Experimental Model of Asthma by Toluene Diisocyanate (TDI)

この論文は国立情報学研究所の学術雑誌公開支援事業により電子化されました。Attention has been paid to respiratory hypersensitivity in workers who are exposed to toluene diisocyanate (TDI) in their workshops. An experimental model of asthma in guinea pigs by TDI has been developed. A 10% TDI solution dissolved in ethyl acetate was painted on the nasal cavities of guinea pigs with a thin cotton applicator once daily for five consecutive days. Three weeks later, the animals were challenged with a 5% TDI solution. Exertional breathing accompanied by the prolongation of expiratory phase was observed among the test animals. The number of the animals suffering from the attacks increased by the repetitive provocations. Although some of the guinea pigs suffered from anaphylaxis by the provocation procedures, the attacks including the anaphylactic shocks hardly brought about deaths in the animals. It was found that passive transfer of the symtom was possible in our experimental system. Both eosinophilic infiltration in the lung and eosinophilia in the peripheral bood were found among the test animals. This experimental model was developed by the appliaction of a simple chemical alone to the respiratory tract of guinea pigs. A significance of the model is discussed with the review of the literatures concerned

Japanese VLBI Network observations of radio-loud narrow-line Seyfert 1 galaxies

We performed phase-reference very long baseline interferometry (VLBI) observations on five radio-loud narrow-line Seyfert 1 galaxies (NLS1s) at 8.4 GHz with the Japanese VLBI Network (JVN). Each of the five targets (RXS J08066+7248, RXS J16290+4007, RXS J16333+4718, RXS J16446+2619, and B3 1702+457) in milli-Jansky levels were detected and unresolved in milli-arcsecond resolutions, i.e., with brightness temperatures higher than 10^7 K. The nonthermal processes of active galactic nuclei (AGN) activity, rather than starbursts, are predominantly responsible for the radio emissions from these NLS1s. Out of the nine known radio-loud NLS1s, including the ones chosen for this study, we found that the four most radio-loud objects exclusively have inverted spectra. This suggests a possibility that these NLS1s are radio-loud due to Doppler beaming, which can apparently enhance both the radio power and the spectral frequency.Comment: 8 pages, 2 figures, accepted for publication in PAS

VLBI Detections of Parsec-Scale Nonthermal Jets in Radio-Loud Broad Absorption Line Quasars

We conducted radio detection observations at 8.4 GHz for 22 radio-loud broad absorption line (BAL) quasars, selected from the Sloan Digital Sky Survey (SDSS) Third Data Release, by a very-long-baseline interferometry (VLBI) technique. The VLBI instrument we used was developed by the Optically ConnecTed Array for VLBI Exploration project (OCTAVE), which is operated as a subarray of the Japanese VLBI Network (JVN). We aimed at selecting BAL quasars with nonthermal jets suitable for measuring their orientation angles and ages by subsequent detailed VLBI imaging studies to evaluate two controversial issues of whether BAL quasars are viewed nearly edge-on, and of whether BAL quasars are in a short-lived evolutionary phase of quasar population. We detected 20 out of 22 sources using the OCTAVE baselines, implying brightness temperatures greater than 10^5 K, which presumably come from nonthermal jets. Hence, BAL outflows and nonthermal jets can be generated simultaneously in these central engines. We also found four inverted-spectrum sources, which are interpreted as Doppler-beamed, pole-on-viewed relativistic jet sources or young radio sources: single edge-on geometry cannot describe all BAL quasars. We discuss the implications of the OCTAVE observations for investigations for the orientation and evolutionary stage of BAL quasars.Comment: 10 pages, no figure, 3 tables, accepted for publication in PAS

Quinazolinobenzodiazepine Derivatives, Novobenzomalvins A–C: Fibronectin Expression Regulators from Aspergillus novofumigatus

Three new quinazolinobenzodiazepine derivatives, novobenzomalvins A (1), B (2), and C (3), have been isolated as fibronectin expression regulators from Aspergillus novofumigatus CBS117520. The structures of 1 to 3 were established by spectroscopic and physicochemical analysis, and chemical investigation including the total synthesis of 1. Treatment with novo-benzomalvins A (1), B (2), C (3), and N-methylnovobenzomalvin A (5) increased the expression of fibronectin in normal human neonatal dermal fibroblast cells

