The transition between isotope-mixing and nonmixing states in hydrogen-deuterium mixture plasmas is observed in the isotope (hydrogen and deuterium) mixture plasma in the Large Helical Device. In the ...nonmixing state, the isotope density ratio profile is nonuniform when the beam fueling isotope species differs from the recycling isotope species and the profile varies significantly depending on the ratio of the recycling isotope species, although the electron density profile shape is unchanged. The fast transition from nonmixing state to isotope-mixing state (nearly uniform profile of isotope ion density ratio) is observed associated with the change of electron density profile from peaked to hollow profile by the pellet injection near the plasma periphery. The transition from nonmixing to isotope-mixing state strongly correlates with the increase of turbulence measurements and the transition of turbulence state from TEM to ion temperature gradient is predicted by gyrokinetic simulation.
Abstract
Thomson scattering measurements with a high-repetition-rate laser have commenced in the Large Helical Device. As an example of the fast phenomena captured by this diagnostic system, ...measurements at a 20 kHz repetition-rate in hydrogen pellet-injected plasmas are presented. Signal processing methods for this measurement have been developed and electron temperature profiles with almost 70 spatial points were evaluated at time intervals of 50
$$\upmu$$
μ
s. After Raman scattering calibration, electron density profiles were derived. Fast changes in the electron temperature and density profiles within 1 ms were observed.
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is frequently activated in cancers and can be counteracted with the clinical mTORC1 inhibitors everolimus and temsirolimus. Although mTORC1 ...and dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. Using the cis-Apc/Smad4 mouse model of locally invasive intestinal adenocarcinoma, we show that administration of everolimus or the dual mTORC1/2 inhibitor AZD8055 significantly reduces the growth of intestinal tumors. In contrast, although everolimus treatment at earlier phase of tumor progression delayed invasion of the tumors, both inhibitors exhibited little effect on blocking invasion of the tumors when administered later in their progression. Biochemical and immunohistochemical analyses revealed that treatment of cis-Apc/Smad4 mice with everolimus or AZD8055 induced marked increases in epidermal growth factor receptor (EGFR) and MEK/ERK signaling in tumor epithelial and stromal cells, respectively. Notably, co-administration of AZD8055 and the EGFR inhibitor erlotinib or the MEK inhibitor trametinib was sufficient to suppress tumor invasion in cis-Apc/Smad4 mice. These data indicate that mTOR inhibitor resistance in invasive intestinal tumors involves feedback signaling from both cancer epithelial and stromal cells, highlighting the role of tumor microenvironment in drug resistance, and support that simultaneous inhibition of mTOR and EGFR or MEK may be more effective in treating colon cancer.
A new temperature controlled material probe was designed for the exposure of W samples to He plasma in the LHD (Large Helical Device). TEM (Transmission Electron Microscopy) analysis allowed the ...study of the impact of He irradiation under high temperatures (up to 600°C) on W microstructure: bubbles and dislocation loops are formed at the surface. A heavily damaged layer rich in both damages is formed at the very surface layer whose thickness increases with the incident fluence; beyond this layer, bubbles are observed much deeper than expected, rising concerns about the consequences for the material properties conservation. Nano-indentation measurements showed that the hardness of exposed tungsten indeed increases as the dislocation loops are formed and large bubbles appear in the material.
Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported ...with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event.
Summary
What is known and objective
There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate‐lowering efficacy. The aim ...of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout.
Methods
A phase 3, multicentre, randomized, double‐blind, double‐dummy, active‐controlled, parallel‐group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 μmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 μmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 μmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.
Results and discussion
Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was −34·3 ± 11·1% in the allopurinol group (n = 105) and −36·3 ± 12·7% in the topiroxostat group (n = 98). Non‐inferiority of the serum urate‐lowering efficacy of topiroxostat to allopurinol was proved by the predefined non‐inferiority margin (95% confidence interval, −5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups.
What is new and conclusion
Topiroxostat 120 mg/day provides non‐inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.
Achievement of reactor relevant plasma condition in Helical type magnetic devices and exploration in its related plasma physics and fusion engineering are the aim of the Large Helical Device (LHD) ...project. In the recent experiments on LHD, we have achieved ion-temperature of 8.1 keV at 1 × 10
19
m
−3
by the optimization of wall conditioning using long pulse discharge by Ion Cyclotron Heating (ICH). The electron temperature of 10 keV at 1.6 × 10
19
m
−3
was also achieved by the optimization of Electron Cyclotron Heating (ECH). For further improvement in plasma performance, the upgrade of the Large Helical Device (LHD), including the deuterium experiment, is planned. In this paper, the recent achievements on LHD and the upgrade of LHD are described.
•More than 10 years’ operation is feasible using the inboard WC shield, where the total TBR is 1.18 with 90% 6Li.•The divertor targets can be efficiently shielded, expanding the range of material ...choice (e.g., Cu alloys).•Flinabe blanket mixed with metal powder is proposed to increase hydrogen solubility and thermal efficiency.•Helical coils by connecting segments of 100kA-class YBCO high-temperature superconductors is proposed.•A multi-path strategy on FFHR-d1 is introduced with sub-ignition options for “before demo, compact and component-test”.
NIFS launched the Fusion Engineering Research Project (FERP) in preparation for DEMO by starting the redesign of the LHD-type helical reactor FFHR-d1. In the first round, the main parameters were selected. The second round is preparing detailed three-dimensional (3D) design of the superconducting magnet support structures, and 3D neutronics analyses, where the diverter targets can be efficiently shielded from fast neutrons. A new Flinabe blanket mixed with metal powder was proposed. Fabrication of helical coils by connecting half-helical-pitch segments of 100kA-class YBCO high-temperature superconductors is proposed as a promising method. Also in progress is improvement of the first round of the core plasma design, ignition start-up analyses, and fueling scenario. As a consequence, a multi-path strategy on FFHR-d1 has been introduced with versions of -d1A, -d1B, and -d1C, where design flexibility is expanded to include subignition with options FFHR-c1 for “before demo, compact, and component-test.”
The toluene solvate crystal of the titled highly congested aromatic ketone-ester compound has been subjected to crystal structural analysis from the viewpoints of the clarification of distribution ...feature of effective non-classical hydrogen bonds and the retention and perturbation of the symmetric nature. The two independent molecules of the title naphthalene derivative, which bears two aroyl groups at the adjacent inner positions and two benzoyloxy groups at the neighboring β-positions, and one disordered solvent toluene molecule are incorporated in the asymmetric unit of P2
1
/c (Z′= 2). In the packing of the solvate crystal, the solvent toluene molecule plays the multi roles of hydrogen donor/acceptor for C-H...π non-classical hydrogen bonds and hydrogen donor for C-H...O = C ones. On the other hand, the role of other benzene rings of the parts of the title compound molecules is confined. The 4-methylbenzoyl groups situated at the molecular inner positions mainly play the role of the hydrogen donor of C-H...π non-classical hydrogen bond. The benzoyloxy groups that extend outward from the molecular body mainly act as the hydrogen acceptors of C-H...O and C-H...π non-classical hydrogen bonds. The naphthalene ring moderately contributes as the hydrogen acceptor for C-H...π non-classical hydrogen bonds and as the hydrogen donor for C-H...O non-classical hydrogen bonds. The roles of the toluene molecule are not limited to a simple filler for the void among the major constituent molecules but proved to position at the pseudo-centrosymmetric center of the counter-configurated pair of molecules of the independent major component compounds to concentrate the effective non-classical hydrogen bonds.
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