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Transient thermoelectric effect (TTE) and transient Nernst effect (TNE) have been measured for La1.86Sr0.14CuO4 crystals. It was found that the TTE and TNE signals are observed only in the vortex liquid states. The former rises with two exponential components of τf∼1 μs and τs∼1 ms, while the latter rises with single exponential component of τs. We suppose that the components of τf and τs result from the motions of single vortex and collective vortices, respectively. [Copyright &y& Elsevier]

Reports a case of lymphoblastic lymphoma expressing a natural killer cell phenotype initially expressed in the skin in Japan. Proliferation of neoplastic cells revealed by a biopsy specimen; Laboratory findings; Administration of combined chemotherapy consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone.

Near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment modality that uses antibody-photoabsorber (IR700) conjugates to destroy specific cells. The reaction between the antibody and photoabsorber is triggered by NIR-light, and this alters the shape and hydrophilicity of the conjugate. This photochemical reaction is responsible for NIR-PIT-induced cell death; however, the detailed mechanism underlying this effect remains unknown. In this study, we demonstrated that actin filaments underneath the cell membrane play an important role in NIR-PIT-induced cell death and that IR700 mediates the photochemical reaction of the conjugates, leading to actin filament aggregation upon NIR-light irradiation. The destruction of cortical actin beneath the cell plasma membrane allows water to flow into the cell based on osmotic conditions, resulting in cell rupture. This sequence of events may constitute the mechanism of NIR-PIT-induced cell death, making NIR-PIT a promising cancer treatment modality.

Purpose: Fire victims often inhale hydrogen cyanide (HCN) gas in addition to carbon monoxide. This study aimed to investigate the current prevalence of HCN inhalation among fire victims and assess the contribution of HCN as a toxic factor in fire-related deaths., Methods: The study included 29 cases of fire-related deaths, where autopsies were conducted at the Department of Legal Medicine, Osaka University, from April 2014 to March 2020. No resuscitation was performed before death was confirmed and blood samples were obtained from both the left and right cardiac chambers. Blood cyanide concentrations were measured. Additionally, a physiologically based pharmacokinetic model, as described by Stamyr et al. (Arch Toxicol 89:1287-1296, 2015), was used to simulate the time course of blood concentration changes for different inhaled HCN concentrations. The inhaled HCN concentration and inhalation time that minimized the difference between the measured and simulated blood concentrations were calculated., Results: Cyanide was detected in the cardiac blood of 76.3% of cases. In all instances, left cardiac blood concentrations were higher than those in the right cardiac blood. The simulations using the physiologically based pharmacokinetic model revealed eight cases where the inhaled HCN concentration exceeded 5000 ppm, with an inhalation time of less than 0.5 min., Conclusions: Many fire victims inhaled HCN gas, and in a few cases, it appears that death occurred rapidly after inhalation of high HCN concentrations. These findings suggest that the contribution of cyanide gas to fire-related deaths warrants closer examination., Competing Interests: Declarations. Conflict of interest: There are no conflicts of interest to declare. Ethical approval: This study was conducted with the approval of the ethical committee of Osaka University Hospital (Approval No. 20120) and the Graduate School of Pharmaceutical Sciences, Osaka University (Yaku-hito, 2020–10)., (© 2025. The Author(s).)

