Postcomparison of [(18) F]-fluorodeoxyglucose uptake in the brain after short-term bright light exposure and no intervention.

OBJECTIVE: Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [(18) F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. METHOD: A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [(18) F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. RESULTS: There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. CONCLUSION: The present findings suggest a possibility that 5-day bright light exposure may increase [(18) F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

Failure to complement abnormal phenotypes of simian virus 40-transformed Werner syndrome cells by introduction of a normal human chromosome 8.

The Werner syndrome (WS) gene (WRN) was isolated by positional cloning, based on mapping to chromosome 8p12, and the WRN protein was recently shown to encode an active helicase. To examine functional complementation of WS phenotypes by expression of the WRN gene, we introduced a normal human chromosome 8 into a SV40-transformed WS fibroblastoid cell line (WS780) by microcell fusion and studied several cellular phenotypes associated previously with WS cell lines, including cell growth rate, 4-nitroquinoline-1-oxide (4NQO) sensitivity, and spontaneous mutation rate and type of mutation at the hypoxanthine-guanine phosphoribosyl transferase locus. The WRN gene was expressed in two of three microcell hybrids introduced with chromosome 8. We failed to observe a difference between normal and WS cell lines in terms of growth rates and spontaneous mutation rates. However, we found that the WS cell line was highly sensitive to 4NQO-induced cytotoxicity and showed an unusually high proportion of deletion mutations at the hypoxanthine-guanine phosphoribosyl transferase locus as compared to a control cell line, as shown previously. Here, we report that these phenotypes were not corrected by introduction of the WRN gene, although the WRN protein was expressed. Our results suggest that the hypersensitivity to 4NQO and the extensive deletion mutations observed in the WS cell line are caused by a defect that is secondary to the WRN gene mutation, possibly a repair gene defect that controls the phenotypes of hypersensitivity to carcinogen(s) and/or the extensive deletion mutations.

Suppressive effect of ascorbic acid on the mutagenesis induced by the bystander effect through mitochondrial function.

Here, we focused on suppressive effect of ascorbic acid (AsA) on changes in mitochondrial function and mutagenesis by the radiation- induced bystander effect (RIBE). In mammalian cell lines, medium transfer assay was performed and conditioned medium including secreted factors after X-irradiation were examined to detect the RIBE. We found that the membrane potential and increased levels of superoxide radical (O2(-)) in mitochondria were modulated in cells treated with conditioned medium from irradiated cells. The result of the present study also demonstrated that increases in reactive oxygen species (ROS) levels led to the induction of gene mutations. Interestingly, the modulations in mitochondria, in addition to mutation inductions by RIBE, were completely suppressed by treatment with AsA in cells treated with conditioned medium. These results suggest that mutagenesis, which may have resulted from secreted factors involving the RIBE, may be induced by ROS that are localized in mitochondria and may be relieved by AsA.

Experimental verification of beam characteristics for cyclotron-based epithermal neutron source (C-BENS).

A cyclotron-based epithermal neutron source has been developed for boron neutron capture therapy. This system consists of a cyclotron accelerator producing 1.1-mA proton beams with an energy of 30 MeV, a beam transport system coupled with a beryllium neutron production target, and a beam-shaping assembly (BSA) with a neutron collimator. In our previous work, the BSA was optimized to obtain sufficient epithermal neutron fluxes of ~10(9) cm(-2) s(-1) using a Monte Carlo simulation code. In order to validate the simulation results, irradiation tests using multi-foil activation at the surface of a gamma-ray shield located behind the collimator and water phantom experiments using a collimated epithermal neutron beam were performed. It was confirmed experimentally that the intensity of the epithermal neutrons was 1.2×10(9) cm(-2) s(-1).

Significance of manipulating tumour hypoxia and radiation dose rate in terms of local tumour response and lung metastatic potential, referring to the response of quiescent cell populations.

