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Brainstem metastases are challenging to manage owing to the critical neurological structures involved. Although stereotactic radiotherapy (SRT) offers targeted high doses while minimizing damage to adjacent normal tissues, the optimal dose fractionation remains undefined. This study evaluated the efficacy and safety of multifraction SRT with an inhomogeneous dose distribution. This retrospective study included 31 patients who underwent 33 treatments for 35 brainstem lesions using linear accelerator-based multifraction SRT (30 Gy in five fractions, 35 Gy in five fractions or 42 Gy in 10 fractions) with an inhomogeneous dose distribution (median isodose, 51.9%). The outcomes of interest were local failure, toxicity and symptomatic failure. The median follow-up time after brainstem SRT for a lesion was 18.6 months (interquartile range, 10.0-24.3 months; range, 1.8-39.0 months). Grade 2 toxicities were observed in two lesions, and local failure occurred in three lesions. No grade 3 or higher toxicities were observed. The 1-year local and symptomatic failure rates were 8.8 and 16.7%, respectively. Toxicity was observed in two of seven treatments with a gross tumor volume (GTV) greater than 1 cc, whereas no toxicity was observed in treatments with a GTV less than 1 cc. No clear association was observed between the biologically effective dose of the maximum brainstem dose and the occurrence of toxicity. Our findings indicate that multifraction SRT with an inhomogeneous dose distribution offers a favorable balance between local control and toxicity in brainstem metastases. Larger multicenter studies are needed to validate these results and determine the optimal dose fractionation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Aims: This study aimed to assess the effects of chlorine dioxide (ClO2) in water on whiteleg shrimp Penaeus vannamei, evaluating its impact on the stomach microbiota, gill transcriptome, and pathogens., Methods and Results: ClO2 was added to the aquarium tanks containing the shrimp. The application of ClO2 to rearing water was lethal to shrimp at concentrations above 1.2 ppm. On the other hand, most of the shrimp survived at 1.0 ppm of ClO2. Microbiome analysis showed that ClO2 administration at 1.0 ppm significantly reduced the α-diversity of bacterial community composition in the shrimp stomach, and this condition persisted for at least 7 days. Transcriptome analysis of shrimp gill revealed that ClO2 treatment caused massive change of the gene expression profile, including stress response genes. However, after 7 days of the treatment, the gene expression profile was similar to that of shrimp in the untreated control group, suggesting a recovery to the normal state. This 1.0-ppm ClO2 significantly reduced shrimp mortality in artificial challenges with an acute hepatopancreatic necrosis disease-causing Vibrio parahaemolyticus and white spot syndrome virus, which were added to rearing water., Conclusions: The use of ClO2 at appropriate concentrations effectively eliminates a significant portion of the bacteria in the shrimp stomach and pathogens in the water. The results of this study provide fundamental knowledge on the disinfection of pathogens in water using ClO2 and the creation of semi germ-free shrimp, which has significantly decreased microbiome in the stomach., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Objectives: A portable respiratory training system with a gyroscope sensor (gyroscope respiratory training system [GRTS]) was developed and the feasibility of respiratory training was evaluated., Methods: Simulated respiratory waveforms from a respiratory motion phantom and actual respirator waveforms from volunteers were acquired using the GRTS and Respiratory Gating for Scanners system (RGSC). Respiratory training was evaluated by comparing the stability and reproducibility of respiratory waveforms from patients undergoing expiratory breath-hold radiation therapy, with and without the GRTS. The stability and reproducibility of respiratory waveforms were assessed by root mean square error and gold marker placement-based success rate of expiratory breath-hold, respectively., Results: The absolute mean difference for sinusoidal waveforms between the GRTS and RGSC was 2.0%. Among volunteers, the mean percentages of errors within ±15% of the respiratory waveforms acquired by the GRTS and RGSC were 96.1% for free breathing and 88.2% for expiratory breath-hold. The mean root mean square error and success rate of expiratory breath-hold (standard deviation) with and without the GRTS were 0.65 (0.24) and 0.88 (0.89) cm and 91.0% (6.9) and 89.1% (11.6), respectively., Conclusions: Respiratory waveforms acquired by the GRTS exhibit good agreement with waveforms acquired by the RGSC. Respiratory training with the GRTS reduces inter-patient variability in respiratory waveforms, thereby improving the success of expiratory breath-hold radiation therapy., Advances in Knowledge: A respiratory training system with a gyroscope sensor is inexpensive and portable, making it ideal for respiratory training. This is the first report concerning clinical implementation of a respiratory training system., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The effectiveness of single-fraction 8-Gy radiotherapy for painful bone metastases has been verified in numerous randomized controlled trials. However, few reports have described the effectiveness of single-fraction 8-Gy radiotherapy in painful tumors other than bone metastases. We conducted a retrospective analysis to evaluate the pain response to single-fraction 8-Gy radiotherapy in painful non-bone-metastasis tumors. We included patients who had received single-fraction 8-Gy radiotherapy for such tumors between January 2017 and December 2022, excluding those with brain metastases, hematological tumors and those who received re-irradiation. Pain response assessment was based on the best responses documented in the medical records and conducted by two radiation oncologists. A total of 36 eligible patients were included in this study. The irradiation sites included primary lesions in eight patients, lymph node metastases in eight, muscle metastases in seven, pleural dissemination in four, skin/subcutaneous metastases in four and other sites in five. Pain response was assessed in 24 patients after radiotherapy. Pain response rate was 88% in evaluable patients; 21 of the 24 patients experienced response. The median assessment date for pain response was 37 days (range: 8-156 days) after radiotherapy. Re-irradiation was performed in four patients (11%). Single-fraction 8-Gy radiotherapy seemed to be a promising treatment option for painful non-bone-metastasis tumors and warrants further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0-8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect., Methods: Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78 Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n = 197). In principle, patients received androgen deprivation therapy for 3-6 months before radiation, concurrently, and for 2 years after completion of intensity-modulated radiation therapy., Results: The median follow-up period was 96 months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P = 0.023). Grade Group 5 and younger age (cutoff: 70 years old) were independent predictors of recurrence (P = 0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18 months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P = 0.039) when contrasted with those who had a longer interval to biochemical failure., Conclusions: Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alterations to the resting-state default mode network (rsDMN) are early indicators of memory decline and Alzheimer's disease (AD). Brain regions shared by the rsDMN and memory circuitry are highly sexually dimorphic. However, data are limited regarding the impact of sex and reproductive status on rsDMN connectivity and memory circuitry and function. In the current investigation, rsDMN connectivity was assessed in 180 early midlife adults aged 45 to 55 by sex and reproductive status (87 women; 93 men). Associations between left and right hippocampal connectivity of rsDMN and verbal memory encoding circuitry were examined using linear mixed models, controlled for age and parental socioeconomic status, testing interactions by sex and reproductive status. Relative to men, women exhibited greater rsDMN connectivity between the left and right hippocampus. In relation to rsDMN-memory encoding connectivity, sex differences were revealed across the menopausal transition, such that only postmenopausal women exhibited loss of the ability to decrease rsDMN left-right hippocampal connectivity during memory encoding associated with poorer memory performance. Results demonstrate that sex and reproductive status play an important role in aging of the rsDMN and interactions with memory circuitry/function. This suggests the critical importance of sex and reproductive status when studying early midlife indicators of memory decline and AD risk., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

