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Abstract Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson’s disease (PD). Selegiline, rasagiline, and safinamide are widely used as MAO-B inhibitors worldwide. Although these drugs inhibit MAO-B, there are pharmacological and chemical differences, such as the inhibitory activity, the non-dopaminergic properties in safinamide, and the amphetamine-like structure in selegiline. MAO-B inhibitors may differ in adverse events (AEs). However, differences in actual practical clinics are not fully investigated. A retrospective study was conducted using FAERS, the largest database of spontaneous adverse events. AE signals for MAO-B inhibitors, including selegiline, rasagiline, and safinamide, were detected using the reporting odds ratio method and compared. Hypocomplementemia, hepatic cyst, hepatic function abnormal, liver disorder and cholangitis were detected for selegiline as drug-specific signals. The amphetamine effect was not confirmed for any of the three MAO-B inhibitors. The tyramine reaction was detected as an AE signal only for rasagiline. Moreover, the REM sleep behavior disorder was not detected as an AE signal for safinamide, suggesting that non-dopaminergic effects might be beneficial. Considering the differences in AEs for MAO-B inhibitors will assist with the appropriate PD medication.

Background: Spinal metastasis pain includes both inflammatory and neuropathic pain, and opioids, which have only a ?-opioid receptor-stimulating effect, are generally less effective in neuropathic pain. However, no previous study has been conducted for the comparisons of the efficacy of opioids in treating spinal metastasis pain. Objective: To compare the efficacy of tapentadol and methadone with other opioids for back pain caused by a metastatic spinal tumor. Design: Retrospective cohort study. Setting/Subjects: A total of 274 patients were enrolled, who started a tapentadol extended-release tablet, methadone tablet, hydromorphone extended-release tablet, oxycodone extended-release tablet, or transdermal fentanyl patch for cancer pain due to spinal metastasis in Japan from January 1, 2013 to October 31, 2021. Measurements: The primary endpoint, the difference in the numerical rating scale (NRS) scores before and seven days after each opioid administration, was compared among the five groups. Results: In patients with numbness, a decrease of the NRS score on day seven compared with before starting each opioid was significantly higher in the tapentadol group than those in the hydromorphone, oxycodone, and fentanyl groups and comparable to that in the methadone group. In patients without numbness, no significant differences were observed in decreases of the NRS scores on day seven among the five groups. Conclusions: Tapentadol and methadone may be more effective than hydromorphone, oxycodone, and fentanyl for cancer pain due to spinal metastasis with numbness.

Abstract The aim of this study was to determine the impact at 5 years of sodium‐glucose cotransporter 2 inhibitor (SGLT2i) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM) on liver histopathology and clinical features. In this retrospective study, the histological impacts at 5 years after the start of SGLT2i in NAFLD with T2DM were investigated. Six patients with NAFLD and T2DM were treated for the long term with canagliflozin of SGLT2i, and liver biopsies were obtained at the points of the pretreatment, 24 weeks, 3 years, and 5 years after the start of treatment. The primary outcome was liver histopathological changes at 5 years (defined as decrease in NAFLD activity score of one point or more without worsening in fibrosis stage, compared with the pretreatment). The additional treatment of glucagon‐like peptide 1 receptor agonist (GLP‐1RA) was performed in 2 patients after the point of 3 years, and evaluated as histological worsening. As the primary outcome, histological improvement, no change, and worsening were 50%, 17%, and 33% at 5 years, respectively. Overall, the scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased at 5 years in 67%, 33%, 0%, and 33%, respectively. As the secondary outcomes, homeostasis model assessment of insulin resistance and serum ferritin decreased significantly at 5 years. None developed 3‐point major adverse cardiovascular events. Two patients with the addition of GLP‐1RA on SGLT2i did not show the worsening of steatosis, ballooning, and fibrosis stage at 5 years compared with 3 years. Conclusion: A 5‐year follow‐up study with SGLT2i indicated the favorable histological impact on NAFLD with T2DM.

Mammalian adipose tissues are broadly divided into white adipose tissue (WAT) and thermogenic fat tissue (brown adipose tissue and beige adipose tissue). Uncoupling protein 1 (UCP1) is the central protein in thermogenesis, and cells that exhibit induced UCP1 expression and appear scattered throughout WAT are called beige adipocytes, and their induction in WAT is referred to as “beiging”. Beige adipocytes can differentiate from preadipocytes or convert from mature adipocytes. UCP1 was thought to contribute to non-shivering thermogenesis; however, recent studies demonstrated the presence of UCP1-independent thermogenic mechanisms. There is evidence that thermogenic fat tissue contributes to systemic energy expenditure even in human beings. This review discusses the roles that thermogenic fat tissue plays in energy consumption and offers insight into the possibility and challenges associated with its application in the treatment of obesity and type 2 diabetes.

