Publications by authors named "Takuya Hashimoto"

204 Publications

Identification of the core rumen bacterial taxa and their population dynamics during the fattening period in Japanese Black cattle.

Anim Sci J 2021 Dec;92(1):e13601

Graduate School of Agriculture, Hokkaido University, Hokkaido, Japan.

The rumen microbiota comprises a vast range of bacterial taxa, which may affect the production of high-quality meat in Japanese Black cattle. The aim of this study was to identify core rumen microbiota in rumen fluid samples collected from 74 Japanese Black cattle raised under different dietary conditions using 16S rRNA gene amplicon sequencing. In the rumen of fattening Japanese Black cattle, 10 bacterial taxa, showing >1% average relative abundance and >95% prevalence, irrespective of the dietary conditions and the fattening periods, were identified as the core rumen bacterial taxa, which accounted for approximately 80% of the rumen microbiota in Japanese Black cattle. Additionally, population dynamics of the core rumen bacterial taxa revealed two distinct patterns: Prevotella spp. and unclassified Bacteroidales decreased in the mid-fattening period, whereas unclassified Clostridiales, unclassified Ruminococcaceae, Ruminococcus spp., and unclassified Christensenellaceae increased during the same period. Therefore, the present study reports the wide distribution of the core rumen bacterial taxa in Japanese Black cattle, and the complementary nature of the population dynamics of these core taxa, which may ensure stable rumen fermentation during the fattening period.
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http://dx.doi.org/10.1111/asj.13601DOI Listing
December 2021

Ruptured tibial artery in neurofibromatosis type 1: A case report.

Int J Surg Case Rep 2021 Jun 26;83:106012. Epub 2021 May 26.

Department of Vascular Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan. Electronic address:

Introduction: Neurofibromatosis type 1 (NF-1) or von Recklinghausen's disease, an autosomal dominant genetic disorder, is characterized by a café au lait spot and cutaneous neurofibromas. It typically involves the skin, nerves, bones, muscles, and eyes, and occasionally involves vascular complications and can lead to life-threatening hemorrhage.

Case Presentation: We present the case of a 77-year-old female with a posterior tibial artery rupture with NF-1. She presented with sudden right lower leg swelling, pain, paresthesia, and paralysis; computed tomography images revealed popliteal artery aneurysm with surrounding hematoma, expanding from the posterior aspect of the knee to the calf. Diagnosed with compartment syndrome, due to a ruptured right popliteal artery aneurysm, she underwent prosthetic replacement of the popliteal aneurysm. Intraoperatively, the fragility of the popliteal artery was noted, although no perforation site was recognized despite the aneurysm; active bleeding originated from the hematoma between the calf muscles. Intraoperative digital subtraction angiography revealed an extravasation at the branch of the posterior tibial artery that was managed by coil embolization of the posterior tibial artery.

Clinical Discussion: Although the frequency of NF-1 vasculopathy is unknown, vasculopathy is the second most common cause of mortality in patients with NF-1, after malignancy. The less invasive endovascular approach might be preferable for treating NF-1-related aneurysm. The NF-related vasculopathy lesion sites are diverse, and intraoperative angiography would help confirm the diagnosis.

Conclusion: NF-1-related vasculopathy may be associated with vascular fragility, and the endovascular approach might be preferable. Endovascular-first approach could have helped in correct diagnosis in the present case.
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http://dx.doi.org/10.1016/j.ijscr.2021.106012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188394PMC
June 2021

Hyperpolarized C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in vivo Study.

Chemphyschem 2021 05;22(10):905

Division of Bioengineering & Bioinformatics, Graduate School of Information Science & Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, Hokkaido, 060-0814, Japan.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized C fumarate metabolism to hyperpolarized C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.
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http://dx.doi.org/10.1002/cphc.202100338DOI Listing
May 2021

Thermodynamics and kinetics analyses of high CO absorption properties of LiNaSiO under various CO partial pressures.

Dalton Trans 2021 Apr;50(15):5301-5310

Department of Physics, College of Humanities and Sciences, Nihon University, 3-25-40 Sakurajousui, Setagaya-ku, Tokyo 156-8550, Japan.

The properties of Li3NaSiO4 as a CO2 absorbent were evaluated by thermogravimetry (TG) and X-ray diffraction, which revealed that the CO2 absorption and desorption reaction, Li3NaSiO4 + CO2 ↔ LiNaCO3 + Li2SiO3, is reversible. In scanning-type TG under various CO2 partial pressures (P(CO2)), mass gain ascribed to CO2 absorption started from approximately 400 °C, irrespective of P(CO2). CO2 desorption was observed at a higher temperature, which was considered the approximate equilibrium temperature of the above-mentioned reaction. A pseudo-Ellingham diagram of the reaction between Li3NaSiO4 and CO2, constructed using the obtained approximate equilibrium temperature under each P(CO2), showed similar behavior to that between Li4SiO4 and CO2, especially between 10-2 and 10-1 bar of P(CO2). Kinetics analysis by isothermal TG using the Jander model revealed that the reaction rate of CO2 absorption of Li3NaSiO4 was higher than that of Li4SiO4. The rate-determining step of CO2 absorption by Li3NaSiO4 was the diffusion process at the examined temperatures and P(CO2), which was different from the rate-determining step of the reaction between Li4SiO4 and CO2 under low P(CO2).
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http://dx.doi.org/10.1039/d1dt00531fDOI Listing
April 2021

Validation of the atherothrombotic risk score for secondary prevention in patients with acute myocardial infarction: the J-MINUET study.

