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Abstract In non‐small‐cell lung cancer, continuous immune‐checkpoint inhibitors (ICIs) beyond progression are often used in clinical practice. On the other hand, there is almost no data on whether the concept of continuous ICIs beyond progression can be adopted in small‐cell lung cancer (SCLC). We describe the effectiveness of continuous ICIs beyond progression in SCLC. Medical courses of SCLC patients treated with chemo‐immunotherapy were retrospectively reviewed at our hospital. The study included 36 patients with a median age of 73 years (range 46–83 years) who introduced chemo‐immunotherapy between September 2019 and December 2022. Atezolizumab and durvalumab in combination with platinum plus etoposide were administered in 24 and 12 patients, respectively. The overall response rate was 67% and the disease control rate was 86%. The median progression‐free survival and time to treatment failure (TTF) were 5.1 and 10.3 months, respectively. The median cycle of ICIs was 5 (range 1–42). The median overall survival was 13.6 months. ICIs were administered beyond progression in 14 (39%) patients: five were treated again with chemo‐immunotherapy and local ablative radiotherapy, four with local ablative radiotherapy and continuous ICIs, three with chemo‐immunotherapy, and two with continuous ICIs alone. TTF exceeded 12 months in 12 (86%) of the 14 cases, six of which were still on ICIs. Adverse events ≥grade 3 were observed in 21 (58%) patients. A notable TTF suggested a benefit of continuous ICIs beyond progression. The concept could be suitably adopted and provide a favorable prognosis in selected cases of SCLC that were previously regarded as an aggressive malignancy.

Abstract Background Multiparametric MRI (mpMRI) is widely used for the diagnosis, surveillance, and staging of prostate cancer. However, it has several limitations, including higher costs, longer examination times, and the use of gadolinium-based contrast agents. This study aimed to investigate the accuracy of preoperatively assessed index tumors (ITs) using biparametric MRI (bpMRI)/transrectal ultrasound (TRUS) fusion biopsy compared with radical prostatectomy (RP) specimens. Methods We included 113 patients diagnosed with prostate cancer through bpMRI/TRUS fusion-guided biopsies of lesions with a Prostate Imaging Reporting and Data System (PI-RADS) category ≥ 3. These patients underwent robot-assisted laparoscopic radical prostatectomy (RARP) at our institution between July 2017 and March 2023. We examined the localization of preoperative and postoperative ITs, the highest Gleason score (GS), and tumor diameter in these patients. Results The preoperative cT stage matched the postoperative pT stage in 53 cases (47%), while 31 cases (27%) were upstaged, and 29 cases (26%) were downstaged (Weighted Kappa = 0.21). The preoperative and postoperative IT localizations were consistent in 97 cases (86%). The concordance rate between Gleason groups in targeted biopsies and RP specimens was 51%, with an upgrade in 25 cases (23%) and a downgrade in 27 cases (25%) (Weighted Kappa = 0.42). The maximum diameter of the IT and the maximum cancer core length on biopsy were correlated with the RP tumor's maximum diameter (p

Background: Infants born with weights below the 10th percentile of the expected birth weight for gestational age, defined as small for gestational age (SGA), have an increased risk of neonatal mortality and prematurity-related complications. However, the relationship between SGA and postneonatal (28 days to

Abstract Background Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation. Methods Mouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice. Results Mifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues. Conclusions Mifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.

Background: Myocardial infarction-related left ventricular pseudoaneurysm (LVP), covered by the adjacent pericardial or scar tissue, is a fatal sequela of left ventricular rupture. Whereas hypertrophic cardiomyopathy (HCM) may cause left ventricular true aneurysm. Differentiating LVP from left ventricular true aneurysm is crucial because their natural histories and treatment strategies are distinct. However, the incidence and management of HCM-related LVP remain unknown. Case presentation: An 88-year-old man was admitted to our hospital with sudden-onset chest pain. Upon initial examination, vital signs were stable, and a grade 4/6 systolic murmur was noted. An electrocardiogram revealed atrial fibrillation and poor R-wave progression without ST-T changes or negative T-waves. An echocardiography showed mild left ventricular hypertrophy, mid-ventricular obstruction with a significant intraventricular pressure gradient, left ventricular outflow tract obstruction, and a small left ventricular apical outpouching. Cardiac computed tomography angiography (CCTA) assisted in the diagnosis of LVP, and an accompanying pericardial effusion suggested impending cardiac rupture. Because the patient initially refused our proposed urgent surgery, medication was initiated with continuous hemodynamic monitoring in the intensive care unit; however, the patient's condition did not improve. During a semi-urgent surgical repair of the aneurysmal wall, LVP was observed and confirmed by pathology. Myocardial tissue adjacent to the pseudoaneurysm was consistent with that of HCM. Subsequently, a final diagnosis of HCM-related LVP was made. The postoperative course was notable for transient profound hypotension. Thereafter, the patient died of non-occlusive mesenteric ischemia on day 6. Conclusions: To our knowledge, this is the first reported case of HCM-related LVP mimicking impending cardiac rupture. Our case highlights the importance of considering HCM-related LVP in patients with left ventricular outpouching and CCTA in the LVP diagnosis. In further research, data on the appropriate management of HCM-related LVP should be accumulated.