To explore predictors of the histopathological response to preoperative chemoradiotherapy (CRT) in patients with pancreatic cancer (PC) using dual-energy computed tomography-reconstructed images. This retrospective study divided 40 patients who had undergone preoperative CRT (50-60 Gy in 25 fractions) followed by surgical resection into two groups: the response group (Grades II, III and IV, evaluated from surgical specimens) and the nonresponse group (Grades Ia and Ib). The computed tomography number [in Hounsfield units (HUs)] and iodine concentration (IC) were measured at the locations of the aorta, PC and pancreatic parenchyma (PP) in the contrast-enhanced 4D dual-energy computed tomography images. Logistic regression analysis was performed to identify predictors of histopathological response. Univariate analysis did not reveal a significant relation between any parameter and patient characteristics or dosimetric parameters of the treatment plan. The HU and IC values in PP and the differences in HU and IC between the PP and PC (ΔHU and ΔIC, respectively) were significant predictors for distinguishing the response (n = 24) and nonresponse (n = 16) groups (P < 0.05). The IC in PP and ΔIC had a higher area under curve values [0.797 (95% confidence interval, 0.659-0.935) and 0.789 (0.650-0.928), respectively] than HU in PP and ΔHU [0.734 (0.580-0.889) and 0.721 (0.562-0.881), respectively]. The IC value could potentially be used for predicting the histopathological response in patients who have undergone preoperative CRT., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

In volumetric modulated arc therapy (VMAT), the effect of an increase in skin surface dose due to topical agents might be negligible. We investigated the bolus effects of three types of topical agents in VMAT for head and neck cancer (HNC). Topical agents of different thicknesses (0.1, 0.5 and 2 mm) were prepared. When each topical agent was set, the surface doses were measured for the anterior static field and VMAT, with and without a thermoplastic mask. No significant differences were observed among the three topical agents. For topical agent thicknesses of 0.1, 0.5 and 2 mm, the increases in surface dose for the anterior static field without the thermoplastic mask were 7-9, 30-31 and 81-84%, respectively. With the thermoplastic mask, the corresponding increases were 5, 12-15 and 41-43%, respectively. The increases in surface dose for VMAT without the thermoplastic mask were 5-8, 16-19 and 36-39%, respectively, and those with the thermoplastic mask were 4, 7-10 and 15-19%, respectively. The rate of increase in surface dose with the thermoplastic mask was smaller than that without the thermoplastic mask. The increase in surface dose with topical agents of clinical standard thickness (0.02 mm) was estimated to be 2% with the thermoplastic mask. The increase in surface dose with topical agents in dosimetric simulation, compared with control situation, is not significant in clinical conditions for HNC patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis., Methods: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs)., Results: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]., Conclusion: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528)., (© The Author(s) 2022. Published by Oxford University Press.)