Heart Vessels 2021 Apr 21. Epub 2021 Apr 21.

Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi, Japan.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS2°P) is a contemporary risk scoring system for secondary prevention based on nine clinical factors. However, this scoring system has not been validated in other populations. The aim of this study was to validate the TRS2°P in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI) in a nationwide registry cohort. Among 3283 consecutive patients with AMI enrolled in the Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET), a total of 2611 patients who underwent primary PCI were included in this study. The performance of the TRS2°P to predict major adverse cardiovascular events (MACE) composed of all-cause death, non-fatal MI, and non-fatal stroke up to 3 years in the present cohort was evaluated. The TRS2°P had modest discriminative performance in this J-MINUET cohort with a c-statistic of 0.63, similar to that in the derived cohort (TRA2°P-TIMI50, c-statistic 0.67). A strong graded relationship between the TRS2°P and 3-year cardiovascular event rates was also observed in the J-MINUET cohort. Age ≥ 75 years, Killip ≥ 2, prior stroke, peripheral artery disease, anemia, and non-ST-elevation myocardial infarction were identified as independent factors for the incidence of MACE. The TRS2°P modestly predicted secondary cardiovascular events among patients with AMI treated by primary PCI in a nationwide cohort of Japan. Further studies are needed to develop a novel risk score better predicting secondary cardiovascular events.
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http://dx.doi.org/10.1007/s00380-021-01840-zDOI Listing
April 2021

Characteristics of carotid atherosclerosis in patients with plaque erosion.

J Thromb Thrombolysis 2021 Mar 10. Epub 2021 Mar 10.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0373, Japan.

Plaque erosion (PE) is a major underlying mechanism of acute coronary syndrome (ACS). Patients with PE may have less systemic atherosclerosis. We aimed to clarify the status of carotid atherosclerosis in patients with PE. A total of 115 consecutive patients with ACS who underwent optical coherence tomography (OCT) imaging of the culprit lesion were enrolled. Patients were classified into PE (n = 26), plaque rupture (n = 56) or calcified plaque (CP, n = 33) based on OCT findings of the culprit lesions. The status of carotid atherosclerosis was assessed by the findings of carotid echography. The mean IMT was the lowest in the PE group (1.5 ± 0.6 mm) among the three groups (p = 0.004) with a significant difference between the PE group and the CP group (2.1 ± 0.6 mm, p < 0.001). The plaque score was the lowest in the PE group (6.6 ± 2.5) among the three groups (p = 0.004) with a significant difference between the PE group and the CP group (9.0 ± 2.7, p < 0.001). Multivariate analyses demonstrated that the PE was independently associated with the presence of lower mean IMT (below median; 1.85 mm) (odds ratio 3.34; 95 % confidence interval 1.07-10.4; p = 0.035) and the lack of heterogenous plaque (odds ratio 2.92; 95 % confidence interval 1.02-8.32; p = 0.037). Patients with PE were associated with less atherosclerosis in the carotid artery than other patients with ACS. These findings may help further clarify the distinct pathophysiology of PE. Carotid atherosclerosis and plaque erosion.
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http://dx.doi.org/10.1007/s11239-021-02419-1DOI Listing
March 2021

"Laundry dryer" sign associated with venous thromboembolism.

Asian Cardiovasc Thorac Ann 2021 Mar 10:2184923211001678. Epub 2021 Mar 10.

Department of Vascular Surgery, 26381Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.

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http://dx.doi.org/10.1177/02184923211001678DOI Listing
March 2021

Familial hypercholesterolemia and vulnerability of coronary plaque in patients with coronary artery disease.

Pract Lab Med 2021 Mar 19;24:e00202. Epub 2021 Jan 19.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Objectives: Patients with familial hypercholesterolemia (FH) are at a very high risk of coronary artery diseases. The aim of the present study was to clarify the characteristics of coronary plaque in patients with FH.

Design: and Methods: A total of 569 patients who underwent optical coherence tomography (OCT) imaging of culprit plaque were included. The characteristics of culprit plaque were compared between patients with and without FH.

Results: A total of 38 patients (6.7%) were clinically diagnosed with FH. The location of the culprit plaque was significantly different (p ​< ​0.001) with a trend toward higher frequency of left main lesion in the FH group than in the group with no FH (7.9 vs. 0%). Culprit plaque was significantly shorter in patients with FH than those without FH (28.1 vs. 33.2 ​mm, p ​= ​0.016). A trend toward higher prevalence of plaque with macrophage accumulation in patients with FH than those without FH (50.0 vs. 34.7%, p ​= ​0.056) was observed, although the prevalence of other vulnerable characteristics including thin-cap fibroatheroma (TCFA) was comparable between patients with and without FH. Among patients with FH, significant increases in the prevalence of lipid-rich plaque (p ​= ​0.028) and TCFA (p ​= ​0.003) were observed according to the increase in low-density lipoprotein cholesterol (LDL-C) levels.

