VEGF affects mitochondrial ROS generation in glioma cells and acts as a radioresistance factor.

Vascular endothelial growth factor (VEGF) is closely related to angiogenesis. Anticancer therapy by inhibiting VEGF signaling is well established. However, the role of VEGF in cell-cell communication during the response to ionizing radiation is not well understood. Here, we examined the role of VEGF on radiosensitivity of cells. The addition of recombinant VEGF (rVEGF) on cultured rat C6 glioma cells showed a radioprotective effects on X-ray irradiation and reduced oxidative stress. These effects were also observed by endogenous VEGF in supernatant of C6 glioma cells. Reduction of oxidative stress by VEGF is suggested to underlie the radioprotective effects. The mechanism of VEGF-induced reduction of oxidative stress was indicated by a decreased oxygen consumption rate (OCR) in mitochondria. However, the number of DNA double-strand breaks (DSB) immediately after irradiation was not reduced by the treatment with VEGF. These results suggest that VEGF plays a role in cell survival after irradiation by controlling the oxidative condition through mitochondrial function that is independent of the efficiency of DSB induction.

Influence of Boron Neutron Capture Therapy on Normal Liver Tissue.

Radiation-induced liver diseases, including liver fibrosis, occurs when radiation damages the liver. Basic research on hepatic fibrosis, which is a late radiation injury, is necessary for evaluating adverse liver events occurring after boron neutron capture therapy. This study was conducted to establish a method for analyzing the negative effect such as fibrosis in the liver tissue after boron neutron capture therapy. Female C57BL6 mice were injected with p-boronophenylalanine solution subcutaneously at 2 h before neutron irradiation. Masson trichrome staining was performed to determine the degree of liver fibrosis. The degree of fat accumulation in mouse normal liver tissue after boron neutron capture therapy was evaluated using hematoxylin and eosin staining and triglyceride quantification. Western blotting was performed to determine the expression level of Sonic Hedgehog. Liver fat accumulation and fibrosis were significantly increased in the neutron irradiation group injected with p-boronophenylalanine compared with control group. In addition, Sonic Hedgehog expression was increased in response to boron neutron capture therapy-induced liver injury and was involved in liver fibrosis. Hepatocellular fat accumulation and Hedgehog signaling activation may be indicators of adverse events related to boron neutron capture therapy associated with liver fibrosis.

Development of an irradiation method for superficial tumours using a hydrogel bolus in an accelerator-based BNCT.

The aim of this study is the development of an irradiation method for the treatment of superficial tumours using a hydrogel bolus to produce thermal neutrons in accelerator-based Boron Neutron Capture Therapy (BNCT).To evaluate the neutron moderating ability of a hydrogel bolus, a water phantom with a hydrogel bolus was irradiated with an epithermal neutron beam from a cyclotron-based epithermal neutron source. Phantom simulating irradiation to the plantar position was manufactured using three-dimensional printing technology to perform an irradiation test of a hydrogel bolus. Thermal neutron fluxes on the surface of a phantom were evaluated and the results were compared with the Monte Carlo-based Simulation Environment for Radiotherapy Applications (SERA) treatment planning software. It was confirmed that a hydrogel bolus had the same neutron moderating ability as water, and the calculation results from SERA aligned with the measured values within approximately 5%. Furthermore, it was confirmed that the thermal neutron flux decreased at the edge of the irradiation field. It was possible to uniformly irradiate thermal neutrons by increasing the bolus thickness at the edge of the irradiation field, thereby successfully determining uniform dose distribution. An irradiation method for superficial tumours using a hydrogel bolus in the accelerator-based BNCT was established.

PRDX1 is essential for the viability and maintenance of reactive oxygen species in chicken DT40.