Outcomes and risk score for distal pancreatectomy with celiac axis resection (DP-CAR) : an international multicenter analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Approach to novel functional foods for stress control : 4. Regulation of serotonin transporter by food factors

Serotonin transporters (SERTs) are pre-synaptic proteins specialized for the clearance of serotonin following vesicular release at central nervous system (CNS) and enteric nervous system synapses. SERTs are high affinity targets in vivo for antidepressants such as serotonin selective reuptake inhibitors (SSRIs). These include ‘medical’ psychopharmacological agents such as analgesics and antihistamines, a plant extract called St John’s Wort (Hypericum) . Osteoclasts are the primary cells responsible for bone resorption. They arise by the differentiation of osteoclast precursors of the monocyte/macrophage lineage. The expression of SERTs was increased in RANKL-induced osteoclast-like cells. Using RANKL stimulation of RAW264.7 cells as a model system for osteoclast differentiation, we studied the direct effects of food factor on serotonin uptake. The SSRIs (fluoxetine and fluvoxamine) inhibited markedly (～95%) in serotonin transport in differentiated osteoclast cells. The major components of St. John’s Wort, hyperforin and hypericine were significantly decreased in serotonin transport activity. Thus, a new in vitro model using RANKL-induced osteoclast-like cells may be useful to analyze the regulation of SERT by food factors and SSRIs

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-kappa B, and beta-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors

In vivo radioactive metabolite analysis for individualized medicine: A basic study of a new method of CYP activity assay using 123I-IMP

Introduction: 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) is metabolized and converted to 123I-p-iodoamphetamine (123I-PIA) by CYP2C19 in humans. Since variations in 123I-PIA levels reflect variations in CYP2C19 activity, CYP2C19 activity can be estimated by quantitative analysis of 123I-PIA levels. Thus, 123I-IMP administration can provide diagnostic information not only regarding cerebral blood flow (rCBF) but also regarding metabolic function. The aim of the present study was to detect variations in CYP activity in mice using metabolite analysis. Methods: Metabolism of 125I-IMP in pooled homogenates of mouse liver (MLH) was analyzed by high-performance liquid chromatography (HPLC) in the presence or absence of NADPH. The amount of 125I-PIA generated was calculated as the normalized peak area of the chromatogram. Inhibition of 125I-IMP metabolism was evaluated using the inhibitor SKF-525A. A biodistribution study of 125I-IMP was performed to determine the organ distribution of 125I-IMP/125I-IMP metabolites and the effect of SKF-525A. Variations in CYP activity in vivo were detected by administration of 123I-IMP and/or SKF-525A to mice. The liver and the kidney were then excised, homogenized and analyzed using HPLC. Results: 125I-IMP was metabolized by MLH in the presence of NADPH, and the production of 125I-PIA was inhibited by SKF-525A. SKF-525A did not greatly affect the biodistribution of 125I-IMP/125I-IMP metabolites in vivo. Both 123I-IMP and 123I-PIA were detected in organs of control mice. However, 123I-PIA was not detected in the livers or kidneys of mice treated with SKF-525A. Conclusions: CYP activity in vivo was inhibited by SKF-525A treatment. Variations in CYP activity could be detected in the blood, liver and kidney as changes in the peak area of 123I-PIA. Advances in knowledge and implications for patient care: 123I-IMP metabolite analysis has the potential to provide beneficial information for prediction of the effect of medicines, in addition to its contribution to more accurate rCBF diagnosis that reflects individual CYP activity

Triple knockdown of CDC37, HSP90‐alpha and HSP90‐beta diminishes extracellular vesicles‐driven malignancy events and macrophage M2 polarization in oral cancer

Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones – CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial‐mesenchymal transition (EMT), although their contribution to EVs‐mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer‐derived EVs (MEV) were enriched with HSP90α HSP90β and cancer‐initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV‐driven malignancy events. In metastatic oral cancer patient‐derived tumours, HSP90β was significantly accumulated in infiltrating tumour‐associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90‐enriched MEV‐induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA‐mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV‐driven malignancy events in the tumour microenvironment