A Diels-Alder polymer platform for thermally enhanced drug release toward efficient local cancer chemotherapy.

We reports a novel thermally enhanced drug release system synthesized via a dynamic Diels-Alder (DA) reaction to develop chemotherapy for pancreatic cancer. The anticancer prodrug was designed by tethering gemcitabine (GEM) to poly(furfuryl methacrylate) (PFMA) via N-(3-maleimidopropionyloxy)succinimide as a linker by DA reaction (PFMA-L-GEM). The conversion rate of the DA reaction was found to be approximately 60% at room temperature for 120 h. The reversible deconstruction of the DA covalent bond in retro Diels-Alder (rDA) reaction was confirmed by proton nuclear magnetic resonance, and the reaction was significantly accelerated at 90 °C. A PFMA-LGEM film containing magnetic nanoparticles (MNPs) was prepared for thermally enhanced release of the drug via the rDA reaction. Drug release was initiated by heating MNPs by alternating magnetic field. This enables local heating within the film above the rDA reaction temperature while maintaining a constant surrounding medium temperature. The MNPs/PFMA-L-GEM film decreased the viability of pancreatic cancer cells by 49% over 24 h. Our results suggest that DA/rDA-based thermally enhanced drug release systems can serve as a local drug release platform and deliver the target drug within locally heated tissue, thereby improving the therapeutic efficiency and overcoming the side effects of conventional drugs used to treat pancreatic cancer.

Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers.

Treatment resistance, relapse and metastasis remain critical issues in some challenging cancers, such as chondrosarcomas. Boron-neutron capture therapy (BNCT) is a targeted radiation therapy modality that relies on the ability of boron atoms to capture low energy neutrons, yielding high linear energy transfer alpha particles. We have developed an innovative boron-delivery system for BNCT, composed of multifunctional fluorescent mesoporous silica nanoparticles (B-MSNs), grafted with an activatable cell penetrating peptide (ACPP) for improved penetration in tumors and with gadolinium for magnetic resonance imaging (MRI) in vivo. Chondrosarcoma cells were exposed in vitro to an epithermal neutron beam after B-MSNs administration. BNCT beam exposure successfully induced DNA damage and cell death, including in radio-resistant ALDH+ cancer stem cells (CSCs), suggesting that BNCT using this system might be a suitable treatment modality for chondrosarcoma or other hard-to-treat cancers.

[Two Cases of Penoscrotal Strangulation].

Case 1 (42-year-old man) : The patient was examined for penoscrotal swelling that had continued for 1 month. An annular erosive skin ulcer was observed at the penoscrotal base, with distal swelling. Asking the patient about the history of his condition was difficult due to a history of mental illness. We suspected his symptoms were due to an embedded foreign object. As computed tomography indicated the presence of a subcutaneous foreign object, surgery was performed to remove it. A rubber band was found wrapped twice around the area. After releasing the strangulation, penoscrotal swelling improved. Case 2 (72-year-old man) : Penoscrotal swelling appeared after having an automobile tow hook attached to the penoscrotal base for 2 weeks. The patient was examined at the emergency room because he could not remove it on his own. A rescue squad was called, and they cut the strangulating object with an electric saw. After releasing the strangulation, penoscrotal swelling improved. Although we experienced 2 cases of penoscrotal strangulation involving strangulating objects with different characteristics, improvement was achieved in both by releasing the strangulation. The cases of penoscrotal strangulation reported in Japan with known strangulation type are reviewed.

[A Case of Primary Schwannoma of the Urinary Bladder].

A 68-year-old woman presented with a bladder tumor. She was asymptomatic, and the tumor was incidentally detected with radiological imaging performed during treatment of cervical cancer. Magnetic resonance imaging and computed tomography revealed a solitary submucosal tumor located in the anterior wall of the urinary bladder, with homogeneous contrast enhancement. Cystoscopy showed a submucosal tumor covered by normal mucosa. A paraganglioma was considered in the differential diagnosis, but symptoms suggesting hypercatecholaminemia were not apparent. Moreover, she did not have a family history or symptoms associated with neurofibromatosis-1 (NF-1). She underwent partial cystectomy with a preliminary diagnosis of submucosal bladder tumor. Histopathological diagnosis confirmed a schwannoma arising from the bladder wall. She was followed up without intravesical recurrence or metastases for 6 months. In the literature, only 12 cases of bladder schwannoma have been reported. There was no reported family history or symptoms associated with NF-1 in any of the cases. Although the number of cases is limited, literature review showed a favorable prognosis for bladder schwannoma with local tumor resection in patients without NF-1.

