Publications by authors named "Takashi Yamamoto"

682 Publications

Mathematical modeling and mutational analysis reveal optimal therapy to prevent malignant transformation in grade II IDH-mutant gliomas.

Cancer Res 2021 Jul 31. Epub 2021 Jul 31.

University of Tokyo.

WHO grade II isocitrate dehydrogenase mutant gliomas (IDHmut-LGGs) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8-2.8 times compared to before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs ({less than or equal to} 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, phosphoinositide 3-kinase mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0985DOI Listing
July 2021

α-Methylacyl-CoA racemase: a useful immunohistochemical marker of breast carcinoma with apocrine differentiation.

Hum Pathol 2021 Jul 24. Epub 2021 Jul 24.

Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka 5418567, Japan. Electronic address:

Carcinoma with apocrine differentiation is an androgen receptor (AR)-positive subset of triple-negative breast carcinomas. In addition to carcinoma with apocrine differentiation, other AR-positive triple-negative breast carcinomas occur, albeit less frequently. We found that α-methylacyl-CoA racemase (AMACR), also known as P504S, is overexpressed in carcinoma with apocrine differentiation and non-neoplastic apocrine metaplasia. We aimed to evaluate AMACR as a possible marker of carcinoma with apocrine differentiation. We immunohistochemically examined the expression of AMACR in carcinoma with apocrine differentiation and non-apocrine carcinomas and compared it with that of gross cystic disease fluid protein-15 (GCDFP-15). In total, 212 breast carcinomas were evaluated: 39 carcinomas with apocrine differentiation, 28 ductal carcinomas in situ with apocrine morphology (ADCIS), and 145 non-apocrine breast carcinomas. AMACR was expressed in 38 out of 39 (97.4%) carcinomas with apocrine differentiation and in 27 out of 28 (96.4%) ADCIS, consistent with the expression of GCDFP-15. However, in non-apocrine carcinomas, AMACR expression was observed in 32 out of 145 (22.0%) lesions, whereas GCDFP-15 expression was observed in 91 out of 145 (62.7%) lesions. For carcinoma with apocrine differentiation, AMACR was as sensitive as GCDFP-15 (both 97.1%) but more specific (77.9% vs. 37.2%). In selected cases, AMACR mRNA levels were quantitatively determined relative to that of TATA-binding protein mRNA, and they comprised 5.23, 1.33, and 0.60 for carcinomas with apocrine differentiation, non-apocrine carcinomas, and normal breast tissue, respectively. CONCLUSION: Our findings demonstrate that AMACR expression may be utilized for differentiating carcinoma with apocrine differentiation from non-apocrine carcinomas and indicate that AMACR is a more sensitive carcinoma with apocrine differentiation marker than GCDFP-15.
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http://dx.doi.org/10.1016/j.humpath.2021.07.005DOI Listing
July 2021

Coronary Revascularization in the Past Two Decades in Japan (From the CREDO-Kyoto PCI/CABG Registries Cohort-1, -2, and -3).

Am J Cardiol 2021 Aug 6;153:20-29. Epub 2021 Jul 6.

Department of Cardiology, Koto Memorial Hospital, Higashiomi, Japan.

The treatment of coronary artery disease has substantially changed over the past two decades. However, it is unknown whether and how much these changes have contributed to the improvement of long-term outcomes after coronary revascularization. We assessed trends in the demographics, practice patterns and long-term outcomes in 24,951 patients who underwent their first percutaneous coronary intervention (PCI) (n = 20,106), or isolated coronary artery bypass grafting (CABG) (n = 4,845) using the data in a series of the CREDO-Kyoto PCI/CABG Registries (Cohort-1 [2000 to 2002]: n = 7,435, Cohort-2 [2005 to 2007]: n = 8,435, and Cohort-3 [2011 to 2013]: n = 9,081). From Cohort-1 to Cohort-3, the patients got progressively older across subsequent cohorts (67.0 ± 10.0, 68.4 ± 9.9, and 69.8 ± 10.2 years, p < 0.001). There was increased use of PCI over CABG (73.5%, 81.9%, and 85.2%, p < 0.001) and increased prevalence of evidence-based medications use over time. The cumulative 3-year incidence of all-cause death was similar across the 3 cohorts (9.0%, 9.0%, and 9.3%, p = 0.74), while cardiovascular death decreased over time (5.7%, 5.1%, and 4.8%, p = 0.03). The adjusted risk for all-cause death and for cardiovascular death progressively decreased from Cohort-1 to Cohort-2 (HR:0.89, 95%CI:0.80 to 0.99, p = 0.03, and HR:0.80, 95%CI:0.70 to 0.92, p = 0.002, respectively), and from Cohort-2 to Cohort-3 (HR:0.86, 95%CI:0.78 to 0.95, p = 0.004, and HR:0.77, 95%CI:0.67-0.89, p < 0.001, respectively). The risks for stroke and repeated coronary revascularization also improved over time. In conclusions, we found a progressive and substantial reduction of adjusted risk for all-cause death, cardiovascular death, stroke, and repeated coronary revascularization over the past two decades in Japan.
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http://dx.doi.org/10.1016/j.amjcard.2021.05.015DOI Listing
August 2021

Manifestation purpurique d’un myxome auriculaire infecté.

CMAJ 2021 May;193(21):E788-E789

Départements de cardiologie (Yamamoto, Yamashita) et de chirurgie cardiovasculaire (Hagiwara), Organisation nationale des hôpitaux, Centre médical Nagoya, Aichi, Japon.

