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Background: Severe pediatric cases of hand, foot, and mouth disease (HFMD), herpangina (HA), and associated complications caused by enterovirus 71 (EV71) infection have brought substantial public health impact in Asia. This study aimed to elucidate the epidemiology of these pediatric cases in Japan. Methods: A nationwide survey was conducted using stratified random sampling of hospital pediatric departments. We estimated the number of inpatients with HFMD, HA, and associated complications between April 1 and September 30, 2010, during which EV71 was circulating predominantly. Factors associated with severe cases with ≥7 days of admission, sequelae, or outcome of death were analyzed using multivariate logistic regression. Results: During the 6-month epidemic period, the number of pediatric inpatients aged

André Lins de Medeiros,1 Flavio Jones Saraiva,2 Camila Ishii Iguma,2 Danilo Varela Kniggendorf,1 Guilherme Alves,2 Mario Augusto Pereira Dias Chaves,1 Cesar Vilar,1 Antonio Francisco Pimenta Motta,1 Pedro Carlos Carricondo,1 Celso Takashi Nakano,1 Walton Nosé,1 Wilson Takashi Hida1,21Cataract Sector, Renato Ambrosio Eye Research Center, Brasília, DF, Brazil; 2Cataract Sector, Hospital Oftalmológico De Brasília, Brasília, DF, BrazilCorrespondence: André Lins de MedeirosRenato Ambrosio Eye Research Center, SGAS 607, Hospital Oftalmológico de Brasilia, Brasília 70200-670, BrazilTel +55 5 804 5530Email andre_linz@msn.comPurpose: The aim of this study was to compare the visual outcomes and subjective visual quality between bilateral implantation of an extended depth of focus intraocular lens, J&J Vision Tecnis Symfony® ZXR00 (Group A) and bilateral implantation of a diffractive trifocal intraocular lens, Alcon Acrysof IQ PanOptix® TNFT00 (Group B).Methods: This prospective, nonrandomized, comparative study of consecutive cases assessed 52 eyes of 26 patients operated on by the same surgeon (WTH) and binocularly implanted with multifocal intraocular lenses between May 2016 and July 2018. Binocular visual acuity for far, intermediate and near was tested in all cases. Ophthalmological evaluation included the measurement of binocular uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA) at 40 cm, uncorrected intermediate visual acuity (UIVA) at 70 cm, monocular visual defocus curve and the quality of life (QoL) questionnaire, National Eye Institute Visual Functioning Questionnaire - 25 ( NEI-VFQ 25).Results: Postoperative UDVA was 0.00 and 0.09 logMAR (P

Abstract Background We compared clinical outcomes of carbon ion radiotherapy and transarterial chemoembolization in the treatment of hepatocellular carcinoma. Methods Data of 477 patients with hepatocellular carcinoma who had undergone carbon ion radiotherapy or transarterial chemoembolization between April 2007 and September 2016 were retrospectively reviewed. Treatment naïve patients with single HCC, who underwent carbon ion radiotherapy or transarterial chemoembolization as a primary treatment were included. Clinical outcomes of the treatments were compared after utilizing propensity score matching. Results Of 124 patients who received carbon ion radiotherapy and 353 patients who received transarterial chemoembolization, 31 and 23 patients met our inclusion criteria, respectively. After utilizing propensity score matching, 17 matched pairs of patients from each treatment group were analyzed. The median follow-up durations after carbon ion radiotherapy and transarterial chemoembolization were 43 and 32 months, respectively. The 3-year overall survival, local control, and progression-free survival rates in the carbon ion radiotherapy versus transarterial chemoembolization groups were 88% versus 58% (p

The Japanese government approved COVID-19 vaccine booster doses in November 2021. However, intentions and readiness for booster vaccines among the general population were unknown. This survey measured the intentions for COVID-19 booster vaccination. Among 6172 participants (53.2% female), 4832 (78.3%) accepted booster doses; 415 (6.7%) hesitated. Vaccination intention was associated with higher age, marital status, having children, underlying diseases, and social norms. To evaluate the readiness for vaccination, the seven component (7C) vaccination readiness scale was employed, comprising “Confidence”, “Complacency”, “Constraints”, “Calculation”, “Collective responsibility”, “Compliance”, and “Conspiracy”. Participants with acceptance showed significantly higher 7C scores (p < 0.001) than those who hesitated or were unsure. Multivariable logistic regression analysis revealed that the “social norms” predictor was the strongest predictor of acceptance (adjusted odds ratio (AOR) 4.02, 95% confidence interval (CI): 3.64–4.45). “Constraints” (AOR: 2.27, 95% CI: 2.11–2.45) and “complacency” (AOR: 2.18, 95% CI: 2.03–2.34) were also strongly associated with acceptance, but “compliance” (AOR: 1.24, 95% CI: 1.18–1.31) and “conspiracy” (AOR: 1.42, 95% CI: 1.33–1.52) were weakly associated. The “7C vaccination readiness scale” is useful for measuring vaccine acceptance in the Japanese population. However, “social norms” might be more suitable than “compliance” and “conspiracy” for measuring vaccine acceptance in Japan.

Background: With the goal of global eradication of poliomyelitis due to wild-type viruses within sight, WHO now recommends that infants receive at least one dose of trivalent inactivated poliovirus vaccine (IPV) with bivalent OPV (types 1 and 3) replacing trivalent OPV. Limited manufacturing capacity and new regulations on manufacturers’ use of wild-type viruses is driving the development of IPV based on attenuated Sabin type polioviruses. Takeda are developing a Sabin-based IPV (sIPV) to augment global capacity and supply. Methods: This study was performed to evaluate three dosages (low, medium and high) of the sIPV when administered as a combination vaccine with diphtheria-tetanus-acellular pertussis antigens (DTaP-sIPV) as a three dose primary series or as booster dose in Japanese infants and toddlers. Results: All formulations were immunogenic and well-tolerated with no safety concerns in either infants or toddlers. There was a dosage-dependent induction of neutralizing antibodies against Sabin polioviruses, the only statistically significant differences being between the low-dose and medium- and high-dose sIPVs. There was good correlation of neutralizing antibodies against Sabin and wild-type polioviruses. No sIPV dose had an observable effect on immune responses to DTaP components or the reactogenicity profile of the combined vaccine. Conclusion: When administered as a DTaP-sIPV combination, Takeda’s sIPV vaccine was well-tolerated and highly immunogenic in infant and toddler schedules. The medium-dose formulation offers the optimal balance between immunogenicity and potential dose-sparing to provide a new source of sIPV to enhance the global supply, while mitigating the environmental risks associated with manufacturing vaccines with wild-type viruses.

