👤 Akio Tanaka

Visceral fat (VF), particularly epicardial adipose tissue (EAT), plays a crucial role in the development of coronary artery disease (CAD). Cathelicidin (LL37) is an antimicrobial peptide involved in innate immunity and has been implicated in inflammatory processes. However, the relationship between VF accumulation, cathelicidin, and atherosclerosis remains unclear. Seventy-eight subjects without CAD were enrolled and classified by obesity type: normal-weight (normal; n=20), subcutaneous fat (SF; n=19), and VF (n=39). Plasma LL37 concentrations were compared across groups. LL37 expression in EAT was assessed in 9 patients undergoing open-heart surgery, stratified by CAD status. In animal experiments, angiotensin II-infused wild-type and Apoe LL37 is associated with VF accumulation and CAD. However, these findings are exploratory and warrant prospective validation to determine its potential utility as a biomarker. Show less

The dysregulated immune system, which drives chronic vascular inflammation and remodeling, plays a critical role in the pathogenesis of abdominal aortic aneurysm (AAA). CCR4 (C-C chemokine receptor 4), which is predominantly expressed on T cells and mediates their responses, has been shown to protect against inflammatory diseases including atherosclerosis. However, its role in AAA remains unknown. By analyzing hypercholesterolemic CCR4-deficient ( Genetic deletion of CCR4 on an CCR4 may serve as a potential therapeutic target for AAA. Show less

Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha-1B glycoprotein (A1BG) is a plasma glycoprotein reported to be dysregulated in multiple cancers. In this study, we investigated the functional role of A1BG in HBV-associated HCC progression. Both the HepG2 and HBV-transfected HepG2 cell lines were used to examine the biological effects of A1BG. A1BG expression was modulated using siRNA and a plasmid vector. A series of functional assays were conducted to assess cell proliferation, apoptosis, stemness, migration, and invasion. RNA microarray analysis and gene set enrichment analysis (GSEA) were performed to identify A1BG-regulated pathways. Functionally, A1BG overexpression suppressed cell proliferation, stemness, migration, invasion, and HBV products while promoting apoptosis in both HepG2 and HBV-transfected HepG2 cells. In contrast, opposite effects were shown in the event of A1BG knockdown. Moreover, A1BG expression was reduced in HBV-associated HCC tissues and correlated with advanced pathological stage and poor prognosis. RNA microarray analysis and GSEA revealed the activation of anti-HBV-related genes and suppression of FGFR1 signaling and the matrix metalloproteinase pathway in A1BG-overexpressing cells. This study provides evidence that A1BG may be a novel host factor associated with the in vitro suppression of HBV replication and HCC progression by modulating pathways related to enhanced antiviral effects, reduced proliferative capacity and stemness, and suppression of EMT. These findings suggest that A1BG is a potential therapeutic target in HBV-related HCC. Show less

Glioblastoma, isocitrate dehydrogenase wildtype (GBM, IDH-wt), is a highly aggressive brain tumor with a poor prognosis. Alterations in the fibroblast growth factor receptor (FGFR) gene family-such as FGFR::TACC fusions and FGFR1 mutations-have emerged as potential therapeutic targets; however, their clinical and genetic features in GBM, IDH-wt remain unclear. We analyzed 1076 GBM, IDH-wt cases using comprehensive genomic profiling data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. FGFR alterations were detected in 8.0% of patients, including FGFR::TACC fusions (3.3%) and FGFR1 mutations (2.9%). The FGFR::TACC fusion-positive group was older at diagnosis and showed higher frequencies of TERT promoter mutation and MDM2 amplification, and lower frequencies of EGFR amplification and TP53 mutation, compared with the fusion-negative group. The FGFR1 mutation-positive group was enriched for ATRX, NF1, and PIK3CA mutations and had significantly fewer TERT promoter and PTEN mutations, compared with the mutation-negative group. No significant differences in overall survival were observed, although both groups tended to have longer median overall survival compared with their respective negative groups. This study represents the largest genomic cohort to date of FGFR alterations in GBM, IDH-wt. FGFR::TACC fusion-positive and FGFR1 mutation-positive GBMs exhibited distinct genetic profiles, highlighting the clinical relevance of molecular subclassification and providing insight for future therapeutic strategies. Show less