Macrophages remove apoptotic cells via phagocytosis, also known as efferocytosis, during inflammation to maintain tissue homeostasis. This process is accompanied by various metabolic changes in macrophages including the production of lipid metabolites by fatty acid oxygenases. Among these, highly reactive metabolites, called lipid-derived electrophiles (LDEs), modify cysteines and other nucleophilic amino acids in intracellular proteins. However, the landscape and functions of the modifications by these electrophilic metabolites have been poorly characterized. In this study, we used activity-based protein profiling to quantitatively profile the cysteine reactivity landscape and identify the potential targets of endogenous LDE modification during efferocytosis in mouse peritoneal macrophages. Using this methodology, we identified multiple cysteine sites that are highly likely to be modified by LDEs generated by 12/15-lipoxygenase (12/15-LOX), an efferocytosis-related fatty acid oxygenase that is highly expressed in peritoneal macrophages. Among these, actin-depolymerizing protein Cofilin-1 was found to be a target of 12/15-LOX-derived LDEs. In vitro Cofilin-1 activity was attenuated by 12/15-LOX-derived LDEs, and intracellular actin stabilization and efferocytosis were substantially enhanced by the LDE treatment of mouse peritoneal macrophages. These results highlighted the role of intracellular LDE modification during efferocytosis in macrophages.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor that is approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in Japan based on randomized clinical trial data. The aim of the real-world, retrospective Orbit study was to describe long-term clinical outcomes and management in adults (aged ≥ 20 years) with CLL/SLL treated with ibrutinib, either as first-line (1L) treatment or for relapsed or refractory (RR) disease, in routine clinical practice in Japan between July 2018 and December 2020. A total of 246 patients were registered, and the safety and per-protocol sets included 237 and 234 patients, respectively. After a median follow-up of 35.7 months, the 36-month progression-free survival rate was 80.9% in the 1L CLL cohort and 67.2% in the RR CLL cohort, and the 36-month overall survival rates were 90.8% and 83.7%, respectively. Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3 adverse events of special interest were atrial fibrillation (2.1%), infections (herpesvirus infection, fungal infection, or Pneumocystis jiroveci pneumonia; 1.7%), bleeding (3.8%), and second primary malignancy (2.5%). These findings confirm the long-term, real-world effectiveness and safety of ibrutinib for the treatment of Japanese patients with newly diagnosed or RR CLL/SLL., Competing Interests: Declarations. Conflict of interest: Yosuke Masamoto has received research funding from Kyowa Kirin Co., Ltd.; has received honoraria for lectures from MSD K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., AbbVie GK, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., Janssen Pharmaceutical K.K., SymBio Pharmaceuticals Ltd., Bristol-Myers Squibb K.K., AstraZeneca K.K., Sanofi K.K., Asahi Kasei Pharma Corporation, Yamasa Corporation, Meiji Seika Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., and PharmaEssentia Japan K.K.; has received honoraria for manuscript writing from Janssen Pharmaceutical K.K. and AstraZeneca K.K.; and has participated in data safety monitoring of AbbVie GK and Janssen Pharmaceutical K.K. Go Yamamoto has received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., Sanofi, Nippon kayaku Co., Ltd., Janssen Pharmaceutical K.K., Novartis Pharma K.K., Bristol-Myers Squibb K.K., Meiji Seika Pharma Co., Ltd., Mundipharma K.K., AstraZeneca K.K., and Genmab K.K. Yoshihiro Kameoka has received research funding and honoraria for lectures from Janssen Pharmaceutical K.K. Shuichi Ota has received honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Co. Ltd., AstraZeneca K.K., AbbVie GK, Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Amgen K.K., and Sanofi K.K. Eri Matsuki has received research funding and honoraria from Janssen Pharmaceutical K.K.; and has received consulting fee from Janssen Asia Pacific. Kazutaka Ozeki has received honoraria for lectures from Janssen Pharmaceutical K.K. Takahiro Kumode has received honoraria for lectures from Janssen Pharmaceutical K.K. and Ono Pharmaceutical Co., Ltd. Hideto Tamura has received honoraria for lectures from Sanofi K.K., Bristol-Myers Squibb K.K., and Ono Pharmaceutical Co., Ltd. Ai Omi is an employee of Janssen Pharmaceutical K.K. Kazuhiro Shibayama and Aki Watanabe are employees of Janssen Pharmaceutical K.K.; and own stocks of Johnson & Johnson. Yasushi Isobe has received consulting fees from LSI Medience Corporation. Kensuke Kojima has received honoraria for lectures from Janssen Pharmaceutical K.K., AstraZeneca K.K., and AbbVie GK.; and has received scholarship from Daiichi Sankyo Co., Ltd. and Eisai Co., Ltd. Jun Takizawa has received consulting fees from Janssen Pharmaceutical K.K., AstraZeneca K.K., and AbbVie GK; has received honoraria from Janssen Pharmaceutical K.K., AstraZeneca K.K., AbbVie GK, Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., and Nippon Kayaku Co., Ltd.; and his institution has received research grant from Janssen Pharmaceutical K.K., AstraZeneca K.K., AbbVie GK, Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly Co., Ltd., and Asahi Kasei Corporation. Hirokazu Nagai has received honoraria from AbbVie GK, AstraZeneca K.K., Genmab K.K., Janssen Pharmaceutical K.K., Eli Lilly Co., Ltd., Takeda Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., MSD, Eisai Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Mundipharma K.K., GlaxoSmithKline K.K., Bristol-Myers Squibb K.K., Nippon Kayaku Co., Ltd., Nippon Shinyaku Co., Ltd., and BeiGene Ltd.; and his institute has received research grant from AbbVie GK, AstraZeneca K.K., BeiGene Ltd., Genmab K.K., HUYABIO international, Janssen Pharmaceutical K.K., Eli Lilly Co., Ltd., Takeda Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., MSD, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Haihe Biopharma, Daiichi Sankyo Co., Ltd, Celgene K.K. Zenyaku Kogyo Co., Ltd., Solasia Pharma K.K., Ono Pharmaceutical Co., Ltd., and Regeneron Pharmaceuticals Inc. Junji Suzumiya has received research grant from Eisai Co., Ltd.; has received consulting fees from Eli Lilly Co., Ltd., Zenyaku Kogyo Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Shinyaku Co., Ltd., and Otsuka Pharmaceutical Co., Ltd.; and has received honoraria for lectures from Janssen Pharmaceutical K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Kyowa Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., Novartis Pharma K.K., AbbVie Inc., and SymBio Pharmaceuticals Ltd. Sadao Aoki has received honoraria for lectures from Janssen Pharmaceutical K.K., AbbVie GK, AstraZeneca K.K., and Chugai Pharmaceutical Co., Ltd. Tsuyoshi Muta, Shingo Kurahashi, Takanori Toyama, Naoki Takahashi, Nobuyuki Aotsuka, and Takuro Yoshimura have no conflicts of interests to declare., (© 2024. The Author(s).)

This study aimed to clarify changes in antimicrobial prescribing trends in pediatric clinics before and after the chronic shortage of amoxicillin and amoxicillin-clavulanic acid from 2023 in Japan. Amoxicillin and amoxicillin-clavulanic acid have been in chronic short supply since May 24, 2023 due to increased demand. It is unclear whether this situation has changed the type of oral antimicrobials prescribed by clinics. A retrospective observational study was conducted to analyze antimicrobial prescriptions in pediatric clinics between January and December 2023. The data was collected using information available on a new platform, the Online Monitoring System for Antimicrobial Stewardship at Clinics (OASCIS). The period from March to May was defined as the pre-shortage period, and the period from June to August was defined as the post-shortage period. Antimicrobials were classified using the AWaRe classification proposed by the World Health Organization. The average prescription rate per AWaRe classification in the three months before and after the shortage was compared. A total of 28,888 oral antimicrobial prescriptions were collected. Due to the chronic shortage, the proportion of Access antimicrobials decreased from 53.9 % in the pre-shortage period to 46.8 % in the post-shortage period (p < 0.001). The proportion of Watch antimicrobials increased from 45.9 % to 52.8 % (p < 0.001). Among the Watch antimicrobials, prescriptions for third-generation cephalosporins increased from 18.8 % to 24.7 % (p < 0.001). The chronic shortage of amoxicillin and amoxicillin-clavulanic acid has led to the use of broad-spectrum antimicrobial agents for patients in pediatric clinics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Acute cholecystitis (AC) is an acute inflammatory disease of the gallbladder and one of the most frequent causes of acute abdominal pain. Early cholecystectomy is recommended for mild cholecystitis. However, the optimal surgical timing for moderate-to-severe cholecystitis requiring percutaneous transhepatic gallbladder drainage (PTGBD) remains unclear. We hypothesized that early elective surgery after PTGBD would reduce surgical morbidity., Methods: A retrospective analysis was performed on adult patients who underwent elective surgery for AC after PTGBD at our hospital between January 2011 and December 2020. Patient demographics, perioperative findings, and postoperative morbidity and mortality rates were also investigated. The patients were divided into two groups based on postoperative morbidity, and univariable analysis was performed for preoperative factors. Multivariable logistic regression analysis was performed for the potential independent variables., Results: A total of 891 patients were screened for eligibility, and 259 were included in the analysis. Among these patients, 32 developed postoperative morbidity; however, there was no postoperative mortality. Multivariable analysis revealed that the time from PTGBD to surgery was an independent predictor of surgical morbidity (odds ratio, 1.05; 95% confidence interval: 1.01-1.10)., Conclusion: In early elective surgery for moderate-to-severe AC requiring PTGBD, a shorter interval from biliary drainage to surgery may decrease surgical morbidity., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Saiseikai Utsunomiya Hospital’s Institutional Review Board (No: 2020–78; July 27, 2020), and the requirement for written informed consent was waived due to the retrospective nature of the study. The research was performed in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