Background & Aims: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis. Methods: A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn’s disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases. Results: AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site. Conclusions: PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.

The effect of laser peening-induced compressive residual stress on the fatigue strength improvement of A7075 specimens was investigated. Rotary bending fatigue tests and residual stress distribution measurements using the sequential polishing method were conducted on untreated, shot-peened, and laser-peened specimens. The results revealed that laser peening provides a deeper compressive stress and a deeper fracture origin, resulting in higher fatigue strength. Furthermore, controlling the laser parameters could extend the depth of the compressive stress layer by approximately 5 mm, indicating the possibility of applying laser peening to thicker materials to improve the fatigue strength.

Abstract Two main issues in ethical consumption attract attention: environmental and labor issues. However, few studies have compared the conditions and effects that contribute to ethical purchasing behavior. To fill this gap, we conducted two studies targeting the Japanese food industry. In Study 1, we examined consumers who are accustomed to ethical consumption and clarified the product characteristics valued by consumers with high awareness of ethical issues. In Study 2, we conducted a randomized controlled trial to examine the effects of product concepts of environmental and labor issues on coffee purchase intentions. Study 1 confirmed that environmental and labor issues are emphasized for coffee, whereas recycling is emphasized for tea. This difference is due to the difference in production countries (coffee: developing countries, tea: Japan) and packaging materials (coffee: paper cups, tea: PET bottles). Study 2 showed that labor issues had a greater impact on purchase intention and willingness to pay than that of environmental issues owing to the adoption of producers’ photographs. This study complemented existing literature by comparing the conditions and effects of environmental and labor issues on ethical purchasing behavior. Considering the limited resources of companies and limited ability of consumers to process information, understanding predictive factors is extremely crucial.

Abstract Background Loss of expression of the gene ataxia-telangiectasia mutated (ATM), occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. In this study, we investigated the detailed molecular mechanism through which ATM expression affects the prognosis of patients with pancreatic cancer. Methods The levels of expression of ATM and phosphorylated ATM in patients with pancreatic cancer who had undergone surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ATM-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the invlovement of ATM in pancreatic cancer. Results Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ATM and phosphorylated ATM, respectively. Low expression of phosphorylated ATM substantially reduced overall and disease-free survival in patients with pancreatic cancer. In the pancreatic cancer cell lines with ATM low expression, resistance to gemcitabine was demonstrated. The RNA sequence demonstrated that ATM knockdown induced the expression of MET and NTN1. In ATM knockdown cells, it was also revealed that the protein expression levels of HIF-1α and antiapoptotic BCL-2/BAD were upregulated. Conclusions These findings demonstrate that loss of ATM expression increases tumor development, suppresses apoptosis, and reduces gemcitabine sensitivity. Additionally, loss of phosphorylated ATM is associated with a poor prognosis in patients with pancreatic cancer. Thus, phosphorylated ATM could be a possible target for pancreatic cancer treatment as well as a molecular marker to track patient prognosis.

Both spatially-averaged kinetic energy K and influx-averaged Nusselt number Nuinflux are numerically investigated concerning the three-dimensional thermal convection in a cubic cavity heated from a bottom wall and chilled from its opposite top wall. Nuinflux represents the total influx of heat normalised by an area. Assuming incompressible fluid with a Prandtl number of 7.1 (water) in a Rayleigh-number range of 1.0×104– 1.0×105, the authors solve the three-dimensional Navier-Stokes equations with the Boussinesq approximation, using the finite difference method. As a result, in the Rayleigh-number range, hysteresis effects appear accompanying various steady flow structures. Hence, there can exist multiple values of K and multiple values of Nuinflux for the same Ra due to the different steady flow structures. As Rayleigh number gradually increases or decreases, there exist four stable branches. On the branches, the authors reveal the relation between K and flow structure and the relation between Nuinflux and flow structure. Besides, a steady flow structure becomes oscillatory on one branch, as Rayleigh number gradually increases.

