The mechanism of multistep progression of the transcriptional cascade in activated microglia as approached by a proteome approach.

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.

Roles of CSF2 as a modulator of inflammation during retinal degeneration.

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.

SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process.

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.

Fourier Analysis of Corneal Irregular Astigmatism Due to the Anterior Corneal Surface in Dry Eye.

OBJECTIVES: To evaluate corneal irregular astigmatism due to the anterior corneal surface using Fourier harmonic analysis with a Placido ring-based corneal topographer (Placido-based topographer) and three-dimensional anterior segment optical coherence tomography (OCT) in dry eyes. METHODS: Forty-four eyes of 44 subjects with dry eye and 20 eyes of 20 normal control subjects were enrolled. Corneal topographic data were obtained using a Placido-based topographer and OCT. Dioptric data from the central 3-mm zone of the anterior corneal surface were decomposed using Fourier harmonic analysis. Spherical, regular astigmatism, and irregular astigmatism (asymmetry and higher-order irregularity) refractive error components of the cornea from the two imaging modalities were compared. RESULTS: Both asymmetry and higher-order irregularity values were significantly greater in dry eyes than in control eyes for both the Placido-based topographer and OCT measurements (all P<0.05). In dry eyes, measured values of asymmetry and higher-order irregularities were significantly smaller when obtained with OCT than with the Placido-based topographer (both P<0.001). By contrast, these parameters were not significantly different between the two devices in control eyes. In dry eyes, severity of superficial punctate keratopathy in the central corneal region was correlated with irregular astigmatism. CONCLUSIONS: The amount of corneal irregular astigmatism, quantified using Fourier harmonic analysis, was significantly higher in dry eyes than in normal eyes. Measurements obtained with OCT and the Placido-based topographer differed in subjects with dry eyes. Therefore, caution should be practiced when trying to use these measurements interchangeably.

Clinical results of proton beam therapy for hepatocellular carcinoma over 5 cm.

AIM: This study aimed to evaluate the safety and efficacy of proton beam therapy for large hepatocellular carcinoma (HCC). METHODS: Twenty-four patients with a HCC larger than 5.0 cm were treated with proton beam therapy at our institution between 2008 and 2015. RESULTS: The clinical stage was I in 2 patients, II in 9 patients, and IIIB in 13 patients. Ten of the 24 patients were not surgical candidates because of advanced HCC or old age. Median tumor size was 90 mm (range, 50-180 mm). Median total dose delivered was 72.6 Gray-equivalents (GyE) in 22 fractions (range, 60.8-85.8 GyE). Median follow-up period was 17.5 months (range, 3-70 months). Local control rate at 2 years was 87.0%. The 2-year overall survival rate was 52.4%. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No acute or late treatment-related toxicity of grade 3 or higher, other than dermatitis, was observed. CONCLUSIONS: These results show that proton beam therapy offers an effective and safe method for treating patients with large HCC. Proton beam therapy represents a promising method for treatment of large-volume HCC.

Temporal variations in stump pressure and assessment of images obtained from cone-beam computed tomography during balloon-occluded transarterial chemoembolization.

AIM: Balloon-occluded transcatheter arterial chemoembolization (B-TACE) was used to show the optimized duration of balloon occlusion to start injection of lipiodol in order to maximize lipiodol deposition in the nodule, and to reveal the endpoint of lipiodol injection. METHODS: Of 29 consecutive patients who underwent balloon-occluded TACE between November 2013 and February 2014, we were able to measure stump pressure for 219 nodules in 27 patients. Tumors were counted, measured and could be visually assessed in 20 of these patients at 26 sites. Tumors with multiple feeders were found in eight patients. Arterial blood pressure was measured before, immediately after and 5 min after balloon occlusion prior to intra-arterial injection, as well as before and after balloon deflation after intra-arterial injection. Images were assessed qualitatively by two radiologists as well as quantitatively by calculating the contrast-to-noise ratio. RESULTS: We found no significant difference in pressure between immediately after and 5 min after balloon occlusion. Mean stump pressure before balloon deflation after intra-arterial injection was 70.4 mmHg. We observed a significant increase in qualitative scores after balloon occlusion (P < 0.001), and the mean score in the third-order branch was significantly higher than that in the first-order branch (P = 0.048). CONCLUSION: Our results indicate that intra-arterial injection can be started at any time after balloon occlusion and that 70 mmHg may be considered as a possible indicator of the end-point for arterial injection.

Hypoxic viable tissue in human chronic cerebral ischemia because of unilateral major cerebral artery steno-occlusive disease.

