Microdosimetric quantities of an accelerator-based neutron source used for boron neutron capture therapy measured using a gas-filled proportional counter

Boron neutron capture therapy (BNCT) is an emerging radiation treatment modality, exhibiting the potential to selectively destroy cancer cells. Currently, BNCT is conducted using a nuclear reactor. However, the future trend is to move toward an accelerator-based system for use in hospital environments. A typical BNCT radiation field has several different types of radiation. The beam quality should be quantified to accurately determine the dose to be delivered to the target. This study utilized a tissue equivalent proportional counter (TEPC) to measure microdosimetric and macrodosimetric quantities of an accelerator-based neutron source. The micro- and macro-dosimetric quantities measured with the TEPC were compared with those obtained via the the particle and heavy ion transport code system (PHITS) Monte Carlo simulation. The absorbed dose from events >20 keV/μm measured free in air for a 1-h irradiation was calculated as 1.31 ± 0.02 Gy. The simulated result was 1.41 ± 0.07 Gy. The measured and calculated values exhibit good agreement. The relative biological effectiveness (RBE) that was evaluated from the measured microdosimetric spectrum was calculated as 3.7 ± 0.02, similar to the simulated value of 3.8 ± 0.1. These results showed the PHITS Monte Carlo simulation can simulate both micro- and macro-dosimetric quantities accurately. The RBE was calculated using a single-response function, and the results were compared with those of several other institutes that used a similar method. However, care must be taken when using such a single-response function for clinical application, as it is only valid for low doses. For clinical dose ranges (i.e., high doses), multievent distribution inside the target needs to be considered

Development and evaluation of dose calculation algorithm with a combination of Monte Carlo and point-kernel methods for boron neutron capture therapy

We developed a 'hybrid algorithm' that combines the Monte Carlo (MC) and point-kernel methods for fast dose calculation in boron neutron capture therapy. The objectives of this study were to experimentally verify the hybrid algorithm and to verify the calculation accuracy and time of a 'complementary approach' adopting both the hybrid algorithm and the full-energy MC method. In the latter verification, the results were compared with those obtained using the full-energy MC method alone. In the hybrid algorithm, the moderation process of neutrons is simulated using only the MC method, and the thermalization process is modeled as a kernel. The thermal neutron fluxes calculated using only this algorithm were compared with those measured in a cubic phantom. In addition, a complementary approach was used for dose calculation in a geometry simulating the head region, and its computation time and accuracy were verified. The experimental verification indicated that the thermal neutron fluxes calculated using only the hybrid algorithm reproduced the measured values at depths exceeding a few centimeters, whereas they overestimated those at shallower depths. Compared with the calculation using only the full-energy MC method, the complementary approach reduced the computation time by approximately half, maintaining nearly same accuracy. When focusing on the calculation only using the hybrid algorithm only for the boron dose attributed to the reaction of thermal neutrons, the computation time was expected to reduce by 95% compared with the calculation using only the full-energy MC method. In conclusion, modeling the thermalization process as a kernel was effective for reducing the computation time

Intensity-modulated irradiation for superficial tumors by overlapping irradiation fields using intensity modulators in accelerator-based BNCT

The distribution of the thermal neutron flux has a significant impact on the treatment efficacy. We developed an irradiation method of overlapping irradiation fields using intensity modulators for the treatment of superficial tumors with the aim of expanding the indications for accelerator-based boron neutron capture therapy (BNCT). The shape of the intensity modulator was determined and Monte Carlo simulations were carried out to determine the uniformity of the resulting thermal neutron flux distribution. The intensity modulators were then fabricated and irradiation tests were conducted, which resulted in the formation of a uniform thermal neutron flux distribution. Finally, an evaluation of the tumor dose distribution showed that when two irradiation fields overlapped, the minimum tumor dose was 27.4 Gy-eq, which was higher than the tumor control dose of 20 Gy-eq. Furthermore, it was found that the uniformity of the treatment was improved 47% as compared to the treatment that uses a single irradiation field. This clearly demonstrates the effectiveness of this technique and the possibility of expanding the indications to superficially located tumors

Development of optimization method for uniform dose distribution on superficial tumor in an accelerator-based boron neutron capture therapy system

