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1.  Homologous recombination pathway may play a major role in high-LET radiation-induced DNA double-strand break repair 
Journal of Radiation Research  2014;55(Suppl 1):i83-i84.
Purpose: Particle beams are increasingly applied to various cancer treatments because of their excellent dose localization to tumors while preserving surrounding normal tissues. However, characteristic of DNA damages induced by particle beams and their repair mechanisms are not fully understood. It is known that the majority of DNA double-strand breaks (DSBs) induced by ionizing radiation are repaired either by non-homologous end-joining (NHEJ) or by homologous recombination (HR) pathways. However, it has not been clarified how NHEJ and HR pathways contribute to the repair of DSBs induced by various particle beams [1, 2]. Thus, the purpose of this study is to clarify how these repair pathways contribute to the DSB repair in cells after irradiation with various radiation qualities.
Material and methods: A control Chinese hamster ovary (CHO) cell line (AA8), its mutant cell line deficient of DNA-PKcs (V3), XRCC4 (XR1) and Chinese hamster lung fibroblast cell line deficient of XRCC2 (IRS1) were exposed to gamma rays, protons, carbon ions and iron ions. V3 and XR1 lack NHEJ pathway, while IRS1 lacks HR pathway. After each irradiation, colony survival and gross-chromosome aberration were examined.
Results: It was demonstrated that colony survival was clearly dependent on the presence of NHEJ or HR pathways as well as radiation qualities. Although HR-deficient cells (IRS1) became more sensitive as LET value increased, NHEJ-deficient cells (V3 and XR1) did not further sensitized as LET value increased (Fig.  1). In addition, values of relative biological effectiveness of iron beams were higher in HR-deficient cells than in NHEJ-deficient cells (3.2 in AA8; 2.7 in IRS1; 1.8 in XR1 and V3). These may suggest that HR plays an important role in repairing DNA lesions induced by high-LET radiation. As for the incidence of total chromosomal aberration, we found that its incidence increased as LET values increased in wild-type (AA8) and NHEJ-deficient cells (V3, XR1), but not in HR-deficient cells (IRS1) (Table  1). However, occurrence of chromosome-type aberrations increased as LET values increased in all cell lines analysed here. This may indicate that the chromosomal aberrations occur from not only unrepaired damages but also the repair process of error-prone NHEJ pathway, suggesting that limited capacity of NHEJ to repair DSBs induced by high-LET irradiation may cause increased number of chromosome-type aberrations.
Conclusions: Taken together, although NHEJ pathway is the major pathway to repair DSBs induced by various types of radiation, HR pathway may play more important roles as LET value increases. Fig. 1.Radio sensitivity after gamma ray and iron beam. Clonogenic survival curves of AA8 (closed circle); XR1 (open circle); V3 (closed square) and IRS1 (open square) after irradiation with gamma ray (dashed) and iron beam (dotted). NHEJ-deficient cells are more sensitive to gamma ray, but HR-deficient cells are most sensitive to iron beam. Table 1.Chromatid and chromosome type aberration per chromosomeCell linesTypeControlProtonCarbonIronAA8 (wild-type)Chromatid0.860.240.611.07Chromosome0.051.180.743.44XR1 (NHEJ)Chromatid0.053.181.553.41Chromosome02.592.504.96V3 (NHEJ)Chromatid0.483.372.417.89Chromosome0.165.264.978.01IRS1 (HR)Chromatid0.028.2610.357.59Chromosome0.014.247.438.18
doi:10.1093/jrr/rrt181
PMCID: PMC3941540  PMID: 24586008
high LET particle; NHEJ and HR pathway; chromosome aberration
2.  Reviewer acknowledgement 2013 
Contributing reviewers
The editors of BioPsychoSocial Medicine would like to thank all our reviewers who have contributed to the journal in Volume 7 (2013).
doi:10.1186/1751-0759-8-2
PMCID: PMC3932729  PMID: 24565380
3.  A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma 
Background
Proton-beam radiotherapy (PBT) has been shown to be effective to hepatocellular carcinoma (HCC) as a nonsurgical local treatment option. However, HCC still remains as one of the most difficult cancers to be cured because of frequent recurrences. Thus, methods to inhibit the recurrence need to be explored. To prevent the HCC recurrence, we here report on a prospective phase I study of ‘in situ’ tumor vaccination using CalTUMP, a newly developed immunoadjuvant consisting of BCG extract bound to hydroxyapatite and microparticulated tuberculin, following local PBT for HCC.