Rosette-forming glioneuronal tumors (RGNTs) are rare, World Health Organization grade 1 tumors that typically arise around the fourth ventricle. However, cerebral hemisphere RGNTs have recently been reported, with some exhibiting clinical features resembling low-grade epilepsy-associated tumor (LEAT). We report a case of multifocal RGNT in a patient with drug-refractory epilepsy. A 14-year-old woman was incidentally found to have multifocal brain tumor involving the left temporal lobe and bilateral thalamus, she developed drug-resistant epilepsy ten years later and underwent surgery. Partial tumor resection and anterior temporal lobectomy were performed. Histopathology revealed a glioneuronal tumor with oligodendroglia-like cells, neurocytic rosette, and perivascular pseudorosette, exhibiting an infiltrative growth pattern extending into the white matter. Genetic analysis revealed Fibroblast Growth Factor Receptor 1 mutation. The methylation profile analysis matched the low-grade glioneuronal tumor class but did not yield to any subclass category. Finally, the tumor was diagnosed as RGNT-like low-grade glioneuronal tumor with dysembryoplastic neuroepithelial tumor (DNT) features. Cases presenting with a LEAT-like clinical course and exhibiting histopathological features of RGNT are often difficult to definitively distinguish from DNT based on histological and genetic findings. Epilepsy-associated RGNT may harbor genetic profiles distinct from those of prototypical RGNTs, highlighting the need for further investigation. Show less

High-level cognitive skill development relies on genetic and environmental factors, tied to brain structure and function. Inter-individual variability in language and music skills has been repeatedly associated with the structure of the auditory cortex: the shape, size and asymmetry of the transverse temporal gyrus (TTG) or gyri (TTGs). TTG is highly variable in shape and size, some individuals having one single gyrus (also referred to as Heschl's gyrus, HG) while others presenting duplications (with a common stem or fully separated) or higher-order multiplications of TTG. Both genetic and environmental influences on children's cognition, behavior, and brain can to some to degree be traced back to familial and parental factors. In the current study, using a unique MRI dataset of parents and children (135 individuals from 37 families), we ask whether the anatomy of the auditory cortex is related to reading skills, and whether there are intergenerational effects on TTG(s) anatomy. For this, we performed detailed, automatic segmentations of HG and of additional TTG(s), when present, extracting volume, surface area, thickness and shape of the gyri. We tested for relationships between these and reading skill, and assessed their degree of familial similarity and intergenerational transmission effects. We found that volume and area of all identified left TTG(s) combined was positively related to reading scores, both in children and adults. With respect to intergenerational similarities in the structure of the auditory cortex, we identified structural brain similarities for mother-child pairs of the 1st TTG (HG) (in terms of volume, area and thickness for the right HG, and shape for the left HG) and of the lateralization of all TTG(s) surface area for father-child pairs. Both the HG and TTG-lateralization findings were significantly more likely for parent-child dyads than for unrelated adult-child pairs. Furthermore, we established characteristics of parents' TTG that are related to better reading abilities in children: fathers' small left HG, and a small ratio of HG to planum temporale. Our results suggest intergenerational transmission of specific structural features of the auditory cortex (not directly linked to children's reading outcomes); these may arise from genetics and/or from shared environment. Show less

The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues. This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes. Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8 CD8 Show less

Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression. Show less

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

Bladder cancer (BCa) is a lethal cancer, but early-detection offers an opportunity to improve prognosis. Our objective was to develop a urine-based multi-marker panel for BCa detection across multiple longitudinal cohort studies in a nested case-control study. Longitudinal cohorts included healthy participants enrolled in the Southern Community Cohort Study (SCCS), Singapore Chinese Health Study (SCHS), Shanghai Women/Men Health Study (SWMHS), and Multiethnic Cohort (MEC). We measured the levels of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGF) in spot-voided urine samples using the multiplex immunoassay Oncuria. Single urine specimens collected from 274 participants who would go on to develop BCa in the ensuing 3‒60 months (i.e., cases) were age/sex-matched to 274 cancer-free controls. We used generalized estimating equation models, logistic regression analysis, and random forest algorithms to analyze the data. Differences in the individual biomarker levels between cases and controls were noted for ANG at 12 months ( Additional testing is needed; however preliminary results demonstrate that a multiplex immunoassay may be able to facilitate the early detection of BCa in at-risk patients. Identification of BCa at an early stage may lead to improved patient outcomes. Using large multinational patient populations, we tested the performance of the Oncuria multiplex assay to accurately predict the risk of developing bladder cancer by simultaneously analyzing the concentrations of 10 protein biomarkers in urine samples. The online version contains supplementary material available at 10.1186/s12967-025-07511-1. Show less

