Anti-oxidative Amino Acid L-ergothioneine Modulates the Tumor Microenvironment to Facilitate Adjuvant Vaccine Immunotherapy

Cancer vaccines consist of a tumor-associated antigen (TAA) and adjuvant. These vaccines induce and activate proliferation of TAA-specific cytotoxic T lymphocytes (CTLs), suppressing tumor growth. The therapeutic efficacy of TAA-specific CTLs depends on the properties of tumor microenvironment. The environments make immunosuppressive by function of regulatory T cells and tumor-associated myeloid cells; thus, regulation of these cells is important for successful cancer immunotherapy. We report here that L-ergothioneine (EGT) with the adjuvant Toll-like receptor 2 (TLR2) ligand modulated suppressive microenvironments to be immune-enhancing. EGT did not augment DC-mediated CTL priming or affect CTL activation in draining lymph node and spleen. However, EGT decreased the immuno-suppressive function of tumor-associated macrophages (TAMs). TLR2 stimulation accompanied with EGT administration downregulated expression of PD-L1, CSF-1R, arginase-1, FAS ligand, and TRAIL in TAMs, reflecting reduction of CTL suppression. An anti-oxidative thiol-thione residue of EGT was essential to dampening CTL suppression. The effect was specific to the thiol-thione residue of EGT because no effect was observed with another anti-oxidant N-acetyl-L-cysteine (NAC). A CTL-suppressive environment made by TLR2 is relieved to be improved by the addition of EGT, which may ameliorate the efficacy of vaccine immunotherapy

Inhibitory Effects of Glycyrrhetinic Acid on DNA Polymerase and Inflammatory Activities

We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols α, β, κ, and λ, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-κB (NF-κB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition

Development of MONSAKUN Touch and Practical Use in Class: Realization of Lesson of Posing of Arithmetical Word Problems

和若しくは差で解ける算数文章問題を対象とした単文統合型の作問学習支援システム“モンサクン”は数年に渡り複数の小学校の授業で利用されている．しかしながら，これらの授業では既に対象領域の学習を終えている2年生以上を対象としていたため，付加的な学習としての位置づけになっていた．本研究では，対象領域を学習中である1年生を対象に，単文統合型の作問の実施を目指した．このためにはシステムと授業の融合が必要となるため，(1) システムの通常教室での利用，(2) 作問状況のリアルタイムでの把握，(3) 作問法の教授，が解決すべき課題となった．本論文ではこれらの課題を解決するために行った，(I) モンサクンのタブレット化，(II) 作問状況モニタリングと集計・可視化機能の実現，(III) 作問法の教授法の考案，を述べる．またシステムを用いた9時限に渡る実践を行い，その分析結果から，システムが十分に利用可能であったこと，学習者の問題解決能力や作問能力の向上が見られたことが確認できたので，これを報告する

Evaluation of Problem Structure Comprehension as Effect of Learning by Sentence Integration Problem-Posing

筆者らは，単文統合型の作問学習支援システムを開発し，このシステムを利用した算数授業を実践的に行っている．本研究では，このシステムを用いた作問学習の効果として期待される，算数の文章題の構造的把握の度合いの測定を，作問学習を行ったグループとそれ以外，及び作問能力が高いグループとそれ以外，の比較において行ったので報告する．算数の文章題を構造的に把握していれば，問題に関する部分的な情報から残りの情報を予測できるであろうと仮定し，算数の文章題に関するプライミングテストを作成・実施した．結果として，作問学習を行ったグループが行わなかったグループより高いスコアを示し，また，作問に関して高い能力を示している場合においても，作問学習の効果が高かったことが示された