[Sarcomatoid Urothelial Carcinoma of the Bladder Including an Osteosarcoma Element].

A 68-year-old Japanese man was referred to Tsukuba University Hospital for bladder cancer treatment. He had undergone a transurethral resection of a bladder tumor (TURBT) at a local hospital, but the pathological specimen did not contain muscle layer. Abdominal computed tomography (CT) and magnetic resonance imaging revealed a 3 cm non-papillary bladder tumor with muscle invasion, but there was no apparent calcification. The patient underwent re-TURBT at our hospital for diagnosis and staging. A non-papillary pedunculated tumor was identified in the bladder dome, and it contained a small papillary part. The non-papillary part was stony hard and difficult to cut with electrocautery, whereas the small papillary part was easily cut. Histologically, the non-papillary part was composed of sarcomatous elements including osteosarcoma, chondrosarcoma, and spindle cell sarcoma. The papillary part was composed of high-grade urothelial carcinoma and spindle cell sarcoma. Muscularis propria was not present in the specimen. Since the staging study with CT was negative for metastases, we performed a total cystectomy with an ileal conduit under the clinical diagnosis of muscle-invasive sarcomatoid urothelial carcinoma. The pathological findings were identical to those of the re-TURBT specimens, and our diagnosis was pTxN0 sarcomatoid urothelial carcinoma. The patient received adjuvant chemotherapy with two courses of gemcitabine and cisplatin. There was neither recurrence nor metastases during the 20-month follow-up. Reports of sarcomatoid urothelial carcinoma of the bladder with an osteosarcoma element are rare, and only eight other cases hane been reported in the Japanese literature.

Wound healing delays in α-Klotho-deficient mice that have skin appearance similar to that in aged humans - Study of delayed wound healing mechanism.

Skin atrophy and delayed wound healing are observed in aged humans; however, the molecular mechanism are still elusive. The aim of this study was to analyze the molecular mechanisms of delayed wound healing by aging using α-Klotho-deficient (kl/kl) mice, which have phenotypes similar to those of aged humans. The kl/kl mice showed delayed wound healing and impaired granulation formation compared with those in wild-type (WT) mice. The skin graft experiments revealed that delayed wound healing depends on humoral factors, but not on kl/kl skin tissue. The mRNA expression levels of cytokines related to acute inflammation including IL-1ß, IL-6 and TNF-α were higher in wound lesions of kl/kl mice compared with the levels in WT mice by RT-PCR analysis. LPS-induced TNF-α production model using spleen cells revealed that TNF-α production was significantly increased in the presence of FGF23. Thus, higher levels of FGF23 in kl/kl mouse may have a role to increase TNF-α production in would lesion independently of α-Klotho protein, and impair granulation formation and delay wound healing.

Measuring total mercury due to small-scale gold mining activities to determine community vulnerability in Cihonje, Central Java, Indonesia.

This research is comparative study of gold mining and non-gold mining areas, using four community vulnerability indicators. Vulnerability indicators are exposure degree, contamination rate, chronic, and acute toxicity. Each indicator used different samples, such as wastewater from gold mining process, river water from Tajum river, human hair samples, and health questionnaire. This research used cold vapor atomic absorption spectrometry to determine total mercury concentration. The result showed that concentration of total mercury was 2,420 times than the maximum content of mercury permitted in wastewater based on the Indonesian regulation. Moreover, the mercury concentration in river water reached 685 ng/l, exceeding the quality threshold standards of the World Health Organization (WHO). The mercury concentration in hair samples obtained from the people living in the research location was considered to identify the health quality level of the people or as a chronic toxicity indicator. The highest mercury concentration--i.e. 17 ng/mg, was found in the gold mining respondents. Therefore, based on the total mercury concentration in the four indicators, the community in the gold mining area were more vulnerable to mercury than communities in non-gold mining areas. It was concluded that the community in gold mining area was more vulnerable to mercury contamination than the community in non-gold mining area.

Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts.

Keloids are benign dermal fibrotic tumors arising during the wound healing process. The mechanisms of keloid formation and development still remain unknown, and no effective treatment is available. Resveratrol, a dietary compound, has anticancer properties and, from recent studies, it has been suggested that resveratrol may have an antifibrogenic effect on organs such as the liver and kidney. Based on this idea, we investigated its effect on the regulation of extracellular matrix expression, proliferation, and apoptosis of keloid fibroblasts. Type I collagen, α-smooth muscle actin, and heat shock protein 47 expression decreased in resveratrol-treated keloid fibroblasts in a dose-dependent manner. In addition, resveratrol diminished transforming growth factor-ß1 production by keloid fibroblasts. We also demonstrated that it suppressed their proliferation and induced apoptosis of the fibroblasts. Conversely, resveratrol did not decrease type I collagen, α-smooth muscle actin, and heat shock protein 47 mRNA expression in normal skin fibroblasts and barely suppressed cell proliferation. Our data indicate that resveratrol may have an antifibrogenic effect on keloid fibroblasts without any adversely effects on normal skin fibroblasts, suggesting the potential application of resveratrol for the treatment of keloids.

Evaluation of SCCVII tumor cell survival in clamped and non-clamped solid tumors exposed to carbon-ion beams in comparison to X-rays.

The aim of this study was to measure the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) for survival of cells within implanted solid tumors following exposure to 290MeV/nucleon carbon-ion beams or X-rays. Squamous cell carcinoma cells (SCCVII) were transplanted into the right hind legs of syngeneic C3H male mice. Irradiation with either carbon-ion beams with a 6-cm spread-out Bragg peak (SOBP, at 46 and 80keV/µm) or X-rays was delivered to 5-mm or less diameter tumors. We defined three different oxygen statuses of the irradiated cells. Hypoxic and normoxic conditions in tumors were produced by clamping or not clamping the leg to avoid blood flow. Furthermore, single-cell suspensions were prepared from non-irradiated tumors and directly used to determine the radiation response of aerobic cells. Single-cell suspensions (aerobic condition) were fully air-saturated. Single-cell suspensions were prepared from excised and trypsinized tumors, and were used for in vivo-in vitro colony formation assays to obtain cell survival curves. The RBE values increased with increasing LET in SOBP beams. The maximum RBE values in three different oxygen conditions; hypoxic tumor, normoxic tumor and aerobic cells, were 2.16, 1.76 and 1.66 at an LET of 80keV/µm, respectively. After X-ray irradiation the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.87±0.13 and 2.52±0.11, respectively. The OER values of carbon-ion irradiated samples were small in comparison to those of X-ray irradiated samples. However, no significant changes of the OER at proximal and distal positions within the SOBP carbon-ion beams were observed. To conclude, we found that the RBE values for cell survival increased with increasing LET and that the OER values changed little with increasing LET within the SOBP carbon-ion beams.

Strategies for Preclinical Studies Evaluating the Biological Effects of an Accelerator-Based Boron Neutron Capture Therapy System.

This review discusses the strategies of preclinical studies intended for accelerator-based (AB)-boron neutron capture therapy (BNCT) clinical trials, which were presented at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy held from April 20 to 22, 2022. Clinical studies of BNCT have been conducted worldwide using reactor neutron sources, with most targeting malignant brain tumors, melanoma, or head and neck cancer. Recently, small accelerator-based neutron sources that can be installed in hospitals have been developed. AB-BNCT clinical trials for recurrent malignant glioma, head and neck cancers, high-grade meningioma, melanoma, and angiosarcoma have all been conducted in Japan. The necessary methods, equipment, and facilities for preclinical studies to evaluate the biological effects of AB-BNCT systems in terms of safety and efficacy are described, with reference to two examples from Japan. The first is the National Cancer Center, which is equipped with a vertical downward neutron beam, and the other is the University of Tsukuba, which has a horizontal neutron beam. The preclinical studies discussed include cell-based assays to evaluate cytotoxicity and genotoxicity, in vivo cytotoxicity and efficacy of BNCT, and radioactivation measurements.