Serum hepatitis B core‐related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e‐antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow‐up of 11.0 years, 22 patients developed HCC (11.8/1,000 person‐years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log‐rank test; P

Adipose-derived stem cells are expected to be applied to regenerative medicine for various incurable diseases including liver cirrhosis. Although microRNAs contained in extracellular vesicles (EV-miRNAs) have been implicated in their regenerative effects, the precise mechanism has not been fully elucidated. Tamoxifen-inducible adipocyte-specific insulin receptor knockout (iFIRKO) mice are known to exhibit acute adipose tissue regeneration with increased numbers of adipose stem and progenitor cells (ASPCs). Because adipose tissue is the major source of circulating EV-miRNAs, we investigated alterations in serum EV-miRNAs in iFIRKO mice. A comprehensive analysis using miRNA sequencing on serum EVs revealed that most EV-miRNAs were decreased due to the loss of mature adipocytes, but there were 19 EV-miRNAs that were increased in the serum of iFIRKO mice. Among them, miR-144-3p and miR-486a-3p were found to be increased in the liver as well as serum EVs. While the expression levels of pri-miR-144-3p and pri-miR-486a-3p were not increased in the liver, they were elevated in the adipose tissue, suggesting that these miRNAs may be delivered from ASPCs increased in the adipose tissue to the liver via EVs. Increased hepatocyte proliferation was observed in the liver of iFIRKO mice, and we found that both miR-144-3p and miR-486a-3p have a function to promote hepatocyte proliferation by suppressing Txnip expression as a target gene. miR-144-3p and miR-486a-3p can be candidate therapeutic tools for conditions requiring hepatocyte proliferation, such as liver cirrhosis, and our current study suggests that examining EV-miRNAs secreted in vivo may lead to the discovery of miRNAs involved in regenerative medicine that have not been identified by in vitro analysis.

ObjectivePrimary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of Cushing syndrome, is often diagnosed as a bilateral adrenal incidentaloma with subclinical cortisol production. Circulating microRNAs (miRNAs) are a characteristic of adrenocortical adenomas, but miRNA expression in PBMAH has not been investigated. We aimed to evaluate the circulating miRNA expression in patients with PBMAH and compare them with those in patients with non-functioning adrenocortical adenoma (NFA) and cortisol-producing adrenocortical adenoma (CPA).MethodsmiRNA profiling of plasma samples from four, five, and five patients with NFA, CPA, and PBMAH, respectively, was performed. Selected miRNA expressions were validated using quantitative RT-PCR.ResultsPBMAH samples showed distinct miRNA expression signatures on hierarchical clustering while NFA and CPA samples were separately clustered. PBMAH was distinguished from the adenoma group of NFA and CPA by 135 differentially expressed miRNAs. Hsa-miR-1180-3p, hsa-miR-4732-5p, and hsa-let-7b-5p were differentially expressed between PBMAH and adenoma (P = 0.019, 0.006, and 0.003, respectively). Furthermore, PBMAH could be classified into two subtypes based on miRNA profiling: subtype 1 with a similar profile to those of adenoma and subtype 2 with a distinct profile. Hsa-miR-631, hsa-miR-513b-5p, hsa-miR-6805-5p, and hsa-miR-548av-5p/548k were differentially expressed between PBMAH subtype 2 and adenoma (P = 0.027, 0.027, 0.027, and 1.53E-04, respectively), but not between PBMAH, as a whole, and adenoma.ConclusionCirculating miRNA signature was identified specific for PBMAH. The existence of subtype-based miRNA profiles may be associated with the pathophysiological heterogeneity of PBMAH.

Abstract Background Reliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined. Methods We retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors. Results A score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%. Conclusions Our results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients.

Magneto-optical Faraday devices, such as optical isolators, require a structure to apply a magnetic field to the incorporated magneto-optical material. The application of a magnetic field hinders the miniaturization and integration of these devices. Nanogranular films show Faraday rotation angles up to 40 times larger than Bi-YIG in the optical communication band (1,550 nm). Nanogranular films are submicron-to several-micrometer-thick and contribute to the miniaturization and integration of optical devices. Here, we introduce (Co-Pt)–(CaF2) nanogranular films exhibiting a magnetic-field-free magneto-optical Faraday effect, which are Co3Pt alloy that are hard magnets with residual magnetization. These nanogranular films exhibit the Faraday effect without requiring a magnetic field owing to their residual magnetization.