BackgroundCoronavirus disease (COVID-19)-associated acute pericarditis has recently received much attention owing to its high frequency associated with pericardial tamponade (PT), showing unfavorable prognosis. However, early diagnosis and treatment remain challenging in cases of non-specific signs and symptoms.Case presentationA 64-year-old man was admitted to our hospital for acute osteomyelitis of the toes and was properly treated with antimicrobial agents. Three days after admission, the patient developed mild COVID-19 without pneumonia, for which early anti-COVID-19 agents were initiated. Nevertheless, the patient developed hemorrhagic PT due to acute pericarditis 2 weeks later, which was confirmed by cardiac magnetic resonance, requiring an urgent pericardiocentesis. Although cytological analysis of the hemorrhagic pericardial fluid strongly suggested adenocarcinoma, the atypical cells were eventually proven to be mesothelial cells with reactive atypia. Furthermore, lymph nodes swelling with abnormal 2-[18F]-fluoro-2-deoxy-D-glucose accumulation on imaging were suggestive of malignancy. However, biopsy examination revealed multiple non-caseating granulomas in the lymph node, unlikely due to malignancy. Eventually, the temporal association of the preceding COVID-19 with the occurrence of subacute PT without other identifiable cause led to a final diagnosis of COVID-19-associated acute pericarditis. With anti-inflammatory and corticosteroids treatment, the patient's symptoms involving the pericardial structure and function were completely resolved along with improvements in size of the affected lymphadenopathies.ConclusionsWe encountered a unique case of COVID-19-associated acute pericarditis exhibiting hemorrhagic PT. This case underscores the residual risk of delayed pericardial involvement even in patients with mild COVID-19 who receive early treatment, and the recognition that COVID-19 may cause various cytomorphological and histological features. Additionally, the importance of considering this rare entity as a cause of hemorrhagic pericardial effusions should be highlighted.

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human induced pluripotent stem (iPS) cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM.

Abstract Subspace clustering methods which embrace a self-expressive model that represents each data point as a linear combination of other data points in the dataset provide powerful unsupervised learning techniques. However, when dealing with large datasets, representation of each data point by referring to all data points via a dictionary suffers from high computational complexity. To alleviate this issue, we introduce a parallelizable multi-subset based self-expressive model (PMS) which represents each data point by combining multiple subsets, with each consisting of only a small proportion of the samples. The adoption of PMS in subspace clustering (PMSSC) leads to computational advantages because the optimization problems decomposed over each subset are small, and can be solved efficiently in parallel. Furthermore, PMSSC is able to combine multiple self-expressive coefficient vectors obtained from subsets, which contributes to an improvement in self-expressiveness. Extensive experiments on synthetic and real-world datasets show the efficiency and effectiveness of our approach in comparison to other methods.

While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function.

Abstract We previously reported the Rho-associated coiled-coil containing protein kinase (ROCK)-mediated di-phosphorylation of myosin light chain (MLC) and actin bundle formation at the cell periphery as early events of the endothelial barrier disruption. We herein examined the role of RhoA during early events of barrier disruption. Treatment of cultured porcine aortic endothelial cells with simvastatin prevented the decrease in trans-endothelial electrical resistance, MLC di-phosphorylation and peripheral actin bundle formation seen 3 min after thrombin stimulation. Co-treatment with geranylgeranyl pyrophosphate rescued the thrombin-induced events. Thrombin increased a GTP-bound form of RhoA and phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at the ROCK site. The intracellular introduction of the inhibitory protein of RhoA inhibited the thrombin-induced di-phosphorylation of MLC. However, knockdown of either one of RhoA, RhoB or RhoC failed to inhibit thrombin-induced MLC di-phosphorylation. The findings suggest that Rho proteins play a critical role during early events of thrombin-induced barrier disruption.