Radiation dose and image quality of CT fluoroscopy with partial exposure mode

PURPOSEThe present study aimed to evaluate the scan technique of computed tomography (CT)-guided puncture procedures using partial exposure mode (PEM) on the radiation dose of the operator’s hand and image quality.METHODSRadiation dose was evaluated using three types of scanning methods: one-shot scan (OS), OS with a bismuth shield added (OSBismuth), and a half-scan (i.e., PEM) capable of an adjustable exposure angle. Dose evaluation was performed using a torso phantom, while a circular phantom simulating the liver parenchyma and lesions was used for image quality evaluation. For each scanning method, four measurements were made to determine the radiation dose to the operator's hand and the dose distribution on the surface of the patient's torso; the output-dose profile was determined from five measurements. Image quality was evaluated in terms of contrast and contrast-to-noise ratio (CNR). Analysis of variance (ANOVA) or Friedman test were used for comparison between groups as appropriate. The post hoc tests were Tukey’s honestly difference (HSD) test for parametric data or Wilcoxon signed rank test with Bonferroni correction for nonparametric data.RESULTSThe PEM yielded a radiation dose to the operator’s hand that was 84% (0.35 vs. 2.33 mGy) lower than that of the OS. The dose to the patient’s torso was reduced by 35% and 68% for the OSBismuth and PEM, respectively, relative to that of the OS. Compared with the CNR of the other two scanning methods (OS, 2.9±0.1; OSBismuth, 2.9±0.1), the PEM increased the standard deviation and decreased the CNR (2.1±0.04, Tukey’s HSD, P < 0.001 for all). Images acquired with PEM showed visibility equivalent to that of other scanning methods when window conditions were adjusted.CONCLUSIONThis study demonstrated that CT-guided puncture procedure using PEM effectively reduces the operator's exposure to radiation while minimizing image quality deterioration

Interactive Learning Environment for Posing 1-step Multiplication Word Problem and Its Experimental Use

筆者らはこれまでに，1 回の加減で解決できる算数文章題を対象として，三文構成モデルによる作問学習支援システムを開発している．本研究では，システムを小学校2年生で学習する乗算の領域へと拡張するものであり，システムの拡張から1クラス9時限の実践利用までを行ったので，報告する．結果としては，システムを利用することで問題解決能力はあっても，構造の理解が浅い学習者に対して，構造理解を深められることを示唆する結果が得られた

Normal Values of Diffusion Tensor Magnetic Resonance Imaging Parameters in the Cervical Spinal Cord

Study DesignProspective study.PurposeWe evaluated the usefulness of diffusion tensor imaging (DTI) in diagnosing patients with cervical myelopathy by determining the accuracy of normal DTI parameter values.Overview of LiteratureDTI can visualize white matter tracts in vivo and quantify anisotropy. DTI is known to be more sensitive than conventional magnetic resonance imaging (MRI) in detecting subtle pathological changes of the spinal cord.MethodsA total of 31 normal subjects (13 men and 18 women; age, 23-87 years; mean age, 46.0 years) were included in this study. The patients had no symptoms of myelopathy or radiculopathy. A Philips Achieva 3-Tesla MRI with SE-type Single Shot EPI was used to obtain diffusion tensor images. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured as DTI parameters on axial sections of several cervical levels. Subjects were divided into two groups: >40 years (n=16) and ≤40 years (n=15). A paired t-test was used to compare significant differences between the groups. ADC and FA values were most stable on axial sections.ResultsFor all subjects, mean ADC and FA values were 1.06±0.09×10-3 mm2/sec and 0.68±0.05, respectively. ADC was significantly higher in subjects >40 years of age than in those ≤40 years. There was no significant difference in FA values between the two groups. The mean ADC value was significantly higher in normal subjects >40 years of age than in those ≤40 years.ConclusionsIt is important to consider age when evaluating cervical myelopathy by DTI

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma

Simple Summary Synovial sarcoma (SS) is associated with a high risk of recurrence and poor prognosis, and no biomarker useful in monitoring tumor burden exists. We identified monocarboxylate transporter 1 (MCT1) expressed in extracellular vesicles (EVs) derived from synovial sarcoma as a potential such marker. Circulating levels of MCT1(+)CD9(+) EVs were significantly correlated with tumor volume in a SS mouse model. Serum levels of MCT1(+)CD9(+) EVs reflected tumor burden and treatment response in SS patients. Patients with MCT1 expression on the plasma membrane have significantly worse overall survival than those with nuclear expression. Silencing of MCT1 reduced the malignant phenotype including cellular viability, migration, and invasion of SS cells. MCT1 may thus be a promising novel target for liquid biopsies and a novel therapeutic target. The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1(+)CD9(+) EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1(+)CD9(+) EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1(+)CD9(+) EVs and indicates the therapeutic potential of MCT1 in SS