👤 Kenji Takeuchi

Stroke patients are prone to reduced daytime physical activity (PA) and poor nighttime sleep quality. Sleep may influence daytime PA; however, few studies have examined this relationship using objective assessments. This study aimed to investigate the association between PA and sleep among stroke patients in a convalescent rehabilitation ward. This was a cross-sectional study of stroke patients. PA and sleep were measured using a wearable device. PA was categorized into sedentary behavior (SB), light physical activity (LPA), and moderate to vigorous physical activity (MVPA). Sleep was assessed using sleep efficiency (SE), defined as the percentage of time spent asleep while in bed. Associations between SE and each PA parameter were analyzed using correlation and multiple regression analyses. A total of 76 patients (mean age 70.0 ± 12.0 years, 41 males) were analyzed. Median SE was 85.3% (interquartile range [IQR]: 81.2-89.0). The mean duration of daytime PA was 195.2 ± 67.5 min/day for SB, 319.5 ± 46.9 min/day for LPA, and 79.8 (IQR: 50.7-103.1) min/day for MVPA. SE was significantly correlated with MVPA ( In stroke patients undergoing convalescent rehabilitation, SE was associated with SB and MVPA. These findings suggest that improving SE may reduce SB and increasing MVPA during inpatient rehabilitation. Show less

To evaluate whether integrating Apolipoprotein B (ApoB) into the Systematic Coronary Risk Evaluation 2 (SCORE2) cardiovascular risk prediction framework improves its predictive accuracy and clinical applicability within the UK Biobank population. A 10-year prospective cohort study was conducted with 448 303 UK Biobank participants eligible for SCORE2 calculation. Three approaches were employed: (i) threshold analysis to determine the optimal ApoB cutoff for cardiovascular disease (CVD) risk prediction using Youden's Index, (ii) assessment of the synergistic effect of SCORE2 and ApoB through concordant and discordant classifications, and (iii) recalibration of the SCORE2 model by incorporating ApoB as an additional predictor. Each 0.2 g/L increase in ApoB was associated with an increased subdistribution hazard for CVD events [subdistribution hazard ratio (SHR): 1.13; 95% CI: 1.11-1.14, P < 0.001], accounting for non-cardiovascular death as a competing risk. Threshold analysis identified an optimal ApoB cutoff at 1.18 g/L; however, it demonstrated limited discriminatory performance (area under the curve 0.54), with low sensitivity (32.4%), and moderate specificity (74.4%). Individuals with both low ApoB (<1.18 g/L) and low SCORE2 risk (<5%) had a lower CVD incidence rate (232.51 per 100 000 person-years) compared with those identified as low risk by SCORE2 alone (253.69 per 100 000 person-years). Integration of ApoB into the SCORE2 model did not significantly improve the model discrimination, calibration, and net reclassification improvement. Apolipoprotein B exhibited a dose-response relationship with cardiovascular risk but had limited standalone predictive utility within the UK Biobank population. However, combining ApoB with SCORE2 thresholds improved the identification of low-risk individuals, suggesting a complementary role for ApoB in refining cardiovascular risk stratification. Show less

Hepatocellular carcinoma (HCC) arises from various etiologies, including viral hepatitis and non-viral liver diseases. Although comprehensive genomic profiling (CGP) is increasingly applied in oncology, the influence of disease etiology on the genomic landscape of HCC and biomarker applicability remains insufficiently characterized. CGP data from 551 patients with HCC, registered in the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, were analyzed after excluding cases with undefined etiology. We characterized the mutational landscape, compared mutation frequencies among HBV-, HCV-, and non-viral, non-cholestatic (nBnC)-related HCC, assessed the association between homologous recombination repair (HRR)-related gene alterations and tumor mutation burden (TMB), and evaluated the detection rates of actionable mutations in tissue- versus liquid-based CGP. Telomerase reverse transcriptase splice site mutations were the most common genomic alteration and were consistently observed across all etiologic groups. Although mutations in AXIN1 and DDR2 genes showed modest enrichment in HCV- and HBV-related HCC, respectively, the overall mutational profiles remained largely conserved across etiologies. TMB was significantly lower in nBnC-HCC compared to HCV-related HCC but showed no association with HRR-related mutations. The detection rates of targetable mutations were similar between tissue and liquid biopsies; however, only a small proportion of patients received matched therapies. Real-world data indicate a conserved genomic architecture in HCC regardless of etiology, supporting unified therapeutic approaches. The absence of a relationship between HRR alterations and TMB suggests distinct biological mechanisms. Liquid biopsy remains a reliable option when tissues are unavailable in managing patients with HCC. Show less