An 18-month-old boy presented with septic arthritis and osteomyelitis caused by Hypervirulent Klebsiella pneumoniae harboring cardinal virulence genes. The condition necessitated several surgical interventions, and a prolonged course of antibiotic therapy to effectively manage the severe infection and prevent complications, highlighting the challenges posed by Hypervirulent Klebsiella pneumoniae in pediatric cases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n =652; mean age=35.4±14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n =1871; mean age=34±14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n =642; mean age=29.6±13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation ( n =714; mean age=36.3±15.3; female=66.1%), clinical controls ( n =1184; mean age=36.8±15.6; female=63.1%), and healthy controls ( n =1240; mean age= 31.6±15.5; female=61.0%). We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohen's d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure. This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour., Competing Interests: Conflicts of interest ALvH receives consultancy fees from the Augeo foundation. CAZ is a full-time US government employee. He is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. HPB has consulted to the Milken Institute. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. IA received speakers honorarium from Lundbeck. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. AC reports being currently an employee of the Regeneron Genetics Center, and may own Regeneron stock or stock options. JCS acknowledge to be related with the next companies ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant). PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. All other authors report no biomedical financial interests, disclosures or potential conflicts of interest.

Introduction: Practical simulation training with proper haptic feedback and the fragility of the human body is required to overcome the long learning curve associated with laparoscopic inguinal hernia repair (LIHR). However, few hernia models accurately reflect the texture and fragility of the human body. Therefore, in this study, we developed a novel model for transabdominal preperitoneal (TAPP) LIHR training and evaluated its validity., Methods: We developed a high-quality mock peritoneum with a hydrated polyvinyl alcohol layer and a unique two-way crossing cellulose fiber layer. To complete the simulation, the peritoneum was adhered to a urethane foam inguinal base with surgical landmarks. Participants could perform all the procedures required for the TAPP LIHR. Twenty-four surgeons performed TAPP LIHR simulation using a novel simulator. Their opinions were rated on a 5-point Likert scale. Additionally, 6 surgical residents and 10 surgical experts performed the procedure. Their performance was evaluated using the TAPP checklist score and procedure time., Results: Most participants strongly agreed that the TAPP LIHR simulator with an exchangeable peritoneum model was useful. The participants agreed on the model fidelity for tactile sensation, forceps handling, and humanlike anatomy. In comparisons between surgical residents and experts, the experts had significantly higher scores (10.6 vs. 17.2, p < 0.05) and shorter procedure times (92.3 vs. 55.9 min; p < .05) than did surgical residents., Conclusions: We developed a high-quality exchangeable peritoneal model that mimics the human peritoneum's texture and fragility. This model enhances laparoscopic simulation training, potentially shortening TAPP LIHR learning curves., (© 2024 The Author(s). Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Embryo implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The intrauterine environment during the peri-implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimuli and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithelia. Cyclooxygenases (COXs), rate-limiting enzymes involved in prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during implantation, but the role of each COX isozyme in the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (uKO) and COX1/uterine COX2-double-KO (COX1/COX2-DKO) mice. COX2 uKO caused deferred implantation with failed trophoblast invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo implantation. Spatial transcriptome and lipidome analyses revealed unique profiles of prostaglandin synthesis by each COX isozyme and spatiotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal interface to establish early pregnancy.

Background: There is a risk of cephalic vein injury during shoulder arthroscopy. However, limited data regarding its anatomic course are available., Purpose: To analyze the positional relationship and factors affecting the distance between the coracoid tip and cephalic veins., Study Design: Case series; Level of evidence, 4., Methods: A total of 80 contrast-enhanced computed tomography images from 80 patients (mean age, 49.6 ± 20.3 years; 61 men) were retrospectively analyzed. The distance between the center of the coracoid tip and the vertical line through the cephalic vein was measured in the axial (D1) and sagittal (D2) planes. The distance between 1 cm lateral to the center of the coracoid tip and the vertical line through the cephalic vein was measured in the sagittal plane (D3). Each distance was compared according to patient sex and laterality. Associations between each distance and the patient's age, height, weight, and body mass index were investigated., Results: The mean D1 was 18.4 ± 7.3 mm in 59 patients. The mean D2 was 23.4 ± 11.6 mm, and it was within 10 mm in 10 patients (12.5%). The mean D3 was 33.7 ± 12.2 mm. There was no significant difference in D1, D2, and D3 according to patient sex or laterality. A positive correlation was observed only between D3 and patient height ( r = 0.320; P = .034)., Conclusion: The cephalic vein was found to travel a mean of 23.4 mm distal and 33.7 mm distal to 1 cm lateral to the coracoid tip. Therefore, Care should be taken to avoid cephalic vein injury when creating an anterior inferior portal or 5-o'clock portal around these areas., Competing Interests: The authors have declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from Komaki City Hospital (ref No. 201039)., (© The Author(s) 2024.)

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Protein lipidation is a common co- or post-translational modification that plays a crucial role in regulating the localization, interaction and function of cellular proteins. Dysregulation of lipid modifications can lead to various diseases, including cancer, neurodegenerative diseases and infectious diseases. Therefore, the identification of proteins undergoing lipidation and their lipidation sites should provide insights into many aspects of lipid biology, as well as providing potential targets for therapeutic strategies. Bottom-up proteomics using liquid chromatography/tandem mass spectrometry is a powerful technique for the global analysis of protein lipidation. Here, we review proteomic methods for profiling protein lipidation, focusing on the two major approaches: the use of chemical probes, such as lipid alkyne probes, and the use of enrichment techniques for endogenous lipid-modified peptides. The challenges facing these methods and the prospects for developing them further to achieve a comprehensive analysis of lipid modifications are discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society.)