Conclusions: Patients with FH had shorter culprit plaque without significant difference in the prevalence of vulnerable plaque components compared with patients without FH. A higher LDL-C level was associated with higher prevalence of vulnerable plaque in patients with FH.
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http://dx.doi.org/10.1016/j.plabm.2021.e00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895842PMC
March 2021

Is portal vein embolization safe and effective for patients with impaired liver function?

J Surg Oncol 2021 May 3;123(8):1742-1749. Epub 2021 Mar 3.

Koto Hospital, Tokyo, Japan.

Background And Objectives: Portal vein embolization (PVE) is a safe and effective procedure used to increase the safety of extensive hepatectomy for selected patients. However, it is unknown whether PVE is safe for patients with impaired liver functional reserve.

Methods: Patients who underwent PVE from April 2007 to September 2016 in our hospital were retrospectively assessed. According to indocyanine green retention rate at 15 min (ICG-R15), we divided patients into Group A (≤10%), Group B (10%-20%), and Group C (>20%). We described and compared the treatment course and the outcome among the three groups.

Results: A total of 106 patients were assessed and divided into groups A (n = 46), B (n = 49), and C (n = 11). The morbidity and mortality after PVE showed no significant differences among the three groups (A:B:C = 37%:53%:64%, p = .16; A:B:C = 0%:0%:0%, p = 1.00, respectively). The morbidity and mortality after successive hepatectomy also showed no significant differences among the three groups (A:B:C = 55%:71%:78%, p = .19; A:B:C = 0%:2%:0%, p = 1.00, respectively).

Conclusion: A patient with impaired liver functional reserve (ICG-R15 > 20%) can be a candidate for PVE and successive hepatectomy, as safely as a patient with normal and slightly impaired liver functional reserve (ICG-R15 ≤ 20%).
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http://dx.doi.org/10.1002/jso.26447DOI Listing
May 2021

Transcatheter Aortic Valve Replacement in Patients With a Small Annulus - From the Japanese Nationwide Registry (J-TVT).

Circ J 2021 Jun 27;85(7):967-976. Epub 2021 Feb 27.

Department of Cardiovascular Medicine, Kitasato University.

Background: The details and consequences of a small aortic annulus among transcatheter aortic valve replacement (TAVR) patients remain uncertain. This study investigated the short-term outcomes in patients with small annular size and compared the 30-day outcome between intra- and supra-annular devices, with similar outer casing diameter in this subgroup.Methods and Results:Cases registered in the Japanese national TAVR registry between August 2013 and December 2017 were analyzed. Among a total of 5,870 registered patients, 647 (11.0%) had small annulus (area ≤314 mm) measured by multi-detector computed tomography. Patients with a small annulus had a significantly smaller indexed effective orifice area (iEOA, 1.10 cm/m[0.92-1.35] vs. 1.16 cm/m[0.96-1.39], P<0.001) and higher mean pressure gradient (mPG, 10.0 mmHg [6.9-14.2] vs. 8.5 mmHg [6.0-11.5], P<0.001) compared with a normal-sized annulus. Among patients with a small annulus, those receiving a 20 mm intra-annular device had a smaller iEOA (0.94 cm/m[0.78-1.06] vs. 1.07 cm/m[0.8-1.24], P=0.001) and higher mPG (14.0 mmHg [10.0-18.5] vs. 11.0 [7.0-14.0], P<0.001) compared with those receiving a 23-mm supra-annular device, although the incidence of paravalvular leakage (≥moderate) was similar (14.4% vs. 16.5%, P=0.69).

Conclusions: Patients with a small annulus were associated with less hemodynamic improvement. A supra-annular device is associated with better echocardiographic improvement in patients with a small annulus, without increasing paravalvular leakage.
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http://dx.doi.org/10.1253/circj.CJ-20-1084DOI Listing
June 2021

Hyperpolarized C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in vivo Study.

Chemphyschem 2021 05 18;22(10):915-923. Epub 2021 Mar 18.

Division of Bioengineering & Bioinformatics, Graduate School of Information Science & Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, Hokkaido, 060-0814, Japan.

Hyperpolarized [1- C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1- C]fumarate metabolism using parahydrogen-induced polarization (PHIP), a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective and high-yield synthetic pathway of hydrogenation precursor [1- C]acetylenedicarboxylate (ADC) was developed. The trans-selectivity of the hydrogenation reaction of ADC using a ruthenium-based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set-up was used to generate hyperpolarized [1- C]fumarate at sufficient C polarization for ex vivo detection of hyperpolarized C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo C MR spectroscopy and imaging in a murine model of acetaminophen-induced hepatitis.
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http://dx.doi.org/10.1002/cphc.202001038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251594PMC
May 2021

A novel methymycin analog, 12-ketomethymycin N-oxide, produced by the heterologous expression of the large pikromycin/methymycin biosynthetic gene cluster of Streptomyces sp. AM4900.

Biosci Biotechnol Biochem 2021 Mar;85(4):890-894

National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.