BackgroundMedical chart documentation is an essential skill acquired in a clinical clerkship (CC). However, the utility of medical chart writing simulations as a component of the objective structured clinical examination (OSCE) has not been sufficiently evaluated. In this study, medical chart documentation in several clinical simulation settings was performed as part of the OSCE, and its correlation with CC performance was evaluated.MethodsWe created a clinical situation video and images involving the acquisition of informed consent, cardiopulmonary resuscitation, and diagnostic imaging in the emergency department, and assessed medical chart documentation performance by medical students as part of the OSCE. Evaluations were conducted utilizing original checklist (0-10 point). We also analyzed the correlation between medical chart documentation OSCE scores and CC performance of 120 medical students who performed their CC in 2019 as 5th year students and took the Post-CC OSCE in 2020 as 6th year students.ResultsOf the OSCE components, scores for the acquisition of informed consent and resuscitation showed significant correlations with CC performance (PConclusionWe conducted a correlation analysis of CC performance and the quality of medical chart documentation in a simulation setting. Our results suggest that medical chart documentation can be one possible alternative component in the OSCE.

The accuracy and correspondence between the measured concentrations from the survey and predicted concentrations on the basis of the three types of statistical antimicrobial use in Japan was evaluated. A monitoring survey of ten representative antimicrobials: ampicillin (APL), cefdinir (CDN), cefpodoxime proxetil (CPXP), ciprofloxacin (CFX), clarithromycin (CTM), doxycycline (DCL), levofloxacin (LFX), minocycline (MCL), tetracycline (TCL), and vancomycin (VMC), in the influent of sewage treatment plant (STP) located in urban areas of Japan, was conducted. Then, the measured values were verified in comparison with the predicted values estimated from the shipping volumes, sales volumes, and prescription volumes based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). The results indicate that the correspondence ratios between the predicted concentrations calculated on the basis of shipping and NDB volumes and the measured concentrations (predicted concentration/measured concentration) generally agreed for the detected concentration of antimicrobials in the STP influent. The correspondence ratio on the basis of shipping volume was, for CFX, 0.1; CTM, 2.9; LFX, 0.5; MCL, 1.9; and VMC, 1.7, and on the basis of NDB volume the measured concentration was CFX, 0.1; CTM, 3.7; DCL, 0.4; LFX, 0.7; MCL, 1.9; TCL, 0.6; and VMC, 1.6. To our knowledge, this is the first report to evaluate the accuracy of predicted concentrations based on sales, shipping, NDB statistics and measured concentrations for antimicrobials in the STP influent.

Understanding vaccine hesitancy, considering the target region and phase, is an urgent issue to quell the coronavirus disease (COVID-19) pandemic. This study aimed to monitor COVID-19 vaccine hesitancy in the Japanese population during the three phases of vaccine approval and introduction, and evaluate the association of vaccine hesitancy with vaccine confidence and literacy. We conducted web-based cross-sectional surveys during the three phases of COVID-19 vaccine introduction: January 2021, before approval; June, start of vaccination of the elderly; and September, when about 70% of the target population was vaccinated with at least one dose. There were 7210 participants, aged 20–80 years. We evaluated the association of vaccine hesitancy with vaccine confidence and literacy in the three phases using multivariate logistic regression analysis. The proportion of hesitancy in January, June, and September was 17.5%, 65.3%, and 19.4%, respectively. In any phase, lower vaccine confidence and literacy showed a higher adjusted odds ratio (AOR) of vaccine hesitancy in most items (AOR > 1, p < 0.001). Vaccine hesitancy in June had a different trend in perception of COVID-19 compared to that in the January and September surveys. The findings suggested that hesitancy increases transiently during vaccination introduction phases, and changes as the vaccination program progressed or waves of epidemic. Careful risk communication to increase vaccine confidence and literacy is essential to reduce vaccine hesitancy, especially in the introduction phase.

Purpose: We quantified the inter-fractional changes associated with passive carbon-ion radiotherapy using vertical and horizontal beam fields for prostate cancer.Methods: In total, 118 treatment-room computed tomography (TRCT) image sets were acquired from 10 patients. Vertical (anterior–posterior) and horizontal (left–right) fields were generated on the planning target volume identified by treatment planning CT. The dose distribution for each field was recalculated on each TRCT image set at the bone-matching position and evaluated using the dose–volume parameters for the prostate and rectum V95 values. To confirm adequate margins, we generated vertical and horizontal fields with 0-, 2-, 4-, and 6-mm isotropic margins from the prostate and recalculated the dose distributions on all TRCT image sets. Sigmoid functions were fitted to a plot of acceptable ratios (that is, when prostate V95 > 98%) vs. the isotropic margin size to identify the margin at which this ratio was achieved in 95% of patients with a vertical or horizontal field.Results: The prostate V95 values (mean ± standard deviation) were 99.89 ± 0.62% and 99.99 ± 0.00% with vertical and horizontal fields, respectively; this difference was not statistically significant (p = 0.067). The rectum V95 values were 1.93 ± 1.25 and 1.88 ± 0.96 ml with vertical and horizontal fields, respectively; the difference was not statistically significant (p = 0.432). The estimated adequate margins were 2.2 and 3.0 mm for vertical and horizontal fields, respectively.Conclusions: Although there is no significant difference, horizontal fields offer higher reproducibility for prostate dosing than vertical fields in our clinical setting, and 3.0 mm was found to be an adequate margin for inter-fractional changes.

The application of annihilation gamma-ray monitoring to the adaptive therapy of carbon ion radiotherapy (C-ion RT) requires identification of the peak intensity position and confirmation of activated elements with annihilation gamma-rays generated at the C-ion-irradiated site from those transported to unirradiated sites. Real-time monitoring of C-ion-induced annihilation gamma-rays was implemented using a Compton camera in a mouse model. An adult C57BL/6 mouse was anesthetized, and C-ion beams were directed into the abdomen at 1 × 109 particles/s for 20 s. The 511 keV annihilation gamma-rays, generated by the interaction between the irradiated C-ion beam and the target mouse, were detected using a silicon/cadmium telluride (Si/CdTe) Compton camera for 20 min immediately after irradiation. The irradiated site and the peak intensity position of 511 keV gamma emissions due to C-ion beam irradiation on a mouse were observed at the abdomen of the mouse by developing Compton images. Moreover, the positron emitter transport was observed by evaluating the range of gamma-ray emission after the C-ion beam irradiation on the mouse. Our data suggest that by confirming the peak intensity and beam range of C-ion RT with Si/CdTe-based Compton camera, it would be possible to reduce the intra-fractional and inter-fractional dose distribution degradation. Therefore, the results of this study would contribute to the future development of adaptive therapy with C-ion RT for humans.