Methods
Patients with locally advanced recurrent HCC, which had been heavily pretreated with various treatments, were enrolled. PBT was performed with the conventional method to the target HCC. Subsequently, CalTUMP was injected into the same irradiated-tumor three times at one-week intervals. Three dose-levels of CalTUMP (1/10, 1/3, and 1/1) were administered to 3 patients each. Vital signs, blood samples, ultrasound, and computed tomographic scans were monitored to evaluate the safety.
Results
Three intratumoral injections of CalTUMP following PBT (median dose: 72.6 GyE) were accomplished in 9 patients. Transient low-grade fever and minor laboratory changes were observed in 7 patients after CalTUMP injections. No other treatment-related adverse events were observed. Median progression-free survival was 6.0 months (range: 2.1-14.2) and 4 patients were progression-free for more than 1 year.
Conclusions
Intratumoral injection of CalTUMP following PBT was feasible and safe in patients with heavily pre-treated HCC. Further clinical studies to evaluate the efficacy of this in situ tumor vaccination are warranted.
doi:10.1186/1748-717X-8-239
PMCID: PMC3854490  PMID: 24131485
Proton-beam radiotherapy; Hepatocellular carcinoma; Immunotherapy; Immunoadjuvant
4.  Brain metastasis from papillary thyroid carcinomas 
Molecular and Clinical Oncology  2013;1(5):817-819.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and has a relatively favorable prognosis. PTC brain metastases are rare, occurring in 0.1–5% of cases in previous studies. In the present study, we treated 5 cases of PTC brain metastasis in our institute and retrospectively evaluated these patients. A retrospective database was generated from the patient medical records of our institution for the years between 1976 and 2011. The mean patient age at diagnosis was 64.6 years and the average duration from PTC resection to the detection of a brain metastasis using magnetic resonance imaging (MRI) or computed tomography (CT) was 91.7 months. The patients were treated with various combinations of surgery and radiation therapy. All 5 patients died and the mean overall survival following the diagnosis of a brain metastasis was 9.0 months. One patient succumbed to an intratumoral hemorrhage of the metastatic brain tumor. The remaining patients died following metastasis to other organs. Our findings suggest that PTC brain metastases may occur at the end-stage of patient treatment and result in an unfavorable prognosis. Patients with brain metastases also succumbed to the development of metastases to the fetal organs rather than brain.
doi:10.3892/mco.2013.139
PMCID: PMC3915683  PMID: 24649252
brain metastasis; papillary thyroid carcinoma; prognosis
5.  Clinical results of proton beam therapy for advanced neuroblastoma 
Purpose
To evaluate the efficacy of proton beam therapy (PBT) for pediatric patients with advanced neuroblastoma.
Methods
PBT was conducted at 21 sites in 14 patients with neuroblastoma from 1984 to 2010. Most patients were difficult to treat with photon radiotherapy. Two and 6 patients were classified into stages 3 and 4, respectively, and 6 patients had recurrent disease. Seven of the 8 patients who received PBT as the initial treatment were classified as the high risk group. Twelve patients had gross residual disease before PBT and 2 had undergone intraoperative radiotherapy before PBT. Five patients received PBT for multiple sites, including remote metastases. Photon radiotherapy was used in combination with PBT for 3 patients. The PBT doses ranged from 19.8 to 45.5 GyE (median: 30.6 GyE).
Results
Seven patients are alive with no evidence of disease, 1 is alive with disease progression, and 6 died due to the tumor. Recurrence in the treatment field was not observed and the 3-year locoregional control rate was 82%. Severe acute radiotoxicity was not observed, but 1 patient had narrowing of the aorta and asymptomatic vertebral compression fracture at 28 years after PBT, and hair loss was prolonged in one patient.
Conclusion
PBT may be a better alternative to photon radiotherapy for children with advanced neuroblastoma, and may be conducted safely for patients with neuroblastoma that is difficult to manage using photon beams.
doi:10.1186/1748-717X-8-142
PMCID: PMC3693889  PMID: 23758770
Neuroblastoma; Proton therapy; Radiotherapy; Late toxicity; Pediatrics
6.  Reviewer acknowledgement 2012 
The editors of BioPsychoSocial Medicine would like to thank all our reviewers who have contributed to the journal in Volume 6 (2012).
doi:10.1186/1751-0759-7-3
PMCID: PMC3579750  PMID: 23369529
7.  Reproducibility of image quality for moving objects using respiratory-gated computed tomography: a study using a phantom model 
Journal of Radiation Research  2012;53(6):945-953.
