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Abstract The cell culture-based isolation of novel coronavirus SARS-CoV-2 from clinical specimens obtained from patients with suspected COVID-19 is important not only for laboratory diagnosis but also for obtaining live virus to characterize emerging variants. Previous studies report that monkey kidney-derived VeroE6/TMPRSS2 cells allow efficient isolation of SARS-CoV-2 from clinical specimens because these cells show stable expression of the receptor molecule monkey ACE2 and the serine-protease TMPRSS2. Here, we demonstrated that VeroE6 cells overexpressing human ACE2 and TMPRSS2 (Vero E6-TMPRSS2-T2A-ACE2 cells) are superior to VeroE6/TMPRSS2 for isolating SARS-CoV-2 from clinical specimens. These cells showed a 1.6-fold increase in efficiency in SARS-CoV-2 isolation, and were particularly effective for clinical specimens with a relatively low viral load (

Abstract Background Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. Methods This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine–Gray test. Results Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine–Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37–7.32, p = 0.007, and HR = 2.61, 95% CI 1.01–6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. Conclusions In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected or isolated from domestic cats. It is unclear whether cats play an important role in the SARS-CoV-2 transmission cycle. In this study, we examined the susceptibility of cats to SARS-CoV-2, including wild type and variants, by animal experiments. Cats inoculated with wild type, gamma, and delta variants secreted a large amount of SARS-CoV-2 for 1 week after the inoculation from nasal, oropharyngeal, and rectal routes. Only 100 TCID50 of virus could infect cats and replicate well without severe clinical symptoms. In addition, one cat inoculated with wild type showed persistent virus secretion in feces for over 28 days post-inoculation (dpi). The titer of virus-neutralizing (VN) antibodies against SARS-CoV-2 increased from 11 dpi, reaching a peak at 14 dpi. However, the omicron variant could not replicate well in cat tissues and induced a lower titer of VN antibodies. It is concluded that cats were highly susceptible to SARS-CoV-2 infection, but not to the Omicron Variant, which caused the attenuated pathogenicity.

Abstract Background Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. Objective To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. Methods This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. Results Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p

Abstract Olfactory dysfunction is associated with aging and the earliest stages of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases; it is thought to be an early biomarker of cognitive decline. In marmosets, a small non-human primate model used in brain research, olfactory pathway activity during olfactory stimulation has not been well studied because of the difficulty in clearly switching olfactory stimuli inside a narrow MRI. Here, we developed an olfactory-stimulated fMRI system using a small-aperture MRI machine. The olfactory presentation system consisted of two tubes, one for supply and one for suction of olfactory stimulants and a balloon valve. A balloon valve installed in the air supply tube controlled the presentation of the olfactory stimulant, which enabled sharp olfactory stimulation within MRI, such as 30 s of stimulation repeated five times at five-minute intervals. The olfactory stimulation system was validated in vivo and in a simulated system. fMRI analysis showed a rapid increase in signal values within 30 s of olfactory stimulation in eight regions related to the sense of smell. As these regions include those associated with Alzheimer’s and Parkinson’s diseases, olfactory stimulation fMRI may be useful in clarifying the relationship between olfactory dysfunction and dementia in non-human primates.

Abstract Background and objective Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity. Methods We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event. Results Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine–Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81–0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86–0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65–0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78–0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations. Conclusions The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Rules and ethical considerations regarding research on embryo models have been debated across numerous countries. In this paper, we provide insights from our attitude survey conducted among Japanese researchers, including members of the Japanese Society for Regenerative Medicine, and among the general public residing in Japan, the US, the UK, Canada, and Australia. Our survey revealed that many researchers expressed the need for clear guidelines for embryo model research. Furthermore, a minority but significant portion of the general public in each country expressed opposition to research on embryo models but did not oppose research involving real embryos.

Abstract Rabies virus (RABV) causes fatal neurological disease. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) using inactivated-virus vaccines are the most effective measures to prevent rabies. In Japan, HEP-Flury, the viral strain, used as a human rabies vaccine, has historically been propagated in primary fibroblast cells derived from chicken embryos. In the present study, to reduce the cost and labor of vaccine production, we sought to adapt the original HEP-Flury (HEP) to Vero cells. HEP was repeatedly passaged in Vero cells to generate ten- (HEP-10V) and thirty-passaged (HEP-30V) strains. Both HEP-10V and HEP-30V grew significantly better than HEP in Vero cells, with virulence and antigenicity similar to HEP. Comparison of the complete genomes with HEP revealed three non-synonymous mutations in HEP-10V and four additional non-synonymous mutations in HEP-30V. Comparison among 18 recombinant HEP strains constructed by reverse genetics and vesicular stomatitis viruses pseudotyped with RABV glycoproteins indicated that the substitution P(L115H) in the phosphoprotein and G(S15R) in the glycoprotein improved viral propagation in HEP-10V, while in HEP-30V, G(V164E), G(L183P), and G(A286V) in the glycoprotein enhanced entry into Vero cells. The obtained recombinant RABV strain, rHEP-PG4 strain, with these five substitutions, is a strong candidate for production of human rabies vaccine.

