Showing papers by "Osaka University published in 2022"

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Abstract: The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic and epigenomic features. This article is highlighted in the In This Issue feature, p. 587.

Dual Active Centers Bridged by Oxygen Vacancies of Ruthenium Single‐Atom Hybrids Supported on Molybdenum Oxide for Photocatalytic Ammonia Synthesis

Abstract: Photocatalytic synthesis of ammonia (NH3 ) holds significant potential compared with the Haber-Bosch process. However, the reported photocatalysts suffer from low efficiency owing to localized electron deficiency. Herein, Ru-SA (single atoms)/Hx MoO3-y hybrids with abundant of Mon+ (4

Delayed fluorescence from inverted singlet and triplet excited states

Abstract: Hund's multiplicity rule states that a higher spin state has a lower energy for a given electronic configuration1. Rephrasing this rule for molecular excited states predicts a positive energy gap between spin-singlet and spin-triplet excited states, as has been consistent with numerous experimental observations over almost a century. Here we report a fluorescent molecule that disobeys Hund's rule and has a negative singlet-triplet energy gap of -11 ± 2 meV. The energy inversion of the singlet and triplet excited states results in delayed fluorescence with short time constants of 0.2 μs, which anomalously decrease with decreasing temperature owing to the emissive singlet character of the lowest-energy excited state. Organic light-emitting diodes (OLEDs) using this molecule exhibited a fast transient electroluminescence decay with a peak external quantum efficiency of 17%, demonstrating its potential implications for optoelectronic devices, including displays, lighting and lasers.

Fracture dominant in friction stir spot welded joint between 6061 aluminum alloy and galvannealed steel based on microscale tensile testing

Abstract: The macroscale mechanical properties of dissimilar joints are generally influenced by the fracture behavior of joint interface. However, little is known about the dominant factor for the joint properties related with both macroscale fracture behavior and microscale interfacial properties. Herein, microscale tensile testing of the joint interface was coupled with the macroscale fracture evaluation to elucidate the dominant factor of strength in dissimilar joints between 6061 aluminum alloy and high tensile strength galvannealed steel via friction stir spot welding (FSSW). Microstructural analyses revealed the characteristic formation of interfacial microstructure accompanied by friction and Zn discharge during the FSSW process. Microscale tensile testing was performed on the specimen on which the pre-notch was introduced to induce local fracture at the intended position on the joint interface. Results showed the presence of the weakest interface attributed to initial joining defects formed by Zn concentration at the outer area, which were consistent with the outside of the crack arresting area confirmed by macroscale evaluation. These results indicated that the joint strength of dissimilar joints between 6061 aluminum alloy and galvannealed steel is dominated by the local strength of the joining area without defects and suggested a process design for improving dissimilar joints.

Real-world Evaluation of the Efficacy of Neoadjuvant DCF Over CF in Esophageal Squamous Cell Carcinoma

Abstract: Objective: We aimed to evaluate the efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy over cisplatin and 5-fluorouracil (CF) in patients with surgically resectable advanced esophageal squamous cell carcinoma (ESCC), using real-world data from 85 esophageal centers. Background: JCOG1109 trial, which assessed the superiority of DCF over CF, and the superiority of chemoradiotherapy with CF over CF alone demonstrated the significant survival advantage of neoadjuvant DCF in overall survival (OS) over CF for ESCC. Methods: The ESCC patients who received neoadjuvant CF or DCF at 85 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. After propensity score (PS) matching, the OS and recurrence-free survival were compared between CF and DCF. Results: We initially enrolled 4781 patients. After data cleaning and PS matching using pretreatment variables, 1074 patients for each group were selected for subsequent analysis. There was no significant difference in the incidence of postoperative pneumonia and anastomotic leakage. In the survival analysis, OS was significantly longer in DCF group than CF group (hazard ratio, 0.868; 95% confidence interval, 0.770–0.978; P=0.02), as well as recurrence-free survival (hazard ratio, 0.850; 95% confidence interval, 0.761–0.949; P=0.004). The survival advantage of DCF was not observed in patients with 76 years old or older. Conclusions: Neoadjuvant DCF therapy showed a remarkable survival advantage in surgically resectable ESCC patients, especially in patients who were 75 years old or younger. The current real-world evidence will encourage recommendations for DCF as a standard regimen in neoadjuvant chemotherapy–based treatment strategy for ESCC.

