Chornobyl papillary thyroid microcarcinomas with the latency period and radiation exposure.

Introduction: A worldwide increase in the incidence of thyroid cancer during the last decades is largely due to papillary thyroid microcarcinomas (MPTCs), which are mostly low-risk tumors. In view of recent clinical recommendations to reduce the extent of surgery for low-risk thyroid cancer, and persisting uncertainty about the impact of radiation history, we set out to address whether clinicopathological characteristics and prognosis of post-Chornobyl MPTCs were changing with regard to: i) the latency period, ii) probability of causation (POC) of a tumor due to radiation, and iii) tumor size. Methods: Patients (n = 465) aged up to 50 years at diagnosis who lived in April, 1986 in six northern, most radiocontaminated regions of Ukraine were studied. Results: Latency period was statistically significantly associated with the reduction of POC level, tumor size and the frequency of fully encapsulated MPTCs. In contrast, the frequency of oncocytic changes and the BRAFV600E mutation increased. Invasive properties and clinical follow-up results did not depend on latency except for a lower frequency of complete remission after postsurgical radioiodine therapy. The POC level was associated with more frequent extrathyroidal extension, and lymphatic/vascular invasion, less frequent oncocytic changes and BRAFV600E , and did not associate with any clinical indicator. Tumor size was negatively associated with the latency period and BRAFV600E , and had a statistically significant effect on invasive properties of MPTCs: both the integrative invasiveness score and its components such as lymphatic/vascular invasion, extrathyroidal extension and lymph node metastases increased. The frequency of total thyroidectomy, neck lymph node dissection and radioiodine therapy also increased with the larger tumor size. The duration of the latency period, POC level or tumor size did not associate with the chance of disease recurrence. Discussion: In summary, we did not observe overall worsening of the clinicopathological features or treatment results of radiogenic MPTCs that could be associated with the latency period or POC level, suggesting that radiation history did not strongly affect those in the analyzed MPTC patients. However, the increase in the invasive properties with tumor size indicates the need for individual risk stratification for each MPTC patient, regardless of radiation history, for treatment decision-making.

The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age.

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus.

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

Experiences of crisis communication during radiation emergency and risk communication for recovery of the community in Fukushima.

Since 2011, Nagasaki University (Nagasaki, Japan) has been assisting the reconstruction efforts of Kawauchi Village (Fukushima Prefecture), which was the first village to decide to return to their home town after the evacuation due to the accident at the Fukushima Daiichi Nuclear Power Station. In April 2013, Nagasaki University and the Kawauchi Government Office concluded an agreement concerning comprehensive cooperation toward the reconstruction of the village. Furthermore, we began comprehensive support for the residents of Tomioka who returned to their hometown in 2017, and of Ohkuma town in 2020. On the basis of the experiences in Kawauchi, Tomioka and Ohkuma, it is clear that the cooperation of residents, local authorities and specialists is essential for the recovery of areas affected by the accident at the Fukushima Daiichi Nuclear Power Station. Accumulated experiences and practices should be carefully evaluated and recorded to prepare for unexpected nuclear disasters in the future.

Cell competition between anaplastic thyroid cancer and normal thyroid follicular cells exerts reciprocal stress response defining tumor suppressive effects of normal epithelial tissue.

The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.

A Search for Causes of Rising Incidence of Differentiated Thyroid Cancer in Children and Adolescents after Chernobyl and Fukushima: Comparison of the Clinical Features and Their Relevance for Treatment and Prognosis.

The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4-5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.

Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma.

Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is an efficient anti-tumor therapeutic agent that inhibits the activation of EGFR; however, data related to the cellular effects of prolonged cetuximab treatment are limited. In this study, the long-term cellular outcome of prolonged cetuximab treatment and the related molecular mechanism were explored in a head and neck squamous cell carcinoma cell line constitutively expressing a fluorescent ubiquitination-based cell cycle indicator. Fluorescent time-lapse imaging was used to assess clonal growth, cell motility, and cell-cycle progression. Western blot analysis was performed to measure the level of phosphorylation and protein-expression following cetuximab treatment. Over 5 days cetuximab treatment decreased cell motility and enhanced G1 phase cell arrest in the central region of the colonies. Significantly decreased phosphorylation of retinoblastoma, Skp2, and Akt-mTOR proteins, accumulation of p27Kip1, and induction of type II LC3B were observed over 8 days cetuximab treatment. Results of the present study elucidate the cetuximab-dependent inhibition of cell migration, resulting in high cell density-related stress and persistent cell-cycle arrest at G1 phase culminating in autophagy. These findings provide novel molecular insights related to the anti-tumor effects of prolonged cetuximab treatment with the potential to improve future therapeutic strategy.

Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios.

Background: A significant increase in the incidence of papillary thyroid carcinoma (PTC) in subjects exposed to radiation at a young age is a well-documented health consequence of the Chernobyl accident. The ongoing Thyroid Ultrasound Examination (TUE) program in children and adolescents of Fukushima Prefecture in Japan also indicated a high prevalence of PTC although its attribution to radiation exposure is a subject of debate. The objective of this study was to perform histopathological analysis of tumor architecture and invasive properties in (i) radiogenic post-Chernobyl and sporadic PTCs from Ukraine, and (ii) PTCs in patients from Fukushima and other Prefectures of Japan of comparable age groups. Methods: The Ukrainian radiogenic PTCs included 245 PTCs from patients who resided in three highly 131I-contaminated regions and 165 sporadic PTCs diagnosed in residents of the same regions who were born after the accident and therefore not exposed to radioiodine. The Japanese series included 115 PTCs detected during the preliminary and the first full-scale surveys of the TUE in Fukushima and 223 PTCs from patients resident in other Prefectures. All of the subjects were included in the main statistical analysis. Three additional analyses were performed limiting the subjects to children, adolescents, and adults. Results: Ukrainian radiogenic PTC was characterized by the higher frequency of tumors with a dominant solid-trabecular growth pattern and higher invasiveness, more frequent extrathyroidal extension, lymphatic/vascular invasion, regional and distant metastases when compared with sporadic Ukrainian PTC. The integrative "invasiveness score," based on five cancer characteristics, was also higher in the radiogenic group. The differences were most pronounced in children. In contrast, no significant differences in tumor morphology or invasiveness were observed between the two Japanese groups or the three age subgroups. The only statistically significant findings were the higher proportion of male patients, smaller mean tumor size, and higher frequency of T1b tumors in the Fukushima group. Conclusions: The difference in morphological features that indicate biological behavior of PTC between the radiation-related and sporadic groups from Ukraine, together with the lack of such in the two groups from Japan, strongly suggest a nonradiogenic etiology of PTC from Fukushima and other Prefectures.

Hypothyroidism after radiation exposure: brief narrative review.

The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10-20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 "internal radiation therapy" of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3-5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.

The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.

BACKGROUND: Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features. METHODS: We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC). RESULTS: The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ±â€…6.8 mm) than in wild-type BRAF cases (20.9 ±â€…10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis. CONCLUSIONS: The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.

Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1.

Mitophagy plays an important role in the maintenance of mitochondrial homeostasis. PTEN-induced kinase (PINK1), a key regulator of mitophagy, is degraded constitutively under steady-state conditions. During mitophagy, it becomes stabilized in the outer mitochondrial membrane, particularly under mitochondrial stress conditions, such as in treatment with uncouplers, generation of excessive mitochondrial reactive oxygen species, and formation of protein aggregates in mitochondria. Stabilized PINK1 recruits and activates E3 ligases, such as Parkin and mitochondrial ubiquitin ligase (MUL1), to ubiquitinate mitochondrial proteins and induce ubiquitin-mediated mitophagy. Here, we found that the anticancer drug gemcitabine induces the stabilization of PINK1 and subsequent mitophagy, even in the absence of Parkin. We also found that gemcitabine-induced stabilization of PINK1 was not accompanied by mitochondrial depolarization. Interestingly, the stabilization of PINK1 was mediated by MUL1. These results suggest that gemcitabine induces mitophagy through MUL1-mediated stabilization of PINK1 on the mitochondrial membrane independently of mitochondrial depolarization.