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http://dx.doi.org/10.1503/cmaj.201351-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177915PMC
May 2021

Impact of dental health intervention on cardiovascular metabolic risk: a pilot study of Japanese adults.

J Hum Hypertens 2021 May 18. Epub 2021 May 18.

Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan.

This study aimed to determine whether a dental health education program would reduce cardiometabolic risk (obesity, hypertension, dyslipidemia, and hyperglycemia) in people with periodontitis. We used annual check-up data provided by the Japanese company's health insurance union. Of 182 male employees with cardiometabolic risk and periodontal pockets at baseline, 21 participants of the dental health education program and 21 non-participants matched for age, the presence of obesity, and periodontal pocket at baseline were allocated to the intervention (mean age, 53.3 ± 7.0) and the non-intervention groups (mean age, 52.9 ± 7.0), respectively. The program focused on self-removal of dental plaque with a toothbrush and interdental brush and comprised five sessions over 12 months. In the intervention group, waist circumference (cm) and diastolic blood pressure (mmHg) decreased from 88.4 ± 6.3 to 86.8 ± 6.3 and from 85.7 ± 8.2 to 82.6 ± 8.3, respectively (P < 0.05). Intergroup comparison showed significant improvement of systolic blood pressure (mmHg) in the intervention group (-3.7 ± 12.5) compared with the non-intervention group (4.0 ± 15.9) (P < 0.05) with no significant differences in the other parameters. The intervention group had a decrease in plaque accumulation and periodontitis symptoms, such as the depth of periodontal pocket and the presence of periodontal pocket and bleeding on probing, but an increase in the frequency of interdental brushing and duration of tooth brushing. Our findings show that dental self-care may improve blood pressure in people with cardiometabolic risk factors and periodontitis.
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http://dx.doi.org/10.1038/s41371-021-00551-2DOI Listing
May 2021

Mode of death in elderly and super-elderly patients with acute heart failure: Insights from Japanese heart failure registry.

Clin Cardiol 2021 Jun 8;44(6):848-856. Epub 2021 May 8.

Department of Cardiology, Hirakata Kohsai Hospital, Osaka, Japan.

Background: In Japan, both the prevalence of the elderly and super-elderly and those of acute heart failure (AHF) have been increasing rapidly.

Methods: This registry was a prospective multicenter cohort, which enrolled a total of 1253 patients with AHF. In this study, 1117 patients' follow-up data were available and were categorized into three groups according to age: <75 years old (nonelderly), 75-84 years old (elderly), and ≥ 85 years old (super-elderly). The endpoint was defined as all-cause death and each mode of death after discharge during the 3-years follow-up period.

Results: Based on the Kaplan-Meier analysis, a gradually increased risk of all-cause death according to age was found. Among the three groups, the proportion of HF death was of similar trend; however, the proportion of infection death was higher in elderly and super-elderly patients. After adjusting for potentially confounding effects using the Cox and Fine-Gray model, the hazard ratio (HR) of all-cause death increased significantly in elderly and super-elderly patients (HR, 2.60; 95% confidence interval [CI], 1.93-3.54 and HR, 5.04; 95% CI, 3.72-6.92, respectively), when compared with nonelderly patients. The highest sub-distribution HR in detailed mode of death was infection death in elderly and super-elderly patients (HR, 4.25; 95% CI, 1.75-10.33 and HR, 10.10; 95% CI, 3.78-27.03, respectively).

Conclusions: In this population, the risk of all-cause death was found to increase in elderly and super-elderly. Elderly patients and especially super-elderly patients with AHF were at a higher risk for noncardiovascular death, especially infection death.
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http://dx.doi.org/10.1002/clc.23619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207972PMC
June 2021

Analysis of facial expressions in response to basic taste stimuli using artificial intelligence to predict perceived hedonic ratings.

PLoS One 2021 4;16(5):e0250928. Epub 2021 May 4.

Department of Nutrition, Faculty of Health Sciences, Kio University, Nara, Japan.

Taste stimuli can induce a variety of physiological reactions depending on the quality and/or hedonics (overall pleasure) of tastants, for which objective methods have long been desired. In this study, we used artificial intelligence (AI) technology to analyze facial expressions with the aim of assessing its utility as an objective method for the evaluation of food and beverage hedonics compared with conventional subjective (perceived) evaluation methods. The face of each participant (10 females; age range, 21-22 years) was photographed using a smartphone camera a few seconds after drinking 10 different solutions containing five basic tastes with different hedonic tones. Each image was then uploaded to an AI application to achieve outcomes for eight emotions (surprise, happiness, fear, neutral, disgust, sadness, anger, and embarrassment), with scores ranging from 0 to 100. For perceived evaluations, each participant also rated the hedonics of each solution from -10 (extremely unpleasant) to +10 (extremely pleasant). Based on these, we then conducted a multiple linear regression analysis to obtain a formula to predict perceived hedonic ratings. The applicability of the formula was examined by combining the emotion scores with another 11 taste solutions obtained from another 12 participants of both genders (age range, 22-59 years). The predicted hedonic ratings showed good correlation and concordance with the perceived ratings. To our knowledge, this is the first study to demonstrate a model that enables the prediction of hedonic ratings based on emotional facial expressions to food and beverage stimuli.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096070PMC
May 2021

Association Between Physical Status and the Effects of Combination Therapy With Renin-Angiotensin System Inhibitors and β-Blockers in Patients With Acute Heart Failure.