The larval parasitoid Diadegma hiraii (Kusigemati) was evaluated as a potential biological control agent of the soybean pod borer, Leguminivora glycinivorella (Matsumura). The timing of adult emergence after overwintering was ascertained, and land-use factors that enhance population density were analyzed. Host cocoons were collected and exposed to different temperatures and photoperiod regimes. Subsequently, the emergence of parasitoid was monitored. Land-use types were categorized into 4 land-use types (Poaceae, Fabaceae, Brassicaceae, and forest). Adult parasitoid emergence was dependent on temperature, but largely unaffected by photoperiod. The estimated emergence time of parasitoid was 3 months before the occurrence of the host, suggesting that the overwintered generation may lay eggs in alternate hosts. Parasitism rate was positively correlated with the area covered by Poaceae plants within a 500-m radius of the soybean field. Based on the results of the overwintering ecology and landscape analysis, D. hiraii probably completes its life cycle in the agroecosystems. The parasitoid's effectiveness as a biological control agent may be influenced by the arrangement of land-use types in the agroecosystems surrounding soybean fields. However, the pest control provided by D. hiraii is limited because of approximately 30% of parasitism rate. Consequently, a combination of this species and cultural control and/or other biological control agents is suggested for sustainable soybean cultivation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the feasibility of external beam radiotherapy without central shielding in definitive radiotherapy for Japanese patients with cervical cancer., Methods: We retrospectively analysed the data of cervical cancer patients treated with definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy., Results: The study included 167 patients (T1 + 2 = 108, T3 + 4 = 59) from eight Japanese institutions. For three-dimensional-image-guided brachytherapy, intra-cavitary and interstitial brachytherapy was utilized in 33 patients (20%). The median follow-up was 26.6 months (interquartile range, 20-43.2). The maximum rectal D2 (75 Gy)/bladder D2 (90 Gy) constraints were deviated by 6%/10% and 10%/5% for T1 + 2 and T3 + 4, respectively. The 2-year incidence of ≥grade 3 proctitis/cystitis was 4%/1% for T1 + 2 and 10%/2% for T3 + 4. The 2-year local progression-free survival was 89% for T1 + 2 and 82% for T3 + 4. For T1 + 2, the 2-year local progression-free survival for the high-risk clinical target volume D90 ≥ 68 Gy (indicated by receiver operating characteristic analysis; area under the curve = 0.711) was 92% versus 67% for <68 Gy (log-rank; P = 0.019). Cox multivariate analysis indicated that the high-risk clinical target volume D90 was one of independent predictors of local failure (P = 0.0006). For T3 + 4, the 2-year local progression-free survival was 87% for the high-risk clinical target volume <82 cm3 (area under the curve = 0.67) and 43% for ≥82 cm3 (P = 0.0004). Only the high-risk clinical target volume was an independent predictor of local failure (P = 0.0024)., Conclusions: Definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy was feasible for Japanese patients with cervical cancer. Dose de-escalation from the current global standards is suggested for patients with T1 + 2 disease., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Objective: We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot samples in Tokyo., Methods: Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. Samples from 2 cohorts were assayed: Cohort A, 63 "screening positive" neonates who were referred to an endocrinologist (n = 26 with 21OHD; n = 37 false-positive; obtained from 2015 to 2020); and Cohort B, samples (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021., Results: Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences., Conclusion: Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening., Competing Interests: Conflict of Interest: The author declares no conflict of interest associated with this research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We evaluated the basic characteristics and efficacy of our newly developed patient fixation system for head and neck radiotherapy that uses a dedicated mouthpiece and dental impression materials. The present investigation demonstrated that with this system, the changes in the absorbed dose to water depending on the material of the mouthpiece were small, with a maximum of 0.32% for a 10-MV photon beam. For the dental impression material, we selected a silicone material with the lowest Hounsfield unit (HU) value that had little effect on the generation of artifacts and the quality of the X-ray beam. Multiphase magnetic resonance imaging (MRI) revealed that the head-up and -down motions in the thermoplastic shell without the mouthpiece were 5.76 ± 1.54 mm, whereas the motion with the mouthpiece decreased significantly to 1.72 ± 0.92 mm (P = 0.006). Similarly, the head-left and -right motion displacement decreased from 6.32 ± 1.86 mm without the mouthpiece to 1.80 ± 0.42 mm with the mouthpiece (P = 0.003). Regarding the tongue depressor function of the mouthpiece, the median distance from the hard palate to the surface of the tongue was 28.42 mm. The present results indicate that the new immobilization device developed herein that uses a mouthpiece and a thermoplastic shell is useful for suppressing patients' head motions and tongue positions., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study used cine-magnetic resonance imaging (cine-MRI) to evaluate the safety and efficacy of a novel airbag system combined with a shell-type body fixation system in reducing respiratory motion in normal volunteers. The airbag system consists of a six-sided polygon inflatable airbag, a same shape plate, a stiff air supply tube, an air-supply pump and a digital pressure load cell monitor. Piezoelectric sensors were installed in the plate to detect compression pressure load changes; pressure load data were transferred to the digital pressure load cell monitor through Bluetooth. Five volunteers underwent cine-MRI with and without airbag compression to detect differences in the respiratory motion of the organs. The volunteers' physiologic signs were stable during the experiment. The maximum inspiration pressure load was 4.48 ± 0.86 kgf (range, 4.00-6.00 kgf), while the minimum expiration pressure load was 3.69 ± 0.95 kgf (range, 2.8-5.3 kgf). Under airbag compression, the right diaphragm movement was reduced from 19.50 ± 6.43 mm to 9.60 ± 3.61 mm (P < 0.05) in the coronal plane and 23.12 ± 6.30 mm to 11.00 ± 3.69 mm (P < 0.05) in the sagittal plane. The left diaphragm, pancreas and liver in the coronal plane and the right kidney and liver in the sagittal plane also showed significant movement reduction. This novel airbag abdominal compression system was found to be safe during the experiment and successful in the reduction of internal organ respiratory motion and promises to be a convenient and efficient tool for clinical radiotherapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Three-dimensional (3D) observation of a biological sample using serial-section electron microscopy is widely used. However, organelle segmentation requires a significant amount of manual time. Therefore, several studies have been conducted to improve organelle segmentation's efficiency. One such promising method is 3D deep learning (DL), which is highly accurate. However, the creation of training data for 3D DL still requires manual time and effort. In this study, we developed a highly efficient integrated image segmentation tool that includes stepwise DL with manual correction. The tool has four functions: efficient tracers for annotation, model training/inference for organelle segmentation using a lightweight convolutional neural network, efficient proofreading and model refinement. We applied this tool to increase the training data step by step (stepwise annotation method) to segment the mitochondria in the cells of the cerebral cortex. We found that the stepwise annotation method reduced the manual operation time by one-third compared with the fully manual method, where all the training data were created manually. Moreover, we demonstrated that the F1 score, the metric of segmentation accuracy, was 0.9 by training the 3D DL model with these training data. The stepwise annotation method using this tool and the 3D DL model improved the segmentation efficiency of various organelles., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: The 3-year disease-free survival rate of the twice-daily regimen was not inferior to that of the conventional three-times-daily regimen, and the twice-daily regimen did not lead to an increase in adverse events. The effectiveness of the twice-daily regimen highlights an increased number of treatment options for patients. This will facilitate personalized medicine, particularly for elderly or frail patients who may experience more severe side effects from the combination therapy., Background: Tegafur-uracil (UFT)/leucovorin calcium (LV) is an adjuvant chemotherapy treatment for colorectal cancer. We conducted a multicenter randomized trial to assess the noninferiority of a twice-daily compared with a three-times-daily UFT/LV regimen for stage II/III colorectal cancer in an adjuvant setting., Methods: Patients were randomly assigned to group A (three doses of UFT [300 mg/m 2 per day]/LV [75 mg per day]) or B (two doses of UFT [300 mg/m 2 per day]/LV [50 mg per day]). The primary endpoint was 3-year disease-free survival., Results: In total, 386 patients were enrolled between July 28, 2011, and September 27, 2013. The 3-year disease-free survival rates of group A (n = 194) and B (n = 192) were 79.4% and 81.4% (95% confidence interval, 72.6-84.4-74.5-85.9), respectively. The most common grade 3/4 adverse events in group A and B were diarrhea (3.9% vs. 7.3%), neutropenia (2.9% vs. 1.6%), increase in aspartate aminotransferase (4.0% vs. 3.9%), increase in alanine aminotransferase (6.2% vs. 6.8%), nausea (1.7% vs. 3.4%), and fatigue (1.1% vs. 2.3%)., Conclusion: Group B outcomes were not inferior to group A outcomes, and adverse events did not increase., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Lessons Learned: Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild-type unresectable colorectal cancer. It is especially effective for left-sided tumors; therefore, panitumumab as first-line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin-based or irinotecan-based combination regimens., Background: First-line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy-naïve frail or elderly patients with unresectable RAS wild-type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first-line treatment., Methods: We conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities., Results: Thirty-six patients (median age: 81 [range, 67-88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty-three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty-eight patients (77.8%) had left-sided CRC, whereas eight (22.2%) had right-sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4-67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5-87.7). The RR of patients with left- and right-sided tumors was 65.4% (95% CI, 44.3-82.8) and 0.0% (95% CI, 0.0-36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%)., Conclusion: Panitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Objective: To explore radiation oncologists' attitudes and practice patterns of radiotherapy for hormone-naïve prostate cancer with bone metastases in Japan., Methods: An internet-based survey was distributed to board-certified radiation oncologists of the Japanese Society of Radiation Oncology. Three hypothetical cases were assumed: hormone-naïve prostate cancer with single, three or multiple non-symptomatic bone metastases. The respondents described their attitude regarding such cases, treatment methods and the radiotherapy dose fractionation that they would recommend., Results: Among the 1013 board-certified radiation oncologists in Japan, 373 (36.8%) responded to the questionnaire. Most of the respondents (85.0%) believed that radiotherapy may be applicable as a primary treatment for hormone-naïve prostate cancer with bone metastases in some circumstances. For Case 1 (single bone metastasis), 55.0% of the respondents recommended radiotherapy for the prostate and bone metastasis. For Case 2 (three bone metastases), only 24.4% recommended radiotherapy for all lesions, and 31.4% recommended radiotherapy for the prostate only. For Case 3 (multiple bone metastases), 49.1% of the respondents stated that there was no indication for radiotherapy. However, 34% of the respondents still preferred to administer radiotherapy for the prostate. The radiotherapy techniques and dose fractionations varied widely among the respondents., Conclusion: Most of the respondent radiation oncologists believed that radiotherapy may be beneficial for hormone-naïve prostate cancer with bone metastases., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Death feigning is considered to be an adaptive antipredator behaviour. Previous studies on Tribolium castaneum have shown that prey which death feign have a fitness advantage over those that do not when using a jumping spider as the predator. Whether these effects are repeatable across species or whether they can be seen in nature is, however, unknown. Therefore, the present study involved two experiments: (a) divergent artificial selection for the duration of death feigning using a related species T. freemani as prey and a predatory bug as predator, demonstrating that previous results are repeatable across both prey and predator species, and (b) comparison of the death-feigning duration of T. castaneum populations collected from field sites with and without predatory bugs. In the first experiment, T. freemani adults from established selection regimes with longer durations of death feigning had higher survival rates and longer latency to being preyed on when they were placed with predatory bugs than the adults from regimes selected for shorter durations of death feigning. As a result, the adaptive significance of death-feigning behaviour was demonstrated in another prey-predator system. In the second experiment, wild T. castaneum beetles from populations with predators feigned death longer than wild beetles from predator-free populations. Combining the results from these two experiments with those from previous studies provided strong evidence that predators drive the evolution of longer death feigning., (© 2020 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2020 European Society For Evolutionary Biology.)