The main aim of this study is to investigate the material and monetary flows of CDW management and to characterize the distribution of illegally dumped CDW in Hanoi. Construction and demolition waste management has become a source of much concern to the urban authorities and citizens of big cities in Vietnam. It is estimated that 3000 t of CDW were generated per day from construction and demolition activities in Hanoi, but only 45% of the CDW was received at official landfills, while 55% of the CDW was disposed of elsewhere. The consequences of improper waste management are potentially alarming. The study conducted interviews to identify the material and cash flow associated with licensed and unlicensed contractors in CDW classification, transportation, treatment, and disposal, to characterize the distribution of illegally dumped CDW in two districts in Hanoi (urban and suburban districts), and to assess the composition of dumped CDW and environmental assessment of illegally dumped CDW by chemical analyses such as leaching and content tests. The study concluded that illegal dumping was performed mostly by unlicensed private companies. The illegally dumped CDW was mostly composed of mixed materials such as concrete, bricks, stones, and some hazardous materials such as asbestos and gypsum were found. The environmental concern of illegally dumped CDW was mostly dust, blockage of water ways, and inundation of increased suspended solids, whereas the heavy metal leaching concentration of all samples was below the environmental standards in Vietnam., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Proteins can be modified by lipids in various ways, for example, by myristoylation, palmitoylation, farnesylation, and geranylgeranylation-these processes are collectively referred to as lipidation. Current chemical proteomics using alkyne lipids has enabled the identification of lipidated protein candidates but does not identify endogenous lipidation sites and is not readily applicable to in vivo systems. Here, we introduce a proteomic methodology for global analysis of endogenous protein N-terminal myristoylation sites that combines liquid-liquid extraction of hydrophobic lipidated peptides with liquid chromatography-tandem mass spectrometry using a gradient program of acetonitrile in the high concentration range. We applied this method to explore myristoylation sites in HeLa cells and identified a total of 75 protein N-terminal myristoylation sites, which is more than the number of high-confidence myristoylated proteins identified by myristic acid analog-based chemical proteomics. Isolation of myristoylated peptides from HeLa digests prepared with different proteases enabled the identification of different myristoylated sites, extending the coverage of N-myristoylome. Finally, we analyzed in vivo myristoylation sites in mouse tissues and found that the lipidation profile is tissue-specific. This simple method (not requiring chemical labeling or affinity purification) should be a promising tool for global profiling of protein N-terminal myristoylation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Docosahexaenoic acid (DHA) and ultra-long-chain polyunsaturated fatty acids (ULC-PUFAs) are uniquely enriched in membrane phospholipids of retinal photoreceptors. Several studies have shown that di-DHA- and ULC-PUFA-containing phospholipids in photoreceptors have an important role in maintaining normal visual function; however, the molecular mechanisms underlying the synthesis and enrichment of these unique lipids in the retina, and their specific roles in retinal function remain unclear. Long-chain acyl-coenzyme A (CoA) synthetase 6 (ACSL6) preferentially converts DHA into DHA-CoA, which is a substrate during DHA-containing lipid biosynthesis. Here, we report that Acsl6 mRNA is expressed in the inner segment of photoreceptor cells and the retinal pigment epithelial cells, and genetic deletion of ACSL6 resulted in the selective depletion of di-DHA- and ULC-PUFA-containing phospholipids, but not mono-DHA-containing phospholipids in the retina. MALDI mass spectrometry imaging (MALDI-MSI) revealed the selective distribution of di-DHA- and ULC-PUFA-containing phospholipids in the photoreceptor outer segment (OS). Electroretinogram of Acsl6 -/- mice exhibited photoreceptor cell-derived visual impairment, whereas the expression levels and localization of opsin proteins were unchanged. Acsl6 -/- mice exhibited an age-dependent progressive decrease of the thickness of the outer nuclear layers, whereas the inner nuclear layers and OSs were normal. These results demonstrate that ACSL6 facilitates the local enrichment of di-DHA- and ULC-PUFA-containing phospholipids in the retina, which supports normal visual function and retinal homeostasis., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anticancer activity but their mode of action is unknown. These members possess electrophilic functional groups that can might undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine reactivity of the most potent of these alkaloids, dankastatin B, by using activity-based protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion-selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hypersensitivity to dankastatin B-mediated antiproliferative effects in breast cancer cells, thus indicating that VDAC3 was at least partially involved in the anticancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlights the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products., (© 2023 Wiley-VCH GmbH.)

The quality of skeletal muscle is maintained by a balance between protein biosynthesis and degradation. Disruption in this balance results in sarcopenia. However, its underlying mechanisms remain underinvestigated. Selenoprotein P (SeP; encoded by Selenop in mice) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. We created immobilized muscle atrophy model in Selenop knockout (KO) mice. Immobilization (IMM) significantly reduced cross-sectional areas and the size of skeletal muscle fibers, which were ameliorated in KO mice. IMM upregulated the genes encoding E3 ubiquitin ligases and their upstream FoxO1, FoxO3, and KLF15 transcription factors in the skeletal muscle, which were suppressed in KO mice. These findings suggest a possible involvement of SeP-mediated reductive stress in physical inactivity-mediated sarcopenia, which may be a therapeutic target against sarcopenia. NEW & NOTEWORTHY Selenoprotein P (SeP) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. Immobilization (IMM) significantly reduced skeletal muscle mass in mice, which was prevented in SeP knockout (KO) mice. IMM-induced Foxos/KLF15-atrogene upregulation was suppressed in the skeletal muscle of KO mice. These findings suggest that SeP-mediated reductive stress is involved in and may be a therapeutic target for physical inactivity-mediated muscle atrophy.

Commensal bacteria-derived metabolites are critical in regulating the host immune system. Although the impact of gut microbiota-derived hydrophilic metabolites, such as short-chain fatty acids, on immune cell functions and development has been well documented, the immunomodulatory effects of gut microbiota-derived lipids are still of interest. Here, we report that lipid extracts from the feces of specific-pathogen-free (SPF), but not germ-free (GF), mice showed regulatory T (Treg)-cell-inducing activity. We conducted RP-HPLC-based fractionation and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidome profiling and identified two bioactive lipids, 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) and all-trans retinoic acid (atRA), with Treg-inducing activity in vitro. The luminal abundance of 9,10-DiHOME in the large intestine was significantly decreased by dextran sulfate sodium (DSS)-induced colitis, indicating that 9,10-DiHOME may be a potential biomarker of colitis. These observations implied that commensal bacteria-derived lipophilic metabolites might contribute to Treg development in the large intestine., (© 2023. The Author(s).)