Human habenula studies are gradually advancing, primarily through the use of functional magnetic resonance imaging (fMRI) analysis of passive (Pavlovian) conditioning tasks as well as probabilistic reinforcement learning tasks. However, no studies have particularly targeted aversive prediction errors, despite the essential importance for the habenula in the field. Complicated learned strategies including contextual contents are involved in making aversive prediction errors during the learning process. Therefore, we examined habenula activation during a contextual learning task. We performed fMRI on a group of 19 healthy controls. We assessed the manually traced habenula during negative outcomes during the contextual learning task. The Beck Depression Inventory-Second Edition (BDI-II), the State-Trait-Anxiety Inventory (STAI), and the Temperament and Character Inventory (TCI) were also administered. The left and right habenula were activated during aversive outcomes and the activation was associated with aversive prediction errors. There was also a positive correlation between TCI reward dependence scores and habenula activation. Furthermore, dynamic causal modeling (DCM) analyses demonstrated the left and right habenula to the left and right hippocampus connections during the presentation of contextual stimuli. These findings serve to highlight the neural mechanisms that may be relevant to understanding the broader relationship between the habenula and learning processes.

Resting-state fMRI has the potential to help doctors detect abnormal behavior in brain activity and to diagnose patients with depression. However, resting-state fMRI has a bias depending on the scanner site, which makes it difficult to diagnose depression at a new site. In this paper, we propose methods to improve the performance of the diagnosis of major depressive disorder (MDD) at an independent site by reducing the site bias effects using regression. For this, we used a subgroup of healthy subjects of the independent site to regress out site bias. We further improved the classification performance of patients with depression by focusing on melancholic depressive disorder. Our proposed methods would be useful to apply depression classifiers to subjects at completely new sites.

We recently reported the dose-dependent therapeutic effect of 211At-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of 211At-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of 211At-NaAt was measured in normal ICR mice (n = 12), absorbed doses in the major organs were calculated. Groups of ICR mice (n = 60) were injected with 0.1 MBq or 1 MBq of 211At-NaAt, using saline as the control group (n = 30). Body weight and food intake were followed up for 60 days. Blood cell counts and serum level of biochemical parameters were measured 3, 7, 15, 29, 60 days after injection. Histological analyses of the major organs with hematoxylin and eosin staining were performed. Biodistribution study revealed a high-absorbed dose in the thyroid gland, stomach, bladder, heart, lungs, spleen, kidneys, and testis. The 0.1 MBq group showed no abnormalities. The 1 MBq group showed decreased body weight and food intake. Histological analysis showed atrophy and fibrosis in the thyroid gland, a transient hypospermatogenesis in the testis on day 29 was found in one mouse. Hematological toxicity was mild and transient. The total cholesterol, albumin, and total protein increased with no signs of recovery, which was considered to be caused by hypothyroidism. High-dose administration of 211At-NaAt showed transient toxicity in the white blood cells and testis without severe hematological or renal toxicity, suggesting its tolerable safety as targeted alpha-therapy for differentiated thyroid cancer in the 1 MBq group.

A Compton camera is a device for imaging a radio-source distribution without using a mechanical collimator. Ordered-subset expectation-maximization (OS-EM) is widely used to reconstruct Compton images. However, the OS-EM algorithm tends to over-concentrate and amplify noise in the reconstructed image. It is, thus, necessary to optimize the number of iterations to develop high-quality images, but this has not yet been achieved. In this paper, we apply a median filter to an OS-EM algorithm and introduce a median root prior expectation-maximization (MRP-EM) algorithm to overcome this problem. In MRP-EM, the median filter is used to update the image in each iteration. We evaluated the quality of images reconstructed by our proposed method and compared them with those reconstructed by conventional algorithms using mathematical phantoms. The spatial resolution was estimated using the images of two point sources. Reproducibility was evaluated on an ellipsoidal phantom by calculating the residual sum of squares, zero-mean normalized cross-correlation, and mutual information. In addition, we evaluated the semi-quantitative performance and uniformity on the ellipsoidal phantom. MRP-EM reduces the generated noise and is robust with respect to the number of iterations. An evaluation of the reconstructed image quality using some statistical indices shows that our proposed method delivers better results than conventional techniques.

BackgroundIt is unclear how comprehensive evaluations conducted prior to clinical clerkships (CC), such as the objective structured clinical examination (OSCE) and computer-based testing (CBT), reflect the performance of medical students in CC. Here we retrospectively analyzed correlations between OSCE and CBT scores and CC performance.MethodsEthical approval was obtained from our institutional review board. We analyzed correlations between OSCE and CBT scores and CC performance in 94 medical students who took the OSCE and CBT in 2017 when they were 4th year students, and who participated in the basic CC in 2018 when they were 5th year students.ResultsTotal scores for OSCE and CBT were significantly correlated with CC performance (PConclusionOur findings suggest that the OSCE and CBT play important roles in predicting CC performance in Japanese medical education context. Among OSCE components, medical interview and chest examination were suggested to be important for predicting CC performance.

Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans.

Abstract Background Carbon-ion radiotherapy (C-ion RT) provides better dose distribution in cancer treatment compared to photons. Additionally, carbon-ion beams provide a higher biological effectiveness, and thus a higher tumor control probability. However, information regarding the dose constraints for organs at risk in C-ion RT is limited. This study aimed to determine the predictive factors for late morbidities in the rectum and bladder after carbon-ion C-ion RT for uterus carcinomas. Methods Between June 1995 and January 2010, 134 patients with uterus carcinomas were treated with C-ion RT with curative intent; prescription doses of 52.8–74.4 Gy (relative biological effectiveness) were delivered in 20–24 fractions. Of these patients, 132 who were followed up for > 6 months were analyzed. We separated the data in two subgroups, a 24 fractions group and a 20 fractions group. Late morbidities, proctitis, and cystitis were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. The correlations of clinical and dosimetric parameters, V10–V60, D5cc, D2cc, and Dmax, with the incidence of ≥grade 1 morbidities were retrospectively analyzed. Results In the 24 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 64 and 9%, respectively. In addition, in the 20 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 32 and 19%, respectively. Regarding the dose–volume histogram data on the rectum, the D5cc and D2cc were significantly higher in patients with ≥grade 1 proctitis than in those without morbidity. In addition, the D5cc for the bladder was significantly higher in patients with ≥grade 1 cystitis than in those without morbidity. Results of univariate analyses showed that D2cc of the rectum was correlated with the development of ≥grade 1 late proctitis. Moreover, D5cc of the bladder was correlated with the development of ≥grade 1 late cystitis. Conclusions The present study identified the dose–volume relationships in C-ion RT regarding the occurrence of late morbidities in the rectum and bladder. Assessment of the factors discussed herein would be beneficial in preventing late morbidities after C-ion RT for pelvic malignancies. Trial registration Retrospectively registered (NIRS: 16–040).