Burkholderia stabilis FERMP-21014 produces highly active cholesterol esterase in the presence of fatty acids. To develop an overexpression system for cholesterol esterase production, we carried out RNA sequencing analyses to screen strongly active promoters in FERMP-21014. Based on gene expression consistency analysis, we selected nine genes that were consistently expressed at high levels, following which we constructed expression vectors using their promoter sequences and achieved overproduction of extracellular cholesterol esterase under fatty acid-free conditions. Of the tested promoters, the promoter of BSFP&#95;0720, which encodes the alkyl hydroperoxide reductase subunit AhpC, resulted in the highest cholesterol esterase activity (24.3 U mL -1 ). This activity level was 243-fold higher than that of the wild-type strain under fatty acid-free conditions. We confirmed that cholesterol esterase was secreted without excessive accumulation within the cells. The gene expression consistency analysis will be useful to screen promoters applicable to the overexpression of other industrially important enzymes.

Chronic periodontitis is caused by dysbiosis of human oral commensals and especially by increase in Porphyromonas gingivalis. Inhibitors of P. gingivalis growth are expected to serve as effective drugs for the periodontal therapy. In the present study, we isolated new growth inhibitors of P. gingivalis using minimal media for P. gingivalis. The minimal media included the previously reported Globulin-Albumin (GA) and the newly developed Lactalbumin-Ferric chloride (LF) and Globulin-Calcium chloride (GC); all supported growth of the wild-type strain of P. gingivalis but did not support the growth of a mutant defective for a type IX secretion system. GC contains CaCl2, indicating that P. gingivalis requires a calcium ion for growth. Using LF and GA, we screened about 100 000 compounds and identified 73 that strongly inhibited the growth of P. gingivalis. More than half of these candidates would not have been obtained if these minimal media had not been used in our screen. One of our candidate inhibitors was diphenyleneiodonium chloride (DPIC), which showed strong bactericidal activity against P. gingivalis. Excess amounts of flavin adenine dinucleotide or flavin mononucleotide suppressed the inhibitory activity of DPIC, suggesting that DPIC would be a novel potent growth inhibitor., (© FEMS 2019.)

Background: In high-income countries, the number of radiotherapy machine per population reaches a sufficient level. However, the patterns of infrastructure of radiotherapy in high-income countries are not well known., Methods: Among 29 high-income countries with gross national income of $25,000 or more per capita, we selected 23 countries whose total number of newly diagnosed cancer patients in 2012 was reported in the Organisation for Economic Co-operation and Development Health Statistics 2017. The numbers of radiotherapy centers and teletherapy machines in each of these 23 countries were collected using the Dictionary of Radiotherapy Centers database., Results: The number of cancer patients per teletherapy machine was 452.35-1398.22 (median 711.66) with a three-fold variation, whereas the number of cancer patients per radiotherapy center varied even more widely, from 826.16 to 5159.86 (median 2259.83) with a six-fold variation. The average number of teletherapy machines per radiotherapy center also ranged widely, from 1.24 to 8.29 (median 3.11) with a seven-fold variation. The number of teletherapy machines in each country was almost proportional to that of cancer patients, and the number of teletherapy machines per radiotherapy center was inversely related to the number of radiotherapy centers per cancer patients. The number of teletherapy machines per radiotherapy center in Japan was 1.24, the most fragmented among the high-income countries. The percentage of large radiotherapy centers having three or more teletherapy machines in Japan was the smallest among 23 high-income countries., Conclusions: Optimization of the radiotherapy infrastructure in Japan should be carefully considered.

With the advancement of chemotherapy, a laryngeal preservation (LP) strategy was explored with the aim of improving maintenance of quality of life. Induction chemotherapy (ICT) following radiotherapy (RT) was considered a viable option because of its high initial response rate without hampering of overall survival (OS). Subsequently, concurrent chemoradiotherapy (CCRT) using CDDP became the standard of care for LP, showing the best LP ratio. For enhancing treatment intensity, ICT with taxan + CDDP + 5-FU (TPF-ICT) followed by RT showed superiority over ICT with CDDP + 5-FU (PF-ICT) followed by RT. Given that almost all randomized controlled trials investigating ICT include not only operable (endpoint, LP) but also inoperable (endpoint, OS) cases, physicians are faced with a dilemma regarding application in daily practice. In addition, increased treatment intensity causes augmentation of adverse events, which might reduce compliance. Thereafter, cetuximab, an effective drug with fewer adverse effects [bioradiotherapy (BRT)], emerged as another option. However, little evidence has confirmed its superiority over RT (or CCRT) in laryngeal cancer subpopulations. In spite of these developments, the OS of patients with laryngeal cancer has not improved for several decades. In fact, several studies indicated a decrease in OS during the 1990s, probably due to overuse of CCRT. Fortunately, the latter was not the case in most institutions. Currently, no other treatment has better OS than surgery. The eligibility criteria for LP and/or surgery largely depend upon the available expertise and experience, which differ from one institution to another. Therefore, a multidisciplinary team is required for the treatment of LP., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: To reduce the ovarian dose with volumetric modulated arc therapy (VMAT), an original VMAT was designed with two types of arcs to restrict angles and fields (R-VMAT)., Methods: The subjects were 11 patients who underwent ovarian transposition with clips left by a surgeon. Three methods, intensity-modulated radiotherapy (IMRT), standard VMAT (S-VMAT) and R-VMAT, were optimized for assessment of the ovarian dose with the target coverage kept high., Results: The homogeneity and conformity indexes for the planning target volume (PTV) were similar for the three methods. However, the average ± SD of the ovarian mean dose (OMD) was 5.0 ± 1.5, 4.9 ± 1.9 and 3.5 ± 1.4 Gy, and the percentage of ovarian volume exceeding 5 Gy (V5) was 41.5 ± 34.1%, 34.1 ± 38.05% and 8.4 ± 20.5% for IMRT, S-VMAT and R-VMAT, respectively. The OMD and V5 were significantly smaller for R-VMAT than for the other plans (p < 0.01). Correlation values between the OMD and the lateral distance from the ovaries to the PTV surface were 0.86, 0.81 and 0.82 for IMRT, S-VMAT and R-VMAT, respectively., Conclusion: These findings suggest that R-VMAT delivered the lowest dose to the ovaries. To reduce the OMD to less than 3 Gy, ovaries should be transposed laterally 6.1 cm away from the PTV surface when R-VMAT is used. Advances in knowledge: When organs with high susceptibility to radiation, such as ovaries, are near the PTV, R-VMAT is superior to IMRT and S-VMAT.

