Search

Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung diseases, bronchoalveolar lavage (BAL) fluid appearance is diagnostic. This study examines lymphocyte subsets in BAL fluid and peripheral blood of 56 patients with diffuse ILD, excluding idiopathic pulmonary fibrosis (IPF), who underwent BAL for diagnostic purposes. Patients were classified into CEP, SAR, CHP, CTD, and IIP groups, and clinical data, BAL cell analysis, and peripheral blood mononuclear cell analysis were compared. Eosinophils and type 3 innate lymphocytes (ILC3s) were significantly increased in the BAL fluid of the CEP group. Receiver operating characteristic curve analysis identified eosinophils ≥ 8% in BAL cells and ILC3s ≥ 0.0176% in the BAL lymphocyte fraction as thresholds distinguishing CEP. SAR patients exhibited significantly elevated CD4/CD8 ratios in the BAL fluid, with a ratio of 3.95 or higher and type 1 innate lymphoid cell frequency ≥ 0.254% as differentiation markers. High Th1 cell frequency (≥17.4%) in BAL lymphocytes in IIP, elevated serum KL-6 (≥2081 U/mL) and SP-D (≥261 ng/mL) in CHP, and increased BAL neutrophils (≥2.0%) or a low CD4/CD8 ratio (≤1.2) in CTD serve as distinguishing markers for each ILD. Excluding CEP and SAR, CD4 + T cell frequencies, including Th1, Th17, and Treg cells in peripheral blood, may differentiate IIP, CHP, and CTD.

Background: Neprilysin (NEP) is a metalloprotease that has become a therapeutic target for the treatment of heart failure and hypertension. However, the significance of NEP in chronic liver diseases has rarely been investigated. In this study, we investigated the serum NEP levels in patients with chronic liver disease and their relationship with clinical parameters., Methods and Results: Thirty-seven patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR) after antiviral treatment and 73 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled. Serum neprilysin levels were measured using an enzyme-linked immunosorbent assay. The median NEP levels were 2.2 ng/mL in CHC and 4.1 ng/mL in MASLD, with the latter being significantly higher. Notably, in patients with MASLD, a significant correlation was observed between NEP and gamma-glutamyltransferase (GGT) levels at baseline. In contrast, there was no significant correlation between NEP levels and progression of liver fibrosis in either group. In the MASLD group, obesity and lifestyle diseases were significantly more prevalent, and the patients exhibited significantly higher NEP levels. In patients with CHC, NEP levels significantly decreased after SVR. NEP mRNA expression in liver tissues was significantly downregulated following SVR. Furthermore, a significant correlation was observed between the degree of NEP and GGT improvement., Conclusions: Elevated NEP levels were observed in both CHC and MASLD groups. Considering the association between NEP levels and obesity, lifestyle diseases, and GGT levels, this suggests that oxidative stress may be involved in the elevation of NEP levels in patients with CHC and MASLD., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethics approval: This study was approved by the Ethics Committee of Hamamatsu University Hospital (approval number: 23–355). Informed consent to participate: Written informed consent was obtained by all participating patients. Consent to publish: N/A., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC., Materials and Methods: A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS)., Results: A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9 < 1011 U/mL were significant and independent predictive factors of the initial treatment response. Meanwhile, NLR < 3.10 and combination chemotherapy were independently associated with longer OS. Moreover, OS was significantly prolonged in patients with NLR < 3.10, regardless of whether combination chemotherapy or monotherapy. Patients with NLR < 3.10 at baseline had a significantly higher conversion rate to third-line chemotherapy and a longer duration of total chemotherapy., Conclusions: This study suggests that NLR may be a useful marker for predicting the initial treatment response to first-line chemotherapy and the prognosis for patients with advanced PDAC.

Artificial urinary sphincters (AUS) are an effective treatment for male stress urinary incontinence (SUI). However, infection, erosion, mechanical failure, atrophy, and balloon deterioration cause device malfunction in approximately half of patients by 10 years after implantation. Many patients desire to regain urinary continence and require revision surgery (RS), including device removal and simultaneous or delayed implantation. Patients for whom RS is considered should be examined physically and by interview for signs of infection. Urethral erosion should be assessed using cystoscopy. If there is infection or erosion, all devices should be removed first, and a new device should be implanted several months later. During the RS, after strong adhesion around the urethra, transcorporal cuff implantation is a safe choice. Device removal and simultaneous implantation can be performed in the absence of infection or erosion. If a long time has passed since device implantation, the entire device should be replaced due to device aging and deterioration; however, if the time is short, only the defective component need be replaced. Intraoperative assessment of urethral health is necessary for device removal and implantation. If the urethra is healthy, a new cuff can be placed in the same position as the old cuff was removed from; however, if the urethra is unhealthy, the cuff can be implanted in a more proximal/distal position, or a transcorporal cuff implant may be chosen. This article reviews the literature on diagnostic and treatment strategies for recurrent SUI in male patients with AUS and proposes a flowchart for AUS revision., (© 2024 The Japanese Urological Association.)

Background/objectives: The detection of pancreatic cancer (PC) often depends on indirect indicators such as parenchyma atrophy (PPA), main pancreatic duct stenosis, and low echoic areas, particularly when no mass is evident on imaging. While pathological evaluation is the gold standard for differentiating malignant from benign conditions, endoscopic ultrasound-guided fine-needle aspiration/biopsy is not always feasible in such cases. Serial pancreatic juice aspiration cytologic examination (SPACE) via endoscopic nasopancreatic drainage (NPD) has emerged as an alternative diagnostic method, though its accuracy remains underevaluated. This study aimed to evaluate the diagnostic performance of SPACE and explore strategies to enhance its accuracy in diagnosing PC., Methods: This multicenter, retrospective study analyzed patients who underwent SPACE between January 2015 and September 2023. The inclusion criteria focused on cases lacking a clear pancreatic mass but exhibiting indirect signs suggestive of PC. Diagnostic accuracy was determined using surgical pathology or a minimum follow-up period of 12 months as the reference standard., Results: Among 164 patients, 85 (51.8 %) were diagnosed with malignancy. The sensitivity and specificity of SPACE were 74.1 % and 87.3 %, respectively, with a area under the receiver operating characteristic curve (ROC-AUC) of 0.807 (95%CI: 0.748-0.867). Incorporating patient age, CEA and PPA with SPACE results further improved diagnostic performance, yielding a ROC-AUC of 0.828 (95%CI: 0.76-0.897, p = 0.013)., Conclusions: Combining SPACE with clinical and imaging findings significantly enhances diagnostic accuracy in suspected PC cases where conventional imaging fails to detect tumors. This integrated approach has the potential to enhance clinical outcomes by facilitating more accurate patient management., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: Omalizumab, the anti-IgE monoclonal antibody used to treat severe asthma, reduces asthma exacerbations, hospitalizations, and corticosteroid use. Although allergic asthma is a therapeutic target of omalizumab, omalizumab is not effective in all patients with severe allergic asthma and is not always available for long-term use. We retrospectively investigated factors related to long-term (≥2 years) use of omalizumab for severe asthma., Patients and Methods: Of the 116 patients treated with omalizumab for severe asthma at our hospital between 2009 and 2017, 82 were included in this retrospective analysis. Thirty-four were excluded because of adverse events, financial difficulties, or hospital transfers. The number of asthma exacerbations, unscheduled visits, corticosteroid doses, asthma control test scores, pulmonary function test results, and fractional exhaled nitric oxide levels were evaluated., Results: The median age of the study population was 58 years, with 66% female and 26% taking regular oral corticosteroids. After 2 years of treatment, 52 responders were identified using the global evaluation of treatment effectiveness (GETE) score. Improvements in asthma control test scores, airflow limitation, exacerbations, and oral corticosteroid use were observed in the responders. Multivariate analysis revealed that a peripheral blood eosinophil count of ≥200 or a perennial antigen-specific IgE antibody positivity of ≥2 predicted a response at the 2-year mark. However, Kaplan-Meier analysis demonstrated that neither high eosinophil counts nor perennial antigen-specific IgE positivity influenced the prolongation of treatment beyond 2 years, and responders at 2 years underwent omalizumab treatment for a significantly longer period than non-responders (HR = 9.89, p < 0.001), with GETE at 2 years being the only predictor of long-term omalizumab use., Conclusion: In this retrospective study the GETE after 2 years of omalizumab therapy emerged as the most meaningful predictor of the long-term effectiveness of omalizumab treatment in patients with severe asthma, highlighting the benefits of prolonged therapy in certain populations. These findings may guide future therapeutic strategies for severe asthma., Competing Interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi and grants from AstraZeneca, Daikin, Kao Corporation, Sanofi, and TOSOH outside the submitted work. KT reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. Furthermore, KT has a patent (P6840330) on the method of detecting cells, managed by Juntendo University in Japan. He is also part of the Board of Directors of The Japan Lung Cancer Society and The Japanese Respiratory Society. All other authors declare that they have no conflicts of interest in this work., (© 2024 Goto et al.)

