基本情報
研究キーワード
18経歴
3-
2017年4月 - 現在
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2013年4月 - 2017年3月
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2005年4月 - 2013年4月
学歴
3-
2000年4月 - 2005年3月
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1991年4月 - 1995年3月
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1989年4月 - 1991年3月
論文
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Circulation journal : official journal of the Japanese Circulation Society 78(10) 2483-2491 2014年10月 査読有り
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PLOS ONE 9(5) e96005 2014年5月 査読有りStatins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin-dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells.
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CIRCULATION JOURNAL 78(4) 962-966 2014年4月 査読有りBackground: Right atrial pressure (RAP) is commonly estimated using inferior vena cava (IVC) diameter and its respirophasic variations. Although a guideline has been provided for estimation of RAP due to variation in IVC dimensions based on studies in Western subjects, echocardiographic values in Asian subjects are unknown. Methods and Results: We studied 369 patients who underwent IVC ultrasound within 24h of right heart catheterization (RHO). The maximum and minimum IVC diameter during a respiratory cycle and the percent collapse after a sniff test were measured. These IVC parameters were compared with mean RAP measured on RHO. Receiver operating characteristic curves were generated for each IVC parameter to determine the optimal cut-off to detect RAP >10 mmHg. The IVC maximum diameter cut-off for detecting RAP >10 mmHg was 19 mm (sensitivity, 75%; specificity, 78%) and the percent collapse cut-off was 30% (sensitivity, 75%; specificity, 83%). Both cut-offs were smaller than those previously reported in patients from Western countries. When the cut-off values from the existing guideline were applied to the present cohort, the sensitivity and specificity for normal RAP (0-5 mmHg) were 38.6% and 74.2%, respectively, and 60.0% and 92.0% for elevated RAP (>10 mmHg). Conclusions: The optimal IVC maximum diameter and percent collapse cut-offs to detect elevated RAP were smaller in Asian subjects than in a previously reported Western cohort.
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Genome biology 15(4) R63 2014年4月 査読有り
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Circulation Journal 78(Suppl.I) 500-500 2014年3月
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Circulation Journal 78(Suppl.I) 219-219 2014年3月
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GENOME BIOLOGY 15(4) R63 2014年 査読有りBackground: Synergistic transcriptional activation by different stimuli has been reported along with a diverse array of mechanisms, but the full scope of these mechanisms has yet to be elucidated. Results: We present a detailed investigation of hypoxia-inducible factor (HIF) 1 dependent gene expression in endothelial cells which suggests the importance of crosstalk between the peroxisome proliferator-activated receptor (PPAR) beta/delta and HIF signaling axes. A migration assay shows a synergistic interaction between these two stimuli, and we identify angiopoietin-like 4 (ANGPTL4) as a common target gene by using a combination of microarray and ChIP-seq analysis. We profile changes of histone marks at enhancers under hypoxia, PPAR beta/delta agonist and dual stimulations and these suggest that the spatial proximity of two response elements is the principal cause of the synergistic transcription induction. A newly developed quantitative chromosome conformation capture assay shows the quantitative change of the frequency of proximity of the two response elements. Conclusions: To the best of our knowledge, this is the first report that two different transcription factors cooperate in transcriptional regulation in a synergistic fashion through conformational change of their common target genes.
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Arresting Treatment Patterns for Individual Patients in Clinical Big Data: An Exploratory Procedure.2014 AAAI Spring Symposia 2014年
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CIRCULATION 128(22) 2013年11月26日 査読有り
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LIPIDS IN HEALTH AND DISEASE 12 142 2013年10月 査読有りAims: Hypercholesterolemia coexisting with diabetes still requires clinical intervention to manage the high risk of cardiovascular disease it poses. No second-step strategy is established, however, for cases where strong statins fail to bring cholesterol down to target levels. In this study we seek to demonstrate the superior effect of ezetimibe in combination with strong statins to reduce LDL-C in Japanese patients suffering from both T2DM and hyper LDL-cholesterolemia. Methods: T2DM outpatients (109 patients from 16 institutes) who failed to achieve the target LDL-C value were recruited and randomly assigned to two groups, a double-dose-statin group and ezetimibe-plus-statin group. Follow-ups were scheduled at 0, 12, 26, and 52 weeks. The primary endpoint was the percentage change in the level of LDL-C from baseline to 12 weeks. Interim results: We could successfully create randomized (gender, age, LDL-C, HbA1c, etc.) two groups except for slight differences in apolipoprotein-B and sd-LDL. Conclusions: RESEARCH is the first prospective, parallel-group, multicenter study comparing a double dose of strong statin with ezetimibe plus strong statin for T2DM patients. The RESEARCH study will provide reliable evidence with which to establish a clinical strategy for diabetics who fail to achieve the target LDL-C value.