A novel methymycin analog, 12-ketomethymycin N-oxide, was produced by the heterologous expression of the pikromycin/methymycin biosynthetic gene cluster of Streptomyces sp. AM4900 together with 12-ketomethymycin, which was only isolated by the biotransformation of the synthetic intermediate before. Their structures were determined by the spectroscopic data and the chemical derivatization. 12-Ketomethymycin showed a weak cytotoxicity against SKOV-3 and Jurkat cells, although its N-oxide analog did not show any activity. Both showed no antibacterial activities against Escherichia coli and Micrococcus luteus.
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http://dx.doi.org/10.1093/bbb/zbaa111DOI Listing
March 2021

A novel oxazole-containing tetraene compound, JBIR-159, produced by heterologous expression of the cryptic trans-AT type polyketide synthase biosynthetic gene cluster.

J Antibiot (Tokyo) 2021 May 8;74(5):354-358. Epub 2021 Feb 8.

National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.

Using genome mining approach, we identified a novel biosynthetic gene cluster containing trans-AT type PKS genes from Streptomyces versipellis 4083-SVS6. A bacterial artificial chromosome (BAC) clone, pKU503JL68_PN1_P10-C12, accommodating the entire biosynthetic gene cluster was obtained from a BAC library. Heterologous expression of the biosynthetic gene cluster in Streptomyces lividans TK23 led to the production of a novel polyene compound, JBIR-159. We report herein the biosynthetic gene cluster for JBIR-159, and the heterologous expression, isolation, structure determination and a brief biological activity.
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http://dx.doi.org/10.1038/s41429-021-00410-9DOI Listing
May 2021

Evaluation of hemodynamic changes using near-infrared spectroscopy in patients with tic-related obsessive-compulsive disorder.

Psychiatry Clin Neurosci 2021 Jun 24;75(6):191-199. Epub 2021 Mar 24.

Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Japan.

Aim: A tic-related specifier is included in the DSM-5 diagnostic criteria to identify a clinically specific obsessive-compulsive disorder (OCD) subtype. The current study sought to evaluate hemodynamic changes during executive function tasks among OCD patients with and without a lifetime history of tic disorder (TD) and healthy controls, and to investigate the relation between brain activation and clinical variables in each group using structured equation modeling.

Methods: Twenty-nine OCD patients diagnosed according to the DSM-IV-TR and 15 healthy controls were recruited. Patients were divided into two groups according to the presence or absence of a lifetime history of TD (TD+, n = 11; TD-, n = 18). Prefrontal hemodynamic changes were measured using multi-channel near-infrared spectroscopy during the Verbal Fluency Task, Trail-Making Task, and Tower of London (ToL) Task.

Results: There were significant brain activation differences in the frontopolar cortex between OCD patients with and without TD during Verbal Fluency Task and ToL performance. Brain activation in the dorsolateral prefrontal cortex (DLPFC) during the ToL Task in OCD patients with TD exerted a direct causal effect on the severity of compulsions. In addition, we detected a direct causal effect of the severity of obsessions in OCD patients without TD on brain activation in the DLPFC during the ToL Task.

Conclusion: Brain activation in the frontopolar cortex exhibits different hemodynamics depending on the task, and DLPFC function may play a different role in the neural basis of developing OCD symptoms between OCD patients with and without TD.
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http://dx.doi.org/10.1111/pcn.13207DOI Listing
June 2021

Environmental pH stress influences cellular secretion and uptake of extracellular vesicles.

FEBS Open Bio 2021 03 18;11(3):753-767. Epub 2021 Feb 18.

Keio University School of Medicine, Tsukuba, Japan.

Exosomes (extracellular vesicles/EVs) participate in cell-cell communication and contain bioactive molecules, such as microRNAs. However, the detailed characteristics of secreted EVs produced by cells grown under low pH conditions are still unknown. Here, we report that low pH in the cell culture medium significantly affected the secretion of EVs with increased protein content and zeta potential. The intracellular expression level and location of stably expressed GFP-fused CD63 (an EV tetraspanin) in HeLa cells were also significantly affected by environmental pH. In addition, increased cellular uptake of EVs was observed. Moreover, the uptake rate was influenced by the presence of serum in the cell culture medium. Our findings contribute to our understanding of the effect of environmental conditions on EV-based cell-cell communication.
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http://dx.doi.org/10.1002/2211-5463.13107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931216PMC
March 2021

Organoiodine-Catalyzed Enantioselective Intermolecular Oxyamination of Alkenes.

J Am Chem Soc 2021 02 22;143(4):1745-1751. Epub 2021 Jan 22.

Chiba Iodine Resource Innovation Center and Department of Chemistry, Graduate School of Science, Chiba University, 1-33, Yayoi, Inage, Chiba 263-8522, Japan.

Metal-free, catalytic enantioselective intermolecular oxyamination of alkenes is realized by use of organoiodine(I/III) chemistry. The protocol is applicable toward aryl- and alkyl-substituted alkenes with high enantioselectivity and electronically controlled regioselectivity. The oxyaminated products can be easily deprotected in one step to reveal free amino alcohols in high yields without loss of enantioselectivity. A key to our success is the discovery of a virtually unexplored chemical entity, -(fluorosulfonyl)carbamate, as a bifunctional N,O-nucleophile.
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http://dx.doi.org/10.1021/jacs.0c11440DOI Listing
February 2021

Treatment of tumor thrombus in the superior mesenteric vein due to advanced colon cancer with complete surgical resection and chemotherapy: a case report.

Surg Case Rep 2020 Dec 14;6(1):320. Epub 2020 Dec 14.

Department of Coloproctological Surgery, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan.