ASB induced phase transformation in high oxygen doped commercial purity Ti

Abstract: Given that commercial purity titanium (CP-Ti) doped with a high oxygen concentration has recently been reported with high mechanical performance, the present work investigated the failure behavior and its mechanisms of the material under uniaxial impact loading. Besides the strong hardening effect of oxygen, it was found that increasing oxygen content led to increased propensity for adiabatic shear failure in CP-Ti. The texture or grain orientation was also found to have profound influence on the formation of adiabatic shear band (ASB). Microstructural examinations on the postmortem high oxygen CP-Ti suggested that uniform and equi-axed nano-grains were produced within the ASB. The orientations of these nano-grains were analyzed using the precession electron diffraction (PED) technique. It provides direct evidence of phase transformation occurring in ASB. Then we demonstrate that the nano-grains in ASB formed from parent grains by phase transformation, indicating that the α→β→α phase transformation process takes part in ASB evolution and is an underlying mechanism of grain refinement. As such, this result is a supplement for traditional well-accepted dynamic recrystallization mechanism of ASB evolution.

Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non–Cell Autonomous Liver Carcinogenesis

Abstract: In chronic liver diseases (CLD), p53 is constitutively activated in hepatocytes due to various etiologies as viral infection, ethanol exposure, or lipid accumulation. This study was aimed to clarify the significance of p53 activation on the pathophysiology of CLDs. In Kras-mutant liver cancer model, murine double minute 2 (Mdm2), a negative regulator of p53, was specifically deleted in hepatocytes [Alb-Cre KrasLSL-G12D Mdm2fl/fl (LiKM; KrasG12D mutation and Mdm2 loss in the liver)]. Accumulation of p53 and upregulation of its downstream genes were observed in hepatocytes in LiKM mice. LiKM mice showed liver inflammation accompanied by hepatocyte apoptosis, senescence-associated secretory phenotype (SASP), and the emergence of hepatic progenitor cells (HPC). More importantly, Mdm2 deletion promoted non-cell autonomous development of liver tumors. Organoids generated from HPCs harbored tumor-formation ability when subcutaneously inoculated into NOD/Shi-scid/IL2Rγ (null) mice. Treatment with acyclic retinoid suppressed growth of HPCs in vitro and inhibited tumorigenesis in LiKM mice. All of the phenotypes in LiKM mice, including accelerated liver tumorigenesis, were negated by further deletion of p53 in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl p53fl/fl). Activation of hepatic p53 was noted in liver biopsy samples obtained from 182 patients with CLD, in comparison with 23 normal liver samples without background liver diseases. In patients with CLD, activity of hepatic p53 was positively correlated with the expression of apoptosis, SASP, HPC-associated genes and tumor incidence in the liver after biopsy. In conclusion, activation of hepatocyte p53 creates a microenvironment prone to tumor formation from HPCs. Optimization of p53 activity in hepatocytes is important to prevent patients with CLD from hepatocarcinogenesis.This study reveals that activation of p53 in hepatocytes promotes liver carcinogenesis derived from HPCs, which elucidates a paradoxical aspect of a tumor suppressor p53 and novel mechanism of liver carcinogenesis. See related commentary by Barton and Lozano, p. 2824.

