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Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. A single-cell RNA-Seq analysis revealed that osteal macrophages were heterogeneously clustered into 6 subsets that expressed proliferative, inflammatory, antiinflammatory, and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited an increase in subset 3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopausal condition altered the osteal macrophage subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed, and mice that received oxidatively stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in the development of inflammaging in the bone microenvironment. Consistently, depletion of senescent cells and the oxidatively stressed macrophage subset alleviated the excessive bone loss in postmenopausal mice. Our data provided insight into the pathogenesis of osteoporosis and shed light on a therapeutic approach for the treatment or prevention of postmenopausal osteoporosis.

Background: Osteoarthritis (OA) is the most common degenerative joint disease characterized by cartilage degradation and various degrees of inflammation in the synovium. Growing evidence highlights that neutrophil extracellular vesicles (EVs) play a protective role in arthritic joints by promoting the resolution of inflammation and the synthesis of proteoglycans in cartilage. However, this homeostatic function is dependent on the activation state of neutrophils and the surrounding environment/tissues. Hence, we explored the chondroprotective functions of neutrophil-derived EVs under different stimulation conditions and the underlying molecular mechanism., Methods: Human blood-derived neutrophils, murine bone marrow-derived neutrophils, C-28I2 cells and primary chondrocytes were used. Neutrophils were stimulated with different cytokines, and their EVs were isolated for chondrocyte stimulation and further subjected to RNA-sequencing analysis. Two experimental murine OA models were used, and the treatment was performed by intraarticular injections., Results: Conditioned medium from neutrophils stimulated with TGF-β (N-β) had the greatest inhibitory effect on the expression of catabolic factors in stimulated chondrocytes. These protective effects were not impaired when conditioned medium of N-β from AnxA1-deficient mice was used. Consistent with these results, EVs isolated from N-β significantly reduced the expression of catabolic factors in stimulated chondrocytes. Bulk RNA-seq analysis revealed that secreted frizzled-related protein 5 (SFRP5) is upregulated in N-β-EV-stimulated chondrocytes. Furthermore, recombinant SFRP5 treatment significantly reduced the expression of catabolic factors in vitro and catabolic process in experimental murine OA models., Conclusions: The current study emphasizes the potential therapeutic application of neutrophils in OA and provides new knowledge on the molecular mechanisms underlying their function., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cartilage repair is a significant clinical challenge because of the limited intrinsic healing capacity. Current therapeutic strategies, such as cell transplantation therapy, aim to overcome this challenge by replacing damaged tissue with healthy cells. However, the long-term survival and functionality of transplanted cells remain major hurdles., Objective: This study investigated the impact of chondrocyte passaging on glycan profiles and their antigenic properties. We hypothesized that alterations in glycan composition due to passaging may contribute to the enhanced ability to activate macrophages, thereby affecting the outcome of cell transplantation therapy., Methods: Peritoneal macrophages and primary articular chondrocytes were isolated from C57BL/6 mice to establish direct and indirect coculture models. Macrophage activation was assessed by measuring the concentrations of IL-6 and nitric oxide in the culture supernatants or their gene expression. Glycome analysis of various glycoconjugates was performed by glycoblotting methods combined with the SALSA procedure for N-glycans and GSLs and the BEP method for O-glycans., Results: Our results revealed that direct coculture of macrophages with passaged chondrocytes increased the production of proinflammatory cytokines, including IL-6 and NO, as the number of passages increased. With increasing passage number, the expression of GD3 substantially decreased, and the expression of GM3, especially GD1a, significantly increased. Coculturing passaged GM3S knockout chondrocytes with macrophages significantly suppressed IL-6 expression, implying reduced macrophage activation., Conclusion: The observed activation of macrophages due to alterations in the glycan profile of chondrocytes provides a possible explanation for the antigenicity and immune rejection of transplanted cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Homan, Tokuhiro, Onodera, Hanamatsu, Furukawa, Ebata, Matsuoka, Kadoya, Terkawi and Iwasaki.)

Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that primarily affects joints and causes pain, stiffness and swelling. The affected joints exhibit severe inflammation in the synovium and bone erosion, leading to joint deformity. Aging is an important factor facilitating the development of RA, as it is associated with an increase in the number of senescent cells and the production of the autoantibodies and proinflammatory cytokines in tissues. Given that CCN3 is highly expressed in RA joints and that its level is associated with the severity of the disease, we explored its molecular function in joints and therapeutic potential in RA. An analysis of public scRNA-seq data from the RA synovium revealed that CCN3 is expressed by an inflammatory fibroblast subset. Interestingly, stimulation with CCN3 resulted in the activation of the senescence pathway in synoviocytes and osteoclast differentiation in monocytes in vitro. Consistent with these results, the administration of CCN3 into the knee joint and onto the calvarial bone resulted in increased numbers of senescent synoviocytes in the joint and osteoclasts in the bone, respectively. Furthermore, the therapeutic potential of targeting CCN3 was evaluated in an experimental RA model. Administration of the CCN3 antibody significantly suppressed inflammation and osteoclast numbers in the joints of the RA model mice. Our findings suggest that CCN3 contributes to pathological processes in RA and represents a promising therapeutic target for the treatment of RA., Competing Interests: Declaration of competing interest All the authors state that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dedifferentiated liposarcoma is a rare cancer with a poor prognosis. A 52-year-old man presented with a chief complaint of a mass in his left scrotum. He came with suspected testicular tumor, but all the measured tumor markers were negative. Imaging test showed approximately 2 cm diameter mass accompanied by calcification with some substantial components between the testis and epididymis. Left high testicular resection was performed. The tumor had no continuity between the testis and epididymis, and the spermatic cord transection was negative. Pathological findings showed well differentiated fatty component and a dedifferentiated component around the trabecular bone-like tissue. We observed dedifferentiated dysmorphic cells mixed with fatty droplets of unequal size. Immunostaining led to the diagnosis of dedifferentiated liposarcoma. No additional postoperative therapy was performed. The possibility of dedifferentiated liposarcoma should be kept in mind even if mass is confined to the scrotum and consisted of calcification. In the case of an intrascrotal calcified mass with malignant perspective, radical surgery is highly recommended., Competing Interests: Conflict of interestThe authors declare that have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The prognostic factors associated with severe-to-fatal post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remain unclear despite the extensive number of studies on PEP. In total, 3739 ERCP patients with biliary disease with an intact papilla and indicated for ERCP were prospectively enrolled at 36 centers from April 2017 to March 2018. Those with acute pancreatitis diagnosed before ERCP, altered gastrointestinal anatomy, and an American Society of Anesthesiologists (ASA) physical status > 4 were excluded. Univariate and multivariate logistic regression analyses were performed on patient-related factors, operator-related factors, procedure-related factors, and preventive measures to identify potential prognostic factors for severe-to-fatal PEP. Multivariate analyses revealed pancreatic guidewire-assisted biliary cannulation (OR 13.59, 95% CI 4.21-43.83, p < 0.001), post-ERCP non-steroidal anti-inflammatory drug (NSAID) administration (OR 11.54, 95% CI 3.83-34.81, p < 0.001), and previous pancreatitis (OR 6.94, 95% CI 1.45-33.33, p = 0.015) as significant risk factors for severe-to-fatal PEP. Preventive measures included endoscopic biliary sphincterotomy (EST; OR 0.29, 95% CI, 0.11-0.79, p = 0.015) and prophylactic pancreatic stents (PPSs; OR 0.11, 95% CI, 0.01-0.87, p = 0.036). In biliary ERCP, pancreatic guidewire-assisted biliary cannulation, NSAID administration after ERCP, and previous pancreatitis were risk factors for severe-to-fatal PEP, whereas EST and PPS were significant preventive measures for severe-to-fatal PEP.

Cytomegalovirus infection is typically asymptomatic in immunocompetent individuals. A 26-year-old woman was admitted to our hospital with a fever and breathlessness. Chest computed tomography (CT) revealed bilateral diffuse reticulation and nodules. Laboratory investigations showed atypical lymphocytosis and increased transaminases. She was treated with corticosteroid pulse therapy because of acute lung injury, and her clinical condition improved. Based on the presence of cytomegalovirus antibodies, antigen, and polymerase chain reaction findings, she was diagnosed with primary cytomegalovirus pneumonia and treated with valganciclovir. Primary cytomegalovirus pneumonia is very rare in immunocompetent individuals. The efficacy of corticosteroid and valganciclovir against cytomegalovirus pneumonia in this patient is noteworthy.