Increasing the biodiversity in plantations of trees is an important issue because plantations have replaced many natural and semi-natural ecosystems worldwide. Therefore, identifying appropriate management techniques and key factors for enhancing biodiversity in plantations is required. We surveyed butterfly assemblages along forest trails in both plantations and natural forests and measured various environmental variables, including canopy, sub canopy and shrub stem densities, percentage of deciduous trees, flower plant richness, host plant richness, canopy openness and distance to forest edge. We hypothesized that (1) flower and host plant richness increase with an increase in the percentage of deciduous trees and canopy openness; (2) butterfly richness and abundance increase with an increase in forest structural complexity, butterfly resources, canopy openness and distance to forest edge; (3) the responses of plants and butterflies to canopy openness differ in plantations and natural forests; and (4) in plantations, tree-feeding butterflies respond to canopy openness less strongly than herbaceous plant feeding butterflies do because of the low diversity of trees in plantations. Our results generally support these hypotheses. Butterfly resources and butterfly richness and abundance all increase with increasing canopy openness; however, the increases were usually more dramatic in natural forests than in plantations and other factors are less important. In plantations, herbaceous plant feeding butterflies responded to increasing canopy openness more strongly than tree-feeding butterflies. The results of the present study indicate the importance of sunlit forest trails in enhancing butterfly resources, butterfly richness and abundance in plantations. Because at the stand-level management is labour- and cost-intensive, labour- and cost-saving trail management options need to be explored further in terms their effectiveness in increasing biodiversity in plantations.

Little is known about the differences in coronavirus disease (COVID-19) vaccine acceptance and hesitancy between the general population and healthcare workers in Japan. To compare these differences, a nationwide web-based cross-sectional survey was conducted on 19 January 2021, shortly before the initiation of COVID-19 vaccinations in Japan. A total of 6180 men and women aged 20–69 years and 1030 healthcare workers aged 20–69 years were enrolled. Data on COVID-19 vaccine acceptance, basic characteristics, including socioeconomic factors, and confidence in immunization in general were collected. COVID-19 vaccine acceptance was also evaluated under hypothetical vaccine effectiveness and adverse event frequencies. Factors associated with vaccine hesitancy were examined using multinomial logistic regression analysis. The COVID-19 vaccine acceptance rate was 48.6% among the general population and was lower among nurses (45.5%) and medical clerks (40.7%). Women and young adults had significantly higher COVID-19 vaccine hesitancy odds ratios, and current smokers had significantly lower odds ratios. The frequency of adverse events was a COVID-19 vaccine hesitancy factor. Even if these factors were adjusted, COVID-19 vaccine hesitancy among nurses was 1.4 times higher than that among the general population. Thus, interventions to improve health literacy and vaccine hesitancy among the general population and healthcare workers, especially nurses, are needed.

PD-L1 is upregulated in many cancers due to exogenous cellular stress. Here the authors show that PD-L1 is upregulated in response to DNA double strand breaks via STAT and IRF1 signalling.

Abstract Background To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC). Methods Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status ≤2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (Version 4.0). Results Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4–55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80–95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively. The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication. Conclusions C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma. Trial registration UMIN000020571 : date of registration, 14 January 2016, retrospectively registered.

Abstract Background The skin is considered a critical organ at risk in carbon ion radiotherapy (CIRT) for locally advanced malignant bone and soft tissue tumors (MBSTs). The predictive factors for acute skin reactions after CIRT have not been investigated. The present study aimed to identify these factors and evaluate the correlation between the severity of acute skin reactions and skin dose parameters. Methods CIRT with total doses of 64.0–70.4 Gy (relative biological effectiveness [RBE]) was administered to 22 patients with MBSTs. The skin-tumor distance (STD), maximum skin total dose (Dmax), and area of the skin receiving a total dose of X Gy (RBE) were evaluated. Results All patients developed acute skin reactions after CIRT, including Grades 1 and 2 dermatitis in 15 (71%) and 6 (29%) patients, respectively. There was a significant difference in the STD between the two groups (P = 0.007), and the cut-off value of STD for predicting Grade 2 acute skin reactions was 11 mm. There was a significant difference in Dmax between the groups (P

Abstract Objective The celiac trunk normally has three branches; i.e. the left gastric, splenic, and common hepatic artery. It is known that the right hepatic artery occasionally branches from the superior mesenteric artery, while the cystic artery arising from the superior mesenteric artery is extremely rare. A deeper understanding of cystic arterial variations is necessary for all physicians performing examinations and surgical procedures of the hepatobiliary system. Results The cystic artery arising from the superior mesenteric artery was found in the cadaver of an 86-year-old woman during an anatomy dissection class at Aichi Medical University in 2015. In this case, the cystic artery ran along the dorsal side of the portal vein through Calot’s triangle to the gallbladder. The celiac trunk had four abnormal branches, one each to the left gastric, right hepatic, splenic, and left hepatic artery. The middle colic artery was absent and the left colic artery branching from the inferior mesenteric artery was distributed along the whole length of the transverse colon. In all cases of the cystic artery arising from the superior mesenteric artery, the vessel ran along the dorsal side of the portal vein; in addition, the right hepatic artery arose from the superior mesenteric artery.

We evaluated isolates obtained from children with Mycoplasma pneumoniae infection throughout Japan during 2008–2015. The highest prevalence of macrolide-resistant M. pneumoniae was 81.6% in 2012, followed by 59.3% in 2014 and 43.6% in 2015. The prevalence of macrolide-resistant M. pneumoniae among children in Japan has decreased.

Mouthpieces are used to fix the positions of the lower jaw and teeth during carbon-ion radiotherapy for head and neck tumors. We used a customized mouthpiece to reduce radiation mucositis by displacing the tongue. Acute radiation mucositis gradually increased for the palate and tongue after approximately six irradiation fractions (maximal mean grade: palate, 2.5 during radiation fractions 15; tongue, 0.8 during radiation fractions 12 and 13). The mean grade of mucositis was significantly lower for the tongue than for the palate from irradiation fraction six until two weeks after irradiation. Keywords: Carbon-ion radiotherapy, Head and neck tumor, Customized mouthpiece

