Osaka University Research Articles

Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan

The loss of corneal epithelial stem cells from the limbus at the edge of the cornea has severe consequences for vision, with the pathological manifestations of a limbal stem-cell deficiency (LSCD) difficult to treat. Here, to the best of our knowledge, we report the world's first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD. This non-randomised, single-arm, clinical study involved four eyes of four patients with LSCD at the Department of Ophthalmology, Osaka University Hospital. They comprised a woman aged 44 years with idiopathic LSCD (patient 1), a man aged 66 years with ocular mucous membrane pemphigoid (patient 2), a man aged 72 years with idiopathic LSCD (patient 3), and a woman aged 39 years with toxic epidermal necrosis (patient 4). Allogeneic human iPSC-derived corneal epithelial cell sheets (iCEPSs) were transplanted onto affected eyes. This was done sequentially in two sets of HLA-mismatched surgeries, with patients 1 and 2 receiving low-dose cyclosporin and patients 3 and 4 not. The primary outcome measure was safety, ascertained by adverse events. These were monitored continuously throughout the 52-week follow-up period, and during an additional 1-year safety monitoring period. Secondary outcomes, reflective of efficacy, were also recorded. This study is registered with UMIN, UMIN000036539 and is complete. Patients were enrolled between June 17, 2019 and Nov 16, 2020. We had 26 adverse events during the 52-week follow-up period (consisting of 18 mild and one moderate event in treated eyes, and seven mild non-ocular events), with nine recorded in the additional 1-year safety monitoring period. No serious adverse events, such as tumourigenesis or clinical rejection, occurred during the whole 2-year observational period. At 52 weeks, secondary measures of efficacy showed that the disease stage had improved, corrected distance visual acuity was enhanced, and corneal opacification had diminished in all treated eyes. Corneal epithelial defects, subjective symptoms, quality-of-life questionnaire scores and corneal neovascularisation mostly improved or were unchanged. Overall, the beneficial efficacy outcomes achieved for patients 1 and 2 were better than those achieved for patients 3 and 4. iCEPS transplantation for LSCD was found to be safe throughout the study period. A larger clinical trial is planned to further investigate the efficacy of the procedure. The Japan Agency for Medical Research and Development, the Ministry of Education, Culture, Sports, Science, and Technology-Japan, and the UK Biotechnology and Biological Sciences Research Council.

Impact of financial literacy and education on breast and cervical cancer screening participation in Japan.

Despite government efforts, the uptake of screening for breast and cervical cancers among Japanese women remains low. This study employs financial literacy and financial education as proxies for rational decision-making to explore their potential to enhance cancer screening practices in Japan. Using data from Osaka University's Preference Parameters Study, mean comparison tests and probit regression models are utilized to examine the association between breast and cervical cancer screening and financial literacy and financial education. The results of probit regression show that individuals with higher levels of financial education tend to participate in both breast and cervical cancer screening. In contrast, individuals with higher financial literacy are likely to participate in breast cancer screening, whereas no significant impact is observed for cervical cancer screening. Furthermore, our findings reveal that financial education positively influences both breast and cervical cancer screening. Factors such as employment, marriage, higher education, increased household income, and greater assets demonstrate robust positive relationships with breast and cervical cancer screening. Meanwhile, psychological factors including happiness, a myopic view of the future, anxiety about later life, and perceived health status have no significant associations, except for a positive association between anxiety about life and cervical cancer screening. Our study suggests the development of targeted educational programs that leverage financial literacy and financial education to raise awareness about the importance of breast and cervical cancer screening.

Genetic and epigenetic factors affecting carotid intima-media thickness in monozygotic twins.

The intima-media thickness (IMT) of the carotid artery, an indicator of subclinical atherosclerosis, varies in close association with various factors such as diabetes and immune response. The extent of changes in IMT varies among individuals owing to both genetic and epigenetic factors. In this study, we aimed to identify single nucleotide polymorphisms (SNPs) and DNA methylation patterns that affect carotid IMT in monozygotic (MZ) twins. We measured the maximum IMT (IMT-Cmax) and the mean IMT in the common carotid artery wall using ultrasonography in 107 pairs of MZ twins recruited from the Osaka University Twin Registry. The genotyping of SNPs and the measurement of methylation levels were performed using a beads array, and the expression of each gene was determined by RNA sequencing. Linear regression analysis was performed on each of the two groups: one group consisted of twins randomly selected from each pair, and the other group consisted of co-twins. We identified a CpG site (cg02432467) on HS3ST6 as a significant epigenetic factor in both IMT-Cmax and mean IMT analyses. The methylation level at another site (cg07927379) was negatively correlated with LINC01006 expression and IMT-Cmax. Furthermore, there were significant differences in AP2A2 expression and mean IMT among individuals with each genotype of the rs10902263 polymorphism. We identified genetic and epigenetic factors associated with carotid IMT that may be useful for individualized assessments.