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus that is associated with long-term morbidity and mortality. Pathomorphological findings of LN are broadly divided into proliferative lupus nephritis (PLN) and membranous lupus nephritis (MLN). PLN is characterized by diffuse global or segmental proliferative glomerulonephritis with significant infiltration of inflammatory cells. Type 1 T-helper (Th1) cells, which predominate under inflammatory conditions, and NETosis, as the process of forming neutrophil extracellular traps (NETs), are key factors in the development of PLN. Meanwhile, MLN is characterized by diffuse membranous nephropathy (MN) with global granular subepithelial immune deposits. MLN patients usually experience massive proteinuria, and occasionally show an unfavorable renal prognosis despite aggressive treatment, similar to PLN patients. Intriguingly, in some instances, MLN patients do not show the general immunoserological characteristics of SLE, such as low serum complement and elevated anti-DNA antibody titers. Several reports have indicated an association between Th2 cell dominance and the development of MLN. Moreover, exostosin 1 (EXT1) and exostosin 2 (EXT2) on the glomerular basement membrane have recently been discovered as novel putative antigens for secondary MN, and have been shown to be up-regulated in patients with MLN. To date, many studies have focused on the dissimilarities between PLN and MLN. However, the reason for two polar morphological forms existing within the same disease is not completely clear. The present review addresses published observations on this topic in addition to providing our assertion regarding characteristic NETosis and glomerular EXT1/EXT2 expressions between PLN and MLN. Show less

We tested whether elevated 1 h post-load glucose (1hPG) was associated with decreased leg fat (relative to body fat) and serum concentrations of lipoprotein lipase (LPL), a rate-limiting enzyme for lipid storage in subcutaneous leg fat. Body fat mass and distribution, as measured by DXA, surrogate measures of insulin sensitivity, and insulin secretion inferred from serum insulin kinetics during a 75-g oral glucose tolerance test, as well as serum adipokines and LPL, were assessed in 164 Japanese female university students and 94 middle-aged parents. They all had normal glucose tolerance. Students provided their birth weight. Elevated 1hPG was found in 6% of daughters and 22% of parents. Multivariate logistic regression analyses revealed that log insulinogenic index (IGI) (OR: 0.031, 95% CI 0.003-0.30, p = 0.003) and serum LPL (OR: 0.90, 95% CI 0.83-0.98, p = 0.01) were associated with elevated 1hPG independently of serum adiponectin and birth weight in young Japanese. In middle-aged Japanese, the ratio of leg fat to body fat (OR: 0.66, 95% CI 0.44-0.97, p = 0.03), log IGI (OR: 0.002, 95% CI 0.00003-0.07, p = 0.001), and Matsuda index (OR: 0.67, 95% CI 0.47-0.96, p = 0.03) were related to elevated 1hPG independently of fat mass index, the ratio of trunk fat to body fat, LPL, and homeostasis model assessment insulin resistance. A decreased amount of leg fat in middle-aged Japanese with elevated 1hPG may be explained hypothetically by a prolonged deficiency of LPL. Show less

Brown adipose tissue (BAT), a thermogenic tissue that plays an important role in systemic energy expenditure, has histological and functional sex differences. BAT thermogenic activity is higher in female mice than in male mice. However, the molecular mechanism underlying this functional sex difference has not been fully elucidated. Herein, we demonstrate the role and mechanism of PGC-1α in this sex difference. Inducible adipocyte-specific PGC-1α knockout (KO) mice display mitochondrial morphological defects and decreased BAT thermogenesis only in females. Expression of carbohydrate response-element binding protein beta (Chrebpβ) and its downstream de novo lipogenesis (DNL)-related genes are both reduced only in female KO mice. BAT-specific knockdown of ChREBPβ displays decreased DNL-related gene expression and mitochondrial morphological defects followed by reduced BAT thermogenesis in female wild-type mice. Lipidomics reveals that, PGC-1α increases ether-linked phosphatidylethanolamine (PE) and cardiolipin(18:2) Show less

