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1.  Pertussis outbreak in university students and evaluation of acellular pertussis vaccine effectiveness in Japan 
Background
Recent studies worldwide have reported increasing numbers of adults diagnosed with Bordetella pertussis despite receiving childhood vaccinations. This study describes a pertussis outbreak at a university medical faculty campus and examines the effectiveness of diphtheria, tetanus, and pertussis (DTaP) vaccination completed during infancy in Japan.
Methods
After the outbreak, self-administered questionnaires and serum samples were collected from students on campus to determine the incidence of pertussis and underlying diseases. Pertussis was diagnosed on the basis of clinical criteria and serum anti-pertussis toxin antibody levels. Using data collected from 248 first and second grade students who had submitted copies of their vaccination records, we evaluated the effectiveness of DTaP vaccination in infancy against adult pertussis.
Results
Questionnaire responses were obtained from 636 students (of 671 registered students; 95% response rate). Of 245 students who reported a continuous cough during the outbreak period, 84 (attack rate: 13.2%) were considered “probable” pertussis cases that met clinical criteria. The outbreak occurred mainly in first and second grade students in the Faculty of Medicine. Of 248 students who provided vaccination records, 225 had received 4 DTaP doses (coverage: 90.7%); the relative risk of the complete vaccination series compared to those with fewer than 4 doses or no doses for probable cases was 0.48 (95% confidence interval: 0.24-0.97).
Conclusions
Waning protection was suspected due to over time. Booster vaccination for teenagers and development of highly efficacious pertussis vaccines are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0777-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-0777-3
PMCID: PMC4323135  PMID: 25656486
Pertussis; Outbreak; Vaccine effectiveness
2.  Carbon-Ion Beam Irradiation Kills X-Ray-Resistant p53-Null Cancer Cells by Inducing Mitotic Catastrophe 
PLoS ONE  2014;9(12):e115121.
Background and Purpose
To understand the mechanisms involved in the strong killing effect of carbon-ion beam irradiation on cancer cells with TP53 tumor suppressor gene deficiencies.
Materials and Methods
DNA damage responses after carbon-ion beam or X-ray irradiation in isogenic HCT116 colorectal cancer cell lines with and without TP53 (p53+/+ and p53-/-, respectively) were analyzed as follows: cell survival by clonogenic assay, cell death modes by morphologic observation of DAPI-stained nuclei, DNA double-strand breaks (DSBs) by immunostaining of phosphorylated H2AX (γH2AX), and cell cycle by flow cytometry and immunostaining of Ser10-phosphorylated histone H3.
Results
The p53-/- cells were more resistant than the p53+/+ cells to X-ray irradiation, while the sensitivities of the p53+/+ and p53-/- cells to carbon-ion beam irradiation were comparable. X-ray and carbon-ion beam irradiations predominantly induced apoptosis of the p53+/+ cells but not the p53-/- cells. In the p53-/- cells, carbon-ion beam irradiation, but not X-ray irradiation, markedly induced mitotic catastrophe that was associated with premature mitotic entry with harboring long-retained DSBs at 24 h post-irradiation.
Conclusions
Efficient induction of mitotic catastrophe in apoptosis-resistant p53-deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status, suggesting its biological advantage over X-ray treatment.
doi:10.1371/journal.pone.0115121
PMCID: PMC4274003  PMID: 25531293
3.  Assessing cumulative dose distributions in combined radiotherapy for cervical cancer using deformable image registration with pre-imaging preparations 
Background
The purpose of the study was to evaluate the feasibility of deformable image registration (DIR) in assessing cumulative dose distributions of the combination of external beam radiotherapy (EBRT) and fractionated intracavitary brachytherapy (ICBT) for cervical cancer.
Materials and methods
Three-dimensional image data sets of five consecutive patients were used. The treatment plan consisted of whole pelvic EBRT (total dose: 45 Gy in 25 fractions) combined with computed tomography (CT)-based high-dose rate ICBT (≥24 Gy in 4 fractions to the high risk clinical target volume (HR-CTV)). Organs at risk and HR-CTV were contoured on each CT images and dose-volume parameters were acquired. Pre-imaging preparations were performed prior to each ICBT to minimize the uncertainty of the organ position. Physical doses of each treatment were converted to biologically equivalent doses in 2 Gy daily fractions by the linear quadratic model. Three-dimensional dose distributions of each treatment were accumulated on CT images of the first ICBT using DIR with commercially available image registration software (MIM Maestro®). To compare with DIR, 3D dose distributions were fused by rigid registration based on bony structure matching. To evaluate the accuracy of DIR, the Dice similarity coefficient (DSC) was measured between deformed contours and initial contours.