Acrylamide may affect the sex hormone system in the prepubertal period. This study examined the cross-sectional associations between dietary acrylamide intake and sex hormone levels among preschool-age Japanese children. The study was conducted in 2006 among 230 boys and 198 girls aged 3-6 years in Aichi, Japan. Acrylamide intake was assessed using 3-day diet records. Urinary concentrations of estrone, estradiol, testosterone, and androst-5-ene-3β, 17β diol (hereafter referred to as androstenediol) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Sex hormone levels were adjusted for urinary creatinine levels. The estimated acrylamide intake was 1.00 μg/kg of body weight per day. After controlling for age and other covariates, acrylamide intake was significantly positively associated with urinary levels of testosterone and androstenediol in boys. On average, boys in the highest quartile of acrylamide intake had 96.9% higher testosterone (95% confidence interval: -1.8, 295; P for trend = 0.048) and 34.5% higher androstenediol levels (95% confidence interval: -5.9, 92.3; P for trend = 0.04) than boys in the lowest quartile. In girls, there were no significant associations between acrylamide intake and the hormones measured. Acrylamide intake may alter androgen metabolism in preschool-age boys. Because this is a first observation, our findings require confirmation in additional studies., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early laryngeal, especially glottic, cancer is a good candidate for radiotherapy because obvious early symptoms (e.g. hoarseness) make earlier treatment possible and with highly successful localized control. This type of cancer is also a good model for exploring the basic principles of radiation oncology and several key findings (e.g. dose, fractionation, field size, patient fixation, and overall treatment time) have been noted. For example, unintended poor outcomes have been reported during transition from 60Cobalt to linear accelerator installation in the 1960s, with usage of higher energy photons causing poor dose distribution. In addition, shell fixation made precise dose delivery possible, but simultaneously elevated toxicity if a larger treatment field was necessary. Of particular interest to the radiation therapy community was altered fractionation gain as a way to improve local tumor control and survival rate. Unfortunately, this interest ceased with advancements in chemotherapeutic agents because alternate fractionation could not improve outcomes in chemoradiotherapy settings. At present, no form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy. In addition, the substantial workload associated with this technique made it difficult to add extra fractionation routinely in busy clinical hospitals. Hypofractionation, on the other hand, uses a larger single fractionation dose (2-3 Gy), making it a reasonable and attractive option for T1-T2 early glottic cancer because it can improve local control without the additional workload. Recently, Japan Clinical Oncology Group study 0701 reprised its role in early T1-T2 glottic cancer research, demonstrating that this strategy could be an optional standard therapy. Herein, we review radiotherapy history from 60Cobalt to modern linear accelerator, with special focus on the role of alternate fractionation., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Aggregatibacter actinomycetemcomitans is an oral pathogen for aggressive periodontitis, and encodes a triheme c-containing membrane-bound enzyme, quinol peroxidase (QPO) that catalyzes peroxidase activity using quinol in the respiratory chain. In the previous work, we have characterized recombinant QPO purified from the membrane fraction of Escherichia coli harboring a plasmid containing QPO gene. Irreversible inactivation of QPO by high concentration of H2O2 exhibited pseudo-first order kinetics. Analysis of initial-rate kinetics of QPO may suggest that enzyme catalytic mechanism is explained by a Ping Pong Bi Bi system rather than sequential systems. In addition, the redox reactions of cytochrome c in the presence of several values of [Q1H2]/[Q1] were at equilibrium, and only about 2/3 of the cytochrome c of QPO is reduced at high ratios of [Q1H2]/[Q1]. These results indicated that one of the three heme c moieties of QPO is maintained in an oxidized form even at increased ratios of [Q1H2]/[Q1], suggesting that QPO is reduced in the absence of H2O2 and only two of the three heme c moieties are reduced in the presence of high concentration of the Q1H2. Product inhibition of QPO accorded with our theoretical model for the reaction mechanism. Considered together, the enzymatic kinetics data for QPO confirm the Ping Pong Bi Bi system., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Objective: To estimate selective neck irradiation omitting surgical Sublevel IIb., Methods: Bilateral necks of 47 patients (94 necks) were subjected to definitive radiotherapy for supraglottic cancer. Sixty-nine and 25 necks were clinically node negative (cN-) and clinically node positive (cN+), respectively. We subdivided Sublevel IIb by the international consensus guideline for radiotherapy into Sublevel IIb/a, directly posterior to the internal jugular vein, and Sublevel IIb/b, which was behind Sublevel IIb/a and coincided with surgical Sublevel IIb. Bilateral (Sub)levels IIa, III, IV and IIb/a were routinely irradiated, whereas Sublevel IIb/b was omitted from the elective clinical target volume in 73/94 treated necks (78%)., Results: Two patients presented with ipsilateral Sublevel IIb/a metastases. No Sublevel IIb/b metastasis was observed. Five patients experienced cervical lymph node recurrence; Sublevel IIb/a recurrence developed in two patients, whereas no Sublevel IIb/b recurrence occurred even in the cN- necks of cN+ patients or cN0 patients. The 5-year regional control rates were 91.5% for Sublevel IIb/b-omitted patients and 77.8% for Sublevel IIb/b treated patients., Conclusions: Selective neck irradiation omitting Sublevel IIb/b did not compromise regional control and could be indicated for cN- neck of supraglottic cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: We report the response to pre-operative gemcitabine-based chemoradiotherapy for pancreatic adenocarcinoma., Methods: Thirty-five consecutive patients with borderline resectable pancreatic adenocarcinoma of UICC Stage II or III with portal vein invasion or tumor abutment of artery received radiotherapy (twice daily fractions of 1.5 Gy, 5 days/week, total dose: 36 Gy; 30 Gy for Phase I Level 1) with weekly intravenous infusions of gemcitabine (400, 600 and 800 mg/m(2)) at Days 1 and 8 for Phase I and 800 mg/m(2) for Phase II. Restaging was repeated after completion of chemoradiotherapy., Results: Twenty-six of the 35 (74.3%) patients underwent resection. The dose-limiting toxicities were Grade 4 neutropenia and thrombocytopenia. The recommended regimen was total radiation dose of 36 Gy with gemcitabine 800 mg/m(2). Surgical resection was conducted in 11 of the 15 (73.3%) patients in Phase I study and 15 of the 20 (75.0%) in Phase II. After recommended dose chemoradiotherapy and surgical resection, the median disease-free survival was 17.4 months (5-year survival rate = 14.3%). The median overall survival time and 5-year survival rate were 41.2 months and 28.6%, respectively, for the 21 patients who underwent resection and 10.0 months and 0%, respectively, for those 5 who did not (P = 0.004)., Conclusion: Our pre-operative gemcitabine-based chemoradiotherapy was well tolerated and safe., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The purpose of this study was to perform dosimetry analyses comparing high-dose-rate brachytherapy (HDR-BT) with simulated stereotactic body radiotherapy (SBRT). We selected six consecutive patients treated with HDR-BT monotherapy in 2010, and a CyberKnife SBRT plan was simulated for each patient using computed tomography images and the contouring set used in the HDR-BT plan for the actual treatment, but adding appropriate planning target volume (PTV) margins for SBRT. Then, dosimetric profiles for PTVs of the rectum, bladder and urethra were compared between the two modalities. The SBRT plan was more homogenous and provided lower dose concentration but better coverage for the PTV. The maximum doses in the rectum were higher in the HDR-BT plans. However, the HDR-BT plan provided a sharper dose fall-off around the PTV, resulting in a significant and considerable difference in volume sparing of the rectum with the appropriate PTV margins added for SBRT. While the rectum D5cm(3) for HDR-BT and SBRT was 30.7 and 38.3 Gy (P < 0.01) and V40 was 16.3 and 20.8 cm(3) (P < 0.01), respectively, SBRT was significantly superior in almost all dosimetric profiles for the bladder and urethra. These results suggest that SBRT as an alternative to HDR-BT in hypofractionated radiotherapy for prostate cancer might have an advantage for bladder and urethra dose sparing, but for the rectum only when proper PTV margins for SBRT are adopted., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Hibernation-specific protein (HP) is a plasma protein that regulates hibernation in chipmunks. The HP complex (HP20c) consists of three homologous proteins, HP20, HP25 and HP27, all produced by liver and belonging to the C1q family. To date, HP20c has not been identified in any mammalian species except chipmunk and ground squirrel hibernators. Here, we report a bovine HP20 gene isolated from liver tissue and aortic endothelial cells. Total homology between bovine and chipmunk variants was 63% at the amino acid level. Gene expression was highest in the liver. Western blot revealed HP20 protein in foetal, newborn, calf and adult serum, with highest concentrations in the adult. Similar proteins were detected in sera of other ruminants but not in humans, bears, mice or rats. Bovine HP20 protein was found mainly in ovaries, stomach, heart, kidneys, lungs, testes and prostate, but not in the skeletal muscle. Native HP20 was purified from bovine adult serum as a complex containing 25 and 27 kDa proteins. Mass spectrometry revealed that these proteins are orthologues of chipmunk HP25 and HP27, respectively. Interestingly, bovine HP20 was highly expressed in cattle serum after fasting. Native bovine HP20c may be a useful tool for investigating HP function.