Cholesterol crystal embolism (CCE) is a rare but serious complication of atherosclerotic plaque rupture, often occurring after endovascular interventions. We report the case of a 73-year-old man who developed CCE following mechanical thrombectomy (MT) for an acute ischemic stroke (AIS) due to left internal carotid artery occlusion. The patient, with a history of hypertension and hyperlipidemia, underwent successful MT with complete recanalization. However, four weeks after the procedure, he presented with blue toe syndrome and acute kidney injury. Histopathological analysis of a skin biopsy confirmed the diagnosis of CCE. The patient's renal function partially improved with corticosteroid therapy. Clinicians should maintain a high level of suspicion for CCE in patients who develop renal dysfunction or peripheral ischemia after MT, particularly in those with significant atherosclerotic risk factors. Early detection and timely intervention are critical for improving outcomes. Further research is warranted to clarify the incidence and optimal management of CCE in the context of MT for AIS., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pyae Kyaw et al.)

Background: Although the impact of aerobic exercise (AE) and resistance training (RT) on peritoneal dialysis (PD) patients is well established, the impact of exercise programs on residual kidney function (RKF) has not been elucidated., Methods: Patients were randomly assigned to either the exercise ( n  = 25) or control groups ( n  = 30). Patients in the exercise group performed AE three times a week and RT twice a week at home for 24 weeks. The control group did not receive any specific intervention. The primary outcome was RKF, assessed by residual glomerular filtration rate (rGFR). Secondary outcomes included urinary protein levels, distance covered in the incremental shuttle walking test (ISWT), and glycated hemoglobin (HbA1c) percentages., Results: Linear mixed-effects models showed no significant changes in mean rGFR between the exercise and control groups at 12 weeks (-0.40; 95% confidence interval (CI): -2.17, 1.36; p  = 0.65) and at 24 weeks (0.65; 95% CI: -1.15, 2.45; p  = 0.48). There was a trend toward improvement in mean urinary protein level and ISWT results, and a significant decrease in mean HbA1c percentage at 24 weeks in the exercise group (-1.07, 95% CI: -2.29, 0.15, p  = 0.09; 37.7, 95% CI: -10.1, 85.5, p  = 0.12; -0.57, 95% CI: -0.97, -0.18, p  = 0.005, respectively) compared to the control group., Conclusion: The 24-week home-based exercise program did not demonstrate beneficial effects on RKF in incident PD patients. Nonetheless, it may have an impact on reducing urinary protein levels and HbA1c percentages., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We describe a case of a 47-year-old male patient with initially unresectable intrahepatic cholangiocarcinoma of the right liver lobe with tumor thrombi extending from the right bile duct to the common and left bile ducts. Conventional chemotherapy with gemcitabine and cisplatin for 19 months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated. After 6 months of pemigatinib therapy, significant shrinking of the tumor and disappearance of the tumor thrombi in the common and left bile duct were observed. Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7 months., (© 2024. The Author(s).)

Background & Aims: Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence., Methods: The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins., Results: CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs., Conclusions: Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Numerous health concerns, primarily kidney injury, have been reported with the use of Beni-kōji CholesteHelp, a functional food containing red yeast rice. Here, we describe 2 cases of kidney injury caused by beni-kōji. The first case had normal kidney function before consuming the product. After several months of use, she developed hypertension. After 6 months of supplement consumption, her estimated glomerular filtration rate (eGFR) dropped to 22.5 mL/min/1.73 m 2 . A spot urine sample showed a urinary protein-to-creatinine ratio of 2.03 g/g, leading to the diagnosis of Fanconi syndrome. Kidney biopsy showed tubular degeneration. Thirty-five days after discontinuing the supplement, proteinuria resolved and the eGFR returned to baseline level. The second case, who had diabetes and normal kidney function, experienced severe kidney injury (eGFR, 3.5 mL/min/1.73 m 2 ) after 4 months of Beni-kōji CholesteHelp use. He required hemodialysis for >2 weeks but recovered kidney function after the product was discontinued. Kidney biopsy showed tubular injury similar to the first case and glomeruli changes consistent with diabetic nephropathy. These cases indicate that beni-kōji use is associated with tubular toxicity. Further studies are required to identify the precise etiology and mechanism of kidney injury., (© 2024 The Authors.)