The Contribution of Genetic Variants to the Risk of Papillary Thyroid Carcinoma in the Kazakh Population: Study of Common Single Nucleotide Polymorphisms and Their Clinicopathological Correlations.

Objective: Risk for developing papillary thyroid carcinoma (PTC), the most common endocrine malignancy, is thought to be mediated by lifestyle, environmental exposures and genetic factors. Recent progress in the genome-wide association studies of thyroid cancer leads to the identification of several genetic variants conferring risk to this malignancy across different ethnicities. We set out to elucidate the impact of selected single nucleotide polymorphisms (SNPs) on PTC risk and to evaluate clinicopathological correlations of these genetic variants in the Kazakh population for the first time. Methods: Eight SNPs were genotyped in 485 patients with PTC and 1,008 healthy control Kazakh subjects. The association analysis and multivariable modeling of PTC risk by the genetic factors, supplemented with rigorous statistical validation, were performed. Result: Five of the eight SNPs: rs965513 (FOXE1/PTCSC2, P = 1.3E-16), rs1867277 (FOXE1 5'UTR, P = 7.5E-06), rs2439302 (NRG1 intron 1, P = 4.0E-05), rs944289 (PTCSC3/NKX2-1, P = 4.5E-06) and rs10136427 (BATF upstream, P = 9.8E-03) were significantly associated with PTC. rs966423 (DIRC3, P = 0.07) showed a suggestive association. rs7267944 (DHX35) was associated with PTC risk in males (P = 0.02), rs1867277 (FOXE1) conferred the higher risk in subjects older than 55 years (P = 7.0E-05), and rs6983267 (POU5F1B/CCAT2) was associated with pT3-T4 tumors (P = 0.01). The contribution of genetic component (unidirectional independent effects of rs965513, rs944289, rs2439302 and rs10136427 adjusted for age and sex) to PTC risk in the analyzed series was estimated to be 30-40%. Conclusion: Genetic factors analyzed in the present work display significant association signals with PTC either on the whole group analysis or in particular clinicopathological groups and account for about one-third of the risk for PTC in the Kazakh population.

Factors Influencing the Proportion of Non-examinees in the Fukushima Health Management Survey for Childhood and Adolescent Thyroid Cancer: Results From the Baseline Survey.

BACKGROUND: After the Fukushima Daiichi Nuclear Power Plant accident, a preliminary ultrasound-based screening for thyroid cancer was conducted to establish a baseline for subsequent evaluations. In this survey, we assessed the relationship between the proportion of non-examinees and characteristics of the target populations. METHODS: After summarizing a regional difference of non-examinees among the population of 359,200 (primary evaluation) and 2,246 (confirmatory testing) individuals who were living in Fukushima Prefecture on March 11, 2011, we estimated odds ratios (ORs) for each characteristic, including age, sex, area of residence, and moving after the accident, based on the proportion of non-examinees for the primary examination and the confirmatory testing, using a multivariate logistic regression model. RESULTS: The dataset included 64,117 non-examinees (primary evaluation) and 194 (confirmatory testing). The logistic regression result indicated that girls were not likely to be non-examinees compared to boys, with adjusted OR of 0.80 (95% confidence interval [CI], 0.78-0.81) for the primary evaluation. Odds were lowest for children 6-10 years old (OR 0.26; 95% CI, 0.25-0.27), and higher for those 11-15 years old (OR 1.28; 95% CI, 1.25-1.32) and over 16 years old (OR 5.30; 95% CI, 5.16-5.43) when compared to children 0-5 years old. Individuals residing in the western part of the prefecture showed higher ORs. There was a higher proportion of non-examinees among those who moved after the accident compared to those who did not in the primary evaluation (OR 1.72; 95% CI, 1.64-1.79). CONCLUSIONS: In addition to demographic characteristics, a change of residence could be a potential factor that influenced the proportion of non-examinees. Our results will help proper interpretation of reports and prospective management of the survey.