Background: Tumor thrombus in the superior mesenteric vein secondary to colon cancer is rare. We report a case of tumor thrombus in the superior mesenteric vein and liver metastasis due to advanced colon cancer that was treated with chemotherapy and complete surgical resection.

Case Presentation: A 72-year-old man after transverse colectomy with lymph node dissection for advanced colon cancer was diagnosed with tumor thrombus in the superior mesenteric vein and liver metastasis. He underwent adjuvant chemotherapy and had complete surgical tumor resection involving tumor thrombectomy and hepatectomy. There has been no recurrence at 36 months after surgery.

Conclusion: Herein, we report a rare case of tumor thrombus in the superior mesenteric vein related to advanced colon cancer. The combination of chemotherapy and complete surgical tumor resection may provide long-term survival.
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http://dx.doi.org/10.1186/s40792-020-01091-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736432PMC
December 2020

Sodium-Glucose Cotransporter-2 Inhibitor Immediately Decreases Serum Uric Acid Levels in Type 2 Diabetic Patients.

Med Sci Monit 2020 Oct 2;26:e926086. Epub 2020 Oct 2.

Department of Internal Medicine 1, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

BACKGROUND Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antihyperglycemic drugs for type 2 diabetes. SGLT2 inhibitors ameliorate cardiovascular morbidity and mortality as well as kidney disease progression by reducing body weight (BW), blood pressure (BP), visceral adiposity, albuminuria, and serum uric acid and blood glucose levels. However, it is not clear which effects are pronounced, and what mechanisms are associated with these effects. MATERIAL AND METHODS This study recruited patients with type 2 diabetes who were prescribed an SGLT2 inhibitor for the first time in our outpatient department. Clinical parameters were measured before and 6 months after the administration of the SGLT2 inhibitor, without the addition of new drugs and dose changes for all prescribed drugs. RESULTS This study recruited 24 patients with type 2 diabetes. No significant differences in BP, glycated hemoglobin (HbA1c) levels, and low-density lipoprotein cholesterol levels were observed after SGLT2 inhibitor administration. In contrast, BW and serum uric acid levels decreased significantly, and the fractional excretion of uric acid (FEUA) increased significantly after administration. While no significant relationships were observed between serum uric acid and FEUA with respect to the percentage changes from baseline values, the percentage changes in serum uric acid levels from baseline were significantly and positively associated with those in serum creatinine levels. CONCLUSIONS Serum uric acid levels were immediately decreased owing to the administration of SGLT2 inhibitor, but BP, blood glucose, and serum lipid levels were unchanged. These changes in serum uric acid levels may be associated with changes in renal function.
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http://dx.doi.org/10.12659/MSM.926086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537479PMC
October 2020

Clinical outcome of biodegradable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with diabetes.

Cardiovasc Diabetol 2020 10 1;19(1):162. Epub 2020 Oct 1.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.

Background: Diabetes mellitus is a risk for increased incidence of adverse clinical events after percutaneous coronary intervention. However, the difference in the incidence of adverse clinical events according to stent type in patients with diabetes remains to be elucidated. In the present study, we aimed to compare the clinical outcomes between patients treated with the biodegradable polymer sirolimus-eluting stents (BP-SES) and the durable polymer everolimus-eluting stents (DP-EES) among patients with diabetes.

Methods: Among 631 lesions in 510 consecutive patients treated with either BP-SES or DP-EES, 165 lesions in 141 patients with diabetes mellitus and stable angina pectoris were identified and classified into the BP-SES group (48 lesions in 44 patients) and the DP-EES group (117 lesions in 100 patients). The incidence of adverse clinical events after stent implantation was compared between the 2 groups.

Results: There was no significant difference in the prevalence of conventional risk factors, lesion characteristics, and procedural characteristics between the 2 groups. During median 386 [334-472] days follow-up, the incidence of target lesion revascularization (11.4 vs. 2.0%, p = 0.003) and device-oriented clinical endpoint (13.6 vs. 6.0%, p = 0.035) in the BP-SES group was significantly greater than that in the DP-EES group. A univariate model demonstrated that the BP-SES usage was significantly associated with the higher incidence of target lesion revascularization (odds ratio, 6.686; 95% confidence interval, 1.234-36.217; p = 0.028).

Conclusion: BP-SES was associated with the greater incidence of TLR than the DP-EES in patients with diabetes mellitus. Further studies with larger cohorts and longer follow-up are required to confirm the present results.
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http://dx.doi.org/10.1186/s12933-020-01145-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531093PMC
October 2020

Thermodynamic analyses of the orthorhombic-to-tetragonal phase transition in PrNdNiO under controlled oxygen partial pressures.

Dalton Trans 2020 Sep 19;49(34):11931-11941. Epub 2020 Aug 19.

Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan.