Purpose: To assess the feasibility of applying trans-applicator intracavitary ultrasonography to image-guided brachytherapy for cervical cancer. Material and methods : For this experiment, a phantom was created and included a polyethylene tube, intended to simulate a tandem applicator, which was inserted into chicken meat and embedded in agar, along with magnetic reso­nance imaging (MRI)-compatible ovoid applicators. Three-dimensional images of the phantom were obtained using computed tomography (CT), MRI (T2-weighted), and intracavitary ultrasonography sectional images acquired at 1 mm slice intervals. Intracavitary ultrasonography images were acquired from within the simulated tandem applicator using a radial transducer. Magnetic resonance imaging and intracavitary ultrasonography images were manually registered onto CT images. The chicken meat was contoured as the target volume independently on the CT, MRI, and intracavitary ultrasonography images, and the Dice similarity coefficient was used to compare the target volumes. The dose distributions of a sample brachytherapy plan were also evaluated. Results : Computed tomography, MRI, and intracavitary ultrasonography all visualized the three-dimensional phantom volumes. Intracavitary ultrasonography images depicted the meat with high echoic signals and a border clearly distinguishable from the surrounding agar. The Dice similarity coefficient values for the target volumes on CT vs. MRI, CT vs. intracavitary ultrasonography, and MRI vs. intracavitary ultrasonography were 0.966, 0.965, and 0.971, respectively, indicating similar contouring with the three modalities. Among the modalities, the differences in D 50 , D 90 , D 98 , and D 100 values were 1.8%, 2.9%, 3.7%, and 2.9%, respectively. Conclusions : Three-dimensional reconstructed trans-applicator intracavitary ultrasonographic images clearly depicted meat tissue within the phantom, and could thus be used for brachytherapy planning. This study proves the concept of trans-applicator intracavitary ultrasonography for intracavitary brachytherapy. Further research such as development of intracavitary ultrasonography system, 3D reconstruction method, ultrasonography-compatible applicators, and ultrasonography-based target concept is warranted to assess the potential clinical application.

Discretization errors due to the digitization of computed tomography images and the calculation grid are a significant issue in radiation therapy. Such errors have been quantitatively reported for a fixed multifield intensity-modulated radiation therapy using traditional linear accelerators. The aim of this study is to quantify the influence of the calculation grid size on the dose distribution in TomoTherapy. This study used ten treatment plans for prostate cancer. The final dose calculation was performed with “fine” (2.73 mm) and “normal” (5.46 mm) grid sizes. The dose distributions were compared from different points of view: the dose-volume histogram (DVH) parameters for planning target volume (PTV) and organ at risk (OAR), the various indices, and dose differences. The DVH parameters were used Dmax, D2%, D2cc, Dmean, D95%, D98%, and Dmin for PTV and Dmax, D2%, and D2cc for OARs. The various indices used were homogeneity index and equivalent uniform dose for plan evaluation. Almost all of DVH parameters for the “fine” calculations tended to be higher than those for the “normal” calculations. The largest difference of DVH parameters for PTV was Dmax and that for OARs was rectal D2cc. The mean difference of Dmax was 3.5%, and the rectal D2cc was increased up to 6% at the maximum and 2.9% on average. The mean difference of D95% for PTV was the smallest among the differences of the other DVH parameters. For each index, whether there was a significant difference between the two grid sizes was determined through a paired t-test. There were significant differences for most of the indices. The dose difference between the “fine” and “normal” calculations was evaluated. Some points around high-dose regions had differences exceeding 5% of the prescription dose. The influence of the calculation grid size in TomoTherapy is smaller than traditional linear accelerators. However, there was a significant difference. We recommend calculating the final dose using the “fine” grid size.

Summary: BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C-dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR. : Following induction of DNA double-strand break, a pro-end-joining environment is created in G2 by transient 53BP1 phosphorylation and RIF1 recruitment. Here, Isono et al. show that, if timely repair does not ensue, BRCA1 promotes 53BP1 dephosphorylation and RIF1 release, favoring repair by homologous recombination. Keywords: ATM, DNA-end resection, BRCA1, 53BP1, RIF1, PP4C, NHEJ, HR

Background: Rotavirus vaccines were introduced in Japan in November 2011. We evaluated the subsequent reduction of the health-care burden of rotavirus gastroenteritis. Methods: We conducted active surveillance for rotavirus gastroenteritis among children under 5 years old before and after the vaccine introduction. We surveyed hospitalization rates for rotavirus gastroenteritis in children in Tsu City, Mie Prefecture, Japan, from 2007 to 2015 and surveyed the number of outpatient visits at a Tsu City clinic from 2010 to 2015. Stool samples were obtained for rotavirus testing and genotype investigation. We assessed rotavirus vaccine coverage for infants living in Tsu City. Results: In the pre-vaccine years (2007-2011), hospitalization rates for rotavirus gastroenteritis in children under 5 years old were 5.5, 4.3, 3.1 and 3.9 cases per 1000 person-years, respectively. In the post-vaccine years (2011-2015), the rates were 3.0, 3.5, 0.8 and 0.6 cases per 1000 person-years, respectively. The hospitalization rate decreased significantly in the 2013-2014 and 2014-2015 seasons compared to the average of the seasons before vaccine introduction (p < 0.0001). In one pre-vaccine year (2010-2011), the number of outpatient visits due to the rotavirus infection was 66. In the post-vaccine years (2011-2015), the numbers for each season was 23, 23, 7 and 5, respectively. The most dominant rotavirus genotype shifted from G3P[8] to G1P[8] and to G2P[4]. The coverage of one dose of rotavirus vaccine in Tsu City was 56.5% in 2014. Conclusion: After the vaccine introduction, the hospitalization rates and outpatient visits for rotavirus gastroenteritis greatly decreased.

Purpose: Mediastinal and hilar lymph node metastasis is one of the recurrence patterns after definitive treatment of lung cancer. Salvage radiotherapy (RT) can be a treatment option for lymph node metastasis. However, the usefulness of additional RT remains unclear after surgery or RT for the primary lung tumor. We retrospectively evaluated the efficacy and safety of hypofractionated carbon-ion RT for isolated lymph node metastasis.Methods and Materials: Between April 2013 and August 2016, 15 consecutive patients with isolated lymph node metastasis underwent carbon-ion RT. The pretreatment evaluations confirmed the isolated lymph node metastasis and the absence of local recurrence or distant metastasis, which was oligometastatic disease. The median age was 72 (range, 51–83) years, with 11 male patients. The first treatments for primary lung tumors were carbon-ion RT for 8 patients and surgery for 7 patients. There were 9 adenocarcinomas, 4 squamous cell carcinomas, 1 adenosquamous cell carcinoma, and 1 mucoepidermoid carcinoma. Most patients (93%) were irradiated with 52.8 Gy relative biological effectiveness in 12 fractions for 3 weeks. There were no patients treated with concurrent or adjuvant therapy such as chemotherapy, molecular-targeted therapy, or immunotherapy. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0).Results: The median follow-up for surviving patients was 28 months. One patient experienced local lymph node recurrence, and the 2-year local control rate was 92% for all patients. Distant metastasis was observed in 7 patients, and 2-year progression-free survival rate was 47%. During follow-up, there were 4 deaths from lung cancer, and the 2-year overall survival rate was 75%. There were 2 patients with acute grade 2 esophagitis and 2 with late grade 2 cough, which were improved by conservative therapy. There were no other grade 2 or higher adverse events.Conclusions: Hypofractionated carbon-ion RT showed excellent local control and overall survival without severe toxicities in lung cancer patients with isolated lymph node metastasis after surgery or carbon-ion RT for primary lung tumors. A multi-institutional prospective study is required to establish the efficacy and safety of carbon-ion RT.