Circ Rep 2021 Mar 13;3(4):217-226. Epub 2021 Mar 13.

Department of Cardiology, Hirakata Kohsai Hospital Osaka Japan.

This study investigated whether combination therapy (CT) with renin-angiotensin system inhibitors and β-blockers improved endpoints in acute heart failure (AHF). AHF patients were recruited to this prospective multicenter cohort study between April 2015 and August 2017. Patients were divided into 3 categories based on ejection fraction (EF), namely heart failure (HF) with reduced EF (HFrEF), HF with midrange EF (HFmrEF), and HF with preserved EF (HFpEF), and a further into 2 groups according to physical status (those who could walk independently outdoors and those who could not). The composite endpoint included all-cause mortality and hospitalization for HF. Data at the 1-year follow-up were available for 1,018 patients. The incidence of the composite endpoint was significantly lower in the CT than non-CT group for HFrEF patients, but not among HFmrEF and HFpEF patients. For patients who could walk independently outdoors, a significantly lower rate of the composite endpoint was recorded only in the HFrEF group. The differences were maintained even after adjustment for comorbidities and prescriptions, with hazard ratios (95% confidence intervals) of 0.39 (0.20-0.76) and 0.48 (0.22-0.99), respectively. In this study, CT was associated with the prevention of adverse outcomes in patients with HFrEF. Moreover, CT prevented adverse events only among patients without a physical disorder, not among those with a physical disorder.
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http://dx.doi.org/10.1253/circrep.CR-20-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024019PMC
March 2021

Pou5f3.3 is involved in establishment and maintenance of hematopoietic cells during Xenopus development.

Tissue Cell 2021 Mar 22;72:101531. Epub 2021 Mar 22.

Department of Life Science, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo, 171-8501, Japan. Electronic address:

Three POU family class V gene homologues are expressed in the development of Xenopus. In contrast to the expression of Pou5f3.1 and Pou5f3.2 in organogenesis, Pou5f3.3 is expressed during oogenesis in ovary. We investigated the expression and function of Pou5f3.3 in organogenesis of Xenopus laevis. RT-PCR and immunohistochemical analysis indicated that Pou5f3.3 was expressed in a small number of adult liver cells and blood cells. Immunocytochemical investigation proved that Bmi1, a marker for hematopoietic progenitor cells, was co-expressed in Pou5f3.3-expressing small spherical cells in the peripheral blood. In anemic induction by intraperitoneal injection of phenyl hydrazine, the number of Pou5f3.3-expressing cells significantly increased within 3 days after phenyl hydrazine injection. In CRISPR/Cas mutagenesis of Pou5f3.3, Bmi1-positive hematopoietic progenitor cell count decreased in the hematopoietic dorsal-lateral plate (DLP) region, resulting in a considerable reduction in peripheral blood cells. CRISPR/Cas-induced hematopoietic deficiency was completely rescued by Pou5f3.3 supplementation, but not by Pou5f3.1 or Pou5f3.2. Transplantation experiments using the H2B-GFP transgenic line demonstrated that DLP-derived Pou5f3.3-positive and Bmi1-positive cells were translocated into the liver and bone through the bloodstream. These results suggest that Pou5f3.3 plays an essential role in the establishment and maintenance of hematopoietic progenitor cells during Xenopus development.
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http://dx.doi.org/10.1016/j.tice.2021.101531DOI Listing
March 2021

Changes in demographics, clinical practices and long-term outcomes of patients with ST segment-elevation myocardial infarction who underwent coronary revascularisation in the past two decades: cohort study.

BMJ Open 2021 03 31;11(3):e043683. Epub 2021 Mar 31.

Division of Cardiology, Kokura Memorial Hospital, Kitakyushu, Japan.

Objective: To evaluate changes in demographics, clinical practices and long-term clinical outcomes of patients with ST segment-elevation myocardial infarction (STEMI) before and beyond 2010.

Design: Multicentre retrospective cohort study.

Setting: The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) AMI Registries Wave-1 (2005-2007, 26 centres) and Wave-2 (2011-2013, 22 centres).

Participants: 9001 patients with STEMI who underwent coronary revascularisation (Wave-1: 4278 patients, Wave-2: 4723 patients).

Primary And Secondary Outcome Measures: The primary outcome was all-cause death at 3 years. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, target vessel revascularisation, ischaemia-driven target vessel revascularisation, any coronary revascularisation and any ischaemia-driven coronary revascularisation.

Results: Patients in Wave-2 were older, more often had comorbidities and more often presented with cardiogenic shock than those in Wave-1. Patients in Wave-2 had shorter onset-to-balloon time and door-to-balloon time, were more frequently implanted drug-eluting stents, and received guideline-directed medication than those in Wave-1. The cumulative 3-year incidence of all-cause death was not significantly different between Wave-1 and Wave-2 (15.5% and 15.7%, p=0.77). The adjusted risk of all-cause death in Wave-2 relative to Wave-1 was not significant at 3 years (HR 0.92, 95% CI 0.83 to 1.03, p=0.14), but lower beyond 30 days (HR 0.86, 95% CI 0.75 to 0.98, p=0.03). The adjusted risks of Wave-2 relative to Wave-1 were significantly lower for definite stent thrombosis (HR 0.59, 95% CI 0.43 to 0.81, p=0.001) and for any coronary revascularisation (HR 0.75, 95% CI 0.69 to 0.81, p<0.001), but higher for major bleeding (HR 1.34, 95% CI 1.20 to 1.51, p=0.005).

