102 results on '"Atsushi Tamura"'
Search Results
2. [Total Aortic Arch Replacement for TypeⅠEndoleak after Thoracic Endovascular Aortic Repair using the Chimney Graft Technique:Report of a Case]
- Author
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Atsushi, Tamura, Kei, Kazuno, Takamichi, Yoshizaki, and Mariko, Hori
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Aged, 80 and over ,Male ,Blood Vessel Prosthesis Implantation ,Treatment Outcome ,Aortic Aneurysm, Thoracic ,Endovascular Procedures ,Humans ,Blood Vessel Prosthesis - Abstract
Here we report a case of total aortic arch replacement for typeⅠendoleak after thoracic endovascular aortic repair( TEVAR) using the concomitant chimney graft technique. An 81-year-old man was admitted with sudden back pain. Six years prior, he had undergone TEVAR for treatment of a distal aortic arch aneurysm. Preoperative computed tomography revealed an 80-mm-diameter arch aneurysm and typeⅠendoleak. The back pain was caused by impending aneurysmal rupture;therefore, urgent total arch replacement was performed. One stent was cut from the main endograft and anastomosed to its distal side. The bare metal stent in the left common carotid artery was removed and reconstructed at a healthy distal artery. Postoperative computed tomography revealed no endoleak of the aneurysm, and the patient's postoperative course was uneventful.
- Published
- 2022
3. Nail squamous cell carcinoma: A hidden high-risk human papillomavirus reservoir for sexually transmitted infections
- Author
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Atsushi Tamura, Yuko Kuriyama, Akira Shimizu, Osamu Ishikawa, and Michiko Hasegawa
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Male ,medicine.medical_specialty ,Skin Neoplasms ,Sexually Transmitted Diseases ,Dermatology ,Nail Diseases ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,Anal cancer ,Penile cancer ,Papillomaviridae ,Disease Reservoirs ,Cervical cancer ,Vaginal cancer ,business.industry ,Papillomavirus Infections ,HPV infection ,virus diseases ,Vulvar cancer ,medicine.disease ,Vulvar intraepithelial neoplasia ,female genital diseases and pregnancy complications ,stomatognathic diseases ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Penile Intraepithelial Neoplasia ,Female ,business - Abstract
Human papillomavirus (HPV) causes cervical cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, and oropharyngeal cancer. Squamous cell carcinoma (SCC) in the genital region in particular is recognized to be caused by HPV infection, and intraepithelial lesions of the penis and vulva are termed penile intraepithelial neoplasia and vulvar intraepithelial neoplasia, respectively. Although SCC of the nail apparatus is recognized as being associated with high-risk HPVs, it is not well-known in general medicine, and its analysis has been insufficient. In this article, we reviewed 136 cases of HPV-associated nail SCC and SCC in situ and delineated their clinical characteristics. We found that half of the cases were high-risk HPV-associated. Almost all of the types were high-risk α-HPVs. This disease had a male dominance and left hand digit 3 and right hand digits 1-3 were typically affected. In this review, 24% of the cases of nail SCC had a history of other HPV-associated diseases, suggesting the possibility of genitodigital transmission. We propose that nail SCC is a hidden high-risk HPV-associated reservoir and should be recognized as a sexually transmitted infection.
