On this unique occasion celebrating the 100th anniversary of the founding of the Japan Endocrine Society (JES), it is a great honor and pleasure for me to have this deeply appreciated opportunity to ...introduce to the junior and young members my modest background and reasons for aspiring to Endocrinology. First, I would like to refer to the famous proverb, "When you drink water, think of its source," an idiomatic translation for "Don't forget where your happiness comes from." The Dutch physician J.L.C. Pompe van Meerdervoort (1829-1908) established the "Igakudenshusho" and "Nagasaki Yojosho" in 1857 and 1861, respectively, which were the first modern western-style medical school and hospital in Japan.
Just two years have passed since the Tokyo Electric Power Company-Fukushima Daiichi Nuclear Power Plant (NPP) accident, a multidimensional disaster that combined to destroy the local infrastructure ...on which the safety system depended and gave a serious impact to the world. Countermeasures including evacuation, sheltering, and control of the food chain were implemented in a timely manner by the Japanese government. However, there is a clear need for improvement, especially in the areas of nuclear safety and protection and also in the management of the radiation health risk during and even after the accident. To date there have been no acute radiation injuries. The radiation-related physical health consequences to the general public, including evacuees, are likely to be much lower than those arising from the Chernobyl nuclear reactor accident, because the radiation fallout and the subsequent environmental contamination were much more limited. However, the social, psychological, and economic impacts of the Fukushima NPP accident are expected to be considerable. Currently, continued monitoring and characterization of the levels of radioactivity in the environment and foods in Fukushima are vital for obtaining informed consent to the decisions on living in the areas already radiocontaminated and returning back to the evacuated areas once re-entry is permitted; it is also important to perform a realistic assessment of the radiation doses on the basis of measurements. We are currently implementing the official plans of the Fukushima Health Management Survey, which includes a basic survey for the estimation of the external doses that were received during the first 4 mo after the accident and four more detailed surveys (thyroid ultrasound examination, comprehensive health check-up, mental health and life-style survey, and survey of pregnant women and nursing mothers), with the aim to take care of the health of all of the residents of the Fukushima Prefecture for a long time. Introduction of the Sinclair Lecture (Video 2:01, http://links.lww.com/HP/A24).
The accidents that occurred at the Fukushima Daiichi Nuclear Power Plant after the Great East Japan Earthquake on 11 March 2011 have resulted in long-term, ongoing anxiety among the residents of ...Fukushima, Japan. Soon after the disaster, Fukushima Prefecture launched the Fukushima Health Management Survey to investigate long-term low-dose radiation exposure caused by the accident. Fukushima Medical University took the lead in planning and implementing this survey. The primary purposes of this survey are to monitor the long-term health of residents, promote their future well-being, and confirm whether long-term low-dose radiation exposure has health effects. This report describes the rationale and implementation of the Fukushima Health Management Survey.
This cohort study enrolled all people living in Fukushima Prefecture after the earthquake and comprises a basic survey and 4 detailed surveys. The basic survey is to estimate levels of external radiation exposure among all 2.05 million residents. It should be noted that internal radiation levels were estimated by Fukushima Prefecture using whole-body counters. The detailed surveys comprise a thyroid ultrasound examination for all Fukushima children aged 18 years or younger, a comprehensive health check for all residents from the evacuation zones, an assessment of mental health and lifestyles of all residents from the evacuation zones, and recording of all pregnancies and births among all women in the prefecture who were pregnant on 11 March. All data have been entered into a database and will be used to support the residents and analyze the health effects of radiation.
The low response rate (<30%) to the basic survey complicates the estimation of health effects. There have been no cases of malignancy to date among 38 114 children who received thyroid ultrasound examinations. The importance of mental health care was revealed by the mental health and lifestyle survey and the pregnancy and birth survey. This long-term large-scale epidemiologic study is expected to provide valuable data in the investigation of the health effects of low-dose radiation and disaster-related stress.
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.