The mechanism of hepatocarcinogenesis after sustained virological response (SVR) in hepatitis C virus (HCV) patients is unclear. We compared gene profiles of hepatocellular carcinoma (HCC) between HCV-SVR, steatotic liver disease (SLD), and HCV-non-SVR patients. This study analyzed 126 resected HCCs from patients with HCV and SLD, classifying them as HCV-SVR (n = 22), HCV-non-SVR (n = 56), and SLD (n = 48). Deep sequencing of 2910 hotspots in 55 cancer-related genes was conducted to examine mutations and copy number variations in both cancerous and background liver tissues. The HCV-SVR group comprised more patients who consumed alcohol (45.5% vs. 15.7%, p = 0.008), were obese (54.5% vs. 17.9%, p = 0.002), and had dyslipidemia (18.2% vs. 3.6%, p = 0.029) and hyperuricemia (18.2% vs. 3.6%, p = 0.029) than the HCV-non-SVR group. Mutational profiling of the HCV-SVR HCC showed significantly lower alteration rates of AXIN1 (13.6% vs. 42.9%, p = 0.016), ARID2 (9.1% vs. 39.3%, p = 0.013), and TP53 (9.1% vs. 32.1%, p = 0.030) than HCV-non-SVR patients. Compared with HCV-non-SVR-HCC, SLD-HCCs showed significantly lower rates of TERT promoter mutations (62.5% vs. 85.7%, p = 0.004), ARID2 alterations (12.5% vs. 39.3%, p = 0.003), and AXIN1 alterations (12.5% vs. 42.9%, p = 0.002). HCV-SVR/MASH/MASLD/ALD-HCC had significantly lower alteration rates of the Wnt/β-catenin (41.4% vs. 60.7%, p = 0.048) and chromatin remodeling pathways (27.1% vs. 48.2%, p = 0.026) than HCV-non-SVR-HCC. HCV-SVR HCC is linked to alcohol use and metabolic diseases, showing a mutational profile similar to SLD-HCC. Show less

Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure-activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors. Show less

Long noncoding RNAs (lncRNAs) are involved in various biological events. Previously we reported that lncRNA CCDC26 controls myeloid leukemia cell proliferation and mortality by regulating the proto-oncogene KIT. However, the mechanism of lncRNA CCDC26 effects on carcinogenesis and cell differentiation remains unclarified. To investigate the mechanism of lncRNA CCDC26 activity, we analyzed its protein partners using the S1 aptamer/cross-linking-immunoprecipitation (S1-CLIP) experiment. We identified a cytoskeleton protein (vimentin), chromatin proteins (chromobox 1/5 transcription factors [CBX1 and CBX5]) and a nuclear splicing-related protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) as its interaction partners. As lncRNA CCDC26 is ubiquitously present in the cell (in cytoplasm, nucleoplasm, and chromatin cellular fractions); these results evidence that lncRNA CCDC26 is a unique multifunctional lncRNA that functions by interacting with several proteins in multiple intracellular compartments. We further identified the sequence through which it interacts with proteins by using a series of truncated-lncRNA CCDC26 fragments and RNA immunoprecipitation (RIP) experiments. Furthermore, using RIP, we identified the vimentin domain required for the lncRNA CCDC26 binding. Notably, CCDC26 knockdown reduced CBX1/CBX5 binding at certain gene promoters, correlating with increased gene expression. These findings suggest that CCDC26 may regulate transcription by interacting with CBX1 and CBX5. Show less