Adverse events during intrahospital transport of critically ill patients: A systematic review and meta-analysis

Abstract: Intrahospital transport of critically ill patients is often necessary for diagnostic procedures, therapeutic procedures, or admission to the intensive care unit. The aim of this study was to investigate and describe safety and adverse events during intrahospital transport of critically ill patients.A systematic search was performed of MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to June 3, 2020, and of the International Clinical Trials Platform Search Portal and ClinicalTrials.gov for ongoing trials. We selected prospective and retrospective cohort studies published in English on intrahospital transport of critically ill patients, and then performed a meta-analysis. The primary outcome was the incidence of all adverse events that occurred during intrahospital transport. The secondary outcomes were death due to intrahospital transport or life-threatening adverse events, minor events in vital signs, adverse events related to equipment, durations of ICU and hospital stay, and costs.A total of 12,313 intrahospital transports and 1898 patients from 24 studies were included in the meta-analysis. Among 24 studies that evaluated the primary outcome, the pooled frequency of all adverse events was 26.2% (95% CI: 15.0-39.2) and the heterogeneity among these studies was high (I2 = 99.5%). The pooled frequency of death due to intrahospital transport and life-threatening adverse events was 0% and 1.47% each, but heterogeneity was also high.Our findings suggest that adverse events can occur during intrahospital transport of critically ill patients, and that the frequency of critical adverse events is relatively low. The results of this meta-analysis could assist in risk-benefit analysis of diagnostic or therapeutic procedures requiring intrahospital transport of critically ill patients.UMIN000040963.

Electroweak baryogenesis in aligned two Higgs doublet models

Abstract: We evaluate the baryon number abundance based on the charge transport scenario of top quarks in the CP-violating two Higgs doublet model, in which Yukawa interactions are aligned to avoid dangerous flavor changing neutral currents, and coupling constants of the lightest Higgs boson with the mass $125~\mathrm{GeV}$ coincide with those in the standard model at tree level to satisfy the current LHC data. In this model, the severe constraint from the electric dipole moment of electrons, which are normally difficult to be satisfied, can be avoided by destructive interferences between CP-violating phases in Yukawa interactions and scalar couplings in the Higgs potential. Viable benchmark scenarios are proposed under the current available data and basic theoretical bounds. We find that the observed baryon number can be reproduced in this model, where masses of additional Higgs bosons are typically $300$--$400~\mathrm{GeV}$. Furthermore, it is found that the triple Higgs boson coupling is predicted to be $35$--$55~\%$ larger than the standard model value.

An interactive approach to investigate brightness perception of daylighting in Immersive Virtual Environments: Comparing subjective responses and quantitative metrics

Abstract: Daylighting plays an eminent role in the performance of indoor environments and their occupants, thus necessitating the need to investigate daylight perception of potential occupants at early design stages. The present study introduces an interactive approach to collect and visualize brightness perception of daylighting in a large-scale immersive virtual environment, using a game engine as a daylight simulation tool. The developed system allows users to explore building models freely at different day times set in virtual reality and report their perceptions in real time. Following a validation study (N=36) to investigate the consistency of brightness perceptions in a real environment and its virtual replica, a set of 24 participants were recruited to use the system to report their brightness perception in a virtual model of a daylit art museum, through snapshotting the scenes where they perceive as one of the following in terms of daylighting: (very dark, dark, bright, or very bright). Using an output of 419 snapshots, a “Perceptual Light Map” (PLM) was developed to visualize the collective brightness perception of participants as a heat map. Subjective responses were found to be positively correlated with four daylight metrics, with the highest correlation to mean luminance and the lowest to luminance ratio. The findings of this exploratory study represent a step towards a user-oriented supplement tool to the existing quantitative daylight metrics, validating game engines’ adequacy as a daylight simulation tool, and illustrating the potentials of immersion and interaction principles for the perception of daylit spaces in virtual reality.

Adverse events during intrahospital transport of critically ill patients: A systematic review and meta-analysis.