Introduction Brain and spinal cord metastases from testicular cancer occur rarely, and metastases with seminoma are extremely rare. Case presentation A 42‐year‐old man who was diagnosed with seminoma and multiple metastases underwent first‐line and salvage chemotherapy. Brain metastases were noted; consequently, surgery, third‐line chemotherapy, and whole‐brain irradiation were performed. Subsequently, paralysis developed, and spinal cord metastases were detected. He received fourth‐line chemotherapy but died. Pathological autopsy revealed metastases only in the spinal cord. The cause of death was considered respiratory failure due to cervical spinal cord involvement from spinal metastases. Conclusion Brain and spinal cord metastases from seminoma are rare. Thus, similar future cases should be treated appropriately.

Objective: We evaluated the impact of the duration between the biopsy and surgery on the biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP). Methods: We retrospectively evaluated 302 patients who underwent RARP in our institution from April 2010 to December 2017. Patients were categorized into 2 groups, an interval between biopsy and surgery of 180 days or less (Group A) and longer than 180 days (Group B). Factors retrospectively analyzed for the BCR for the interval between the biopsy and RARP included patient's characteristics, intraoperative and postoperative results. The Kaplan–Meier method and Cox proportional hazards regression model were used to evaluate the predictors of BCR. Results: The median follow-up was 42 months, with 24 patients developing BCR at a mean of 13.5 months after RARP. There was no difference in the rate of BCR in Group A and Group B. Multivariate analysis showed that BMI (

Purpose: Congenital protein C deficiency leads to a prothrombotic state that may result in potentially sight- and life-threatening thromboembolic attacks. In this report, we report two cases of infants with compound heterozygous protein C deficiency who underwent lensectomies and vitrectomies for the treatment of traction retinal detachments (TRDs). Observations: One two-month-old and one three-month-old female neonates with leukocoria and purpura fulminans received a diagnosis of protein C deficiency and were referred to ophthalmology. In both cases, the right eye had a total retinal detachment that was considered inoperable, while the left eye had a partial TRD for which surgery was performed. Of the two operated eyes, one resulted in a total retinal detachment, while the other eye has remained stable with no retinal detachment progression three months after surgery. Conclusions: Compound heterozygous congenital protein C deficiency may lead to the rapid development of severe TRDs with poor visual and anatomical prognoses. Early diagnosis and surgery for the treatment of partial TRDs with low disease activity may help prevent progression towards total retinal detachments in these infants.

Abstract The human being dynamically and highly controls the head–trunk with redundant mechanical structures to maintain a stable upright standing position that is inherently unstable. The posture control strategies are also affected by the differences in the conditions of sensory inputs. However, it is unclear how the head–trunk segmental properties are altered to respond to situations that require appropriate changes in standing posture control strategies. We used a data-driven approach to conduct a multipoint measurement of head–trunk sway control in a quiet standing position with differences in the conditions of sensory inputs. Healthy young subjects with 22 accelerometers attached to their backs were evaluated for head–trunk vibration during quiet standing under two conditions: one with open eyes and one with closed eyes. The synchronization of the acceleration and the instantaneous phase was then calculated. The results showed that the synchronization of acceleration and instantaneous phase varied depending on the visual condition, and there were some continuous coherent patterns in each condition. Findings were that the structural redundancy of the head–trunk, which is multi-segmental and has a high mass ratio in the whole body, must be adjusted adaptively according to the conditions to stabilize upright standing in human-specific bipeds.

Abstract In this paper, the problem of clustering data points that lie near or on a union of independent low‐dimensional subspaces is addressed. To this end, the popular spectral clustering‐based algorithms usually follow a two‐stage strategy that initially builds an affinity matrix and then applies spectral clustering. However, an inappropriate affinity matrix that does not sufficiently connect data points lying on the same subspace will easily lead to the issue of over‐segmentation. To alleviate this issue, building the affinity matrix based on subspace hypotheses generated by an iterative sampling operation according to the Random Cluster Model under the framework of energy minimisation is proposed. Specifically, each hypothesis is generated from a large number of data points by sampling a component in a K‐nearest neighbour graph. Extensive experiments on synthetic data and real‐world datasets show that the proposed method can improve the connectivity of the affinity matrix and provide competitive results against state‐of‐the‐art methods.

Summary: Salivary gland cancers (SGCs) are heterogeneous tumors, and precision oncology represents a promising therapeutic approach; however, its impact on SGCs remains obscure. This study aimed to establish a translational model for testing molecular-targeted therapies by combining patient-derived organoids and genomic analyses of SGCs. We enrolled 29 patients, including 24 with SGCs and 5 with benign tumors. Resected tumors were subjected to organoid and monolayer cultures, as well as whole-exome sequencing. Organoid and monolayer cultures of SGCs were successfully established in 70.8% and 62.5% of cases, respectively. Organoids retained most histopathological and genetic profiles of their original tumors. In contrast, 40% of the monolayer-cultured cells did not harbor somatic mutations of their original tumors. The efficacy of molecular-targeted drugs tested on organoids depended on their oncogenic features. Organoids recapitulated the primary tumors and were useful for testing genotype-oriented molecular targeted therapy, which is valuable for precision medicine in patients with SGCs.