Smart Nanofiber Mesh with Locally Sustained Drug Release Enabled Synergistic Combination Therapy for Glioblastoma.

This study aims to propose a new treatment model for glioblastoma (GBM). The combination of chemotherapy, molecular targeted therapy and radiotherapy has been achieved in a highly simultaneous manner through the application of a safe, non-toxic, locally sustained drug-releasing composite Nanofiber mesh (NFM). The NFM consisted of biodegradable poly(ε-caprolactone) with temozolomide (TMZ) and 17-allylamino-17-demethoxygeldanamycin (17AAG), which was used in radiation treatment. TMZ and 17AAG combination showed a synergistic cytotoxicity effect in the T98G cell model. TMZ and 17AAG induced a radiation-sensitization effect, respectively. The NFM containing 17AAG or TMZ, known as 17AAG-NFM and TMZ-NFM, enabled cumulative drug release of 34.1% and 39.7% within 35 days. Moreover, 17AAG+TMZ-NFM containing both drugs revealed a synergistic effect in relation to the NFM of a single agent. When combined with radiation, 17AAG+TMZ-NFM induced in an extremely powerful cytotoxic effect. These results confirmed the application of NFM can simultaneously allow multiple treatments to T98G cells. Each modality achieved a significant synergistic effect with the other, leading to a cascading amplification of the therapeutic effect. Due to the superior advantage of sustained drug release over a long period of time, NFM has the promise of clinically addressing the challenge of high recurrence of GBM post-operatively.

Efficient neutron capture therapy of glioblastoma with pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl)butyric acid (PBC-IP).

Boron neutron capture therapy (BNCT) has been applied for clinical trials on glioblastoma patients since 1950s, however, the low survival rate under the treatments has hampered the widespread use of BNCT. In this study, we developed a novel boron agent, PBC-IP, which consists of three functional groups: FRα-targeting, 10B resource (twelve 10B atoms in the molecule), and albumin-binding moieties. PBC-IP was selectively taken up by glioma cell lines such as C6, F98, and U87MG cells and accumulated 10- to 20-fold higher than L-4­boronophenylalanine (BPA). PBC-IP administrated intravenously to the human glioblastoma (U87MG) xenograft model showed higher boron accumulation in tumors (29.8 µg [10B]/g at 6 h) than BPA (9.6 µg [10B]/g at 3 h) at a 25 mg [10B]/kg dose, effectively suppressing tumor growth after thermal neutron irradiation. PBC-IP administrated via convection-enhanced delivery (CED) accumulated in the F98 glioma orthotopic rat model, achieving 26.5 µg [10B]/g in tumors with tumor/normal (T/N) brain and tumor/blood (T/B) boron ratios of 37.8 and 94.6, respectively, 3 h after CED. Survival at 180 days after BNCT was 50% in the PBC-IP group and 70% in the combined BPA and PBC-IP groups, with no residual brain tumors.

Microdosimetric study on influence of low energy photons on relative biological effectiveness under therapeutic conditions using 6 MV linac.

