ABSTRACT
This study aimed to identify the required capabilities and workload of medical staff in accelerator-based boron neutron capture therapy (BNCT). From August to September 2022, a questionnaire related to the capabilities and workload in the accelerator-based BNCT was administered to 12 physicians, 7 medical physicists and 7 radiological technologists engaged in BNCT and 6 other medical physicists who were not engaged in BNCT to compare the results acquired by those engaged in BNCT. Only 6-21% of patients referred for BNCT received it. Furthermore, 30-75% of patients who received BNCT were treated at facilities located within their local district. The median required workload per treatment was 55 h. Considering additional workloads for ineligible patients, the required workload reached ~1.2 times longer than those for only eligible patients' treatment. With respect to capabilities, discrepancies were observed in treatment planning, quality assurance and quality control, and commissioning between medical physicists and radiological technologists. Furthermore, the specialized skills required by medical physicists are impossible to acquire from the experience of conventional radiotherapies as physicians engaged in BNCT were specialized not only in radiation oncology, but also in other fields. This study indicated the required workload and staff capabilities for conducting accelerator-based BNCT considering actual clinical conditions. The workload required for BNCT depends on the occupation. It is necessary to establish an educational program and certification system for the skills required to safely and effectively provide BNCT to patients.
ABSTRACT
This study aims to evaluate the feasibility of using a commercially available boron neutron capture therapy (BNCT) dose calculation program (NeuCure® Dose Engine) in terms of calculation accuracy and computation time. Treatment planning was simulated under the following calculation parameters: 1.5-5.0 mm grid sizes and 1-10% statistical uncertainties. The calculated monitor units (MUs) and computation times were evaluated. The MUs calculated on grid sizes larger than 2 mm were overestimated by 2% compared with the result of 1.5 mm grid. We established the two-step method for the routine administration of BNCT: multiple calculations involved in beam optimization should be done at a 5 mm grid and a 10% statistical uncertainty (the shortest computation time: 10.3 ± 2.1 min) in the first-step, and final dose calculations should be performed at a 2 mm grid and a 10% statistical uncertainty (satisfied clinical accuracy: 6.9 ± 0.3 h) in the second-step.
ABSTRACT
The ocular cytokine network plays pivotal roles in terms of the initiation and progression of retinal degeneration. Several types of immunocompetent cells such as microglia participate in inflammation, and a temporal transition in the molecular events of inflammation has been hypothesized. We previously found that the Csf2 gene was induced in the early phase of retinal degeneration. CSF2 participates in the transcriptional activation of several cytokines expressed by microglia; however, whether CSF2 is essential in this context is not known. In this work, we approach this question by using anti-CSF2 neutralizing bntibody and the protein synthesis inhibitor cycloheximide (CHX). We first revealed that CSF2 positively regulated the cytokine induction cascade using a CSF2-neutralizing antibody (anti-CSF2) to treat the microglial cell line that were activated by lipopolysaccharide (LPS). LPS or Lipid A stimulation in the presence of the protein synthesis inhibitor cycloheximide (CHX) led to cytokine superinduction, but suppression of the expression of a few cytokines was also noted in MG5 cells. To examine transitions of the molecular events within LPS-activated microglia, we next performed proteome analysis of MG5 cells stimulated with LPS for 0, 4, and 9 h. The Database for Annotation, Visualization, and Integrated Discovery analysis of differentially expressed proteins showed that various mRNA-modifying molecules were induced after LPS stimulation, in addition to molecules involved in inflammation. However, the numbers of common proteins founded in the comparison between the induced proteins of 4 and 9 h were only one-third and one-half of induced proteins at 4 and 9 h, respectively, suggesting dynamic transition of the induced proteins. LPS-induced mRNA-modifying proteins were almost completely suppressed by CHX, as expected, suggesting that transient induction of transcription-editing proteins plays an important role in terms of the phenotype of inflammation that develops in microglia after LPS stimulation.
Subject(s)
Cytokines , Lipopolysaccharides , Microglia , Proteome , Microglia/metabolism , Microglia/drug effects , Lipopolysaccharides/pharmacology , Animals , Proteome/metabolism , Cell Line , Cytokines/metabolism , Cycloheximide/pharmacology , Mice , Transcription, Genetic/drug effects , Inflammation/metabolismABSTRACT
BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.