Background and purpose: Favorable clinical outcomes of carbon-ion radiotherapy for pelvic recurrence of rectal cancer have been described by previous prospective phase I/II and II studies; however, these studies were performed at a single institution. Therefore, we conducted a prospective observational study aimed at exploring whether carbon-ion radiotherapy for post-operative pelvic recurrence of rectal cancer provides a less invasive local treatment strategy with higher cure rates than other anticancer treatments.Materials and methods: Patients (1) with pelvic recurrence of rectal cancer, as confirmed by histology or diagnostic imaging; (2) without distant metastasis; (3) who had undergone curative resection of their primary disease and regional lymph nodes, without gross or microscopic residual disease; and (4) with radiographically measurable tumors were included in this study. The total carbon-ion radiotherapy dose for all patients was 73.6 Gy [relative biological effectiveness (RBE)] administered in 16 fractions once daily for 4 days a week (Tuesday to Friday).Results: A total of 28 patients were enrolled between October 2011 and July 2017. The median follow-up duration was 38.9 months. The 3-year overall survival, local control, and progression-free survival rates were 92, 86, and 31%, respectively. At the time of the analysis, 4 patients had local recurrence, and 7 had died of rectal cancer. None of the patients developed grade 3 or higher acute toxicities. Late toxicities occurred in 2 and 7 patients who developed grade 3 pelvic infection and grade 2 peripheral neuropathy, respectively.Conclusion: Carbon-ion radiotherapy for pelvic recurrence of rectal cancer showed favorable clinical outcomes and is a highly curative and less invasive local treatment.

Purpose: To perform a prospective study to evaluate the efficacy and safety of isolated recurrent tumor re-irradiation with carbon-ion radiotherapy (RT).Methods and Materials: The inclusion criteria were clinically proven recurrent tumors, measurable by computed tomography or magnetic resonance imaging, patients ≥ 16 years old, performance status scores between 0 and 2, isolated tumor at a previously irradiated site, and a life expectancy > 6 months. The exclusion criteria were tumor invasion into the gastrointestinal tract or a major blood vessel, uncontrolled infection, early recurrence (16 months) between the first RT and re-irradiation had significantly better outcomes than the shorter interval group (≤ 16 months).Conclusions: Re-irradiation, using carbon-ion RT with radical intent, had favorable local control and overall survival rates without severe toxicities for selected patients. Re-irradiation has the potential to improve clinical outcomes for isolated, local, recurrent tumors; further investigations are required to confirm the therapeutic efficacy.

The human triceps surae (two gastrocnemii and soleus) has aponeuroses in the proximal and distal aspects, the latter of which insert into the calcaneus by sharing the common Achilles tendon. These tendinous tissues are known to have elasticity and upon muscle contraction the aponeurosis is stretched both longitudinally (along the muscle's line of action) and transversely. Higher aponeurosis transverse deformability has been documented, but there is a paucity of information on the morphology and mechanical properties of human aponeurosis. This study aimed to identify morphological and mechanical characteristics of the human triceps surae aponeuroses. Twenty-five triceps surae muscle-tendon units were procured from 13 human donors (formalin fixed, 6 males, 7 females) aged 67-91 years. Specimens of aponeuroses were excised from the eight regions (posterior and anterior regions of the gastrocnemius medialis and lateralis, medial and lateral parts of soleus; proximal, middle, and distal sites each, 2-4 cm × 2-4 cm). Aponeurosis thickness was measured using a digital caliper. Uniaxial tensile tests were implemented to determine the mechanical properties of specimens loaded longitudinally (along the muscle's line of action) and transversely. The aponeurosis thickness showed significant differences between muscles and sites, while Young's modulus showed direction-dependent (longitudinal vs. transverse) differences within sites. Results show different morphology and mechanical properties of aponeuroses between synergist muscles. The reason for site-dependent differences in stiffness is due to a reduced aponeurosis thickness rather than a reduction in the material property. The anisotropic elastic feature (differences between longitudinal and transverse directions) of the aponeuroses was more pronounced than previous in vivo findings, suggesting inherent material design of the aponeurosis that matches three-dimensional contractile behavior of muscle fibers.

BackgroundRecently, the clinical outcome of prostate cancer treated by hypofractionated radiation therapy has been reported. However, there are few reports from Japan. In Hidaka Hospital, hypofractionated intensity-modulated radiotherapy (HIMRT) for prostate cancer was initiated in 2007. The purpose of this study is to analyze the long-term outcome.MethodsNinety-two patients with localized prostate cancer treated with HIMRT at Hidaka Hospital between 2007 and 2009 were retrospectively analyzed. HIMRT was delivered using TomoTherapy. The prescription dose was 66 Gy at 95% of the PTV in 22 fractions performed 3 days a week over 7 weeks in all patients. The overall survival rate, biochemical relapse-free rate, and acute and late toxicities were evaluated.ResultsThe median follow-up duration was 78 (range 14-100) months. The median age at the start of the HIMRT was 72 (range 46-84) years. The disease characteristics were as follows: stage T1c, 45; T2a, 20; T2b, 5; T2c, 1; T3a, 13; T3b, 6; T4, 2; Gleason score 6, 13; 7, 44; 8, 20; 9, 15; 10, 0; pretreatment PSA ≤10 ng/mL, 42; 10 to ≤20, 27; and >20, 23. According to the D'Amico classification system, 10, 37, and 45 patients were classified as low-risk, intermediate-risk, and high-risk. The overall survival rate, the cause-specific survival rate, and the biochemical relapse-free rate at 5 years was 94.7%, 100% and 98.9%, respectively. Severe acute toxicity (grade 3 or more) was not observed. The late urinary toxicity was 52.2% in grade 0, 28.3% in grade 1, 19.6% in grade 2, and 2.2% in grade 3. The late rectal toxicity was 78.3% in grade 0, 7.6% in grade 1, 9.8% in grade 2, and 4.3% in grade 3.ConclusionsThe present study demonstrated that HIMRT using TomoTherapy for prostate cancer has a favorable outcome with tolerable toxicity.

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output.