Abstract Background COVID-19 patients with preexisting interstitial lung disease (ILD) were reported to have a high mortality rate; however, this was based on data from the early stages of the pandemic. It is uncertain how their mortality rates have changed with the emergence of new variants of concern as well as the development of COVID-19 vaccines and treatments. It is also unclear whether having ILD still poses a risk factor for mortality. As COVID-19 continues to be a major concern, further research on COVID-19 patients with preexisting ILD is necessary. Methods We extracted data on COVID-19 patients between January 2020–August 2021 from a Japanese nationwide insurance claims database and divided them into those with and without preexisting ILD. We investigated all-cause mortality of COVID-19 patients with preexisting ILD in wild-type-, alpha-, and delta-predominant waves, to determine whether preexisting ILD was associated with increased mortality. Results Of the 937,758 adult COVID-19 patients, 7,333 (0.8%) had preexisting ILD. The proportion of all COVID-19 patients who had preexisting ILD in the wild-type-, alpha-, and delta-predominant waves was 1.2%, 0.8%, and 0.3%, respectively, and their 60-day mortality was 16.0%, 14.6%, and 7.5%, respectively. The 60-day mortality significantly decreased from the alpha-predominant to delta-predominant waves (difference − 7.1%, 95% confidence intervals (CI) − 9.3% to − 4.9%). In multivariable analysis, preexisting ILD was independently associated with increased mortality in all waves with the wild-type-predominant, odds ratio (OR) 2.10, 95% CI 1.91–2.30, the alpha-predominant wave, OR 2.14, 95% CI 1.84–2.50, and the delta-predominant wave, OR 2.10, 95%CI 1.66–2.66. Conclusions All-cause mortality rates for COVID-19 patients with preexisting ILD decreased from the wild-type- to the more recent delta-predominant waves. However, these patients were consistently at higher mortality risk than those without preexisting ILD. We emphasize that careful attention should be given to patients with preexisting ILD despite the change in the COVID-19 environment.

Splenosis occurs as a result of autotransplantation of splenic tissue following splenic injury or splenectomy. A 56-year-old man with esophageal cancer underwent thoracoscopic-assisted subtotal esophagectomy accompanied by three-field lymph node dissection, and retrosternal gastric tube reconstruction. The spleen was injured during the surgery and was removed. A retrosternal nodule of 12 mm in diameter was detected near the reconstructed gastric tube on computed tomography (CT) performed 3 years and 6 months postoperatively.Retrospectively, the nodule was observed in the same area on early postoperative CT and gradually increased in size. No accessory spleen was identified on the preoperative CT. Splenosis was suspected, and 99mTc-Sn-colloid single photon emission computed tomography (SPECT)/CT was performed. It revealed intense uptake in the retrosternal nodule, consistent with the diagnosis of thoracic splenosis. Subsequently, the patient has been under observation without treatment. 99mTc-labeled colloid SPECT/CT allowed confident diagnosis of thoracic splenosis following esophageal cancer surgery. This examination is considered valuable for the evaluation of ectopic splenic tissue.

Abstract Background Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. Methods This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. Results Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12). Conclusions Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

The effective dose (ED) in computed tomography (CT) may be calculated by multiplying the dose–length product (DLP) by a conversion factor. As children grow, automatic exposure control increases the DLP, while the conversion factor decreases; these two changes affect the ED in opposite ways. The aim of this study was to investigate the methods of ED estimation according to age in pediatric brain CT. We retrospectively analyzed 980 brain CT scans performed for various clinical indications in children. The conversion factor at each age, in integer years, was determined based on the values at 0, 1, 5, and 10 years provided by the International Commission on Radiological Protection (ICRP), using a curve (curve method) or lines (linear method). In the simple method, the ED was estimated using the ICRP conversion factor for the closest age. We also analyzed the ED estimated by a radiation dose management system. Although the median DLP at each age increased with age, the median ED estimated by the curve method was highest at 0 years, decreased with age, and then plateaued at 9 years. The linear method yielded mildly different results, especially at 2 and 3 years. The ED estimated by the simple method or the radiation dose management system showed inconsistent, up-and-down changes with age. In conclusion, the ED in pediatric brain CT decreases with age despite increased DLP. Determination of the conversion factor at each age using a curve is expected to contribute to estimating the ED in pediatric CT according to age.

Introduction: The rules for human fetal tissue (HFT) research in Japan are unclear. Methods: In this paper, we conducted a web survey to examine the attitudes of Japanese researchers (n=535) and the public (n=3,000) toward HFT research. Results: The results demonstrated that 5.8% of researchers and 18.8% of the public explicitly opposed HFT research, and 71.8% of the researchers thought that the rules for HFT research need to be clarified. Even among researchers who intended to consider conducting HFT research, 74.2% responded that the rules should be clarified. Although different from attitudes to make decisions regarding HFT donation, being non-religious and in their reproductive age among women in the public group were factors for accepting attitudes toward HFT research. Conclusion: To establish the rules, it is necessary to develop a system that can adequately protect vulnerable women who are asked to provide HFT.