We investigate production of primordial black holes from first-order electroweak phase transition in the framework of the nearly aligned Higgs effective field theory, in which non-decoupling quantum effects are properly described. Since the mass of such primordial black holes is evaluated to be about 10−5 of the solar mass, current and future microlensing observations such as Subaru HSC, OGLE, PRIME and Roman Space Telescope may be able to probe the electroweak phase transition. We study parameter regions where primordial black holes can be produced by the first-order electroweak phase transition, and explore their detectability at these observations. Complementarity of primordial black hole observations, gravitational wave observations and collider experiments is also discussed for testing the nature of the electroweak phase transition.

Background: The Japanese apricot (Prunus mume Sieb. et Zucc.) is popularly known as ume in Japan, and the heated concentrate of ume juice, called ume extract, is commonly consumed as food. A neutralized, diluted ume extract (dUE) reported as MK615 solution exhibits hepatoprotective properties. However, the active substance contributing to its hepatoprotective efficacies has not been explored. We aimed to identify and characterize the active substance underlying the hepatoprotective potential of ume extract. Our results are described in two parts and whereas the objective of this part (Part 1) was to identify the active substance, in Part 2, we elucidated its chemical structure. Methods: The components of ume extract were fractionated stepwise, and their hepatoprotective activities were evaluated using a D-galactosamine-induced liver injury rat model. The fractionated components were characterized qualitatively and quantitatively using high-performance liquid chromatography (HPLC) analysis and were dosed to rats, equalizing the content of the main components. Finally, a purified active substance was isolated by crystallization, and its hepatoprotective activity was verified. The molecular mass and formula of the active substance were elucidated by high-resolution mass spectrometry. Results: The dUE, but not the components from unheated ume juice concentrate, showed hepatoprotective activity. Focusing on the components peculiar to the ume extract, a fraction rich in a water-soluble substance, tentatively named unknown 1 (UK1), was found to have hepatoprotective activity. It was observed that both the UK1-rich fraction and dUE suppressed the hepatic expression of nitric oxide synthase 2 (Nos2). Furthermore, the purified UK1 (≥93.88% purity, containing 6.11% hydrate water) was demonstrated to have hepatoprotective activity comparable to that of dUE. UK1 has the molecular formula C10H11NO9, with a molecular weight of 289, corresponding to a novel compound. Conclusions: Our findings revealed that UK1, which is likely to be a previously unknown, bioactive component in ume extract, is the major hepatoprotective substance in dUE.

Background: This report represents the second part (Part 2) of a two-part report on investigating a novel hepatoprotective substance in ume extract. The heated juice concentrate of Japanese apricot (Ume, Prunus mume Sieb. et Zucc.), popularly called ume extract, is known for its health benefits. In Part 1 of this study (presented in this issue together), we reported the identification of the active substance underlying the hepatoprotective potential of ume extract for the first time. The substance, tentatively referred to unknown 1 (UK1), was shown to have the molecular formula C10H11NO9 with a molecular weight of 289. Here (in Part 2), we aimed to decipher the structure of UK1. Moreover, we show that UK1 is formed by heating the components of ume juice. Methods: The purified UK1 (≥93.88% purity, containing 6.11% hydrate water) was subjected to nuclear magnetic resonance (NMR) spectroscopic analysis. The structure of UK1 was elucidated by one-dimension (1D)-NMR (1H, 13C, and DEPT135) and 2D-NMR (COSY, HSQC, and HMBC) experiments. Further, the artificial synthesis of UK1 was attempted by heating aqueous solutions containing citric acid and L-asparagine (L-Asn) or L-aspartic acid (L-Asp). The synthetic experiments were performed using a series of solutions of varying concentrations (1-fold, 5-fold, 10-fold, and 15-fold) of citric acid and L-Asn (molar ratio 5: 1). The molar ratio of citric acid and L-Asn (5: 1) was specified to mimic that in ume juice. Results: The chemical structure of UK1 was determined as 2-[3-(carboxymethyl)-3-hydroxy-2,5-dioxopyrrolidin-1-yl]butanedioic acid. More simply, UK1 was identified as an imide in which citric acid was bound to Asp. UK1 could be synthesized by heating (110 °C for 4 h) a solution containing citric acid and L-Asn, or citric acid and L-Asp. The yield of UK1 was dependent on the concentrations of citric acid and L-Asn. Conclusions: The findings of this study further validate the conclusions made in Part 1 that UK1 is a novel hepatoprotective substance in ume extract. Based on the structure, UK1 is referred to as “ASP citrimide.” This study demonstrates that ASP citrimide is formed by the association of citric acid and L-Asn (or L-Asp) during the heat concentration of ume juice.