Pseudomonas aeruginosa is an opportunistic pathogen that causes severe infections, such as pneumonia and bacteremia. Several studies demonstrated that flagellar motility is an important virulence factor for P. aeruginosa infection. In this study, we determined whether sulfated vizantin affects P. aeruginosa flagellar motility in the absence of direct antimicrobial activity. We found that 100 μM sulfated vizantin suppressed P. aeruginosa PAO1 from penetrating through an artificial mucin layer by affecting flagellar motility, although it did not influence growth nor bacterial protease activity. To further clarify the mechanism in which sulfated vizantin suppresses the flagellar motility of P. aeruginosa PAO1, we examined the effects of sulfated vizantin on the composition of the flagellar filament and mRNA expression of several flagella-related genes, finding that sulfated vizantin did not influence the composition of the flagellar complex (fliC, motA, and motB) in P. aeruginosa PAO1, but significantly decreased mRNA expression of the chemotaxis-related genes cheR1, cheW, and cheZ. These results indicated that sulfated vizantin is an effective inhibitor of flagellar motility in P. aeruginosa.

Several recent studies have claimed that rodents have good visual recognition abilities. However, the extent to which rats can recognize other rats and distinguish between males and females using visual information alone remains unclear. In the present study, we investigated the ability of rats to visually recognize mirror, video-recorded, and still images and to discriminate between images of males and females. Rats were tested in a place preference apparatus with a mirror, a video-recorded image of a rat, or a still image of a rat at one end. The data were assessed using t-test with Bonferroni correction. Male and female rats spent significantly more time in the mirror chamber and the video-recorded image chamber than in their respective blank chambers (P < 0.05), and male rats also spent more time in the chamber containing a still image. Furthermore, it was found that male rats exhibited significantly more sniffing behavior around the mirror than in the blank chamber (P < 0.05), whereas female rats were no significant differences in the sniffing behaviors in the mirror, moving or still image experiments. Identical results were obtained regardless of whether the rat in the image was the same or opposite sex. These results indicate that rats can process the differences in mirror, video-recorded, and still images as visual information, but are unable to use this information to distinguish between the sexes.

1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) induces both necrosis/necroptosis and apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells. The present study was conducted to understand the mechanism for DAPE-induced apoptosis of NCI-H28 cells. DAPE induced caspase-independent apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells, and the effect of DAPE was prevented by antioxidants or an inhibitor of NADPH oxidase (NOX). DAPE generated reactive oxygen species (ROS) and inhibited activity of thioredoxin (Trx) reductase (TrxR). DAPE decreased an association of apoptosis signal-regulating kinase 1 (ASK1) with thioredoxin (Trx), thereby releasing ASK1. DAPE activated p38 mitogen-activated protein kinase (MAPK), which was inhibited by an antioxidant or knocking-down ASK1. In addition, DAPE-induced NCI-H28 cell death was also prevented by knocking-down ASK1. Taken together, the results of the present study indicate that DAPE stimulates NOX-mediated ROS production and suppresses TrxR activity, resulting in the decrease of reduced Trx and the dissociation of ASK1 from a complex with Trx, allowing sequential activation of ASK1 and p38 MAPK, to induce apoptosis of NCI-H28 MPM cells.

This study proposes a driver assistance system that provides an appropriate pedal operation by considering information on the pre-preceding vehicle. The system calculates the risk of collision by taking into account not only the preceding vehicle, but also the pre-preceding vehicle ahead of the preceding car. The computed numerical risk is then translated into the visual interface that assists the driver to make an appropriate acceleration and deceleration in carfollowing. Several participants who participated in driving simulator experiments were instructed to follow a preceding as well as a visible pre-preceding vehicles with and without the driver assistance system. It was found that the assistance system succeeded in reducing the relative velocity with the pre-preceding vehicle and in eliminating the unnecessary acceleration and deceleration of the following vehicle. Safety and fuel economy were also significantly improved by introducing the proposed system.

Background/Aims: Phosphatidylinositol (PI) regulates a variety of cell processes. The present study investigated the antitumor action of 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol)(DOPI) and 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-myo-inositol)(DPPI) on human malignant pleural mesothelioma (MPM) cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells. Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide (PI) and annexin V (AV), enzymatic caspase assay, and nuclear staining using DAPI were carried out, and mitochondrial membrane potentials and intracellular distribution of apoptosis-inducing factor (AIF) were monitored in cells with and without the siRNA silencing the Bid-targeted gene. Results: Both DOPI and DPPI reduced cell viability for all the investigated MPM cell lines in a concentration (0.01-100 µM)-dependent manner. DOPI and DPPI significantly increased TUNEL-positive cells and the population of PI-negative/AV-positive and PI-positive/AV-positive cells, corresponding to early apoptosis and late apoptosis/secondary necrosis, respectively. DOPI and DPPI perturbed mitochondrial membrane potentials in MSTO-211H cells, but no significant activation of caspase-3, -4, -8, and -9 was obtained. DOPI and DPPI upregulated expression of Bid in MSTO-211H cells. DOPI and DPPI significantly increased nuclear localization of AIF without affecting expression of the mRNAs and proteins in MSTO-211H cells, which was inhibited by knocking-down Bid. In the DAPI staining, nuclear fragmentation and condensation were found. Conclusion: The results of the present study indicate that DOPI and DPPI facilitate Bid-mediated AIF release from the mitochondria, to accumulate AIF in the nucleus and induce caspase-independent apoptosis of MPM cells.

Background/Aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b-4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53-91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade ≥2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b-4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is ongoing to prospectively evaluate these patients and establish the use of carbon-ion radiotherapy.

Background/Aims: Accumulating evidence has suggested that free fatty acids (FFAs) interact with protein kinases and protein phosphatases. The present study examined the effect of FFAs on protein phosphatases and Akt. Methods: Activities of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein tyrosine phosphatase 1B (PTP1B) were assayed under the cell-free conditions. Phosphorylation of Akt was monitored in MSTO-211H human malignant pleural mesothelioma cells without and with knocking-down phosphatidylinositol 3 kinase (PI3K) or 3-phosphoinositide-dependent protein kinase-1 (PDK1). Results: In the cell-free assay, unsaturated FFAs (uFFAs) such as oleic, linoleic and linolenic acid and saturated FFAs (sFFAs) such as stearic, palmitic, myristic, and behenic acid markedly reduced PTP1B activity, with the potential for uFFAs greater than that for sFFAs. All the investigated sFFAs inhibited PP2A activity, but otherwise no inhibition was obtained with uFFAs. Both uFFAs and sFFAs had no effect on PP1 activity. Oleic acid phosphorylated Akt both on Thr308 and Ser473, while stearic acid phosphorylated Akt on Thr308 alone. The effects of oleic and stearic acid on Akt phosphorylation were abrogated by the PI3K inhibitor wortmannin or the PDK1 inhibitor BX912 and also by knocking-down PI3K or PDK1. Conclusion: The results of the present study indicate that uFFAs and sFFAs could activate Akt through a pathway along a PI3K/PDK1/Akt axis in association with PTP1B inhibition.