Results
The cumulative dose distributions were successfully illustrated on the CT images using DIR. Mean DSCs of the HR-CTV, rectum, and bladder were 0.46, 0.62 and 0.69, respectively, with rigid registration; and 0.78, 0.76, and 0.87, respectively, with DIR (p <0.05). The mean DSCs derived from our DIR procedure were comparable to those of previous reports describing the quality of DIR algorithms in the pelvic region. DVH parameters derived from the 2 methods showed no significant difference.
Conclusions
Our results suggest that DIR-based dose accumulation may be acceptable for assessing cumulative dose distributions to assess doses to the tumor and organs at risk in combined radiotherapy for cervical cancer under pre-imaging preparations.
doi:10.1186/s13014-014-0293-4
PMCID: PMC4296553  PMID: 25526986
Radiotherapy; Cervical cancer; Deformable image registration
4.  Optimal hypofractionated conformal radiotherapy for large brain metastases in patients with high risk factors: a single-institutional prospective study 
Background
A single-institutional prospective study of optimal hypofractionated conformal radiotherapy for large brain metastases with high risk factors was performed based on the risk prediction of radiation-related complications.
Methods
Eighty-eight patients with large brain metastases ≥10 cm3 in critical areas treated from January 2010 to February 2014 using the CyberKnife were evaluated. The optimal dose and number of fractions were determined based on the surrounding brain volume circumscribed with a single dose equivalent (SDE) of 14 Gy (V14) to be less than 7 cm3 for individual lesions. Univariate and multivariate analyses were conducted.
Results
As a result of optimal treatment, 92 tumors ranging from 10 to 74.6 cm3 (median, 16.2 cm3) in volume were treated with a median prescribed isodose of 57% and a median fraction number of five. In order to compare the results according to the tumor volume, the tumors were divided into the following three groups: 1) 10–19.9 cm3, 2) 20–29.9 cm3 and 3) ≥30 cm3. The lesions were treated with a median prescribed isodose of 57%, 56% and 55%, respectively, and the median fraction number was five in all three groups. However, all tumors ≥20 cm3 were treated with ≥ five fractions. The median SDE of the maximum dose in the three groups was 47.2 Gy, 48.5 Gy and 46.5 Gy, respectively. Local tumor control was obtained in 90.2% of the patients, and the median survival was nine months, with a median follow-up period of seven months (range, 3-41 months). There were no significant differences in the survival rates among the three groups. Six tumors exhibited marginal recurrence 7-36 months after treatment. Ten patients developed symptomatic brain edema or recurrence of pre-existing edema, seven of whom required osmo-steroid therapy. No patients developed radiation necrosis requiring surgical resection.
Conclusion
Our findings demonstrate that the administration of optimal hypofractionated conformal radiotherapy based on the dose-volume prediction of complications (risk line for hypofractionation), as well as Kjellberg’s necrosis risk line used in single-session radiosurgery, is effective and safe for large brain metastases or other lesions in critical areas.
doi:10.1186/s13014-014-0231-5
PMCID: PMC4203932  PMID: 25322826
Large brain metastases; Hypofractionated conformal radiotherapy; Multi-session radiosurgery; Prediction of complications; Radiation necrosis; Brain edema; Optimal dose and fraction; V14
5.  Can combined intracavitary/interstitial approach be an alternative to interstitial brachytherapy with the Martinez Universal Perineal Interstitial Template (MUPIT) in computed tomography-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumors? 
Background
Interstitial brachytherapy (ISBT) is an optional treatment for locally advanced gynecological tumours for which conventional intracavitary brachytherapy (ICBT) would result in suboptimal dose coverage. However, ISBT with Martinez Universal Perineal Interstitial Template (MUPIT), in which ~10-20 needles are usually applied, is more time-consuming and labor-intensive than ICBT alone, making it a burden on both practitioners and patients. Therefore, here we investigated the applicability of a combined intracavitary/interstitial (IC/IS) approach in image-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumours for which interstitial brachytherapy (ISBT) was performed.