- Published
- 2019
4. Terminal Structure of Triethylene Glycol-Tethered Chains on β-Cyclodextrin-Threaded Polyrotaxanes Dominates Temperature Responsivity and Biointeractions
- Author
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Atsushi Tamura, Moe Ohashi, and Nobuhiko Yui
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chemistry.chemical_classification ,Coacervate ,Cyclodextrin ,Rotaxanes ,Chemical structure ,beta-Cyclodextrins ,Rational design ,Temperature ,Chemical modification ,Surfaces and Interfaces ,Condensed Matter Physics ,Polyethylene Glycols ,chemistry.chemical_compound ,chemistry ,Electrochemistry ,Biophysics ,Alkoxy group ,Humans ,General Materials Science ,Attention ,Ethylene glycol ,Spectroscopy ,Triethylene glycol - Abstract
Pharmacological and biomedical applications of cyclodextrin (CD)-threaded polyrotaxanes (PRXs) have gained increasing attention. We had previously investigated the therapeutic effects of oligo(ethylene glycol) (OEG)-modified β-CD PRXs in congenital metabolic disorders. Although the chemical modification of PRXs is crucial for these applications, the influences of the chemical structure of OEG modified on PRXs were not completely understood. The current study focuses on the terminal group structures of triethylene glycol (TEG)-tethered chains, wherein three series of TEG-tethered PRXs (TEG-PRXs) with various TEG terminal group structures (hydroxy, methoxy, and ethoxy) were synthesized to investigate their physicochemical properties and biointeractions. The methoxy and ethoxy-terminated TEG-PRXs exhibited temperature-dependent phase transitions in phosphate buffer saline and formed coacervate droplets above their cloud points. A comprehensive analysis revealed that the hydrophobicity of the terminal group structures of the TEG-tethered chains played a dominant role in exhibiting temperature-dependent phase transition. Furthermore, the hydrophobicity of the terminal group structures of TEG-tethered chains on PRXs also affected the interactions with lipids and proteins, with the hydrophobic ethoxy-terminated TEG-tethered chains showing the highest interactions. However, in normal human skin fibroblasts, the moderately hydrophobic methoxy-terminated TEG-modified PRXs showed the highest intracellular uptake levels. As a result, we concluded that methoxy-terminated TEG is a suitable chemical modification for the biomedical applications of PRXs due to the negligible temperature responsivity around physiological temperature and significant intracellular uptake levels. The findings of this study shall contribute significantly to the rational design of PRXs and CD-based materials for future pharmacological and biomedical applications.
- Published
- 2021
5. The Claudins: From Tight Junctions to Biological Systems
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Atsushi Tamura, Sachiko Tsukita, and Hiroo Tanaka
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endocrine system diseases ,Double row ,digestive system ,Biochemistry ,Tight Junctions ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Cell adhesion ,Claudin ,Molecular Biology ,Barrier function ,030304 developmental biology ,0303 health sciences ,Tight junction ,urogenital system ,Cell adhesion molecule ,Chemistry ,digestive, oral, and skin physiology ,Epithelial Cells ,Epithelium ,Cell biology ,medicine.anatomical_structure ,Paracellular transport ,Claudins ,tissues ,030217 neurology & neurosurgery - Abstract
Claudins are cell-cell adhesion molecules located at the tight junctions (TJs) between cells in epithelial cell sheets. The claudin family in mammals consists of 27 four-transmembrane domain proteins. Claudins are responsible for the paracellular barrier function of TJs, and in some cases confer paracellular channel functions to the paracellular barriers of TJs. Based on recent breakthroughs in the molecular structure of claudins, the hypothetical 'antiparallel double row model' was proposed, which suggests how claudins polymerize in a linear fashion and form TJ strands with paracellular barrier and channel functions. Meanwhile, ongoing studies at the cell and tissue levels are clarifying how the paracellular barrier and/or channel functions of claudin-based TJs, which are both robust and flexible, organize various biological systems.
