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Considering that iodine is highly volatile and has low solubility in water, it is utilized as an antiseptic in its complex form (iodophor) with a carrier material. Herein, we prepared the polysorbate 80-iodine complex and investigated its properties. In the presence of 0%, 0.01%, 0.1%, and 1% polysorbate, Pseudomonas putida NBRC 100650 growth was inhibited at 75, 75, 50, and 25 ppm iodine, respectively, indicating that high concentrations of polysorbate 80 enhanced the antibacterial activity of iodine. Absorption spectra of the mixtures of polysorbate 80 and iodine were analyzed; we observed that two peaks at 287 and 350 nm, derived from triiodide ions, shifted to the longer wavelength side in the presence of 0.1% and 1% polysorbate 80. Further, when 1% polysorbate 80 was added to the mixture of soluble starch and iodine, the peak around 580 nm arising from the amylose-iodine complex disappeared, indicating that polysorbate 80 captured iodine from the starch-iodine complex. We also found that polysorbate 80 retained iodine for approximately 4 months and prevented its volatilization; moreover, the mixture did not lose its growth inhibitory activity upon storage for approximately 4 months. Collectively, our data indicated that polysorbate 80 firmly retains low concentrations of iodine and that the polysorbate 80-iodine complex can serve as an antiseptic that can be stably stored for a long time.

Significance Glucagon-like peptide-1 receptor agonists have become established as a leading class of diabetes medications. However, these peptide-based drugs are administered by subcutaneous injection or, in one case, by a complex oral dosing regimen. We now report the discovery of LY3502970, a potent and selective small-molecule GLP-1R agonist. LY3502970 exhibits preclinical pharmacology equivalent to a marketed injectable GLP-1R agonist and possesses pharmacokinetic properties compatible with oral dosing in humans. Cryoelectron microscopy (cryo-EM) studies reveal an ECD-driven receptor binding mode for LY3502970 that provides a favorable pharmacological profile., Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

Ferrous saponite is a secondary mineral that can be used to reveal the redox state of past aqueous environments on Mars. In mineralogical analyses for ferrous saponite formed in laboratory simulations or contained in future returned samples from Mars, its oxidation by the Earth’s air could be problematic due to the high redox sensitivity. Here, we performed micro X-ray diffraction and scanning transmission X-ray microscopy analyses for a single particle of synthesized ferrous saponite without any exposure to air. The sample was reanalyzed after air exposure for 10–18 h to assess the adequacy of our anoxic preparation/measurement methods and the impacts of air on the sample. We found that the crystal structures agreed with ferrous saponite, both before and after air exposure, however, ferrous iron in saponite was partially oxidized, at least until 0.1–1 μm from the surface, after air exposure at the submicron scale, forming micro-vein-like Fe(III)-rich features. Together with our results of infrared spectroscopy of ferrous saponite, we showed that oxidation of octahedral iron occurred rapidly and heterogeneously, even in a short time of air exposure without any structural rearrangement. Since ferrous saponite is expected to exist on carbonaceous asteroids and icy dwarf planets, our methodology is also applicable to mineralogical studies of samples returned from these bodies.

研究グループは、大豆発酵製品であるイムバランスが喘息による気道炎症を抑制する効果があることを動物モデルで明らかにしました。気管支喘息は慢性的な気道炎症により喘鳴や呼吸困難などの症状が現れますが、根本的な治療方法がなく、新たな予防・治療法の確立が望まれています。大豆の摂取とアレルギー疾患との関連は過去にも疫学的に報告されており、大豆の成分に何らかの抗アレルギー作用がある可能性が示唆されています。そこで、本研究グループは、喘息モデルマウスにイムバランスを添加した飼料を与えて気道炎症に及ぼす影響を調査しました。その結果、イムバランス投与群では、BALF(気管支肺胞洗浄液)中の好酸球数が有意に減少し、気管支周囲の炎症や粘液産生が抑制されていることを発見しました。また、好酸球性炎症を誘導するBALF中のTh2サイトカインや血清IgEの発現も有意に抑制されていました。この発見により、今後イムバランスが気管支喘息における治療方法の新規候補として期待されます。, The fermented soy product ImmuBalance contains many active ingredients and its beneficial effects on some allergic diseases have been reported. We hypothesized that ImmuBalance could have potential effects on airway inflammation in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts and levels of cytokines. Lung tissues were examined for cell infiltration and mucus hypersecretion. Oral administration of ImmuBalance significantly inhibited ovalbumin-induced eosinophilic inflammation and decreased Th2 cytokine levels in bronchoalveolar lavage fluid (p < 0.05). In addition, lung histological analysis showed that ImmuBalance inhibited inflammatory cell infiltration and airway mucus production. Our findings suggest that supplementation with ImmuBalance may provide a novel strategy for the prevention or treatment of allergic airway inflammation.