The purpose of this study was to evaluate the influence of manipulating intratumour oxygenation status and radiation dose rate on local tumour response and lung metastases following radiotherapy, referring to the response of quiescent cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-ray irradiation at high dose rate (HDR) or reduced dose rate (RDR) following treatment with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (proliferating + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Following HDR irradiation, nicotinamide and MTH enhanced the sensitivity of the total and Q-cell populations, respectively. The decrease in sensitivity at RDR irradiation compared with HDR irradiation was slightly inhibited by MTH, especially in Q cells. Without gamma-ray irradiation, nicotinamide treatment tended to reduce the number of lung metastases. With gamma-rays, in combination with nicotinamide or MTH, especially the former, HDR irradiation decreased the number of metastases more remarkably than RDR irradiation. Manipulating both tumour hypoxia and irradiation dose rate have the potential to influence lung metastasis. The combination with the acute hypoxia-releasing agent nicotinamide may be more promising in HDR than RDR irradiation in terms of reducing the number of lung metastases.

Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with {gamma}-irradiation and cisplatin treatment in vivo.

The purpose of this investigation was to compare the effect on intratumour quiescent (Q) cells in vivo of hexamethylenetetramine (HMTA) or tirapazamine (TPZ) in combination with gamma-irradiation and cisplatin treatment. Squamous cell carcinoma (SCC) VII tumour-bearing mice were administered 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. The mice then received HMTA or TPZ intraperitoneally or continuously with or without gamma-irradiation or cisplatin treatment. Other tumour-bearing mice received HMTA or TPZ intraperitoneally immediately after gamma-irradiation. Immediately after gamma-irradiation or cisplatin treatment following HMTA or TPZ, or 24 h after gamma-irradiation followed by HMTA or TPZ, the response of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of all tumour cells (P + Q) was determined from the BrdU-non-treated tumours. HMTA was more toxic to the subset of Q cells than to the population of tumour cells as a whole, similar to the findings for TPZ. The radiosensitising effect of HMTA was similar to that of TPZ in both all cells and Q cells. The recovery-inhibiting effect of HMTA was reliable, but not as great as that of TPZ. The cisplatin sensitivity-enhancing effect of HMTA was similar to or slightly greater than that of TPZ. Continuous administration of both HMTA and TPZ resulted in higher radiosensitivity- and cisplatin sensitivity-enhancing effects than did a single i.p. administration. We concluded that, in terms of the total tumour cell killing effect, including killing of Q cells, gamma-irradiation and cisplatin treatment combined with continuous HMTA administration is a promising strategy given that HMTA is used in clinics.

Improvement of dose distribution in phantom by using epithermal neutron source based on the Be(p,n) reaction using a 30 MeV proton cyclotron accelerator.

In order to generate epithermal neutrons for boron neutron capture therapy (BNCT), we proposed the method of filtering and moderating fast neutrons, which are emitted from the reaction between a beryllium target and 30 MeV protons accelerated by a cyclotron, using an optimum moderator system composed of iron, lead, aluminum, calcium fluoride, and enriched (6)LiF ceramic filter. At present, the epithermal-neutron source is under construction since June 2008 at Kyoto University Research Reactor Institute. This system consists of a cyclotron to supply a proton beam of about 1 mA at 30 MeV, a beam transport system, a beam scanner system for heat reduction on the beryllium target, a target cooling system, a beam shaping assembly, and an irradiation bed for patients. In this article, an overview of the cyclotron-based neutron source (CBNS) and the properties of the treatment neutron beam optimized by using the MCNPX Monte Carlo code are presented. The distribution of the RBE (relative biological effectiveness) dose in a phantom shows that, assuming a (10)B concentration of 13 ppm for normal tissue, this beam could be employed to treat a patient with an irradiation time less than 30 min and a dose less than 12.5 Gy-eq to normal tissue. The CBNS might be an alternative to the reactor-based neutron sources for BNCT treatments.

Preferential expression of an intact WRN gene in Werner syndrome cell lines in which a normal chromosome 8 has been introduced.

Werner syndrome (WS) is a premature aging syndrome caused by mutations in the WRN gene. All mutations of the WRN gene reported thus far are predicted to produce the truncated WRN proteins. The mRNAs that contain chain-termination mutations are supposed to be unstable due to degradation by nonsense-mediated mRNA decay (NMD). In the present study, we investigated the expressions of intact and nonsense-mutated WRN genes in Werner syndrome cell lines in which a normal chromosome 8 had been introduced by microcell fusion. We demonstrate here that the expression of the mutated WRN gene that produces nonsense mRNAs remains at low levels, resulting in the preferential expression of the intact WRN gene in the WS microcell hybrids. This result supports the idea that imperfect messages containing premature termination codons are eliminated by the RNA surveillance system, suggesting the significance of the NMD mechanism in the etiology of Werner syndrome.