Background: There is no consensus on the necessity of endoscopic sphincterotomy (ES) to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) after endoscopic stenting in patients with malignant biliary obstruction. We investigated the incidence of PEP after endoscopic biliary stenting for malignant biliary obstruction with or without ES in a multicenter prospective cohort study., Methods: We enrolled 807 patients who underwent endoscopic biliary stenting for malignant biliary obstruction with a native papilla at 36 hospitals between April 2017 and March 2018. The incidence of PEP in patients with or without ES was compared for subgroups based on stent type, placement method, and patient background. Univariate and multivariate analysis was performed to investigate the incidence of PEP in all stenting patients., Results: Plastic and metal stents (MS) were inserted in 598 and 209 patients, respectively. The incidence of PEP in patients with or without ES was 7.9% and 7.4%, respectively among all stenting patients. The incidences of PEP with or without ES in plastic stent insertion patients, patients with MS insertion, stent insertions across the papilla, stent insertions across the papilla in patients without main pancreatic duct obstruction, and fully covered MS insertions across the papilla were compared. There was no overall significant difference in the incidence of PEP between those with or without ES. Multivariate logistic regression analysis for the incidence of PEP in all stenting patients revealed obstruction of the main pancreatic duct at the pancreatic head and epinephrine spraying on the papilla were significant factors; there was no significant difference in the incidence of PEP between patients with or without ES., Conclusion: Endoscopic sphincterotomy may not contribute to the prevention of PEP after endoscopic biliary stenting for malignant biliary obstruction, even in cases of insertion with a fully covered MS across the papilla., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Genomic profile analysis using next-generation sequencing can potentially elucidate the pathogenesis of rare cancers. Ductal adenocarcinoma, a rare subtype of prostate cancer, has an aggressive nature. This is the first study to analyze the genomic profile of ductal adenocarcinoma in an Asian population., Methods: We identified 12 patients newly diagnosed with ductal adenocarcinoma of the prostate at two hospitals, and nine patients (75.0%) had the pure type. Genomic assessment was performed using either the PleSSision testing platform or FoundationOne CDx., Results: At least one genomic alteration occurred in 11 patients (91.7%), and the most frequently mutated gene was tumor suppressor protein p53 (TP53), which was found in six cases (50.0%). Alterations characteristic of this cohort were found in four cases (33.3%) of retinoblastoma transcriptional corepressor 1 (RB1), which was only observed in the pure type. Compared to previous study results, the frequency of genetic alterations in the phosphoinositide 3-kinase (PI3K) pathway (n = 3; 25.0%) and Wnt-β-catenin pathway (n = 5; 41.7%) was comparable, but no alterations in the DNA damage repair (DDR) pathway were observed. None of the patients presented high tumor mutation burden or microsatellite instability., Conclusions: We found that the Asian cohort with ductal adenocarcinoma had actionable alterations, and a high frequency of alterations in TP53 and RB1 reflected the aggressive nature of the tumor. Genetic analysis using next-generation sequencing is expected to help elucidate the pathogenesis of ductal adenocarcinoma., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aurantiochytrium limacinum can accumulate high amounts of omega-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA). Although salinity affects the DHA content, its impact on the metabolic pathway responsible for DHA production in A. limacinum is not completely understood. To address this issue, we investigated the transcriptional profile of A. limacinum under hypoosmotic stress. We first cultured A. limacinum under typical and low salinity for RNA sequencing, respectively. Transcriptome analyses revealed that 933 genes exhibited significant changes in expression under hypoosmotic conditions, of which 81.4% were downregulated. Strikingly, A. limacinum downregulated genes related to polyketide synthesis and fatty acid synthase pathways, while upregulating β-oxidation-related genes. In accordance with this, DHA production significantly decreased under hypoosmotic conditions, while antioxidant-related genes were significantly upregulated. Considering that β-oxidation of fatty acids generates energy and reactive oxygen species (ROS), our results suggest that A. limacinum utilizes fatty acids for energy to survive under hypoosmotic conditions and detoxifies ROS using antioxidant systems., (© The Author(s) 2022. Published by Oxford University Press on behalf of Applied Microbiology International.)

A 77-year-old female presented with loss of consciousness, blood pressure of 90/60 mmHg, and heart rate of 47 bpm. At admission, highly sensitive Trop-T and lactate were elevated, and an electrocardiogram revealed an infero-posterior ST elevation myocardial infarction. Echocardiography revealed a depressed left ventricular ejection fraction with abnormal wall motion in the infero-posterior region and hyperkinetic apical movement along with severe mitral regurgitation (MR). Coronary angiography showed a hypoplastic right coronary artery, 100% thrombotic occlusion of the dominant left circumflex (LCx) artery, and 75% stenosis in the left anterior descending (LAD) artery. Substantial hemodynamic improvement with the reduction of acute ischemic MR was achieved by the initiation of an Impella 2.5, which is a transvalvular axial flow pump, and successful percutaneous coronary intervention (PCI) was conducted with stents to the LCx. The patient was weaned off the Impella 2.5 in 5 days, received staged PCI to LAD, and was later discharged after completion of the staged PCI to LAD.

Patients with acute myocardial infarction (AMI) triaged as life-threatening are transferred to our emergency medical care center (EMCC). However, data on these patients remain limited. We aimed to compare the characteristics and AMI prognosis of patients transferred to our EMCC with those transferred to our cardiovascular intensive care unit (CICU) using whole and propensity-matched cohorts.We analyzed the data of 256 consecutive AMI patients transferred from the scene to our hospital by ambulance between 2014 and 2017. The EMCC and CICU groups comprised 77 and 179 patients, respectively. There were no significant between-group age or sex differences. Patients in the EMCC group had more disease severity score and had the left main trunk identified as the culprit more frequently (12% versus 0.6%, P < 0.001) than those in the CICU group; however, the number of patients with multiple culprit vessels did not differ. The EMCC group had a longer door-to-reperfusion time (75 [60, 109] minutes versus 60 [40, 86] minutes, P< 0.001) and a higher in-hospital mortality (19% versus 4.5%, P < 0.001), especially from non-cardiac causes (10% versus 0.6%, P < 0.001), than the CICU group. However, peak myocardial creatine phosphokinase did not significantly differ between the groups. The EMCC group had a significantly higher 1-year post-discharge mortality than the CICU group (log-rank, P = 0.032); this trend was maintained after propensity score matching, although the difference was not statistically significant (log-rank, P = 0.094).AMI patients transferred to the EMCC exhibited more severe disease and worse overall in-hospital and non-cardiac mortality than those transferred to the CICU.