Abstract To realize first-order electroweak phase transition, it is necessary to generate a barrier in the thermal Higgs potential, which is usually triggered by scalar degree of freedom. We instead investigate phase transition patterns in pure fermion extensions of the standard model, and find that additional fermions with mass hierarchy and mixing could develop such a barrier and realize a strongly first-order phase transition in such models. In the Higgs potential with polynomial parametrization, the barrier can be generated in the following two patterns by fermionic reduction effects: (I) positive quadratic term, negative cubic term and positive quartic term or (II) positive quadratic term, negative quartic term and positive higher dimensional term, such as dimensional 6 operator.

IntroductionIndividuals with neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and specific learning disorders (SLD) have various types of sensory characteristics.MethodsThis study investigated sensory issues in individuals with neurodevelopmental disorders using a web-based questionnaire for qualitative and quantitative analysis, categorized the contents of their three most distressful sensory issues, and evaluated their order of priority.ResultsAuditory problems were reported as the most distressing sensory issue among the participants. In addition to auditory problems, individuals with ASD frequently reported more tactile problems, and individuals with SLD reported more visual problems. Among the individual sensory issues, in addition to aversion to sudden, strong, or specific stimuli, some participants reported confusions regarding multiple stimuli presenting concurrently. Additionally, the sensory issues related to foods (i.e., taste) was relatively more common in the minor group.ConclusionThese results suggest that the diversity of sensory issues experienced should be carefully considered when aiding persons with neurodevelopmental disorders.

Ductal ectasia with metaplasia and focal epithelial proliferation in the oral cavity does not correspond to any existing salivary gland lesion. A 72-year-old man presented with a mass in the buccal mucosa, which was excised and initially diagnosed as a cystadenoma. An upper lip mass on the right side, which developed later, was also excised. The lesions were histologically similar, and since they were multifocal and in non-contiguous and independent sites with multiple dilated cystic structures that did not destroy the lobar architecture, the final diagnosis was confirmed as ductal ectasia with metaplasia and focal epithelial proliferation. This condition may mimic various neoplastic lesions. Keywords: Salivary ducts, salivary gland disease, salivary gland neoplasm, mucocele, metaplasia.

Arabinogalactan-proteins (AGPs) are mysterious extracellular glycoproteins in plants. Although AGPs are highly conserved, their molecular functions remain obscure. The physiological importance of AGPs has been extensively demonstrated with β-Yariv reagent, which specifically binds to AGPs and upon introduction into cells, causes various deleterious effects including growth inhibition and programmed cell death. However, structural features of AGPs that determine their functions have not been identified with β-Yariv reagent. It is known that AGPs are decorated with large type II arabinogalactans (AGs), which are necessary for their functions. Type II AGs consist of a β-1,3-galactan main chain and β-1,6-galactan side chains with auxiliary sugar residues such as L-arabinose and 4-O-methyl-glucuronic acid. While most side chains are short, long side chains such as β-1,6-galactohexaose (β-1,6-Gal6) also exist in type II AGs. To gain insight into the structures important for AGP functions, in vivo structural modification of β-1,6-galactan side chains was performed in Arabidopsis. We generated transgenic Arabidopsis plants expressing a fungal endo-β-1,6-galactanase, Tv6GAL, that degrades long side chains specifically under the control of dexamethasone (Dex). Two of 6 transgenic lines obtained showed more than 40 times activity of endo-β-1,6-galactanase when treated with Dex. Structural analysis indicated that long side chains such as β-1,6-Gal5 and β-1,6-Gal6 were significantly reduced compared to wild-type plants. Tv6GAL induction caused retarded growth of seedlings, which had a reduced amount of cellulose in cell walls. These results suggest that long β-1,6-galactan side chains are necessary for normal cellulose synthesis and/or deposition as their defect affects cell growth in plants.