PURPOSE: Microdosimetry has been developed for the evaluation of radiation quality, and single-event dose-mean lineal energy y(D) is well-used to represent the radiation quality. In this study, the changes of the relative biological effectiveness (RBE) values under the therapeutic conditions using a 6 MV linac were investigated with a microdosimetric method. METHODS: The y(D) values under the various irradiation conditions for x-rays from a 6 MV linac were measured with a tissue-equivalent proportional counter (TEPC) at an extremely low dose rate of a few tens of microGy/min by decreasing the gun grid voltage of the linac. According to the microdosimetric kinetic model (MK model), the RBE(MK) values for cell killing of the human salivary gland (HSG) tumor cells can be derived if the y(D) values are obtained from TEPC measurements. The Monte Carlo code GEANT4 was also used to calculate the photon energy distributions and to investigate the changes of the y(D) values under the various conditions. RESULTS: The changes of the y(D) values were less than approximately 10% when the field size and the depth in a phantom varied. However, in the measurements perpendicular to a central beam axis, large changes were observed between the y(D) values inside the field and those outside the field. The maximum increase of approximately 50% in the y(D) value outside the field was obtained compared with those inside the field. The GEANT4 calculations showed that there existed a large relative number of low energy photons outside of the field as compared with inside of the field. The percentages of the photon fluences below 200 keV outside the field were approximately 40% against approximately 8% inside the field. By using the MK model, the field size and the depth dependence of the RBEMK values were less than approximately 2% inside the field. However, the RBEMK values outside the field were 6.6% higher than those inside the field. CONCLUSIONS: The increase of the RBE(MK) values by 6.6% outside the field was observed. This increase is caused by the change of the photon energy distributions, especially the increase of the relative number of low energy photons outside the field.

Development of an Imaging Technique for Boron Neutron Capture Therapy.

The development of 4-10B-borono-2-18F-fluoro-L-phenylalanine (18FBPA) for use in positron emission tomography (PET) has contributed to the progress of boron neutron capture therapy (BNCT). 18FBPA has shown similar pharmacokinetics and distribution to 4-10B-borono-L-phenylalanine (BPA) under various conditions in many animal studies. 18FBPA PET is useful for treatment indication. A higher 18FBPA accumulation ratio of the tumor to the surrounding normal tissue (T/N ratio) indicates that a superior treatment effect is expected. In clinical settings, a T/N ratio of higher than 2.5 or 3 is often used for patient selection. Moreover, 18FBPA PET is useful for predicting the 10B concentration delivered to the tumor and surrounding normal tissues, enabling high-precision treatment planning. Precise dose prediction using 18FBPA PET data has greatly improved the treatment accuracy of BNCT. However, the methodology used for the data analysis of 18FBPA PET findings varies; thus, data should be evaluated using a consistent methodology so as to be more reliable. In addition to PET applications, the development of 18FBPA as a contrast agent for magnetic resonance imaging that combines gadolinium and 10B is also in progress.

A Critical Review of Radiation Therapy: From Particle Beam Therapy (Proton, Carbon, and BNCT) to Beyond.

In this paper, we discuss the role of particle therapy-a novel radiation therapy (RT) that has shown rapid progress and widespread use in recent years-in multidisciplinary treatment. Three types of particle therapies are currently used for cancer treatment: proton beam therapy (PBT), carbon-ion beam therapy (CIBT), and boron neutron capture therapy (BNCT). PBT and CIBT have been reported to have excellent therapeutic results owing to the physical characteristics of their Bragg peaks. Variable drug therapies, such as chemotherapy, hormone therapy, and immunotherapy, are combined in various treatment strategies, and treatment effects have been improved. BNCT has a high dose concentration for cancer in terms of nuclear reactions with boron. BNCT is a next-generation RT that can achieve cancer cell-selective therapeutic effects, and its effectiveness strongly depends on the selective 10B accumulation in cancer cells by concomitant boron preparation. Therefore, drug delivery research, including nanoparticles, is highly desirable. In this review, we introduce both clinical and basic aspects of particle beam therapy from the perspective of multidisciplinary treatment, which is expected to expand further in the future.

Non-isotope enriched phenylboronic acid-decorated dual-functional nano-assembles for an actively targeting BNCT drug.

