Phase behavior of oxidized Ce and Gd-doped (U,Zr)O₂

Re-criticality analysis of the fuel debris at the Fukushima Dai-ichi Nuclear Power Plant is the key step to ensure the safe retrieval and storage of the fuel debris. Knowledge of the amount and distribution of Pu and Gd within the fuel debris greatly contributes to such analysis as they directly affect the fission-chain reaction. However, little is known about how Pu-doped and Gd-doped (U, Zr)O₂ solid solutions oxidize and whether phases concentrated in Pu or Gd form. In this study, CeO₂ is used as a surrogate material for PuO₂ because of the similarities in their crystal structures and valence states. (U₀.₉-xZr₀.₁Cex)O₂ and (U₀.₉-xZr₀.₁Gdx)O₂ solid solutions are prepared by sintering under an argon atmosphere and oxidized at 1073 K in air for 2 hours to simulate heavily oxidized fuel debris. Samples doped with 5 at% Ce and Gd contain only an orthorhombic-U3O8-x phase after oxidation, but its diffraction peaks’ intensities decrease as the amount of dopant increases. The phase transformation of (U₀.₉-xZr₀.₁Gdx)O₂, with further oxidation, is found to be cubic-(U, Zr, Gd)O₂+x → orthorhombic-(U, Zr, Gd)₃O₇±x → orthorhombic-(U, Zr, Gd)₃O₈-x. SEM/EDS analysis reveals that Ce and Gd are uniformly distributed in the (U₀.₉-xZr₀.₁REx)O₂ (RE = Ce, Gd) samples after oxidation

Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats

&#65279;To clarify to what extent topically administered drug molecules horizontally permeate into tissues surrounding the administration site, the intramuscular lateral concentration profile of acetaminophen was investigated in vivo using the microdialysis method in rats. When acetaminophen was intramuscularly administered for 6 hr in a pinpoint manner at a constant rate of 3 &#956;g/min, it was clearly detected in the muscle surrounding the administration site, being 17.5 &#956;g/ml when measured at a 2 mm distance from the administration site. The concentration in the muscle was decreased as the distance increased, and those measured at 5 mm and 40 mm were 0.35 &#956;g/ml and 0.09 &#956;g/ml, respectively. In addition, it was shown that the concentration in the muscle at 40 mm reflected the compound’s concentration in plasma, but not the compound’s horizontal permeation from the administration site. With these observations, the intramuscular distribution profile of acetaminophen was numerically characterized according to Fick’s law. As a result, it was revealed that horizontal permeation is the primary process accountable for the increased intramuscular concentration only in the area adjacent to the administration site, and the radius of the adjacent area was calculated to be 5.80 mm for acetaminophen. </p

Perioperative therapy for non-small cell lung cancer - Current status and future perspective -

　Lung cancer is the leading cause of cancer-related death. Surgery has been playing a pivotal role in the treatments with curative intent for non-small cell lung cancer (NSCLC). However, the outcome after surgery alone remains unsatisfactory. During the last two decades, several attempts have been made to improve the postoperative outcome. Metaanalysis demonstrated that adjuvant cisplatin-based chemotherapy achieved 4-5% of benefit in the 5-year survival as compared to surgery alone. Preoperative induction chemotherapy also yielded a 5% improvement of the 5-year survival rate, showing a similar efficacy with adjuvant chemotherapy. Induction chemoradiotherapy enhanced local control, whereas it was not associated with any survival benefit. Recently, the development of new drugs, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, represents a major treatment advance for patients with lung cancer. Several attempts have been made to apply these drugs to perioperative treatments.　In this review, we sought to summarize the developments of perioperative therapy in the treatments of NSCLC, and discuss the future perspectives

A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice

Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RB(high)CD4(+) T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-gamma-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs

Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells

Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor–mediated proliferation of lymphocytes. However, we show that Cbl-b–deficient DT40 B cells display reduced phospholipase C (PLC)-γ2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-γ2 and helped the association of PLC-γ2 with Bruton's tyrosine kinase (Btk), as well as B cell linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH2-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-γ2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-γ2 complex formation

Kaplan–Meier survival analysis and Cox regression analyses regarding right ventricular septal pacing: Data from Japanese pacemaker cohort

AbstractThe presented data were obtained from 982 consecutive patients receiving their first pacemaker implantation with right ventricular (RV) lead placement between January 2008 and December 2013 at two centers in Japan. Patients were divided into RV apical and septal pacing groups. Data of Kaplan–Meier survival analysis and Cox regression analysis are presented. Refer to the research article “Implications of right ventricular septal pacing for medium-term prognosis: propensity-matched analysis” (Mizukami et al., in press) [1] for further interpretation and discussion

Pharmacokinetic analysis of new synthetic antimalarial N-251

Background With the emergence and growing number of drug-resistant Plasmodium falciparum, a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice. Results PK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. Cmax was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability (F) was approximately 23%. Additionally, Tmax, Cmax, AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251. Conclusions N-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251

Transient Receptor Potential 1 Regulates Capacitative Ca2+ Entry and Ca2+ Release from Endoplasmic Reticulum in B Lymphocytes〉

Capacitative Ca2+ entry (CCE) activated by release/depletion of Ca2+ from internal stores represents a major Ca2+ influx mechanism in lymphocytes and other nonexcitable cells. Despite the importance of CCE in antigen-mediated lymphocyte activation, molecular components constituting this mechanism remain elusive. Here we demonstrate that genetic disruption of transient receptor potential (TRP)1 significantly attenuates both Ca2+ release-activated Ca2+ currents and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release from endoplasmic reticulum (ER) in DT40 B cells. As a consequence, B cell antigen receptor–mediated Ca2+ oscillations and NF-AT activation are reduced in TRP1-deficient cells. Thus, our results suggest that CCE channels, whose formation involves TRP1 as an important component, modulate IP3 receptor function, thereby enhancing functional coupling between the ER and plasma membrane in transduction of intracellular Ca2+ signaling in B lymphocytes

Chalcopyrite ZnSnSb_2: A Promising Thermoelectric Material

Ternary compounds with a tetragonal chalcopyrite structure, such as CuGaTe2, are promising thermoelectric (TE) materials. It has been demonstrated in various chalcopyrite systems, including compounds with quaternary chalcopyrite-like structures, that the lattice parameter ratio, c/a, being exactly 2.00 to have a pseudo-cubic structure is key to increase the degeneracy at the valence band edge and ultimately achieve high TE performance. Considering the fact that ZnSnSb_2 with a chalcopyrite structure is reported to have c/a close to 2.00, it is expected to have multiple valence bands leading to a high p-type zT. However, there are no complete investigations on the high temperature TE properties of ZnSnSb_2 mainly because of the difficulty of obtaining a single-phase ZnSnSb_2. In the present study, pure ZnSnSb_2 samples with no impurities are synthesized successfully using a Sn flux-based method and TE properties are characterized up to 585 K. Transport properties and thermal analysis indicate that the structure of ZnSnSb_2 remains chalcopyrite with no order–disorder transition and clearly show that ZnSnSb_2 can be made to exhibit a high zT in the low-to-mid temperature range through further optimization