Background: Oscillometry devices (also termed forced oscillation technique) devices such as MasterScreen-IOS® (Jaeger, Hochberg, Germany) and MostGraph-01® (Chest, Tokyo, Japan) are useful for obtaining physiological assessments in patients with obstructive lung diseases, including asthma. However, as oscillometry measurements have not been fully compared between MasterScreen-IOS® and MostGraph-01® in patients with asthma, it is unknown whether there are differences in the measurements between the devices. This study aimed to determine whether there is any difference in oscillometry measurements obtained using the two devices in patients with asthma., Methods: Oscillometry measurements obtained using MasterScreen-IOS® and MostGraph-01® were retrospectively evaluated in 95 patients with asthma at Juntendo University Hospital between October 2009 and November 2009., Results: There was a strong positive correlation in the measurements between the two devices. However, the values of R5, R20, ALX and Fres were lower when measured with MostGraph-01® than with MasterScreen-IOS®, and vice versa for the values of X5. The results were used in correction equations to convert oscillometry parameters measured using MasterScreen-IOS® to those measured using MostGraph-01®., Conclusions: To our knowledge, this is the first report to compare MostGraph-01® and MasterScreen-IOS® devices using practical clinical data obtained in patients with asthma. The values obtained by both devices can be interpreted in a similar way, although there is slight variation. The conversion equations produced in this study may assist to compare the oscillometry measurements obtained by each of the two devices., Competing Interests: The authors have read the journal’s policy and have the following competing interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, Sanofi, and TOSOH outside the submitted work. KT reports grants from Asahi Kasei Pharma Corporation, Bayer Yakuhin, Chugai, Daiichi Sankyo, Eli Lilly, Kyorin, Kyowa Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, Nippon Shinyaku, Nipro, Novartis, Ono, Pfizer, Sanofi, Shionogi, Taiho, Takeda, Teijin, and Tsumura; and personal fees from Abbott Japan, AstraZeneca, Bristol-Myers, Chugai, Eli Lilly, Janssen, Kyorin, Meiji Seika, Merck, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific, and Viatris outside the submitted work. KT has a patent (P6840330) on the method of detecting cells managed by Juntendo University in Japan. HK is one of the holders of the patent related to MostGraph-01®. The royalties are paid to Tohoku University, not to individuals. Lecture fees were paid to HK from Chest Co. Ltd. All other authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no additional patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Harada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Summary: An 89-year-old woman presented with a 6-year history of occasional episodes of impaired consciousness that were relieved by ingestion of a snack. Three months before presenting to our hospital, she had been hospitalized in a local hospital with subdural hematoma caused by a head contusion, where previously unrecognized hypoglycemia was discovered. Fasting plasma glucose concentration was 37 mg/dL, with a relatively high serum level of insulin (34.9 µU/mL). Computed tomography showed a 14 mm hyperenhancing tumor in the tail of the pancreas and she was referred to our hospital for further investigation. A prolonged fasting test revealed the plasma glucose concentration reduced to 43 mg/dL (2.4 mmol/L) at 8 h after the last meal. Serum insulin, proinsulin, and C-peptide concentrations were 21.1 µU/mL, 16.9 pmol/L, and 2.72 ng/mL, respectively. Subsequent intravenous administration of 1 mg of glucagon increased the plasma glucose concentration to 76 mg/dL (4.2 mmol/L). Moreover, the insulin-to-C-peptide molar ratio was 0.14. These data indicated the presence of insulinoma. Interestingly, serum anti-insulin antibodies were elevated (21.1 U/mL), although she had no history of taking exogenous insulin injection, alpha lipoic acid, or sulfhydryl group-containing agents. Human leukocyte antigen (HLA) typing revealed HLA-DRB1*0407 and HLA-DRB1*1405 alleles. Treatment with diazoxide prevented hypoglycemia, but was discontinued due to weight gain and leg edema. Elevated serum anti-insulin antibodies persisted almost 1 year after the diagnosis of insulinoma. We present a rare case of insulinoma concomitant with serum anti-insulin antibodies., Learning Points: Insulinoma presenting with concomitant anti-insulin antibodies appears rare. Insulin/C-peptide molar ratio and serum insulin concentration are useful for differentiating insulinoma and autoimmune syndrome. Flash glucose monitoring systems appear suitable for evaluating treatment outcomes.

The present study examined whether male resveratrol intake affected mitochondrial DNA copy number (mt-cn) and telomere length (TL) in blastocysts fathered by young and aged male mice. C57BL/6N male mice supplied with water or water containing 0.1 mM resveratrol were used for embryo production at 14-23 and 48-58 weeks of age. Two-cell-stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 3 days until the blastocyst stage. Mt-cn and TL levels were measured by real-time polymerase chain reaction. Resveratrol intake did not affect body weight or water consumption. Resveratrol intake increased the expression levels of SIRT1 in the liver, the antioxidative ability of serum, and extended TL in the heart, whereas there was no significant difference in mt-cn in the heart or TL in sperm. The rate of blastocyst development was significantly lower in aged male mice than in younger mice, and resveratrol intake increased the total number of blastocysts derived from both young and aged males. Resveratrol intake did not affect mt-cn or TL in blastomeres of blastocyst-stage embryos derived from young mice, but significantly increased both mt-cn and TL in blastomeres of blastocysts derived from aged fathers. In conclusion, resveratrol intake increased mt-cn and TL levels in blastocysts derived from aged male mice.

Telomere length (TL) and mitochondrial DNA copy number (mt-cn) are associated with embryonic development. Here, we investigated the correlation between TL and mt-cn in bovine embryos to determine whether TL regulates mt-cn. TL and mt-cn were closely correlated in embryos derived from six bulls. Treatment of embryos with a telomerase inhibitor (TMPyP) and siTERT shortened the TL and reduced mt-cn in blastocysts. RNA-sequencing of blastocysts developed with TMPyP revealed differentially expressed genes associated with transforming growth factor-β1 signaling and inflammation. In conclusion, TL regulates mt-cn in embryos., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: To suppress the incidence of end-stage kidney disease, we need to identify chronic kidney disease (CKD) patients with a high risk of rapid decline in the estimated glomerular filtration rate (eGFR). However, the current status of eGFR slope and its associated factors in the Japanese population have not been fully elucidated., Methods: Among examinees aged 40-70 years in the 2014 Specific Health Checkup conducted by the National Health Insurance in Kobe, Japan (n = 61,985), we prospectively observed 7291 examinees with CKD stage G3 from 2014 to 2018., Results: Until 2018, 4221 examinees continued to undergo annual SHCs for a total of five checkups per subject and had available records of all necessary data. The median eGFR change was -0.22 ml/min/1.73 m 2 /year. Only 9.2% of those subjects showed rapid eGFR decline (faster than -2.0 ml/min/1.73 m 2 /year). Logistic regression analysis identified diabetes, smoking habits, high urinary protein levels, older age, high systolic blood pressure, and low serum low-density lipoprotein cholesterol levels as independent predictors for rapid eGFR decline. Hemoglobin A1c levels did not contribute to the eGFR slope in CKD stage-G3 subjects with diabetes and proteinuria., Conclusion: Most Japanese CKD stage-G3 subjects had a very slow decline in eGFR. A small proportion of CKD individuals who have a predictive factor of rapid eGFR decline should receive considerable attention from a nephrologist., (© 2024. The Author(s).)