Conclusions: We could not demonstrate improvement in 3-year mortality risk from Wave-1 to Wave-2, but we found reduction in mortality risk beyond 30 days. We also found risk reduction for definite stent thrombosis and any coronary revascularisation, but an increase in the risk of major bleeding from Wave-1 to Wave-2.
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http://dx.doi.org/10.1136/bmjopen-2020-043683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016093PMC
March 2021

Anodic Oxidation of Phenols: A Key Step for the Synthesis of Natural Products.

Chem Rec 2021 Mar 23. Epub 2021 Mar 23.

Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama, 223-8522, Japan.

Natural products have played a significant role not only in discovery of drugs but also in development of organic chemistry by providing the synthetic challenges. Inspired by biosynthesis where enzymes catalyze a multi-step reaction, we have investigated the natural product synthesis utilizing electrochemical reactions as the key step. Electrochemical organic synthesis, so-called electro-organic synthesis, enables to control the reactivity of substrates simply by tuning electrolysis conditions. In this Personal Account, we overview the recent progress of our research projects about natural product synthesis, in which anodic oxidation of phenol compounds affords the important frameworks such as diaryl ether, spirodienone, and spiroisoxazoline.
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http://dx.doi.org/10.1002/tcr.202100032DOI Listing
March 2021

Infected atrial myxoma presenting with purpura.

CMAJ 2021 Mar;193(10):E340

Departments of Cardiology (Yamamoto, Yamashita), and Cardiovascular Surgery (Hagiwara), National Hospital Organization Nagoya Medical Center, Aichi, Japan.

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http://dx.doi.org/10.1503/cmaj.201351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034313PMC
March 2021

Study of Radiation Characteristics of Intrinsic Josephson Junction Terahertz Emitters with Different Thickness of BiSrCaCuO Crystals.

Materials (Basel) 2021 Feb 28;14(5). Epub 2021 Feb 28.

Algae Biomass and Energy System R & D Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan.

The radiation intensity from the intrinsic Josephson junction high-Tc superconductor Bi2Sr2CaCu2O8+δ terahertz emitters (Bi2212-THz emitters) is one of the most important characteristics for application uses of the device. In principle, it would be expected to be improved with increasing the number of intrinsic Josephson junctions in the emitters. In order to further improve the device characteristics, we have developed a stand alone type of mesa structures (SAMs) of Bi2212 crystals. Here, we understood the radiation characteristics of our SAMs more deeply, after we studied the radiation characteristics from three SAMs (S1, S2, and S3) with different thicknesses. Comparing radiation characteristics of the SAMs in which the number of intrinsic Josephson junctions are ∼ 1300 (S1), 2300 (S2), and 3100 (S3), respectively, the radiation intensity, frequency as well as the characteristics of the device working bath temperature are well understood. The strongest radiation of the order of few tens of microwatt was observed from the thickest SAM of S3. We discussed this feature through the N2-relationship and the radiation efficiency of a patch antenna. The thinner SAM of S1 can generate higher radiation frequencies than the thicker one of S3 due to the difference of the applied voltage per junctions limited by the heat-removal performance of the device structures. The observed features in this study are worthwhile designing Bi2212-THz emitters with better emission characteristics for many applications.
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http://dx.doi.org/10.3390/ma14051135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957731PMC
February 2021

The complete chloroplast genome of a pantropical legume, .

Mitochondrial DNA B Resour 2021 Feb 3;6(2):295-296. Epub 2021 Feb 3.

Iriomote Station, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa, Japan.

We assembled a complete chloroplast genome of a pantropical legume, (Fabaceae). The chloroplast genome was 158,059 bp in length that was composed of a 77,752 bp large single copy region, a 18,993 bp small single copy region, and a pair of 30,657 bp inverted repeats. We detected 135 genes that consisted of 90 protein-coding genes, 37 tRNA genes, eight rRNA genes, and three pseudogenes ( and a pair of ).
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http://dx.doi.org/10.1080/23802359.2020.1859341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872567PMC
February 2021

Global political responsibility for the conservation of albatrosses and large petrels.

Sci Adv 2021 Mar 3;7(10). Epub 2021 Mar 3.

U.S. Geological Survey, Western Ecological Research Center, Santa Cruz Field Station, 2885 Mission St, Santa Cruz, CA 95060, USA.

Migratory marine species cross political borders and enter the high seas, where the lack of an effective global management framework for biodiversity leaves them vulnerable to threats. Here, we combine 10,108 tracks from 5775 individual birds at 87 sites with data on breeding population sizes to estimate the relative year-round importance of national jurisdictions and high seas areas for 39 species of albatrosses and large petrels. Populations from every country made extensive use of the high seas, indicating the stake each country has in the management of biodiversity in international waters. We quantified the links among national populations of these threatened seabirds and the regional fisheries management organizations (RFMOs) which regulate fishing in the high seas. This work makes explicit the relative responsibilities that each country and RFMO has for the management of shared biodiversity, providing invaluable information for the conservation and management of migratory species in the marine realm.
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http://dx.doi.org/10.1126/sciadv.abd7225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929510PMC
March 2021

Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation.

Nat Metab 2021 02 18;3(2):196-210. Epub 2021 Feb 18.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogenesis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore, acetylome analysis of Hmgcs2 KO cells revealed enhanced acetylation of mitochondrial proteins. These findings suggest that neonatal ketogenesis protects the energy-producing capacity of mitochondria by preventing the hyperacetylation of mitochondrial proteins.
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http://dx.doi.org/10.1038/s42255-021-00342-6DOI Listing
February 2021

Quantitative assessment of erector spinae muscles and prognosis in elderly patients with pneumonia.