- Published
- 2019
6. A microtubule‐LUZP1 association around tight junction promotes epithelial cell apical constriction
- Author
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Kazuhiro Aoki, Akira T. Komatsubara, Atsushi Tamura, Hiroka Kashihara, Hiroo Tanaka, Kazuto Tsukita, Yuhei Goto, Takeshi Matsui, Tomoki Yano, Shogo Nakayama, Hatsuho Kanoh, Tomoaki Mizuno, Sachiko Tsukita, and Ryosuke Takahashi
- Subjects
Myosin light-chain kinase ,tight junction ,Phosphatase ,Myosins ,Biology ,actomyosin‐based circumferential rings ,Microtubules ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Tight Junctions ,Adherens junction ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Microtubule ,Myosin ,Sf9 Cells ,otorhinolaryngologic diseases ,Animals ,Humans ,apical constriction ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,General Immunology and Microbiology ,Tight junction ,General Neuroscience ,Post-translational Modifications, Proteolysis & Proteomics ,Epithelial Cells ,Apical constriction ,Articles ,Adherens Junctions ,LUZP1 ,Actins ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,apical microtubules ,Actin Cytoskeleton ,HEK293 Cells ,Neurulation ,Cell Adhesion, Polarity & Cytoskeleton ,Chickens ,030217 neurology & neurosurgery - Abstract
Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di‐phosphorylated myosin light chain (ppMLC)‐driven contraction of actomyosin‐based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions (AJs). Here, we revealed a ppMLC‐triggered system at TJ‐associated CRs for vertebrate apical constriction involving microtubules, LUZP1, and myosin phosphatase. We first identified LUZP1 via unbiased screening of microtubule‐associated proteins in the AJC‐enriched fraction. In cultured epithelial cells, LUZP1 was found localized at TJ‐, but not at AJ‐, associated CRs, and LUZP1 knockout resulted in apical constriction defects with a significant reduction in ppMLC levels within CRs. A series of assays revealed that ppMLC promotes the recruitment of LUZP1 to TJ‐associated CRs, where LUZP1 spatiotemporally inhibits myosin phosphatase in a microtubule‐facilitated manner. Our results uncovered a hitherto unknown microtubule‐LUZP1 association at TJ‐associated CRs that inhibits myosin phosphatase, contributing significantly to the understanding of vertebrate apical constriction., The neural tube‐closure regulator LUZP1 drives apical constriction of epithelial cells by inhibiting myosin phosphatase activity in a microtubule‐dependent manner
- Published
- 2020
7. ER stress-mediated autophagic cell death induction through methylated β-cyclodextrins-threaded acid-labile polyrotaxanes
- Author
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Kei Nishida, Nobuhiko Yui, and Atsushi Tamura
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0301 basic medicine ,Programmed cell death ,Rotaxanes ,Pharmaceutical Science ,Poloxamer ,02 engineering and technology ,Methylation ,03 medical and health sciences ,Organelle ,Gene expression ,Autophagy ,Humans ,Cyclodextrins ,Chemistry ,Endoplasmic reticulum ,beta-Cyclodextrins ,Hydrogen-Ion Concentration ,Polyrotaxane ,Endoplasmic Reticulum Stress ,021001 nanoscience & nanotechnology ,Cell biology ,030104 developmental biology ,Cell Death Induction ,Unfolded protein response ,Lysosomes ,0210 nano-technology ,HeLa Cells - Abstract
Autophagy plays a pivotal role in the development and prevention of numerous diseases, and the induction of autophagy is regarded as a potential therapeutic approach for intractable diseases. In this study, the induction of autophagy by methylated β-cyclodextrins (Me-β-CDs)-threaded acid-labile polyrotaxane (Me-PRX) that can release the threaded Me-β-CDs in response to acidic pH in lysosomes was investigated. We hypothesized that the Me-β-CDs released from the Me-PRX interact with the membrane of organelles and cause autophagy. The Me-PRX preferentially accumulated in endoplasmic reticulum (ER) and caused ER stress, which was confirmed by gene expression analysis and the expression of an ER stress-marker protein. Accompanying the ER stress, cells treated with Me-PRX showed autophagy, which was not observed in cells treated with non-labile Me-PRX, other chemically modified PRXs, or free Me-β-CD. Furthermore, the Me-PRX treatment induced autophagic cell death and caused cell death even in apoptosis-resistant cells. Overall, this study demonstrates that the acid-labile Me-PRX induces ER stress-mediated autophagic cell death, and the Me-PRX would be a promising candidate to induce effective cell death in apoptosis-resistant malignant tumors.
