Electron holography observation of individual ferrimagnetic lattice planes.

Atomic-scale observations of a specific local area would be considerably beneficial when exploring new fundamental materials and devices. The development of hardware-type aberration correction1,2 in electron microscopy has enabled local structural observations with atomic resolution3-5 as well as chemical and vibration analysis6-8. In magnetic imaging, however, atomic-level spin configurations are analysed by electron energy-loss spectroscopy by placing samples in strong magnetic fields9-11, which destroy the nature of the magnetic ordering in the samples. Although magnetic-field-free observations can visualize the intrinsic magnetic fields of an antiferromagnet by unit-cell averaging12, directly observing the magnetic field of an individual atomic layer of a non-uniform structure is challenging. Here we report that the magnetic fields of an individual lattice plane inside materials with a non-uniform structure can be observed under magnetic-field-free conditions by electron holography with a hardware-type aberration corrector assisted by post-digital aberration correction. The magnetic phases of the net magnetic moments of (111) lattice planes formed by opposite spin orderings between Fe3+ and Mo5+ in a ferrimagnetic double-perovskite oxide (Ba2FeMoO6) were successfully observed. This result opens the door to direct observations of the magnetic lattice in local areas, such as interfaces and grain boundaries, in many materials and devices.

Kerr-Enhanced Optical Spring.

We propose and experimentally demonstrate the generation of enhanced optical springs using the optical Kerr effect. A nonlinear optical crystal is inserted into a Fabry-Perot cavity with a movable mirror, and a chain of second-order nonlinear optical effects in the phase-mismatched condition induces the Kerr effect. The optical spring constant is enhanced by a factor of 1.6±0.1 over linear theory. To our knowledge, this is the first realization of optomechanical coupling enhancement using a nonlinear optical effect, which has been theoretically investigated to overcome the performance limitations of linear optomechanical systems. The tunable nonlinearity of demonstrated system has a wide range of potential applications, from observing gravitational waves emitted by binary neutron star postmerger remnants to cooling macroscopic oscillators to their quantum ground state.

RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

AIM: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. METHODS: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. RESULTS: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. CONCLUSION: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

Multifunctional chemical inhibitors of the florigen activation complex discovered by structure-based high-throughput screening.

Structure-based high-throughput screening of chemical compounds that target protein-protein interactions (PPIs) is a promising technology for gaining insight into how plant development is regulated, leading to many potential agricultural applications. At present, there are no examples of using high-throughput screening to identify chemicals that target plant transcriptional complexes, some of which are responsible for regulating multiple physiological functions. Florigen, a protein encoded by FLOWERING LOCUS T (FT), was initially identified as a molecule that promotes flowering and has since been shown to regulate flowering and other developmental phenomena such as tuber formation in potato (Solanum tuberosum). FT functions as a component of the florigen activation complex (FAC) with a 14-3-3 scaffold protein and FD, a bZIP transcription factor that activates downstream gene expression. Although 14-3-3 is an important component of FAC, little is known about the function of the 14-3-3 protein itself. Here, we report the results of a high-throughput in vitro fluorescence resonance energy transfer (FRET) screening of chemical libraries that enabled us to identify small molecules capable of inhibiting FAC formation. These molecules abrogate the in vitro interaction between the 14-3-3 protein and the OsFD1 peptide, a rice (Oryza sativa) FD, by directly binding to the 14-3-3 protein. Treatment with S4, a specific hit molecule, strongly inhibited FAC activity and flowering in duckweed, tuber formation in potato, and branching in rice in a dose-dependent manner. Our results demonstrate that the high-throughput screening approach based on the three-dimensional structure of PPIs is suitable in plants. In this study, we have proposed good candidate compounds for future modification to obtain inhibitors of florigen-dependent processes through inhibition of FAC formation.

Efficacy and safety of pembrolizumab and axitinib as first-line treatment for patients with advanced renal cell carcinoma: Real-world experience in Japan.