The behavior of the structural orthorhombic-tetragonal phase transition of PrNdNiO, a candidate material for solid oxide fuel cells and oxygen permeation membranes, was investigated by differential scanning calorimetry and thermogravimetry (TG), under controlled oxygen partial pressures, P(O). The structural phase transition temperature, T, of PrNdNiO increased with increasing Nd content, x, or increasing P(O). The phase transitions of all compositions involved discrete variations in the oxygen content, Δδ, which were observed in the TG curves under various P(O) values. Δδ of PrNdNiO with 0.5 ≤x≤ 1.5 were between those of NdNiO and PrNiO, regardless of P(O), and were slightly increased with decreasing P(O). It was proposed that the effect of the valence change of the Pr ion on Δδ was decreased with increasing Nd content. The standard enthalpy change, ΔH°, and entropy change, ΔS°, of the phase transition were estimated from the Ellingham diagrams and van't Hoff plots, which were prepared from the relationship between P(O) and T using an ideal solution model. ΔS° was decreased with increasing Nd content for the specimens with 0.0 ≤x≤ 1.5. The ΔH° of PrNdNiO with 0.0 ≤x≤ 1.5 was almost constant for all Nd contents. The increase in the phase transition temperature of PrNdNiO with increasing x from 0.0 to 1.5 was successfully explained using the calculated values of ΔH° and ΔS°.
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http://dx.doi.org/10.1039/d0dt02119aDOI Listing
September 2020

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives.

Nat Commun 2020 08 11;11(1):4022. Epub 2020 Aug 11.

National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, Japan.

One major bottleneck in natural product drug development is derivatization, which is pivotal for fine tuning lead compounds. A promising solution is modifying the biosynthetic machineries of middle molecules such as macrolides. Although intense studies have established various methodologies for protein engineering of type I modular polyketide synthase(s) (PKSs), the accurate targeting of desired regions in the PKS gene is still challenging due to the high sequence similarity between its modules. Here, we report an innovative technique that adapts in vitro Cas9 reaction and Gibson assembly to edit a target region of the type I modular PKS gene. Proof-of-concept experiments using rapamycin PKS as a template show that heterologous expression of edited biosynthetic gene clusters produced almost all the desired derivatives. Our results are consistent with the promiscuity of modular PKS and thus, our technique will provide a platform to generate rationally designed natural product derivatives for future drug development.
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http://dx.doi.org/10.1038/s41467-020-17769-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419507PMC
August 2020

Achilles tendon thickening is associated with higher incidence of adverse cardiovascular event in patients with coronary artery disease.

Heart Vessels 2021 Feb 6;36(2):163-169. Epub 2020 Aug 6.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

Achilles tendon thickening (ATT) is a marker of high risk for coronary artery disease (CAD). However, the association between the presence of ATT and the incidence of cardiovascular events in patients with CAD is unclear. A total of 406 consecutive patients who underwent percutaneous coronary intervention (PCI) and ATT assessment were analyzed. ATT was defined as the Achilles tendon thickness of 9 mm or more on radiography. The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between patients with ATT and those without ATT. MACE included cardiac death, non-fatal myocardial infarction, stroke, target vessel revascularization (TVR), and non-TVR. ATT was found in 67 patients (16.5%). The incidence of cardiac death (3.2 vs. 0.0%, p = 0.001), TVR (12.7 vs. 4.0%, p = 0.005) and MACE (20.6 vs. 9.6%, p = 0.011) was significantly higher in the ATT group than the no ATT group. Patients with ATT had significantly higher incidence of cardiac death (5.6 vs. 0%, p < 0.001) than those without ATT even if they did not meet the diagnostic criteria of familial hypercholesterolemia. A multivariate model demonstrated that ATT was independently associated with the MACE at 1-year (Hazard ratio, 2.09; 95% Confidence Interval, 1.09-4.00, p = 0.026). The presence of ATT was independently associated with 1-year recurrence of cardiovascular events in patients with CAD undergoing PCI. Assessment of ATT might be useful for risk stratification of secondary cardiovascular events.
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http://dx.doi.org/10.1007/s00380-020-01679-wDOI Listing
February 2021

Short interposition with a small-diameter prosthetic graft for flow reduction of a high-flow arteriovenous fistula.

J Vasc Surg 2021 01 28;73(1):285-290. Epub 2020 May 28.

Department of Vascular Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. Electronic address:

Objective: The objective of this study was to evaluate the outcome of a short interposition using a small-diameter prosthetic graft as a flow-limiting procedure to manage symptomatic high-flow arteriovenous fistula (AVF).

Methods: A retrospective review of medical records on a case series was conducted. From June 2004 to April 2017, there were 25 patients with clinical symptoms of high output cardiac failure and progressive dilation of aneurysmal fistula vein due to high-flow AVF (≥1.5 L/min) who underwent short interposition with a 5-mm prosthetic graft at Saitama Medical Center. The primary outcome was the relief of clinical symptoms; other outcome measures included technical success, surgical complications, patency of vascular access, and postoperative changes in local and systemic hemodynamics as assessed by Doppler ultrasound.

Results: Twenty-five patients underwent short interposition for cardiac indications (n = 16) and aneurysmal dilation (n = 9). The technical success rate was 100%. The clinical symptoms were relieved in 24 patients (96.0%). Mean reduction in access blood flow was 52.4%. Cumulative primary unassisted patency rates (± standard error) at 1 year, 2 years, and 3 years were 76.2% ± 9.3%, 70.4% ± 10.3%, and 58.1% ± 11.6%, respectively. Secondary patency rates (± standard error) at 1 year, 2 years, and 3 years were 81.8% ± 8.2%, 71.5% ± 9.9%, and 71.5% ± 9.9%, respectively. Complications included access occlusion due to late thrombosis (n = 5 [21.7%]) and graft infection (n = 1 [4.3%]) in the median follow-up period of 3.9 years.