Bromodomain-containing protein 8 (BRD8) is a subunit of the NuA4/TIP60-histone acetyltransferase complex. Although BRD8 has been considered to act as a co-activator of the complex, its biological role remains to be elucidated. Here, we uncovered that BRD8 accumulates in colorectal cancer cells through the inhibition of ubiquitin-dependent protein degradation by the interaction with MRG domain binding protein. Transcriptome analysis coupled with genome-wide mapping of BRD8-binding sites disclosed that BRD8 transactivates a set of genes independently of TIP60, and that BRD8 regulates the expression of multiple subunits of the pre-replicative complex in concert with the activator protein-1. Depletion of BRD8 induced cell-cycle arrest at the G1 phase and suppressed cell proliferation. We have also shown that the bromodomain of BRD8 is indispensable for not only the interaction with histone H4 or transcriptional regulation but also its own protein stability. These findings highlight the importance of bromodomain as a therapeutic target., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

A hepatic crown-like structure (hCLS) formed by macrophages accumulating around lipid droplets and dead cells in the liver is a unique feature of nonalcoholic steatohepatitis (NASH) that triggers progression of liver fibrosis. As hCLS plays a key role in the progression of NASH fibrosis, hCLS formation has emerged as a potential therapeutic target. n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential suppressive effects on NASH fibrosis; however, the mechanisms underlying this effect are poorly understood. Here, we report that n-3 PUFA-enriched Fat-1 transgenic mice are resistant to hCLS formation and liver fibrosis in a NASH model induced by a combination of high-fat diet, CCl4 and a Liver X receptor (LXR) agonist. Liquid chromatography-tandem mass spectrometry-based mediator lipidomics revealed that the amount of endogenous n-3 PUFA-derived metabolites, such as 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), and 19,20-epoxy docosapentaenoic acid (19,20-EpDPE), was significantly elevated in Fat-1 mice, along with hCLS formation. In particular, DHA-derived 19,20-EpDPE produced by Cyp4f18 attenuated the hCLS formation and liver fibrosis in a G protein-coupled receptor 120 (GPR120)-dependent manner. These results indicated that 19,20-EpDPE is an endogenous active metabolite that mediates the preventive effect of n-3 PUFAs against NASH fibrosis., Competing Interests: Declaration of competing interest We declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The Wnt/β-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Background: There is currently no established imaging method for assessing liver reserve capacity prior to carbon-ion radiotherapy (CIRT) for liver tumors. In order to perform safe CIRT, it is essential to estimate the post-therapeutic residual reserve capacity of the liver., Purpose: To evaluate the ability of pre-treatment 99m Tc-galactosyl human serum albumin ( 99m Tc-GSA) scintigraphy to accurately estimate the residual liver reserve capacity in patients treated with CIRT for liver tumors., Materials and Methods: This retrospective study evaluated patients who were performed CIRT for liver tumors between December 2018 and September 2020 and underwent 99m Tc-GSA scintigraphy before and 3 months after CIRT, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month before CIRT were evaluated. The maximal removal rate of 99m Tc-GSA (GSA-Rmax) was analyzed for the evaluation of pre-treatment liver reserve capacity. Then, the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using liver SPECT images fused with the Gd-EOB-DTPA-enhanced MRI. GSA-RL before CIRT and GSA-Rmax at 3 months after CIRT were compared using non-parametric Wilcoxon signed-rank test and linear regression analysis., Results: Overall, 50 patients were included (mean age ± standard deviation, 73 years ± 11; range, 29-89 years, 35 men). The median GSA-RL was 0.393 [range, 0.057-0.729] mg/min, and the median GSA-Rmax after CIRT was 0.369 [range, 0.037-0.780] mg/min (P = .40). The linear regression equation representing the relationship between the GSA-RL and GSA-Rmax after CIRT was y = 0.05 + 0.84x (R 2 = 0.67, P < .0001). There was a linear relationship between the estimated and actual post-treatment values for all patients, as well as in the group with impaired liver reserve capacity (y = - 0.02 + 1.09x (R 2 = 0.62, P = .0005))., Conclusions: 99m Tc-GSA scintigraphy has potential clinical utility for estimating the residual liver reserve capacity in patients undergoing carbon-ion radiotherapy for liver tumors., Trial Registration: UMIN000038328, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000043545 ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.

