Phase-separated super-enhancers confer an innate radioresistance on genomic DNA.

Recently, biomolecular condensates formed through liquid-liquid phase separation have been widely reported to regulate key intracellular processes involved in cell biology and pathogenesis. BRD4 is a nuclear protein instrumental to the establishment of phase-separated super-enhancers (SEs) to direct the transcription of important genes. We previously observed that protein droplets of BRD4 became hydrophobic as their size increase, implying an ability of SEs to limit the ionization of water molecules by irradiation. Here, we aim to establish if SEs confer radiation resistance in cancer cells. We established an in vitro DNA damage assay that measures the effect of radicals provoked by the Fenton reaction on DNA integrity. This revealed that DNA damage was markedly reduced when BRD4 underwent phase separation with DNA. Accordingly, co-focal imaging analyses revealed that SE foci and DNA damage foci are mutually exclusive in irradiated cells. Lastly, we observed that the radioresistance of cancer cells was significantly reduced when irradiation was combined with ARV-771, a BRD4 de-stabilizer. Our data revealed the existence of innately radioresistant genomic regions driven by phase separation in cancer cells. The disruption of these phase-separated components enfolding genomic DNA may represent a novel strategy to augment the effects of radiotherapy.

Development of an Automatic Chronological Record Creation System Using Voice AI to Facilitate Information Aggregation and Sharing in the Event of a Disaster.

OBJECTIVE: In the event of a disaster, the chain of command and communication of each relevant agency is important. In this study, a chronological record creation system using voice AI (V-CRS) was developed, and an experiment was conducted to determine whether the obtained information could be quickly and easily summarized in chronological order. METHODS: After a lecture by Japanese Disaster Medical Assistant (DMAT) Team members and 8 medical clerks on how to use the developed tool, a comparison experiment was conducted between manual input and V-CRS utilization of the time to compile disaster information. RESULTS: Results proved that V-CRS can collect information gathered at headquarters more quickly than handwriting. It was also suggested that even medical clerks who have never been trained to record information during disasters could record information at the same speed as trained DMAT personnel. CONCLUSION: V-CRS can transcribe audio information even in situations where technical terms and physical units must be recorded, such as radiation disasters. It has been proven that anyone can quickly organize information using this method, to some extent.

Immune status of people living in the Tande-Tande sub-village (Indonesia), an area with high indoor radon concentration.

On Earth, there are significant variations in terms of exposure to naturally occurring radiation among different areas. Radon, a naturally-occurring radioactive gas that is the primary cause of lung cancer in nonsmokers and the second most prevalent cause among smokers, poses a considerable risk. Indoor radon, in particular, constitutes the most substantial source of natural radiation to which individuals are exposed. This study assessed the immune status of a population chronically exposed to high indoor radon concentration in Indonesia. Fifty-seven subjects from the Tande-Tande sub-village (high indoor radon concentration area) were compared to fifty-three participants living in the Topoyo village (low concentration area). We contrasted the immunological conditions of these two populations by measuring levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-4 (IL-4), and IL-10 in serum. Moreover, we also measured levels of the nuclear factor kappa B (NF-κB), superoxide dismutase (SOD), glutathione peroxidase (GPX), and protein kinase B in its phosphorylated (pAkt) and non-phosphorylated form (Akt) in peripheral blood mononuclear cells (PBMCs) of a subset of participants (31 from each population). TNF-α, IFN-γ, and IL-4 levels in Tande-Tande sub-village inhabitants were significantly lower than those in the control group living in the Topoyo village (p = 0.001, p = 0.017, and p = 0.002). The concentration of IL-10 also tended to be lower in people living in the high indoor radon concentration area, but it did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.106). Protein levels of NF-κB, pAkt, and Akt in Tande-Tande sub-village inhabitants also did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.234, p = 0.210, and p = 0.657). Similarly, activities of SOD and GPX did not differ significantly between the two populations (p = 0.569 and p = 0.949). Overall, despite their chronic exposure to high indoor radon concentrations, our study revealed no increase in the levels of TNF-α, IFN-γ, IL-10, IL-4, SOD, and GPX in the inhabitants of Tande-Tande sub-village compared with people living in the Topoyo village. Furthermore, our study demonstrated no activation in the Akt pathway, as indicated by the pAkt/Akt ratio observed in PBMC lysates of individuals residing in the Tande-Tande sub-village.