Methods
Twenty-one consecutive patients with gynecological malignancies treated with computed tomography-guided ISBT using MUPIT were analyzed as cases for this dosimetric study. For each patient, the IC/IS plan using a tandem and 1 or 2 interstitial needles, which was modeled after the combined IC/IS approach, was generated and compared with the IS plan based on the clinical ISBT plan, while the IC plan using only the tandem was applied as a simplified control. Maximal dose was prescribed to the high-risk clinical target volume (HR-CTV) while keeping the dose constraints of D2cc bladder < 7.0 Gy and D2cc rectum < 6.0 Gy. The plan with D90 HR-CTV exceeding 6.0 Gy was considered acceptable.
Results
The average D90 HR-CTV was 77%, 118% and 140% in the IC, IC/IS and IS plans, respectively, where 6 Gy corresponds to 100%. The average of the ratio of D90 HR-CTV to D2cc rectum (gain factor (GF) rectum) in the IC, IC/IS and IS plans was 0.8, 1.3 and 1.5 respectively, while GFbladder was 0.9, 1.4 and 1.6, respectively. In the IC/IS plan, D90 HR-CTV, GFrectum and GFbladder exceeded 100%, 1.0 and 1.0, respectively, in all patients.
Conclusions
These data demonstrated that the combined IC/IS approach could be a viable alternative to ISBT for gynecological malignancies with bulky and/or irregularly shaped tumours.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0222-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13014-014-0222-6
PMCID: PMC4205298  PMID: 25319341
6.  HLA Class I Expression and Its Alteration by Preoperative Hyperthermo-Chemoradiotherapy in Patients with Rectal Cancer 
PLoS ONE  2014;9(9):e108122.
Objective
Enhancing immunologic responses, including human leukocyte antigen (HLA) class I expression on tumor cells and recognition and elimination of tumor cells by tumor-specific cytotoxic T lymphocyte (CTL), is considered a novel concept of radiotherapy. The present study examined patients who underwent preoperative hyperthermo-chemoradiotherapy (HCRT) for locally advanced rectal cancer to assess the correlation between HLA class I expression and clinical outcome.
Materials and Methods
Seventy-eight patients with locally advanced rectal adenocarcinoma who received preoperative HCRT were enrolled. The median age of the patients was 64 years (range, 33–85 years) and 4, 18, and 56 patients had clinical stage I, II and III disease, respectively. Formalin-fixed and paraffin-embedded tissues excised before and after HCRT were subjected to immunohistochemical analysis with an anti-HLA class I-A, B, C antibody. HLA class I expression was graded according to tumor cell positivity.
Results
In pre-HCRT, the number of specimens categorized as Grade 0 and 1 were 19 (24%) and 58 (74%), respectively. Only 1 patient (1%) showed Grade 2 expression. However, 6 (8%), 27 (35%), 7 (9%), and 12 (15%) post-HCRT specimens were graded as Grade 0, 1, 2, and 3, respectively. There was a significant increase in HLA class I expression in post-HCRT specimens (p<0.01). However, neither pre- nor post-HCRT HLA class I expression affected overall survival and distant metastasis-free survival in clinical stage III patients. Univariate analysis revealed that Post-HCRT HLA class I expression showed a significant negative relationship with LC (p<0.05). Nevertheless, multivariate analysis showed that there was no correlation between HLA class I expression and clinical outcome.
Conclusion
HCRT increased HLA class I expression in rectal cancer patients. However, multivariate analysis failed to show any correlation between the level of HLA class I expression and prognosis.
doi:10.1371/journal.pone.0108122
PMCID: PMC4178123  PMID: 25259797
7.  Mirror-symmetric Magneto-optical Kerr Rotation using Visible Light in [(GeTe)2(Sb2Te3)1]n Topological Superlattices 
Scientific Reports  2014;4:5727.
Interfacial phase change memory (iPCM), that has a structure of a superlattice made of alternating atomically thin GeTe and Sb2Te3 layers, has recently attracted attention not only due to its superior performance compared to the alloy of the same average composition in terms of energy consumption but also due to its strong response to an external magnetic field (giant magnetoresistance) that has been speculated to arise from switching between topological insulator (RESET) and normal insulator (SET) phases. Here we report magneto-optical Kerr rotation loops in the visible range, that have mirror symmetric resonances with respect to the magnetic field polarity at temperatures above 380 K when the material is in the SET phase that has Kramers-pairs in spin-split bands. We further found that this threshold temperature may be controlled if the sample was cooled in a magnetic field. The observed results open new possibilities for use of iPCM beyond phase-change memory applications.
doi:10.1038/srep05727
PMCID: PMC4101470  PMID: 25030304
8.  Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems 
Scientific Reports  2014;4:5398.
Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine – a key neurotransmitter of the central nervous system – thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.
doi:10.1038/srep05398
PMCID: PMC4066245  PMID: 24954021
9.  Comparison of the radiosensitivities of neurons and glial cells derived from the same rat brain 
Non-proliferating cells, such as mature neurons, are generally believed to be more resistant to X-rays than proliferating cells, such as glial and vascular endothelial cells. Therefore, the late adverse effects of radiotherapy on the brain have been attributed to the radiation-induced damage of glial and vascular endothelial cells. However, little is known about the radiosensitivities of neurons and glial cells due to difficulties in culturing these cells, particularly neurons, independently. In the present study, primary dissociated neurons and glial cultures were prepared separately from the hippocampi and cerebrum, respectively, which had been obtained from the same fetal rat on embryonic day 18. X-irradiations of 50 Gy were performed on the cultured neurons and glial cells at 7 and 21 days in vitro (DIV). The cells were fixed at 24 h after irradiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was then performed to measure the apoptotic indices (AIs). The AIs of non-irradiated and irradiated neurons at 7 DIV were 23.7±6.7 and 64.9±4.8%, and those at 21 DIV were 52.1±17.4 and 44.6±12.5%, respectively. The AIs of non-irradiated and irradiated glial cells at 7 DIV were 5.8±1.5 and 78.4±3.3% and those at 21 DIV were 9.6±2.6 and 86.3±4.9%, respectively. Glial cells and neurons were radiosensitive at 7 DIV. However, while glial cells were radiosensitive at 21 DIV, neurons were not.
doi:10.3892/etm.2014.1802
PMCID: PMC4113551  PMID: 25120594
neuron; glia; radiation; apoptosis
10.  Functional Properties of CD8+ Lymphocytes in Patients with Pleural Plaque and Malignant Mesothelioma 
Journal of Immunology Research  2014;2014:670140.
It is known that asbestos exposure can cause malignant mesothelioma (MM) and that CD8+ T cells play a critical role in antitumor immunity. We examined the properties of peripheral blood CD8+ lymphocytes from asbestos-exposed patients with pleural plaque (PL) and MM. The percentage of CD3+CD8+ cells in PBMCs did not differ among the three groups, although the total numbers of PBMCs of the PL and MM groups were lower than those of the healthy volunteers (HV). The percentage of IFN-γ+ and CD107a+ cells in PMA/ionomycin-stimulated CD8+ lymphocytes did not differ among the three groups. Percentages of perforin+ cells and CD45RA− cells in fresh CD8+ lymphocytes of PL and MM groups were higher than those of HV. Percentages of granzyme B+ and perforin+ cells in PMA/ionomycin-stimulated CD8+ lymphocytes were higher in PL group compared with HV. The MM group showed a decrease of perforin level in CD8+ lymphocytes after stimulation compared with patients with PL. These results indicate that MM patients have characteristics of impairment in stimulation-induced cytotoxicity of peripheral blood CD8+ lymphocytes and that PL and MM patients have a common character of functional alteration in those lymphocytes, namely, an increase in memory cells, possibly related to exposure to asbestos.
doi:10.1155/2014/670140
PMCID: PMC4087265  PMID: 25045719
11.  Updates on clinical studies of selenium supplementation in radiotherapy 
To establish guidelines for the selenium supplementation in radiotherapy we assessed the benefits and risks of selenium supplementation in radiotherapy. Clinical studies on the use of selenium in radiotherapy were searched in the PubMed electronic database in January 2013. Sixteen clinical studies were identified among the 167 articles selected in the initial search. Ten articles were observational studies, and the other 6 articles reported studies on the effects of selenium supplementation in patients with cancer who underwent radiotherapy. The studies were conducted worldwide including European, American and Asian countries between 1987 and 2012. Plasma, serum or whole blood selenium levels were common parameters used to assess the effects of radiotherapy and the selenium supplementation status. Selenium supplementation improved the general conditions of the patients, improved their quality of life and reduced the side effects of radiotherapy. At the dose of selenium used in these studies (200–500 μg/day), selenium supplementation did not reduce the effectiveness of radiotherapy, and no toxicities were reported. Selenium supplementation may offer specific benefits for several types of cancer patients who undergo radiotherapy. Because high-dose selenium and long-term supplementation may be unsafe due to selenium toxicity, more evidence-based information and additional research are needed to ensure the therapeutic benefits of selenium supplementation.
doi:10.1186/1748-717X-9-125
PMCID: PMC4073179  PMID: 24885670
Selenium; Supplementation; Clinical studies; Radiotherapy
12.  Cranial irradiation induces bone marrow-derived microglia in adult mouse brain tissue 
Journal of Radiation Research  2014;55(4):713-719.