BackgroundTriple-negative breast cancer (TNBC) cells are a highly formidable cancer to treat. Nonetheless, by continued investigation into the molecular biology underlying the complex regulation of TNBC cell activity, vulnerabilities can be exposed as potential therapeutic targets at the molecular level. We previously revealed that lysyl oxidase-like 4 (LOXL4) promotes the invasiveness of TNBC cells via cell surface annexin A2 as a novel binding substrate of LOXL4, which promotes the abundant localization of integrin-β1 at the cancer plasma membrane. However, it has yet to be uncovered how the LOXL4-mediated abundance of integrin-β1 hastens the invasive outgrowth of TNBC cells at the molecular level.MethodsLOXL4-overexpressing stable clones were established from MDA-MB-231 cells and subjected to molecular analyses, real-time qPCR and zymography to clarify their invasiveness, signal transduction, and matrix metalloprotease (MMP) activity, respectively.ResultsOur results show that LOXL4 potently promotes the induction of matrix metalloprotease 9 (MMP9) via activation of nuclear factor-κB (NF-κB). Our molecular analysis revealed that TNF receptor-associated factor 4 (TRAF4) and TGF-β activated kinase 1 (TAK1) were required for the activation of NF-κB through Iκβ kinase kinase (IKKα/β) phosphorylation.ConclusionOur results demonstrate that the newly identified LOXL4-mediated axis, integrin-β1-TRAF4-TAK1-IKKα/β-Iκβα-NF-κB-MMP9, is crucial for TNBC cell invasiveness.

BackgroundOur earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain.MethodsCell invasion was assessed using a transwell-based assay, protein–protein interactions by an immunoprecipitation–Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography.ResultsWe revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion.ConclusionWe have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.

Fas-associated factor 1 (FAF1) is a death-promoting protein identified as an interaction partner of the death receptor Fas. The downregulation and mutation of FAF1 have been reported in a variety of human tumors, but there have been few studies on lung cancer. Here, we investigated the prognostic significance of FAF1 expression in non-small-cell lung cancer (NSCLC), and whether aberrant FAF1 expression may be involved in the pathogenesis and prognosis of NSCLC. FAF1 expression was examined in NSCLC specimens as well as human lung cancer cell lines. In addition, changes in cell viability and apoptosis upon regulating FAF1 expression were investigated in lung cancer cell lines. As a result, high FAF1 expression was significantly associated with a poor prognosis in NSCLC. In lung cancer cell lines, FAF1 downregulation hindered cell viability and tended to promote early apoptosis. In conclusion, this is the first study of the clinical significance of FAF1 in NSCLC, showing that FAF1 overexpression is associated with a poor prognosis in NSCLC and that FAF1 acts as a dangerous factor rather than an apoptosis promoter in NSCLC.

Abstract The Aira caldera, located in southern Kyushu, Japan, originally formed 100 ka, and its current shape reflects the more recent 30 ka caldera-forming eruptions (hereafter, called the AT eruptions). This study aimed to delineate the detailed two-dimensional (2D) seismic velocity structure of the Aira caldera down to approximately 15 km, by means of the travel-time tomography analysis of the seismic profile across the caldera acquired in 2017 and 2018. A substantial structural difference in thickness in the subsurface low-velocity areas in the Aira caldera between the eastern and western sides, suggest that the Aira caldera comprises at least two calderas, identified as the AT and Wakamiko calderas. The most interesting feature of the caldera structure is the existence of a substantial high-velocity zone (HVZ) with a velocity of more than 6.8 km/s at depths of about 6–11 km beneath the central area of the AT caldera. Because no high ratio of P- to S-wave velocity zones in the depth range were detected from the previous three-dimensional velocity model beneath the AT caldera region, we infer that the HVZ is not an active magma reservoir but comprises a solidified and cool remnant. In addition, a poorly resolved low-velocity zone around 15 km in depth suggests the existence of a deep active magma reservoir. By superimposing the distribution of the known pressure sources derived from the observed ground inflation and the volcanic earthquake distribution onto the 2D velocity model, the magma transportation path in the crust was imaged. This image suggested that the HVZ plays an important role in magma transportation in the upper crust. Moreover, we estimated that the AT magma reservoir in the 30 ka Aira caldera-forming eruptions has the total volume of 490 km3 DRE and is distributed in a depth range of 4–11 km. Graphical Abstract

Abstract Background The nutritional status during early life can have enduring effects on an animal’s metabolism, although the mechanisms underlying these long-term effects are still unclear. Epigenetic modifications are considered a prime candidate mechanism for encoding early-life nutritional memories during this critical developmental period. However, the extent to which these epigenetic changes occur and persist over time remains uncertain, in part due to challenges associated with directly stimulating the fetus with specific nutrients in viviparous mammalian systems. Results In this study, we used medaka as an oviparous vertebrate model to establish an early-life high-fat diet (HFD) model. Larvae were fed with HFD from the hatching stages (one week after fertilization) for six weeks, followed by normal chow (NC) for eight weeks until the adult stage. We examined the changes in the transcriptomic and epigenetic state of the liver over this period. We found that HFD induces simple liver steatosis, accompanied by drastic changes in the hepatic transcriptome, chromatin accessibility, and histone modifications, especially in metabolic genes. These changes were largely reversed after the long-term NC, demonstrating the high plasticity of the epigenetic state in hepatocytes. However, we found a certain number of genomic loci showing non-reversible epigenetic changes, especially around genes related to cell signaling, liver fibrosis, and hepatocellular carcinoma, implying persistent changes in the cellular state of the liver triggered by early-life HFD feeding. Conclusion In summary, our data show that early-life HFD feeding triggers both reversible and persistent epigenetic changes in medaka hepatocytes. Our data provide novel insights into the epigenetic mechanism of nutritional programming and a comprehensive atlas of the long-term epigenetic state in an early-life HFD model of non-mammalian vertebrates.