Abstract: Introduction Intrahospital transport of critically ill patients is often necessary for diagnostic procedures, therapeutic procedures, or admission to the intensive care unit. The aim of this study was to investigate and describe safety and adverse events during intrahospital transport of critically ill patients. Material and methods A systematic search was performed of MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to June 3, 2020, and of the International Clinical Trials Platform Search Portal and ClinicalTrials.gov for ongoing trials. We selected prospective and retrospective cohort studies published in English on intrahospital transport of critically ill patients, and then performed a meta-analysis. The primary outcome was the incidence of all adverse events that occurred during intrahospital transport. The secondary outcomes were death due to intrahospital transport or life-threatening adverse events, minor events in vital signs, adverse events related to equipment, durations of ICU and hospital stay, and costs. Results A total of 12,313 intrahospital transports and 1898 patients from 24 studies were included in the meta-analysis. Among 24 studies that evaluated the primary outcome, the pooled frequency of all adverse events was 26.2% (95% CI: 15.0–39.2) and the heterogeneity among these studies was high (I2 = 99.5%). The pooled frequency of death due to intrahospital transport and life-threatening adverse events was 0% and 1.47% each, but heterogeneity was also high. Conclusions Our findings suggest that adverse events can occur during intrahospital transport of critically ill patients, and that the frequency of critical adverse events is relatively low. The results of this meta-analysis could assist in risk-benefit analysis of diagnostic or therapeutic procedures requiring intrahospital transport of critically ill patients. Trial registration: UMIN000040963.

Backcasting-Based Method for Designing Roadmaps to Achieve a Sustainable Future

Abstract: Much attention has been paid internationally to the adoption of sustainable development goals to achieve sustainable outcomes. Although roadmapping is widely used by companies and other organizations to plan long-term strategies, relatively few studies have examined the development of roadmapping methods aiming at sustainability. To address this challenge, in this article, a backcasting-based method to design roadmaps that could be used to facilitate decision making and plan sustainable futures is proposed. By drawing on the concept of backcasting, the proposed roadmap design method consists of two phases: defining a sustainable vision, and describing the pathways that are required to realize that vision. In order to develop pathways that bridge the gap between the present and the vision, we develop a roadmap template called a “four-arrow model.” To demonstrate the proposed method, roadmaps are developed for Japanese manufacturing from the present to 2050 by organizing an expert workshop. As a result, two different roadmaps that connected sustainable visions and associated pathways are successfully developed. The number of ideas generated through the workshop indicates that the proposed method encouraged brainstorming and concept development. Future research will focus on making the roadmap design process more comprehensive by conducting industrial case studies.

Projecting prevalence of frailty and dementia and the economic cost of care in Japan from 2016 to 2043: a microsimulation modelling study

Abstract: Dementia and frailty often accompany one another in older age, requiring complex care and resources. Available projections provide little information on their joint impact on future health-care need from different segments of society and the associated costs. Using a newly developed microsimulation model, we forecast this situation in Japan as its population ages and decreases in size.In this microsimulation modelling study, we built a model that simulates an individual's status transition across 11 chronic diseases (including diabetes, coronary heart disease, and stroke) as well as depression, functional status, and self-reported health, by age, sex, and educational strata (less than high school, high school, and college and higher), on the basis of nationally representative health surveys and existing cohort studies. Using the simulation results, we projected the prevalence of dementia and frailty, life expectancy with these conditions, and the economic cost for formal and informal care over the period 2016-43 in the population of Japan aged 60 years and older.Between 2016 and 2043, life expectancy at age 65 years will increase from 23·7 years to 24·9 years in women and from 18·7 years to 19·9 years in men. Years spent with dementia will decrease from 4·7 to 3·9 years in women and 2·2 to 1·4 years in men. By contrast, years spent with frailty will increase from 3·7 to 4·0 years for women and 1·9 to 2·1 for men, and across all educational groups. By 2043, approximately 29% of women aged 75 years and older with a less than high school education are estimated to have both dementia and frailty, and so will require complex care. The expected need for health care and formal long-term care is anticipated to reach costs of US$125 billion for dementia and $97 billion for frailty per annum in 2043 for the country.Japan's Government and policy makers should consider the potential social challenges in caring for a sizable population of older people with frailty and dementia, and a widening disparity in the burden of those conditions by sex and by educational status. The future burden of dementia and frailty should be countered not only by curative and preventive technology innovation, but also by social policies to mitigate the health gap.Japan Society for the Promotion of Science, Hitachi - the University of Tokyo Laboratory for a sustainable society, and the National Institute of Ageing.

Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Abstract: Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.