ABSTRACT
NeuCure® is the only accelerator-based boron neutron capture therapy (BNCT) system in the world with pharmaceutical approval. Until now, only flat collimators (FCs) on the patient side have been installed. However, in some cases of head and neck cancer patients, positioning the patient close enough to the collimator when using FCs was difficult. Thus, there are concerns about the prolongation of the irradiation time and overdose to normal tissues. To address these issues, a collimator with a convex-extended section on the patient side (extended collimators [ECs]) was developed, and its pharmaceutical approval was obtained in February 2022. This study evaluated the physical characterization and usefulness of each collimator using a simple geometry water phantom model and human model. In the water phantom model, the thermal neutron fluxes at 2 cm depth on the central axis were 5.13 × 108, 6.79 × 108, 1.02 × 109, and 1.17 × 109n/cm2/s for FC(120), FC(150), EC50(120), and EC100(120), respectively, when the distance from the irradiation aperture was kept constant at 18 cm. With ECs, the relative off-axis thermal neutron flux decreased steeply. In the hypopharyngeal cancer human model, the tumor dose changes were within <2%, but the maximum oral mucosa doses were 7.79, 8.51, 6.76, and 4.57 Gy-Eq, respectively. The irradiation times were 54.3, 41.3, 29.2, and 24.8 min, respectively. In cases where positioning the patient close to the collimator is difficult, the use of ECs may reduce the dose to normal tissues and shorten the irradiation time.
Subject(s)
Boron Neutron Capture Therapy , Head and Neck Neoplasms , Humans , Monte Carlo Method , Neutrons , Head and Neck Neoplasms/radiotherapy , Water , Pharmaceutical PreparationsABSTRACT
Colony-stimulating factor 2 (CSF2) is a potent cytokine that stimulates myeloid cells, such as dendritic cells and macrophages. We have been analyzing the roles of microglia in retinal degeneration through the modulation of inflammation in the eye, and examined the roles of CSF2 in this process. Both subunits of the CSF2 receptor are expressed in microglia, but no evidence suggesting the involvement of CSF2 in inflammation in the degenerating eye has been reported. We found that Csf2 transcripts were induced in the early phase of in vitro mouse adult retina culture, used as degeneration models, suggesting that CSF2 induction is one of the earliest events occurring in the pathology of retinal degeneration. The administration of CSF2 into the retina after systemic NaIO3 treatment increased the number of microglia. To examine the roles of CSF2 in retinal inflammation, we overexpressed CSF2 in retinal explants. Induction of CSF2 activated microglia and Müller glia, and the layer structure of the retina was severely perturbed. CC motif chemokine ligand 2 (Ccl2) and C-X-C motif chemokine ligand 10 (Cxcl10), both of which are expressed in activated microglia, were strongly induced by the expression of CSF2 in the retina. The addition of CSF2 to primary retinal microglia and the microglial cell lines MG5 and BV2 showed statistically significant increase in Ccl2 and Il1b transcripts. Furthermore, CSF2 induced proliferation, migration, and phagocytosis in MG5 and/or BV2. The effects of CSF2 on microglia were mild, suggesting that CSF2 induced strong inflammation in the context of the retinal environment.
Subject(s)
Retinal Degeneration , Animals , Chemokines/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor , Inflammation/metabolism , Ligands , Mice , Microglia/metabolism , Retina/pathology , Retinal Degeneration/metabolism , Retinal Degeneration/pathologyABSTRACT
Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.
Subject(s)
Lipopolysaccharides , Retinal Degeneration , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Electroretinography , Light , Lipopolysaccharides/pharmacology , Photoreceptor Cells, Vertebrate , Rats , Retina , Retinal Degeneration/drug therapy , Retinal Degeneration/etiologyABSTRACT
We aimed to evaluate dosimetric effects of ipsilateral shoulder position variations (ISPVs) in sitting-positioned boron neutron capture therapy (BNCT) for lower neck tumor. The ISPVs were simulated using deformed shoulder images that can simulate arbitrary shape. The dose-volume parameters for the tumor in the rotated shoulder plans considerably varied compared with that for the mucosa. Even in a small number of cases, these differences were clearly observed among patients. The ISPVs in lower neck BNCT have great dosimetric effects.