NIMG-06. AUTOMATED VOLUMETRY OF MENINGIOMAS IN CONTRAST-ENHANCED T1-WEIGHTED MRI USING DEEP LEARNING

Abstract BACKGROUND With the widespread use of MRI equipment and brain docks, there are more opportunities to perform follow-up observation for meningiomas. In recent years, attempts have been made to predict prognosis by using tumor volume as a highly objective imaging biomarker. On the other hand, manual lesion extraction by a reader with anatomical knowledge is indispensable for volume measurement, which requires a certain amount of labor and time. This is a major barrier to the generation of evidence and clinical application in this field. OBJECTIVE To establish the clinical significance of tumor volume as an imaging biomarker in meningiomas, and to develop a simple and highly reproducible application for automated volume measurement using artificial intelligence, and to investigate its accuracy and potential for clinical application. METHODS 178 patients with meningiomas who underwent MRI at Osaka University Hospital were included in the study. Contrast-enhanced T1-weighted images were used for manual lesion extraction by two neurosurgeons. These annotated image data were randomly divided into training (90%) and testing (10%). The deeplabV3 model was used to train the artificial intelligence, and leave-one-out cross-validation was used to train and validate the automated model. The test data were used for comparison, and the agreement rate (Dice index) on the images of the automatically extracted regions and the error rate of the calculated tumor volume (mean square error rate: RMSPE) were used as indices of measurement performance. RESULTS The average agreement rate between the automatically extracted area and the test data was 92.3±5.1%. The error rate of tumor volume was 9.5±1.2%. CONCLUSION This application using artificial intelligence was considered to have a certain validity in the accuracy of automatic lesion extraction. This method, which enables simple tumor volume measurement, is expected to create new imaging biomarkers that will contribute to the optimization and personalization of meningioma treatment.

Influence of the rotation of the diverting loop ileostomy in rectal cancer surgery on small-bowel obstruction: A multicenter prospective study conducted by the Clinical Study Group of Osaka University, Colorectal Group

AimsWhether rotation of a diverting loop ileostomy during rectal cancer surgery, for reducing the catastrophic effect of an anastomotic leakage, affects the incidence of small-bowel obstruction has not been fully investigated. The purpose of this study is to explore whether technical maneuvers in diverting loop ileostomy creation, including its rotation, are associated with increased incidence of small-bowel obstruction in rectal tumor surgery. MethodsThis multicenter prospective study was conducted by the Clinical Study Group of Osaka University, which comprises 24 major institutions. Patients with rectal adenocarcinoma scheduled for laparoscopic/robotic low anterior resection or intersphincteric resection with a diverting loop ileostomy were included. A total of 451 patients were prospectively enrolled between July 2015 and April 2021. The primary endpoint was the relevance of loop ileostomy rotation to the incidence of small-bowel obstruction; the secondary endpoints included the origin of the small-bowel obstruction and length of hospital stay. ResultsSmall-bowel obstruction was observed in 10.8% in the nonrotated group and 12.3% in the rotated group, with no significant difference (P > .99). The only risk factor identified for small-bowel obstruction was distance from the ileocecal valve, with a significant difference in 16 patients (7.3%) with a distance of ≤30 cm and 16 patients (15.4%) in a distance of >30 cm (P = .028). ConclusionRotation of the diverting loop ileostomy had no significant effect on the incidence of small-bowel obstruction.