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INTERNATIONAL JOURNAL OF CARDIOLOGY 168(2) 1429-1434 2013年9月 査読有りBackground: Restenosis after percutaneous coronary intervention (PCI) is still a great concern even in the recent drug-eluting stent (DES) era. As less invasive and sensitive parameter to detect restenosis is needed, this study was aimed to assess whether the clinical implication of temporal change in plasma BNP levels might be a useful indicator of restenosis after DES implantation. Methods and results: 847 consecutive patients who underwent elective PCI using silorimus-eluting sent (SES) between 2005 and 2009 were analyzed. Primary endpoint was subsequent target-lesion revascularization (TLR) after PCI. There was no significant difference in either baseline (TLR + vs. TLR-: 107.2 +/- 172.2 vs. 96.2 +/- 175.5 pg/mL, P=0.53) or follow-up plasma B-type natriuretic peptide (BNP) levels (TLR + vs. TLR-: 88.6 +/- 111.6 vs. 68.5 +/- 226.0 pg/mL, P=0.35) between patients with and without subsequent TLR. Conversely, ratio of follow-up to baseline BNP was significantly higher in patients with TLR (TLR + vs. TLR-: 1.55 +/- 1.58 vs. 1.07 +/- 1.04, P<0.001). Multivariate analysis using logistic regression showed log transformed BNP-ratio was an independent predictor of TLR (adjusted odds ratio (aOR): 1.94, 95%CI: 1.42-2.66, P<0.001). A closer relationship between BNP elevation greater than 2-fold and subsequent TLR was found (aOR: 2.69, 95%CI: 1.27-5.69, P<0.009). Furthermore, propensity score matching analysis showed that the incidence of subsequent TLR was significantly higher in patients with BNP elevation (P<0.001). Conclusion: Serial measurement of plasma BNP levels and its change might be a useful approach to predict restenosis in patients without typical chest symptoms receiving SES. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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HYPERTENSION RESEARCH 36(6) 559-563 2013年6月 査読有りThe Japanese Society of Hypertension (JSH) updated its hypertension management guidelines in 2009. One of the most significant changes with respect to the 2004 version was the stance towards the use of diuretics: in 2004, their use was cautioned against, but in 2009, it was actively promoted. The purpose of this study was to measure the impact of this change in guidelines on prescription patterns for antihypertensive medications, and to investigate the overall trend in the use of antihypertensives. We used monthly claims data obtained from a database company. Data of patients who were 20 or more years old and prescribed antihypertensives were extracted and analyzed. There were 66 223 patients who were prescribed antihypertensives (mean age 53.6 +/- 11.0). Of these, 38 130 were men and 28 093 were women. The two most prescribed classes of antihypertensives were angiotensin receptor blockers, whose usage steadily increased over a 7-year period, and calcium channel blockers. Prescriptions for antihypertensives in these two classes were also more likely to be continued than those for other antihypertensive classes. The prescription rate for diuretics increased from December 2006 (P<0.0001), but the rate of increase was the same before and after 2009 (P=0.09). The clinical guidelines published in 2009 had no apparent impact on the trend of diuretic prescriptions, despite the radical change in stance concerning the use of antihypertensives. Further effort to disseminate the content of these guidelines, so that it is reflected in actual clinical practice, may be warranted.