OBJECTIVES: The objective of this study was to assess the clinical outcomes following combined treatment with pembrolizumab and axitinib as first-line therapy for patients with advanced RCC. METHODS: This study retrospectively included 47 consecutive Japanese patients who were diagnosed with advanced RCC and subsequently received pembrolizumab and axitinib between February 2020 and January 2022. Efficacy and safety of this combined therapy in these patients were comprehensively investigated. RESULTS: The 47 included patients were classified into the following 3 groups by the IMDC system: favorable, 7 (14.9%); intermediate, 24 (51.1%) and poor, 16 (34.0%). Responses to this combined therapy in the 47 patients were as follows: CR, 8 (17.0%); PR, 20 (42.6%); SD, 16 (34.0%) and PD, 3 (6.4%); thus, the ORR was 59.6%. During the observation period, disease progression and death occurred in 19 (40.4%) and 9 (19.1%) patients, respectively, and the median PFS and OS were 18 months and not reached, respectively. Univariate analyses identified the following significant predictors for poor prognostic outcomes: lack of nephrectomy, liver metastasis, bone metastasis, elevated CRP and IMDC poor risk for PFS; and lack of nephrectomy, non-CCC and elevated CRP for OS. AEs and those corresponding to grade ≥ 3 occurred in all (100%) and 30 (63.8%) patients, respectively. CONCLUSIONS: To our knowledge, this is the first study focusing on real-world outcomes following pembrolizumab and axitinib for treatment-naïve advanced Japanese RCC patients, which showed the efficacy and safety of this combined therapy being similar or even superior to those in clinical trial.

Differential impact of proton pump inhibitor on survival outcomes of patients with advanced urothelial carcinoma treated with chemotherapy versus pembrolizumab.

OBJECTIVES: We clarified the effect of concomitant proton pump inhibitor use on oncological outcomes in patients with advanced urothelial carcinoma treated either with chemotherapy or immune checkpoint inhibitor. METHODS: We retrospectively reviewed patients with advanced urothelial carcinoma who received paclitaxel-gemcitabine therapy or pembrolizumab after platinum-based chemotherapy. The patients were divided into four groups based on the treatment regimen and the concomitant use of proton pump inhibitor. We compared survival outcomes between the groups and determined which factors predicted overall survival. RESULTS: Among the 60 and 75 patients treated with paclitaxel-gemcitabine and pembrolizumab, 15 and 29 used a concomitant proton pump inhibitor. Progression-free and overall survival was significantly shorter in patients who were administered pembrolizumab with concomitant proton pump inhibitor compared to those without. The use of a concomitant proton pump inhibitor had no effect on survival outcomes in patients who received paclitaxel-gemcitabine therapy. Furthermore, progression-free and overall survival were significantly shorter in patients treated with paclitaxel-gemcitabine therapy compared to those treated with pembrolizumab among patients without concomitant proton pump inhibitor. In contrast, there was no difference in survival outcomes between the two regimens among patients with concomitant proton pump inhibitor. Concomitant proton pump inhibitor use was associated with poor overall survival only in patients treated with pembrolizumab. CONCLUSION: The use of a concomitant proton pump inhibitor use had no impact on oncological outcomes in patients with advanced urothelial carcinoma treated with paclitaxel-gemcitabine therapy, different from those treated with pembrolizumab.

Significance of second progression-free survival in patients with advanced urothelial cancer who received platinum-based combination chemotherapy followed by pembrolizumab.