BACKGROUND AND PURPOSE: Positron emission tomography (PET) with radiolabeled 2-nitroimidazoles directly detects hypoxic but viable tissue present in an acute ischemic area in the human brain. This study using PET with 1-(2-(18)F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole ((18)F-FRP170) aimed to determine whether tissue with an abnormally elevated uptake of (18)F-FRP170 exists in human chronic cerebral ischemia because of unilateral atherosclerotic major cerebral artery steno-occlusive disease. METHODS: (18)F-FRP170 PET was performed, and cerebral blood flow and metabolism were assessed using (15)O-gas PET in 20 healthy subjects and 52 patients. A region of interest (ROI) was automatically placed in 3 segments of the middle cerebral artery territory in both cerebral hemispheres with a 3-dimensional stereotaxic ROI template using SPM2, and each PET value was determined in each ROI. The ratio of values in the affected versus contralateral hemispheres was calculated for the (18)F-FRP170 PET image. RESULTS: A significant correlation was observed between oxygen extraction fraction and (18)F-FRP170 ratios (ρ=0.509; P<0.0001) in a total of 156 ROIs in 52 patients. The specificity and positive-predictive value for a combination of an elevated oxygen extraction fraction and a moderately reduced cerebral oxygen metabolism for detection of an abnormally elevated (18)F-FRP170 ratio (19 ROIs: 12%) were significantly greater than those for the individual categories (elevated oxygen extraction fraction, moderately reduced cerebral oxygen metabolism, or reduced cerebral blood flow). CONCLUSIONS: Tissues with abnormally elevated uptake of (18)F-FRP170 exist in human chronic cerebral ischemia characterized by a combination of misery perfusion and moderately reduced oxygen metabolism because of unilateral atherosclerotic major cerebral artery steno-occlusive disease.

The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer.

BACKGROUND: The aim of this study was to investigate the prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictive marker prior to treatment of cervical cancer with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT). METHODS: Fifty-six patients with squamous cell carcinoma (SCC) of the uterine cervix who underwent RT or CCRT from 2005-2013 at the Hirosaki University Hospital were retrospectively identified using electronic databases. Patients were divided into a high NLR group (≥2.5) and a low NLR group (<2.5). The efficacy of RT and CCRT in the two groups was compared. RESULT: Of the 56 patients, 35 were in the high NLR group and 21 were in the low NLR group. In comparison to a high NLR, a low NLR was significantly associated with a complete response (P < 0.001). When cancer was divided into stages I/II and III/IV, patients with a low NLR had a significantly better therapeutic outcome than those with a high NLR (P < 0.05). Multivariate analysis showed that only the NLR was a significant prognostic factor for progression-free survival (PFS) and overall survival (OS). Patients with a high NLR had significantly shorter PFS and OS than those with a low NLR. CONCLUSION: Results showed that a low NLR before treatment could predict a good response to RT or CCRT at all stages of uterine cervical cancer. The NLR may be a promising parameter on which to base the choice of a therapeutic strategy to treat SCC of the uterine cervix.

Comparison of osteoradionecrosis of the jaw after superselective intra-arterial chemoradiotherapy versus conventional concurrent chemoradiotherapy of oral cancer.

PURPOSE: The purpose of the present study was to compare the incidence of osteoradionecrosis between superselective intra-arterial chemoradiotherapy and intravenous chemoradiotherapy and to verify the risk factors for osteoradionecrosis. MATERIALS AND METHODS: Of the 79 patients with oral cancer, 40 were treated with intra-venous chemoradiotherapy and 39 were treated with superselective intra-arterial chemoradiotherapy. The incidence of, and risk factors for, osteoradionecrosis were evaluated using statistical analysis. RESULTS: Of the 79 patients, 4 (10%) of 40 in the intravenous chemoradiotherapy and 7 (17.9%) of 39 in the superselective intra-arterial chemoradiotherapy group developed osteoradionecrosis of the jaw. No significant difference was found between the 2 groups. Although the chemoradiotherapy methods, anatomic tumor location, smoking behavior, alcohol consumption, condition of teeth, teeth extraction before radiation, and progression of dental caries were considered predisposing factors for the occurrence of osteoradionecrosis, only progressive dental caries resulted in a significant difference for osteoradionecrosis. CONCLUSIONS: The present study is the first report comparing the incidence of osteoradionecrosis between superselective intra-arterial chemoradiotherapy and intravenous chemoradiotherapy. The administration methods of anticancer drugs were not related to the incidence of osteoradionecrosis in our study. From our study, dental caries is the most important risk factor for osteoradionecrosis; therefore, a radiation caries prevention program is crucial to control osteoradionecrosis.

Outcomes after stereotactic body radiotherapy for lung tumors, with emphasis on comparison of primary lung cancer and metastatic lung tumors.