Primordial black holes can be produced by density fluctuations generated from delayed vacuum decays of first-order phase transition. The primordial black holes generated at the electroweak phase transition have masses of about 10−5 solar mass. Such primordial black holes in the mass range can be tested by current and future microlensing observations, such as Subaru HSC, OGLE, PRIME and Roman telescope. Therefore, we may be able to explore new physics models with strongly first-order electroweak phase transition via primordial black holes. We examine this possibility by using models with first-order electroweak phase transition in the standard model effective field theory with dimension 6 and 8 operators. We find that depending on parameters of the phase transition a sufficient number of primordial black holes can be produced to be observed by above mentioned experiments. Our results would suggest that primordial black holes can be used as a new probe of models with strongly first-order electroweak phase transition, which has complementarity with measurements of the triple Higgs boson coupling at future collider experiments and observations of gravitational waves at future space-based interferometers.

Abstract Background Pancreatic serous cystic neoplasm (SCN) is an uncommon exocrine neoplasm, which is believed to be a benign entity. However, some of these neoplasms may occasionally attain metastatic ability. Von Hippel–Lindau disease (VHL) manifests a dominantly inherited systemic syndrome accompanied by several benign or malignant tumors, including cystic tumors, in various organs. We describe here a long-term survival case who underwent surgical resection for metachronous liver metastases of pancreatic SCN associated with VHL disease. Case presentation A 35-year-old woman with VHL underwent total pancreatectomy and right nephrectomy for pancreatic SCN and renal cell carcinoma, respectively. At the 4th year follow-up examination after the resection, contrast-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed arterially hyper-enhanced neoplastic lesions in the segment VI and VIII of the liver. Partial resections of the liver were performed 53 months after the initial surgery. At the 6th month follow-up examination from the second surgery, one and two tumors located in the liver segment III, and VIII, respectively, were detected by contrast-enhanced CT and Gd-EOB-DTPA-enhanced MRI. Anterior segmentectomy and partial resection of the segment III were performed 66 months after the initial surgery and 13 months after the second, respectively. The tumors were pathologically diagnosed as liver metastases of pancreatic SCN synonymous with serous cystadenocarcinoma. She remains disease-free without recurrence 6.5 years after the last operation. Conclusions This is the first report of a case of metastatic SCN associated with VHL. Surgical resection might confer a favorable prognosis in patients of pancreatic SCN with liver metastases.

In this study, we examined the difference in expenditure patterns between foreign resident visitors and foreign tourist visitors at a nature-based destination. We also examined the effects of sociodemographic profiles, travel characteristics, and perceived importance on expenditure patterns during off-peak and peak seasons. Generally, the results revealed low average daily expenditure compared with other nature-based destinations. Whereas no differences were observed during the off-peak season, the sociodemographic characteristics, travel characteristics, perceived importance, and expenditure pattern differed between foreign resident and foreign tourist visitors during the peak season. These results suggest that patterns of expenditure and perceived importance of foreign visitors are influenced by the seasonality of a nature-based destination. On the other hand, foreign resident visitors and foreign tourist visitors differ in their characteristics, perceived importance of destination attributes, and expenditure patterns, particularly during the peak season. Longer periods of residence in the host country might result in foreign resident visitors becoming local visitors. Our findings contribute to practical knowledge of the segmentation of foreign visitors at nature-based destinations.

Keiji Kawatani et al. developed a panel of Down syndrome (DS) isogenic astrocytes derived from iPSCs to observe the consequence of DS on astrocyte precursor proliferation, differentiation, and gene expression. Their results suggest a dose-dependent effect of DYRK1A and PIGP on DS-derived astrocyte precursor proliferation, and represent a valuable resource and cellular model for future DS research.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis involving small-to-medium-sized vessels characterized by asthma, vasculitis, and peripheral eosinophilia. EGPA-associated eosinophilic myocarditis (EM) occurs rarely, yet can be fatal if left untreated. Moreover, the accurate diagnosis of EGPA-associated EM without vasculitis is exceptionally difficult because of the overlapping features with EM of other causes. We report a case of probable EGPA with subclinical neurological involvement that presented with acute EM. The constellation of peripheral eosinophilia, left ventricular dysfunction, and normal epicardial coronary arteries raised suspicion of acute EM, which was confirmed by cardiac magnetic resonance (CMR) investigation and endomyocardial biopsy (EMB). Prompt systemic administration of corticosteroids completely restored and normalized myocardial structure and function. Although the patient's history suggested the presumed hypersensitivity myocarditis, EMB revealed EM without vasculitis, not hypersensitivity, leading to a tentative diagnosis of idiopathic hypereosinophilic syndrome. Interestingly, the characteristic findings of vasculitis on CMR imaging strongly suggested EGPA-associated EM. Although the patient had no clinical neurological manifestations, a nerve conduction study confirmed mononeuritis multiplex, leading to the final diagnosis of probable EGPA. Therefore, this case highlights the diagnostic challenge associated with EGPA and the diagnostic synergy of CMR and EMB for an exploratory diagnosis of EGPA-associated EM.