OBJECTIVES: The present study comprehensively investigated the significance of several factors reflecting the therapeutic effects of anticancer treatment on overall survival (OS) in advanced urothelial cancer (UC) patients receiving sequential systemic therapy. METHODS: This study included 101 consecutive advanced UC patients who received first-line platinum-based combination chemotherapy followed by second-line pembrolizumab. The impacts of the following factors on OS in these patients were analyzed: responses to chemotherapy, responses to pembrolizumab, progression-free survival (PFS) with chemotherapy, PFS with pembrolizumab, and second PFS (PFS2). RESULTS: The median age of patients was 71 years, and 35 and 66 had UC in the upper urinary tract and bladder, respectively. objective response rate to first-line chemotherapy and second-line pembrolizumab were 37.6% and 19.8%, respectively. Median PFS with chemotherapy, pembrolizumab, and PFS2 were 5, 4, and 9 months, respectively. Uni- and multivariate analyses of the five factors examined identified PFS with pembrolizumab and PFS2 as independent surrogates for OS, with PFS2 (hazard ratio [HR] = 0.23) being more closely associated with OS than PFS with pembrolizumab (HR = 0.31). Furthermore, uni- and multivariate analyses of various prognostic parameters showed the independent impacts of baseline performance status (PS) and neutrophil-to-lymphocyte ratio (NLR) on PFS2. CONCLUSIONS: The present results suggest the potential of PFS2 as an optimal surrogate for OS in advanced UC patients receiving standard sequential systemic therapy and indicate that intensive treatment needs to be considered for those with poor PS and/or high NLR prior to the introduction of first-line chemotherapy.

Big Five Personality Traits, Social Networks, and Depression Among Older Adults in Japan: A Multiple Mediation Analysis.

This study examines the mediating effect of social network size on depression among older adults in Japan in association with the Big Five personality traits: extraversion, agreeableness, conscientiousness, neuroticism, and openness. Cross-sectional data were obtained from 739 older adults (Mean age = 75.13, SD = 6.86) residing in Tokyo. Multiple mediation analyses estimated total, indirect, and direct effects between personality and depression. Extraversion was associated with the number of kin and friend networks and agreeableness with the number of kin networks. Moreover, these social networks partially mediated the effects of extraversion and agreeableness on depression. The findings show that personality traits such as extraversion and agreeableness are associated with social network size, which contributes to better mental health in old age.

[Psychosocial mediators between socioeconomic status and oral health among urban-dwelling older adults].

Objectives　This study examined the psychosocial mediators that most effectively mediate the socioeconomic status (SES)-based differences in oral health (OH) among urban-dwelling older adults.Methods　A representative sample of individuals aged ≥65 years living in two areas with different residential SES in Tokyo produced 739 effective participants. OH was based on the total score of subjective sense of health, number of remaining teeth, and oral function. SES was evaluated by education and income. Based on the socioecological model, mediators were assessed using self-esteem, social support, and depression.Results　 Based on the multiple mediation analysis, no significant effects were observed for specific psychosocial factors. However, the overall psychosocial factors showed significant effects as the mediating factor between income and OH. The mediating effect of overall psychosocial factors was not significant regarding years of education and oral health.Conclusion　A hybrid of life-stage preventive activities and overall reduction of psychosocial risk factors may eliminate the differences in OH by SES.

Photothermal effect in macroscopic optomechanical systems with an intracavity nonlinear optical crystal.

Intracavity squeezing is a promising technique that may improve the sensitivity of gravitational wave detectors and cool optomechanical oscillators to the ground state. However, the photothermal effect may modify the occurrence of optomechanical coupling due to the presence of a nonlinear optical crystal in an optical cavity. We propose a novel method to predict the influence of the photothermal effect by measuring the susceptibility of the optomechanical oscillator and identifying the net optical spring constant and photothermal absorption rate. Using this method, we succeeded in precisely estimating parameters related to even minor photothermal effects, which could not be measured using a previously developed method.

Long-Term Outcomes in Elderly Patients After Deferral of Coronary Revascularization Guided by Fractional Flow Reserve.