To treat superficial tumors using accelerator-based boron neutron capture therapy (ABBNCT), a technique was investigated, based on which, a single-neutron modulator was placed inside a collimator and was irradiated with thermal neutrons. In large tumors, the dose was reduced at their edges. The objective was to generate a uniform and therapeutic intensity dose distribution. In this study, we developed a method for optimizing the shape of the intensity modulator and irradiation time ratio to generate a uniform dose distribution to treat superficial tumors of various shapes. A computational tool was developed, which performed Monte Carlo simulations using 424 different source combinations. We determined the shape of the intensity modulator with the highest minimum tumor dose. The homogeneity index (HI), which evaluates uniformity, was also derived. To evaluate the efficacy of this method, the dose distribution of a tumor with a diameter of 100 mm and thickness of 10 mm was evaluated. Furthermore, irradiation experiments were conducted using an ABBNCT system. The thermal neutron flux distribution outcomes that have considerable impacts on the tumor’s dose confirmed a good agreement between experiments and calculations. Moreover, the minimum tumor dose and HI improved by 20 and 36%, respectively, compared with the irradiation case wherein a single-neutron modulator was used. The proposed method improves the minimum tumor volume and uniformity. The results demonstrate the method’s efficacy in ABBNCT for the treatment of superficial tumors

Effect of Cetuximab and EGFR Small Interfering RNA Combination Treatment in NSCLC Cell Lines with Wild Type EGFR and Use of KRAS as a Possible Biomarker for Treatment Responsiveness

[Background] The epidermal growth factor receptor (EGFR) is a therapeutic target for patients with non-small cell lung cancer (NSCLC). Cetuximab is an anti-EGFR monoclonal antibody that inhibits EGFR signaling and proliferation of colorectal cancer and head and neck cancers. Since only few NSCLC patients benefit from cetuximab therapy, we evaluated a novel combination treatment using cetuximab and EGFR small interfering RNA (siRNA) to strongly suppress EGFR signaling and searched for a biomarker in NSCLC cell lines harboring wild-type EGFR. [Methods] Alterations in EGFR and its downstream genes in five NSCLC cell lines (A549, Lu99, 86-2, Sq19 and Ma10) were assessed through sequencing. The protein expression levels of these molecules were assessed through western blotting. The effect of combination treatment was determined through cell proliferation assay, caspase-3/7 assay, invasion assay, and migration assay. [Results] All cell lines were harboring wild-type EGFR, whereas KRAS, PTEN, TP53 and TP53 were mutated in A549 and Lu99; Lu99 and Sq19; Lu99, 86-2, Sq19 and Ma10; and A549, 86-2, and Sq19 cell lines, respectively. PTEN was not expressed in Sq19, and LKB1 was not expressed in both A549 and Sq19. TP53 was not expressed in both A549 and Lu99. The combination of cetuximab and EGFR siRNA significantly suppressed cell proliferation in 86-2, Sq19 and Ma10, which express wild-type KRAS. It induced apoptosis in A549, 86-2 and Ma10 cells, which express wild type PTEN. The combination treatment had no effect either on cell invasion nor migration in all cell lines. [Conclusion] EGFR targeted therapy using the combination of cetuximab and EGFR siRNA is effective in NSCLC cell lines harboring wild-type EGFR. Wild-type KRAS may act as a potential biomarker for response to combination treatment by the induction of apoptosis in cells with wild-type PTEN

Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts

Background : Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, is involved in the pathogenesis of rheumatoid arthritis (RA). The omega-3 unsaturated fatty acid-derived metabolites resolvin (Rv) D1, RvE1, and maresin-1 (MaR1) have been reported as anti-inflammatory lipid mediators and are known as specialized pro-resolving mediators (SPMs). In this study, we aimed to investigate the anti-inflammatory effects of SPMs on TNF-α-induced responses in synovial fibroblasts. Methods: We investigated the effects of SPMs on gene expression and/or production of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), interleukin (IL)-6, and matrix metalloproteinase (MMP)-3, which are involved in TNF-α-induced synovitis in RA or OA synovial fibroblasts, by quantitative real-time PCR. We also investigated the effects of SPMs on the mitogen-activated protein kinase (MAPK) signaling pathway by western blotting. Anti-inflammatory effects of SPMs were evaluated by applying SPMs to cultured synovial fibroblasts, followed by TNF-α stimulation. Results: The induction of COX-2, mPGES-1, IL-6, and MMP-3 by TNF-α in synovial fibroblasts was not suppressed by omega 3-derived SPMs regardless of their origin such as RA or OA. SPMs had no effect on lipid mediator receptor gene expression induce by TNF-α and did not inhibit the TNF-α-activated MAPK signaling pathway. The production of COX-2 and IL-6 protein was significantly decreased by p38 inhibitor. Conclusion: Despite reports on the anti-inflammatory effect of omega 3-derived SPMs, its anti-inflammatory effect on TNF-α-induced responses was not observed in synovial fibroblasts. The reason may be that SPMs have no suppressive effect on p38 activation, which plays an important role in the production of inflammatory cytokines in synovial fibroblasts