In recent years, the importance of hydraulic power generation has further increased because of the movement toward decarbonization and the need to control floods in Japan. For this reason, demand for dam discharge valves has been increasing. However, it is necessary to improve the reliability of valve systems due to their complicated two-phase flows. Therefore, in this study we attempt to apply a link-sleeve valve (LSV), which is usually used for public water supply, as a dam discharge valve. In general, to prevent cavitation erosion, vibration, and noise, air is injected into the downstream pipe of a dam discharge system. Since LSVs are designed to operate in a pressured water supply system, however, the characteristics of air‒water two-phase flows in LSVs have not been investigated. To clarify the characteristics of air entrainment by water jets in an LSV, experiments were conducted using a small-scale LSV model. The results showed that this entrainment is analogous to that which occurs with a jet pump or an ejector at a high water flow rate, while air suction behavior shows complicated characteristics at low water flow rates. This means that air entrainment occurs due to the water jet and that air reverse flow occurs due to the positive pressure gradient in the pipe at a high water flow rate. The present findings could be useful for improving the potential use of LSVs as a lower-maintenance alternative to dedicated dam discharge valves.

Abstract Background Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. Methods We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. Results Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. Conclusions Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3–73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit–risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.

Abstract Background In this study, we investigated the effect of preoperative prostate morphology, especially intravesical prostatic protrusion (IPP), on continence after robot-assisted radical prostatectomy (RARP). Methods Retrospective analysis was applied to patients who underwent RARP between October 2010 and July 2014. The following parameters were assessed in all patients: age, body mass index (BMI), prostate-specific antigen, magnetic resonance imaging and pressure-flow studies findings. The impact of preoperative and intraoperative factors on postoperative urinary incontinence (UI) was assessed using multivariate logistic regression analysis. To evaluate the effects of IPP, the patients were divided into groups according to the IPP length: Group 1,

Abstract Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS.

Abstract In this paper we address the problem of geometric multi-model fitting using a few weakly annotated data points, which has been little studied so far. In weak annotating (WA), most manual annotations are supposed to be correct yet inevitably mixed with incorrect ones. SuchWA data can naturally arise through interaction in various tasks. For example, in the case of homography estimation, one can easily annotate points on the same plane or object with a single label by observing the image. Motivated by this, we propose a novel method to make full use of WA data to boost multi-model fitting performance. Specifically, a graph for model proposal sampling is first constructed using the WA data, given the prior that WA data annotated with the same weak label has a high probability of belonging to the same model. By incorporating this prior knowledge into the calculation of edge probabilities, vertices (i.e., data points) lying on or near the latent model are likely to be associated and further form a subset or cluster for effective proposal generation. Having generated proposals, a-expansion is used for labeling, and our method in return updates the proposals. This procedure works in an iterative way. Extensive experiments validate our method and show that it produces noticeably better results than state-of-the-art techniques in most cases.

Abstract Background Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown. Methods We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data. Results A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50–89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32–31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15–6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03–4.68; p = 0.0402) were significantly associated with non-response to treatment. Conclusion In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.

Hot springs are a major tourism resource in nature-based tourism, and the hot springs market is one of the biggest sectors in wellness tourism markets. In the present study, we examine factors contributing to tourism demand for major hot spring resorts in Japan using ordinary least squares regression models and generalized linear mixed models, and compare the estimation results. The results show that significant factors in most of our models are quality of accommodations and the degree of dependence on inbound demand. Furthermore, the number of non-Japanese languages supported on websites of hot spring resorts has a significant impact on inbound demand. Since the results of the present study cover more than 80 hot spring sites, the results highlight common important factors for hot spring resorts. Such widely applicable factors have been missing in previous studies, and the present study fills this research gap.