Objective: This experimental study aimed to assess the efficacy of hydrogen gas inhalation against spinal cord ischemia-reperfusion injury and reveal its mechanism by measuring glutamate concentration in the ventral horn using an in vivo microdialysis method., Methods: Male Sprague-Dawley rats were divided into the following 6 groups: sham, only spinal ischemia, 3% hydrogen gas (spinal ischemia + 3% hydrogen gas), 2% hydrogen gas (spinal ischemia + 2% hydrogen gas), 1% hydrogen gas (spinal ischemia + 1% hydrogen gas), and hydrogen gas dihydrokainate (spinal ischemia + dihydrokainate [selective inhibitor of glutamate transporter-1] + 3% hydrogen gas). Hydrogen gas inhalation was initiated 10 minutes before the ischemia. For the hydrogen gas dihydrokainate group, glutamate transporter-1 inhibitor was administered 20 minutes before the ischemia. Immunofluorescence was performed to assess the expression of glutamate transporter-1 in the ventral horn., Results: The increase in extracellular glutamate induced by spinal ischemia was significantly suppressed by 3% hydrogen gas inhalation (P &lt; .05). This effect was produced in increasing order: 1%, 2%, and 3%. Conversely, the preadministration of glutamate transporter-1 inhibitor diminished the suppression of spinal ischemia-induced glutamate increase observed during the inhalation of 3% hydrogen gas. Immunofluorescence indicated the expression of glutamate transporter-1 in the spinal ischemia group was significantly decreased compared with the sham group, which was attenuated by 3% hydrogen gas inhalation (P &lt; .05)., Conclusions: Our study demonstrated hydrogen gas inhalation exhibits a protective and concentration-dependent effect against spinal ischemic injury, and glutamate transporter-1 has an important role in the protective effects against spinal cord injury., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

This study, which included serological and cellular immunity tests, evaluated whether coronavirus disease 2019 (COVID-19) vaccination adequately protected healthcare workers (HCWs) from COVID-19. Serological investigations were conducted among 1600 HCWs (mean ± standard deviation, 7.4 ± 1.4 months after the last COVID-19 vaccination). Anti-SARS-CoV-2 antibodies N-Ig, Spike-Ig (Roche), N-IgG, Spike-IgM, and -IgG (Abbott), were evaluated using a questionnaire of health condition. 161 HCWs were analyzed for cellular immunity using T-SPOT ® SARS-CoV-2 kit before, and 52 HCWs were followed up until 138.3 ± 15.7 days after their third vaccination. Spike-IgG value was 954.4 ± 2282.6 AU/mL. Forty-nine of the 1600 HCWs (3.06%) had pre-existing SARS-CoV-2 infection. None of the infectious seropositive HCWs required hospitalization. T-SPOT value was 85.0 ± 84.2 SFU/10 6 cells before the third vaccination, which increased to 219.4 ± 230.4 SFU/10 6 cells immediately after, but attenuated later (to 111.1 ± 133.6 SFU/10 6 cells). Poor counts (< 40 SFU/10 6 cells) were present in 34.8% and 38.5% of HCWs before and after the third vaccination, respectively. Our findings provide insights into humoral and cellular immune responses to repeated COVID-19 vaccinations. COVID-19 vaccination was effective in protecting HCWs from serious illness during the original Wuhan-1, Alpha, Delta and also ongoing Omicron-predominance periods. However, repeated vaccinations using current vaccine versions may not induce sufficient cellular immunity in all HCWs., (© 2022. The Author(s).)

The linear synthesis of 4'-C-aminoethoxy thymidine (AEoT) nucleoside phosphoramidite was accomplished using deoxythymidine as the starting material. This analog was incorporated into several oligonucleotides, the applicability of which as antisense oligonucleotides (ASOs) was then evaluated. The AEoT-modified DNA/RNA duplex exhibited improved thermal stability compared to unmodified and 4'-C-aminoethyl thymidine (4'-AET) modified heteroduplexes. The serum stability of AEoT-modified DNA was notably increased by several-folds compared to that of unmodified DNA. Furthermore, RNase H-dependent cleavage of the modified-DNA/RNA hybrids was found to be sustained. In addition, the modified antisense and unmodified oligonucleotides also displayed relatively comparable inhibition of the KRAS gene in human lung cancer cells. This study strengthens our understanding of the potential application of 4'-C-aminoethoxy-modified nucleotides as ASO therapeutics., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Healthcare workers (HCWs), especially frontline workers against coronavirus disease 2019 (COVID-19), are considered to be risky because of occupational exposure to infected patients. This study evaluated the correlation between seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies among HCWs and the implementation of personal protective equipment (PPE) & infection prevention and control (IPC). We recruited 1237 HCWs from nine public COVID-19-designated hospitals in Shiga Prefecture, central Japan, between 15-26 February 2021. All participants answered a self-administered questionnaire and provided blood samples to evaluate SARS-CoV-2 antibodies. A total of 22 cases (1·78%) were seropositive among the 1237 study participants. An unavoidable outbreak of SARS-CoV-2 had occurred at the terminal care unit of one hospital, before identifying and securely isolating this cluster of cases. Excluding with this cluster, 0·68% of HCWs were suspected to have had previous SARS-CoV-2 infections. Binomial logistic regression from individual questionnaires and seropositivity predicted a significant correlation with N95 mask implementation under aerosol conditions (p = 8.63e-06, aOR = 2.47) and work duration in a red zone (p = 2.61e-04, aOR = 1.99). The institutional questionnaire suggested that IPC education was correlated with reduced seropositivity at hospitals. Seroprevalence and questionnaire analyses among HCWs indicated that secure implementation of PPE and re-education of IPC are essential to prevent SARS-CoV-2 infection within healthcare facilities. Occupational infections from SARS-CoV-2 in healthcare settings could be prevented by adhering to adequate measures and appropriate use of PPE. With these measures securely implemented, HCWs should not be considered against as significantly risky or dirty by local communities., Competing Interests: The authors have declared that no competing interests exist.