BACKGROUND: Peroxiredoxin 1 (PRDX1) is a member of a ubiquitous family of thiol peroxidases that catalyze the reduction of peroxides, including hydrogen peroxide. It functions as an antioxidant enzyme, similar to catalase and glutathione peroxidase. PRDX1 was recently shown act as a sensor of reactive oxygen species (ROS) and play a role in ROS-dependent intracellular signaling pathways. To investigate its physiological functions, PRDX1 was conditionally disrupted in chicken DT40 cells in the present study. RESULTS: The depletion of PRDX1 resulted in cell death with increased levels of intracellular ROS. PRDX1-depleted cells did not show the accumulation of chromosomal breaks or sister chromatid exchange (SCE). These results suggest that cell death in PRDX1-depleted cells was not due to DNA damage. 2-Mercaptoethanol protected against cell death in PRDX1-depleted cells and also suppressed elevations in ROS. CONCLUSIONS: PRDX1 is essential in chicken DT40 cells and plays an important role in maintaining intracellular ROS homeostasis (or in the fine-tuning of cellular ROS levels). Cells deficient in PRDX1 may be used as an endogenously deregulated ROS model to elucidate the physiological roles of ROS in maintaining proper cell growth.

BNCT for primary synovial sarcoma.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.

Boron neutron capture therapy for clear cell sarcoma.

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS.

Proposal for determining absolute biological effectiveness of boron neutron capture therapy-the effect of 10B(n,α)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size.

The relationship between the radiation dose delivered to a tumor and its effect is not completely predictable. Uncertainty in the estimation of the boron concentration in a tumor, variation in the radiation sensitivity of the tumor cells, and the complexity of the interactions between the four types of radiation comprising the boron neutron capture therapy (BNCT) dose contribute to this uncertainty. We reanalyzed the data of our previous papers to investigate the variation in radiosensitivity of tumor cells to the 10B(n,α)7Li dose: the dose generated by the reaction of thermal neutrons and 10B, hereafter the 'boron-neutron dose'. The radiosensitivities of five tumors (EL4, SAS/neo, SAS/mp53, SCCVII and B16-BL6 melanoma) were examined. For the combination of p-boron-L-phenylalanine (BPA: C9H12BNO4) with neutron irradiation, D0, the cell survival curve for the boron-neutron dose was the smallest for the SAS/neo, followed by the EL4, SAS/mp53, SCCVII and B16-BL6 melanoma, in that order. For the combination of mercaptoundecahydrododecaborate (BSH: Na2B12H11SH) with neutron irradiation, D0 was the smallest for the EL4, followed by the SAS/neo, B16-BL6melanoma, SAS/mp53 and SCCVII, in that order. The relationships between these D0 values and the nucleocytoplasmic ratios (Xncs) or cell size indices (Xcs) obtained by histopathological microslide image were as follows: (D0 = 0.1341Xnc-1.586, R2 = 0.9721) for all tumor types with BPA-BNCT, and D0 = 0.0122Xcs-0.1319 (R2 = 0.9795) for four tumor types (all except the B16-BL6 melanoma) with BSH-BNCT. Based on these results, we proposed a new biologically equivalent effectiveness factor: the absolute biological effectiveness (ABE) factor. The ABE factor is Gy/D0. Thus, the ABE dose is the physical dose multiplied by the ABE factor, and refers to the dose needed to decrease the cell survival rate to e-ABE dose/Gy.

Acquisition of radioresistance by IL-6 treatment is caused by suppression of oxidative stress derived from mitochondria after γ-irradiation.

Interleukin (IL)-6 is a multifunctional cytokine and is one of the radiation-induced bystander factors. This study aimed to clarify the mechanism of acquisition of radioresistance through the control of reactive oxygen species (ROS) by IL-6. We used a rat glioma cell line (C6) as tumor cells and a rat astrocyte cell line (RNB) as non-tumor cells. Our results showed that the surviving fraction of C6 cells after 6 Gy irradiation was increased by the addition of IL-6, but that this was not the case in RNB cells. In addition, the number of 53BP1 foci in C6 cells at 30 min after γ-irradiation were decreased by IL-6. Levels of ROS in whole C6 cells, and superoxide in the mitochondria of C6 cells immediately after γ-irradiation, were reduced by IL-6, but this was not observed in RNB cells. The mitochondrial membrane potential detected by JC-1 in C6 and RNB cells was inhibited by IL-6 alone. Therefore, it was concluded that IL-6 leads specifically to radioresistance in tumor cells by inhibition of increases in ROS after γ-irradiation.

