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1.  Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells 
Scientific Reports  2016;6:28944.
Methylmercury (MeHg) modifies cellular proteins via their thiol groups in a process referred to as “S-mercuration”, potentially resulting in modulation of the cellular signal transduction pathway. We examined whether low-dose MeHg could affect Akt signaling involved in cell survival. Exposure of human neuroblastoma SH-SY5Y cells of up to 2 μM MeHg phosphorylated Akt and its downstream signal molecule CREB, presumably due to inactivation of PTEN through S-mercuration. As a result, the anti-apoptotic protein Bcl-2 was up-regulated by MeHg. The activation of Akt/CREB/Bcl-2 signaling mediated by MeHg was, at least in part, linked to cellular defence because either pretreatment with wortmannin to block PI3K/Akt signaling or knockdown of Bcl-2 enhanced MeHg-mediated cytotoxicity. In contrast, increasing concentrations of MeHg disrupted Akt/CREB/Bcl-2 signaling. This phenomenon was attributed to S-mercuration of CREB through Cys286 rather than Akt. These results suggest that although MeHg is an apoptosis-inducing toxicant, this environmental electrophile is able to activate the cell survival signal transduction pathway at lower concentrations prior to apoptotic cell death.
PMCID: PMC4928048  PMID: 27357941
2.  A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis†  
Neuro-Oncology Practice  2016;3(4):272-280.
Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN.
Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month.
Of the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%).
Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.
PMCID: PMC5099992  PMID: 27833757
Bevacizumab; brain radiation necrosis; positron emission tomography; vascular endothelial growth factor
Neuro-Oncology  2014;16(Suppl 5):v17.
Recent radiotherapeutic modalities including particle radiotherapy, IMRT, and SRS are able to irradiate tumor tissue with high absorbed doses. These radiation therapies are promising to provide a longer survival in patients with CNS malignant tumors, compared to conventional X-ray radiotherapy. Simultaneously radiation necrosis (RN) has been a serious problem in such patients. However, there is no effective treatment for progressive RN so far. VEGF has been reported to play an important role in the progression of RN. Some clinical reports including ours demonstrate good results of bevacizumab treatment for RN. However, so far, no country gives a permission to use bevacizumab for symptomatic radiation necrosisin the brain as on label use. We initiated a nation-wide multicenter clinical trial in Japan, with the correct diagnosis of RN by amino-acid PET, to obtain a new drug approval (NDA) applications from Japanese FDA, based on public knowledge. Primary endpoint was the improvement of cerebral edema in periodic MRI. Secondary endpoint were safety, reduction of steroids, improvement of KPS and recurrence rate of RN within a year. The back ground of the patients are as follows; primary brain tumors such as GBM, metastatic brain tumors and head and neck cancers are 28 cases (68.3%), 12 cases (29.3%) and 1 case (2.4%), respectively. Applied radiation modalities are as follows; external beam radio-therapy 17 cases, SES 29 cases, hypo-fractionated IMRT 4 cases, proton beam particle radiation 3 cases and boron neutron capture therapy 1 case. Totally 41 cases of patients' enrollment finished. Last patient, last visit was in April 2014. The results are now opening and hopefully we can present them in SNO meeting.
PMCID: PMC4217820
4.   Generation of low-flux X-ray micro-planar beams and their biological effect on a murine subcutaneous tumor model 
Journal of Radiation Research  2015;56(5):768-776.
We generated low-flux X-ray micro-planar beams (MPBs) using a laboratory-scale industrial X-ray generator (60 kV/20 mA) with custom-made collimators with three different peak/pitch widths (50/200 μm, 100/400 μm, 50/400 μm). To evaluate normal skin reactions, the thighs of C3H/HeN mice were exposed to 100 and 200 Gy MPBs in comparison with broad beams (20, 30, 40, 50, 60 Gy). Antitumor effects of MPBs were evaluated in C3H/HeN mice with subcutaneous tumors (SCCVII). After the tumors were irradiated with 100 and 200 Gy MPBs and 20 and 30 Gy broad beams, the tumor sizes were measured and survival analyses were performed. In addition, the tumors were excised and immunohistochemically examined to detect γ-H2AX, ki67 and CD34. It was shown that antitumor effects of 200 Gy MPBs at 50/200 μm and 100/400 μm were significantly greater than those of 20 Gy broad beams, and were comparable with 30 Gy broad beams. γ-H2AX-positive cells demonstrated clear stripe-patterns after MPB irradiation; the pattern gradually faded and intermixed over 24 h. The chronological changes in ki67 positivity did not differ between MPBs and broad beams, whereas the CD34-positive area decreased significantly more in MPBs than in broad beams. In addition, it was shown that skin injury after MPB irradiation was significantly milder when compared with broad-beam irradiation at equivalent doses for achieving the same tumor control effect. Bystander effect and tumor vessel injury may be the mechanism contributing to the efficacy of MPBs.