To investigate the reproducibility of computed tomography (CT) imaging quality in respiratory-gated radiation treatment planning is essential in radiotherapy of movable tumors. Seven series of regular and six series of irregular respiratory motions were performed using a thorax dynamic phantom. For the regular respiratory motions, the respiratory cycle was changed from 2.5 to 4 s and the amplitude was changed from 4 to 10 mm. For the irregular respiratory motions, a cycle of 2.5 to 4 or an amplitude of 4 to 10 mm was added to the base data (i.e. 3.5-s cycle, 6-mm amplitude) every three cycles. Images of the object were acquired six times using respiratory-gated data acquisition. The volume of the object was calculated and the reproducibility of the volume was decided based on the variety. The registered image of the object was added and the reproducibility of the shape was decided based on the degree of overlap of objects. The variety in the volumes and shapes differed significantly as the respiratory cycle changed according to regular respiratory motions. In irregular respiratory motion, shape reproducibility was further inferior, and the percentage of overlap among the six images was 35.26% in the 2.5- and 3.5-s cycle mixed group. Amplitude changes did not produce significant differences in the variety of the volumes and shapes. Respiratory cycle changes reduced the reproducibility of the image quality in respiratory-gated CT.
doi:10.1093/jrr/rrs039
PMCID: PMC3483843  PMID: 22966173
Respiratory-gated CT; thorax phantom; respiratory motion; lung cancer
8.  In vitro stemness characterization of radio-resistant clones isolated from a medulloblastoma cell line ONS-76 
Journal of Radiation Research  2012;54(1):61-69.
One-third of patients with medulloblastoma die due to recurrence after various treatments including radiotherapy. Although it has been postulated that cancer stem-like cells are radio-resistant and play an important role in tumor recurrence, the “stemness” of medulloblastoma cells surviving irradiation has not yet been elucidated. Using a medulloblastoma cell line ONS-76, cells that survived gamma irradiation were investigated on their “stemness” in vitro. From 10 500 cells, 20 radio-resistant clones were selected after gamma ray irradiation (5 Gy × two fractions) using the replica micro-well technique. These 20 resistant clones were screened for CD133 positivity by flow cytometry followed by side population assay, tumor sphere formation assay and clonogenic survival assay. Results revealed CD133 fractions were significantly elevated in three clones, which also exhibited significantly increased levels of tumor sphere formation ability and side population fraction. Clonogenic survival assay demonstrated that their radio-resistance was significantly higher than the parental ONS-76. This may support the hypothesis that a small number of cancer stem-like cells (CSCs) are the main culprits in local recurrence after radiotherapy, and disruption of the resistance mechanism of these CSCs is a critical future issue in improving the outcome of patients with medulloblastoma.
doi:10.1093/jrr/rrs078
PMCID: PMC3534279  PMID: 22951319
medulloblastoma; radiation; CD133; cancer stem-like cell
9.  Influence of secondary neutrons induced by proton radiotherapy for cancer patients with implantable cardioverter defibrillators 
Background
Although proton radiotherapy is a promising new approach for cancer patients, functional interference is a concern for patients with implantable cardioverter defibrillators (ICDs). The purpose of this study was to clarify the influence of secondary neutrons induced by proton radiotherapy on ICDs.
Methods
The experimental set-up simulated proton radiotherapy for a patient with an ICD. Four new ICDs were placed 0.3 cm laterally and 3 cm distally outside the radiation field in order to evaluate the influence of secondary neutrons. The cumulative in-field radiation dose was 107 Gy over 10 sessions of irradiation with a dose rate of 2 Gy/min and a field size of 10 × 10 cm2. After each radiation fraction, interference with the ICD by the therapy was analyzed by an ICD programmer. The dose distributions of secondary neutrons were estimated by Monte-Carlo simulation.
Results
The frequency of the power-on reset, the most serious soft error where the programmed pacing mode changes temporarily to a safety back-up mode, was 1 per approximately 50 Gy. The total number of soft errors logged in all devices was 29, which was a rate of 1 soft error per approximately 15 Gy. No permanent device malfunctions were detected. The calculated dose of secondary neutrons per 1 Gy proton dose in the phantom was approximately 1.3-8.9 mSv/Gy.