Loxoprofen Sodium, a Non-Selective NSAID, Reduces Atherosclerosis in Mice by Reducing Inflammation

Recently, it is suggested that the use of nonsteroidal anti-inflammatory drugs (NSAID) may contribute to the occurrence of cardiovascular events, while the formation of atherosclerotic lesions is related to inflammation. Loxoprofen sodium, a non-selective NSAID, becomes active after metabolism in the body and inhibits the activation of cyclooxygenase. We fed apoE−/− mice a western diet from 8 to 16 weeks of age and administered loxoprofen sodium. We measured atherosclerotic lesions at the aortic root. We examined serum levels of cholesterol and triglycerides with HPLC, platelet aggregation, and urinary prostaglandin metabolites with enzyme immune assay. Atherosclerotic lesion formation was reduced to 63.5% and 41.5% as compared to the control in male and female apoE−/− mice treated with loxoprofen sodium respectively. Urinary metabolites of prostaglandin E2, F1α, and thromboxane B2, and platelet aggregation were decreased in mice treated with loxoprofen sodium. Serum levels of cholesterol and triglycerides were not changed. We conclude that loxoprofen sodium reduced the formation of early to intermediate atherosclerotic lesions at the proximal aorta in mice mediated by an anti-inflammatory effect

ゾルーゲル転移を示す生体適合ポリマー材料の開発と応用 (1)

We investigated the release behavior of glucagon-like peptide-1 (GLP-1) from a biodegradable injectable polymer (IP) hydrogel. This hydrogel shows temperature-responsive irreversible gelation due to the covalent bond formation through a thiol-ene reaction. In vitro sustained release of GLP-1 from an irreversible IP formulation (F(P1/D+PA40)) was observed compared with a reversible (physical gelation) IP formulation (F(P1)). Moreover, pharmaceutically active levels of GLP-1 were maintained in blood after subcutaneous injection of the irreversible IP formulation into rats. This system should be useful for the minimally invasive sustained drug release of peptide drugs and other water-soluble bioactive reagents.P.4~P.14Title: Peptide Drug Release Behavior from Biodegradable Temperature-Responsive Injectable Hydrogels Exhibiting Irreversible GelationJournal: Gels Doi:https://doi.org/10.3390/gels3040038本研究の⼀部は 2016-2017 年度関⻄⼤学研究拠点形成⽀援経費において，研究課題「ゾル−ゲル転移を⽰す⽣体適合ポリマー材料の開発と応⽤」として研究費を受け，その成果を公表するものである

近赤外線スペクトロスコピィを用いた覚醒剤精神病と統合失調症の鑑別

Despite some slight differences in symptomatology, differential diagnosis of methamphetamine-induced psychosis (MAP) versus schizophrenia can be challenging because both disorders present a large overlap in their clinical symptoms. However, a recent study has shown that near-infrared spectroscopy (NIRS) performed during a cognitive task can be a powerful tool to differentiate between these two disorders. Here, we evaluated verbal fluency task performance during NIRS in 15 patients diagnosed with MAP and 19 with schizophrenia matched for age and sex. We used prefrontal probes and a 24-channel NIRS machine to measure the relative concentrations of oxyhaemoglobin every 0.1 s during the task. For each patient, the neurocognitive function and clinical psychopathology were evaluated using the Positive and Negative Symptom Scale (PANSS), and the Brief Assessment of Cognition in Schizophrenia (BACS). Oxyhaemoglobin changes in the prefrontal cortex were significantly higher in the MAP group compared to those in the schizophrenia group, particularly in the right dorsolateral prefrontal cortex. In contrast, we found no significant difference in PANSS and BACS scores. Our findings suggest that NIRS measurement could be applied to differentiate patients with MAP from those with schizophrenia, even in cases where clinical symptoms are similar.博士（医学）・甲第645号・平成28年3月15日This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0