The feasibility of boron neutron capture therapy (BNCT) greatly depends on the selective accumulation of 10B in tumors. The p-boronophenylalanine-fructose (BPA-f) complex has been established as a conventional BNCT agent due to its preferential uptake into tumors, which is driven by amino acid transporters. However, the retention of BPA-f in tumors is highly limited because of an antiport mechanism, which is regulated by a gradient of amino acid concentration across the cancer cell membrane. Thus, to preserve a high 10B concentration in tumors, patients are inevitably subjected to a constant intravenous infusion. To this end, we employed a phenylboronic acid (PBA)-decorated polymeric nanoparticle (NanoPBA) as a sialic acid-targeting BNCT agent. In this manner, the PBA can exhibit dual functionalities, i.e., exhibiting a neutron capture capacity and hypersialyated cancer cell targeting effect. Our developed NanoPBA possesses a supramolecular structure composed of a core and shell comprised of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) segments, respectively. The PBA moiety is installed at the PEG end, providing an unusually strong targeting effect, supposedly via multivalent binding onto the cancer cell membrane. As in BNCT, we verified the feasibility of NanoPBA against a B16 melanoma-bearing mouse model. By virtue of efficient tumor targeting, even at a 100-fold lower dose than BPA-f, the NanoPBA achieved a potent antitumor effect.

Lethal DNA Lesions Caused by Direct and Indirect Actions of X rays are Repaired via Different DSB Repair Pathways under Aerobic and Anoxic Conditions.

We examined lethal damages of X rays induced by direct and indirect actions, in terms of double-strand break (DSB) repair susceptibility using two kinds of repair-deficient Chinese hamster ovary (CHO) cell lines. These CHO mutants (51D1 and xrs6) are genetically deficient in one of the two important DNA repair pathways after genotoxic injury [homologous recombination (HR) and non-homologous end binding (NHEJ) pathways, respectively]. The contribution of indirect action on cell killing can be estimated by applying the maximum level of dimethylsulfoxide (DMSO) to get rid of OH radicals. To control the proportion of direct and indirect actions in lethal damage, we irradiated CHO mutant cells under aerobic and anoxic conditions. The contributions of indirect action on HR-defective 51D1 cells were 76% and 57% under aerobic and anoxic conditions, respectively. Interestingly, these percentages were similar to those of the wild-type cells even if the radiosensitivity was different. However, the contributions of indirect action to cell killing on NHEJ-defective xrs6 cells were 52% and 33% under aerobic and anoxic conditions, respectively. Cell killing by indirect action was significantly affected by the oxygen concentration and the DSB repair pathways but was not correlated with radiosensitivity. These results suggest that the lethal damage induced by direct action is mostly repaired by NHEJ repair pathway since killing of NHEJ-defective cells has significantly higher contribution by the direct action. In other words, the HR repair pathway may not effectively repair the DSB by direct action in place of the NHEJ repair pathway. We conclude that the type of DSB produced by direct action is different from that of DSB induced by indirect action.

Polymer-conjugated glucosamine complexed with boric acid shows tumor-selective accumulation and simultaneous inhibition of glycolysis.

We synthesized unique water-soluble synthetic-polymer, styrene-maleic acid copolymer (SMA) conjugated glucosamine (SG); which formed a stable complex with boric acid (BA). This complex had a mean particle size of 15 nm by light scattering, and single peak in gel permeation chromatography. The particles were taken up by tumor cells five times faster than free BA in vitro and liberated BA at acidic tumor pH (5-7). Liberated BA inhibited glycolysis and resulted in tumor suppression in vivo. Intravenously injected SGB-complex did bind with albumin, and plasma half-life was about 8 h in mice, and accumulated to tumor tissues about 10 times more than in normal organs. IC50 of SGB-complex for HeLa cells under pO2 of 6-9% was about 20 µg/ml (free BA equivalent), 150 times more potent than free BA. Neutron irradiation of human oral cancer cells with SGB-complex resulted in 16 times greater cell-killing than that without SGB-complex. In vivo antitumor effect was evaluated after neutron irradiation only once in SCC VII tumor bearing mice and significant tumor suppression was confirmed. These results indicate that SGB-complex is a unique multifunctional anticancer agent with much more potent activity under low pO2 conditions as in large advanced cancers.

Apparent absence of a proton beam dose rate effect and possible differences in RBE between Bragg peak and plateau.