Several kinds of hydroxyapatites (HAp) prepared by modification of Ca2+-HAp with transition metal (Fe2+, Fe3+, Co2+, Ni2+, Cu2+ and Zn2+) or aluminum (Al3+) ions were evaluated via a gas bag-detection tube method whether they could be used as novel deodorant materials. The samples treated with divalent cation (Fe2+, Co2+, Ni2+, Cu2+ and Zn2+) retained hydroxyapatite structure as well as Ca2+-HAp, whereas those treated with trivalent cation (Al3+ and Fe3+) showed lower crystallinity than Ca2+-HAp. 5–8 wt% cation of the samples was introduced by modification with divalent metal cations, whereas about 40 wt% cation of the samples was introduced with relatively larger surface area and higher content of adsorbed water for trivalent cations. For NH3 gas, modification of Ca2+-HAp with a divalent metal cation enhanced its adsorption ability, and that with a trivalent metal cation resulted in considerable improvement of the ability. On the other hand, modification of Ca2+-HAp with Cu2+ ion gave it remarkable H2S gas adsorption ability in comparison to that with other metal cations. However, adsorption ability for H2S of some polycrystalline powders including Cu2+ was not higher than that of Cu2+-modified HAp. The effect of the incorporated cation on adsorption ability for NH3 molecules may be based not only on a simple Lewis acid-base reaction but also on specific surface area and adsorbed water content, and the effect for H2S molecules based on the specific local electron density around the cation present on/in the material.

Adding fatty acids to an oil-in-water (O/W) emulsion changes the stability of the emulsion. In this study, we prepared a series of O/W emulsions consisting of oil (triolein/fatty acid mixture), water and a range of surfactants (sucrose fatty acid esters) with varying hydrophilic-lipophilic balance (HLB) in order to determine the effects of alkyl chain length and the degree of unsaturation of the fatty acid molecules on the stability of the emulsions. As a result, sucrose fatty acid esters with HLB = 5-7 were suitable for obtaining O/W emulsions. In addition, the creaming phenomenon was inhibited for 30 days or more when fatty acids having a linear saturated alkyl chain with 14 or more carbon atoms were added. These findings are useful for designing stable O/W emulsions for food and cosmetic products.

Inspired by the symbol calculus of linear differential operators of infinite order applied to the Borel transformed WKB solutions of simple-pole type equation [Kamimoto et al. (RIMS Kokyuroku Bessatsu B 52:127–146, 2014)], which is summarized in Section 1, we introduce in Section 2 the space of simple resurgent functions depending on a parameter with an infra-exponential type growth order, and then we define the assigning operator \({\mathscr{A}}\) which acts on the space and produces resurgent functions with essential singularities. In Section 3, we apply the operator \({\mathscr{A}}\) to the Borel transforms of the Voros coefficient and its exponentiation for the Whittaker equation with a large parameter so that we may find the Borel transforms of the Voros coefficient and its exponentiation for the boosted Whittaker equation with a large parameter. In Section 4, we use these results to find the explicit form of the alien derivatives of the Borel transformed WKB solutions of the boosted Whittaker equation with a large parameter. The results in this paper manifest the importance of resurgent functions with essential singularities in developing the exact WKB analysis, the WKB analysis based on the resurgent function theory. It is also worth emphasizing that the concrete form of essential singularities we encounter is expressed by the linear differential operators of infinite order.