To develop an easy independent patient-specific quality assurance (QA) method using a benchmark plan for high-dose-rate intracavitary brachytherapy for cervix cancer, we conducted benchmark treatment planning with various sizes and combinations of tandem-ovoid and tandem-cylinder applications with 'ideal' geometry outside the patient. Two-dimensional-based treatment planning was conducted based on the Manchester method. We predicted the total dwell time of individual treatment plans from the air kerma strength, total dwell time and prescription dose of the benchmark plan. In addition, we recorded the height (dh), width (dw) and thickness (dt) covered with 100% isodose line. These parameters were compared with 169 and 29 clinical cases for tandem-ovoid or tandem-cylinder cases, respectively. With regard to tandem-ovoid cases, differences in total dwell time, dh, dt and dw between benchmark and individual plans were on average -0.2% ± 3.8%, -1.0 mm ± 2.6 mm, 0.8 mm ± 1.3 mm and -0.1 mm ± 1.5 mm, respectively. With regard to tandem-cylinder cases, differences in total dwell time, dh(front) (the distance from tandem tip to tandem ring), dt and dw between benchmark and individual plans were on average -1.5% ± 3.1%, -1.5 mm ± 4.9 mm, 0.1 mm ± 1.0 mm and 0.2 mm ± 0.8 mm, respectively. Of two cases, more than 13% differences in total dwell time were observed between benchmark plans and the clinical cases, which turned out to be due to the use of the wrong source position setting. These results suggest that our method is easy and useful for independent verification of patient-specific treatment planning QA.

Introduction: Oxidative stress is induced by both cigarette smoking and acute exercise. It has also been reported that exercise can induce plasma oxidative stress in young cigarette smokers. However, no previous report has demonstrated that exercise induces pulmonary oxidative stress in cigarette smokers. The aim of this study was to determine whether pulmonary oxidative stress is induced by maximal exercise in cigarette smokers as measured by reactive oxygen species generation and total antioxidant content., Methods: Fifteen male smokers (mean age: 25.9 ± 2.9 years) and 18 male nonsmokers (mean age: 24.2 ± 4.3 years) participated in this study. Hydrogen peroxide (H(2)O(2)) concentration and biological antioxidant potential (BAP) in exhaled breath condensate (EBC) were measured at baseline and after maximal exercise in the Wingate anaerobic test., Results: A significant interaction of group by time was observed for EBC H2O2 concentration (p = .015). After exercise, EBC H(2)O(2) concentrations were significantly increased in the smoking group (p = .030) but not in the nonsmoking group. There were no significant changes in EBC BAP in either group., Conclusions: These findings indicate that in cigarette smokers, maximal exercise induces pulmonary oxidative stress, which may lead to oxidative damage in the lungs.

We present a case, considered to be a form of the Koebner phenomenon, of bullous pemphigoid that was exacerbated mainly within the irradiated field after breast conservative radiotherapy. In May 2009, a 60-year-old woman was diagnosed with bullous pemphigoid, which was treated with steroid therapy. The following month, she was diagnosed with breast cancer (invasive ductal carcinoma, pT1cN0M0). After breast conservative surgery in December 2009, conservative radiotherapy to the right breast was performed (50 Gy in 25 fractions). Portal skin showed no serious change (up to grade 1 skin erythema) and no bullous neogenesis during conservative radiotherapy. However, 2 months after conservative radiotherapy, new blisters became exacerbated mainly within the irradiated field but also in the area outside the irradiated field. Increasing the dosage of oral steroid and minocycline resulted in relief of bullous pemphigoid, although patchy skin pigmentation remained especially in the irradiated skin.

Background: To investigate the treatment results of intracranial meningiomas treated with hypofractionated stereotactic radiation therapy in three to five fractions., Methods: Thirty-one patients (32 lesions) with intracranial meningioma were treated with hypofractionated stereotactic radiation therapy in three to five fractions using CyberKnife. Fifteen lesions were diagnosed as Grade I (World Health Organization classification) by surgical resection and 17 lesions were diagnosed as meningioma based on radiological findings. The median follow-up time was 48 months. The median planning target volume was 6.3 cm(3) (range, 1.4-27.1), and the prescribed dose (D90≤) ranged from 21 to 36 Gy (median, 27.8) administrated in three to five fractions., Results: Five-year overall and progression-free survival rate of all 31 patients with intracranial meningioma was 86 and 83%, respectively. Five-year progression-free rate of all 32 lesions was 87%. Six of the 31 patients (19%) developed marked peritumoral edema, three of whom were asymptomatic and three symptomatic, the latter with late adverse effects of more than or equal to Grade 3. The mean planning target volume of the six lesions with marked peritumoral edema was 15.6 cm(3), and for the remaining 26 lesions without marked peritumoral edema was 7.1 cm(3) (P = 0.004). The threshold diameter of 2.56 cm for meningioma was calculated from the planning target volume (11 cm(3)) and was used as marker of developing peritumoral edema (P = 0.003)., Conclusions: Tumor volume is a significant indicative factor for peritumoral edema in intracranial meningioma treated with hypofractionated stereotactic radiation therapy in three to five factions.