Background: Bronchial thermoplasty (BT) improves clinical outcomes and quality of life for patients with severe asthma and has shown sustained reductions in airway narrowing and air trapping in previous CT studies. However, there is a lack of a comprehensive analysis, including CT evaluation, of clinical outcomes in Japanese patients who have undergone BT for severe asthma. This study aimed to evaluate the impact of BT in Japanese asthma patients, with a focus on the CT metric "WA at Pi10" to assess airway disease., Methods: Twelve patients with severe persistent asthma who underwent BT were assessed using ACQ6, AQLQ, pulmonary function tests, FeNO measurement, blood sampling, and chest CT before BT and one year after the third procedure for the upper lobes., Results: The median age of the patient was 62.0 years, 7/12 (58.3%) were male, 4/12 (33.3%) used regular oral corticosteroids, and 8/12 (66.7%) received biologics. Median FEV 1 % was 73.6%, and median peripheral eosinophil count was 163.8/μL. After one year of BT, ACQ6 scores improved from 2.4 to 0.8 points ( p = 0.007), and AQLQ scores improved from 4.3 to 5.8 points ( p < 0.001). Significant improvements were also observed in asthma exacerbations, unscheduled visits due to exacerbations, FeNO, and √WA at Pi10 ( p < 0.05). The baseline mucus score on the CT findings was negatively correlated with FEV 1 (r = -0.688, p = 0.013) and with the maximum mid-expiratory flow rate (r = -0.631, p = 0.028), and positively correlated with the peripheral blood eosinophil count (r = -0.719, p = 0.008). Changes in √WA at Pi10 after one year were positively correlated with changes in the mucus score (r = 0.742, p = 0.007)., Conclusion: This study has limitations, including its single-arm observational design and the small sample size. However, BT led to a symptomatic improvement in patients with severe asthma. The validated "√WA at Pi10" metric on CT effectively evaluated the therapeutic response in Japanese asthma patients after BT., Competing Interests: NH reports personal fees from AstraZeneca, GlaxoSmithKline, Kyorin, Novartis, and Sanofi; and grants from AstraZeneca, Daikin, and TOSOH, outside of the submitted work. KTa reports grants and personal fees from Chugai Pharmaceutical Co., Ltd.; and grants from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers K.K., Eli Lilly Japan K.K., KYORIN Pharmaceutical Co., Ltd., MSD K.K., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., TEIJIN PHARMA LIMITED, and TAIHO PHARMACEUTICAL CO., LTD.; and personal fees from AstraZeneca, outside of the submitted work. All other authors declare that they have no conflicts of interest., (© 2024 Abe et al.)

In this study, we examined the effects of paternal aging on the mitochondrial DNA copy number (mt-cn), telomere length (TL), and gene expression in mouse embryos. The effects of vitrification on the mt-cn and TL of the embryos derived from young and aged male parents (YF and AF, respectively) were examined. C57BL/6N male mice were used for embryo production at 13-23 and 50-55 weeks of age. Two-cell stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 24 h until the 8-cell stage, followed by embryo vitrification. Fresh and vitrified-warmed embryos were incubated for 2 days until the blastocyst stage, and mt-cn and TL were investigated. The cell-free mitochondrial DNA copy number (cf-mt-cn) in the spent culture medium (SCM) of the embryos was then investigated. RNA sequencing of blastocysts revealed that metabolic pathways, including oxidative phosphorylation and mTOR pathways, were enriched in differentially expressed genes. The mt-cn and TL of AF-derived blastocysts were lower and shorter, respectively, than those of YF-derived blastocysts. Paternal aging did not affect the blastocyst rate after vitrification. Vitrification of the 8-cell stage embryos did not affect the mt-cn of the blastocysts. However, it increased the cf-mt-cn (cell-free mt-cn) in the SCM of both YF- and AF-derived embryos. Vitrification did not affect the TL of either YF- or AF-derived embryos. Thus, paternal aging affected the mt-cn and TL of the embryos, but vitrification did not affect these parameters in either age groups.

Intradialytic hypotension (IDH) is a common complication during hemodialysis that increases cardiovascular morbidity and mortality. Aortic stenosis (AS) is a cause of IDH. Transcatheter aortic valve replacement (TAVR) has become an established treatment for patients with severe AS. However, whether TAVR reduce the frequency of IDH has not been investigated. This study aims to verify the efficacy of TAVR for reduction of the frequency of IDH. Consecutive hemodialysis patients who underwent TAVR at Sendai Kosei Hospital from February 2021 to November 2021 with available records 1 month before and 3 months after TAVR were included in the study. IDH was defined as a decrease in systolic blood pressure by 20 mmHg or a decrease in the mean blood pressure by 10 mmHg associated with hypotensive symptoms or requiring intervention. Patients with ≥ 3 episodes of IDH in ten hemodialysis sessions comprised the IDH group. Overall, 18/41 (43.9%) patients were classified into the IDH group. In ten hemodialysis sessions, IDH events were observed 2.1, 4.3, and 0.4 times in the overall cohort, IDH group, and non-IDH group, respectively. After TAVR, the incidence of IDH decreased from 43.2 to 10.3% (p < 0.0001) and IDH improved significantly in 15 patients in the IDH group. The result suggested that severe AS was the major cause of IDH in this cohort, and TAVR may be an effective treatment option for reduction of the frequency of IDH in patients with severe AS., (© 2024. The Author(s).)

A new nondestructive inspection method, the magnetic hammer test (MHT), which uses a compact and highly sensitive tunnel magnetoresistance (TMR) sensor, is proposed. This method complements the magnetic flux leakage method and eliminates the issues of the hammer test. It can therefore detect weak magnetic fields generated by the natural vibration of a pipe with a high signal-to-noise ratio. In this study, several steel pipes with different wall thicknesses were measured using a TMR sensor to demonstrate the superiority of MHT. The results of the measurement show that wall thickness can be evaluated with the accuracy of several tens of microns from the change in the natural vibration frequency of the specimen pipe. The pipes were also inspected underwater using a waterproofed TMR sensor, which demonstrated an accuracy of less than 100 μm. The validity of these results was by simulating the shielding of magnetic fields and vibration of the pipes with the finite element method (FEM) analysis. The proposed noncontact, fast, and accurate method for thickness testing of long-distance pipes will contribute to unmanned, manpower-saving nondestructive testing (NDT) in the future.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. The current standard treatment for advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. However, the response rate to chemotherapy is only 50%, owing to cisplatin resistance, and there is a need for novel therapies. Because the invasiveness of bladder cancer greatly influences patient prognosis, a mechanistic analysis of the invasive function can lead to therapeutic targets. Sialidases, which remove sialic acid residues from the nonreducing ends of sugar chains and catalyze the initial reaction in the degradation of sugar chains, are predicted to be involved in cell invasion and motility. However, the involvement of sialidases in bladder cancer, especially their relationship with the invasive ability, remains unclear. Here, using patient tissues and multiple bladder cancer cell lines, we show that the sialidase NEU3 is highly expressed in bladder cancer. Analysis of NEU3's function using its siRNA-mediated knockdown revealed that NEU3 contributes to bladder cancer invasiveness. Mechanistic analysis showed that NEU3 activates ERK and PI3K signaling. Our results show that NEU3 is involved in the malignancy of bladder cancer, and its suppression may lead to novel treatments for bladder cancer.