BACKGROUND: Little evidence is available regarding the long-term outcome in elderly patients after deferral of revascularization based on fractional flow reserve (FFR).Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicenter registry), 1,262 patients were divided into 2 groups according to age: elderly and younger patients (aged ≥75 or <75 years, respectively). The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). Cumulative 5-year incidence of TVF was not significantly different between elderly and younger patients (14.3% vs. 10.8%, P=0.12). Cardiac death occurred more frequently in elderly patients than younger patients (4.4% vs. 0.8%, P<0.001), whereas TVMI and CDTVR did not differ between groups (1.3% vs. 0.9%, P=0.80; 10.7% vs. 10.1%, P=0.80, respectively). FFR values in lesions with diameter stenosis <50% were significantly higher in elderly patients than in younger patients (0.88±0.07 vs. 0.85±0.07, P=0.01), whereas this relationship was not observed in those with diameter stenosis ≥50%. CONCLUSIONS: Elderly patients had no excess risk of ischemic events related to the deferred coronary lesions by FFR, although FFR values in mild coronary artery stenosis were modestly different between elderly and younger patients.

Comprehensive assessments of immuno-oncology drug-based combination therapies as first-line treatment for advanced renal cell carcinoma.

Over the last decade, there have been substantial progress in the field of systemic therapy for advanced renal cell carcinoma. Through the transition from treatment with cytokines to molecular-targeted agents, and currently to immuno-oncology drugs, the prognostic outcomes of patients with advanced renal cell carcinoma have been markedly improved. In particular, based on the promising outcomes of recently conducted pivotal randomized clinical trials, immuno-oncology drug-based combination therapy by either dual immune checkpoint inhibition or combined inhibition of an immune checkpoint and tyrosine kinase, is currently regarded as a standard of care for treatment-naïve advanced renal cell carcinoma patients. However, insufficient data are available with respect to the selection of optimal systemic therapies for advanced renal cell carcinoma in the first-line setting due to the lack of a head-to-head comparison between approved immuno-oncology drug-based combination therapies. In this review, therefore, we summarize interesting findings associated with first-line combination therapies for advanced renal cell carcinoma obtained from both randomized clinical trials and real-world clinical practices, in order to present useful guidance to help make treatment decisions for patients with treatment-naïve advanced renal cell carcinoma.

Higher-Order Structure of Human Chromosomes Observed by Electron Diffraction and Electron Tomography.

It is well known that two DNA molecules are wrapped around histone octamers and folded together to form a single chromosome. However, the nucleosome fiber folding within a chromosome remains an enigma, and the higher-order structure of chromosomes also is not understood. In this study, we employed electron diffraction which provides a noninvasive analysis to characterize the internal structure of chromosomes. The results revealed the presence of structures with 100­200 nm periodic features directionally perpendicular to the chromosome axis in unlabeled isolated human chromosomes. We also visualized the 100­200 nm periodic features perpendicular to the chromosome axis in an isolated chromosome whose DNA molecules were specifically labeled with OsO4 using electron tomography in 300 keV and 1 MeV transmission electron microscopes.

The Prognostic Impact of Pericardial Fat Volumes in Resected Non-small Cell Lung Cancer.

BACKGROUND: Pericardial fat (PF) has not been considered a prognostic biomarker for overall survival (OS) in lung cancer. This study was designed to elucidate the impact of PF on prognosis of resected non-small cell lung cancer patients. METHODS: We retrospectively reviewed a total of 349 patients who underwent lung resection and received high-resolution computed tomography in our institute. PF volume was calculated. PF extended vertically from the diaphragm to the bifurcation of the right main pulmonary artery. Propensity score matched analysis was used to compare OS between the high- and low-PF groups. RESULTS: PF volume increased according to body mass index (p < 0.001). Receiver operating characteristics (ROC) curve analysis for 3-year OS showed the possibility of better predictivity of PF than body-mass index (area under the curve, 0.66 vs. 0.61, p = 0.010). Cutoff level of PF volume was determined based on the ROC with 122 cm3. Five-year OS was poorer in the low-PF group (63.5% vs. 73.4%; p = 0.002). After propensity score matching, each group consisted of 89 cases. Five-year OS was poorer in the low-PF group (66.5% vs. 82.7%; p = 0.008). A Cox proportional hazards model showed low-PF volume was associated with poorer OS (hazard ratio, 2.14; p = 0.009). The number of respiratory-related deaths was higher in the low-PF group (10/89 vs. 2/89, p = 0.032). CONCLUSIONS: Low-PF volume may be associated with poor OS with an increase in the number of respiratory-related deaths. Patients with low-PF volume require careful follow-up after surgery.