Subject(s)
Boron Neutron Capture Therapy , Head and Neck Neoplasms , Boron Compounds , Boron Neutron Capture Therapy/methods , Head and Neck Neoplasms/radiotherapy , Humans , Neoplasm Recurrence, Local , Shoulder/pathology , Sitting PositionABSTRACT
The irradiation field of boron neutron capture therapy (BNCT) consists of multiple dose components including thermal, epithermal and fast neutron, and gamma. The objective of this work was to establish a methodology of dosimetric quality assurance (QA), using the most standard and reliable measurement methods, and to determine tolerance level for each QA measurement for a commercially available accelerator-based BNCT system. In order to establish a system of dosimetric QA suitable for BNCT, the following steps were taken. First, standard measurement points based on tissue-administered doses in BNCT for brain tumors were defined, and clinical tolerances of dosimetric QA measurements were derived from the contribution to total tissue relative biological effectiveness factor-weighted dose for each dose component. Next, a QA program was proposed based on TG-142 and TG-198, and confirmed that it could be assessed whether constancy of each dose component was assured within the limits of tolerances or not by measurements of the proposed QA program. Finally, the validity of the BNCT QA program as an evaluation system was confirmed in a demonstration experiment for long-term measurement over 1 year. These results offer an easy, reliable QA method that is clinically applicable with dosimetric validity for the mixed irradiation field of accelerator-based BNCT.
Subject(s)
Boron Neutron Capture Therapy , Brain Neoplasms , Boron Neutron Capture Therapy/methods , Brain Neoplasms/radiotherapy , Gamma Rays , Humans , Neutrons , Radiometry , Relative Biological EffectivenessABSTRACT
The dosimetric effect of set-up error in boron neutron capture therapy (BNCT) for head and neck cancer remains unclear. In this study, we analyzed the tendency of dose error by treatment location when simulating the set-up error of patients. We also determined the tolerance level of the set-up error in BNCT for head and neck cancer. As a method, the distal direction was shifted with an interval of 2.5 mm, from 0.0 mm to +20.0 mm and compared with the dose at the reference position. Similarly, the horizontal direction and vertical direction were shifted, with an interval of 5.0 mm, from -20.0 mm to +20.0 mm. In addition, cases with 3.0 mm and 5.0 mm simultaneous shifts in all directions were analyzed as the worst-case scenario. The dose metrics of the minimum dose of the tumor and the maximum dose of the mucosa were evaluated. From unidirectional set-up error analysis, in most cases, the set-up errors with dose errors within ±5% were Δdistal < +2.5 mm, Δhorizontal < ±5.0 mm and Δvertical < ±5.0 mm. In the simulation of 3.0 mm shifts in all directions, the errors in the minimum tumor dose and maximum mucosal dose were -3.6% ±1.4% (range, -5.4% to -0.6%) and 2% ±1.4% (range, 0.4% to 4.5%), respectively. From these results, if the set-up error was within ±3.0 mm in each direction, the dose errors of the tumor and mucosa could be suppressed within approximately ±5%, which is suggested as a tolerance level.
Subject(s)
Boron Neutron Capture Therapy , Head and Neck Neoplasms , Boron Neutron Capture Therapy/methods , Computer Simulation , Head and Neck Neoplasms/radiotherapy , Humans , Radiometry , Radiotherapy DosageABSTRACT
The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14-48 days) for oral mucositis, 40 days (IQR, 24-56 days) for dermatitis, 58 days (IQR, 53-80 days) for dysgeusia and 156 days (IQR, 82-163 days) for alopecia. In the FF beam group, parotitis (P = 0.007) was less frequent, while oral mucositis (P = 0.032), fatigue (P = 0.002), conjunctivitis (P = 0.001), epistaxis (P = 0.001) and abdominal discomfort (P = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT.