Recently, several target antigens of membranous nephropathy (MN), such as phospholipase A2 receptor (PLA2R) and exostosin 1/exostosin 2 (EXT1/2), have been discovered. A 30-year-old woman was referred to our hospital with nephrotic range proteinuria and microscopic hematuria. She was first noted to have proteinuria before pregnancy, and her proteinuria worsened in the postpartum period. A renal biopsy showed MN. Immunofluorescence microscopy showed IgG, IgA, IgM, C3, C4, and C1q depositions in the mesangial area and glomerular capillary walls (GCWs). Regarding the IgG subclass, IgG1 and IgG3 were detected on glomeruli. Electron microscopy showed subepithelial electron-dense deposits (EDDs). EDDs were also detected in paramesangial and subendothelial areas. The diagnosis of membranous lupus nephritis (MLN) was suspected, but she did not fulfill the criteria for systemic lupus erythematosus. Neither anti-nuclear antibody nor hypocomplementemia were detected. We further evaluated glomerular EXT1/2 expressions, which were evident on GCWs. In addition, PLA2R was also detected on GCWs, although serum antibody for PLA2R was negative. She responded to immunosuppressive therapy with decreased proteinuria. In the present case, glomerular PLA2R expression implied the possibility of primary MN. However, pathological findings with a full-house staining pattern and glomerular EXT1/2 expressions were very similar to those of lupus-associated MN. Glomerular PLA2R expression appeared not to reflect immunocomplexes of PLA2R and autoantibody when considering the results for glomerular IgG subclass and the absence of serum anti-PLA2R antibody. Collectively, it is plausible that this was a case of a relatively young postpartum female who developed latent MLN rather than primary MN. Show less

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries. Show less

It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) is a leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence of PAH in SSc patients. This study included 72 SSc patients and 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets in peripheral blood lymphocytes, and the serum levels of interleukin (IL)-17A, IL-17A/F, IL-17B. IL-17C, IL-17D. IL-1β, IL-6, IL-21, IL-22, and IL-23. The frequency of Th17 cells was significantly increased in SSc patients compared to HC and was positively correlated with the modified Rodnan skin scores. Furthermore, the serum levels of IL-17A, IL-17D, IL-1β, and IL-6 were significantly increased in SSc patients compared to HC. SSc patients with detected IL-17A showed high levels of IL-17A/F, IL-1β, IL-6, and IL-22, and high frequency of Th17 cells. Interestingly, these patients exhibited the reduced lung functions and increased prevalence of PAH significantly compared to patients with undetected IL-17A. Similarly, SSc patients with detected IL-17A and high IL-6 (≥1.2 pg/mL) exhibited the decreased lung functions and increased prevalence of PAH compared to patients with undetected IL-17A and low IL-6. We found that SSc patients with high levels of serum IL-17A or both IL-17A and IL-6 show reduced lung functions and high prevalence of PAH. Consequently, it is highly probable that Th17/IL-17A axis is critical for the prevalence of PAH in SSc patients. Show less

Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10 We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking. Show less

We previously demonstrated that the Alzheimer's disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-β (Aβ) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory impairment. Here, we aimed to exclude the possible effect of environmental factors associated with the difference in ambient temperature (23 °C vs. 30 °C) and to further clarify the effects of elevated body temperature on AD-like pathologies. We generated uncoupling protein 1 (UCP1) deletion in Tg2576 mice, Tg2576/UCP1 Show less

Recent developments in mass spectrometry (MS) have revealed target antigens for membranous nephropathy (MN), including phospholipase A2 receptor and exostosin 1/exostosin 2 (EXT1/2). EXT1/2 are known antigens of autoimmune disease-related MN, especially membranous lupus nephritis. We describe the case of an elderly man who developed nephrotic syndrome followed by progressive renal dysfunction. A 78-year-old man presented with rapidly progressive renal dysfunction with proteinuria and hematuria. Three years previously, he had developed leg edema but did not receive any treatment. Laboratory tests showed elevated anti-nuclear antibody (Ab), anti-dsDNA Ab titer, and hypocomplementemia, indicating systemic lupus erythematous. Myeloperoxidase anti-neutrophil cytoplasmic Ab (ANCA) and anti-glomerular basement membrane (GBM) Ab were also detected. The renal pathologic findings were compatible with crescentic glomerulonephritis (GN), whereas non-crescentic glomeruli exhibited MN without remarkable endocapillary or mesangial proliferative change. Immunofluorescence microscopy revealed glomerular IgG, C3, and C1q deposition. All IgG subclasses were positive in glomeruli. Anti-PLA2R Ab in serum was negative. MS analysis was performed to detect the antigens of MN, and EXT1/2 was detected in glomeruli. Therefore, we reached a diagnosis of membranous lupus nephritis concurrent with both ANCA-associated vasculitis and anti-GBM-GN. The simultaneous occurrence of these three diseases is extremely rare. This is the first report of EXT1/2-related membranous lupus nephritis concurrent with ANCA-associated vasculitis and anti-GBM-GN. This case demonstrates the usefulness of MS in diagnosing complicated cases of MN. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

ONO-1301 is a novel long-lasting prostaglandin (PG) I The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH. Show less

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4₁₁₆₆ + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS. Show less