Abstract Background Hepatitis C virus is the leading cause of liver cirrhosis and hepatocellular carcinoma in Japan. We aimed to examine the long-term (> 20 years) mortality and hepatocellular carcinoma rates and associated risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis (Child–Pugh B or C). Methods Cumulative survival and hepatocellular carcinoma rates were determined using Kaplan–Meier analysis. Independent risk factors were identified by multivariate analysis. A two-tailed P-value of

Controlling the magnetic anisotropy of nanoparticles is a crucial but challenging step for developing new magnetic functions. Here, we demonstrate a simple approach to controlling the shape of Co nanoparticles in a Co-SiO2 nanogranular film from oblate to prolate spheroid by varying the substrate rotation speed during the tandem fabrication process without changing the film composition (Co:SiO2 = 3:7). Changing the nanoparticles from oblate to prolate, increasing perpendicular length of ellipsoidal nanoparticles, changes the magnetic anisotropy axis of Co–SiO2 nanogranular films from in-plane to out-of-plane, which indicates that the shape anisotropy profoundly affects the magnetic properties. Despite the small tunneling current of a few tens of nanoamperes, a maximum tunneling magnetoresistance effect of up to 2.8 % was realized under an applied magnetic field of 12 kOe in the film plane. Achieving both in-plane and perpendicular spin-dependent tunneling, the anisotropic nanogranular films imply direction controllable tunneling materials as future topological nanoarchitecture. Such high-resistivity nanogranular films with a controllable magnetic nanoparticle shape facilitate the design of new magneto-optical devices with high withstand voltages.

Abstract Background The prognostic factors of morbidity and mortality in patients with lean NAFLD (body mass index

Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC). Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy. Results: Heterogeneous enhancement patterns (Type-3 and -4), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (Type-2) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors (p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01–0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06–8.05; p = 0.039). Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC.

Cardiovascular risks of cold exposure and the subsequent activation of the β3-AR pathway limit the application of beige fat thermogenesis for the treatment of obesity. Here, the authors show that optogenetics light-activated Ca2+ cycling in adipocytes triggers a fat-specific “cold-mimetic” thermogenesis response protecting mice against diet-induced obesity.

The impact of circulating microRNA‐122 (miR‐122) on mortality in patients with histopathologically confirmed nonalcoholic fatty liver disease (NAFLD) remains unclear. We analyzed the overall survival rates in 441 Japanese patients with histopathologically confirmed NAFLD after a median follow‐up period of 4.7 years. We also determined the clinicopathologic, genetic, and epigenetic parameters, including serum miR‐122 levels, for prediction of mortality. Of the 441 study patients, 21 (4.8%) died during the follow‐up period. The cumulative survival rates were 95.4% and 90.6% at the end of 5 and 10 years, respectively. Multivariate analysis identified history of liver cancer (presence; hazard ratio [HR], 4.94; 95% confidence interval [CI], 1.84‐13.3), serum miR‐122 (

Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.

Mammals have two types of thermogenic adipocytes: brown adipocytes and beige adipocytes. Thermogenic adipocytes express high levels of uncoupling protein 1 (UCP1) to dissipates energy in the form of heat by uncoupling the mitochondrial proton gradient from mitochondrial respiration. There is much evidence that UCP1 is the center of BAT thermogenesis and systemic energy homeostasis. Recently, UCP1 independent thermogenic pathway identified in thermogenic adipocytes. Importantly, the thermogenic pathways are different in brown and beige adipocytes. Ca2+-ATPase 2b calcium cycling mechanism is selective to beige adipocytes. It remains unknown how the multiple thermogenic mechanisms are coordinately regulated. The discovery of UCP1-independent thermogenic mechanisms potential offer new opportunities for improving obesity and type 2 diabetes particularly in groups such as elderly and obese populations who do not possess UCP1 positive adipocytes.

Abstract Background The incidence of liver-related events, cardiovascular events and type 2 diabetes mellitus in patients with histopathologically confirmed NAFLD remains unclear. Methods We retrospectively investigated the incidence of liver events, cardiovascular events, malignancy, and type 2 diabetes mellitus in 402 Japanese patients with histopathologically confirmed NAFLD for a median follow-up of 4.2 years. We also investigated predictors of the development of hepatocellular carcinoma and type 2 diabetes mellitus in these patients. Results The rate of liver-related events per 1000 person years was 4.17 (hepatocellular carcinoma, 3.67; hepatic encephalopathy, 1.60; esophago-gastric varices, 2.43; ascites, 0.80; and jaundice, 0.40). The rate of cardiovascular events and type 2 diabetes mellitus was 5.73 and 9.95, respectively. Overall mortality was 3.33 (liver-related events, 1.25; cardiovascular events, 0.42; and malignancies other than hepatocellular carcinoma, 0.83), in patients free of previous or current malignancies. Multivariate analyses identified old age (≥70 years) and advanced fibrosis stage 4 as significant determinants of hepatocellular carcinoma development, and hepatocyte steatosis (> 33%), female sex, and serum ferritin (≤80 μg/l) as significant determinants of type 2 diabetes mellitus development in these patients. Conclusions Our results highlighted the importance of cardiovascular and liver-related events in Japanese patients with histopathologically-confirmed NAFLD. Hepatocellular carcinoma was the most common liver-related event, and the incidence of hepatocellular carcinoma was more than half of that of cardiovascular events.