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Journal of Cardiology 61(6) 387-392 2013年6月 査読有りBackground: Although increased attention is given to assess absolute values of serum cholesterol profiles as optimal markers for preventing future cardiovascular (CV) events, changes in cholesterol profiles also have the potential to be associated with CV disease outcome in Japanese patients with acute coronary syndrome (ACS). Methods: From the database of the Japanese Coronary Artery Disease (JCAD) study, 2664 patients with ACS who had serial measurements of serum cholesterol profile parameters were enrolled. These patients were followed-up for a mean period of 2.7 years. The endpoint was all CV events. Baseline clinical characteristics of patients with and without CV events were adjusted by the propensity score matching analysis. Results: None of the serum absolute cholesterol profiles at baseline and 6 months later was associated with CV events, except for baseline serum total cholesterol level. However, large improvements in cholesterol profiles correlated with better CV disease outcome. Conclusions: This subanalysis of JCAD demonstrated the importance of serial assessment of serum cholesterol profiles for secondary prevention of CV events in Japanese patients with ACS. Changes in serum cholesterol profiles, rather than their absolute values, correlated with future CV events. © 2013.
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Hypertension research : official journal of the Japanese Society of Hypertension 36(2) 140-150 2013年2月 査読有り
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CIRCULATION JOURNAL 77(1) 43-44 2013年1月 査読有り
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International Heart Journal 54(2) 93-97 2013年 査読有りThere have been few reports concerning the trends in antidiabetic drug use in Japan. In 2009, a dipeptidyl peptidase- 4 inhibitor (DPP4I), an antidiabetic with a new mechanism of action, was made available. This study was conducted to analyze the antidiabetic prescription trends in Japan in recent years and the influence of DPP4Is on those trends. We used monthly claims data obtained from a database company. Data from patients 20 years of age or older and who were prescribed antidiabetics were extracted and analyzed. A total of 18,457 patients were prescribed antidiabetics (mean age, 53.6 ± 11.0). The sulfonylurea prescription rate decreased while that of biguanides increased. After the introduction of DPP4Is, use of these agents rapidly increased and the rate further increased one year after DPP4I introduction. DPP4Is also became the most prescribed antidiabetics for those prescribed antidiabetics for the first time. The decrease in the use of sulfonylureas and the increase in the use of biguanides are in accordance with trends observed in the United States and Europe, and probably reflect Japanese physicians' awareness of cumulating evidence gained from studies such as the UK Prospective Diabetes Study (UKPDS). The rapid increase in the DPP4I prescription rate might be the result of several factors including their safety profiles, which were highlighted in clinical studies published just prior to the drugs becoming available. However, there is little data regarding the efficacy of DPP4Is in reducing diabetes related complications, which should be determined in future studies.
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Proceedings of ECMLPKDD2013 Workshop on Reinforcement Learning with Generalized Feedback 2013年 査読有り
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Proceedings of ICML2013 Workshop on Role of Machine Learning in Transforming Healthcare 2013年 査読有り
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人工知能学会全国大会論文集 2013 1E45-1E45 2013年<p>日々蓄積される臨床データから有益な示唆を得るため、強化学習を利用したい。 本発表では、病気の治療過程を観測・行動の系列、医者の処方を方策と捉えて、 循環器内科の治療履歴データに対して強化学習によって方策推定した結果を報告する。 </p>
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CIRCULATION 126(21) 2012年11月20日 査読有り
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The EMBO journal 31(23) 4404-4414 2012年11月 査読有り
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MOLECULAR AND CELLULAR BIOLOGY 32(15) 3018-3032 2012年8月 査読有り
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International heart journal 53(3) 170-175 2012年5月 査読有り
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Atherosclerosis 221(1) 148-153 2012年3月 査読有り
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Clinica chimica acta; international journal of clinical chemistry 413(5-6) 577-581 2012年3月 査読有り
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American heart journal 163(2) 268-273 2012年2月 査読有り
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Gene expression 15(4) 183-198 2012年 査読有り
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Development and implementation of an advanced coronary angiography and intervention database system.International heart journal 53(1) 35-42 2012年 査読有り
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The American journal of cardiology 108(12) 1801-1807 2011年12月15日 査読有り