Abstract Adult T‐cell leukaemia/lymphoma (ATL) remains incurable. The NF‐κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF‐β‐activated kinase 1 (TAK1), an IκB kinase‐activating kinase, triggers the activation of NF‐κB. The resorcylic acid lactone LL‐Z1640‐2 is a potent irreversible inhibitor of TAK1/extracellular signal‐regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL‐Z1640‐2 against ATL. LL‐Z1640‐2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL‐Z1640‐2 as well as the NF‐κB inhibitor BAY11‐7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF‐κB‐IRF4‐MYC axis. The treatment with LL‐Z1640‐2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL‐Z1640‐2 against IL‐2‐responsive ATL cells in the presence of IL‐2. Therefore, LL‐Z1640‐2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL‐Z1640‐2.

We investigated the relationships between radiation dose indices and body size indices in adult body computed tomography (CT). A total of 3200 CT scans of the thoracic, abdominal, abdominopelvic, or thoraco-abdominopelvic regions performed using one of four CT scanners were analyzed. Volume CT dose index (CTDIvol) and dose length product (DLP) were compared with various body size indices derived from CT images (water-equivalent diameter, WED; effective diameter, ED) and physical measurements (weight, weight/height, body mass index, and body surface area). CTDIvol showed excellent positive linear correlations with WED and ED. CTDIvol also showed high linear correlations with physical measurement-based indices, whereas the correlation coefficients were lower than for WED and ED. Among the physical measurement-based indices, weight/height showed the strongest correlations, followed by weight. Compared to CTDIvol, the correlation coefficients with DLP tended to be lower for WED, ED, and weight/height and higher for weight. The standard CTDIvol values at 60 kg and dose increase ratios with increasing weight, estimated using the regression equations, differed among scanners. Radiation dose indices closely correlated with body size indices such as WED, ED, weight/height, and weight. The relationships between dose and body size differed among scanners, indicating the significance of dose management considering body size.

Introduction: Restrictions on financial gains from the sale of human body parts is a leading policy issue surrounding the use of human tissues and cells. However, discrepancies exist between regulations and reality. In stem cell research, in which diverse sources of tissues and cells can be used, unclear regulations can impede research. Thus, using the Japanese system as a case study, we examined the challenges in the implementation of the “no payment” or the mu-shou principle in stem-cell research over the years. Methods: We reviewed 28 Japanese laws and governmental guidelines and summarized the scope of restrictions on payments for the donation and supply of human biological samples (HBS). Results: As part of restrictions on financial rewards, the mu-shou principle emerged in Japanese laws and administrative documents in the 1990s. Although the Japanese mu-shou generally means “free” or “gratis” in English, its interpretation in research and development settings remains ambiguous. Traditionally, this principle was used to deny remuneration to donors. However, it is also inconsistently applied while processing and transferring human tissue after donation, which creates confusion among the various stakeholders. Recent policies have interpreted the principle in multiple ways: (1) treating the use of HBS for cell-processing as a non-profit activity; (2) a flexible interpretation of the principle to broaden the scope of user payments; and (3) removal of the principle itself to allow for commercial use. Conclusions: The inconsistencies in the monetary payment requirements for HBS could hinder research and development. After scrutinizing the principle's background, an effective approach is needed that considers the concerns of the providers, users, and society alike.

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic has dramatically changed because of virus mutations, vaccine dissemination, treatment development and policies, among other factors. These factors have a dynamic and complex effect on the characteristics and outcomes of patients. Therefore, there is an urgent need to understand those changes and update the evidence. We used a large-scale real-world data set of 937,758 patients with COVID-19 from a nationwide claims database that included outpatients and inpatients in Japan to investigate the changes in their characteristics, outcomes and risk factors for severity/mortality from the early pandemic to the delta variant-predominant waves. The severity of COVID-19 was defined according to the modified World Health Organization clinical-progression ordinal scale. With changing waves, mean patient age decreased, and proportion of patients with comorbidities decreased. The incidences of “severe COVID-19 or death (i.e. ≥severe COVID-19)” and “death” markedly declined (5.0% and 2.9%, wild-type-predominant; 4.6% and 2.2%, alpha variant-predominant and 1.4% and 0.4%, delta variant-predominant waves, respectively). Across the wave shift, risk factors for ≥ severe COVID-19 and death, including older age, male, malignancy, congestive heart failure and chronic obstructive pulmonary disease, were largely consistent. The significance of some factors, such as liver disease, varied as per the wave. This study, one of the largest population-based studies on COVID-19, showed that patient characteristics and outcomes changed during the waves. Risk factors for severity/mortality were similar across all waves, but some factors were inconsistent. These data suggest that the clinical status of COVID-19 will change further with the coming epidemic wave.

Although the clinical benefits of computed tomography (CT) are undoubtedly high, radiation doses received by patients are also relatively high; therefore, radiation dose management is mandatory to optimize CT radiation doses and prevent excessive radiation events. This article describes CT dose management practice at a single facility. Many imaging protocols are used in CT depending on the clinical indications, scan region, and CT scanner; thus, managing the protocols is the first step for optimization. The appropriateness of the radiation dose for each protocol and scanner is verified, while answering whether the dose is the minimum to obtain diagnostic-quality images. Moreover, examinations with exceptionally high doses are identified, and the cause and clinical validity of the high dose are assessed. Daily imaging practice should follow standardized procedures, avoiding operator-dependent errors, and information required for radiation dose management should be recorded at each examination. The imaging protocols and procedures are reviewed for continuous improvement based on regular dose analysis and multidisciplinary team collaboration. The participation of many staff members in the dose management process is expected to contribute to promoting radiation safety through increased staff awareness.