Sci Rep 2021 Feb 22;11(1):4319. Epub 2021 Feb 22.

Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

Erector spinae muscle (ESM) size has been reported as a predictor of prognosis in patients with some respiratory diseases. This study aimed to assess the association of ESM size on all-cause in-hospital mortality among elderly patients with pneumonia. We retrospectively included patients (age: ≥ 65 years) admitted to hospital from January 2015 to December 2017 for community-acquired pneumonia who underwent chest computed tomography (CT) on admission. The cross-sectional area of the ESM (ESMcsa) was measured on a single-slice CT image at the end of the 12th thoracic vertebra and adjusted by body surface area (BSA). Cox proportional hazards regression models were used to assess the influence of ESMcsa/BSA on in-hospital mortality. Among 736 patients who were admitted for pneumonia, 702 patients (95%) underwent chest CT. Of those, 689 patients (98%) for whom height and weight were measured to calculate BSA were included in this study. Patients in the non-survivor group were significantly older, had a greater frequency of respiratory failure, loss of consciousness, lower body mass index, hemoglobin, albumin, and ESMcsa/BSA. Multivariate analysis showed that a lower ESMcsa/BSA independently predicted in-hospital mortality after adjusting for these variables. In elderly patients with pneumonia, quantification of ESMcsa/BSA may be associated with in-hospital mortality.
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http://dx.doi.org/10.1038/s41598-021-83995-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900176PMC
February 2021

Demographics, practice patterns and long-term outcomes of patients with non-ST-segment elevation acute coronary syndrome in the past two decades: the CREDO-Kyoto Cohort-2 and Cohort-3.

BMJ Open 2021 02 22;11(2):e044329. Epub 2021 Feb 22.

Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: To evaluate patient characteristics and long-term outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) in the past two decades.

Design: Multicenter retrospective study.

Setting: The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) Registry Cohort-2 (2005-2007) and Cohort-3 (2011-2013).

Participants: 3254 patients with NSTEACS who underwent first coronary revascularisation.

Primary And Secondary Outcome Measures: The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, any coronary revascularisation and target vessel revascularisation.

Results: Patients in Cohort-3 were older and more often had heart failure at admission than those in Cohort-2. The prevalence of PCI, emergency procedure and guideline-directed medical therapy was higher in Cohort-3 than in Cohort-2. In patients who received PCI, the prevalence of transradial approach, drug-eluting stent use and intravascular ultrasound use was higher in Cohort-3 than in Cohort-2. There was no change in 3-year adjusted mortality risk from Cohort-2 to Cohort-3 (HR 1.00, 95% CI 0.83 to 1.22, p=0.97). Patients in Cohort-3 compared with those in Cohort-2 were associated with lower adjusted risks for stroke (HR 0.65, 95% CI 0.46 to 0.92, p=0.02) and any coronary revascularisation (HR 0.76, 95%CI 0.66 to 0.87, p<0.001), but with higher risk for major bleeding (HR 1.25, 95% CI 1.06 to 1.47, p=0.008). The unadjusted risk for definite stent thrombosis was lower in Cohort-3 than in Cohort 2 (HR 0.29, 95% CI 0.11 to 0.67, p=0.003).

Conclusions: In the past two decades, we did not find improvement for mortality in patients with NSTEACS. We observed a reduction in the risks for definite stent thrombosis, stroke and any coronary revascularisation, but an increase in the risk for major bleeding.
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http://dx.doi.org/10.1136/bmjopen-2020-044329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903127PMC
February 2021

Extrinsic compression of the left main coronary artery: A rare cause of cardiogenic shock.

Radiol Case Rep 2021 Mar 14;16(3):714-717. Epub 2021 Jan 14.

Department of Cardiology, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku Nagoya-shi, Aichi 460-0001, Japan.

A left main coronary artery (LMCA) stenosis due to extrinsic compression by mediastinal tumor is a rare finding. In this case reports, we present a 63-year-old woman, who was transferred to the emergency department with chief complains of persistent chest and back pain. An electrocardiogram revealed diffuse ST-segment depression (elevation in lead aVR). Contrast-enhanced computed tomography (CT) showed a huge cystic mass above the left atrium. After the CT examination, she was temporarily in shock. Compression of the LMCA was evident on the CT angiography and a diagnosis of acute myocardial infarction due to compression of the LMCA by a tumor was made. An emergent resection of the tumor was performed. Histopathological assessment of the resected cyst revealed that it was a schwannoma. She made an uneventful postoperative recovery. A follow-up 3-dimensional CT scan performed after the operation confirmed no evidence of LMCA compression.
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http://dx.doi.org/10.1016/j.radcr.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815471PMC
March 2021

CRISPR-Cas9 editing of non-coding genomic loci as a means of controlling gene expression in the sea urchin.

Dev Biol 2021 04 19;472:85-97. Epub 2021 Jan 19.

Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI, 02912, USA. Electronic address:

We seek to manipulate gene function here through CRISPR-Cas9 editing of cis-regulatory sequences, rather than the more typical mutation of coding regions. This approach would minimize secondary effects of cellular responses to nonsense mediated decay pathways or to mutant protein products by premature stops. This strategy also allows for reducing gene activity in cases where a complete gene knockout would result in lethality, and it can be applied to the rapid identification of key regulatory sites essential for gene expression. We tested this strategy here with genes of known function as a proof of concept, and then applied it to examine the upstream genomic region of the germline gene Nanos2 in the sea urchin, Strongylocentrotus purpuratus. We first used CRISPR-Cas9 to target established genomic cis-regulatory regions of the skeletogenic cell transcription factor, Alx1, and the TGF-β signaling ligand, Nodal, which produce obvious developmental defects when altered in sea urchin embryos. Importantly, mutation of cis-activator sites (Alx1) and cis-repressor sites (Nodal) result in the predicted decreased and increased transcriptional output, respectively. Upon identification of efficient gRNAs by genomic mutations, we then used the same validated gRNAs to target a deadCas9-VP64 transcriptional activator to increase Nodal transcription directly. Finally, we paired these new methodologies with a more traditional, GFP reporter construct approach to further our understanding of the transcriptional regulation of Nanos2, a key gene required for germ cell identity in S. purpuratus. With a series of reporter assays, upstream Cas9-promoter targeted mutagenesis, coupled with qPCR and in situ RNA hybridization, we concluded that the promoter of Nanos2 drives strong mRNA expression in the sea urchin embryo, indicating that its primordial germ cell (PGC)-specific restriction may rely instead on post-transcriptional regulation. Overall, we present a proof-of-principle tool-kit of Cas9-mediated manipulations of promoter regions that should be applicable in most cells and embryos for which CRISPR-Cas9 is employed.
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http://dx.doi.org/10.1016/j.ydbio.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956150PMC
April 2021

Spectroscopic analysis in molecular simulations with discretized Wiener-Khinchin theorem for Fourier-Laplace transformation.

Phys Rev E 2020 Dec;102(6-1):063302

Department of Physics and Informatics, Yamaguchi University, Yamaguchi 753-8512, Japan.

The Wiener-Khinchin theorem for the Fourier-Laplace transformation (WKT-FLT) provides a robust method to obtain the single-side Fourier transforms of arbitrary time-domain relaxation functions (or autocorrelation functions). Moreover, by combining an on-the-fly algorithm with the WKT-FLT, the numerical calculations of various complex spectroscopic data in a wide frequency range become significantly more efficient. However, the discretized WKT-FLT equation, obtained simply by replacing the integrations with the discrete summations, always produces two artifacts in the frequency-domain relaxation function. In addition, the artifacts become more apparent in the frequency-domain response function converted from the relaxation function. We find the sources of these artifacts that are associated with the discretization of the WKT-FLT equation. Taking these sources into account, we derive discretized WKT-FLT equations designated for both the frequency-domain relaxation and response functions with the artifacts removed. The use of the discretized WKT-FLT equations with the on-the-fly algorithm is illustrated by a flow chart. We also give application examples for the wave-vector-dependent dynamic susceptibility in an isotropic amorphous polyethylene and the frequency-domain response functions of the orientation vectors in an n-alkane crystal.
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http://dx.doi.org/10.1103/PhysRevE.102.063302DOI Listing
December 2020

Comparison of Outcomes of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting Among Patients With Three-Vessel Coronary Artery Disease in the New-Generation Drug-Eluting Stents Era (From CREDO-Kyoto PCI/CABG Registry Cohort-3).

Am J Cardiol 2021 04 14;145:25-36. Epub 2021 Jan 14.

Department of Cardiovascular Surgery, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.

There is a scarcity of data comparing long-term clinical outcomes between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three-vessel coronary artery disease (3VD) in the new-generation drug-eluting stents era. CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who had undergone first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. We identified 2525 patients with 3VD (PCI: n = 1747 [69%], and CABG: n = 778 [31%]). The primary outcome measure was all-cause death. Median follow-up duration was 5.7 (interquartile range: 4.4 to 6.6) years. The cumulative 5-year incidence of all-cause death was significantly higher in the PCI group than in the CABG group (19.8% vs 13.2%, log-rank p = 0.001). After adjusting confounders, the excess risk of PCI relative to CABG for all-cause death remained significant (HR, 1.45; 95% CI, 1.14 to 1.86; p = 0.003), which was mainly driven by the excess risk for non-cardiovascular death (HR, 1.88; 95% CI, 1.30 to 2.79; p = 0.001), while there was no excess risk for cardiovascular death between PCI and CABG (HR, 1.19; 95% CI, 0.87 to 1.64; p = 0.29). There was significant excess risk of PCI relative to CABG for myocardial infarction (HR, 1.77; 95% CI, 1.19 to 2.69; p = 0.006), whereas there was no excess risk of PCI relative to CABG for stroke (HR, 1.24; 95% CI, 0.83 to 1.88; p = 0.30). In conclusion, in the present study population reflecting real-world clinical practice in Japan, PCI compared with CABG was associated with significantly higher risk for all-cause death, while there was no excess risk for cardiovascular death between PCI and CABG.
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http://dx.doi.org/10.1016/j.amjcard.2020.12.076DOI Listing
April 2021

Improvement of fatty acid productivity of thraustochytrid, Aurantiochytrium sp. by genome editing.

J Biosci Bioeng 2021 Apr 30;131(4):373-380. Epub 2020 Dec 30.

Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530, Japan. Electronic address:

Thraustochytrid strains belonging to the genus Aurantiochytrium accumulate significant amounts of lipids including polyunsaturated fatty acids and carotenoids and, therefore, are expected to be used for industrial production of various valuable materials. Although various efforts such as chemical mutagenesis and homologous gene recombination have been made to improve lipid productivity of Aurantiochytrium species, low specificity and efficiency in the conventional methods hinder the research progress. Here, we attempted to apply a genome editing technology, the CRISPR-Cas9 system as an alternative molecular breeding technique for Aurantiochytrium species to accelerate the metabolic engineering. The efficiency of specific gene knock-in by the homologous recombination increased more than 10-folds by combining the CRISPR-Cas9 system. As a result of disrupting the genes associated with β-oxidation of fatty acids by the improved method, the genome edited strains with higher fatty acid productivity were isolated, demonstrating for the first time that the CRISPR-Cas9 system was effective for molecular breeding of the strains in the genus Aurantiochytrium to improve lipid productivity.
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http://dx.doi.org/10.1016/j.jbiosc.2020.11.013DOI Listing
April 2021

TALEN-mediated generation of Nkx3.1 knockout rat model.

Prostate 2021 02 28;81(3):182-193. Epub 2020 Dec 28.

Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.

Background: Recent developments in gene editing, using transcriptional activator-like effector nucleases (TALENs), have greatly helped the generation of genetically engineered animal models. The NK3 homeobox 1 (NKX3.1) protein plays important roles in prostate development and protein production, and functions as a tumor suppressor. Recently, NKX3.1 was shown to be associated with breast cancer in humans.

Methods: Our aim was to create a new rat model to elucidate the functions of NKX3.1. To that end, we generated Nkx3.1 knockout rats using TALENs and analyzed their phenotype. TALEN-mediated Nkx3.1 knockout was confirmed by T7 endonuclease I (T7E1) assay and DNA sequencing. Prostate weight and fertility were evaluated in the knockout rats, besides determining the proportion of epithelial cells and messenger RNA (mRNA) expression of genes associated with carcinogenesis. Breast tumors were examined by histopathology.

Results: Results suggested Nkx3.1 knockout rats have reduced fertility, decreased prostate weights, and increased epithelial cell layers. The mRNA expression of genes related to prostate carcinogenesis, namely Ar, Akt, and Pi3k, also increased. Moreover, the Nkx3.1 knockout rats often developed malignant breast tumors.

Conclusions: We, therefore, successfully created the first Nkx3.1 knockout rat model, using TALEN-mediated gene targeting, and used it to identify defects associated with Nkx3.1 deficiency, not previously observed in mice. Loss of Nkx3.1 in rats led to lower reproductive capacity, and decreased prostate weights, apart from the risk of developing breast cancer. We, thus, proposed Nkx3.1 knockout rats as reliable models for studying the role of NKX3.1 in decreased prostate weights, fertility, and breast cancer, as well as in prostate cancer.
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http://dx.doi.org/10.1002/pros.24095DOI Listing
February 2021

Malignant gastrointestinal neuroectodermal tumor with BRAF mutation and a history of malignant melanoma: A case report.

Mol Clin Oncol 2021 Feb 4;14(2):23. Epub 2020 Dec 4.

Department of Orthopedic Surgery, Osaka International Cancer Institute, Osaka 541-8567, Japan.

Malignant gastrointestinal neuroectodermal tumors (GNETs), also called clear-cell sarcoma-like tumors of the gastrointestinal tract, are rare and highly aggressive tumors originating in the gastrointestinal tract. These tumors are generally immunohistochemically positive for S-100 protein (S-100) and SRY-related HMG-box 10 (SOX10), and often contain EWSR1-ATF1 or EWSR1-CREB1. The histological features of GNETs overlap with those of clear-cell sarcoma of the tendons and aponeuroses. However, GNETs immunohistochemically lack melanocyte-specific markers and often demonstrate positivity for CD56, synaptophysin and neuron-specific enolase. The present case reports a woman with a history of desmoplastic malignant melanoma exhibiting a BRAF mutation, which later transformed into a GNET of the small intestine with both a BRAF mutation and two subtypes of EWSR1-ATF1 fusion genes. Tumor cells were revealed to be weakly immunoreactive or negative for S-100 and SOX10, lacked markers of melanocytic differentiation and were focally positive for CD56. Combination therapy with dabrafenib mesylate and trametinib dimethyl sulfoxide proved to be temporarily effective against this tumor. The present case is relatively unique as, to the best of our knowledge, there is no case of GNET with a history of melanoma. Furthermore, there is no report of GNET exhibiting both a BRAF mutation and an EWSR1-ATF1 fusion gene. Further accumulation of similar cases is necessary to elucidate the pathological significance of this GNET having a BRAF mutation.
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http://dx.doi.org/10.3892/mco.2020.2185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739819PMC
February 2021

PHF24 is expressed in the inhibitory interneurons in rats.

Exp Anim 2021 Feb 29;70(1):137-143. Epub 2020 Oct 29.

Laboratory of Veterinary Pathology, Osaka Prefecture University, 1-58 Ourai-kita, Izumisano, Osaka 598-8531, Japan.