Conclusions: Short interposition with a prosthetic graft is a simple, effective, and durable treatment option for end-stage renal disease patients with cardiac symptoms and progressive dilation of the fistula vein due to high-flow AVF, offering clinical symptom resolution while preserving the autologous behavior of the initial access.
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http://dx.doi.org/10.1016/j.jvs.2020.05.035DOI Listing
January 2021

TGFβ (Transforming Growth Factor-Beta)-Activated Kinase 1 Regulates Arteriovenous Fistula Maturation.

Arterioscler Thromb Vasc Biol 2020 07 28;40(7):e203-e213. Epub 2020 May 28.

Department of Surgery (H.H., S.-R.L., H.B., J.G., T.H., T.I., X.G., T.W., K.W., S.L., S.O., B.Y., A.D.), Yale University School of Medicine, New Haven, CT.

Objective: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFβ [transforming growth factor-beta]-activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells.

Conclusions: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.
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http://dx.doi.org/10.1161/ATVBAHA.119.313848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316601PMC
July 2020

Identification, cloning and heterologous expression of biosynthetic gene cluster for desertomycin.

J Antibiot (Tokyo) 2020 09 26;73(9):650-654. Epub 2020 May 26.

National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.

From our in-house microbial genome database of secondary metabolite producers, we identified a candidate biosynthetic gene cluster for desertomycin from Streptomyces nobilis JCM4274. We report herein the cloning of the 127-kb entire gene cluster for desertomycin biosynthesis using bacterial artificial chromosome vector. The entire biosynthetic gene cluster for desertomycin was introduced in the heterologous host, Streptomyces lividans TK23, with an average yield of more than 130 mg l.
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http://dx.doi.org/10.1038/s41429-020-0319-0DOI Listing
September 2020

Endothelial glycocalyx and severity and vulnerability of coronary plaque in patients with coronary artery disease.

Atherosclerosis 2020 06 24;302:1-7. Epub 2020 Apr 24.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Background And Aims: Endothelial glycocalyx covers the endothelium and maintains vascular integrity. However, its association with the severity and vulnerability of coronary artery disease (CAD) remains to be elucidated.

Methods: A total of 259 consecutive patients with stable CAD requiring percutaneous coronary intervention (PCI) were prospectively enrolled. Patients were classified into 2 groups according to the median value of serum syndecan-1, which is a core component of the endothelial glycocalyx (lower syndecan-1 group [syndecan-1 <99.0 ng/mL], n = 130; higher syndecan-1 group [syndecan-1 ≥99.0 ng/mL], n = 129). Severity of CAD and focal plaque vulnerability in culprit lesion were evaluated using angiography and optical coherence tomography.

Results: There was no significant difference in clinical characteristics between the lower syndecan-1 group and the higher syndecan-1 group other than the prevalence of family history of CAD (19 vs. 32%, p = 0.022), prior PCI history (45 vs. 60%, p = 0.015) and estimated glomerular filtration rate (57.8 ± 17.2 vs. 50.9 ± 25.6 ml/min/1.73 m, p = 0.011). Although disease severity on angiogram was comparable between the 2 groups, the prevalence of lipid-rich plaque (40 vs. 19%, p = 0.004) and thin-cap fibroatheroma (20 vs. 6%, p = 0.006) was significantly higher in the lower syndecan-1 group than the higher syndecan-1 group. Lower syndecan-1 level was independently associated with higher prevalence of lipid-rich plaque (odds ratio 3.626, 95% confidence interval 1.535-8.566, p = 0.003).

Conclusions: Lower syndecan-1 level was associated with higher prevalence of vulnerable plaque in patients with CAD. This finding suggests the association between impaired endothelial glycocalyx and the development of vulnerable plaque.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.04.014DOI Listing
June 2020

Novel volumetric analysis for stent expansion after drug-eluting stent implantation: An optical coherence tomography study.

Catheter Cardiovasc Interv 2020 11 23;96(5):E501-E507. Epub 2020 Mar 23.

Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.

Objectives: To assess the clinical significance of a novel optical coherence tomography (OCT)-derived volumetric parameter of stent expansion by comparing it with the conventional parameters in real-world practice.

Background: The clinical significance of novel parameters in real-world practice including longer and smaller stents remains to be elucidated.

Methods: A total of 226 de novo lesion treated with drug-eluting stents in 208 consecutive patients were enrolled. Stent expansion was retrospectively assessed on the final OCT images after stent implantation. The novel parameter was the minimum expansion index (MEI) calculated using a novel algorithm that yields the ideal lumen area in each frame by taking into account vessel tapering. The device-oriented clinical end point (DoCE) included cardiac death, target vessel-related myocardial infarction, ischemia-driven target lesion revascularization.

Results: The MEI in the lesions with a DoCE (n = 22) at 2 years and cases without a DoCE (n = 204) was 64.3 ± 12.0% and 78.5 ± 14.6%, respectively (p < .001). In the receiver operating characteristic curve analyses, the areas under the curve for the MEI (0.787; p < .001) were larger than that for %stent expansion (0.718; p = .001) and minimum stent area (0.664; p = .004) in predicting the DoCE. The best cutoff of MEI for predicting the DoCE was 74.0.

