Air-Stable Li3SbS4-LiI Electrolytes Synthesized via an Aqueous Ion-Exchange Process and the Unique Temperature Dependence of Conductivity.

The stability of sulfide-based solid electrolytes (SEs) in ambient air is a critical criterion for the application of all-solid-state lithium-ion batteries. Air-stable Li3SbS4-LiI SEs were synthesized using a unique process in an aqueous solution under ambient air, i.e., an ion-exchange (IE) process. The crystalline structure of Li3SbS4 obtained by this process was confirmed by X-ray diffraction (XRD) patterns. The ionic conductivity of the obtained SE was 8.5 × 10-8 S cm-1 at 50 °C. The SEs of Li3SbS4-LiI were also synthesized via the IE process. The temperature dependence of the Li3SbS4-LiI SEs' ionic conductivities showed a unique behavior; for example, the conductivities of 60Li3SbS4·40LiI (LSbSI) rapidly increased upon heating from 1.8 × 10-7 S cm-1 at 26.5 °C to 8.4 × 10-3 S cm-1 at 65 °C. The LiI layers on LSbSI are responsible for the unique temperature dependence of conductivity determined by differential scanning calorimetry-XRD measurement. Further, the dehydrated LSbSI obtained by milling and annealing showed a high conductivity of 1.3 × 10-4 S cm-1 at a low temperature of 25 °C. A cathode composite containing the active material of Ti2S and the LSbSI SE obtained via the IE process was prepared by freeze-drying. The all-solid-state cell using the cathode composite, which consists of Li-In/SE/TiS2-LSbSI, showed good performance at 60 °C as a lithium-ion secondary battery.

Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect.

Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration.

Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models.

BACKGROUND: Recently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models. METHODS: Herein, murine breast MM48 and colon MC38 xenografts were used to analyze the pharmacological activity of aPD-1 and aPD-L1 mAbs. The PK of the mAbs in the tumor-bearing mice was investigated at low and high doses using two radioisotopes (Indium-111 and Iodine-125) to evaluate the accumulation and degradation of the mAbs. RESULTS: aPD-1 mAb showed antitumor effect in a dose-dependent manner, indicating that the tumor model was sensitive to PD-1/PD-L1 blockade therapy, whereas aPD-L1 mAb failed to suppress tumor growth. The PK study showed that aPD-L1 mAb was accumulated largely in normal organs such as the spleen, liver, and kidney, resulting in low blood concentration and low distributions to tumors at a low dose, even though the tumors expressed PD-L1. Sufficient accumulation of aPD-L1 mAb in tumors was achieved by administration at a high dose owing to the saturation of target-mediated binding in healthy organs. However, degradation of aPD-L1 mAb in tumors was greater than that of aPD-1 mAb, which resulted in poor outcome presumably due to less inhibition of PD-L1 by aPD-L1 mAb than that of PD-1 by aPD-1 mAb. CONCLUSION: According to the PK studies, aPD-1 mAb showed linear PK, whereas aPD-L1 mAb showed non-linear PK between low and high doses. Collectively, the poor PK characteristics of aPD-L1 mAb caused lower antitumor activity than of aPD-1 mAb. These results clearly indicated that aPD-L1 mAb required higher doses than aPD-1 mAb in clinical setting. Thus, targeting of PD-1 would be more advantageous than PD-L1 in terms of PK.

Heart rate variability can clarify students' level of stress during nursing simulation.

Simulation is regarded as an effective educational method for the delivery of clinical scenarios. However, exposure to unfamiliar environments during simulation can cause excessive stress among students, possibly leading to unnatural speech/behavior and poor skill learning (Yerkes-Dodson's law). Thus, assessing students' stress in a simulation can provide educators with a better understanding of their mental state. This study sought to clarify stress changes throughout the progression of the simulation by measuring heart rate variability and students' subjective reactions in 74 nursing students. Heart rate variability was calculated in terms of its high-frequency (HF) and low-frequency/high-frequency (LF/HF) components during 4 phases-the break, patient care, reporting, and debriefing. Students were interviewed about stress experienced during the simulation. The results showed that HF decreased significantly from the break to the patient care and reporting phases. Furthermore, LF/HF increased significantly from the break to the reporting phases. Approximately 55 students felt stressed during the simulation, 24 of whom felt most stressed during the reporting phase. Therefore, the reporting phase involved high objective and subjective stress. It may be possible that the educator's evaluative attitude increased students' stress. Therefore, a stress intervention during the reporting phase might further improve students' performance during that phase. The debriefing phase did not significantly differ from the break phase for objective stress, and students did not report feeling stressed. Thus, in this phase, they were released from the stress of the reporting phase and the unfamiliar environment. During this phase, they might be able to learn what they could not understand owing to high stress in the patient care and reporting phases. This study provides objective and subjective evidence of students' stress during simulation, and indicates the necessity of providing support during the reporting phase and the importance of debriefing when using clinical scenarios for teaching clinical skills.