- Published
- 2018
8. Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease
- Author
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Atsushi Tamura and Nobuhiko Yui
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Rotaxanes ,Pharmaceutical Science ,Poloxamer ,02 engineering and technology ,Pharmacology ,Biology ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Humans ,Cells, Cultured ,chemistry.chemical_classification ,Cyclodextrins ,Drug Carriers ,Mice, Inbred BALB C ,Cyclodextrin ,Cholesterol ,Metabolic disorder ,Neurodegeneration ,Therapeutic effect ,Niemann-Pick Disease, Type C ,Fibroblasts ,Polyrotaxane ,021001 nanoscience & nanotechnology ,medicine.disease ,Mice, Mutant Strains ,2-Hydroxypropyl-beta-cyclodextrin ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Niemann-pick type c disease ,Female ,0210 nano-technology - Abstract
Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl β-cyclodextrin (HP-β-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile β-CD-based polyrotaxanes (PRXs) comprising multiple β-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of β-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded β-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-β-CD. In this study, the therapeutic effect of the PRXs in a mouse model of NPC disease was investigated. Weekly administration of the PRXs significantly prolonged the life span and suppressed neurodegeneration in mice, even at a dose of 500mg/kg, a markedly lower dose than previously reported for HP-β-CD. Detailed analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild-type mice. Acid-labile PRX is therefore a promising candidate for potentiating the efficacy of β-CD in the treatment of NPC disease.
- Published
- 2018
9. Acid-Induced Intracellular Dissociation of β-Cyclodextrin-Threaded Polyrotaxanes Directed toward Attenuating Phototoxicity of Bisretinoids through Promoting Excretion
- Author
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Kei Nishida, Moe Ohashi, Nobuhiko Yui, and Atsushi Tamura
- Subjects
0301 basic medicine ,Rotaxanes ,medicine.drug_class ,Dimer ,Pharmaceutical Science ,Retinal Pigment Epithelium ,010402 general chemistry ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Cell Line ,Excretion ,Macular Degeneration ,Retinoids ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Humans ,Photosensitivity Disorders ,Retinoid ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Retinal pigment epithelium ,Cyclodextrin ,beta-Cyclodextrins ,Hydrogen-Ion Concentration ,eye diseases ,0104 chemical sciences ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Biophysics ,Molecular Medicine ,Cytokine secretion ,sense organs ,Phototoxicity ,Acids ,Intracellular - Abstract
In the retinal pigment epithelium of patients with age-related macular degeneration (AMD), excess N-retinylidene-N-retinylethanolamine (A2E), a dimer of all-trans-retinal, accumulats to induce inflammatory cytokine secretion and phototoxic effects. Therefore, the reduction of intracellular A2E is a promising approach for the prevention and treatment of AMD. In this study, acid-labile β-cyclodextrin (β-CD)-threaded polyrotaxanes (PRXs) were synthesized and investigated their effects on the removal of A2E accumulated in retinal pigment epithelium cells (ARPE-19) in comparison to nonlabile PRXs and 2-hydroxypropyl β-CD (HP-β-CD) were examined. GC-MS and HPLC studies strongly suggest that the acid-labile PRXs dissociated into their constituent molecules in cells by lysosomal acidification and threaded β-CDs were considered to be released from the PRXs. The released β-CDs formed an inclusion complex with A2E, which promoted the excretion of A2E. Indeed, the acid-labile PRXs effectively reduced intracellular A2E level at approximately a 10-fold lower concentration than HP-β-CD. Accompanied with A2E removal, the toxicity and phototoxicity of A2E were attenuated by treatment with acid-labile PRXs. Because the nonlabile PRX failed to reduce intracellular A2E level and attenuate phototoxicity, intracellular release of threaded β-CDs from the acid-labile PRX might contribute to reducing intracellular A2E. We conclude that acid-labile PRXs are promising candidates for the treatment of macular diseases through the removal of toxic metabolites.