Cyp4f18 catalyzes the conversion of n-3 polyunsaturated fatty acids (PUFAs) into omega-3 epoxides, such as 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) and 19,20-epoxydocosapentaenoic acid (19,20-EpDPE) from eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), respectively. Cyp4f18-deficient mice spontaneously develop psoriasis-like dermatitis. A significant increase in the number of IL-17A-positive gamma delta (γδ) T cells in the skin and enlargement of draining lymph nodes was observed. These symptoms were drastically suppressed by antibiotic treatment. Cyp4f18 is highly expressed in dendritic cells (DCs), and Cyp4f18-deficient bone marrow-derived dendritic cells (BMDCs) show markedly increased expression levels of cytokines such as IL-23 and IL-1β in response to lipopolysaccharide (LPS) stimulation. Lipidomic analysis of lymph nodes and BMDCs revealed a significant decrease in a series of omega-3 epoxidized metabolites. Among them, 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), a vicinal diol derived from EPA omega-3 epoxidation suppressed IL-23 production in LPS-stimulated BMDCs in Cyp4f18-deficient mice. These results demonstrate that Cyp4f18 endogenously produces omega-3-epoxidized metabolites in the draining lymph nodes, and these metabolites contribute to skin homeostasis by suppressing the excessive activation of the IL-23/IL-17 axis initiated by DCs., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Light-based therapies are promising for treating diseases including cancer, hereditary conditions, and protein-related disorders. However, systems, methods, and devices that deliver light deep inside the body are limited. This study aimed to develop an endovascular therapy-based light illumination technology (ET-BLIT), capable of providing deep light irradiation within the body., Methods: The ET-BLIT system consists of a catheter with a single lumen as a guidewire and diffuser, with a transparent section at the distal end for thermocouple head attachment. The optical light diffuser alters the emission direction laterally, according to the optical fibre's nose-shape angle. If necessary, after delivering the catheter to the target position in the vessel, the diffuser is inserted into the catheter and placed in the transparent section in the direction of the target lesion., Findings: ET-BLIT was tested in an animal model. The 690-nm near-infrared (NIR) light penetrated the walls of blood vessels to reach the liver and kidneys without causing temperature increase, vessel damage, or blood component alterations. NIR light transmittance from the diffuser to the detector within the organ or vessel was approximately 30% and 65% for the renal and hepatic arteries, respectively., Interpretation: ET-BLIT can be potentially used in clinical photo-based medicine, as a far-out technology. ET-BLIT uses a familiar method that can access the whole body, as the basic procedure is comparable to that of endovascular therapy in terms of sequence and technique. Therefore, the use of the ET-BLIT system is promising for many light-based therapies that are currently in the research phase., Funding: Supported by Programme for Developing Next-generation Researchers (Japan Science and Technology Agency); JSPS KAKENHI (18K15923, 21K07217); JST-CREST (JPMJCR19H2); JST-FOREST-Souhatsu (JPMJFR2017); The Uehara Memorial Foundation; Yasuda Memorial Medical Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; The Japan Health Foundation; Takahashi Industrial and Economic Research Foundation; AICHI Health Promotion Foundation; and Princess Takamatsu Cancer Research Fund., Competing Interests: Declaration of interests Nothing to declare., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The effects of daily teriparatide (20 μg) (D-PTH), weekly high-dose teriparatide (56.5 μg) (W-PTH), or bisphosphonates (BPs) on areal bone mineral density (aBMD), bone turnover markers (BTMs), volumetric BMD (vBMD), microarchitecture, and estimated strength were investigated in postmenopausal osteoporosis patients., Methods: The study participants were 131 women with a history of fragility fractures. They were randomized to receive D-PTH, W-PTH, or BPs (alendronate or risedronate) for 18 months. Dual-energy X-ray absorptiometry (DXA), BTMs, and high-resolution peripheral quantitative CT (HR-pQCT) parameters were evaluated at baseline and after 6 and 18 months of treatment. The primary endpoint was the change (%) in cortical thickness (Ct.Th) after 18 months' treatment compared with baseline., Results: DXA showed that D-PTH, W-PTH, and BPs increased lumbar spine aBMD (+12.0%, +8.5%, and +6.8%) and total hip aBMD (+3.0%, +2.1%, and +3.0%), but D-PTH and W-PTH decreased 1/3 radius aBMD (-4.1%, -3.0%, -1.4%) after 18 months. On HR-pQCT, D-PTH increased trabecular vBMD (Tb.vBMD) at the distal radius and tibia after 18 months (+6.4%, +3.7%) compared with the BPs group, decreased cortical volumetric tissue mineral density (Ct.vTMD) (-1.8%, -0.9%) compared with the other groups, increased Ct.Th (+1.3%, +3.9%), and increased failure load (FL) (+4.7%, +4.4%). W-PTH increased Tb.vBMD (+5.3%, +1.9%), maintained Ct.vTMD (-0.7%, +0.2%) compared with D-PTH, increased Ct.Th (+0.6%, +3.6%), and increased FL (+4.9%, +4.5%). The BPs increased Tb.vBMD only in the radius (+2.0%, +0.2%), maintained Ct.vTMD (-0.6%, +0.3%), increased Ct.Th (+0.5%, +3.4%), and increased FL (+3.9%, +2.8%)., Conclusions: D-PTH and W-PTH comparably increased Ct.Th, the primary endpoint. D-PTH had a strong effect on trabecular bone. Although D-PTH decreased Ct.vTMD, it increased Ct.Th and total bone strength. W-PTH had a moderate effect on trabecular bone, maintained Ct.vTMD, and increased Ct.Th and total bone strength to the same extent as D-PTH., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in the development and progression of colorectal cancer. Previously, we identified a set of candidate genes that were regulated by this signaling pathway, and the present study focused on motile sperm domain containing 1 ( MOSPD1 ). Immunohistochemical staining revealed that the expression of MOSPD1 was elevated in tumor cells from colorectal cancer tissues compared with in non-tumor cells. Using ChIP-seq data and the JASPAR database, the regulatory region(s) in the MOSPD1 gene as a target of the Wnt/β-catenin signaling pathway were searched, and a region containing three putative TCF-binding motifs in the 3'-flanking region was identified. Additional analyses using reporter assay and ChIP-quantitative PCR suggested that this region harbors enhancer activity through an interaction with transcription factor 7 like 2 (TCF7L2) and β-catenin. In addition, chromatin conformation capture assay revealed that the 3'-flanking region interacts with the MOSPD1 promoter. These data suggested that MOSPD1 was regulated by the β-catenin/TCF7L2 complex through the enhancer element located in the 3'-flanking region. These findings may be helpful for future studies regarding the precise regulatory mechanisms of MOSPD1., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022, Spandidos Publications.)

Importance: Interpreting results from randomized clinical trials (RCTs) for COVID-19, which have been published rapidly and in vast numbers, is challenging during a pandemic., Objective: To evaluate the robustness of statistically significant findings from RCTs for COVID-19 using the fragility index., Design, Setting, and Participants: This cross-sectional study included COVID-19 trial articles that randomly assigned patients 1:1 into 2 parallel groups and reported at least 1 binary outcome as significant in the abstract. A systematic search was conducted using PubMed to identify RCTs on COVID-19 published until August 7, 2021., Exposures: Trial characteristics, such as type of intervention (treatment drug, vaccine, or others), number of outcome events, and sample size., Main Outcomes and Measures: Fragility index., Results: Of the 47 RCTs for COVID-19 included, 36 (77%) were studies of the effects of treatment drugs, 5 (11%) were studies of vaccines, and 6 (13%) were of other interventions. A total of 138 235 participants were included in these trials. The median (IQR) fragility index of the included trials was 4 (1-11). The medians (IQRs) of the fragility indexes of RCTs of treatment drugs, vaccines, and other interventions were 2.5 (1-6), 119 (61-139), and 4.5 (1-18), respectively. The fragility index among more than half of the studies was less than 1% of each sample size, although the fragility index as a proportion of events needing to change would be much higher., Conclusions and Relevance: This cross-sectional study found a relatively small number of events (a median of 4) would be required to change the results of COVID-19 RCTs from statistically significant to not significant. These findings suggest that health care professionals and policy makers should not rely heavily on individual results of RCTs for COVID-19.