Analytical Technique Optimization on the Detection of ß-cyclocitral in Microcystis Species.

ß-Cyclocitral, specifically produced by Microcystis, is one of the volatile organic compounds (VOCs) derived from cyanobacteria and has a lytic activity. It is postulated that ß-cyclocitral is a key compound for regulating the occurrence of cyanobacteria and related microorganisms in an aquatic environment. ß-Cyclocitral is sensitively detected when a high density of the cells is achieved from late summer to autumn. Moreover, it is expected to be involved in changes in the species composition of cyanobacteria in a lake. Although several analysis methods for ß-cyclocitral have already been reported, ß-cyclocitral could be detected using only solid phase micro-extraction (SPME), whereas it could not be found at all using the solvent extraction method in a previous study. In this study, we investigated why ß-cyclocitral was detected using only SPME GC/MS. Particularly, three operations in SPME, i.e., extraction temperature, sample stirring rate, and the effect of salt, were examined for the production of ß-cyclocitral. Among these, heating (60 °C) was critical for the ß-cyclocitral formation. Furthermore, acidification with a 1-h storage was more effective than heating when comparing the obtained amounts. The present results indicated that ß-cyclocitral did not exist as the intact form in cells, because it was formed by heating or acidification of the resulting intermediates during the analysis by SPME. The obtained results would be helpful to understand the formation and role of ß-cyclocitral in an aquatic environment.

Impact of periprocedural anticoagulation therapy on the incidence of silent stroke after atrial fibrillation ablation in patients receiving direct oral anticoagulants: uninterrupted vs. interrupted by one dose strategy.

AIMS: Data on the comparison between uninterrupted and interrupted by one dose strategies for direct oral anticoagulant (DOAC) use during the periprocedural period of atrial fibrillation (AF) ablation are scarce. The purpose of this study is to investigate the feasibility of uninterrupted DOAC strategy by evaluating the incidence of silent stroke (SS) and perioperative trends in coagulation markers compared with the interrupted strategy. METHODS AND RESULTS: We randomly divided 200 consecutive patients receiving DOACs, who underwent AF ablation into uninterrupted group (UG = 100) and interrupted by one dose group (IG = 100). The rate of SS confirmed by post-operative magnetic resonance imaging and periprocedural trends in coagulation markers was investigated. A significant difference in SS incidence was found between the UG and IG (UG 4%, IG 17%, P < 0.005), although there were no differences in the rate of complications including bleeding and symptomatic thrombo-embolic events between the two groups. Intraoperative cardioversion [odds ratio (OR) 7.27, 95% confidence interval (CI) 1.76-30.0; P < 0.01] and the length of procedure time (OR 1.03, 95% CI 1.01-1.05; P < 0.05) independently predicted the occurrence of SS in the IG. A significant increase in prothrombin fragment 1 + 2 (PF1 + 2) values was observed in the IG compared with the UG on the operative and first post-operative days. CONCLUSION: Silent stroke incidence in the IG was significantly higher than that in the UG; this seems to be supported by the difference in PF1 + 2 values between the UG and IG. Intraoperative cardioversion and procedure time predicted the occurrence of SS in the IG.

Current-Driven Motion of Domain Boundaries between Skyrmion Lattice and Helical Magnetic Structure.