Dual specific phosphatases (DUSPs) are a family of phosphatases, including DUSP4, DUSP5, and DUSP6, that function as negative regulators of the RAF/MEK/ERK pathway. These DUSPs have been extensively studied in various human cancers, particularly those with KRAS mutations. Our previous research indicated that these DUSPs are downregulated by KRAS knockdown in KRAS mutant lung cancer cell lines and upregulated in an hTERT/Cdk4-immortalized normal human bronchial cell line HBEC3-KT expressing mutant KRAS Show less

Metabolic syndrome (MetS) is linked to later-life cognitive decline and brain aging, but early detection of vulnerability in midlife remains challenging. This study applied two methods to detect subtle changes in midlife adults with MetS: (1) latent profile analysis (LPA) to identify cognitive performance patterns and (2) an MRI-derived brain-predicted age metric to assess structural brain aging. Participants were cognitively unimpaired, community-dwelling adults from prior studies on metabolic and brain health ( MetS prevalence differed across cognitive profiles (χ Cognitive profiles and brain-predicted age metrics identify early vulnerability in midlife MetS, underscoring the importance of early intervention. Show less

IgM-related AL amyloidosis is a rare and distinct clinical entity, often associated with underlying lymphoproliferative disorders such as Waldenström's macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL). Unlike non-IgM AL amyloidosis, it exhibits unique organ involvement patterns and generally poorer prognosis. We report a 66-year-old woman diagnosed with WM complicated by systemic IgM-κ AL amyloidosis. She received combination chemotherapy with rituximab and bendamustine (BR), resulting in a reduction of serum IgM levels. Despite the hematologic improvement, her liver dysfunction rapidly progressed, and she died of hepatic failure just two months after diagnosis. Pathological autopsy revealed massive IgM-κ amyloid deposition in the liver and multiple organs, with no residual lymphoma in the bone marrow or lymph nodes. These findings suggest that extensive hepatic amyloid infiltration was already present at diagnosis, and that organ response could not be achieved despite hematologic improvement. This case highlights the aggressive nature of IgM-related AL amyloidosis and the critical importance of early detection, especially when liver dysfunction is observed. Current therapies targeting the underlying clone may not be sufficient in cases with advanced organ involvement, emphasizing the urgent need for novel strategies to facilitate amyloid clearance and protect organ function. Show less

Long-persistent luminescence (LPL) materials have applications from safety signage to bioimaging; however, existing organic LPL (OLPL) systems do not align with human scotopic vision, which is sensitive to blue light. We present a strategy to blueshift the emissions in binary OLPL systems by upconverting the charge-transfer (CT) to a locally excited (LE) singlet state. Through rigorous steady-state and time-resolved photoluminescence spectroscopy and wavelength-resolved thermoluminescence measurements, we provide the direct experimental evidence for this upconversion in OLPL systems featuring small energy offsets between the lowest-energy CT and LE singlet states. These systems exhibited strong room temperature LPL, particularly when extrinsic electron traps are added. Importantly, the developed OLPL system achieved Class A (ISO 17398) LPL, matching well with human scotopic vision. The findings not only elucidate the role of small energy offsets in modulating LPL but also provide potential avenues for enhancing the efficiency and applicability of OLPL materials. Show less

AA amyloidosis is a rare renal complication of Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). A 66-year-old man with WM/LPL presented with nephrotic syndrome. A renal biopsy showed AA amyloidosis. Chemotherapy resulted in the remission of hematologic and nephrotic syndromes. Two years into follow-up, he became infected with coronavirus disease 2019 and had massive proteinuria, despite no relapse of WM/LPL. A second renal biopsy confirmed a diagnosis of AA amyloidosis. However, increased prednisolone did not improve proteinuria. The patient ultimately died of cryptococcal meningitis. This case highlights the diverse spectrum of renal involvement in monoclonal IgM-secreting diseases and difficulty in managing fatal complications. Show less

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Show less

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. While prostate-specific antigen is a widely used biomarker, its specificity is limited. This study investigated the prognostic significance of gene subsets associated with the ubiquitin-proteasome pathway in PCa. We analyzed transcriptomic and clinical data of 94 early-onset (age <55) patients with prostate cancer using public dataset. Differentially expressed genes linked to the ubiquitin-proteasome system were identified across cancer progression stages. Kaplan-Meier survival analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) modeling were applied to assess their prognostic potential. Differential expression of The identified gene subset provides novel prognostic insights into PCa progression and survival. These findings highlight potential biomarkers and therapeutic targets within the ubiquitin-proteasome pathway, offering new avenues for personalized treatment strategies. Show less