Design of Moderator Assemblies for Fast, Epithermal, or Thermal Neutron–Dominated n-γ Mixed Fields Using a D-D Neutron Source

The treatment field of boron neutron capture therapy (BNCT) is a n-γ mixed field. In the Osaka University BNCT project, a material-filtered radio-photoluminescence glass dosimeter (RPLGD) was proposed for the simultaneous measurement of neutron and gamma-ray doses. In this study, to validate the material-filtered RPLGD, various types of n-γ mixed fields are designed by irradiating different moderator assemblies with a D-D neutron source at the OKTAVIAN facility, Osaka University, Japan. The n-γ mixed fields are classified into fast neutron–, epithermal neutron–, or thermal neutron–dominated fields and a gamma-ray-only field with the specific characteristics as follows: (1) the dose ratios of gamma ray to neutron are 1.0% to 977.0% for the fast neutron–dominated field, 5.0% to 921.1% for the epithermal neutron–dominated field, 5.0% to 921.1% for the thermal neutron–dominated field, and 11880.6% for the gamma-ray-only field; (2) the proportions of fast, epithermal, and thermal neutron doses to total neutron dose are 98.4% to 100.0% for the fast neutron–dominated field, 74.0% to 85.4% for the epithermal neutron–dominated field, and 90.1% to 90.8% for the thermal neutron–dominated field, respectively; and (3) the maximum gamma-ray energy is up to 12 MeV.

Measurement of γ-Rays Generated by Neutron Interaction with 16O at 30 MeV and 250 MeV

Abstract Deep understanding of $\gamma$-ray production from the fast neutron reaction in water is crucial for various physics studies at large-scale water Cherenkov detectors. We performed test experiments using quasi-mono energetic neutron beams ($E_n = 30$ and 250 MeV) at Osaka University’s Research Center for Nuclear Physics to measure $\gamma$-rays originating from the neutron–oxygen reaction with a high-purity germanium detector. Multiple $\gamma$-ray peaks which are expected to be from excited nuclei after the neutron–oxygen reaction were successfully observed. We measured the neutron beam flux using an organic liquid scintillator for the cross section measurement. With a spectral fitting analysis based on the tailored $\gamma$-ray signal and background templates, we measured cross sections for each observed $\gamma$-ray component. The results will be useful to validate neutron models employed in ongoing and future water Cherenkov experiments.

Dynamic susceptibility contrast‑enhanced perfusion magnetic resonance imaging parameters for predicting MGMT promoter methylation and prognostic value in newly diagnosed patients with glioblastoma.

O6-methylguanine DNA methyltransferase (MGMT) promoter methylation is an important clinical biomarker of newly diagnosed glioblastoma. Previous radiological studies using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion have aimed to predict MGMT methylation status non-invasively in gliomas with radiological characteristics. The possibility of predicting MGMT methylation status using DSC-MRI perfusion with a radiological approach remains controversial. The present study aimed to evaluate the usefulness of MRI perfusion parameters as non-invasive markers to predict MGMT methylation status and prognosis in newly diagnosed glioblastoma patients. Thus, 50 patients with histologically confirmed primary glioblastoma, IDH-wildtype who underwent tumor resection at Osaka University Hospital (Suita, Japan) between January 2017 and January 2023 were included in this study. The mean cerebral blood volume (CBV) ratio (rCBV) and cerebral blood flow (CBF) ratio (rCBF) for tumors with MGMT methylation (mean rCBV:2.09 and mean rCBF:3.08) were significantly higher compared with those for tumors without MGMT methylation (mean rCBV:1.33 and mean rCBF:1.85; P<0.05). While patients with MGMT methylation had longer progression-free survival (PFS) compared with those without MGMT methylation (P<0.05), there was no significant difference in OS with or without MGMT methylation (P=0.06). By contrast, there was no association between MRI perfusion parameters and OS or PFS in patients with glioblastoma. Furthermore, the association between CBV, CBF, MGMT promotor methylation status, OS, and PFS were explored. There was no significant prognostic difference between low vascularity tumors (rCBV <1.3 or rCBF <1.8) with or without MGMT methylation. On the other hand, high vascularity tumors (rCBF ≥1.8) with MGMT promotor methylation were associated to longer OS and PFS compared with those without. However, there was no association between MGMT methylation status and OS or PFS in patients with high rCBV (rCBV ≥1.3). The present study indicated that CBV and CBF could be used to predict the MGMT methylation status in glioblastomas. However, the prognostic value of tumor vascularity and MGMT methylation status may be limited.

Examination of Sarcopenia with Obesity as a Prognostic Factor in Patients with Colorectal Cancer Using the Psoas Muscle Mass Index

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients.