To utilize magnetic skyrmions, nanoscale vortex-like magnetic structures, experimental elucidation of their dynamics against current application in various circumstances such as in confined structure and mixture of different magnetic phases is indispensable. Here, we investigate the current-induced dynamics of the coexistence state of magnetic skyrmions and helical magnetic structure in a thin plate of B20-type helimagnet FeGe in terms of in situ real-space observation using Lorentz transmission electron microscopy. Current pulses with various heights and widths were applied, and the change of the magnetic domain distribution was analyzed using a machine-learning technique. The observed average driving direction of the two-magnetic-state domain boundary is opposite to the applied electric current, indicating ferromagnetic s-d exchange coupling in the spin-transfer torque mechanism. The evaluated driving distance tends to increase with increasing the pulse duration time, current density (>1 × 109 A/m2), and sample temperature, providing valuable information about hitherto unknown current-induced dynamics of the skyrmion-lattice ensemble.

Present clinical practices of stereotactic irradiation for metastatic brain tumors in Japan: results of questionnaire survey of the Japanese Radiation Oncology Study Group (JROSG) working subgroup for neurological tumors.

BACKGROUND: To determine the current practice of stereotactic irradiation (STI) for brain metastases in Japan by a questionnaire survey. METHODS: A questionnaire was distributed to 313 institutions performing STI with one of the following machines: Gamma Knife (GK), CyberKnife (CK), Novalis (Nov), or other linear accelerator (LINAC)-based systems (OLS). The participation was voluntary. RESULTS: There were 163 responding institutions. The total number of STI treatments between April 2013 and March 2014 was 10,684. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) were performed in 8624 (80.7%) and 2060 (19.3%) cases, respectively. Whole-brain radiation therapy (WBRT) was performed for a total of 3515 cases. For a case model of a 1.5-cm solitary brain metastasis in a non-eloquent area, the most common GTV-PTV margin was 2 mm (22 of 114 institutions), and an institutional standard fraction was 1 (75 of 114 institutions). The doses for the model case also varied from 13.0 to 26.0 Gy (Median 20 Gy) when converted to SRS (α/ß = 10). A prescription point was at the PTV margin the most. The median dose constraints which were converted to SRS (α/ß = 3) to organs at risk were 12.2, 12.7, and 13.7 Gy for optic nerves, cavernous sinus, and brainstem, respectively. CONCLUSIONS: STI for brain metastases in current practice varied significantly among institutions. These different strategies relied mostly on the type of treatment machine used. It is thus necessary to establish a common guideline to express dose prescriptions and plan qualities for different STI machines.

Microbial Degradation of Amino Acid-Containing Compounds Using the Microcystin-Degrading Bacterial Strain B-9.

Strain B-9, which has a 99% similarity to Sphingosinicella microcystinivorans strain Y2, is a Gram-negative bacterium with potential for use in the degradation of microcystin-related compounds and nodularin. We attempted to extend the application area of strain B-9 and applied it to mycotoxins produced by fungi. Among the tested mycotoxins, only ochratoxin A was completely hydrolyzed to provide the constituents ochratoxin α and l-phenylalanine, and levels of fumonisin B1 gradually decreased after 96 h. However, although drugs including antibiotics released into the aquatic environment were applied for microbial degradation using strain B-9, no degradation occurred. These results suggest that strain B-9 can only degrade amino acid-containing compounds. As expected, the tested compounds with amide and ester bonds, such as 3,4-dimethyl hippuric acid and 4-benzyl aspartate, were readily hydrolyzed by strain B-9, although the sulfonamides remained unchanged. The ester compounds were characteristically and rapidly hydrolyzed as soon as they came into contact with strain B-9. Furthermore, the degradation of amide and ester compounds with amino acids was not inhibited by the addition of ethylenediaminetetraacetic acid (EDTA), indicating that the responsible enzyme was not MlrC. These results suggest that strain B-9 possesses an additional hydrolytic enzyme that should be designated as MlrE, as well as an esterase.