Prediction of hub genes and key pathways associated with the radiation response of human hematopoietic stem/progenitor cells using integrated bioinformatics methods.

Hematopoietic stem cells (HSCs) are indispensable for the maintenance of the entire blood program through cytokine response. However, HSCs have high radiosensitivity, which is often a problem during radiation therapy and nuclear accidents. Although our previous study has reported that the combination cytokine treatment (interleukin-3, stem cell factor, and thrombopoietin) improves the survival of human hematopoietic stem/progenitor cells (HSPCs) after radiation, the mechanism by which cytokines contribute to the survival of HSPCs is largely unclear. To address this issue, the present study characterized the effect of cytokines on the radiation-induced gene expression profile of human CD34+ HSPCs and explored the hub genes that play key pathways associated with the radiation response using a cDNA microarray, a protein-protein interaction-MCODE module analysis and Cytohubba plugin tool in Cytoscape. This study identified 2,733 differentially expressed genes (DEGs) and five hub genes (TOP2A, EZH2, HSPA8, GART, HDAC1) in response to radiation in only the presence of cytokines. Furthermore, functional enrichment analysis found that hub genes and top DEGs based on fold change were enriched in the chromosome organization and organelle organization. The present findings may help predict the radiation response and improve our understanding of this response of human HSPCs.

The Acute Radiation Syndrome-Mitigator Romiplostim and Secreted Extracellular Vesicles Improved Survival in Mice Acutely Exposed to Myelosuppressive Doses of Ionizing Radiation.

In cases of accidental high-dose total-body irradiation (TBI), acute radiation syndrome (ARS) can cause death. We reported that the thrombopoietin receptor agonist romiplostim (RP) has the potential to completely rescue mice exposed to lethal TBI. Extracellular vesicles (EVs) are involved in cell-to-cell communication, and the mechanism of RP action may be related to EVs that reflect the radio-mitigative information. We investigated the radio-mitigative effects of EVs on mice with severe ARS. C57BL/6 mice exposed to lethal TBI were treated with RP, and the EVs were isolated from the serum and intraperitoneally injected into other mice with severe ARS. The 30-day survival rate of lethal TBI mice drastically improved by 50-100% with the administration of EVs in the sera collected weekly from the mice in which radiation damage was alleviated and mortality was avoided by the administration of RP. Four responsive miRNAs, namely, miR-144-5p, miR-3620-5p, miR-6354, and miR-7686-5p showed significant expression changes in an array analysis. In particular, miR-144-5p was expressed only in the EVs of RP-treated TBI mice. Specific EVs may exist in the circulating blood of mice that escaped mortality with an ARS mitigator, and their membrane surface and endogenous molecules may be the key to the survival of mice with severe ARS.

DAP3-mediated cell cycle regulation and its association with radioresistance in human lung adenocarcinoma cell lines.

Mitochondria play important roles in the cellular response to various types of stress, including that triggered by ionizing radiation. We have previously reported that the mitochondrial ribosomal protein death-associated protein 3 (DAP3) regulates the radioresistance of human lung adenocarcinoma (LUAD) cell lines A549 and H1299. However, the underlying mechanism of this regulation remains to be elucidated. To this end, we have herein investigated the role of DAP3 in the cell cycle regulation after irradiation. Notably, the DAP3 knockdown attenuated the radiation-induced increase of the G2/M cell population. Furthermore, western blotting analysis has revealed that the DAP3 knockdown decreased the expression of proteins related to the G2/M arrest, such as those of the phosphorylated cdc2 (Tyr15) and the phosphorylated checkpoint kinase 1 (Ser296), in irradiated A549 cells and H1299 cells. Moreover, by using a chk1 inhibitor, we were able to demonstrate that chk1 is involved in the radiation-induced G2/M arrest in both A549 and H1299 cells. Notably, the chk1 inhibitor was able to enhance the radiosensitivity of H1299 cells, while both chk1 inhibitor-abolished G2 arrest and inhibition of chk2-mediated events such as downregulation of radiation-induced p21 expression were required for enhancing radiosensitivity of A549 cells. Collectively, our findings reveal a novel role of DAP3 to regulate G2/M arrest through pchk1 in irradiated LUAD cells and suggest that chk1-mediated G2/M arrest regulates the radioresistance of H1299 cells, whereas both the chk1-mediated G2/M arrest and the chk2-mediated events contribute to the radioresistance of A549 cells.