Rabies is a fatal encephalitic infectious disease caused by the rabies virus (RABV). RABV is highly neurotropic and replicates in neuronal cell lines in vitro. The RABV fixed strain, HEP-Flury, was produced via passaging in primary chicken embryonic fibroblast cells. HEP-Flury showed rapid adaptation when propagated in mouse neuroblastoma (MNA) cells. In this study, we compared the growth of our previously constructed recombinant HEP (rHEP) strain—based on the sequence of the HEP (HEP-Flury) strain—with that of the original HEP strain. The original HEP strain exhibited higher titer than rHEP and a single substitution at position 80 in the matrix (M) protein M(D80N) after incubation in MNA cells, which was absent in rHEP. In vivo, intracerebral inoculation of the rHEP-M(D80N) strain with this substitution resulted in enhanced viral growth in the mouse brain and a significant loss of body weight in the adult mice. The number of viral antigen-positive cells in the brains of adult mice inoculated with the rHEP-M(D80N) strain was significantly higher than that with the rHEP strain at 5 days post-inoculation. Our findings demonstrate that a single amino acid substitution in the M protein M(D80N) is associated with neurovirulence in mice owing to adaptation to mouse neuronal cells.

Oxidative stress from an excess of radical compounds generally impacts apoptosis and inflammation. The use of probiotics, therefore, has emerged as a favorable tool to suppress the formation of reactive oxygen species. In the present study, we investigated the antioxidant activity of plant-derived Lactiplantibacillus (L.) plantarum MSC-5T fermented in Eriobotrya japonica (EJ) aqueous extract. In the in vitro study, the extract fermented with the MSC-5T strain markedly decreased the cell death of H2O2-induced HEK293 cells. In addition, the fermented extract showed a protective effect against fungal toxin ochratoxin A (OTA) and citrinin (CTN). Regarding the evaluation of glutathione homeostasis, it can be clearly seen that pretreatment of HEK293 cells with fermented EJ extract greatly increased glutathione (GSH) levels, while unfermented extract did not affect the cellular GSH content. Furthermore, we identified a bioactive compound as pyrocatechol, which displayed significant antioxidation activity. The extract fermented for 48 h with the MSC-5T strain in EJ extract produces 167.4 μg/mL pyrocatechol.

Background Idiopathic pleuroparenchymal fibroelastosis (iPPFE), a progressive fibrotic disease, is characterised by upper lobe–dominant lung fibrosis involving the pleura and subpleural lung parenchyma. However, no prognostic markers have been established for this condition. Associations between blood leucocyte levels and mortality have been reported in patients with idiopathic pulmonary fibrosis; therefore, we hypothesised that peripheral leucocyte levels are associated with mortality risk in patients with iPPFE.Methods This retrospective study longitudinally assessed peripheral leucocyte counts at the time of diagnosis and 1 year after diagnosis in two cohorts of 127 patients with iPPFE (69 and 58 patients in Seirei and Hamamatsu cohorts, respectively).Results A comprehensive assessment of peripheral leucocytes revealed that the neutrophil–lymphocyte ratio (NLR) was associated with mortality in patients with iPPFE after adjusting for age, sex and forced vital capacity in multivariate analyses (adjusted HR, 1.131; 95% CI, 1.032 to 1.227). When the patients were classified based on the median NLR, those with a high NLR had shorter survival than those with a low NLR (median, 32.2 vs 79.8 months; HR, 2.270; 95% CI, 1.416 to 3.696). Interestingly, the results of the NLR classification by median were longitudinally preserved in >70% of patients, and patients with consistently high NLR were at a higher risk of mortality than others (median, 24.8 vs 79.6 months; HR, 3.079; 95% CI, 1.878 to 5.031). Compared with the gender–age–physiology model, a composite model comprising age, sex and NLR could successfully stratify patients with iPPFE into three groups according to mortality risk.Conclusion The assessment of peripheral leucocyte counts is easy and might be useful in evaluating disease severity and mortality risk in patients with iPPFE. Our study suggests the importance of focusing on peripheral leucocyte levels in daily practice.

We investigated the effect of post-labeling delay (PLD) on the evaluation of brain tumor blood flow using arterial spin labeling (ASL) magnetic resonance (MR) imaging to assess the need for imaging with two PLDs. Retrospective analysis was conducted on 63 adult patients with brain tumors who underwent contrast-enhanced MR imaging including ASL imaging with PLDs of both 1525 and 2525 ms on a 1.5 T or 3 T MR unit. Blood flow was estimated in the tumors and normal-appearing brain parenchyma, and tumor blood flow was normalized by parenchymal flow. Estimates of tumor blood flow, parenchymal flow, and normalized tumor flow showed no statistically significant differences between PLDs of 1525 and 2525 ms. Close correlations between different PLDs were found, with the closest correlation for normalized tumor flow. These results were similarly observed for the 1.5 T and 3 T units. The blood flow estimates obtained using ASL MR imaging in patients with brain tumors were highly concordant between PLDs of 1525 and 2525 ms, irrespective of the magnetic field strength. It is indicated that imaging with a single, standard PLD is acceptable for ASL assessment of brain tumor perfusion and that additional imaging with a long PLD is not required.