Objectives Afatinib is an effective treatment in patients who have epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC), but its toxicities often require dose adjustment. Exploratory analyses of previous trials have suggested that reducing the dose of afatinib can decrease treatment-related adverse events without negatively affecting effectiveness. The aim of this study was to assess the efficacy and safety of low starting dose of afatinib with dose modification according to its toxicity in patients with EGFR mutation-positive NSCLC. Materials and methods This study was a multicenter, single-arm, open-label phase II trial. Treatment-naive patients with advanced NSCLC positive for common EGFR mutations received afatinib starting in a dose of 20 mg/day. If tolerated, the dose was increased in 10-mg increments up to 50 mg/day. The primary endpoint was progression-free survival (PFS). Results From February 2015 through March 2016, 46 patients were enrolled. The median age was 73 years (range, 43–86), and 35 patients (72%) were women.EGFR mutation subtypes included exon 19 deletion (54%) and Leu858Arg point mutation (46%). Most patients had a performance status of 0 or 1 (91%) and a histological diagnosis of adenocarcinoma (98%). As of the data cut-off date of June 2017, the median follow-up was 18.9 months. The median PFS was 15.2 months (95% CI: 13.2–not estimable). The 1-year overall survival rate was 95.6% (95% CI: 89.7%–100%). The objective response rate was 81.8% (95% CI, 81.3%–98.6%). Adverse events of grade 3 or higher occurred in 14 patients (30.4%) and included rash/acne in 4 patients (8.7%), paronychia in 4 patients (8.7%), diarrhea in 2 patients (4.3%). There was no treatment-related death. Conclusions Low starting dose of afatinib therapy showed promising clinical efficacy and good tolerability. Further investigations are warranted.

Activation of glucagon-like peptide-1 receptors (GLP-1R) is a promising approach for the treatment of type 2 diabetes mellitus (T2D), and several peptide analogues of GLP-1 have been successfully developed. Here we identified a new orally active non-peptide GLP-1R agonist, OWL833, and examined its efficacy in cynomolgus monkeys. The agonistic activity of OWL833 was evaluated by measuring cAMP accumulation in cells expressing mammal GLP-1Rs and other glucagon family receptors. In the cells expressing human or cynomolgus monkey GLP-1R, OWL833 promoted cAMP accumulation to the same level achieved by GLP-1, and its EC50 values for human and cynomolgus monkey GLP-1Rs were the same at 1.1 nmol/L. In contrast, OWL833 showed no stimulatory activity on human glucagon, GIP, and GLP-2 receptors. The predicted bioavailability and T1/2 of OWL833 in human based on rodent and non-rodent experimental data are 30% and ∼18 hour, respectively. After OWL833 followed by glucose was intravenously injected in cynomolgus monkeys, OWL833 decreased the blood glucose level via insulin secretion to the same extent as effective concentrations of exenatide, a GLP-1 peptide mimetic, in clinic. Doses of 0.and 0.1 mg/kg OWL833 given orally to cynomolgus monkeys reduced their food intake by 25% and 45%, respectively, as compared with vehicle group, and the effect on food intake was equal to that of 0.3 and 0.6 µg/kg subcutaneous injections of exenatide. No critical finding was observed in the subchronic toxicity studies in rats and cynomolgus monkeys. These findings demonstrate that OWL833 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion, and that it exhibits an anti-feeding activity similar to exenatide. In conclusion, OWL833 has potential as a once-daily, orally active, non-peptide GLP-1 receptor agonist. Disclosure T. Kawai: Employee; Self; Chugai Pharmaceutical Co., Ltd. F. Tanino: Employee; Self; Chugai Pharmaceutical Co., Ltd. M. Fukazawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. K. Ogawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Nagao: Employee; Self; Chugai Pharmaceutical Co., Ltd. H. Yoshino: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Komatsu: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Suzuki: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Kawabe: Employee; Self; Chugai Pharmaceutical Co., Ltd..