Postnatal hematopoietic progenitor cells do not contribute to microglial homeostasis in adult mice under normal conditions. However, previous studies using whole-body irradiation and bone marrow (BM) transplantation models have shown that adult BM cells migrate into the brain tissue and differentiate into microglia (BM-derived microglia; BMDM). Here, we investigated whether cranial irradiation alone was sufficient to induce the generation of BMDM in the adult mouse brain. Transgenic mice that express green fluorescent protein (GFP) under the control of a murine stem cell virus (MSCV) promoter (MSCV-GFP mice) were used. MSCV-GFP mice express GFP in BM cells but not in the resident microglia in the brain. Therefore, these mice allowed us to detect BM-derived cells in the brain without BM reconstitution. MSCV–GFP mice, aged 8–12 weeks, received 13.0 Gy irradiation only to the cranium, and BM-derived cells in the brain were quantified at 3 and 8 weeks after irradiation. No BM-derived cells were detected in control non-irradiated MSCV-GFP mouse brains, but numerous GFP-labeled BM-derived cells were present in the brain stem, basal ganglia and cerebral cortex of the irradiated MSCV-GFP mice. These BM-derived cells were positive for Iba1, a marker for microglia, indicating that GFP-positive BM-derived cells were microglial in nature. The population of BMDM was significantly greater at 8 weeks post-irradiation than at 3 weeks post-irradiation in all brain regions examined. Our results clearly show that cranial irradiation alone is sufficient to induce the generation of BMDM in the adult mouse.
doi:10.1093/jrr/rru015
PMCID: PMC4100007  PMID: 24706998
microglia; bone marrow-derived microglia; cranial irradiation; transgenic mice
13.  Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model 
PLoS ONE  2014;9(3):e92572.
Purpose
There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity.
Methods and Materials
C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry.
Results
In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy.
Conclusions
Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a promising treatment in combination with radiotherapy.
doi:10.1371/journal.pone.0092572
PMCID: PMC3970971  PMID: 24686897
14.  Increase in cell motility by carbon ion irradiation via the Rho signaling pathway and its inhibition by the ROCK inhibitor Y-27632 in lung adenocarcinoma A549 cells 
Journal of Radiation Research  2014;55(4):658-664.
This study aimed to investigate the effect of carbon ion (C-ion) irradiation on cell motility through the ras homolog gene family member (Rho) signaling pathway in the human lung adenocarcinoma cell line A549. Cell motility was assessed by a wound-healing assay, and the formation of cell protrusions was evaluated by F-actin staining. Cell viability was examined by the WST-1 assay. The expression of myosin light chain 2 (MLC2) and the phosphorylation of MLC2 at Ser19 (P-MLC2-S19) were analyzed by Western blot. At 48 h after irradiation, the wound-healing assay demonstrated that migration was significantly greater in cells irradiated with C-ion (2 or 8 Gy) than in unirradiated cells. Similarly, F-actin staining showed that the formation of protrusions was significantly increased in cells irradiated with C-ion (2 or 8 Gy) compared with unirradiated cells. The observed increase in cell motility due to C-ion irradiation was similar to that observed due to X-ray irradiation. Western-blot analysis showed that C-ion irradiation (8 Gy) increased P-MLC2-S19 expression compared with in unirradiated controls, while total MLC2 expression was unchanged. Exposure to a non-toxic concentration of Y-27632, a specific inhibitor of Rho-associated coiled-coil-forming protein kinase (ROCK), reduced the expression of P-MLC2-S19 after C-ion irradiation (8 Gy), resulting in a significant reduction in migration. These data suggest that C-ion irradiation increases cell motility in A549 cells via the Rho signaling pathway and that ROCK inhibition reduces that effect.
doi:10.1093/jrr/rru002
PMCID: PMC4099995  PMID: 24659807
non-small cell lung carcinoma (NSCLC); cell motility; carbon ion (C-ion) irradiation; ras homolog gene family member (Rho); Rho-associated coiled-coil-forming protein kinase (ROCK)
15.  Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats 
Journal of Radiation Research  2014;55(4):665-673.
Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury.
doi:10.1093/jrr/rru005
PMCID: PMC4099997  PMID: 24566720
radiation-induced liver injury; liver fibrosis; transforming growth factor-beta 1; alpha smooth muscle actin; apoptosis
16.  Dose–volume histogram parameters of high-dose-rate brachytherapy for Stage I–II cervical cancer (≤4cm) arising from a small-sized uterus treated with a point A dose-reduced plan 
Journal of Radiation Research  2014;55(4):788-793.
We investigated the rectal dose-sparing effect and tumor control of a point A dose-reduced plan in patients with Stage I–II cervical cancer (≤4 cm) arising from a small-sized uterus. Between October 2008 and August 2011, 19 patients with Stage I–II cervical cancer (≤4 cm) were treated with external beam radiotherapy (EBRT) for the pelvis and CT-guided brachytherapy. Seven patients were treated with brachytherapy with standard loading of source-dwell positions and a fraction dose of 6 Gy at point A (conventional brachy-plan). The other 12 patients with a small uterus close to the rectum or small intestine were treated with brachytherapy with a point A dose-reduction to match D2cc of the rectum and <6 Gy as the dose constraint (‘point A dose-reduced plan’) instead of the 6-Gy plan at point A (‘tentative 6-Gy plan’). The total doses from EBRT and brachytherapy were added up and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2). The median doses to the high-risk clinical target volume (HR-CTV) D90 in the conventional brachy-plan, tentative 6-Gy plan and point A dose-reduced plan were 62 GyEQD2, 80 GyEQD2 and 64 GyEQD2, respectively. The median doses of rectal D2cc in the corresponding three plans were 42 GyEQD2, 62 GyEQD2 and 51 GyEQD2, respectively. With a median follow-up period of 35 months, three patients developed Grade-1 late rectal complications and no patients developed local recurrence. Our preliminary results suggested that CT-guided brachytherapy using an individualized point A dose-reduced plan might be useful for reducing late rectal complications while maintaining primary tumor control.
doi:10.1093/jrr/rru006
PMCID: PMC4099998  PMID: 24566721
cervical cancer; CT-guided brachytherapy; small-sized uterus; late rectal complication; point A dose
17.  Chromatin-regulating proteins as targets for cancer therapy 
Journal of Radiation Research  2014;55(4):613-628.
Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow's cancer therapy, including radiotherapy and molecularly targeted chemotherapy.
doi:10.1093/jrr/rrt227
PMCID: PMC4099987  PMID: 24522270
chromatin remodeling; histone modification; histone acetyltransferase; SWI/SNF complex; synthetic lethality; BRM
18.  Nationwide Surveillance of Macrolide-Resistant Mycoplasma pneumoniae Infection in Pediatric Patients 
We conducted nationwide surveillance to investigate regional differences in macrolide-resistant (MR) Mycoplasma pneumoniae strains in Japan. The prevalence of MR M. pneumoniae in pediatric patients gradually increased between 2008 and 2012. Although regional differences were observed, high levels of MR genes were detected in all seven surveillance areas throughout Japan and ranged in prevalence from 50% to 93%. These regional differences were closely related to the previous administration of macrolides.
doi:10.1128/AAC.00663-13
PMCID: PMC3719750  PMID: 23716043
19.  Activated spinal astrocytes are involved in the maintenance of chronic widespread mechanical hyperalgesia after cast immobilization 
Molecular Pain  2014;10:6.
Background
In the present study, we examined spinal glial cell activation as a central nervous system mechanism of widespread mechanical hyperalgesia in rats that experienced chronic post-cast pain (CPCP) 2 weeks after cast immobilization. Activated spinal microglia and astrocytes were investigated immunohistologically in lumbar and coccygeal spinal cord segments 1 day, 5 weeks, and 13 weeks following cast removal.
Results
In the lumbar cord, astrocytes were activated after microglia. Astrocytes also were activated after microglia in the coccygeal cord, but with a delay that was longer than that observed in the lumbar cord. This activation pattern paralleled the observation that mechanical hyperalgesia occurred in the hindleg or the hindpaw before the tail. The activating transcription factor 3 (ATF3) immune response in dorsal root ganglia (DRG) on the last day of cast immobilization suggested that nerve damage might not occur in CPCP rats. The neural activation assessed by the phosphorylated extracellular signal-regulated kinase (pERK) immune response in DRG arose 1 day after cast removal. In addition, L-α-aminoadipate (L-α-AA), an inhibitor of astrocyte activation administered intrathecally 5 weeks after cast removal, inhibited mechanical hyperalgesia in several body parts including the lower leg skin and muscles bilaterally, hindpaws, and tail.