Summary Past nuclear disasters, such as the atomic bombings in 1945 and major accidents at nuclear power plants, have highlighted similarities in potential public health effects of radiation in both ...circumstances, including health issues unrelated to radiation exposure. Although the rarity of nuclear disasters limits opportunities to undertake rigorous research of evidence-based interventions and strategies, identification of lessons learned and development of an effective plan to protect the public, minimise negative effects, and protect emergency workers from exposure to high-dose radiation is important. Additionally, research is needed to help decision makers to avoid premature deaths among patients already in hospitals and other vulnerable groups during evacuation. Since nuclear disasters can affect hundreds of thousands of people, a substantial number of people are at risk of physical and mental harm in each disaster. During the recovery period after a nuclear disaster, physicians might need to screen for psychological burdens and provide general physical and mental health care for many affected residents who might experience long-term displacement. Reliable communication of personalised risks has emerged as a challenge for health-care professionals beyond the need to explain radiation protection. To overcome difficulties of risk communication and provide decision aids to protect workers, vulnerable people, and residents after a nuclear disaster, physicians should receive training in nuclear disaster response. This training should include evidence-based interventions, support decisions to balance potential harms and benefits, and take account of scientific uncertainty in provision of community health care. An open and joint learning process is essential to prepare for, and minimise the effects of, future nuclear disasters.
Abstract
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 p27
Kip1
, 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.
► We report first time that ionizing radiation induces mitochondrial dynamic changes. ► Radiation-induced mitochondrial fission was caused by Drp1 localization. ► We found that radiation causes ...delayed ROS from mitochondria. ► Down regulation of Drp1 rescued mitochondrial dysfunction after radiation exposure.
Ionizing radiation is known to increase intracellular level of reactive oxygen species (ROS) through mitochondrial dysfunction. Although it has been as a basis of radiation-induced genetic instability, the mechanism involving mitochondrial dysfunction remains unclear. Here we studied the dynamics of mitochondrial structure in normal human fibroblast like cells exposed to ionizing radiation. Delayed mitochondrial O2- production was peaked 3days after irradiation, which was coupled with accelerated mitochondrial fission. We found that radiation exposure accumulated dynamin-related protein 1 (Drp1) to mitochondria. Knocking down of Drp1 expression prevented radiation induced acceleration of mitochondrial fission. Furthermore, knockdown of Drp1 significantly suppressed delayed production of mitochondrial O2-. Since the loss of mitochondrial membrane potential, which was induced by radiation was prevented in cells knocking down of Drp1 expression, indicating that the excessive mitochondrial fission was involved in delayed mitochondrial dysfunction after irradiation.
Absorption of energy from ionizing radiation by the genetic material in the cell leads to damage to DNA, which in turn leads to cell death, chromosome aberrations and gene mutations. While early or ...deterministic effects result from organ and tissue damage caused by cell killing, latter two are considered to be involved in the initial events that lead to the development of cancer. Epidemiological studies have demonstrated the dose-response relationships for cancer induction and quantitative evaluations of cancer risk following exposure to moderate to high doses of low-linear energy transfer radiation. A linear, no-threshold model has been applied to assessment of the risks resulting from exposure to moderate and high doses of ionizing radiation; however, a statistically significant increase has hardly been described for radiation doses below 100 mSv. This review summarizes our current knowledge of the physical and biological features of low-dose radiation and discusses the possibilities of induction of cancer by low-dose radiation.
There is currently no reliable treatment for secondary lymphedema caused by lymph node dissection or radiotherapy; however, stem cell-based regenerative medicine is emerging as a promising remedy for ...such complications. The purpose of this study was to examine the effects of adipose-derived stem cells on lymphangiogenesis involving human dermal lymphatic endothelial cells exposed to ionizing radiation.
Proliferation, migration, and tube formation were analyzed in human dermal lymphatic endothelial cells that were co-cultured with adipose-derived stem cells or cultured in adipose-derived stem cell-conditioned medium. The levels of lymphangiogenic factors secreted from adipose-derived stem cells were analyzed by enzyme-linked immunosorbent assays and Western blotting.
Co-culturing with adipose-derived stem cells and the use of adipose-derived stem cell-conditioned medium both significantly promoted proliferation, migration, and tube formation in nonirradiated human dermal lymphatic endothelial cells. The authors also found that irradiated adipose-derived stem cells had similar alleviative effects on irradiated human dermal lymphatic endothelial cells. Enzyme-linked immunosorbent assays and Western blotting analysis revealed that irradiating adipose-derived stem cells increased their secretion of basic fibroblast growth factor in a dose-dependent manner, whereas it caused no detectable change in their secretion of vascular endothelial growth factor A or C, or hepatocyte growth factor.
These results demonstrated that factors secreted by adipose-derived stem cells contribute to the promotion of lymphangiogenesis in irradiated human dermal lymphatic endothelial cells. The authors' findings also suggest that radiation potentiates the paracrine effects of adipose-derived stem cells by stimulating basic fibroblast growth factor protein expression.
Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies ...demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).
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