Subject(s)
Boron Neutron Capture Therapy , Carcinoma, Squamous Cell , Head and Neck Neoplasms , Stomatitis , Boron Neutron Capture Therapy/adverse effects , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/radiotherapy , Humans , Neoplasm Recurrence, Local , Stomatitis/etiologyABSTRACT
Intractable late urinary toxicity is a serious complication after radiotherapy for patients with localized prostate cancer (LPC). We assessed clinical factors correlated with severe late urinary toxicity in LPC treated with curative image-guided intensity-modulated radiation therapy (IMRT). A total of 452 patients with LPC treated with IMRT between 2002 and 2016 were retrospectively analyzed. Among them, 432 patients received androgen deprivation therapy (ADT). The median total irradiated doses were 80 (range, 76-80) Gy. Each daily dose was 2 Gy per fraction. The median follow-up was 83 (range, 4-210) months. Late urinary toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03. Grade 3 late urinary toxicity was observed in 27 patients. No cases with grade ≥ 4 late urinary toxicity were observed. The 5-, 10-, and 12.5-year grade 3 late urinary toxicity-free survival rates were 97%, 91.8% and 88.1%, respectively. Age, risk classification, total irradiated dose, ADT duration, antithrombotic therapy (AT), cardiovascular disease, hypertension (HT), diabetes mellitus (DM), dyslipidemia (DL), prior transurethral resection of the prostate (TURP) and prior high-intensity focused ultrasound (HIFU) were investigated for correlations with grade 3 late urinary toxicity. In univariate analysis, AT and prior HIFU and no other studied factors, were correlated with grade 3 late urinary toxicity. AT and prior HIFU appear to be predictive of grade 3 late urinary toxicity. Patients with LPC with these relevant clinical factors should be carefully followed up by sharing detailed information with the urology department.
ABSTRACT
Cellular immortalization enables indefinite expansion of cultured cells. However, the process of cell immortalization sometimes changes the original nature of primary cells. In this study, we performed expression profiling of poly A-tailed RNA from primary and immortalized corneal epithelial cells expressing Simian virus 40 large T antigen (SV40) or the combination of mutant cyclin-dependent kinase 4 (CDK4), cyclin D1, and telomere reverse transcriptase (TERT). Furthermore, we studied the expression profile of SV40 cells cultured in medium with or without serum. The profiling of whole expression pattern revealed that immortalized corneal epithelial cells with SV40 showed a distinct expression pattern from wild-type cells regardless of the presence or absence of serum, while corneal epithelial cells with combinatorial expression showed an expression pattern relatively closer to that of wild-type cells.
Subject(s)
Antigens, Polyomavirus Transforming/genetics , Epithelium, Corneal/cytology , Epithelium, Corneal/metabolism , Transcriptome , Cyclin D1/genetics , Cyclin-Dependent Kinase 4/genetics , Epithelial Cells/metabolism , Humans , Primary Cell Culture , Proteolysis , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Telomerase/genetics , UbiquitinABSTRACT
Lung cancer with low average iodine density measured via contrast-enhanced computed tomography (CT) using dual-energy CT technology has shown a reduced local control rate after stereotactic body radiotherapy (SBRT). The current study therefore investigated the relationship between low iodine density tumor area and its ratio and local recurrence after SBRT. Dual-energy CT was performed on the day before SBRT initiation, with a low iodine density tumor area being defined as that with an iodine density of <1.81 mg cm-3. The low iodine density tumor area, the ratio between the low iodine density tumor area and the entire tumor, and the local recurrence rate were then determined. No correlation was observed between the low iodine density tumor area and the local recurrence rate. However, tumors with a large low iodine density tumor area ratio showed an increased local recurrence rate, with the prognostic accuracy almost similar to that in previous studies using average iodine densities. Our results therefore suggest that the low iodine density tumor area ratio was a useful prognostic index after SBRT, with an accuracy comparable with that of the average iodine density.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/radiotherapy , Iodine/chemistry , Lung Neoplasms/pathology , Lung Neoplasms/radiotherapy , Radiosurgery , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Cardiac Output , Female , Humans , Lung Neoplasms/diagnostic imaging , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Prognosis , ROC Curve , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND AND PURPOSE: Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer. MATERIALS AND METHODS: In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS). RESULTS: Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4-76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%). CONCLUSION: These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.
Subject(s)
Boron Neutron Capture Therapy , Head and Neck Neoplasms , Cyclotrons , Head and Neck Neoplasms/radiotherapy , Humans , Neoplasm Recurrence, Local/radiotherapy , NeutronsABSTRACT
Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protects neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce heat shock proteins (Hsps). Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.