Developing of a multi-angle and varied walking conditions dataset for human gait recognition

The field of Human Gait Recognition (HGR) leverages unique walking patterns for non-invasive, discreet biometric identification. This study highlights the importance of comprehensive datasets in the development, testing, and validation of HGR algorithms. While current datasets, such as those from Carnegie Mellon University Motion of Body (CMU MoBo), Southampton (SOTON), Chinese Academic of Science Institute of Automation (CASIA B), and Osaka University Institute of Scientific Industrial Research (OU-ISIR), have advanced in scale and complexity, they often lack diversity and comprehensive sample representation. To address this gap, we introduce the TecNM Gait-DS dataset (Tecnologico Nacional de Mexico), specifically designed for Latin American populations, featuring 13 viewing angles and five walking variations. Utilizing a Self-Supervised Vision Transformer DINO (Deeper Into Neural Networks) model for view angle classification, our evaluation demonstrates significant improvements in classification accuracy. This dataset not only enhances sample diversity but also supports the development of more robust HGR systems. Our results underscore the potential for improved accuracy and ethical considerations in HGR, advocating for ongoing refinement of datasets to achieve optimal performance and societal acceptance.

Clinical Outcomes of Left Ventricular Assist Device Bleeding Complication.

Bleeding complications have emerged as major causes of morbidity and mortality in patients with implantable left ventricular assist devices (LVAD). We hypothesized that the hemodynamics after LVAD implantation may influence the occurrence of bleeding complications after LVAD implantation. We retrospectively evaluated 78 patients who underwent continuous-flow LVAD implantation and hemodynamic ramp test after LVAD implantation between July 2017 and July 2023 at Osaka University. The bleeding complication occurred in 13 patients. The rates of freedom from bleeding complications at 1, 3, and 5 years were 94%, 85%, and 74%. Gastrointestinal bleeding, nose bleeding, and intraperitoneal hemorrhage occurred in six, three, and two patients, respectively. Preoperative average brachial-ankle pulse wave velocity (baPWV) was positively associated with bleeding complication (1,276 ± 280 vs. 1,098 ± 190 cm/s p = 0.04). In the hemodynamic ramp test, systemic vascular resistance (SVR) in patients with bleeding complications was higher than that in patients without bleeding complications (SVR: 1,359 ± 341 vs. 1,150 ± 217 dyne sec/cm5, p = 0.01). High preoperative baPWV and high SVR in the hemodynamic ramp test were significantly associated with bleeding complications after LVAD implantation. Arteriosclerosis is a risk factor for bleeding complications after LVAD implantation.

Functional landscape of genome-wide postzygotic somatic mutations between monozygotic twins.

Monozygotic (MZ) twins originate from a single fertilized egg, making them genetically identical at the time of conception. However, postzygotic somatic mutations (PZMs) can introduce genetic differences after separation. Although whole-genome sequencing (WGS) sheds light on somatic mutations in cancer genomics, its application in genomic studies of MZ twins remains limited. In this study, we investigate PZMs in 30 healthy MZ twin pairs from the Osaka University Center for Twin Research using WGS (average depth = 23.8) and a robust germline-calling algorithm. We find high genotype concordance rates (exceeding 99%) in MZ twins. We observe an enrichment of PZMs with variant allele frequency around 0.5 in twins with highly concordant genotypes. These PZMs accumulate more frequently in non-coding regions compared with protein-coding regions, which could potentially influence gene expression. No significant association is observed between the number of PZMs and age or sex. Direct sequencing confirms a missense mutation in the ANKRD35 gene among the PZMs. By applying a genome-wide mutational signature pattern technique, we detect an age-related clock-like signature in these early postzygotic somatic mutations in MZ twins. Our study provides insights that contribute to a deeper understanding of genetic variation in MZ twins.

Demonstration of shape analysis of neutron resonance transmission spectrum measured with a laser-driven neutron source

Laser-driven neutron sources (LDNSs) can generate strong short-pulse neutron beams, which are valuable for scientific studies and engineering applications. Neutron resonance transmission analysis (NRTA) is a nondestructive technique used for determining the areal density of each nuclide in a material sample using pulsed thermal and epithermal neutrons. Herein, we report the first successful NRTA performed using an LDNS driven by the Laser for Fast Ignition Experiment at the Institute of Laser Engineering, Osaka University. The key challenge was achieving a well-resolved resonance transmission spectrum for material analysis using an LDNS with a limited number of laser shots in the presence of strong background noise. We addressed this by employing a time-gated 6Li\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{6}{\ extrm{Li}}$$\\end{document}-glass scintillation neutron detector to measure the transmission spectra, reducing the impact of electromagnetic noise and neutron and gamma-ray flashes. Output waveforms were recorded for each laser shot and analyzed offline using a counting method. This approach yielded a spectrum with distinct resonances, which were attributed to 115In\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{115}\\,{\ extrm{In}}$$\\end{document} and 109Ag\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{109}{\ extrm{Ag}}$$\\end{document}, as confirmed through neutron transmission simulation. The spectrum was analyzed using the least-square nuclear-resonance fitting program, REFIT, demonstrating the possibility of using an LDNS for nondestructive areal-density material characterization.