Background: Mepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment., Methods: Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent., Results: The frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice., Conclusions: This study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the epithelial-mesenchymal transition (EMT) and asthma; however, the role of mitogen-activated protein kinase kinase kinase 19 (MAP3K19) remains uncertain. Therefore, we investigated the involvement of MAP3K19 in in vitro EMT and ovalbumin (OVA)-induced asthma murine models. The involvement of MAP3K19 in the EMT and the production of cytokines and chemokines were analyzed using a cultured bronchial epithelial cell line, BEAS-2B, in which MAP3K19 was knocked down using small interfering RNA. We also evaluated the involvement of MAP3K19 in the OVA-induced asthma murine model using Map3k19-deficient (MAP3K19 -/- ) mice. Transforming growth factor beta 1 (TGF-β1) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) induced the MAP3K19 messenger RNA (mRNA) expression in the BEAS-2B cells. The knockdown of MAP3K19 enhanced the reduction in E-cadherin mRNA and the production of regulated upon activation normal T cell express sequence (RANTES) via stimulation with TWEAK alone or with the combination of TGF-β1 and TWEAK. Furthermore, the expression of MAP3K19 mRNA was upregulated in both the lungs and tracheas of the mice in the OVA-induced asthma murine model. The MAP3K19 -/- mice exhibited worsened eosinophilic inflammation and an increased production of RANTES in the airway epithelium compared with the wild-type mice. These findings indicate that MAP3K19 suppressed the TWEAK-stimulated airway epithelial response, including adhesion factor attenuation and RANTES production, and suppressed allergic airway inflammation in an asthma mouse model, suggesting that MAP3K19 regulates allergic airway inflammation in patients with asthma.

Introduction: Gastric outlet obstruction caused by upper tract urothelial carcinoma is rare., Case Presentation: A 78-year-old man presented to the hospital with nausea and vomiting. No hematuria was observed. Computed tomography revealed a tumor in the right renal pelvis and duodenal stenosis. Gastrojejunostomy was performed to treat the symptoms of the gastric outlet obstruction so that the patient could resume oral intake and outpatient chemotherapy. Chemotherapy was unsuccessful, and the patient died 9 months after the gastrojejunostomy. Histological assessment of an autopsy specimen revealed plasmacytoid urothelial carcinoma with direct infiltration of the duodenal wall, which caused the stenosis., Conclusion: Autopsy revealed a right renal pelvis cancer causing gastric outlet obstruction. Early gastrojejunostomy enabled oral intake and outpatient visits., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Background & Aims: Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs., Methods: Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression., Results: Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes., Conclusions: Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Summary: Unawareness of postprandial hypoglycemia for 5 years was identified in a 66-year-old man at a local clinic. The patient was referred to our hospital because of this first awareness of hypoglycemia (i.e. lightheadedness and impaired consciousness) developing after lunch. In a 75 g oral glucose tolerance test, the plasma glucose concentration was decreased to 32 mg/dL (1.8 mmol/L) at 150 min with relatively high concentrations of insulin (8.1 μU/mL), proinsulin (70.3 pmol/L), and C-peptide (4.63 ng/mL). In a prolonged fasting test, the plasma glucose concentration was decreased to 43 mg/dL (2.4 mmol/L) at 66 h with an insulin concentration of 1.4 μU/mL and a C-peptide concentration of 0.49 ng/mL. Computed tomography showed an 18 mm hyperenhancing tumor in the uncinate process of the pancreas. A selective arterial calcium stimulation test showed an elevated serum insulin concentration in the superior mesenteric artery. The patient was then diagnosed with insulinoma and received pancreaticoduodenectomy. Continuous glucose monitoring (CGM) using the Dexcom G6 system showed unawareness of hypoglycemia mainly during the daytime before surgery. When the sensor glucose value was reduced to 55 mg/dL (3.1 mmol/L), the Dexcom G6 system emitted an urgent low glucose alarm to the patient four times for 10 days. Two months after surgery, an overall increase in daily blood glucose concentrations and resolution of hypoglycemia were shown by CGM. We report a case of insulinoma with unawareness of postprandial hypoglycemia in the patient. The Dexcom G6 system was helpful for assessing preoperative hypoglycemia and for evaluating outcomes of treatment by surgery., Learning Points: Insulinoma occasionally leads to postprandial hypoglycemia. The CGM system is useful for revealing the presence of unnoticed hypoglycemia and for evaluating treatment outcomes after surgical resection. The Dexcom G6 system has an urgent low glucose alarm, making it particularly suitable for patients who are unaware of hypoglycemia.

Vitrification is an important assisted reproductive technology, although it induces mitochondrial dysfunction in embryos. Herein, we aimed to investigate whether age-associated accumulation of advanced glycation end-products (AGEs) in oocytes impairs the recovery of embryos from cryopreservation-induced mitochondrial dysfunction/damage. Mouse eight-cell stage embryos developed in vitro were vitrified and warmed and incubated up to the blastocyst stage. AGE levels in oocytes were higher in both aged mice and AGE accumulation mouse models (MGO-mice) than those in young and control mice. In addition, the level of SIRT1 upregulation was lower for embryos of aged and MGO-mice than that for embryos of young and control mice. The highest mitochondrial DNA (mtDNA) content was detected in blastocysts derived from vitrified embryos of aged and MGO-mice. The spent culture medium of blastocysts derived from both aged and MGO-mice contained higher mtDNA content than that of the blastocysts derived from young and control mice. EX527 increased mtDNA content in the spent culture medium of vitrified embryos derived from young mice. In addition, p62 aggregate levels were higher in vitrified embryos of control mice than those in vitrified embryos of MGO-mice. The SIRT1 activator, resveratrol, increased p62 aggregation levels in vitrified embryos derived from young and aged mice, whereas vitrification did not affect p62 aggregation levels in embryos from aged mice. Therefore, age-associated AGE accumulation induces decreased responsive SIRT1 upregulation following vitrified-warmed treatment and impairs mitochondrial quality control activity in vitrified embryos., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Metastatic renal cell carcinoma (RCC) is not sufficiently responsive to anticancer drugs, and thus, developing new drugs for advanced RCC remains vital. We previously reported that the treatment of globotriaosylceramide (Gb3)-expressing cells with catfish ( Silurus asotus ) egg lectin (SAL) increased the intracellular uptake of propidium iodide (PI) and sunitinib (SU). Herein, we investigated whether SAL pretreatment affects the intracellular uptake and cytotoxic effects of molecular-targeted drugs in RCC cells. We analyzed Gb3 expression in TOS1, TOS3, TOS3LN, and ACHN human RCC cells. Surface Gb3 expression was higher in TOS1 and TOS3 cells than in TOS3LN and ACHN cells. In the PI uptake assay, 41.5% of TOS1 cells and 21.1% of TOS3 cells treated with SAL were positive for PI. TOS1 cell viability decreased to 70% after treatment with 25 µM SU alone and to 48% after pretreatment with SAL (50 µg/mL). Time-series measurements of the intracellular fluorescence of SU revealed significantly enhanced SU uptake in SAL-treated TOS1 cells compared to control cells. SAL treatment did not increase PI uptake in normal renal cells. Our findings suggest that adequate cytotoxic activity may be achieved even when SU is administered at a sufficiently low dose not to cause side effects in combination with SAL.