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ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES 28(10) 1148-1155 2011年11月 査読有りBackground: The subendocardial myocardium normally has higher systolic strain than the subepicardial myocardium and can be damaged first in face of ischemia. We investigated the reproducibility and feasibility of novel three-layer speckle tracking system and compared the diagnostic accuracy with experienced visual interpretation. Methods: An ameroid constrictor was placed around the proximal left circumflex (LCX) coronary artery in 19 pigs. Four weeks later, subtotal stenosis was confirmed in all pigs by coronary angiogram. Two dead pigs and three pigs with pathological infarction were excluded. Transthoracic left ventricle (LV) short-axis echocardiograms were recorded at rest before and 4 weeks after the operation. LV posterior wall motion was scored by two experienced doctors and analyzed by the speckle tracking system (n = 14). Results: Strain variables gave reasonable intra/interobserver reproducibility (mean absolute percentage errors = 13/19, intraclass correlation coefficients = 0.97/0.92). All strain variables and visual wall-motion scores changed significantly during stenosis (P < 0.05). Of all variables, endocardial strains, particularly the circumferential strain demonstrated the highest area under curve (AUC), showing better diagnostic accuracy than experienced visual interpretation (sensitivity 0.93 vs. 0.79, specificity 0.93 vs. 0.73, AUC 0.95 vs. 0.77, P < 0.05). Conclusion: Three-layer speckle tracking is a feasible and reproducible modality. In particular, endocardial speckle tracking provides incremental value in accurately identifying regional ischemia even in the rest echocardiography. (Echocardiography 2011;28:1148-1155)
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Circulation journal : official journal of the Japanese Circulation Society 75(9) 2062-2070 2011年9月 査読有り
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Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 7 13-19 2011年9月 査読有り
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Molecular and cellular biology 31(11) 2196-2209 2011年6月 査読有り
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Epigenetically coordinated GATA2 binding is necessary for endothelium-specific endomucin expression.The EMBO journal 30(13) 2582-2595 2011年6月 査読有り
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Journal of cardiology 57(3) 311-315 2011年5月 査読有り
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RUSSIAN JOURNAL OF CARDIOLOGY (2) 111-119 2011年 査読有りNicorandil has cardioprotective effects in the ischemic myocardium, mimicking ischemic preconditioning, and is thus expected to improve the prognosis of ischemic heart disease (IHD). As part of the Japanese Coronary Artery Disease (JCAD) Study, a multi-centre collaborative prospective observational study of a large cohort of coronary artery disease patients, the effect of nicorandil on outcome was examined. In total, 2,558 patients with nicorandil treatment and controls subjected to propensity score matching were eligible among 13,812 patients registered in the JCAD study. The mean follow-up interval was 2,7 years. The primary endpoint, death from all causes, was significantly lower, by 35% (hazard ratio 0,65, p=0,0008), in the nicorandil group than in the control group. There were also significant reductions in secondary endpoints, including cardiac death (56%), fatal myocardial infarction (56%), cerebral or vascular death (71%), and congestive heart failure (33%) in the nicorandil group, with no excess of deaths from other non-cardiovascular causes. Treatment with nicorandil reduced the number of deaths from all causes to a similar extent with or without treatment with sulfonylureas. The reduction in cardiovascular death with nicorandil was large in patients with IHD, which has important implications for treatment.
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Circulation journal : official journal of the Japanese Circulation Society 74(11) 2441-2447 2010年11月 査読有り
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Heart and vessels 25(6) 453-459 2010年11月 査読有り
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International heart journal 51(5) 299-302 2010年9月 査読有り
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Circulation journal : official journal of the Japanese Circulation Society 74(5) 962-969 2010年5月 査読有り
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Relationship between renal dysfunction and severity of coronary artery disease in Japanese patients.Circulation journal : official journal of the Japanese Circulation Society 74(4) 786-791 2010年4月 査読有り
MISC
67共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2014年4月 - 2017年3月
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日本学術振興会 科学研究費助成事業 2011年4月 - 2014年3月
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日本学術振興会 科学研究費助成事業 2010年 - 2012年
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日本学術振興会 科学研究費助成事業 2005年 - 2006年