O54 THE EFFECT OF SACUBITRIL/VALSARTAN TREATMENT ON HYPERTENSIVE PATIENTS

Background and Objective: Sacubitril/Valsartan was approved in Japan in 2020 for the treatment of heart failure and subsequently for the treatment of hypertension. It is a drug with a novel mechanism of action that inhibits both angiotensin receptors and neprilysin. Besides its cardioprotective and antihypertensive effects, a subanalysis of previous clinical trials in heart failure patients has shown that it tends to slow the rate of decline in renal function, and is expected to have therapeutic effects against CKD. However, its effect on renal function in hypertensive patients is unknown. In this study, we examined renal prognosis in patients with essential hypertension. Methods: 166 consecutive patients who received an initial dose of ARNI(Sacubitril/Valsartan) (N=104) or ARB (Azilsartan) (N=42) and had blood tests performed before and within 3 months after the first dose at Osaka University Hospital from June 2020 to April 2023 were analyzed retrospectively. Results: ARNI tended to be administered to elderly patients and patients with impaired renal function in both male and female patients. eGFR did not decrease in the ARNI group at either 3 or 12 months post-dose. eGFR decreased over time in the ARB group at 3 and 12 months post-dose. 5 patients on ARNI had drug discontinuations that were thought to be due to adverse drug events (hypotension in 2, numbness in 1, dizziness in 1, syncope in 1 patient). Conclusions: In this study, ARNI tended to be administered in more elderly hypertensive patients. Although there were a few treatment interruptions due to adverse drug events, the adverse effects on renal function were rather minor compared to ARBs, and under careful management, ARNI may be a useful antihypertensive treatment modality even in elderly patients and patients with impaired renal function.

289. OUTCOME OF CONVERSION SURGERY FOR ESOPHAGEAL CANCER WITH SYNCHRONOUS ABDOMINAL PARAAORTIC LYMPH NODE METASTASIS

Abstract Background and Purpose Stage IVb esophageal cancer with distant metastasis has a poor prognosis with a 5-year survival rate of approximately 10%. Among distant metastases, the treatment strategy for esophageal cancer with metastasis to the #16 para-aortic lymph node has not been defined, and the significance of surgical resection is not clear. Methods Using the database of Osaka University and related institutions, we selected 41 cases of thoracic esophageal cancer with simultaneous #16 metastasis that underwent surgical resection between 2005 and 2021, and examined treatment outcomes. Results Patient background was median age 64 (43-76) years, gender M/F = 32/9, and primary site of occupancy Ut/Mt/Lt = 1/17/23. Tumor progression was cT factor T1/T2/T3/T4 =0/6/25/10, cN factor N0/N1/N2/N3 =0/13/19/9. Chemotherapy was administered as initial therapy in 38 patients, and CRT was administered in 3. Primary esophageal resection was performed in all 41 patients, and metastases were resected in 36 patients (88%). 38 patients (93%) were eligible for R0 resection. Pathologically, pT0-2/T3-4=22(54%)/19(46%), pN0/1/2-3 8(20%)/6(15%)/27(66%), and pN2 or higher were common. The 3-/5-year survival rate for all patients was 22.8%/19.0%. In all cases, pN0-1 had significantly better survival than pN2-3 (p=0.0252). Conclusion Conversion surgery for esophageal cancer with simultaneous #16 metastasis had a relatively good outcome, suggesting that the pN factor may be a prognostic factor.

Stereotactic Ablative Radiotherapy for Early-stage Lung Cancer in Patients With Left Ventricular Assist Device: A Case Series.