The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice. Show less

Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Here, we discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age in rats, correlating with age-dependent metabolic decline and increased adiposity. This "age-related ciliopathy" is promoted by overnutrition-induced upregulation of leptin-melanocortin signaling and inhibited or reversed by dietary restriction or the knockdown of ciliogenesis-associated kinase 1 (CILK1). Forced shortening of MC4R-bearing cilia in hypothalamic neurons by genetic approaches impaired neuronal sensitivity to melanocortin and resulted in decreased brown fat thermogenesis and energy expenditure and increased appetite, finally developing obesity and leptin resistance. Therefore, despite its acute anti-obesity effect, chronic leptin-melanocortin signaling increases susceptibility to obesity by promoting the age-related shortening of MC4R-bearing cilia. This study provides a crucial mechanism for age-related obesity, which increases the risk of metabolic syndrome. Show less

In a series of studies on blood-brain barrier transportable peptides, a soybean dipeptide, Tyr-Pro, penetrated the mouse brain parenchyma after oral intake and improved short and long memory impairment in acute Alzheimer's model mice. Here, we aimed to clarify the anti-dementia effects of this peptide administered to SAMP8 mice prior to dementia onset. At the end of the 25-week protocol in 16-week-old SAMP8 mice, Tyr-Pro (10 mg/kg/day) significantly improved the reduced spatial learning ability compared with that in the control and amino acid (Tyr + Pro) groups as indicated by the results of Morris water maze tests conducted for five consecutive days. The hippocampus and cortex regions of SAMP8 harvested after the test showed lower amyloid ß (Aß) accumulation in the Tyr-Pro group than those in the control and amino acid groups. Consistent with the lower level of Aß, decreased expression of ß-secretase (BACE1) and markedly increased expression (4-times higher) of insulin degrading enzyme (IDE) were obtained compared to those in the control group. Collectively, we demonstrated that long-term daily intake of the dipeptide Tyr-Pro in SAMP8 mice may be sufficient for maintaining cognitive ability by preventing excess Aß accumulation through downregulated BACE1 and particularly upregulated IDE. Show less

Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy. Show less

Cardio-ankle vascular index (CAVI) is an arterial stiffness index that correlates inversely with body mass index (BMI) and subcutaneous fat area. Lipoprotein lipase (LPL) that catalyzes the hydrolysis of serum triglycerides is produced mainly in adipocytes. Serum LPL mass reflects LPL expression in adipose tissue, and its changes correlate inversely with changes in CAVI. We hypothesized that LPL derived from subcutaneous adipose tissue (SAT) suppresses the progression of arteriosclerosis and examined the relationship of LPL gene expression in different adipose tissues and serum LPL mass with CAVI in Japanese patients with severe obesity undergoing laparoscopic sleeve gastrectomy (LSG). This study was a single-center retrospective database analysis. Fifty Japanese patients who underwent LSG and had 1-year postoperative follow-up data were enrolled (mean age 47.5 years, baseline BMI 46.6 kg/m2, baseline HbA1c 6.7%). SAT and visceral adipose tissue (VAT) samples were obtained during LSG surgery. LPL gene expression was analyzed by real-time PCR. Serum LPL mass was measured by ELISA using a specific monoclonal antibody against LPL. At baseline, LPL mRNA expression in SAT correlated positively with serum LPL mass, but LPL mRNA expression in VAT did not. LPL mRNA expression in SAT was correlated, and serum LPL mass tended to correlate inversely with the number of metabolic syndrome symptoms, but LPL mRNA expression in VAT did not. LPL mRNA expression in SAT and CAVI tended to correlate inversely in the group with visceral-to-subcutaneous fat ratio of 0.4 or higher, which is considered metabolically severe. Serum LPL mass increased 1 year after LSG. Change in serum LPL mass at 1 year after LSG tended to be an independent factor inversely associated with change in CAVI. Serum LPL mass reflected LPL mRNA expression in SAT in Japanese patients with severe obesity, and LPL mRNA expression in SAT was associated with CAVI in patients with visceral obesity. The change in serum LPL mass after LSG tended to independently contribute inversely to the change in CAVI. This study suggests that LPL derived from SAT may suppress the progression of arteriosclerosis. Show less