Abstract Background This study was designed to test the hypothesis that blockade of vascular endothelial growth factor (VEGF) suppresses degenerative changes in articular cartilage from patients with osteoarthritis (OA). Methods Articular cartilage from eight OA patients was subjected to explant culture for 2 days in the presence or absence of 10 ng/ml recombinant interleukin (IL)-1β. The blocking effect of VEGF was examined by the addition of 10 or 100 ng/ml of bevacizumab. The culture media were harvested, and markers for cartilage degradation were measured by sandwich enzyme-linked immunoassay. Total RNA was isolated from cartilage tissues, and gene expressions associated with the anabolic response were examined by the quantitative real-time polymerase chain reaction. Results Bevacizumab significantly reduced concentrations of matrix metalloproteinase (MMP)-2, MMP-3, and cartilage oligomeric matrix protein in the culture media with and without IL-1β. Significant suppressive effects of bevacizumab on MMP-9 and MMP-13 were shown only in the presence of IL-1β. Gene expression of Col2a1 was significantly increased by the addition of bevacizumab in the absence of IL-1β. Conclusion Bevacizumab inhibits catabolic reactions and stimulates anabolic function in articular cartilage derived from OA patients directly, suggesting a protective effect on articular cartilage from OA progression.

We investigated the relationship between the head size and radiation dose in pediatric brain computed tomography (CT) to evaluate the validity of automatic exposure control (AEC). Phantom experiments were performed to assess image noise with and without AEC, and indicated that AEC decreased differences in noise between slices of different section sizes. Retrospective analysis was conducted on 980 pediatric brain CT scans where the tube current was determined using AEC. The water equivalent diameter (WED) was employed as an index of the head size, and mean WED for each image set (WEDmean) and WED for each slice (WEDslice) were used for analysis. For the image-set-based analysis, volume CT dose index (CTDIvol) was compared to WEDmean. For the slice-based analysis, the tube current was compared to WEDslice using 20 of the 980 sets. Additionally, CTDIvol and WEDmean were compared between male and female patients matched for age, weight, or WEDmean. CTDIvol increased with increasing WEDmean, and an exponential curve was closely fitted to the relationship. Tube current changed similarly to the change in WEDslice for each image set, and an exponential curve was well-fitted to the plots of tube current against WEDslice when data from the 20 sets were pooled together. Although CTDIvol and WEDmean were slightly but significantly larger for male than female patients after matching for age or weight, a sex-dependent difference in CTDIvol was not found after matching for WEDmean. This study indicated successful dose modulation using AEC according to the head size for each patient and each slice location. The application of AEC to pediatric brain CT is recommended for radiation dose optimization.

This paper presents a comparison of the 2021 guidelines for stem cell research and clinical translation outlined by the International Society for Stem Cell Research (ISSCR) with the current regulations in Japan regarding the performance of such research. This paper provides a convenient English-language summary of the Japanese regulations, and illustrates the difference between the ISSCR guidelines and Japanese regulations regarding the conditions of implementation of study activities using human embryos or stem cells, for researchers outside Japan. The regulations governing the performance of research activities using human embryos or stem cells in Japan are relatively complex and comprise a range of laws and guidelines; the specific rules applied depend on the characteristics of each study. Therefore, even similar research activities may differ in terms of not only the guidelines or laws implemented, but also the procedures required. Such situations may confuse researchers.

Abstract MEK inhibitors (MEKi) have limited efficacy in KRAS mutant lung adenocarcinoma (LUAD) patients, and this is attributed to both intrinsic and adaptive mechanisms of drug resistance. While many studies have focused on the former, there remains a dearth of data regarding acquired resistance to MEKi in LUAD. We established trametinib-resistant KRAS mutant LUAD cells through dose escalation and performed targeted MSK-IMPACT sequencing to identify drivers of MEKi resistance. Comparing resistant cells to their sensitive counterparts revealed alteration of genes associated with trametinib response. We describe a state of “drug addiction” in resistant cases where cells are dependent on continuous culture in trametinib for survival. We show that dependence on ERK2 suppression underlies this phenomenon and that trametinib removal hyperactivates ERK, resulting in ER stress and apoptosis. Amplification of KRAS G12C occurs in drug-addicted cells and blocking mutant-specific activity with AMG 510 rescues the lethality associated with trametinib withdrawal. Furthermore, we show that increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study determines the drug-addicted phenotype in lung cancer is associated with KRAS amplification and demonstrates that toxic acquired genetic changes can develop de novo in the background of MAPK suppression with MEK inhibitors. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.

Estimation of the standard radiation dose at each imaging facility is required for radiation dose management, including establishment and utilization of the diagnostic reference levels. We investigated methods to estimate the standard dose for pediatric brain computed tomography (CT) using a small number of data. From 980 pediatric brain CT examinations, 25, 50, and 100 examinations were randomly extracted to create small, medium, and large datasets, respectively. The standard dose was estimated by applying grouping and curve-fitting methods for 20 datasets of each sample size. For the grouping method, data were divided into groups according to age or body weight, and the standard dose was defined as a median value in each group. For the curve-fitting methods, logarithmic, power, and bilinear functions were fitted to plots of radiation dose against age or weight, and the standard dose was calculated at the designated age or weight using the derived equation. When the sample size was smaller, the random variations of the estimated standard dose were larger. Better estimation of the standard dose was achieved with the curve-fitting methods than with the grouping method. Power fitting appeared to be more effective than logarithmic and bilinear fittings for suppressing random variation. Determination of the standard dose for pediatric brain CT by the curve-fitting method is recommended to improve radiation dose optimization at facilities performing the imaging procedure infrequently.