BACKGROUND: The goal of this study was to determine the prognostic factors associated with an improved overall outcome after stereotactic body radiotherapy (SBRT) for primary lung cancer and metastatic lung tumors. METHODS: A total of 229 lung tumors in 201 patients were included in the study. SBRT of 45 Gy in 3 fractions, 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions was typically used to treat 172 primary lungs cancer in 164 patients and 57 metastatic lung tumors in 37 patients between January 2001 and December 2011. Prognostic factors for local control (LC) and overall survival (OS) were analyzed using a Cox proportional hazards model. RESULTS: The median biologically effective dose was 105.6 Gy based on alpha/beta = 10 (BED10). The median follow-up period was 41.9 months. The 3-year LC and OS rates were 72.5% and 60.9%, and the 5-year LC and OS rates were 67.8% and 38.1%, respectively. Radiation pneumonitis of grades 2, 3 and 5 occurred in 22 patients, 6 patients and 1 patient, respectively. Multivariate analyses revealed that tumor origin (primary lung cancer or metastatic lung tumor, p < 0.001), tumor diameter (p = 0.005), BED10 (p = 0.029) and date of treatment (p = 0.011) were significant independent predictors for LC and that gender (p = 0.012), tumor origin (p = 0.001) and tumor diameter (p < 0.001) were significant independent predictors for OS. CONCLUSIONS: SBRT resulted in good LC and tolerable treatment-related toxicities. Tumor origin and tumor diameter are significant independent predictors for both overall survival and local control.

Prediction of maintained mucosal healing in patients with Crohn's disease under treatment with infliximab using diffusion-weighted magnetic resonance imaging.

BACKGROUND: Maintenance of mucosal healing may lead to a better outcome in patients with Crohn's disease (CD). Magnetic resonance diffusion-weighted imaging (MR-DWI) scans 1 year after infliximab (IFX) induction therapy were assessed as predictors of maintained response, or remission, through 3 years of treatment in patients with CD. SUMMARY: MR-DWI and endoscopy data were prospectively collected throughout IFX treatment. Altogether, 86 lesions from 13 patients given IFX as induction (weeks 0, 2 and 6) and maintenance (5 mg/kg every 8 weeks beginning at week 14) therapy were analyzed with MR-DWI for 0.5-1.5 years from the starting point. Mucosal findings were confirmed by endoscopy at 1 and 3 years (gold standard). Of the 86 lesions, 65 were graded '0' and 21 were graded '1' based on their hyperintensity (HI; or lack thereof) on MR-DWI. Two years after the first evaluation, 7 of 15 false-negative lesions had turned positive based on colonoscopy findings, and 60 of 62 true-negative lesions had not. Thus, 0.03% of those predicted to remain in remission had relapsed (negative predictive value 0.9677, p < 0.0001). MR-DWI-HI at 1 year coincided with the presence of endoscopic inflammation, with sensitivity of 66.67%, specificity of 80.52%, and an area under the curve (AUC) value of 0.7359 (0.5479-0.9240, p = 0.0211). The AUC value of MR-DWI-HI at 3 years was 0.8402 (0.7460-0.9343, p = 0.001) with sensitivity of 94.12% and specificity of 73.91%. KEY MESSAGE: A definition of the response on the basis of MR-DWI-HI might be helpful for optimizing treatment for patients with CD under treatment with IFX.

Both radical prostatectomy following treatment with neoadjuvant LHRH agonist and estramustine and radiotherapy following treatment with neoadjuvant hormonal therapy achieved favorable oncological outcome in high-risk prostate cancer: a propensity-score matching analysis.

BACKGROUND: To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT). METHODS: We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70 to 76 Gy administered at 2 Gy/fraction. RESULTS: Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival rates were 98.3% and 92.1% in the RP and RT groups, respectively (P=0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P=0.878). CONCLUSIONS: Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have an important impact on decision making in treatment of high-risk Pca.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

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.

Evaluation of calculation accuracy and computation time in a commercial treatment planning system for accelerator-based boron neutron capture therapy.

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.

A national survey of medical staffs' required capability and workload for accelerator-based boron neutron capture therapy.

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.

Characterization and clinical utility of different collimator shapes in accelerator-based BNCT systems for head and neck cancer.

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.

A simplified method to generate serotonergic neurons from mouse embryonic stem and induced pluripotent stem cells.

We have developed a new simple method to induce serotonergic neurons from embryonic stem (ES) and induced pluripotent stem cells. When ES or induced pluripotent stem cells were cultured on a thick gel layer of Matrigel, most colonies extended TuJ1-positive neurites. We found that noggin, a known antagonist of bone morphogenic protein, induces ES cells to express genes involved in serotonergic differentiation, such as Nkx2.2, Pet-1, Sonic hedgehog, tryptophan hydroxylase 2, and serotonin transporter, as well as increases high potassium-induced release of serotonin. To concentrate serotonergic neurons, ES cells carrying Pet-1-enhancer-driven enhanced green fluorescent protein were differentiated and sorted into about 80% pure cultures of serotonergic neurons. Whole cell voltage-clamp recordings showed a voltage-dependent current in dissociated neurons. This simplified method provides an alternative option for serotonergic differentiation of pluripotent stem cells and will likely contribute a deeper understanding regarding the nature of serotonergic neurons and open new therapeutic perspectives for the treatment of psychiatric disorders.

Profile analysis of adverse events after boron neutron capture therapy for head and neck cancer: a sub-analysis of the JHN002 study.

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.

Dosimetric effects of the ipsilateral shoulder position variations in the sitting-positioned boron neutron capture therapy for lower neck tumor.

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.

Determining a methodology of dosimetric quality assurance for commercially available accelerator-based boron neutron capture therapy system.

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.