Cytotoxic Activity of Unique Synthesized Five-membered Heterocyclic Compounds Coordinated with Tiopronin Monovalent.

BACKGROUND: We recently synthesized a compound in which 5-mercapto-1-methyltetrazole (MM4) was coordinated to tiopronin monovalent (TPN-Au(I)) and reported its cytotoxic activity against human leukemia cells in vitro. OBJECTIVE: We further synthesized other heterocyclic compounds coordinated with TPN-Au(I) and assessed their cytotoxic activity against hepatocellular carcinoma HepG2 and lung cancer cell line H1299 in vitro. METHODS: Seven kinds of compounds were synthesized by introducing a five-membered heterocyclic compound into TPN-Au(I). The number of viable cells was counted by a trypan blue dye exclusion assay. Fluorescence conjugated-Annexin V and propidium iodide were used for the apoptosis analysis. RESULTS: Seven compounds were successfully synthesized. Among these compounds, TPN-Au(I)-MTZ (3- mercapto-1,2,4-triazole), TPN-Au(I)-MMT (2-mercapto-5-methyl-1,3,4-thiadiazole), and TPN-Au(I)-MMTT (2-mercapto-5-methylthio-1,3,4-thiadiazole) effectively suppressed the proliferation and induced apoptosis in HepG2 cells. In addition, TPN-Au(I)-MMTT and TPN-Au(I)-MMT also showed effective cytotoxicity against H1299 cells. CONCLUSION: The present results showed that introduction of some five-membered heterocyclic compounds, especially MMT and MMTT, to TPN-Au(I) improved the cytotoxicity against solid cancer cells.

Chromosome aberrations, micronucleus frequency, and catalase concentration in a population chronically exposed to high levels of radon.

PURPOSE: To deepen our knowledge on the effects of high levels of indoor radon exposure, we assessed the frequencies of unstable and stable chromosome aberrations and micronucleus (MN), as well as the concentration of an endogenous antioxidant (catalase, CAT), in blood samples of individuals chronically exposed to high indoor radon concentrations in Indonesia (Tande-Tande sub-village, Mamuju, West Sulawesi). Moreover, we also investigated the occurrence of a radio-adaptive response (RAR) in Tande-Tande sub-village inhabitants using the G2 MN assay. MATERIALS AND METHODS: The frequencies of dicentric (DC), acentric (AF), ring (R), and translocation (Tr) chromosomes in Tande-Tande inhabitants were compared to those in people living in a reference area with low levels of indoor radon levels (Topoyo village, Indonesia). The number of MN per 1000 binucleated cells (BNC) and CAT concentration per total protein was quantified and compared between groups. Lastly, we irradiated (2 Gy) phytohemagglutinin-stimulated samples in vitro and measured the frequency of MN to verify the occurrence of a RAR in Tande-Tande sub-village inhabitants. RESULTS AND CONCLUSION: The frequencies of DC, AF, and Tr did not differ between Tande-Tande inhabitants and control subjects (p = 0.350, 0.521, 0.597). The frequency of MN in Tande-Tande inhabitants was significantly lower than that in the control group (p = 0.006). Similarly, CAT concentration in Tande-Tande inhabitants was also significantly lower than that in the control population (p < 0.001). Significant negative correlations were identified for MN number and CAT concentration versus indoor radon concentration, annual effective dose, or cumulative dose both within groups and when all data were analyzed together. Our findings indicate that, despite the high indoor radon levels, Tande-Tande inhabitants are not under oxidative stress, since this group had lower CAT concentration and MN frequency than those in the control group. The negative correlation between MN frequency and indoor radon concentration, annual effective dose, and cumulative dose suggests the occurrence of an RAR phenomenon in Tande-Tande sub-village inhabitants. This interpretation is also supported by the results of the G2 MN assay, which revealed lower MN frequencies after in vitro irradiation of samples from Tande-Tande sub-village inhabitants than those in samples from the control group (p = 0.0069, for cumulative MN frequency; p = 0.0146, for radiation-induced MN only).

Oxidative Modification Status of Human Serum Albumin Caused by Chronic Low-Dose Radiation Exposure in Mamuju, Sulawesi, Indonesia.