The epithelial-mesenchymal transition (EMT) is a phenomenon, in which epithelial cells acquire a mesenchymal cell phenotype. It is important during wound healing; however, chronic inflammation leads to excessive EMT and causes tissue barrier dysfunction with hyperplasia. EMT is induced by several cytokines, such as interleukin (IL)-4 and IL-13. Additionally, IL-4 and IL-13 are known to increase in atopic dermatitis (AD) characterized by intense itching and eczema. Therefore, we assumed that there was commonality between the respective EMT and AD phenotypes. Herein, we evaluated EMT marker expression in AD skin and demonstrated that EMT-maker Snai1 and Twist expression were increased in AD mice model and patients with AD. Moreover, the epithelial-marker keratin 5 and mesenchymal marker Vimentin were co-expressed in the skin epidermis of mice with AD, suggesting the existence of hybrid epithelial-mesenchymal (E/M) cells possessing both epithelial and mesenchymal characteristics. In fact, we found that ΔNp63a, a stabilizing factor for hybrid E/M cells, was upregulated in the skin epidermis of the AD model mouse. Interestingly, increased expression of EMT markers was observed even at a nonlesion site in a patient with AD without initial inflammation or scratching. Therefore, EMT-like phenomena may occur independently of wound healing in skin of patients with AD. Show less

Recent genome-wide association studies have revealed that nonalcoholic fatty liver disease (NAFLD) is correlated with genetic polymorphisms. However, the effects of genetic variation on nutritional metabolism and NAFLD are complex and further studies are still needed. This study aimed to assess the nutritional characteristics interacting with the correlation between genetic predisposition and NAFLD. We assessed the 2013-2017 health examination data of 1191 adults aged ≥40 y living in Shika town, Ishikawa Prefecture, Japan. Adults with moderate or heavy alcohol consumption and hepatitis were excluded, and 464 participants who underwent genetic analyses were included in the study. Abdominal echography was performed to diagnose fatty liver condition, and dietary intake and nutritional balance were evaluated using the brief self-administered diet history questionnaire. NAFLD-related gene polymorphisms were identified using Japonica Array v2 (Toshiba). Among the 31 single nucleotide polymorphisms, only the polymorphism T-455C in the apolipoprotein C3 ( The polymorphism T-455C in the Show less

Neoatherosclerosis (NA), which refers to neointimal atherosclerosis within a stent, is considered one of the underlying causes of late-phase stent failure following a newer generation drug-eluting stent (DES) placement procedure. Even contemporary guideline-directed medical therapy may be insufficient to prevent NA. This study aimed to investigate how intricately lipid markers are associated with NA formation in the early phase of treatment with well-maintained low-density lipoprotein cholesterol (LDL-C) levels. We enrolled 114 consecutive patients undergoing statin treatment and percutaneous coronary intervention (PCI) with current-generation DES for coronary artery disease. At a median 12 months after PCI, optical coherence tomography (OCT) was performed. Various lipid markers, including LDL-C, triglyceride (TG), triglyceride-rich lipoprotein cholesterol (TRL-C), non-high-density lipoprotein cholesterol (non-HDL-C), malondialdehyde-modified LDL (MDA-LDL), and several apolipoproteins, were also evaluated. NA was observed in 17 (14.9%) patients. The LDL-C level was equivalent in patients with or without NA (77.2 vs. 69.8 mg/dL; p=0.15). However, the levels of TG, apolipoprotein C3 (apoC3), TRL-C, non-HDL-C, and apolipoprotein B (apoB), and MDA-LDL were significantly higher in the patients with NA. Furthermore, multivariate logistic regression adjusting for HbA1c and stent duration revealed apoC3, TRL-C, non-HDL-C, apoB, and MDA-LDL levels as risk factors for NA. However, when apoB was included as a covariate, other factors became nonsignificant. Abnormal triglyceride-rich lipoprotein metabolism and high atherogenic apoB-containing lipoprotein particle numbers are associated with the formation of NA in patients undergoing statin treatment at a median 12 months post-PCI. 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

Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN. Show less