Conclusions: The novel MEI was better than the conventional %stent expansion and minimum stent area for predicting DoCE.
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http://dx.doi.org/10.1002/ccd.28871DOI Listing
November 2020

Temperature-Responsive Molecular Assemblies Using Oligo(Ethylene Glycol)-Attached Polyamidoamine Dendron Lipids and their Functions as Drug Carriers.

J Funct Biomater 2020 Mar 13;11(1). Epub 2020 Mar 13.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Temperature-responsive nanocarrier systems using external stimuli are one of the most widely investigated stimuli-responsive strategies because heat is easy and safe to use for hyperthermia and controlled drug delivery. Polyamidoamine dendron lipids (PAMAM-DLs) composed of PAMAM dendron as head group and two alkyl chains can exhibit temperature-responsive morphological change through the attachment of suitable moieties to terminal of PAMAM dendron. In this study, oligo(ethylene glycol)s including ethoxy- or methoxy-diethylene glycols were attached to the terminals of PAMAM-DL, and temperature-responsive properties of their self-assemblies were evaluated by calorimetric and turbidity measurements. In the evaluation of temperature-responsive properties, ethoxy diethylene glycol (EDEG)-attached PAMAM-DL composed of two saturated alkyl chains and PAMAM dendron with 1st generation had lipid bilayer structure and suitable cloud point for the application as drug carrier. performances of the assemblies combining EDEG-attached PAMAM-DLs with cholesteryl-oxy-poly(ethylene glycol) (PEG-Chol) was evaluated using doxorubicin (DOX) as an anticancer drug. Cellular uptake of DOX-loaded EDEG-attached PAMAM-DL/PEG-Chol assemblies was promoted at 42 °C rather than 37 °C, resulting in an effective decrease in cell viability.
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http://dx.doi.org/10.3390/jfb11010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151555PMC
March 2020

Preparation of photothermal-chemotherapy nanohybrids by complexation of gold nanorods with polyamidoamine dendrimers having poly(ethylene glycol) and hydrophobic chains.

J Mater Chem B 2020 04 13;8(14):2826-2833. Epub 2020 Mar 13.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

The combination of anticancer drugs and laser hyperthermia could lead to efficient cancer treatment with less-adverse effects. This study combined anticancer drug-loaded functional dendrimers and light-responsive gold nanorods to fabricate nanohybrids that can provide anticancer-drug delivery and subsequent heat generation under near-infrared laser irradiation. A condensation reaction was used to conjugate poly(ethylene glycol)-modified polyamidoamine dendrimers to carboxylated gold nanorod surfaces. Oleoyl groups were incorporated into dendrimers to improve the drug loading capacity. Doxorubicin loading capacity was improved by incorporation of oleoyl chains into dendrimers in the nanohybrid, indicating increased hydrophobic interaction between anticancer drugs and nanohybrids. The nanohybrids exhibited heat generation properties under near infrared laser irradiation. They released anticancer drugs over time. The combination of doxorubicin-loaded nanohybrids and laser irradiation showed markedly better cytotoxicity than that of the nanohybrids used with lasers and drug-loaded nanohybrids without the use of lasers. After intravenous or intratumoral injection of nanohybrids to tumor-bearing mice, a sharp temperature increase was observed at the tumor site under laser irradiation. Especially, intratumorally injected doxorubicin-loaded nanohybrids showed almost complete tumor growth suppression under laser irradiation. The results demonstrate that functional dendrimer-gold nanorod nanohybrids are promising as multi-functional nanomaterials to achieve synergistic effects of anticancer drugs and heat ablation to support effective cancer treatments.
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http://dx.doi.org/10.1039/c9tb02163aDOI Listing
April 2020

Light-Activatable Transfection System Using Hybrid Vectors Composed of Thermosensitive Dendron Lipids and Gold Nanorods.

Pharmaceutics 2020 Mar 7;12(3). Epub 2020 Mar 7.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

Background: Gene delivery to target cells is crucially important to establish gene therapy and regenerative medicine. Although various virus-based and synthetic molecule-based gene vectors have been developed to date, selective transfection in a site or a cell level is still challenging. For this study, both light-responsive and temperature-responsive synthetic gene vectors were designed for spatiotemporal control of a transfection system.

Methods: 11-Mercaptoundecanoic acid-coated gold nanorods were mixed with polyamidoamine dendron-bearing lipids of two types having amino-terminus or ethoxydiethylene glycol-terminus to obtain hybrid vectors. Hybrid vectors were mixed further with pDNA. Then we investigated their physicochemical properties and transfection efficacy with or without near infrared laser irradiation.

Results: Hybrid vectors formed complexes with pDNA and exhibited enhanced photothermal property under near infrared laser irradiation compared with parent gold nanorods. Transfection efficacy of complexes was promoted considerably by brief laser irradiation soon after complex application to the cells. Analysis of intracellular distribution revealed that laser irradiation promoted the adsorption of complexes to the cells and cytosolic release of pDNA, which is derived from the change in surface hydrophobicity of complexes through dehydration of temperature-responsive groups.

Conclusions: Hybrid vector is promising as a light-activatable transfection system.
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http://dx.doi.org/10.3390/pharmaceutics12030239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150951PMC
March 2020
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