The recently discovered high-level natural background radiation area (HBRA) of Mamuju in Indonesia provides a unique opportunity to study the biological effects of chronic low-dose radiation exposure on a human population. The mean total effective dose in the HBRA was approximately 69.6 mSv y-1 (range: 47.1 to 115.2 mSv y-1), based on a re-evaluation of the individual radiation exposure dose; therefore, proteomic analyses of serum components and oxidative modification profiling of residents living in the HBRA were reconducted using liquid chromatography-tandem mass spectrometry. The analysis of the oxidative modification sequences of human serum albumin revealed significant moderate correlations between the radiation dose and the modification of 12 sequences, especially the 111th methionine, 162nd tyrosine, 356th tyrosine, and 470th methionine residues. In addition, a dose-dependent variation in 15 proteins of the serum components was detected in the serum of residents exposed to chronic low-dose radiation. These findings suggest that the alterations in the expression of specific proteins and the oxidative modification responses of serum albumin found in exposed humans may be important indicators for considering the effects of chronic low-dose radiation exposure on living organisms, implying their potential utility as biomarkers of radiation dose estimation.

Serum Proteomic and Oxidative Modification Profiling in Mice Exposed to Total Body X-Irradiation.

The details of the dose-dependent response of serum proteins exposed to ionizing radiation, especially the oxidative modification response in amino acid sequences of albumin, the most abundant protein, are unknown. Thus, a proteomic analysis of the serum components from mice exposed to total body X-irradiation (TBI) ranging from 0.5 Gy to 3.0 Gy was conducted using LC-MS/MS. The analysis of oxidative modification sequences of albumin (mOMSA) in TBI mouse serum revealed significant moderate or strong correlations between the X-irradiation exposure dose and modification of 11 mOMSAs (especially the 97th, 267th and 499th lysine residues, 159th methionine residue and 287th tyrosine residues). In the case of X-irradiation of serum alone, significant correlations were also found in the 14 mOMSAs. In addition, a dose-dependent variation in six proteins (Angiotensinogen, Odorant-binding protein 1a, Serine protease inhibitor A3K, Serum paraoxonase/arylesterase 1, Prothrombin and Epidermal growth factor receptor) was detected in the serum of mice exposed to TBI. These findings suggest the possibility that the protein variation and serum albumin oxidative modification responses found in exposed individuals are important indicators for considering the effects of radiation on living organisms, along with DNA damage, and suggests their possible application as biomarkers of radiation dose estimation.

Detection of biological responses to low-dose radiation in humans.

It has been considered difficult to detect the biological effects of low-dose radiation exposure below approximately 100 mSv in humans. Serum proteomic analysis and oxidative modification profiling were conducted with blood samples collected from residents of a newly discovered high-level natural background radiation area (annual effective dose approximately 50 mSv y-1) and normal-level area (1.22 mSv y-1) in Mamuju, Indonesia, where many people have been living for generations. Dose-dependent oxidative modifications in amino acid sequences of human serum albumin, especially the 162nd and 356th tyrosine residues and 111th and 470th methionine residues, were found. None of these findings have been reported in humans exposed to chronic low-dose radiation. It can be used as a biomarker not only for the assessment of the presence or absence of radiation exposure but also for dose prediction in living organisms for chronic radiation. These results suggest that traces of radiation exposure are recorded in serum albumin and that there is a possibility of a new methodology that can evaluate biological responses below 100 mSv.

An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice.

The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only completely rescues irradiated mice but also shows mitigative effects on their hematopoiesis and multiple organ injury, including that of the lung, bone marrow, small intestine, and liver. However, the mechanism by which RP functions as a radiomitigator remains unclear. In the present study, we applied a metabolomics approach, which has the ability to reflect the status of an organism directly and accurately, helping to elucidate the biology of treatment responses. Our results showed that the disruption of several metabolites and pathways in response to total body irradiation was partially corrected by RP administration. Notably, RP-corrected metabolites and pathways have been reported to be indicators of DNA damage and lung, bone marrow, small intestine, and liver injury. Taken together, the present findings suggested that the radiomitigative effect of RP is partially involved in the recovery of organ injury, and the identified metabolites may be a useful biomarker of the survival likelihood following radiation exposure.

Cytotoxic Activity of a Unique Monomeric Heterogeneous Two-Coordinate Ligand Monovalent Gold Complex with Tiopronin and a Heterocyclic Mercapto-Tetrazole Compound.