Radiotherapy-induced malfunction of pacemakers and cardiac defibrillators has been reported, and corresponding guidelines have been developed in various countries. Although several studies have reported the effects of radiotherapy in patients with implantable left ventricular assist device (LVAD), its safety remains unclear. Herein, we report three cases of stereotactic ablative radiotherapy (SABR) using CyberKnife for early-stage lung cancer in patients with implantable LVAD. Three patients in their 50s or 60s, including two women and one man, who had LVADs due to dilated or ischemic cardiomyopathy and performance status of 0 or 1, were diagnosed with stage IA2 lung cancer (cT1bN0M0) by imaging only. All three patients were deemed inoperable due to cardiac comorbidity and underwent SABR at the Osaka University Hospital. The total radiation dose was 42-52 Gy, administered in four fractions. All treatment plans were designed to keep the LVAD dose below 2 Gy. In all patients, SABR was completed without acute adverse events or LVAD malfunction. During the follow-up period of 3-29 months, no disease progression or chronic adverse events were observed in any of the patients. This case series indicated that SABR using CyberKnife is a safe treatment option for early-stage lung cancer in patients with LVAD by reducing the dose to the LVAD.

Bacterial sepsis causes more dramatic pathogenetic changes in the Th1 pathway than does viral (COVID-19) sepsis: a prospective observational study of whole blood transcriptomes

ObjectivesThis study aimed to comprehensively compare host responses of patients with bacterial sepsis and those with viral (COVID-19) sepsis by analyzing messenger RNA (mRNA) and microRNA (miRNA) profiles to shed light on their distinct pathophysiological mechanisms.DesignProspective observational study.SettingWhole blood RNA sequencing was used to analyze mRNA and miRNA profiles of patients diagnosed as having bacterial sepsis or viral (COVID-19) sepsis at the Department of Trauma and Emergency Medicine, Osaka University Graduate School of Medicine.PatientsTwenty-two bacterial sepsis patients, 35 viral (COVID-19) sepsis patients, and 15 healthy subjects admitted to the department were included. We diagnosed bacterial sepsis patients according to the sepsis-3 criterion that the Sequential Organ Failure Assessment score must increase to 2 points or more among patients with suspected infections. Viral (COVID-19) sepsis patients were diagnosed using SARS-CoV-2 RT-PCR testing, and presence of pneumonia was assessed through chest computed tomography scans.InterventionsNone.Measurements and main resultsFor RNA sequencing, 14,500 mRNAs, 1121 miRNAs, and 2556 miRNA-targeted mRNAs were available for analysis in the bacterial sepsis patients. Numbers of genes showing upregulated: downregulated gene expression (false discovery rate < 0.05, |log2 fold change| > 1.5) were 256:2887 for mRNA, 53:5 for miRNA, and 49:2507 for miRNA-targeted mRNA. Similarly, in viral (COVID-19) sepsis patients, 14,500 mRNAs, 1121 miRNAs, and 327 miRNA-targeted mRNAs were analyzed, with numbers of genes exhibiting upregulated: downregulated gene expression of 672:1147 for mRNA, 3:4 for miRNA, and 165:162 for miRNA-targeted mRNA. This analysis revealed significant differences in the numbers of upregulated and downregulated genes expressed and pathways between the bacterial sepsis and viral (COVID-19) sepsis patients. Bacterial sepsis patients showed activation of the PD-1 and PD-L1 cancer immunotherapy signaling pathway and concurrent suppression of Th1 signaling.ConclusionOur study illuminated distinct molecular variances between bacterial sepsis and viral (COVID-19) sepsis. Bacterial sepsis patients had a greater number of upregulated and downregulated genes and pathways compared to viral (COVID-19) sepsis patients. Especially, bacterial sepsis caused more dramatic pathogenetic changes in the Th1 pathway than did viral (COVID-19) sepsis.

(Invited) Computational Analysis of the Excited States in the Film States of Non-Fullerene Acceptors