Conclusions
With the present experimental settings, the probability was approximately 1 power-on reset per 50 Gy, which was below the dose level (60-80 Gy) generally used in proton radiotherapy. Further quantitative analysis in various settings is needed to establish guidelines regarding proton radiotherapy for cancer patients with ICDs.
doi:10.1186/1748-717X-7-10
PMCID: PMC3283465  PMID: 22284700
Proton radiotherapy; Secondary neutrons; Implantable cardioverter defibrillator; Soft error; Monte-Carlo simulation
10.  Electroencephalogram abnormalities in panic disorder patients: a study of symptom characteristics and pathology 
Background
Since the 1980s, a high EEG abnormality rate has been reported for patients with panic disorder. However, how the EEG abnormalities of panic disorder patients are related to the clinical features and pathology of these patients has yet to be clarified. In this study we investigated whether or not EEG abnormalities are related to the 13 symptoms in the DSM-IV criteria for a diagnosis of panic attacks.
Methods
Subjects were 70 patients diagnosed with panic disorder.
Logistic regression analysis was performed with EEG findings as dependent variables and age, sex and with or without the 13 symptoms as independent variables.
Results
(1)EEG findings for panic disorder patients with EEG abnormalities: Of the 17 patients, 13 had repeated slow waves in the θ-band; the most prevalent EEG abnormality found in this study. Paroxysmal abnormality interpreted as epileptiform was found in only two cases. (2)Nausea or abdominal distress (37.7% vs 82.45%, OR-12.5), derealization or depersonalization (7.5% vs 47.1%, OR = 13.9,) and paresthesias (43.4% vs 64.7%, OR = 7.9,) were extracted by multivariate analysis as factors related to EEG abnormalities.
Conclusion
Of the 70 patients studied, 17 had EEG abnormalities. Among these 17 cases, "repeated slow waves in the θ-band" was the most common abnormality. The factors identified as being related to EEG abnormalities are nausea or abdominal distress, derealization or depersonalization, and paresthesias. The study indicated that physiological predispositions are closely related to panic attacks.
doi:10.1186/1751-0759-4-9
PMCID: PMC2940923  PMID: 20731860
11.  Stress and psychological factors before a migraine attack: A time-based analysis 
Background
The objective of this study is to examine the stress and mood changes of Japanese subjects over the 1–3 days before a migraine headache.
Methods
The study participants were 16 patients with migraines who consented to participate in this study. Each subject kept a headache diary four times a day for two weeks. They evaluated the number of stressful events, daily hassles, domestic and non-domestic stress, anxiety, depressive tendency and irritability by visual analog scales. The days were classified into migraine days, pre-migraine days, buffer days and control days based on the intensity of the headaches and accompanying symptoms, and a comparative study was conducted for each factor on the migraine days, pre-migraine days and control days.
Results
The stressful event value of pre-migraine days showed no significant difference compared to other days. The daily hassle value of pre-migraine days was the highest and was significantly higher than that of buffer days. In non-domestic stress, values on migraine days were significantly higher than on other days, and there was no significant difference between pre-migraine days and buffer days or between pre-migraine days and control days. There was no significant difference in the values of domestic stress between the categories. In non-domestic stress, values on migraine days were significantly higher than other days, and there was no significant difference between pre-migraine days and buffer days or between pre-migraine days and control days.
There was little difference in sleep quality on migraine and pre-migraine days, but other psychological factors were higher on migraine days than on pre-migraine days.
Conclusion
Psychosocial stress preceding the onset of migraines by several days was suggested to play an important role in the occurrence of migraines. However, stress 2–3 days before a migraine attack was not so high as it has been reported to be in the United States and Europe. There was no significant difference in the values of psychological factors between pre-migraine days and other days.
doi:10.1186/1751-0759-2-14
PMCID: PMC2556692  PMID: 18799013
12.  Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumour growth and angiogenesis in human glioblastoma xenografts. 
Neuro-Oncology  2003;5(1):1-7.
We evaluated the effectiveness of vascular endothelial growth factor (VEGF) blockade alone and in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine), a cytotoxic agent commonly used in the treatment of malignant gliomas, to eradicate tumors of human glioblastoma cell lines implanted in SCID (severe combined immunodeficiency) mice. ACNU, but not cisplatin and etoposide, elevated VEGF expression in a glioma cell line in vitro. VEGF antibody alone inhibited glioma growth in vivo as a result of angiogenesis inhibition. The combination with ACNU resulted in an additive effect for inhibition of glioma growth. ACNU also induced VEGF up-regulation in glioma tissues, which was decreased with VEGF antibody treatment. One of the mechanisms of the additive effect of the VEGF antibody and ACNU combination is the blockade of VEGF up-regulation induced by ACNU. As such, the combination of antiangiogenic therapy with conventional therapy is promising for glioma treatment in the future.
PMCID: PMC1920668  PMID: 12626127

Results 1-12 (12)