Background: Owing to the lack of definite diagnostic modalities, it is challenging to distinguish malignant cases of cholangiocarcinoma (CCA), which often causes biliary tract obstruction, from benign ones. Here, we investigated a novel lipid biomarker of CCA in bile-derived small extracellular vesicles (sEVs) and developed a simple detection method for clinical application., Methods: Bile samples from seven patients with malignant diseases (hilar CCA = 4, distal CCA = 3) and eight patients with benign diseases (gallstones = 6, primary sclerosing cholangitis = 1, autoimmune pancreatitis = 1) were collected through a nasal biliary drainage tube. sEVs were isolated via serial ultracentrifugation and characterized using nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting (with CD9, CD63, CD81, and TSG101). Comprehensive lipidomic analysis was performed using liquid chromatography-tandem mass spectrometry. Using a measurement kit, we further confirmed whether lipid concentrations could be used as a potential CCA marker., Results: Lipidomic analysis of bile sEVs in the two groups identified 209 significantly increased lipid species in the malignant group. When focusing on lipid class, phosphatidylcholine (PC) level was 4.98-fold higher in the malignant group than in the benign group (P = 0.037). The receiver operating characteristic (ROC) curve showed a sensitivity of 71.4%, a specificity of 100%, and an area under the curve (AUC) of 0.857 (95% confidence interval [CI]:0.643-1.000). Using a PC assay kit, the ROC curve showed a cutoff value of 16.1 μg/mL, a sensitivity of 71.4%, a specificity of 100%, and an AUC of 0.839 (95% CI: 0.620-1.000)., Conclusion: PC level in sEVs from human bile is a potential diagnostic marker for CCA and can be assessed by a commercially available assay kit., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate (DS) and heparan sulfate (HS) throughout the body, which causes several somatic and central nervous symptoms. Although enzyme-replacement therapy (ERT) is currently available to treat MPS I, it does not alleviate central nervous disorders, as it cannot penetrate the blood-brain barrier. Here we evaluate the brain delivery, efficacy, and safety of JR-171, a fusion protein comprising humanized anti-human transferrin receptor antibody Fab and IDUA, using monkeys and MPS I mice. Intravenously administered JR-171 was distributed in major organs, including the brain, and reduced DS and HS concentrations in the central nervous system and peripheral tissues. JR-171 exerted similar effects on peripheral disorders similar to conventional ERT and further reversed brain pathology in MPS I mice. We found that JR-171 improved spatial learning ability, which was seen to deteriorate in the vehicle-treated mice. Further, no safety concerns were noted in repeat-dose toxicity studies in monkeys. This study provides nonclinical evidence that JR-171 might potentially prevent and even improve disease conditions in patients with neuronopathic MPS I without serious safety concerns., Competing Interests: S.K., Y.K., E.Y., A.Y., H.M., A. Imakiire, N.T., S.T., A.M., J.I., A. Inoue, R.Y., K.M., T.H., K.T., and H.S. are employees and/or stockholders of JCR Pharmaceuticals Co., Ltd., (© 2023 The Author(s).)

Improving crop yield potential through an enhanced response to rising atmospheric CO 2 levels is an effective strategy for sustainable crop production in the face of climate change. Large-sized panicles (containing many spikelets per panicle) have been a recent ideal plant architecture (IPA) for high-yield rice breeding. However, few breeding programs have proposed an IPA under the projected climate change. Here, we demonstrate through the cloning of the rice (Oryza sativa) quantitative trait locus for MORE PANICLES 3 (MP3) that the improvement in panicle number increases grain yield at elevated atmospheric CO 2 levels. MP3 is a natural allele of OsTB1/FC1, previously reported as a negative regulator of tiller bud outgrowth. The temperate japonica allele advanced the developmental process in axillary buds, moderately promoted tillering, and increased the panicle number without negative effects on the panicle size or culm thickness in a high-yielding indica cultivar with large-sized panicles. The MP3 allele, containing three exonic polymorphisms, was observed in most accessions in the temperate japonica subgroups but was rarely observed in the indica subgroup. No selective sweep at MP3 in either the temperate japonica or indica subgroups suggested that MP3 has not been involved and utilized in artificial selection during domestication or breeding. A free-air CO 2 enrichment experiment revealed a clear increase of grain yield associated with the temperate japonica allele at elevated atmospheric CO 2 levels. Our findings show that the moderately increased panicle number combined with large-sized panicles using MP3 could be a novel IPA and contribute to an increase in rice production under climate change with rising atmospheric CO 2 levels., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

A 61-year-old Japanese woman presented with epigastric pain and jaundice. Imaging showed the presence of primary distal cholangiocarcinoma (DCC). A subtotal stomach-preserving pancreaticoduodenectomy was performed, followed by chemotherapy using S-1. However, second-line chemotherapy with gemcitabine and cis-diamminedichloroplatinum was required for the treatment of hepatic metastasis of the DCC 3 months following the surgery. Nine months after the surgery, the serum calcium and parathyroid hormone-related peptide concentrations were high, at 16.5 mg/dL and 28.7 pmol/L, respectively, which suggested the presence of humoral hypercalcemia of malignancy (HHM) secondary to the DCC. Moreover, marked leukocytosis, with a white blood cell count of 40,400/μL, was also present. The patient died 11 months after the diagnosis of DCC. Because hypercalcemia of malignancy is associated with a poor prognosis, and HHM and leukocytosis caused by DCC are very rare, we have presented the present case in detail and provide a review of the existing literature.

A 59-year-old woman presented to our hospital with liver dysfunction. Imaging revealed multiple lesions in the liver. The patient was diagnosed with peliosis hepatis using percutaneous and laparoscopic biopsies. However, her condition worsened with the appearance of new, obvious mass-forming lesions. Therefore, she underwent a second percutaneous biopsy of these lesions and was diagnosed with hepatic angiosarcoma. Her condition progressed rapidly, and she died two weeks after the diagnosis. Diagnosis of hepatic angiosarcoma in the early stages is difficult. It should be noted that hepatic angiosarcoma may be associated with the development of peliosis hepatis.

Objectives: To establish a novel quantitative method that automatically excludes the red bone marrow and accurately quantifies the tumor volume on whole-body magnetic resonance imaging using updated imaging software. To also evaluate the association between the quantified tumor volume and the prognosis of patients with metastatic prostate cancer., Methods: This prospective analysis included patients diagnosed with metastatic hormone-sensitive or metastatic castration-resistant prostate cancer between 2017 and 2022. We developed an imaging software (Attractive BD&#95;Score) that analyzed whole-body diffusion-weighted and in-phase and opposed-phase T1-weighted images to automatically exclude the red bone marrow. The quantified tumor volume was compared with that quantified by traditional whole-body diffusion-weighted imaging without red bone marrow exclusion. Prostate-specific antigen progression-free survival, time-to-pain progression, and overall survival were evaluated to assess the prognostic value of the quantified tumor volume., Results: The quantified tumor volume was significantly smaller than that quantified by the traditional method in metastatic hormone-sensitive (median: 81.0 ml vs. 149.4 ml) and metastatic castration-resistant (median: 29.4 ml vs. 63.5 ml) prostate cancer. A highly quantified tumor volume was associated with prostate-specific antigen progression-free survival (p = 0.030), time-to-pain progression (p = 0.003), and overall survival (p = 0.005) in patients with metastatic hormone-sensitive prostate cancer and with poor prostate-specific antigen progression-free survival (p = 0.001) and time-to-pain progression (p = 0.005) in patients with metastatic castration-resistant prostate cancer., Conclusions: Our imaging method could accurately quantify the tumor volume in patients with metastatic prostate cancer. The quantified tumor volume can be clinically applied as a new prognostic biomarker for metastatic prostate cancer., (© 2022 The Japanese Urological Association.)