The number of patients with non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease (IBD) is increasing. This study elucidates the effect of both NASH and IBD on hepatocellular carcinoma (HCC) using a mouse model combining NASH and IBD. The melanocortin 4 receptor-deficient (Mc4r-KO) mice were divided into four groups with or without a high-fat diet (HFD) and with or without dextran sulfate sodium (DSS) to induce colitis, and the differences in liver damage and occurrence of HCC were analyzed. In the HFD + DSS group, the body weight, liver weight/body weight ratio, and serum levels of albumin and alanine aminotransferase were significantly lower than those in the HFD group. We further found that steatosis was significantly lower and lobular inflammation was significantly higher in the HFD + DSS group than those in the HFD group, and that individual steatosis and lobular inflammation state in the HFD + DSS mice varied. We detected HCC only in the HFD + DSS group, and mice with severe steatosis and mild colitis were found to be at high risk of HCC. Presently, the prediction of HCC is very difficult. In some cases, severe colitis reverses the fat accumulation due to appetite loss. Our findings clearly showed that severe steatohepatitis and mild colitis are simultaneously essential for the occurrence of HCC in patients with NASH and IBD. Show less

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired ( Show less

Left ventricular noncompaction cardiomyopathy (LVNC) is a heart muscle disorder morphologically characterized by reticulated trabeculations and intertrabecular recesses in the left ventricular (LV) cavity. LVNC is a genetically and phenotypically heterogeneous condition, which has been increasingly recognized with the accumulation of evidence provided by genotype-phenotype correlation analyses. Here, we report 2 sporadic adult cases of LVNC; both developed acute heart failure as an initial clinical manifestation and harbored causal sarcomere gene mutations. One case was a 57-year-old male with digenic heterozygote mutations, p.R1344Q in myosin heavy chain 7 (MYH7) and p.R144W in troponin T2, cardiac type (TNNT2), who showed morphological characteristics of LVNC in the lateral to apical regions of the LV together with a comorbidity of non-transmural myocardial infarction, resulting from a coronary artery stenosis. After the removal of ischemic insult and standard heart failure treatment, LVNC became less clear, and LV function gradually improved. The other case was a 36-year-old male with a heterozygote mutation, p.E334K in myosin binding protein C3 (MYBPC3), who exhibited cardiogenic shock on admission with morphological characteristics of LVNC being most prominent in the apical segment of the LV. The dosage of beta-blocker was deliberately increased in an outpatient clinic over 6 months following hospitalization, which remarkably improved the LV ejection fraction from 21% to 54.3%. Via a combination of imaging and histopathological and genetic tests, we have found that these cases are not compatible with a persistent phenotype of primary cardiomyopathy, but their morphological features are changeable in response to treatment. Thus, we point out phenotypic plasticity or undulation as a noticeable element of LVNC in this case report. Show less

The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-l-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH. Show less

Currently, there are no approved drugs for treating non-alcoholic steatohepatitis (NASH); however, mesenchymal stem cells (MSCs) and their small extracellular vesicles (sEVs), which possess immunomodulatory activities, are potential candidates. This study aimed to develop a mouse model of NASH with rapid accumulation of fibrosis using the pre-established melanocortin type-4 receptor knockout ( By providing a WD combined with LPS treatment, we successfully developed a NASH model with rapid accumulation of fibrosis. Both human MSCs and their sEVs decreased serum alanine transaminase levels and inflammatory markers based on qRT-PCR. Histological analysis showed that MSC or sEV treatment did not affect fat accumulation. However, an improvement in fibrosis in the groups treated with MSCs and their sEVs was observed. Furthermore, after administering MSCs and sEVs, there was a significant increase in anti-inflammatory macrophages in the liver. We successfully developed a NASH model with rapid accumulation of fibrosis and confirmed the anti-inflammatory and anti-fibrotic effects of MSCs and their sEVs, which may be options for future therapy. Show less

Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transgenic rodent models thus far. As the results of pharmacological studies of CETP modification are largely controversial in humans, further knowledge about the impact of CETP on atherogenic phenotypes is required to evaluate its clinical utility for the prevention of cardiovascular and other organ damage associated with metabolic syndrome. Therefore, we newly generated a human CETP-transgenic (Tg[hCETP]) strain on the genetic background of spontaneously hypertensive rats (SHRs), which are characterized by the spontaneous occurrence of hypertension and insulin resistance. This allowed us to assess the in vivo role of CETP on cardiometabolic phenotypes in combination with hypertension. In Tg[hCETP] SHRs fed normal rat chow, systolic blood pressure was markedly elevated by 20-37 mmHg throughout the study period, and the development of fatty liver was accelerated with appreciable changes in the plasma lipid profile (HDL cholesterol reduction and triglyceride elevation). These phenotypic changes are in accordance with the assumption of proatherogenic effects inducible by the overexpression of CETP. However, with plasma LDL cholesterol levels concomitantly reduced, no apparent progression of atherosclerosis was detected in either the aorta or coronary arteries of Tg[hCETP] SHRs fed a high-fat, high-cholesterol diet. Our data provide new insight into the multifaceted regulation of cardiometabolic phenotypes via the modification of CETP. Show less