Conclusions
These findings suggest that activation of lumbar cord astrocytes is an important factor in widespread mechanical hyperalgesia in CPCP.
doi:10.1186/1744-8069-10-6
PMCID: PMC3907371  PMID: 24456903
Cast immobilization; Chronic post-cast pain; Widespread hyperalgesia; Complex regional pain syndrome (CRPS) Type I; Microglia; Astrocytes
20.  Histological Study on the Left Common Iliac Vein Spur 
Annals of Vascular Diseases  2014;7(3):261-265.
The spur occasionally seen in a left common iliac vein was investigated by anatomical and histological examination of cadavers so the occurrence mechanism could be discussed. Spurs were found in six cases of the 28 cadavers (21.4%) and they were classified into few different kinds of composition of endosporia, tunica media and adventitia. It is considered that there may be different formation mechanisms and stages even in cases of similar anatomical finding. (*English translation of J Jpn Coll Angiol 2013; 53: 43-47)
doi:10.3400/avd.oa.14-00082
PMCID: PMC4180687  PMID: 25298827
spur; compression; May-Thurner syndrome; left common iliac vein
21.  Low opsonic activity to the infecting serotype in pediatric patients with invasive pneumococcal disease 
Vaccine  2012;31(5):10.1016/j.vaccine.2012.11.010.
Serotype-specific protective immunity of pediatric patients with invasive pneumococcal disease (IPD) has not been fully investigated. To determine the protective immunity to the infecting serotype, the serotype-specific immunoglobulin G (IgG) levels and opsonophagocytic assay (OPA) titers were examined in twenty-four pediatric patients whose serum was collected within one month of IPD episode in between May 2008 and June 2011 in Japan. The median age (range) of IPD patients was 17 (10–108) months and 63% were boys. The levels of serotype-specific IgG to the infecting serotype were higher than 0.2 μg/ml in all of 17 patients tested. By contrast, the OPA titers were < 8 to the infecting serotype in all of 17 patients tested. The avidities of 19F or 6B-specific IgG level higher than 5.0 μg/ml, but undetectable OPA titers, were confirmed to be lower than those with high OPA titers. Our data demonstrated that although the levels of serotype-specific IgG to the infecting serotype were higher than 0.2 μg/ml in sera of pediatric patients with IPD, the OPA titers were low during one month after the IPD episode. Impaired opsonic activities in these patients may be, in part, explained by the low avidities of serotype-specific IgG. Impaired serum opsonic activity in children immediately after the episode of IPD suggests their susceptibility to the infecting serotype of pneumococci.
doi:10.1016/j.vaccine.2012.11.010
PMCID: PMC3829722  PMID: 23153440
invasive pneumococcal diseases; serotype-specific IgG; opsonophagocytic activity; pneumococcal vaccine; children
22.  Radiotherapy plus Concomitant Adjuvant Temozolomide for Glioblastoma: Japanese Mono-Institutional Results 
PLoS ONE  2013;8(11):e78943.
This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m2/day, every day) and adjuvant TMZ (200 mg/m2/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01); the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.
doi:10.1371/journal.pone.0078943
PMCID: PMC3827088  PMID: 24265731
23.  Therapeutic Efficacy of Macrolides, Minocycline, and Tosufloxacin against Macrolide-Resistant Mycoplasma pneumoniae Pneumonia in Pediatric Patients 
The importance of macrolide-resistant (MR) Mycoplasma pneumoniae has become much more apparent in the past decade. We investigated differences in the therapeutic efficacies of macrolides, minocycline, and tosufloxacin against MR M. pneumoniae. A total of 188 children with M. pneumoniae pneumonia confirmed by culture and PCR were analyzed. Of these, 150 patients had a strain with an MR gene and 134 had one with an A-to-G mutation at position 2063 of M. pneumoniae 23S rRNA domain V. Azithromycin (n = 27), clarithromycin (n = 23), tosufloxacin (n = 62), or minocycline (n = 38) was used for definitive treatment of patients with MR M. pneumoniae. Defervescence within 48 h after the initiation of antibiotic therapy was observed in 41% of the patients in the azithromycin group, 48% of those in the clarithromycin group, 69% of those in the tosufloxacin group, and 87% of those in the minocycline group. The average number of days of fever after the administration of antibiotic treatment was lower in the minocycline and tosufloxacin groups than in the macrolide groups. The decrease in the M. pneumoniae burden, as estimated by the number of DNA copies, after 48 to 96 h of treatment was more rapid in patients receiving minocycline (P = 0.016) than in those receiving tosufloxacin (P = 0.049), azithromycin (P = 0.273), or clarithromycin (P = 0.107). We found that the clinical and bacteriological efficacies of macrolides against MR M. pneumoniae pneumonia was low. Our results indicated that minocycline rather than tosufloxacin can be considered the first-choice drug for the treatment of M. pneumoniae pneumonia in children aged ≥8 years.