Non-fullerene acceptors are currently widely used as the acceptors of organic thin film solar cells due to their high efficiency. However, the molecular mechanism is still unclear. We have studied the excited states in the film states of non-fullerene acceptors together with experimental collaborators by using theoretical methods. In this presentation, we will present recent progress of our research. For example, we will talk about the excited states in the film states of ITIC. ITIC is a popular acceptor-donor-acceptor-type non-fullerene acceptor. Recently, our collaborator, Prof. Yamakata at Okayama University, Japan, found that the charge separation can take place in ITIC acceptor film even without donor molecules. We investigated this phenomenon by using MD simulations and quantum chemical calculations. MD simulations of the ITIC film showed that the acceptor parts of ITIC are stacked with each other. The dominant angle between two stacked ITIC was found to be ~180 degrees, making J-type dimer. On the other hand, it was also found that there are quite a few V-type dimers with the angles less than 90 degrees. Quantum chemical calculations revealed that the dipole moment in the excited state of J-type dimer is almost zero whereas that of V-type dimer is quite large, indicating strong charge-transfer excited state. Therefore, it is considered that the charge separation of ITIC film can take place in the V-type dimers. We also investigated the excited states in the film states of ITIC analogs. Recently, our collaborator, Prof. Ie at Osaka University, Japan, synthesized several ITIC analogs with different sidechains and found the different efficiency of solar cells. We theoretically investigated the excited states in the film sates of ITIC analogs as in the case of ITIC. It is found that the modification of side chains can change the distributions of angles between two stacked molecules and excited-state properties. These findings highlight the importance of controlling stacking structures in the film state for the efficiency of organic thin film solar cells.

The foremost and greatest barrier to end-stage heart failure treatment: the impact of caregiver shortage.

We examined the number of patients abandoning cardiac replacement therapy due to the inability to secure a designated caregiver. At Osaka University Hospital Heart Center, when we receive a consultation for a patient with severe heart failure from another hospital, a heart failure team makes a visit to the referring hospital as soon as possible. We retrospectively analyzed this hospital-visit database. We received 199 severe heart failure consultations from 2016-2023. Issues identified during hospital visits included age ≥ 65years (8%), inability to confirm the patient's intention (8.5%), and explicit refusal of therapy (2.5%). Medical problems included multiple organ failure (18.1%), obesity (13.1%), diabetes (9.5%), malignancy (5.5%), chronic dialysis (1.0%), and other systemic diseases (12.6%). Adherence problems included poor medication compliance (3.5%), history of heavy drinking (2.5%), and smoking (2.0%). Social problems included inadequate family support in 16.1% of patients. Of the 199 patients, 95 (48.0%) proceeded to a heart transplant and LVAD indication review meeting at Osaka University Hospital. The remaining 104 patients (52.0%) did not proceed to the meeting. Reasons included improvement of heart failure with conservative treatment in 37 cases (35.6%), death before discussion in 21 cases (20.2%), medical contraindications in 18 cases (18.3%), lack of caregivers in 18 cases (18.3%; 9.5% of 199 cases), and patient refusal in 5 cases (4.8%). Approximately 10% of patients consulted at Osaka University Hospital Heart Center for severe heart failure abandoned cardiac replacement therapy due to the lack of caregivers.

G-CSF induces neutrophil extracellular traps formation and promotes ovarian cancer peritoneal dissemination.

Epithelial ovarian cancer is characterized by aggressive peritoneal dissemination. Neutrophils are mobilized to peritoneal cavity in some patients with ovarian cancer dissemination; however, its pathological significance remains unknown. This study aimed to investigate the role of neutrophil extracellular traps (NETs) in ovarian cancer dissemination. We conducted a retrospective analysis of clinical data and samples from 340 patients with ovarian cancer who underwent primary surgery between 2007 and 2016 at the Osaka University Hospital. In vitro, NETs formation was induced by stimulating human peripheral neutrophils. The human ovarian cancer cell line, OVCAR8, was cocultured with NETs. For an ovarian cancer dissemination mouse model, we performed an intraperitoneal injection of OVCAR8 cells into nude mice. The association between NETs and peritoneal dissemination was explored, and model mice were treated with the PAD4 inhibitor GSK484 to assess antitumor efficacy. Neutrophilia (neutrophil count >7000/mm3) correlated with shorter survival, advanced peritoneal dissemination, elevated granulocyte colony-stimulating factor (G-CSF) levels, increased neutrophil count in ascites, and augmented NETs foci in peritoneal dissemination sites. In vitro assays revealed that G-CSF stimulated neutrophils to form NETs, promoting cancer cell adhesion. In vivo investigations revealed that G-CSF-producing tumor-bearing mice had accelerated peritoneal dissemination and poor prognosis. NETs formation was pathologically observed at the peritoneal dissemination sites. Inhibition of NETs formation by GSK484 significantly delayed peritoneal dissemination in vivo. In conclusion, G-CSF was associated with intra-abdominal NETs formation and increased peritoneal dissemination. NETs represent potential therapeutic targets for ovarian cancer, particularly in patients with neutrophilia.