Background/Aims: Our earlier studies suggested crosstalk between IRS/PI3 kinase/PDK1/Akt/Rac1/ROCK and (Shc2/Grb2/SOS)/Ras/Raf/MEK/ERK pathways downstream PDGF-ββ receptor responsible for chemotaxis and proliferation of malignant mesothelioma cells. The present study was conducted to obtain evidence for this. Methods: To assess activation of Akt, MEK, and ERK, Western blotting was carried out on MSTO-211H malignant mesothelioma cells using antibodies against phospho-Thr308-Akt, phopho-Ser473-Akt, Akt, phospho-MEK, MEK, phopho-ERK1/2, and ERK1/2. To knock-down Akt, PI3 kinase, PDK1, and Rac1, siRNAs silencing each-targeted gene were constructed and transfected into cells. To monitor Rac1 activity, FRET monitoring was carried out on living and fixed cells. Results: ERK was activated under the basal conditions in MSTO-211H cells, and the activation was prevented by inhibitors for PI3 kinase, PDK1, Akt, and Rac1 or by knocking-down PI3 kinase, PDK1, Akt, and Rac1. Akt was also activated under the basal conditions, and the activation was suppressed by a MEK inhibitor and an ERK1/2 inhibitor. In the FRET analysis, Rac1 was activated under the basal conditions, and the activation was inhibited by a MEK inhibitor and an ERK1/2 inhibitor. Conclusion: The results of the present study show that ERK could be activated by PI3 kinase, PDK1, Akt, and Rac1 and that alternatively, Akt and Rac1 could be activated by MEK and ERK in MSTO-211H cells.

This study examines the driver assistance system to judge whether a passage (GO) or a stop (NOGO) at a signalized intersection ahead. The assistance system indicates the evaluation indices on the road ahead virtually. The proposed assistance system informs a driver visually of the distance which the vehicle can traverse by maintaining the current velocity until the red signal onset using the signal information. If the remaining distance to the intersection is longer than the indicated distance, the system also indicates a stopping distance by assuming the ordinary deceleration. The driving simulator experiments are carried out to evaluate the proposed assistance system. The assistance system encourages the earlier deceleration before turning to the amber signal and prevents the emergency braking behavior or the risky passage through the intersection. In addition, the assistance system shortens drivers' reaction time to the emergency deceleration of the preceding vehicle compared with the onboard monitor indication in the own vehicle. Indicating evaluation indices on the road ahead virtually helps the driver to decelerate earlier and avoid the higher deceleration. These effects make it possible to suppress the collision risk to the preceding vehicle and contribute the safety driving.

BACKGROUND AND PURPOSE:Carbon-ion radiotherapy of prostate cancer is challenging in patients with metal implants in one or both hips. Problems can be circumvented by using fields at oblique angles. To evaluate the influence of setup and range uncertainties accompanying oblique field angles, we calculated rectal dose changes with oblique orthogonal field angles, using a device with fixed fields at 0° and 90° and a rotating patient couch. MATERIAL AND METHODS:Dose distributions were calculated at the standard angles of 0° and 90°, and then at 30° and 60°. Setup uncertainty was simulated with changes from -2 mm to +2 mm for fields in the anterior-posterior, left-right, and cranial-caudal directions, and dose changes from range uncertainty were calculated with a 1 mm water-equivalent path length added to the target isocenter in each angle. The dose distributions regarding the passive irradiation method were calculated using the K2 dose algorithm. RESULTS:The rectal volumes with 0°, 30°, 60°, and 90° field angles at 95% of the prescription dose were 3.4±0.9 cm3, 2.8±1.1 cm3, 2.2±0.8 cm3, and 3.8±1.1 cm3, respectively. As compared with 90° fields, 30° and 60° fields had significant advantages regarding setup uncertainty and significant disadvantages regarding range uncertainty, but were not significantly different from the 90° field setup and range uncertainties. CONCLUSIONS:The setup and range uncertainties calculated at 30° and 60° field angles were not associated with a significant change in rectal dose relative to those at 90°.

Hirohiko Kakizaki1, Yasuhiro Takahashi2, Takashi Nakano3, Ken Asamoto3, Shinsuke Kinoshita1, Masayoshi Iwaki1Departments of 1Ophthalmology and 3Anatomy, Aichi Medical University, Nagakute, Aichi, Japan; 2Department of Ophthalmology and Visual Sciences, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, JapanAbstract: The nomenclature of each part of the lacrimal canaliculus, for example the vertical portion, does not always reflect the true course. Since we have sometimes observed findings suggesting the so called vertical portion of the lower lacrimal canaliculus inclined laterally, we re-examined the course of the vertical portion. Twenty-eight postmortem lower eyelids in 16 Japanese were examined and divided into 2 groups. The first group was 14 lower eyelids of 7 cadavers. Eyelids were incised sagittally from the lower lacrimal punctum. The second group was 14 lower eyelids of 9 cadavers; these were incised from the lower lacrimal punctum with 5 degrees lateral inclination to the sagittal plane. In the first group, 10 canaliculi of 7 cadavers were interrupted at the halfway point of the vertical portion. Four canaliculi of 4 cadavers included the whole length of the vertical portion. In the second group, all specimens included the whole length of the vertical portion. Most vertical portions of the lower lacrimal canaliculus demonstrated a laterally inclined course of approximately 5 degrees, although some took a completely vertical course.Keywords: vertical portion, lacrimal canaliculus, lower, laterally

Yasuhiro Takahashi1, Hirohiko Kakizaki2, Takashi Nakano3, Ken Asamoto3, Masayoshi Iwaki21Department of Ophthalmology and Visual Sciences, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Osaka, Japan; 2Department of Ophthalmology; 3Anatomy, Aichi Medical University, Nagakute, Aichi, JapanAbstract: The purpose of this study was to examine the inferior oblique muscle (IOM) thickness in Asians by the quasi-sagittal plane of the orbits. Specimens were examined from 23 orbits of 18 Asians (9 orbits in males, 14 in females), aged 63 to 97 years at death. All specimens were fixed in 10% buffered formalin before use. The orbital contents were incised parallel to the optic nerve, after which the lengths of both short and long axes of the IOM were measured and the ratio of short to long axes was calculated. The mean lengths of each short or long axis of the IOM were 2.27 ± 0.49 mm and 7.23 ± 0.97 mm, respectively. The average ratio was 0.32 ± 0.07. There were no significant differences in laterality or gender. This study determined the normal IOM thickness in Asian cadavers, the outcome of which could be useful for detection of IOM involvement in Graves’ orbitopathy.Keywords: inferior oblique muscle, Asian, thickness, quasi-sagittal plane