PMCID: PMC4577006  PMID: 26141370
micro-planar beams; antitumor effects; skin reaction; bystander effect
5.  Reviewer acknowledgement 2014 
Contributing reviewers
The BioPsychoSocial Medicine editorial team would like to thank the following colleagues who contributed to peer review for the journal in Volume 8 (2014).
PMCID: PMC4324041  PMID: 25674155
6.  Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress 
Neuro-Oncology  2013;15(9):1186-1199.
Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions.
Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or γ-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress–related genes was analyzed by immunoblotting.
Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and γ-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells.
Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM.
PMCID: PMC3748914  PMID: 23658321
autophagy; celecoxib; ER stress; glioblastoma; hypoxia; radiosensitivity
7.  Development of a novel, short, self-completed questionnaire on empowerment for patients with type 2 diabetes mellitus and an analysis of factors affecting patient empowerment 
Patient empowerment has recently been proposed as an important concept in self-management for effective glycemic control. A concise self-completed questionnaire for patients with type 2 diabetes mellitus was created to comprehensively evaluate their empowerment on the basis of self-managed dietary/exercise behaviors, psychological impact, and family support. The reliability and validity of this short questionnaire were tested and factors relating to patient empowerment were analyzed.
The self-completed empowerment questionnaire was based on questionnaires for self-managed dietary and exercise behaviors, the Appraisal of Diabetes Scale, and the Diabetes Family Behavior Checklist. The questionnaire was trialed on 338 male and female patients with type 2 diabetes mellitus who lived with family. The validity and reliability of the questionnaire were investigated and stepwise multiple linear regression analysis was used to identify factors that affect patient empowerment.
The self-completed patient empowerment questionnaire included 13 questions on background data (e.g., age, gender, and HbA1c) and 18 questions within five scales to assess self-managed dietary behaviors, self-managed exercise behaviors, and psychological impact of diabetes, as well as positive and negative feedback in patient-family communication. The questionnaire showed sufficient internal consistency, construct validity, reproducibility, factorial construct validity, and concurrent validity. The results were generally satisfactory, and the questionnaire reflected the particular characteristics of treatment methods. Multiple linear regression analysis showed that patient empowerment was strongly affected by the number of disease-related symptoms, age, and gender.
The results suggest that the concise self-completed empowerment questionnaire developed here is useful for measuring the empowerment of individual patients and evaluating the impact of symptoms and therapies on empowerment.
PMCID: PMC4151376  PMID: 25183994
Type 2 diabetes mellitus; Empowerment questionnaire; Appraisal of diabetes scale; Diabetes family behavior checklist; Self-managed behavior
8.  Effects of gender, age, family support, and treatment on perceived stress and coping of patients with type 2 diabetes mellitus 
We previously found that the empowerment of patients with type 2 diabetes mellitus can be strongly affected by gender and age in addition to self-managed diet and exercise behaviors and treatment. This study was to examine the effects of gender, age, family support, and treatment on the perceived stress and coping of patients with type 2 diabetes mellitus living with family.
A survey was conducted of 140 adults with type 2 diabetes mellitus who were living with family. There was no significant difference in hemoglobin A1c (HbA1c) between male and female. Perceived stress and coping were measured with the Japanese version of the Appraisal of Diabetes Scale and the Lazarus Type Stress Coping Inventory. Stepwise regression analysis and path analysis were performed to identify factors that affect the perceived stress and coping of patients.
(1) Perceived stress and coping were strongly affected by gender. (2) Perceived stress and coping were affected by age for males, but perceived stress was not affected by age for females. However, females showed a greater “psychological impact of diabetes” than did males. Females aged between 50 and 69 years engaged in active problem solving, but awareness of diabetes was low. (3) Treatment regimens had an effect on HbA1c for both sexes, and diet therapy affected the awareness of diabetes of males and coping of females. (4) For females, “sense of self-control” was strongly associated with coping, and those who were living with non-spouse family members had a greater psychological impact of diabetes than those living with only their spouse. (5) For males, coping was strongly affected by living with their spouse.
The results suggest that perceived stress, coping, and diet regimen are deeply associated with gender and age and that a male with type 2 diabetes mellitus living with his spouse is strongly dependent on support from the spouse. It is important to take into account gender, age, and family environment to provide patients with an individualized approach to addressing perceived stress and to provide education program for coping that can maximize treatment and maintain better, continuous glycemic control.
PMCID: PMC4114439  PMID: 25075211
Appraisal of Diabetes Scale; Type 2 diabetes mellitus; Stress Coping Inventory; Gender; Spouse
9.  Direct measurement of a patient's entrance skin dose during pediatric cardiac catheterization 
Journal of Radiation Research  2014;55(6):1122-1130.