We develop the exact WKB analysis of an M2P1T (merging two simple poles and one simple turning point) Schrodinger equation. Our emphasis is put on the analysis of the singularity structure of its Borel transformed WKB solutions near fixed singular points relevant to the two simple poles contained in the potential of the equation. In Part I, we focus our attention on the construction and analytic properties of a WKB-theoretic transformation that transforms an M2P1T equation to an algebraic Mathieu equation. That transformation plays an important role in Part II ( [7] ) when we discuss the singularity structure of Borel transformed WKB solutions of an M2P1T equation.

We develop the exact WKB analysis of an M2P1T (merging two simple poles and one simple turning point) Schrodinger equation. In Part II, using a WKB-theoretic transformation to the algebraic Mathieu equation constructed in Part I, we calculate the alien derivative of its Borel transformed WKB solutions at each fixed singular point relevant to the simple poles through the analysis of Borel transformed WKB solutions of the Legendre equations. In the course of the calculation of the alien derivative we make full use of microdifferential operators whose symbols are given by the infinite series that appear in the coefficients of the algebraic Mathieu equation and the Legendre equation.

Background The phase II trial evaluated the efficacy and safety of low starting dose of afatinib in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). In primary analysis, progression free survival (PFS) met the primary endpoint. Here, we report updated survival outcomes. Methods This study was a multi-center, single-arm, open-label phase II trial. Treatment-naive patients with common EGFR mutation-positive NSCLC were treated with afatinib starting at a dose of 20 mg/day. If tolerated, the dose is increased by 10- mg increments up to 50mg/day. PFS and overall survival (OS) were re-evaluated at the final data cut-off point (October 2018). Results 46 patients were enrolled. Median age was 73 years (range, 43-86). The median follow-up was 31.9 months. Median PFS of entire population was 15.2 months (95% confident interval (CI), 13.2–21.2), and 2-year PFS rate was 27.7% (95% CI, 17.1-44.7). Median OS was not estimated, and the 2-year overall survival was 76.1% (95% CI, 64.7-89.5). Performance status (PS) and existence of brain metastases at study entry were revealed to have significant impact on the survival with Cox-regression test. Among patients with disease progression on afatinib (n = 36), rebiopsy was performed on 29 patients, and T790M was proved positive on 14 patients. Twelve out of the 14 patients positive for T790M received osimertinib as a second line therapy. Median time from enrollment to progression on the osimertinib (PFS2) was 32.6 months (95%CI: 20.5-NE). Conclusions Low starting dose afatinib therapy demonstrated promising OS outcome. PS and existence of brain metastases were predictive factors of this therapy. Clinical trial identification UMIN 000016444. Legal entity responsible for the study Kyoto Thoracic Oncology Research Group. Funding Has not received any funding. Disclosure T. Yokoyama: Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Ono pharmaceutical; Honoraria (self): MSD. H. Yoshioka: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Eli Lilly Japan; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Merck Serono; Honoraria (self): Kyowa Kirin; Honoraria (self): AstraZeneca; Honoraria (self): Ono pharmaceutical; Honoraria (self): Daiichi Sankyo; Honoraria (self): MSD. D. Fujimoto: Honoraria (self), Research grant / Funding (self): AstraZeneca KK; Honoraria (self): Ono Pharmaceutical Co Lt; Honoraria (self): Bristol-Myers Squibb Co Ltd; Honoraria (self): Taiho Pharmaceutical Co ; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical Co Ltd; Honoraria (self): MSD KK; Honoraria (self): Boehringer Ingelheim Japan Inc; Honoraria (self): Eli Lilly Japan KK. K. Hirano: Honoraria (self): Boehringer Ingelheim Japan. T. Ishida: Honoraria (self): Boehringer Ingelheim Japan. T. Hirai: Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

Effects of particle size distribution on physical properties such as viscosity, heat and mechanical properties of injection-molded hydroxyapatite (HA)/poly lactic acid (PLA) were investigated. The melting temperature of PLA was shifted to a lower temperature because of the dispersion of HA particles. However, the cold crystallization temperature shifted to a lower temperature at high HA composition, suggesting that HA particles acted as a nuclear agent. x c,PLA of the composites with bimodal particle size distribution showed the lowest of all three composites, suggesting that mobility of PLA polymer chain was reduced by bimodal particle size distribution, which means the increase of restriction at interface between polymer matrix and particle. Melt flow rate (MFR) increased because of dispersed HA particle. The reason was thought that hydrolysis degradation of PLA occurred during melt-mixing process is accelerated by HAp particle dispersion. The MFR of composites increased concomitantly with increased par...