Aims: Astaxanthin-producing protist Aurantiochytrium limacinum can accumulate higher amounts of astaxanthin under light conditions; however, little is known about the impact of light exposure on its metabolism. Here, we investigated the transcriptional profile of A. limacinum under light conditions., Methods and Results: Transcriptomic analyses revealed that 962 genes of A. limacinum showed a significant change in expression under light conditions, most of which (94.5%) were downregulated. Furthermore, gene ontology enrichment analysis indicated that A. limacinum mainly downregulated genes associated with cell motility, proliferation and gene expression processes, whose activities depend on ATP as an energy source. Additionally, the quantification of carotenoid and its transcripts suggested that β-carotene and astaxanthin biosynthesis pathways were rate-limiting and tightly regulated steps, respectively. In comparison, these processes were enhanced under light conditions., Conclusions: Considering that astaxanthin accumulation was highly correlated with reactive oxygen species (ROS) levels in microalgae, our results suggest that A. limacinum reduces ATP consumption to decrease the occurrence of ROS in mitochondria while accumulating astaxanthin to prevent ROS damage., Significance and Impact of Study: This study provides novel insights into the impact of light exposure on A. limacinum metabolism, thereby facilitating a complete understanding of this protist for efficient astaxanthin production., (© 2022 Society for Applied Microbiology.)

Background: Ovarian clear cell carcinomas (OCCCs) have been recurrent and refractory among the present treatments, so novel therapeutics are urgently needed., Objective: The present study accumulates the proof of concept to examine the feasibility of RDH10 as a therapeutic target for treating OCCCs., Methods: Immunohistochemically, RDH10 expression was evaluated in 111 primary epithelial ovarian cancers, including 55 OCCCs, 31 ovarian endometrioid carcinomas and 25 ovarian serous carcinomas. The spherogenecity provoked by RDH10 was evaluated in OCCC cells. To analyze whether RDH10 promotes carbohydrate storage via the vitamin A-gluconeogenesis pathway, phosphoenolpyruvate carboxykinase 1 (PCK1) protein levels and intracellular carbohydrate content were measured in response to modified RDH10 expression., Results: Abundant RDH10 was expressed specifically in OCCCs. RDH10 promoted spherogenecity and intracellular carbohydrate storage via modulation of PCK1 expression in OCCC cells., Conclusions: In the present study, abundant RDH10 contributed to cancer cell stemness and intracellular carbohydrate storage in OCCCs. RDH10 is a potentially, new therapeutic candidate for treating OCCC cases.

Background: The present study aimed to evaluate the reliability of hemodynamic changes induced by lung recruitment maneuver (LRM) in predicting stroke volume (SV) increase after fluid loading (FL) in prone position., Methods: Thirty patients undergoing spine surgery in prone position were enrolled. Lung-protective ventilation (tidal volume, 6-7 mL/kg; positive end-expiratory pressure, 5 cmH 2 O) was provided to all patients. LRM (30 cmH 2 O for 30 s) was performed. Hemodynamic variables including mean arterial pressure (MAP), heart rate, SV, SV variation (SVV), and pulse pressure variation (PPV) were simultaneously recorded before, during, and at 5 min after LRM and after FL (250 mL in 10 min). Receiver operating characteristic curves were generated to evaluate the predictability of SVV, PPV, and SV decrease by LRM (ΔSV LRM ) for SV responders (SV increase after FL > 10%). The gray zone approach was applied for ΔSV LRM ., Results: Areas under the curve (AUCs) for ΔSV LRM , SVV, and PPV to predict SV responders were 0.778 (95% confidence interval: 0.590-0.909), 0.563 (0.371-0.743), and 0.502 (0.315-0.689), respectively. The optimal threshold for ΔSV LRM was 30% (sensitivity, 92.3%; specificity, 70.6%). With the gray zone approach, the inconclusive values ranged 25 to 75% for ΔSV LRM (including 50% of enrolled patients)., Conclusion: In prone position, LRM-induced SV decrease predicted SV increase after FL with higher reliability than traditional dynamic indices. On the other hand, considering the relatively large gray zone in this study, future research is needed to further improve the clinical significance., Trial Registration: UMIN Clinical Trial Registry UMIN000027966 . Registered 28th June 2017., (© 2021. The Author(s).)