BACKGROUND: The importance of the role of NF-κB is recognized in situations such as malignant transformation and metastasis of cancer, and it has been suggested that inhibiting this role can be one of the cancer treatment strategies. Gold preparations such as auranofin are known to have an indirect NF-κB inhibitory effect. OBJECTIVE: We synthesized a novel gold complex [tiopronin monovalent gold-5-mercapto- 1-methyl tetrazole, abbreviated as TPN-Au(I)-MM4], with different physical properties and chemical structure from auranofin, and evaluated its cytotoxic activity and radiation sensitizing effect on human THP1 cells. METHODS: The number of viable cells was counted by the trypan blue dye exclusion method. The cell death evaluation was performed by FITC-Annexin V+ and PI staining. In investigating the radiation sensitizing effect of TPN-Au(I)-MM4, this compound [10 or 25 µM] was added into the culture medium 1 h before X-ray irradiation. RESULTS: In the cells treated with 25 µM TPN-Au(I)-MM4 for 72 h, a decrease in the proliferation of THP1 cells was observed [The relative values of viable cells in the control group and the 25 µM treatment group were approximately 6.8 and 4.2, respectively]. In the combination of 25 µM of the compound treatment and X-ray irradiation, an increase of approximately 3.0-fold was observed in 2 Gy irradiation and approximately 1.4-fold in 4 Gy irradiation as in comparison to the case of irradiation alone. CONCLUSION: These results suggest that TPN-Au(I)-MM4 reduces the proliferation of THP1 cells through the induction of cell death, and the combined use of TPN-Au(I)-MM4 and X-ray irradiation shows effective cytotoxicity against THP1 cells.

Discovery of a Novel Small-molecule Interleukin-6 Inhibitor Through Virtual Screening Using Artificial Intelligence.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine involved in various cell functions and diseases. Thus far, several IL-6 inhibitors, such as humanized monoclonal antibody have been used to block excessive IL-6 signaling causing autoimmune and inflammatory diseases. However, anti-IL-6 and anti-IL-6 receptor monoclonal antibodies have some clinical disadvantages, such as a high cost, unfavorable injection route, and tendency to mask infectious diseases. While a small-molecule IL-6 inhibitor would help mitigate these issues, none are currently available. OBJECTIVE: The present study evaluated the biological activities of identified compounds on IL-6 stimulus. METHODS: We virtually screened potential IL-6 binders from a compound library using INTerprotein's Engine for New Drug Design (INTENDD®) followed by the identification of more potent IL-6 binders with artificial intelligence (AI)-guided INTENDD®. The biological activities of the identified compounds were assessed with the IL-6-dependent cell line 7TD1. RESULTS: The compounds showed the suppression of IL-6-dependent cell growth in a dose-dependent manner. Furthermore, the identified compound inhibited expression of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 in a dose-dependent manner. CONCLUSION: Our screening compound demonstrated an inhibitory effect on IL-6 stimulus. These findings may serve as a basis for the further development of small-molecule IL-6 inhibitors.

Comprehensive exposure assessments from the viewpoint of health in a unique high natural background radiation area, Mamuju, Indonesia.

Mamuju is one of the regions in Indonesia which retains natural conditions but has relatively high exposure to natural radiation. The goals of the present study were to characterize exposure of the entire Mamuju region as a high natural background radiation area (HNBRA) and to assess the existing exposure as a means for radiation protection of the public and the environment. A cross-sectional study method was used with cluster sampling areas by measuring all parameters that contribute to external and internal radiation exposures. It was determined that Mamuju was a unique HNBRA with the annual effective dose between 17 and 115 mSv, with an average of 32 mSv. The lifetime cumulative dose calculation suggested that Mamuju residents could receive as much as 2.2 Sv on average which is much higher than the average dose of atomic bomb survivors for which risks of cancer and non-cancer diseases are demonstrated. The study results are new scientific data allowing better understanding of health effects related to chronic low-dose-rate radiation exposure and they can be used as the main input in a future epidemiology study.

Support activities in Namie Town, Fukushima undertaken by Hirosaki University.

This paper does not necessarily reflect the views of the International Commission on Radiological Protection.Several radiation monitoring research projects are underway on dose assessment, biological analysis, and risk communication under an agreement with Namie Town. Indoor radon and thoron progeny concentrations have been measured using passive-type monitors to estimate internal doses due to inhalation. In addition, airborne radiocaesium concentrations at five points in Namie Town have been analysed using a high-purity germanium detector to estimate internal doses for comparison with radon. External radiation doses from natural and artificial radionuclides have also been estimated using an in-situ gamma-ray spectrometer. Other support activities are mentioned briefly in this article.