Children with complex congenital heart diseases often require repeated cardiac catheterization; however, children are more radiosensitive than adults. Therefore, radiation-induced carcinogenesis is an important consideration for children who undergo those procedures. We measured entrance skin doses (ESDs) using radio-photoluminescence dosimeter (RPLD) chips during cardiac catheterization for 15 pediatric patients (median age, 1.92 years; males, n = 9; females, n = 6) with cardiac diseases. Four RPLD chips were placed on the patient's posterior and right side of the chest. Correlations between maximum ESD and dose–area products (DAP), total number of frames, total fluoroscopic time, number of cine runs, cumulative dose at the interventional reference point (IRP), body weight, chest thickness, and height were analyzed. The maximum ESD was 80 ± 59 (mean ± standard deviation) mGy. Maximum ESD closely correlated with both DAP (r = 0.78) and cumulative dose at the IRP (r = 0.82). Maximum ESD for coiling and ballooning tended to be higher than that for ablation, balloon atrial septostomy, and diagnostic procedures. In conclusion, we directly measured ESD using RPLD chips and found that maximum ESD could be estimated in real-time using angiographic parameters, such as DAP and cumulative dose at the IRP. Children requiring repeated catheterizations would be exposed to high radiation levels throughout their lives, although treatment influences radiation dose. Therefore, the radiation dose associated with individual cardiac catheterizations should be analyzed, and the effects of radiation throughout the lives of such patients should be followed.
PMCID: PMC4229915  PMID: 24968708
cardiac catheterization; entrance skin dose; pediatric heart disease; dosimetry
10.  RBE and OER within the spread-out Bragg peak for proton beam therapy: in vitro study at the Proton Medical Research Center at the University of Tsukuba 
Journal of Radiation Research  2014;55(5):1028-1032.
There are few reports on the biological homogeneity within the spread-out Bragg peak (SOBP) of proton beams. Therefore, to evaluate the relative biological effectiveness (RBE) and the oxygen enhancement ratio (OER), human salivary gland tumor (HSG) cells were irradiated at the plateau position (position A) and three different positions within a 6-cm-wide SOBP (position B, 26 mm proximal to the middle; position C, middle; position D, 26 mm distal to the middle) using 155-MeV/n proton beams under both normoxic and hypoxic conditions at the Proton Medical Research Center, University of Tsukuba, Japan. The RBE to the plateau region (RBEplateau) and the OER value were calculated from the doses corresponding to 10% survival data. Under the normoxic condition, the RBEplateau was 1.00, 0.99 and 1.09 for positions B, C and D, respectively. Under the hypoxic condition, the RBEplateau was 1.10, 1.06 and 1.12 for positions B, C and D, respectively. The OER was 2.84, 2.60, 2.63 and 2.76 for positions A, B, C and D, respectively. There were no significant differences in either the RBEplateau or the OER between these three positions within the SOBP. In conclusion, biological homogeneity need not necessarily be taken into account for treatment planning for proton beam therapy at the University of Tsukuba.
PMCID: PMC4202301  PMID: 24876271
spread-out Bragg peak; proton; oxygen enhancement ratio; relative biological effectiveness
11.  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
PMCID: PMC3941540
high LET particle; NHEJ and HR pathway; chromosome aberration
12.  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).
PMCID: PMC3932729  PMID: 24565380
13.  A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma 
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.
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.
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.
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.
PMCID: PMC3854490  PMID: 24131485
Proton-beam radiotherapy; Hepatocellular carcinoma; Immunotherapy; Immunoadjuvant
14.  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.
PMCID: PMC3915683  PMID: 24649252
brain metastasis; papillary thyroid carcinoma; prognosis
15.  Clinical results of proton beam therapy for advanced neuroblastoma 
To evaluate the efficacy of proton beam therapy (PBT) for pediatric patients with advanced neuroblastoma.
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).
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.
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.
PMCID: PMC3693889  PMID: 23758770
Neuroblastoma; Proton therapy; Radiotherapy; Late toxicity; Pediatrics
16.  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).
PMCID: PMC3579750  PMID: 23369529
Nagoya Journal of Medical Science  2013;75(1-2):81-92.
Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.
PMCID: PMC4345706  PMID: 23544271
glucocorticoids; hypertension; cardiac atrophy; diastolic dysfunction
18.  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.
PMCID: PMC3483843  PMID: 22966173
Respiratory-gated CT; thorax phantom; respiratory motion; lung cancer
19.  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.
PMCID: PMC3534279  PMID: 22951319
medulloblastoma; radiation; CD133; cancer stem-like cell
20.  Influence of secondary neutrons induced by proton radiotherapy for cancer patients with implantable cardioverter defibrillators 
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.
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.
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.
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.
PMCID: PMC3283465  PMID: 22284700
Proton radiotherapy; Secondary neutrons; Implantable cardioverter defibrillator; Soft error; Monte-Carlo simulation
21.  Electroencephalogram abnormalities in panic disorder patients: a study of symptom characteristics and pathology 
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.
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.
(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.
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.
PMCID: PMC2940923  PMID: 20731860
22.  Stress and psychological factors before a migraine attack: A time-based analysis 
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.
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.
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.
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.
PMCID: PMC2556692  PMID: 18799013
23.  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

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