Competing Interests: The authors declare no conflict of interest.

Benralizumab treatment reduces exacerbations and improves symptom control and quality of life in patients with severe eosinophilic asthma. However, the determination of biomarkers that predict therapeutic effectiveness is required for precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical effectiveness after 1 year of benralizumab treatment in severe asthma in a real-world setting. Thirty-six patients with severe asthma were treated with benralizumab for 1 year. Lymphocyte subsets in peripheral blood samples were analyzed using flow cytometry. Treatment effectiveness was determined based on the ACT score, forced expiratory volume in 1 s (FEV1), and the number of exacerbations. Benralizumab provided symptomatic improvement in severe asthma. Benralizumab significantly decreased peripheral blood eosinophil and basophil counts and the frequencies of regulatory T cells (Tregs), and increased the frequencies of Th2 cells. To our knowledge, this is the first study to show benralizumab treatment increasing circulating Th2 cells and decreasing circulating Tregs. Finally, the ROC curve to discriminate patients who achieved clinical effectiveness of benralizumab treatment revealed that the frequency of circulating Th17 cells and FeNO levels might be used as parameters for predicting the real-world response of benralizumab treatment in patients with severe asthma., Competing Interests: N.H. reports personal fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi and grants from AstraZeneca, Daikin, Kao, Kyorin, SRL Medisearch, and TOSOH, outside the submitted work. K.I. reports grants from Shino-test Co., Ltd. during the conduct of the study and grants from AstraZeneca, outside the submitted work. In addition, K.I. has patents licensed in Japan and the United States managed by Shino-test Co., Ltd., Saga University, and Kurume University. S.M. reports personal fees from Amgen, Asahi Kasei, Astellas, Biogen, Bristol-Myers, Chugai, Eisai, and Ono and grants from Bristol-Myers and Pfizer, outside the submitted work. In addition, S.M. has a patent (JP 6730708) on a method for evaluating selective IL-4 production by Juntendo University in Japan. K.T. reports grants and personal fees from Boehringer Ingelheim, Chugai, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, Taiho, and Takeda; grants from Asahi Kasei, Astellas, Bayer Yakuhin, Daiichi Sankyo, Kyowa Kirin, Nipro pharma, Nipro Kayaku, Nippon Shinyaku, Sanofi, Shionogi, Teijin, and Tsumura; personal fees from Abbott, AstraZeneca, Bristol-Myers, Eisai, Janssen, Meiji Seika, Merck, MSD, Sumitomo Dainippon, Thermo Fisher Scientific, and Viatris outside the submitted work. In addition, K.T. has a patent (P6840330) on a method for detecting cells managed by Juntendo University in Japan. The rest of the authors have no competing interests to declare.

Rifaximin, a non-absorbable antibiotic, has been demonstrated to be effective against hepatic encephalopathy (HE); however, its efficacy on liver functional reserve remains unknown. Here, we evaluated the efficacy of rifaximin on the liver functional reserve and serological inflammation-based markers in patients with cirrhosis. A retrospective study was conducted on patients who received rifaximin for more than three months at our hospital between November 2016 and October 2021. The recurrence and grade of HE, serological ammonia levels, Child-Pugh score (CPS), and serological inflammation-based markers such as the neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), and CRP to albumin ratio (CAR) were evaluated. The correlations between serological inflammation-based markers and liver functional reserve were evaluated. HE grades, serum ammonia levels, and inflammation-based markers significantly improved at three months compared with those at baseline. Patients with improved albumin levels showed significantly higher CRP improvement rates at both 3 and 12 months. Patients with an improvement in CAR at 3 months demonstrated a significant improvement in CPS at 12 months. Rifaximin improved the liver functional reserve in patients with cirrhosis. Improvements in inflammation-based markers, particularly CRP and albumin, may be involved in this process.

No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing hepatitis B virus (HBV) reactivation has yet been reported. This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis., (© 2023 Wiley Periodicals LLC.)

This is the first case confirmed the association between PI development and nintedanib by the reproducibility of PI development. In patients taking a combination treatment with corticosteroid and nintedanib, clinicians should be careful regarding the development of PI although the patient improved only after discontinuation of nintedanib treatment., Competing Interests: Motoyasu Kato received research funding, speaker horneria, and consultation fee from Boehringer Ingelheim. Kazuhisa Takahashi received research funding from Boehringer Ingelheim., (© 2023 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

Introduction: Various methods for vascular access (VA) management have been studied. We investigated the usefulness of a new, simple, and quantitative VA management method using the Pocket LDF® laser blood flowmeter (hereinafter "LDF") that noninvasively measures peripheral circulation flow., Methods: Peripheral circulation flow was measured in 82 patients (43 men) on maintenance hemodialysis with an arteriovenous fistula (AVF). The shunt symmetry index (SSI) was calculated as peripheral circulation flow in the AVF limb divided by that in the non-AVF limb. SSI was used for microcirculation evaluation and also compared by AVF site. Patients undergoing vascular access interventional therapy (VAIVT) underwent ultrasound evaluation (Doppler ultrasonography) of the AVF and SSI measurement before and after VAIVT. SSI was compared between those who did and did not require VAIVT, and the cutoff value for SSI was determined by receiver operating characteristic curve (ROC) analysis., Results: As many as 86% of the patients who were measured peripheral circulation flow had SSI &lt;1.0, which indicates that AVF reduced peripheral circulation flow. All patients who underwent VAIVT showed a decrease in SSI to &lt;1.0 after VAIVT, probably due to improvement of stenosis. SSI differed significantly between patients who did and did not require VAIVT (1.20 ± 0.49 vs. 0.65 ± 0.33, p &lt; 0.001), which indicates that SSI is affected by the presence of stenosis in the proximal vein of the VA anastomosis. In patients with SSI ≥1.0, stenosis of the proximal vein of the AVF caused stasis of blood flow, resulting in increased peripheral blood flow. AVF site seems to have no impact on peripheral circulation flow. The SSI cutoff value for the screening of proximal vein stenosis was 1.06 (sensitivity: 0.69, specificity: 0.93, area under the curve: 0.81)., Conclusion: Based on the ROC analysis, we recommend considering AVF ultrasound for SSI &gt;1.06. Our results suggest the usefulness of the described VA management method using the LDF., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Immunoaffinity mass spectrometry as an approach for diagnostic biomarker assays combines the advantages of antibody selectivity with the multiplexing and analytical performance of mass spectrometry. A method has been developed to detect and quantify three protein biomarkers for a diabetic kidney disease prognostic assay, PromarkerD. The methodology reflects an immunoaffinity approach compatible with higher throughput and robust clinical application. After preparation and purification of antibody-bead conjugates for the three target proteins, an immunoaffinity capture step provides a solution for reduction, alkylation, and digestion on-bead. Targeted mass spectrometry provides a quantitative measure of each biomarker in a rapid 8 min run using a microflow LCMS workflow., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