Simulation study on radiation exposure of emergency medical responders from radioactively contaminated patients.

Emergency medical responders (EMRs) who treat victims during a radiation emergency are at risk of radiation exposure. In this study, the exposure dose to EMRs treating hypothetically contaminated patients was estimated using a Monte Carlo simulation, and the findings may be useful for educating EMRs and reducing their anxiety. The Monte Carlo simulation estimated radiation doses for adult computational phantoms based on radioactive contamination conditions and radiation dosages from previous studies. At contamination conditions below the typical upper limit of general Geiger-Müller survey meters, the radiation doses to EMRs were estimated to be less than 1 µSv per hour. In cases with greater contamination due to mishandling of an intense radioactive source (hundreds of GBq), the radiation doses to EMRs could reach approximately 100 mSv per hour. These results imply that a radiological accident with a highly radioactive source could expose EMR to significant radiation that exceeds their dose limit. Thus, authorities and other parties should ensure that EMRs receive appropriate education and training regarding measures that can be taken to protect themselves from the possibility of excessive radiation exposure. The results of this study may provide EMRs with information to take appropriate protective measures, although it is also important that they not hesitate to perform lifesaving measures because of concerns regarding radiation.

Discriminative Measurement of Absorbed Dose Rates in Air from Natural and Artificial Radionuclides in Namie Town, Fukushima Prefecture.

Ten years have elapsed since the accident at the Fukushima Daiichi Nuclear Power Plant in 2011, and the relative contribution of natural radiation is increasing in Fukushima Prefecture due to the reduced dose of artificial radiation. In order to accurately determine the effective dose of exposure to artificial radiation, it is necessary to evaluate the effective dose of natural as well as artificial components. In this study, we measured the gamma-ray pulse-height distribution over the accessible area of Namie Town, Fukushima Prefecture, and evaluated the annual effective dose of external exposure by distinguishing between natural and artificial radionuclides. The estimated median (range) of absorbed dose rates in air from artificial radionuclides as of 1 April 2020, is 133 (67-511) nGy h-1 in the evacuation order cancellation zone, and 1306 (892-2081) nGy h-1 in the difficult-to-return zone. The median annual effective doses of external exposures from natural and artificial radionuclides were found to be 0.19 and 0.40 mSv in the evacuation order cancellation zone, and 0.25 and 3.9 mSv in the difficult-to-return zone. The latest annual effective dose of external exposure discriminated into natural and artificial radionuclides is expected to be utilized for radiation risk communication.

DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells.

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.

A unique high natural background radiation area - Dose assessment and perspectives.

The biological effects of low dose-rate radiation exposures on humans remains unknown. In fact, the Japanese nation still struggles with this issue after the Fukushima Dai-ichi Nuclear Power Plant accident. Recently, we have found a unique area in Indonesia where naturally high radiation levels are present, resulting in chronic low dose-rate radiation exposures. We aimed to estimate the comprehensive dose due to internal and external exposures at the particularly high natural radiation area, and to discuss the enhancement mechanism of radon. A car-borne survey was conducted to estimate the external doses from terrestrial radiation. Indoor radon measurements were made in 47 dwellings over three to five months, covering the two typical seasons, to estimate the internal doses. Atmospheric radon gases were simultaneously collected at several heights to evaluate the vertical distribution. The absorbed dose rates in air in the study area vary widely between 50 nGy h-1 and 1109 nGy h-1. Indoor radon concentrations ranged from 124 Bq m-3 to 1015 Bq m-3. That is, the indoor radon concentrations measured exceed the reference levels of 100 Bq m-3 recommended by the World Health Organization. Furthermore, the outdoor radon concentrations measured were comparable to the high indoor radon concentrations. The annual effective dose due to external and internal exposures in the study area was estimated to be 27 mSv using the median values. It was found that many residents are receiving radiation exposure from natural radionuclides over the dose limit for occupational exposure to radiation workers. This enhanced outdoor radon concentration might be as a result of the stable atmospheric conditions generated at an exceptionally low altitude. Our findings suggest that this area provides a unique opportunity to conduct an epidemiological study related to health effects due to chronic low dose-rate radiation exposure.