This report presents initial experience with imaging-aided high-dose-rate interstitial brachytherapy (HDR-ISBT) for post-operative recurrence of uterine carcinoma. Fourteen patients presenting with post-operative recurrence of uterine carcinoma (nine cervix and five corpus) between July 2005 and October 2008 were enrolled in this study (median follow-up: 37 months, range: 6-59 months). We implanted magnetic resonance imaging (MRI)-compatible plastic applicators using our own ambulatory technique. HDR-ISBT treatment consisted of twice-a-day irradiation of 6 Gy each with at least a six-hour interval to provide the total prescribed dose. Treatment was based on treatment planning-computed tomography with MRI as a reference. Seven patients were treated with a combination of ISBT (median 30 Gy/5 fractions; range: 27-33 Gy) and external beam radiation therapy (EBRT), and the other seven with brachytherapy only (median 54 Gy/9 fractions; range: 48-54 Gy), one of whom had previously received pelvic EBRT. The three-year estimates of local control and overall survival rates were 77.9% (95% confidence interval (CI): 55.8-100%) and 77.1% (95% CI: 54.2-100%), respectively. Two patients, who had received combined treatment with EBRT showed untoward reactions, including a grade 3 subileus and grade 2 constipation. Another patient, who had been treated with ISBT alone, developed grade 2 urinary constriction. Our imaging-aided HDR-ISBT for post-operative recurrence of uterine carcinoma was found to be practical with promising preliminary results.

We have developed a polystyrene-based well-of-the-well (WOW) system using injection molding to track individual embryos throughout culture using time-lapse cinematography (TLC). WOW culture of bovine embryos following in vitro fertilization was compared with conventional droplet culture (control). No differences between control- and WOW-cultured embryos were observed during development to the blastocyst stage. Morphological quality and inner cell mass (ICM) and trophectoderm (TE) cell numbers were not different between control- and WOW-derived blastocysts; however, apoptosis in both the ICM and TE cells was reduced in WOW culture (P < 0.01). Oxygen consumption in WOW-derived blastocysts was closer to physiological level than that of control-derived blastocysts. Moreover, WOW culture improved embryo viability, as indicated by increased pregnancy rates at Days 30 and 60 after embryo transfer (P < 0.05). TLC monitoring was performed to evaluate the cleavage pattern and the duration of the first cell cycle of embryos from oocytes collected by ovum pickup; correlations with success of pregnancy were determined. Logistic regression analysis indicated that the cleavage pattern correlated with success of pregnancy (P < 0.05), but cell cycle length did not. Higher pregnancy rates (66.7%) were observed for animals in which transferred blastocysts had undergone normal cleavage, identified by the presence of two blastomeres of the same size without fragmentation, than among those with abnormal cleavage (33.3%). These results suggest that our microwell culture system is a powerful tool for producing and selecting healthy embryos and for identifying viability biomarkers.

Gingipains are secreted endopeptidases important for the virulence and proliferation of Porphyromonas gingivalis; however, their secretion and biogenesis process is not yet fully elucidated. The PG0534 gene of P. gingivalis W83 encodes a novel protein, PG534, of unknown function. In a PG0534 deletion mutant 83K25, the activities of Arg-gingipains (RgpA and RgpB) and Lys-gingipain (Kgp) were reduced to 4-22% of those of the wild-type W83, while the activities of secreted exopeptidases DPPIV, DPP-7, and PTP-A were unaffected. This indicates that PG534 is required for the gingipain activity. Immunoblot analysis using anti-Rgp or anti-Kgp antiserum showed that abnormal forms of gingipains were detected in the extracellular fraction from 83K25, suggesting that 83K25 exhibits dysfunctional gingipain secretory activity. Normal carbohydrate biogenesis of lipopolysaccharide is required for production of the active gingipains; however, lipopolysaccharide was not deficient in 83K25. Subcellular fractionation and immunoblot analysis using anti-PG534 antiserum localized PG534 to the outer membrane. In conclusion, we identified PG534 as a novel outer membrane protein required for the biogenesis of gingipains.

Although the use of small segments in step and shoot IMRT provides better dose distribution, extremely small segments decrease treatment accuracy. The purpose of this study was to determine the optimum minimum segment size (MSS) in two-step optimization in prostate step and shoot IMRT with regard to both planning quality and dosimetric accuracy. The XiO treatment planning system and Oncor Impression Plus were used. Results showed that the difference in homogeneity index (HI), defined as the ratio of maximum to minimum doses for planning target volume, between the MSS 1.0 cm and 1.5 cm plans, and 2.0 cm plans, was 0.1%, and 9.6%, respectively. With regard to V107 of PTV, the volume receiving 107% of the prescribed dose of the PTV, the difference between MSS 1.0 cm and 1.5 cm was 2%. However, the value of the MSS 2.0 cm or greater plans was more than 2.5-fold that of the MSS 1.0 cm plan. With regard to maximum rectal dose, a significant difference was seen between the MSS 1.5 cm and 2.0 cm plans, whereas no significant difference was seen between the MSS 1.0 cm and 1.5 cm plans. Composite plan verification revealed a greater than 5% dose difference between planned and measured dose in many regions with the MSS 1.0 cm plan, but in only limited regions in the MSS 1.5 cm plan. Our data suggest that the MSS should be determined with regard to both planning quality and dosimetric accuracy.

Porphyromonas gingivalis transports Arg-gingipains and Lys-gingipain across the outer membrane via an unknown pathway. Recently, we found that the sov gene of P. gingivalis W83 was required for this step. In the present study, we characterized the Sov protein. We constructed a P. gingivalis strain that expresses histidine-tagged Sov instead of Sov. Subcellular fractionations and a histidine-tag pulldown experiment showed that histidine-tagged Sov was present in an outer membrane fraction. Furthermore, antiserum raised against the terminal regions of Sov obstructed the secretion of Arg-gingipains from wild-type W83 cells. A deletion study showed that the region from Phe2495 to the C-terminus Gln2499 of Sov is essential for gingipain secretion. Anti-histidine-tag immunoglobulins interfered with the secretion of Arg-gingipains by P. gingivalis cells that expressed histidine-tagged Sov. In conclusion, we found that Sov is an outer membrane protein participating in the secretion of gingipains and that the C-terminal region of Sov is exposed to the extracellular milieu and involved in the modulation of Sov function.

The qpo gene of Aggregatibacter actinomycetemcomitans encodes a triheme c-containing membrane-bound enzyme, quinol peroxidase (QPO) that catalyzes peroxidation reaction in the respiratory chain and uses quinol as the physiological electron donor. The QPO of A. actinomycetemcomitans is the only characterized QPO, but homologues of the qpo gene are widely distributed among many gram-negative bacteria, including Haemophils ducreii, Bacteroides fragilis, and Escherichia coli. One-third of the amino acid sequence of QPO from the N-terminal end is unique, whereas two-thirds of the sequence from the C-terminal end exhibits high homology with the sequence of the diheme bacterial cytochrome c peroxidase. In order to obtain sufficient protein for biophysical studies, the present study aimed to overproduce recombinant QPO (rQPO) from A. actinomycetemcomitans in E. coli. Coexpression of qpo with E. coli cytochrome c maturation (ccm) genes resulted in the expression of an active QPO with a high yield. Using purified rQPO, we determined the midpoint reduction potentials of the three heme molecules.