Background: Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on photo-absorber, IRDye-700DX (IR700), -antibody conjugates, and near-infrared (NIR) light., Methods: We used HER2-positive SCLC parental cell lines (SBC-3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR-PIT using anti HER2 antibody trastuzumab., Results: We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin-resistance (SBC-3/CDDP). In vitro, the rate of cell death increased with the amount of NIR-light irradiation, and it was significantly higher in SBC-3/CDDP than in SBC-3. In vivo, tumor growth was more suppressed in SBC-3/CDDP group than in SBC-3 group, and survival period tended to be prolonged., Conclusion: In this study, we demonstrated that HER2 targeting NIR-PIT using trastuzumab is promising therapy for HER2-positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR-PIT., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington's disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose to examine the accuracy and reproducibility of the femoral axial offset measured from the retrocondylar plane by computed tomography (CT). Bone specimens of the femur of 15 males and 15 females were analyzed. CT imaging was performed and data of the coordinates were collected (center of femoral head, center of an ellipse around greater trochanter, center of an ellipse around the base of femoral neck, posterior edge of great trochanter, and both posterior condyles). The angle between the line connecting center of the femoral head and center of an ellipse around greater trochanter and the line connecting both posterior condyles was set as anteversion 1. The angle between the line connecting the center of femoral head and center of an ellipse around base of the femoral neck and the line connecting both posterior condyles was set as anteversion 2. The femoral axial offset was measured from the retrocondylar plane. Measurements were performed three times on the same subject, and intrarater reliability (ICC) was determined. In addition, interrater reliability (ICC) was determined by comparing data from three raters. The mean value for anteversion 1 was 20.1° for males and 22.7° for females. The values for anteversion 2 were 16.0° and 19.9° for males and females, respectively. Offset was 34.0 and 33.4 mm in males and females, respectively. Intrarater ICC and interrater ICC exceeded 0.81 for both methods, suggesting that the method of measurement was reliable. Accuracy and reproducibility of the measurement of femoral axial offset from the retrocondylar plane were high., (© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Objective: Sarcopenia (especially muscle mass assessed using gold standard techniques) has been suggested as a poorer predictor of mortality than muscle function in patients undergoing hemodialysis. Appropriate methods to estimate muscle mass for use as a good predictor of clinical outcomes remain to be established. We investigated whether the modified creatinine index (mCI), which is a surrogate marker of muscle mass, could predict mortality and cardiovascular (CV) hospitalizations independent of muscle function and other confounders in patients on hemodialysis., Design and Methods: In this retrospective study, outpatients (n = 542; mean age, 65.3 years; 60% men; median dialysis vintage, 29 months; mean BMI, 22.0 kg/m 2 ) undergoing hemodialysis were investigated. The mCI, handgrip strength, and gait speed were assessed and related to all-cause mortality and a composite of CV hospitalizations and all-cause mortality. Cox proportional and mixed-effects negative binomial models were fit for mortality and the composite outcomes., Results: Patients were followed up for a median 3 years (interquartile range: 1.5-5.7). Each per SD increase of mCI (HR:0.63, 95% CI:0.62-0.65), handgrip strength (HR:0.51, 95% CI:0.48-0.54), and gait speed (HR:0.60, 95% CI:0.56-0.64) were significantly associated with lower all-cause mortality rates after adjusting for covariates. The mCI was consistently found to be an independent predictor of mortality after additional adjustment for handgrip strength or gait speed. Furthermore, sarcopenic conditions [i.e., lower mCI, and lower handgrip strength (HR:3.79, 95% CI:2.09-6.87) or slower gait speed (HR:4.20, 95% CI:2.38-7.41)] were significantly associated with a higher risk of mortality after adjusting for covariates. Associations of mCI with multiple CV hospitalizations and mortality were similar to those between mCI and mortality., Conclusion: The mCI was a good predictor of clinical outcomes and was comparable to muscle function, including handgrip strength and gait speed. The mCI is likely to provide additional diagnostic and prognostic values for sarcopenia in patients on hemodialysis., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Patients undergoing hemodialysis (HD) have different physical activity (PA) patterns on HD and non-HD days. Nonetheless, whether these differences are associated with clinical outcomes remains unclear. We examined the association of PA levels on HD and non-HD days with cardiovascular (CV) hospitalizations and mortality., Methods: Outpatients undergoing HD from 2002 to 2019 were retrospectively enrolled. The number of steps performed over 3 HD days and 4 non-HD days was recorded via accelerometry. Outcomes were all-cause mortality and a composite of CV hospitalizations and mortality. Patients were divided into two groups, each according to the median number of steps performed on HD (2371 steps/day) and non-HD days (3752 steps/day). Further, we categorized them into 4 groups according to each median values: "more active on HD/more active on non-HD (MM)," "more active on HD/less active on non-HD (ML)," "less active on HD/more active on non-HD (LM)," and "less active on HD/less active on non-HD (LL)." Cox and mixed-effects Poisson regression models were used for these outcomes., Results: We analyzed 512 patients (median follow-up, 3.4 years). Higher PA on HD (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.54-0.65), and non-HD (HR, 0.84; 95% CI, 0.80-0.88) was associated with lower mortality risk, respectively. Further, the ML group (HR, 1.20; 95% CI, 1.13-1.28), LM group (HR, 1.82; 95% CI, 1.53-2.17), and LL group (HR, 1.83; 95% CI, 1.65-2.02) had higher mortality risks than the MM group. Associations of PA with multiple CV hospitalizations and mortality were similar to those between PA and mortality., Conclusions: Higher PA on HD and non-HD days was associated with lower risks of CV hospitalizations and mortality. However, higher PA levels on either HD or non-HD days alone did not improve clinical outcomes., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: GPR87 is a G-protein receptor that is specifically expressed in tumour cells, such as lung cancer, and rarely expressed in normal cells. GPR87 is a promising target for cancer therapy, but its ligand is controversial. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy in which a photosensitiser, IRDye700DX (IR700), binds to antibodies and specifically destroys target cells by irradiating them with near-infrared-light. Here, we aimed to develop a NIR-PIT targeting GPR87., Methods: We evaluated the expression of GPR87 in resected specimens of lung cancer and malignant pleural mesothelioma (MPM) resected at Nagoya University Hospital using immunostaining. Humanised anti-GPR87 antibody (huGPR87) was generated by introducing CDRs from mouse anti-GPR87 antibody generated by standard hybridoma method. HuGPR87 was conjugated with IR700 and the therapeutic effect of NIR-PIT was evaluated in vitro and in vivo using lung cancer or MPM cell lines., Findings: Among the surgical specimens, 54% of lung cancer and 100% of MPM showed high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro, and showed therapeutic effects in multiple models in vivo., Interpretation: These results suggest that NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer., Funding: This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217, JSPS), FOREST-Souhatsu, CREST (JST)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