Subject(s)
Diterpenes/pharmacology , Glutamic Acid/toxicity , Hippocampus/drug effects , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Neurons/drug effects , Neuroprotective Agents/pharmacology , Animals , Calcium/metabolism , Cell Death/drug effects , Cell Line , Extracellular Signal-Regulated MAP Kinases/metabolism , HSP70 Heat-Shock Proteins/genetics , HSP70 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Mice , Mitochondria/metabolism , Mitochondria/pathology , Neurons/metabolism , Neurons/pathology , Oxidative Stress/drug effects , Phosphorylation , Reactive Oxygen Species/metabolismABSTRACT
The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 µM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 µM DFO treatment. In cells treated with 5 µM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Neutron Capture Therapy/methods , Indazoles/pharmacology , Neoplasms/drug therapy , Neoplasms/radiotherapy , Radiation-Sensitizing Agents/pharmacology , Cell Hypoxia , Cell Line, Tumor , Cell Survival/drug effects , Deferoxamine/pharmacology , Humans , Hypoxia , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Large Neutral Amino Acid-Transporter 1/metabolism , MCF-7 Cells , Neutrons , Oxygen/metabolism , Phenylalanine/therapeutic use , RNA, Small Interfering/metabolismABSTRACT
Purpose: Photoreceptor degeneration is a major cause of blindness. Microglia are known to play key roles in the pathogenesis and progression of neural degeneration. We examined the possible use of apigenin, which is a naturally occurring flavonoid, for the treatment of photoreceptor degeneration through regulation of microglial activities. Methods: As in vitro analyses, BV2 and MG5 mouse microglia cell lines were stimulated in the presence or absence of apigenin, and their activation profile was examined. In vivo study was done using rd1 photoreceptor degeneration model, and apigenin was administered by intravitreal injection, and pathological feature was examined. Results: Cell survival was not affected by apigenin in either BV2 and MG5. Apigenin suppressed lipopolysaccharide (LPS)-induced chemokine production in both BV2 and MG5 cells, but phagocytosis was suppressed in MG5 cells but not in BV2 cells. Apigenin inhibited LPS-induced M1 activation but could not drive microglia toward the M2 phenotype. Apigenin suppressed the expression of miR-155 in a dose-dependent manner. Furthermore, the Ets protein level was suppressed by treatment of BV2 cells with apigenin. When rd1 mice were treated with apigenin by intravitreal injection, the expression of inflammatory chemokines in the retina was reduced, and activation of microglia and Müller glia was suppressed. Furthermore, the thickness of the outer nuclear layer of the retina of rd1 mice was thicker in apigenin-treated retinas. Conclusions: Taken together, local administration of apigenin to the retina is a potential therapeutic treatment for photoreceptor degeneration, which involves downregulation of microglia in the retina when photoreceptors are damaged.
Subject(s)
Apigenin/pharmacology , Flavonoids/pharmacology , Microglia/drug effects , Photoreceptor Cells, Vertebrate/drug effects , Retinal Degeneration/drug therapy , Animals , Apigenin/administration & dosage , Chemokines/drug effects , Chemokines/metabolism , Down-Regulation , Flavonoids/administration & dosage , Intravitreal Injections/methods , Lipopolysaccharides/metabolism , Mice , MicroRNAs/drug effects , MicroRNAs/metabolism , Microglia/metabolism , Models, Animal , Phagocytosis/drug effects , Photoreceptor Cells, Vertebrate/metabolism , Retina/metabolism , Retinal Degeneration/pathologyABSTRACT
We report the anisotropic thermal expansion of a transparent nanopaper structure comprising cellulose nanofibers (CNFs). The coefficient of thermal expansion (CTE) of the nanopaper in the out-of-plane direction was 44.6 ppm/°C in the temperature range of 25-100°C, which is approximately five times larger than its CTE in the in-plane direction in the same temperature range (8.3 ppm/°C). Such a strong anisotropy in thermal expansion is mainly attributable to the anisotropic CTE values of single CNFs in the fiber axis and cross-sectional directions. We observed anisotropic thermal expansion even in a bioplastic composite containing only 2.5% w/w CNFs.
ABSTRACT
Installation of an accelerator-based boron neutron capture therapy (AB-BNCT) system was started in April 2014â¯at the Southern Tohoku BNCT Research Center (STBRC), and clinical trials began in January 2016. There are two treatment rooms, which have same specifications, and the beam quality equivalency was confirmed both rooms. Here, we describe the design and construction of the first hospital-based AB-BNCT facility in the world with multiple treatment rooms.