Abstract Background Portal vein thrombosis (PVT) is a serious complication in liver cirrhosis with portal hypertension. We examined the treatment, recurrence and prognosis of PVT in cirrhotic patients. Methods The study subjects were all 90 cirrhotic patients with PVT treated with danaparoid sodium (DS) at our department between July 2007 and September 2016. The mean age was 68 years and mean Child-Pugh score was 7. All patients received 2500 U/day of DS for 2 weeks, and repeated in those who developed PVT recurrence after the initial therapy. Results Complete response was noted in 49% (n = 44), partial response (shrinkage ≥70%) in 33% (n = 30), and no change (shrinkage

Background/AimsNoninvasive liver fibrosis evaluation was performed in patients with nonalcoholic fatty liver disease (NAFLD). We used a quantitative method based on the hepatic volume acquired from gadoxetate disodium-enhanced (Gd-EOB-DTPA-enhanced) magnetic resonance imaging (MRI) for diagnosing advanced fibrosis in patients with NAFLD.Methods : A total of 130 patients who were diagnosed with NAFLD and underwent Gd-EOB-DTPA-enhanced MRI were retrospectively included. Histological data were available for 118 patients. Hepatic volumetric parameters, including the left hepatic lobe to right hepatic lobe volume ratio (L/R ratio), were measured. The usefulness of the L/R ratio for diagnosing fibrosis ≥F3–4 and F4 was assessed using the area under the receiver operating characteristic (AUROC) curve. Multiple regression analysis was performed to identify variables (age, body mass index, serum fibrosis markers, and histological features) that were associated with the L/R ratio.Results : The L/R ratio demonstrated good performance in differentiating advanced fibrosis (AUROC, 0.80; 95% confidence interval, 0.72 to 0.88) from cirrhosis (AUROC, 0.87; 95% confidence interval, 0.75 to 0.99). Multiple regression analysis showed that only fibrosis was significantly associated with the L/R ratio (coefficient, 0.121; p

We demonstrate a 4.8-μVrms noise microelectrode array (MEA) based on the complementary-metal-oxide-semiconductor active-pixel-sensors readout technique with disaggregated differential amplifier implementation. The circuit elements of the differential amplifier are divided into a readout pixel, a reference pixel, and a column circuit. This disaggregation contributes to the small area of the readout pixel, which is less than 81 μm2. We observed neuron signals around 100 μV with 432 electrodes in a fabricated prototype chip. The implementation has technological feasibility of up to 12-μm-pitch electrode density and 6,912 readout channels for high-spatial resolution mapping of neuron network activity.

For better understanding of gas and particle motion in a fluidized bed, we numerically solved the locally averaged three-dimensional Navier-Stokes equations and the Lagrangian equations for particle motion while taking into account the collisions between particles, and gas-particle mutual interaction. Finite difference methods were used. This simulation obtained locally averaged variables, such as gas velocities, by averaging point variables over the very small region of one computational cell. Small stress terms caused by fluctuations in locally averaged values were ignored at the present stage. In calculating collisions, particles were regarded as hard spheres with a collision time of zero, meaning that collisions occur between only two particles. Results show that the hard sphere collision model can be used to simulate flow fields in fluidized beds whose particle concentrations are relatively dilute. † This report was originally printed in Kagaku Kogaku Ronbunshu, 22(1), 67-75 (1996) in Japanese, before being translated into English by KONA Editorial Committee with the permission of the editorial committee of the Soc. Chemical Engineers, Japan.

Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10⁻⁵). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P(combined) = 3.59 × 10⁻¹⁶, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

BACKGROUND: Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells. Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA. METHODS: We conducted single-nucleus RNA sequencing of APAs with KCNJ5 mutation and nonfunctional adenomas obtained from 3 and 2 patients, respectively. RESULTS: The single-nucleus RNA sequencing revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of nonfunctional adenoma and APA. In addition, we extracted 2 cell fates in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in 1 of these fates, whereas those related to the regulation of glycolysis were upregulated in the other fate. Furthermore, the total RNA reads in the nucleus were higher in hormonally activated clusters, indicating a marked activation of transcription per cell. CONCLUSIONS: The single-nucleus RNA sequencing revealed intratumoral heterogeneity of APA with KCNJ5 mutation. The observation of 2 cell fates in KCNJ5-mutated APAs provides the postulation that a heterogeneous process of cellular differentiation was implicated in the pathophysiological mechanisms underlying APA tumors. [ABSTRACT FROM AUTHOR]