PURPOSE: Respiration-gated irradiation for a moving target requires a longer time to deliver single fraction in proton radiotherapy (PRT). Ultrahigh dose rate (UDR) proton beam, which is 10-100 times higher than that is used in current clinical practice, has been investigated to deliver daily dose in single breath hold duration. The purpose of this study is to investigate the survival curve and relative biological effectiveness (RBE) of such an ultrahigh dose rate proton beam and their linear energy transfer (LET) dependence. METHODS: HSG cells were irradiated by a spatially and temporally uniform proton beam at two different dose rates: 8 Gy/min (CDR, clinical dose rate) and 325 Gy/min (UDR, ultrahigh dose rate) at the Bragg peak and 1.75 (CDR) and 114 Gy/min (UDR) at the plateau. To study LET dependence, the cells were positioned at the Bragg peak, where the absorbed dose-averaged LET was 3.19 keV/microm, and at the plateau, where it was 0.56 keV/microm. After the cell exposure and colony assay, the measured data were fitted by the linear quadratic (LQ) model and the survival curves and RBE at 10% survival were compared. RESULTS: No significant difference was observed in the survival curves between the two proton dose rates. The ratio of the RBE for CDR/UDR was 0.98 +/- 0.04 at the Bragg peak and 0.96 +/- 0.06 at the plateau. On the other hand, Bragg peak/plateau RBE ratio was 1.15 +/- 0.05 for UDR and 1.18 +/- 0.07 for CDR. CONCLUSIONS: Present RBE can be consistently used in treatment planning of PRT using ultrahigh dose rate radiation. Because a significant increase in RBE toward the Bragg peak was observed for both UDR and CDR, further evaluation of RBE enhancement toward the Bragg peak and beyond is required.

Changes in the SF-8 scores among healthy non-smoking school teachers after the enforcement of a smoke-free school policy: a comparison by passive smoke status.

BACKGROUND: The effects of the enforcement of a smoke-free workplace policy on health-related quality of life (HRQOL) among a healthy population are poorly understood. The present study was undertaken to examine the effects of the enforcement of a smoke-free school policy on HRQOL among healthy non-smoking schoolteachers with respect to their exposure to passive smoke. METHODS: Two self-reported questionnaire surveys were conducted, the first before and the second after the enforcement of a total smoke-free public school policy in Nara City. A total of 1534 teachers were invited from 62 schools, and their HRQOL was assessed using six domains extracted from the Medical Outcomes Survey Short Form-8 questionnaire (SF-8): general health perception (GH), role functioning-physical (RP), vitality (VT), social functioning (SF), mental health (MH), and role functioning-emotional (RE). The participants were divided into two groups according to their exposure to environmental tobacco smoke (ETS) at baseline: participants not exposed to ETS at school (non-smokers), and participants exposed to ETS at school (passive smokers). Changes in each SF-8 score were evaluated using paired t-tests for each group, and their inter-group differences were evaluated using multiple linear regression analyses adjusted for sex, age, school type, managerial position, and attitude towards a smoke-free policy. RESULTS: After ineligible subjects were excluded, 689 teachers were included in the analyses. The number of non-smokers and passive smokers was 447 and 242, respectively. Significant changes in SF-8 scores were observed for MH (0.9; 95% confidence interval [CI], 0.2-1.5) and RE (0.7; 95% CI, 0.0-1.3) in non-smokers, and GH (2.2; 95% CI, 1.2-3.1), VT (1.8; 95% CI, 0.9-2.7), SF (2.7; 95% CI, 1.6-3.8), MH (2.0; 95% CI, 1.0-2.9), and RE (2.0; 95% CI, 1.2-2.8) in passive smokers. In the multiple linear regression analyses, the net changes in the category scores of GH (1.8; 95% CI, 0.7-2.9), VT (1.4, 95% CI, 0.3-2.5), SF (2.5; 95% CI, 1.1-3.9), MH (1.2; 95% CI, 0.1-2.4) and RE (1.6; 95% CI, 0.5-2.7) in passive smokers significantly exceeded those in non-smokers. CONCLUSIONS: A smoke-free school policy would improve the HRQOL of healthy non-smoking teachers who are exposed to ETS.