Objectives: Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens., Design and Setting: A retrospective cohort study at two centres in Japan., Participants: Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included., Interventions: We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm 2 )., Primary and Secondary Outcome Measures: The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes., Results: Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival., Conclusions: Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Because development of acute coronary syndrome (ACS) worsens the prognosis of patients with coronary artery disease, preventing recurrent ACS is crucial. However, the degree to which secondary prevention treatment goals are achieved in patients with recurrent ACS is unknown., Methods: 214 consecutive ACS patients were classified as having First ACS (n=182) or Recurrent ACS (n=32), and the clinical characteristics of these groups were compared. Fifteen patients died or developed cardiovascular (CV) events during hospitalization, and the remaining 199 patients were followed from the date of hospital discharge to evaluate subsequent CV events., Results: Patients in the Recurrent ACS group were older than those in the First ACS group (76.8±10.8 years vs 68.8±13.4 years, p=0.002) and had a higher rate of diabetes mellitus (DM) (65.6% vs 36.8%, p=0.003). The rate of achieving a low-density lipoprotein cholesterol (LDL-C) level of <70 mg/dL in the Recurrent ACS group was only 28.1%, even though 68.8% of these patients were taking statins. An HbA1c level of <7.0% was achieved in 66.7% of patients with recurrent ACS who had been diagnosed with DM. Overall, 12.5% of patients with recurrent ACS had received optimal treatment for secondary prevention. CV events after hospital discharge were noted in 37.9% of the Recurrent ACS group and 21.2% of the First ACS group (log-rank test: p=0.004). However, recurrent ACS was not an independent risk factor for CV events (adjusted hazard ratio: 2.09, 95% confidence interval: 0.95 to 4.63, p=0.068)., Conclusion: Optimal treatment for secondary prevention was not achieved in some patients with recurrent ACS, and achievement of the guideline-recommended LDL-C goal for secondary prevention was especially low in this population.

Background: Modafinil improves wakefulness and attention, is approved in Japan for treatment of narcolepsy, and was reported to be effective for attention-deficit/hyperactivity disorder. However, it was reported to induce emotional instability, including mania, depression, and suicidal ideation. Such side effects may be related to changes in cognitive behavior caused by the effects of modafinil on emotional recognition. However, the effects of modafinil on the neural basis of emotional processing have not been fully verified. We used functional magnetic resonance imaging to investigate the effects of modafinil on the neural basis of auditory emotional processing., Methods: This study adopted a placebo-controlled within-subject crossover design. Data from 14 participants were analyzed. The effects of modafinil on cerebral activation and task performance during an emotional judgement task were analyzed., Results: Task accuracy decreased significantly and response time of emotional judgement was significantly delayed by modafinil, as compared with placebo. Right thalamic activation in auditory emotional processing was significantly less in the modafinil condition than in the placebo condition. In addition, reduction of right thalamic activation by modafinil was positively correlated with accuracy of emotional judgement., Conclusions: Our findings suggest that modafinil acts on the right thalamus and changes behavior and brain function associated with auditory emotional processing. These results indicate that modafinil might change emotional recognition by reducing emotional activation related to social communication.

Good's syndrome is associated with thymoma and acquired immunodeficiency. A 54-year-old man visited our hospital with a complaint of cough. Chest imaging revealed diffuse nodular shadows and anterior mediastinal mass. Hypogammaglobulinemia and a decreased B lymphocyte count were found by a laboratory evaluation. The lung nodules markedly regressed after immunoglobulin therapy. The mediastinal mass and remaining nodule were surgically resected and diagnosed as a type AB thymoma and a necrotizing epithelioid granuloma with T lymphocyte-dominant alveolitis, respectively. The overall appearances of these lesions were mostly in line with the spectrum of granulomatous-lymphocytic interstitial lung disease associated with Good's syndrome.

Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed chromatin DNA and contents of granules, such as myeloperoxidase (MPO) and neutrophil elastase (NE). NETs are usually released from neutrophils undergoing NETosis, a neutrophil-specific cell death mode characterized by the collapse and disappearance of cell membranes and nuclear envelopes. It is well known that production of reactive oxygen species (ROS) triggers NETosis and NET formation. However, details of intracellular signaling downstream of ROS production during NETosis and NET formation remains uncertain. Here, we demonstrated that the peroxidation of phospholipids plays a critical role in NETosis and NET formation induced by phorbol 12-myristate13-acetate (PMA) or immune complex in vitro and by lipopolysaccharide (LPS) in vivo . This phospholipid peroxidation is mediated by the enzymatic activity of MPO. On the other hand, NE, which was previously reported to be released from granules to cytosol by MPO during NET formation, is not required for either the peroxidation of phospholipids or the execution of NETosis, but contributes to chromatin decondensation and nuclear swelling independently of MPO-mediated oxidized phospholipids. Analysis of isolated nuclei clearly demonstrated that oxidized phospholipids and NE differently yet synergistically execute chromatin decondensation and nuclear swelling, and the subsequent release of nuclear contents. These findings indicate the dual roles of MPO in NETosis and NET formation, and provide new insight into the molecular mechanism of these phenomena., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tokuhiro, Ishikawa, Sato, Takita, Yoshikawa, Anzai, Sato, Aoyagi, Arita, Shibuya, Aratani, Shimizu, Tanaka and Yotsumoto.)