In this work, the availability of calcium phosphates for the light emitting layer of a thin-film electroluminescent (TFEL) device was investigated. The goal of this work was to develop an electronic device with ordinary materials such as a calcium phosphate, the principal ingredient of the skeleton of the vertebrate. Compositions of 2CaO·P 2 O 5 (Ca 2 P 2 O 7 ), 3CaO·P 2 O 5 (Ca 3 (PO 4 ) 2 ) and 4CaO·P 2 O 5 (Ca 4 O(PO 4 ) 2 ) were examined as the candidates for the light emitting layer. Before composing the TFEL device, the photoluminescence (PL) properties of the three compositions were investigated in the powder form to evaluate the performance as the light emitting layer. Among the examined calcium phosphates, Eu-doped β-Ca 3 (PO 4 ) 2 showed the best PL properties. It showed typical red-emission from Eu 3+ . The PL intensity was enhanced with the heat-treatment temperature and the optimal temperature was 1250 °C. Then, a TFEL device was prepared by a spray pyrolysis method with the β-Ca 3 (PO 4 ) 2 :Eu 3+ phosphor layer on a BaTiO 3 disk. The TFEL device exhibited the red emission originating in Eu 3+ at 610 nm under applying alternating voltage. Different from the power sample, the intensity of EL decreased with the heat-treatment temperature from 1000 to 1250 °C. The deterioration of EL at the higher temperatures was attributed to chemical interaction between the phosphor layer and the BaTiO 3 disk.

The coaxial helicity injection (CHI) method is one of promising candidates for the non-inductive current drive in the spherical torus (ST) plasma concept. The transient-CHI (T-CHI) method for plasma start-up has been successfully applied to the NSTX device at PPPL for the start-up followed by inductive ramp-up1. The main purpose of the T-CHI experiments on the Helicity Injected Spherical Torus (HIST)2 at University of Hyogo is to understand the physics of the flux closure related to fast magnetic reconnection during the T-CHI start-up process. The recent MHD simulation on T-CHI for NSTX predicts the formation and breakup of an elongated Sweet-Parker (S-P) current sheet and a transient to plasmoid instability3. According to this simulation, the reconnection rate based on the plasmoid instability is faster than that by S-P model and becomes nearly independent of the Lundquist number S. This simulation has motivated us to seek reconnection phenomena observed in T-CHI start-up plasmas on HIST.

A new water-soluble precursor of BaTiO3 was prepared from citratoperoxotitanate and barium citrate as the Ti and Ba sources, respectively. The water-soluble precursor was easily solved in water to form a stable solution, which produced BaTiO3 by heat-treatment at 500 °C and above. A water-based dip-coating technique demonstrated a potential application as the coating solution of BaTiO3. Transparent BaTiO3 films were formed on the quartz-glass substrates with an increment of typically 9 nm per coating with 0.05 mol dm−3 solution. The transmittance of the 180 nm-thick film attained almost 90 % at the maximum and the overall transmittance was above 60 % over the visible region. The polycrystalline film was composed of BaTiO3 grains smaller than 200 nm. Although the film was an insulator, it was not suited for the dielectric application because of the structural problems due to the relatively low density and the thinness of the BaTiO3 layer. The BaTiO3 pellet obtained from the water soluble precursor by condensation, pyrolysis and sintering showed the good dielectric properties with er = 3,500 and tan δ = 0.027 with a sintering temperature of 1,375 °C.

Higher order simple-pole type operators, that is, higher order linear ordinary differential operators with a large parameter η whose coefficients have simple poles at the origin, are discussed from the viewpoint of the exact WKB analysis. Making use of the technique of microdifferential operators, we clarify the singularity structure of the Borel transform of their WKB solutions.