Background There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs).Methods In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest.Results Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician’s decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death.Conclusions In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP.Trial registration number jRCT: 1041190029.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonotic disease caused by the SFTS virus (SFTSV). In Thailand, three human cases of SFTS were reported in 2019 and 2020, but there was no report of SFTSV infection in animals. Our study revealed that at least 16.6% of dogs in Thailand were seropositive for SFTSV infection, and the SFTSV-positive dogs were found in several districts in Thailand. Additionally, more than 70% of the serum samples collected at one shelter possessed virus-neutralization antibodies against SFTSV and the near-complete genome sequences of the SFTSV were determined from one dog in the shelter. The dog SFTSV was genetically close to those from Thailand and Chinese patients and belonged to genotype J3. These results indicated that SFTSV has already spread among animals in Thailand.

Abstract Background Fatty acids have diverse immunomodulatory functions and the potential to be associated with inflammatory responses in sarcoidosis. Methods The serum levels of multiple long-chain fatty acids (LCFAs) were compared between 63 patients with sarcoidosis and 38 healthy controls. The associations of LCFAs with clinical outcomes of sarcoidosis were also evaluated. Results The patients with sarcoidosis had significantly lower levels of n-3 poly-unsaturated fatty acids (PUFAs) (p

Abstract Background The assessment of lung physiology via pulmonary function tests (PFTs) is essential for patients with idiopathic pulmonary fibrosis (IPF). However, PFTs require active participation, which can be challenging for patients with severe respiratory failure, such as during moments of acute exacerbation (AE) of IPF. Recent advances have enabled the re-construction of 3-dimensional computed-tomography (3D-CT) images. This study established a standardisation method and quantitative analysis of lung volume (LV) based on anthropometry using 3D-CT images. Methods This is a retrospective multi-center cohort study. The standardised 3D-CT LV in patients with IPF at diagnosis (n = 140) and during AE (cohort1; n = 61 and cohort2; n = 50) and those of controls (n = 53) were assessed. Results The standardised 3D-CT LVs at IPF diagnosis were less than those of control patients, especially in the lower lung lobes. The standardised 3D-CT LVs were correlated with forced vital capacity (FVC) and validated using the modified Gender-Age-Physiology (GAP) index. The standardised 3D-CT LVs at IPF diagnosis were independently associated with prognosis. During AE, PFTs were difficult to perform, 3D-CT analyses revealed reduced lung capacity in both the upper and lower lobes compared to those obtained at diagnosis. Lower standardised 3D-CT LVs during AE were independently associated with worse outcomes in the two independent cohorts. In particular, volume loss in the upper lobe at AE had prognostic values. Conclusions A novel image quantification method for assessing pulmonary physiology using standardised 3D-CT-derived LVs was developed. This method successfully predicts mortality in patients with IPF and AE of IPF, and may be a useful alternative when PFTs cannot be performed.

Introduction: Breakthroughs in stem cell research (SCR) and regenerative medicine (RM) have attracted significant public attention worldwide. Simultaneously, scientific communities and science policies have tried to establish appropriate governance of SCR and RM. In this context, effective communication between scientific communities and the public is regarded as a key factor. However, the diversity of public attitudes and interests has not been sufficiently examined, especially the differences across countries. Methods: We conducted an international comparison of public attitudes toward SCR and RM. We circulated an internet questionnaire among people in six countries: Japan, South Korea, the United States, the UK, Germany, and France. We collected 100 valid responses from each country, and a total of 600 responses were obtained. Results: Our key findings are the diversity of interests in RM, which can be expressed as user pragmatism, governance and handling of RM, risk, and benefit, and scientific interests. The priority of interests varied across the six countries, and the variations may be influenced by the political, social, cultural, and media contexts of SCR and RM in each country. Conclusion: The implications can contribute to a deeper understanding of the diversity of public attitudes, and bring about an appropriate examination of a wide range of ethical and social concerns of SCR and RM in global contexts.

Background Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is characterised by upper lobe-dominant fibrosis involving the pleura and subpleural lung parenchyma, with advanced cases often complicated by progressive weight loss. Therefore, we hypothesised that nutritional status is associated with mortality in IPPFE. Methods This retrospective study assesses nutritional status at the time of diagnosis and 1 year after diagnosis in 131 patients with IPPFE. Malnutrition-related risk was evaluated using the Geriatric Nutritional Risk Index (GNRI). Results Of the 131 patients, 96 (73.8%) were at malnutrition-related risk at the time of diagnosis according to the GNRI. Of these, 21 patients (16.0%) were classified as at major malnutrition-related risk (GNRI

BackgroundThe immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions.MethodsOne hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored.ResultsThe blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (t = 3.67, FWE-corrected p = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (F = 19.71, p