We report two cases of pazopanib (PAZ)-induced liver injury in patients with metastatic renal cell carcinoma. The first patient was a 70-year-old female who was diagnosed with right renal cell carcinoma and showed tumor embolism in the inferior vena cava. PAZ was started but discontinued after about one month due to a grade four liver injury. The second patient was a 60-year-old male who was diagnosed with left renal cell carcinoma and suspected multiple lung metastases. PAZ was started following a laparoscopic left radical nephrectomy but was stopped after about a month due to a grade three liver injury. We analyzed the plasma PAZ concentrations for treatment evaluation. High plasma PAZ concentrations were observed in both patients after PAZ treatment began. Severe liver injury after PAZ administration may be associated with high plasma PAZ concentrations; hence, we should reduce PAZ dosage early. We also recommend monitoring plasma PAZ concentrations, if possible, so that physicians can either reduce the dosage or discontinue treatment to avoid further liver damage., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ouchi et al.)

To facilitate nerve preservation during robot-assisted radical prostatectomy (RP), hydrodissection (HD) using an injection catheter was performed. HD during RP is a nerve-sparing technique in which an epinephrine solution is injected into the lateral prostatic fascia to separate it from the prostatic capsule. Although the beneficial effects of HD on postoperative sexual function have been reported, HD has rarely been used in robot-assisted RP. The primary reason may be the potential benefits of robotic surgery, such as less bleeding, magnified surgical view, and fine movement of instruments; another possible reason is the difficulty of handling sharp needles in a narrow intra-abdominal surgical space of robot-assisted RP. For safe fluid injection, we performed HD using an injection catheter - commonly used for endoscopic upper gastrointestinal hemostasis - during robot-assisted RP. The required time to accomplish HD and the safety of the procedure were examined in 15 HD of 11 patients. Approximately 2 minutes (median, 118 seconds; interquartile range, 106-174 seconds) were needed for HD using the injection catheter. All patients had no complications, such as injuries to the intestine, vessels, or other organs. Postoperative bleeding did not occur in any patients. HD with an injection catheter enables surgeons to perform simple and safe nerve preservation during robot-assisted RP., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background & Aims: Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs., Methods: Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins., Results: CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK., Conclusions: These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis., Competing Interests: Declaration of Competing Interest The authors disclose no conflicts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial., Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum ( n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort ( n = 60) and evaluated in patients treated with lenvatinib., Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without., Conclusion: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab., Competing Interests: Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Janssen Pharmaceutical K.K.; grants and endowments from MSD, Pharmaceutical K. K., and Chugai Pharmaceutical Co. Ltd.; and research grants from Gilead Sciences Inc. and AbbVie GK. Dr. Goki Suda received research grants from Merck & Co., Gilead Sciences Inc., and Bristol Myers Squibb. The remaining of the authors has no conflicts of interest to disclose., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Aims/introduction: The importance of low-density lipoprotein cholesterol (LDL-C) in the primary prevention of cardiovascular disease has recently been reported in the population aged ≥75 years with hypercholesterolemia. Therefore, the current status of LDL-C management for primary prevention of coronary artery disease in patients aged ≥75 years with type 2 diabetes mellitus was investigated., Materials and Methods: A total of 124 patients aged ≥75 years who had type 2 diabetes mellitus, but no coronary artery disease, were investigated. The patients' background characteristics, LDL-C, glycemic status, ankle-brachial index and cardio-ankle vascular index were compared between patients taking and not taking LDL-C-lowering agents, such as hydroxymethylglutaryl-CoA reductase inhibitors (statins) and ezetimibe. The details of the antihyperlipidemic and antidiabetic agents used in the present study were also examined., Results: LDL-C was significantly lower in patients taking LDL-C-lowering agents (LDLCLT[+]) than in patients not taking them (LDLCLT[-]), although LDL-C was maintained <120 mg/dL in both groups (93.0 mg/dL vs 102.1 mg/dL). Approximately half of the cases in the LDLCLT(+) group received moderate-intensity statins, with pitavastatin being the most prescribed statin. Glycated hemoglobin was significantly lower in the LDLCLT(+) group than in the LDLCLT(-) group (6.9% vs 7.3%). Sodium-glucose transporter 2 inhibitors were more frequently used in the LDLCLT(+) group than in the LDLCLT(-) group. The ankle-brachial index/cardio-ankle vascular index did not differ between the groups., Conclusion: Low-density lipoprotein cholesterol was properly managed for primary prevention of coronary artery disease in patients aged ≥75 years with type 2 diabetes mellitus regardless of the presence or absence of LDL-C-lowering agents., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: In transcatheter aortic valve replacement (TAVR) using SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, CA, USA), some clinicians decrease or increase the delivery balloon volume (VOL) when deploying S3 or conducting post-dilatation. However, the effects of controlling VOL on transcatheter heart valve diameter (THVD) and valve function remain unclear. We assessed associations among VOL, THVD, and effective orifice area (EOA) of S3., Methods: We enrolled patients undergoing TAVR using 23- and 26-mm S3 in Sendai Kousei Hospital between 2017 and 2019. VOL was controlled based on preprocedural computed tomography and intraprocedural transesophageal echocardiography (TEE). THVD were defined as the diameters of transcatheter heart valve at mid-level measured by TEE., Results: In enrolled 332 patients (23-mm, n = 188; 26-mm, n = 144), one (0.3%) and two (0.6%) developed annulus rupture and moderate/severe paravalvular leak, respectively. VOL at deployment was positively correlated with THVD on deployment (23-mm, r = 0.44, p < 0.001; 26-mm, r = 0.57, p < 0.001) and EOA (23-mm, r = 0.23, p = 0.0019; 26-mm, r = 0.22, p = 0.0094). In multiple regression analyses, VOL and post-dilatation were significant determinants of THVD, although aortic annulus area, calcium volume, and pre-dilatation were not. The areas under the receiver operating characteristic curve that were used to evaluate the accuracy of the index obtained by dividing THVD by body surface area (indexed THVD) to predict patient-prosthesis mismatch (PPM) were 0.744 and 0.811 in the 23- and 26-mm cohorts, respectively. A cut-off indexed THVD of ≤11.5 and 12.1 mm/m 2 well predicted PPM (23-mm, odds ratio, 5.20; 95% confidence interval, 1.33-20.3; 26-mm, odds ratio 14.1, 95% confidence interval 2.40-81.0)., Conclusion: VOL was positively correlated with THVD and EOA. Smaller indexed THVD was associated with a higher incidence of PPM. Controlling VOL under on-site THVD evaluation may be useful in reducing the PPM incidence., Competing Interests: Declaration of competing interest Norio Tada, Yusuke Enta, and Masaki Nakashima received lecture fees from Edwards Lifescience. The other authors have no conflict of interest. Norio Tada is a clinical proctor of Edwards Lifescience., (Copyright © 2022 Elsevier Ltd. All rights reserved.)