Gastrointestinal (GI) bleeding worsens the outcomes of critically ill patients in the intensive care unit (ICU). Owing to a lack of corresponding data, we aimed to investigate whether GI bleeding during cardiovascular-ICU (C-ICU) admission in acute cardiovascular (CV) disease patients is a risk factor for subsequent CV events. Totally, 492 consecutive C-ICU patients (40.9% acute coronary syndrome, 22.8% heart failure) were grouped into GI bleeding (n = 27; 12 upper GI and 15 lower GI) and non-GI bleeding (n = 465) groups. Thirty-nine patients died or developed CV events during hospitalization, and 453 were followed up from the date of C-ICU discharge to evaluate subsequent major adverse CV events. The GI bleeding group had a higher Acute Physiology and Chronic Health Evaluation II score (20.2 ± 8.2 vs. 15.1 ± 6.8, p < 0.001), higher frequency of mechanical ventilator use (29.6% vs. 13.1%, p = 0.039), and longer C-ICU admission duration (8 [5-16] days vs. 5 [3-8] days, p < 0.001) than the non-GI bleeding group. The in-hospital mortality rate did not differ between the groups. Of those who were followed-up, CV events after C-ICU discharge were identified in 34.6% and 14.3% of patients in the GI and non-GI bleeding groups, respectively, during a median follow-up period of 228 days (log rank, p < 0.001). GI bleeding was an independent risk factor for subsequent CV events (adjusted hazard ratio: 2.23, 95% confidence interval: 1.06-4.71; p = 0.035). GI bleeding during C-ICU admission was independently associated with subsequent CV events in such settings., (© 2021. Springer Japan KK, part of Springer Nature.)

Background: In the modern US cardiovascular intensive care unit (CICU), the incidence of non-cardiovascular disorders has increased and non-cardiovascular disorders are associated with an increase in morbidity and mortality. In Japan, however, data regarding the association between non-cardiovascular disorders and outcomes in the CICU are limited., Methods: This study examined 490 consecutive admissions to a closed CICU at the Nippon Medical School Hospital from January to December 2017. Characteristics, diagnoses, treatments, and outcomes of admitted patients were identified., Results: The most common primary diagnosis was acute coronary syndrome (50.4%), followed by acute heart failure (20.0%), arrhythmia (6.7%), and non-cardiovascular diseases (3.7%). The mortality rate and median length of stay (LOS) in the CICU were 4.7% and 4 (interquartile range, 2-8) days, respectively. Of all patients, 42.2% (n = 207) developed non-cardiovascular complications such as acute respiratory failure, acute kidney injury, or sepsis during CICU stay. Multivariate logistic regression analysis revealed that acute respiratory failure and sepsis were significantly associated with mortality in the CICU (odds ratio, 11.014 and 25.678, respectively; both p<0.05). The multiple linear regression analysis showed that acute kidney injury was significantly associated with LOS in the CICU (β=0.144, p = 0.002)., Conclusions: Approximately half of patients admitted to the CICU had non-cardiovascular disorders including non-cardiovascular disease and non-cardiovascular complications, which were significantly associated with mortality and LOS in the CICU., (Copyright © 2021. Published by Elsevier Ltd.)

Background: To better understand the nature of magnetic resonance imaging (MRI) findings in schwannomas, especially in the "target sign" of these findings, the histopathological investigation was performed., Methods: The MRI findings were correlated with histopathological features in 22 samples of schwannomas, which were mostly resected from the extremities. The histopathological analyses included alcian blue staining and immunohistochemical staining for S-100 protein, proliferating cell nuclear antigen (PCNA) and epithelial membrane antigen (EMA)., Results: Seven of the 22 samples of schwannomas of the extremities exhibited target signs including a peripheral zone of homogeneously high signal intensity and a central zone of heterogeneous signal intensity in T2-weighted images. Gadolinium-enhanced T1-weighted images demonstrated a central heterogeneous enhancement and a peripheral ring of homogeneously low signal intensity. Histopathologically, S-100 and PCNA were positive only in the central heterogeneous signal area. In contrast, EMA was only stained on the degenerative epi/perineurium in the peripheral zone., Conclusion: In schwannomas of the extremities showing target sign in T2-weighted images, histopathologically, the peripheral areas were suggested to be mucinous degeneration of the epineurium or perineurium, while the central areas were composed of truly neoplastic cells., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Chlamydomonas reinhardtii is a well-established microalgal model species with a shorter doubling time, which is a promising natural source for the efficient production of high-value carotenoids. In the microalgal carotenoid biosynthetic pathway, lycopene is converted either into β-carotene by lycopene β-cyclase or into α-carotene by lycopene ε-cyclase (LCYE) and lycopene β-cyclase. In this study, we overexpressed the LCYE gene in C. reinhardtii to estimate its effect on lycopene metabolism and lutein production. Chlamydomonas transformants (CrLCYE#L1, #L5, and #L6) produced significantly increased amounts of lutein per culture (up to 2.6-fold) without a decrease in cell yields. Likewise, the expression levels of LCYE gene in transformants showed a significant increase compared with that of the wild-type strain. These results suggest that LCYE overexpression enhances the conversion of lycopene to α-carotene, which in turn improves lutein productivity. Interestingly, their β-carotene productivity appeared to increase slightly rather than decrease. Considering that the inhibition of the lycopene cyclization steps often induces higher expression in genes upstream of metabolic branches, this result implies that the redirection from β-carotene to α-carotene by LCYE overexpression might also enhance upstream gene expression, thereby leading to auxiliary β-carotene production.