A 68‒year‒old man was referred to our hospital due to vomiting and light‒headedness. The patient was diagnosed with advanced gastric cancer. Neoadjuvant chemotherapy(S‒1 plus oxaliplatin)was initiated resulting in a partial response(PR) after 5 courses. Total gastrectomy and D1 dissection was performed. The tumor was diagnosed as poorly differentiated adenocarcinoma and the pathological Stage was ypT3, N3b, M1[CY1], ypStage Ⅳ. Ramucirumab plus nab‒paclitaxel was administered due to the appearance of swollen lymph nodes post‒operatively. This treatment maintained PR for 6 courses. However, after an evaluation of progressive disease(PD), nivolumab was initiated as third‒line chemotherapy. After 3 courses, a sudden seizure occurred and a brain metastasis with a diameter of 6 mm was observed. Considering the decrease in CEA level and that the brain metastasis presented as a small lesion, the tumor was inferred to be highly sensitive to nivolumab. We continued nivolumab monotherapy as chemotherapy. Radiotherapy was not performed. Both intra and extra‒cranial metastatic lesions maintained PR for 17 courses. The treatment was changed to irinotecan after evidence of PD was observed. However, after 2 courses(2 years and 3 months from his first visit), the patient died of an unknown cause. To our knowledge, this is the first case of brain metastasis of gastric cancer successfully treated with nivolumab.

Background: The National Clinical Database (NCD) nationwide registry program of gastric cancer started in 2018. The purpose of this study was to report the treatment results of the NCD registry in the form of treatment results of the real world in Japan., Methods: Patients' characteristics, tumor features, treatments, and outcomes were collected using a web-based data entry system. We analyzed the initial NCD database for data on surgically treated gastric cancer patients in 2011., Results: A total of 30,257 patients with malignant gastric tumors were enrolled by the NCD registry program from 501 hospitals in all 47 prefectures. Of these, the status of data entry was not approved in 8.8% of the registered data, and follow-up information was missing in 1.2% of the approved cases. Excluding 1777 cases, which were not resected for primary gastric cancer, 25,306 resected cases included 44.4% of stomach surgeries recorded in the NCD. The 5 year survival rate of the resected cases was 71.3% and the operative mortality rate was 0.41%. The stage-specific 5 year survival rates were as follows: 89.6% for stage IA, 83.8% for stage IB, 77.3% for stage IIA, 69.1% for stage IIB, 58.7% for stage IIIA, 44.1% for stage IIIB, 30.1% for stage IIIC, and 13.4% for stage IV., Conclusions: The NCD gastric cancer registry program demonstrated validity for database construction. The gastric cancer registry is expected to become a nationwide registry with the dissemination of data entry system and method in the NCD.

Background: Although the incidence and mortality have decreased, gastric cancer (GC) is still a public health issue globally. An international study reported higher survival in Korea and Japan than other countries, including the United States. We examined the determinant factors of the high survival in Japan compared with the United States., Methods: We analysed data on 78,648 cases from the nationwide GC registration project, the Japanese Gastric Cancer Association (JGCA), from 2004-2007 and compared them with 16,722 cases from the Surveillance, Epidemiology, and End Results Program (SEER), a United States population-based cancer registry data from 2004-2010. We estimated 5-year relative survival and applied a multivariate excess hazard model to compare the two countries, considering the effect of number of lymph nodes (LNs) examined., Results: Five-year relative survival in Japan was 81.0%, compared with 45.0% in the United States. After controlling for confounding factors, we still observed significantly higher survival in Japan. Among N2 patients, a higher number of LNs examined showed better survival in both countries. Among N3 patients, the relationship between number of LNs examined and differences in survival between the two countries disappeared., Conclusion: Although the wide differences in GC survival between Japan and United States can be largely explained by differences in the stage at diagnosis, the number of LNs examined may also help to explain the gaps between two countries, which is related to stage migration.

Purpose: Positive margins are reported in from 4.8 to 9.5% of all gastric cancer surgeries and they have a negative impact on the overall survival. Few cases with positive duodenal margins have been included in previous studies regarding the prognosis., Methods: This multi-institutional retrospective study included 115 gastric cancer patients with positive duodenal margins following gastrectomy between January 2002 and December 2017. The association between clinicopathological factors and the overall survival was evaluated by univariate and multivariate analyses., Results: The three-year overall survival was 22% and the median survival was 13 months. A multivariate analysis found that distant metastasis, no postoperative chemotherapy, and non-Type 4 disease were significantly associated with a poor survival. Patients without distant metastasis who received postoperative chemotherapy had a 3-year overall survival of 56% and a median survival of 44 months., Conclusion: The patients who underwent post-operative chemotherapy showed a significantly better OS compared with those who did not undergo post-operative chemotherapy, regardless of the existence of distant metastasis. Postoperative chemotherapy may, therefore, improve the prognosis of surgically treated gastric cancer patients with positive duodenal margins.

Objective: The objective of this research was to develop 3D registration analysis method in longitudinal studies of high-resolution peripheral quantitative computed tomography (HR-pQCT), to analyze ranges of bone microstructure parameters in addition to standard parameters, and to test the precision of these measurements., Methods: Scans of HR-pQCT and analysis of bone microstructure were performed at 3 times in 15 subjects. The 3 images were matched 3-dimensionally, and bone microstructures were analyzed in the common region. In addition to standard measurement parameters of geometry, bone mineral density (BMD), trabecular bone, and cortical bone, parameters showing plate to rod-like structure, connectivity, cavity formation of trabecular bone, and bending stability of cortical bone were also measured. Precision was evaluated with the root mean square percent coefficient variance (RMS%CV)., Results: RMS%CV was 0.1%-1.3% for geometry, 0.6%-1.9% for BMD, 0.8%-3.3% for trabecular bone, 2.1%-9.8% for additionally measured trabecular bone, 1.0%-3.4% for cortical bone excluding Ct.Po, 6.0%-6.1% for Ct.Po, and 0.8%-1.5% for additionally measured cortical bone. Precision was higher for 3D registration than for 2D registration in geometry, BV/TV, and Ct.Po., Conclusions: 3D registration analysis of a range of bone microstructural parameters in longitudinal analysis of HR-pQCT showed good precision, offering potential for contributing to future research on osteoporosis and bone metabolic diseases., (Copyright © 2020 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)