Mobile genetic elements (e.g., transposable elements and plasmids) and viruses display significant diversity with various life cycles, but how this diversity emerges remains obscure. We previously reported a novel and giant (180 kb long) mobile element, Teratorn, originally identified in the genome of medaka, Oryzias latipes. Teratorn is a composite DNA transposon created by a fusion of a piggyBac-like DNA transposon (piggyBac) and a novel herpesvirus of the Alloherpesviridae family. Genomic survey revealed that Teratorn-like herpesviruses are widely distributed among teleost genomes, the majority of which are also fused with piggyBac, suggesting that fusion with piggyBac is a trigger for the life-cycle shift of authentic herpesviruses to an intragenomic parasite. Thus, Teratorn-like herpesvirus provides a clear example of how novel mobile elements emerge, that is to say, the creation of diversity. In this review, we discuss the unique sequence and life-cycle characteristics of Teratorn, followed by the evolutionary process of piggyBac-herpesvirus fusion based on the distribution of Teratorn-like herpesviruses (relatives) among teleosts. Finally, we provide other examples of evolutionary associations between different classes of elements and propose that recombination could be a driving force generating novel mobile elements.

BackgroundLOX family members are reported to play pivotal roles in cancer. Unlike their enzymatic activities in collagen cross-linking, their precise cancer functions are unclear. We revealed that LOXL4 is highly upregulated in breast cancer cells, and we thus sought to define an unidentified role of LOXL4 in breast cancer.MethodsWe established the MDA-MB-231 sublines MDA-MB-231-LOXL4 mutCA and -LOXL4 KO, which stably overexpress mutant LOXL4 that loses its catalytic activity and genetically ablates the intrinsic LOXL4 gene, respectively. In vitro and in vivo evaluations of these cells’ activities of cancer outgrowth were conducted by cell-based assays in cultures and an orthotopic xenograft model, respectively. The new target (s) of LOXL4 were explored by the MS/MS analytic approach.ResultsOur in vitro results revealed that both the overexpression of mutCA and the KO of LOXL4 in cells resulted in a marked reduction of cell growth and invasion. Interestingly, the lowered cellular activities observed in the engineered cells were also reflected in the mouse model. We identified a novel binding partner of LOXL4, i.e., annexin A2. LOXL4 catalyzes cell surface annexin A2 to achieve a cross-linked multimerization of annexin A2, which in turn prevents the internalization of integrin β-1, resulting in the locking of integrin β-1 on the cell surface. These events enhance the promotion of cancer cell outgrowth.ConclusionsLOXL4 has a new role in breast cancer progression that occurs via an interaction with annexin A2 and integrin β-1 on the cell surface.

Rationale & Objective: Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. Study Design: Population-based cross-sectional study. Setting & Participants: A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. Exposures: UACR and eGFR levels. Outcomes: The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). Analytical Approach: The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. Results: Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend = 0.009 and

Abstract Background Mucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions. Methods Wild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed. Results Intranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration. Conclusions LAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function.

The diagnostic reference levels (DRLs) for pediatric brain computed tomography (CT) are provided for groups divided according to age. We investigated the relationships of radiation dose indices (volume CT dose index and dose length product) with age and weight, as continuous variables, in pediatric brain CT. In a retrospective analysis, 980 pediatric brain CT examinations were analyzed. Curve fitting was performed for plots of the CT dose indices versus age and weight, and equations to estimate age- and weight-dependent standard dose indices were derived. Standard dose indices were estimated using the equations, and the errors were calculated. The results showed a biphasic increase in dose indices with increasing age and weight, characterized by a rapid initial and subsequent slow increase. Logarithmic, power, and bilinear functions were well fitted to the plots, allowing estimation of standard dose indices at an arbitrary age or weight. Error analysis suggested that weight was mildly better than age and that the best results were obtained with the bilinear function. Curve fitting of the relationship between CT dose indices and age or weight facilitates the determination of standard dose indices in pediatric brain CT at each facility and is expected to aid the establishment and application of the DRLs.

Abstract Background Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), like those with idiopathic pulmonary fibrosis (IPF), might develop an unexpected acute exacerbation (AE)—a rapidly progressing and deadly respiratory decline. Although AE incidence and risk factors in RA-ILD patients are known, their post-AE clinical course remains unknown owing to the rarity of AE-RA-ILD. This multicentre retrospective study evaluated post-AE mortality and prognostic variables in AE-RA-ILD patients and created a mortality prediction model for AE-RA-ILD. Methods This research comprised 58 patients with AE-RA-ILD and 96 with AE-IPF (a control disease). Multivariate Cox regression analysis was performed to identify prognostic variables. A prediction model was created with recursive partitioning (decision tree). Results The post-AE 90-day mortality rate in the overall AE-RA-ILD group was 48.3%; percent predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and PaO2/FiO2 ratio at AE onset (P/F at AE) were independent predictors of mortality. Post-AE 90-day mortality rates were 40.6% and 43.8%, respectively, in AE-RA-ILD and AE-IPF patients propensity score-matched for age, sex, baseline %FVC and P/F at AE (P = 1.0000). In AE-RA-ILD patients, C-indices of baseline %FVC and P/F at AE to predict post-AE 90-day mortality were 0.604 and 0.623, respectively. A decision tree model based on these prognostic factors classified AE-RA-ILD patients into mild, moderate and severe groups (post-AE 90-day mortality rates: 20.8%, 64.0% and 88.9%, respectively; P = 0.0002); the C-index improved to 0.775. Conclusions Post-AE mortality was high in AE-RA-ILD patients similar to AE-IPF patients. The discovered prognostic factors and our mortality prediction model may aid in the management of AE-RA-ILD patients.