Objective: To assess the effect of systemic vascular resistance (SVR) on the reliability of the ClearSight system (Edwards Lifesciences, Irvine, CA) for measuring blood pressure (BP) and cardiac output (CO)., Design: Observational study., Setting: University hospital., Participants: Twenty-five patients undergoing cardiac surgery., Interventions: None., Measurements and Main Results: BP, measured using ClearSight and an arterial line, and CO, measured using ClearSight and a pulmonary artery catheter, were recorded before (T1) and two minutes after phenylephrine or ephedrine administration. Bland-Altman analysis was used to compare BP and CO measurements at T1. A polar plot was used to assess trending abilities. Patients were divided into the following three groups according to the SVR index (SVRI) at T1: low (<1,200 dyne s/cm 5 /m 2 ), normal (1,200-25,00 dyne s/cm 5 /m 2 ), and high (>2,500 dyne s/cm 5 /m 2 ). The bias in BP and CO was -4.8 ± 8.9 mmHg and 0.10 ± 0.81 L/min, respectively, which was correlated significantly with SVRI (p < 0.05). The percentage error in CO was 40.6%, which was lower in the normal SVRI group (33.3%) than the low and high groups (46.3% and 47.7%, respectively). The angular concordance rate was 96.3% and 95.4% for BP and 87.0% and 92.5% for CO after phenylephrine and ephedrine administration, respectively. There was a low tracking ability for CO changes after phenylephrine administration in the low-SVRI group (angular concordance rate 33.3%)., Conclusion: The ClearSight system showed an acceptable accuracy in measuring BP and tracking BP changes in various SVR states; however, the accuracy of CO measurement and its trending ability in various SVR states was poor., Competing Interests: Conflict of Interest Koichi Suehiro has received speaker fees from Edwards Lifesciences., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Bupropion is an antidepressant with less possibility to give rise to emotional blunting as side effect, and it also acts on improving negative self-recognition in a depressive state. Previous neuroimaging studies indicated a change in brain function by facial expression as an effect of antidepressants. As well as facial expression, vocal affective processing is essential for accurately recognizing another's feelings, but to our knowledge, no study has investigated whether bupropion affects the cerebral function of recognition of auditory affective processing. In this study, we aimed to investigate the acute effect of bupropion on cerebral response to vocal affective processing., Methods: Sixteen healthy volunteers (male = 8) participated in this study. With a randomized placebo-controlled within-subject trial, two series of fMRI scans, using either placebo or bupropion (150 mg), were examined. An auditory emotional valence judgement task was performed during fMRI scanning. The acute effects of bupropion on cerebral activation in the emotional circuit and behavioral performance during emotional processing were analyzed., Results: Compared with placebo, bupropion caused a significantly greater activation of emotional voices in the left insula and right superior temporal gyrus, whereas the amygdala was not activated. By bupropion, a significantly greater activation of the positive emotional circuit was observed at the superior temporal gyrus and middle frontal gyrus. As for behavioral performance, no significant difference was observed between placebo and bupropion., Conclusions: Our findings suggest that bupropion enhances the cerebral response to affective processing, especially positive emotional vocalizations, indicating a possible mechanism underlying the therapeutic effects for patients with depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study evaluated the efficacy of a single instillation of pirarubicin with a short retention time for preventing intravesical recurrence of low-risk non-muscle-invasive bladder cancer., Patients and Methods: We analyzed 165 patients with low-risk non-muscle-invasive bladder cancer who underwent transurethral surgery. Single instillation of pirarubicin with 15-min retention time immediate after surgery was performed in 47 (28%) patients. The other patients (118, 72%) were treated without instillation therapy. The primary endpoint was recurrence-free survival., Results: Median overall follow-up was 50 (range=6-134) months. Recurrence-free survival at 1 and 5 years was 91% and 72%, and 79% and 54% in the group treated with pirarubicin, and that treated with surgery alone, respectively (p=0.031). Cox's hazard analysis revealed lack of instillation and larger tumor size (>10 mm) as significant factors for risk of recurrence. No adverse events regarding intravesical chemotherapy were observed., Conclusion: Pirarubicin instillation with 15-min retention time can prevent intravesical recurrence of low-risk bladder tumors., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)