Noda epileptic rat (NER) is a mutant model for epilepsy that exhibits spontaneous generalized tonic-clonic seizure. Epileptogenesis of NER remains to be elucidated; but it is detected an insertion of an endogenous retrovirus sequence in intron 2 of the PHD finger protein 24 (Phf24) gene, encoding Gαi-interacting protein (GINIP). Phf24 is a strong candidate gene for epileptogenesis in NER. PHF24 modulates GABA signaling through interacting with Gαi protein. To clarify the epileptogenesis of NER, we investigated a distribution of PHF24-expressing cells in the central nerve system (CNS). While broad expression of PHF24 was observed in the CNS, characteristic expression was noted in the periglomerular layer of the olfactory bulb and the lamina II of the spinal cord in the control rats. These cells showed co-expression with calbindin or calretinin, inhibitory interneuron markers. In the olfactory bulb, 15.6% and 41.2% of PHF24-positive neurons co-expressed calbindin and calretinin, respectively. Immunoelectron microscopy revealed that PHF24 was located in the presynaptic terminals, synaptic membranes and cytoplasmic matrix of neuronal soma. Our data suggested PHF24 is expressed in the inhibitory interneurons and may play important roles in modulation of the GABA signaling.
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http://dx.doi.org/10.1538/expanim.20-0105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887615PMC
February 2021

Usage of the Sea Urchin Hemicentrotus pulcherrimus Database, HpBase.

Methods Mol Biol 2021 ;2219:267-275

Shimoda Marine Research Center, University of Tsukuba, Shizuoka, Japan.

HpBase ( http://cell-innovation.nig.ac.jp/Hpul/ ) is a database that provides genome and transcriptome resources of the sea urchin Hemicentrotus pulcherrimus. In addition to downloading the bulk data, several analysis tools for resource use are available: gene search, homology search, and genome browsing. HpBase also discloses the protocols for biological experiments using H. pulcherrimus that have been accumulated so far. Therefore, HpBase can assist efficient use of genome resources for researchers from various fields-evolutionary, developmental, and cell biology. In this chapter we present an overview and usage of tools in HpBase.
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http://dx.doi.org/10.1007/978-1-0716-0974-3_17DOI Listing
March 2021

COVID-19 pandemic and the incidence of community-acquired pneumonia in elderly people.

Respir Investig 2020 Sep 18. Epub 2020 Sep 18.

Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

The impact of the COVID-19 pandemic on the incidence of community-acquired pneumonia in elderly people remains uncertain. We compared the number of elderly patients admitted to our hospital for community-acquired pneumonia from January to June 2020 to the numbers from the same period in each of the last three years. The number of patients began decreasing in February 2020, and by April 2020 the number was significantly lower than those from the same period in the three years prior. There is no evidence regarding the impact of general infection control measures, such as wearing a face mask or washing one's hands, on the development of community-acquired pneumonia, because causative bacteria are not believed to be transmitted from human to human. However, these measures might have indirectly contributed to a decreased number of cases through the prevention of common viral infections which could be a trigger of community-acquired pneumonia.
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http://dx.doi.org/10.1016/j.resinv.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500878PMC
September 2020

Single-gene imaging links genome topology, promoter-enhancer communication and transcription control.

Nat Struct Mol Biol 2020 11 21;27(11):1032-1040. Epub 2020 Sep 21.

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Transcription activation by distal enhancers is essential for cell-fate specification and maintenance of cellular identities. How long-range gene regulation is physically achieved, especially within complex regulatory landscapes of non-binary enhancer-promoter configurations, remains elusive. Recent nanoscopy advances have quantitatively linked promoter kinetics and ~100- to 200-nm-sized clusters of enhancer-associated regulatory factors (RFs) at important developmental genes. Here, we further dissect mechanisms of RF clustering and transcription activation in mouse embryonic stem cells. RF recruitment into clusters involves specific molecular recognition of cognate DNA and chromatin-binding sites, suggesting underlying cis-element clustering. Strikingly, imaging of tagged genomic loci, with ≤1 kilobase and ~20-nanometer precision, in live cells, reveals distal enhancer clusters over the extended locus in frequent close proximity to target genes-within RF-clustering distances. These high-interaction-frequency enhancer-cluster 'superclusters' create nano-environments wherein clustered RFs activate target genes, providing a structural framework for relating genome organization, focal RF accumulation and transcription activation.
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http://dx.doi.org/10.1038/s41594-020-0493-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644657PMC
November 2020

Amiodarone bioconcentration and suppression of metamorphosis in Xenopus.

Aquat Toxicol 2020 Nov 6;228:105623. Epub 2020 Sep 6.

Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan. Electronic address:

Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs. Anuran tadpole metamorphosis is a TH-controlled developmental process and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. In the present study, our objective was to clarify the effects of AMD on Xenopus metamorphosis as well as to assess the bioconcentration of this pharmaceutical in the liver. We found that AMD suppressed spontaneous metamorphosis, including tail regression and hindlimb elongation in pro-metamorphic stage tadpoles, which is controlled by endogenous circulating TH, indicating that AMD is a TH antagonist. In transgenic X. laevis tadpoles carrying plasmid DNA containing TH-responsive element (TRE) and a 5'-upstream promoter region of the TH receptor (TR) βA1 gene linked to a green fluorescent protein (EGFP) gene, triiodothyronine (T) exposure induced a strong EGFP expression in the hind limbs, whereas the addition of AMD to T suppressed EGFP expression, suggesting that this drug interferes with the binding of T to TR, leading to the inhibition of TR-mediated gene expression. We also found AMD to be highly bioconcentrated in the liver of pro-metamorphic X. tropicalis tadpoles, and we monitored hepatic accumulation of this drug using mass spectrometry imaging (MSI). Our findings suggest that AMD imposes potential risk to aquatic wildlife by disrupting TH homeostasis, with further possibility of accumulating in organisms higher up in the food chain.
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http://dx.doi.org/10.1016/j.aquatox.2020.105623DOI Listing
November 2020
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