Phosphoglucosamine mutase (GlmM; EC 5.4.2.10) catalyzes the interconversion of glucosamine-6-phosphate to glucosamine-1-phosphate, an essential step in the biosynthetic pathway leading to the formation of the peptidoglycan precursor uridine 5'-diphospho-N-acetylglucosamine. We have recently identified the gene (glmM) encoding the enzyme of Streptococcus gordonii, an early colonizer on the human tooth and an important cause of infective endocarditis, and indicated that the glmM mutation in S. gordonii appears to influence bacterial cell growth, morphology, and sensitivity to penicillins. In the present study, we assessed whether the glmM mutation also affects escape from polymorphonuclear leukocyte (PMN)-dependent killing. Although no differences in attachment to human PMNs were observed between the glmM mutant and the wild-type S. gordonii, the glmM mutation resulted in increased sensitivity to PMN-dependent killing. Compared with the wild type, the glmM mutant induced increased superoxide anion production and lysozyme release by PMNs. Moreover, the glmM mutant is more sensitive to lysozyme, indicating that the GlmM may be required for synthesis of firm peptidoglycans for resistance to bacterial cell lysis. These findings suggest that the GlmM contributes to the resistance of S. gordonii to PMN-dependent killing. Enzymes such as GlmM could be novel drug targets for this organism.

Porphyromonas gingivalis secretes endopeptidase gingipains, which are important virulence factors of this bacterium. Gingipains are transported across the inner membrane via the Sec system, followed by transport across the outer membrane via an unidentified pathway. The latter transport step is suggested to be mediated via a novel protein secretion pathway. In the present study, we report a novel candidate as an essential factor for the latter transport step. The PG0027 gene of P. gingivalis W83 encodes novel protein PG27. In a PG0027 deletion mutant (83K10), the activities of Arg-gingipain and Lys-gingipain were severely reduced, while the activities of secreted exopeptidases DPPIV, DPP-7, and PTP-A were unaffected. Protein localization was investigated by cell-surface biotinylation, subcellular fractionation, and immunoblot analysis. In the wild-type W83, Arg-gingipains in membrane fraction were detected as cell surface proteins. In contrast, in 83K10, Arg-gingipains were trapped in the periplasm and hardly secreted into an extracellular milieu. PG27 was suggested to be exposed to the cell surface by a cell surface biotinylation experiment; however, PG27 was detected in both inner and outer membrane fractions by subcellular fractionation experiments. Taken together, we suggest that PG27 is a unique membrane protein essential for a novel secretion pathway.

Aggregatibacter actinomycetemcomitans is an oral pathogen causing localized aggressive periodontitis (LAP). Recently, we characterized for the first time a quinol peroxidase (QPO) that catalyzes peroxidase activity using quinol in the respiratory chain of A. actinomycetemcomitans for the reduction of hydrogen peroxide. In the present study, we characterized the phenotype of a QPO null mutant. The QPO null mutant shows an oxidative stress phenotype, suggesting that QPO plays a certain role in scavenging endogenously generated reactive oxygen species. Notably, we discovered that the QPO null mutant exhibits a production defect of leukotoxin (LtxA), which is a secreted bacterial toxin and is known to target human leukocytes and erythrocytes. This result suggests that QPO would be considered as a potential drug target to inhibit the expression of LtxA from A. actinomycetemcomitans for the treatment and prevention of LAP.

Maternal smoking during pregnancy can result in both pregnancy complications and reduced size of the fetus and neonate. Among women who smoke, genetic susceptibility to tobacco smoke also is a likely causative factor in adverse pregnancy outcomes. A prospective cohort study was conducted among 460 pregnant women who delivered live singletons in Sapporo, Japan, from 2002 to 2005. Multiple linear regression models were used to estimate associations of maternal smoking and polymorphisms in two genes encoding N-nitrosamine-metabolizing enzymes-NAD(P)H: quinone oxidoreductase 1 (NQO1) and cytochrome P-450 2E1 (CYP2E1)-with birth size. Among infants born to smokers with the NQO1 homozygous wild-type allele, birth weight, birth length, and birth head circumference were significantly reduced (p < 0.01 for each factor). For the homozygous wild-type CYP2E1 allele, birth weight was lower by an estimated 195 g (standard error, 55; p < 0.001) among smokers. These genotypes did not confer adverse effects among women who had never smoked or who quit smoking during the first trimester. The adverse effects of maternal smoking on infant birth size may be modified by maternal genetic polymorphisms in N-nitrosamine-metabolizing enzymes among Japanese subjects. These results may help in directing smoking cessation interventions during pregnancy, especially among susceptible women.

Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is transcribed into three types of mRNA, mitochondrial, non-mitochondrial and nucleolar types, from one gene by alternative transcription using different first exons, Ia and Ib. We investigated the regulatory mechanisms of the expressions of the three types of PHGPx using promoter analysis with luciferase as the reporter gene and electrophoretical mobility shift analysis. Here we report a draft of the positive regulatory region and the core promoter regions of PHGPx in several cell lines. From promoter deletion analysis we identified the three distinct core regions of mitochondrial PHGPx, non-mitochondrial PHGPx and nucleolar PHGPx. The core promoter activity of non-mitochondrial PHGPx was high in L929 cells, but relatively low for mitochondrial and nucleolar PHGPx. We also identified the positive regulatory region of mitochondrial PHGPx by deletion and mutation analysis of 5'-flanking regions of mitochondrial PHGPx. This region could regulate the promoter activity of non-mitochondrial PHGPx; however, up-regulation by this region was normally suppressed by the upstream region in somatic cells. Electrophoretical mobility shift analysis demonstrated that a specific transcription factor complex bound to this region in adult testis, but not in young testis and different sizes of complexes bound to this region between testis and brain.

Cytolethal distending toxin (CDT) is one of the exotoxins produced by Actinobacillus actinomycetemcomitans, an agent of localized aggressive periodontitis. We constructed N-terminal deletion mutants of CdtA using an Escherichia coli expression system and found that ADelta19-47, with a deletion from Asn-19 to Pro-47, showed comparable CDT activity but no apparent heterogeneity of CdtA. The wild-type CDT (wtCDT) and the mutant CDT (ADelta19-47CDT) were purified to homogeneity by introducing a histidine tag into the C-terminal end of CdtB. Both purified wtCDT and purified ADelta19-47CDT showed strong CDT activity and a tripartite structure composed of CdtA (subunit A), 31 kDa CdtB (subunit B), and 18.5 kDa CdtC (subunit C) in nearly a 1:1:1 stoichiometry. Importantly, subunit A was identified as heterogeneous with three CdtA variants in wtCDT, but homogeneous in ADelta19-47CDT. Purified CDTs also showed high stability that was absolutely dependent on the presence of sucrose in the buffer. In conclusion, the region from the Asn-19 to Pro-47 of CdtA contributes to the heterogeneous production of CdtA, but is dispensable for the toxin activity. Furthermore, this study describes an effective protocol for the purification of a native rather than reconstituted CDT, and clarifies the subunit composition of the active CDT holotoxin.