doi:10.1128/AAC.00048-13
PMCID: PMC3632908  PMID: 23459497
24.  Five-fraction CyberKnife radiotherapy for large brain metastases in critical areas: impact on the surrounding brain volumes circumscribed with a single dose equivalent of 14 Gy (V14) to avoid radiation necrosis 
Journal of Radiation Research  2013;55(2):334-342.
The efficacy and toxicity of five-fraction CyberKnife radiotherapy were evaluated in patients with large brain metastases in critical areas. A total of 85 metastases in 78 patients, including tumors >30 cm3 (4 cm in diameter) were treated with five-fraction CyberKnife radiotherapy with a median marginal dose of 31 Gy at a median prescribed isodose of 58%. Changes in the neurological manifestations, local tumor control, and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 28.8 Gy (single dose equivalent to 14 Gy: V14) were measured to evaluate the risk of radiation necrosis. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 28 of 55 patients (50.9%). Local tumor control was obtained in 79 of 85 metastases (92.9%) during a median follow-up of eight months. Symptomatic edema occurred in 10 patients, and two of them (2.6%) required surgical resection because of radiation necrosis. The V14 of these patients was 3.0–19.7 cm3. There were 16 lesions with a V14 of ≥7.0 cm3, and two of these lesions developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7.0 cm3 exhibited edema requiring surgical intervention. We therefore conclude that a high rate of local tumor control and low rates of complications can be obtained after five-fraction CyberKnife radiotherapy for large metastases in critical areas. The V14 of the surrounding brain is therefore a useful indicator for the risk of radiation necrosis in patients with large metastases.
doi:10.1093/jrr/rrt127
PMCID: PMC3951086  PMID: 24187332
large brain metastases; hypofractionated radiotherapy; five-session radiosurgery; radiation necrosis; V14
25.  Combined serum mesothelin and carcinoembryonic antigen measurement in the diagnosis of malignant mesothelioma 
Molecular and Clinical Oncology  2013;1(6):942-948.
Malignant mesothelioma (MM) is a highly aggressive tumor associated with asbestos exposure. The identification of a marker specific for MM may be of considerable value for the early detection of this tumor and may be used in particular to screen groups with a history of asbestos exposure. The aim of this study was to evaluate serum soluble mesothelin-related peptide (SMRP) levels as a diagnostic marker for MM and investigate whether its diagnostic value is enhanced by combination with other biomarkers. Serum SMRP levels were measured using a quantitative enzyme-linked immunosorbent assay in 96 patients with MM, 55 patients with lung cancer and 39 individuals with a history of asbestos exposure. Receiver operating characteristic curves were constructed for performance evaluation. Stepwise logistic regression analysis was used to select marker combinations (MCs). Serum SMRP levels in patients with MM were significantly higher compared to those in the other groups (P<0.001). The sensitivity of SMRP levels in diagnosing MM was 56% and its specificity for MM vs. lung cancer and individuals with asbestos exposure was 87 and 92%, respectively. The area under the curve (AUC) was 0.76 [95% confidence interval (CI): 0.68–0.83] for the differentiation between MM and lung cancer and 0.78 (95% CI: 0.71–0.86) for the differentiation between MM and individuals with asbestos exposure. For the MC of presence of effusion, SMRP and carcinoembryonic antigen (CEA) levels, the AUC for the differentiation between MM and lung cancer (0.92; 95% CI: 0.88–0.97) and the differentiation between MM and individuals with asbestos exposure (0.93; 95% CI: 0.87–1.0) was significantly higher compared to that for SMRP alone (P=0.0001 and 0.0058, respectively). While the specificity of this MC was comparable to SMRP alone, its sensitivity was ∼20% higher compared to that of SMRP alone. Therefore, combining SMRP and CEA improves the diagnostic performance of SMRP alone. A combination of serum biomarkers, including SMRP, may facilitate the non-invasive diagnosis of MM.
doi:10.3892/mco.2013.175
PMCID: PMC3915672  PMID: 24649274
malignant mesothelioma; mesothelin; soluble mesothelin-related peptide; Mesomark™; marker combinations

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