A report that Fukushima residents are concerned about radiation from Land, Food and Radon.

The Great East Japan Earthquake and subsequent TEPCO Fukushima Daiichi nuclear disaster occurred on 11 March 2011, which caused the leakage of radioactive materials into the environment. In this study, we report public concerns about radiation in Fukushima and Tokyo almost one year after the nuclear disaster. We examined the public concerns by analyzing the data from 1022 participants, 555 in Fukushima and 467 in Tokyo. They were asked whether they were concerned about radiation from some of six different types of sources, which could be answered in a binary way, 'yes' or 'no'. We found not only similarities, but also significant differences in the degrees of concerns between Fukushima residents and Tokyo ones. Fukushima residents more concerned about radiation from land, food and radon in larger rate than that of Tokyo ones, while Tokyo residents were concerned about radiation from medical care. Residents in neither location were concerned about radiation from space. Our results suggested that careful risk communication should be undertaken, adaptively organized depending on location and other factors, e.g. comprehension about radiation, presence of the experience of evacuation, and also age and gender of the people.

External effective radiation dose to workers in the restricted area of the Fukushima Daiichi Nuclear Power Plant during the third year after the Great East Japan Earthquake.

Since the Great East Japan Earthquake on 11 March 2011, Iitate Village has continued to be classified as a deliberate evacuation area, in which residents are estimated to receive an annual additional effective radiation dose of >20 mSv. Some companies still operate in Iitate Village, with a special permit from the Cabinet Office Team in Charge of Assisting the Lives of Disaster Victims. In this study, we measured the annual effective radiation dose to workers in Iitate Village from 15 January to 13 December 2013. The workers stayed in Iitate for 10 h and left the village for the remaining 14 h each working day. They worked for 5 days each week in Iitate Village, but stayed outside of the village for the remaining 2 days each week. We found that the effective radiation dose of 70% of the workers was <2 mSv, including natural radiation; the maximum dose was 3.6 mSv. We estimated the potential annual additional effective radiation dose if people returned full-time to Iitate. Our analysis supports the plan for people to return to their home village at the end of 2017.

Protective roles of ascorbic acid in oxidative stress induced by depletion of superoxide dismutase in vertebrate cells.

Superoxide dismutases (SODs) are antioxidant proteins that convert superoxide to hydrogen peroxide. In vertebrate cells, SOD1 is mainly present in the cytoplasm, with small levels also found in the nucleus and mitochondrial intermembrane space, and SOD2 is present in the mitochondrial matrix. Previously, the authors conditionally disrupted the SOD1 or SOD2 gene in DT40 cells and found that depletion of SOD1 caused lethality, while depletion of SOD2 led to growth retardation. The observations from previous work showed that the lethality observed in SOD1-depleted cells was completely rescued by ascorbic acid. Ascorbic acid is a water-soluble antioxidant present in biological fluids; however, the exact target for its antioxidant effects is not known. In this study, the authors demonstrated that ascorbic acid offset growth defects observed in SOD2-depleted cells and also lowered mitochondrial superoxide to physiological levels in both SOD1- or SOD2-depleted cells. Moreover, depletion of SOD1 or SOD2 resulted in the accumulation of intracellular oxidative stress, and this increased oxidative stress was reduced by ascorbic acid. Taken together, this study suggests that ascorbic acid can be applied as a nontoxic antioxidant that mimics the functions of cytoplasmic and mitochondrial SODs.

[Analyzing consumer preference by using the latest semantic model for verbal protocol].

This paper examines consumers' preferences for competing brands by using a preference model of verbal protocols. Participants were 150 university students, who reported their opinions and feelings about McDonalds and Mos Burger (competing hamburger restaurants in Japan). Their verbal protocols were analyzed by using the singular value decomposition method, and the latent decision frames were estimated. The verbal protocols having a large value in the decision frames could be interpreted as showing attributes that consumers emphasize. Based on the estimated decision frames, we predicted consumers' preferences using the logistic regression analysis method. The results indicate that the decision frames projected from the verbal protocol data explained consumers' preferences effectively.

Honesty mediates the relationship between serotonin and reaction to unfairness.

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.