Recent advances in the genetic understanding of acute myeloid leukemia (AML) have improved clinical outcomes in pediatric patients. However, ∼40% of patients with pediatric AML relapse, resulting in a relatively low overall survival rate of ∼70%. The objective of this study was to reveal the comprehensive genetic background of pediatric AML. We performed transcriptome analysis (RNA sequencing [RNA-seq]) in 139 of the 369 patients with de novo pediatric AML who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial and investigated correlations between genetic aberrations and clinical information. Using RNA-seq, we identified 54 in-frame gene fusions and 1 RUNX1 out-of-frame fusion in 53 of 139 patients. Moreover, we found at least 258 gene fusions in 369 patients (70%) through reverse transcription polymerase chain reaction and RNA-seq. Five gene rearrangements were newly identified, namely, NPM1-CCDC28A, TRIP12-NPM1, MLLT10-DNAJC1, TBL1XR1-RARB, and RUNX1-FNBP1. In addition, we found rare gene rearrangements, namely, MYB-GATA1, NPM1-MLF1, ETV6-NCOA2, ETV6-MECOM, ETV6-CTNNB1, RUNX1-PRDM16, RUNX1-CBFA2T2, and RUNX1-CBFA2T3. Among the remaining 111 patients, KMT2A-PTD, biallelic CEBPA, and NPM1 gene mutations were found in 11, 23, and 17 patients, respectively. These mutations were completely mutually exclusive with any gene fusions. RNA-seq unmasked the complexity of gene rearrangements and mutations in pediatric AML. We identified potentially disease-causing alterations in nearly all patients with AML, including novel gene fusions. Our results indicated that a subset of patients with pediatric AML represent a distinct entity that may be discriminated from their adult counterparts. Based on these results, risk stratification should be reconsidered. Show less

Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the To test whether protein-truncating variants (PTVs) at the We sequenced the exons of the Compared with noncarriers, carriers of PTV at Show less

The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann-Pick C1-like 1 ( Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia. Show less

The establishment of neuronal polarity is necessary for proper neuronal wiring. Semaphorin3A (Sema3A), originally identified as a repulsive axon guidance molecule, exerts a wide variety of biological functions through signaling pathways including sequential phosphorylation of collapsin response mediator protein by cyclin-dependent kinase-5 (Cdk5) and glycogen synthase kinase-3β (GSK3β). Sema3A acts on its receptor neuropilin-1 to regulate axonal transport. To delineate mechanism by which Sema3A induces axonal transport, we investigate whether GSK3β is involved in mediating Sema3A-induced axonal transport. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione, an inhibitor of GSK3β, suppressed Sema3A-induced antero- and retrograde axonal transport. Introduction of either GSK3β mutants, GSK3β-L128A or K85M, suppressed Sema3A-induced axonal transport. On the other hand, introduction of GSK3β-R96A did not affect the Sema3A effect, suggesting that unprimed substrates are primarily involved in Sema3A-induced axonal transport. Overexpression of a partial fragment of frequently rearranged in advanced T-cell lymphomas 1 (FRATtide), which interferes the interaction between GSK3β and Axis inhibitor-1 (Axin-1), also suppressed Sema3A-induced transport. siRNA knockdown of Axin-1, an unprimed substrate of GSK3β, suppressed Sema3A-induced antero- and retrograde axonal transport. These results indicate that GSK3β and Axin-1 are involved in Sema3A-induced bidirectional axonal transport. This finding should provide a clue for understanding of mechanisms of a wide variety of biological activities of Sema3A. Show less

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target. Show less

Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ, but not HP1α, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer. Show less

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations. Show less

In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD). We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1 × 10(-30) in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls. Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci-APOB, APOE-C1, CETP, and APOA5-and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p=1.3 × 10(-41)), CETP rs3764261 for HDL-C (p=5.2 × 10(-24)), and APOA5 rs662799 for triglycerides (p=5.8 × 10(-54)). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p=1.7 × 10(-8)), APOA5 rs662799 (p=0.0014), LDLR rs1433099 (p=2.1 × 10(-7)), and APOE rs7412 (p=6.1 × 10(-13)). Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific. Show less