- Published
- 2017
10. A case of bilateral pneumothoraces resulting from tracheostomy for advanced laryngeal cancer
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Akihiro Himeno and Atsushi Tamura
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Thoracostomy ,Chest pain ,03 medical and health sciences ,Postoperative Complications ,Tracheostomy ,0302 clinical medicine ,Hyperventilation ,medicine ,Humans ,Airway Management ,Respiratory system ,030223 otorhinolaryngology ,Laryngeal Neoplasms ,medicine.diagnostic_test ,business.industry ,Pneumothorax ,General Medicine ,Middle Aged ,respiratory system ,medicine.disease ,Endoscopy ,Surgery ,Otorhinolaryngology ,Chest Tubes ,Radiography, Thoracic ,Airway management ,medicine.symptom ,Tomography, X-Ray Computed ,Complication ,Airway ,business ,030217 neurology & neurosurgery - Abstract
Pneumothorax is a possible complication of tracheostomy. We report a rare case of bilateral pneumothoraces resulting from tracheostomy in an advanced laryngeal cancer patient. A 59-year-old man was referred to our clinic for evaluation and treatment of laryngeal tumor. Laryngeal endoscopy showed limited movement of bilateral vocal cords, and computed tomography revealed a tumor lesion extending from the vocal cords to the subglottic area. Three days after the first visit, the patient developed respiratory difficulty, and we elected to perform emergency tracheostomy for airway management. Immediately after the start of the procedure, he began hyperventilating, and complained of respiratory discomfort and chest pain. We then recognized a mediastinal air leak, and we suspected pneumothorax resulting from the tracheostomy. Chest X-ray showed bilateral pneumothoraces; therefore, we inserted bilateral chest drainage tubes, which stabilized his respiratory condition. We speculated that the pathogenesis of the bilateral pneumothoraces was weakened alveolar walls secondary to long-term smoking, and a significant rise in airway pressure because of airway constriction by the neck-extended position and hyperventilation, during tracheostomy.
- Published
- 2017
11. Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186
- Author
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Mamoru Watanabe, Kiichiro Tsuchiya, Atsushi Tamura, Kosuke Fujimoto, Sachiko Tsukita, Masahito Ikawa, Yosuke Shimada, Kiyoshi Takeda, Ryu Okumura, Yoki Furuta, Hiroo Tanaka, Makoto Kinoshita, Daisuke Okuzaki, Hisako Kayama, Shigetsugu Hatakeyama, Atsushi Kumanogoh, and Masashi Narazaki
- Subjects
0301 basic medicine ,Colon ,Ubiquitin-Protein Ligases ,Immunology ,Inflammation ,Occludin ,Permeability ,Tripartite Motif Proteins ,Pathogenesis ,Mice ,03 medical and health sciences ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,Cells, Cultured ,Mice, Knockout ,biology ,Endoplasmic reticulum ,Dextran Sulfate ,Epithelial Cells ,Endoplasmic Reticulum Stress ,digestive system diseases ,Cell biology ,Ubiquitin ligase ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Mucosal immunology ,Mutation ,biology.protein ,Unfolded protein response ,Colitis, Ulcerative ,medicine.symptom ,Carrier Proteins - Abstract
Genome-wide association studies and subsequent deep sequencing analysis have identified susceptible loci for inflammatory bowel diseases (IBDs) including ulcerative colitis (UC). A gene encoding RING finger protein 186 (RNF186) is located within UC-susceptible loci. However, it is unclear whether RNF186 is involved in IBD pathogenesis. Here, we show that RNF186 controls protein homeostasis in colonic epithelia and regulates intestinal inflammation. RNF186, which was highly expressed in colonic epithelia, acted as an E3 ligase mediating polyubiquitination of its substrates. Permeability of small organic molecules was augmented in the intestine of Rnf186-/- mice. Increased expression of several RNF186 substrates, such as occludin, was found in Rnf186-/- colonic epithelia. The disturbed protein homeostasis in Rnf186-/- mice correlated with enhanced endoplasmic reticulum (ER) stress in colonic epithelia and increased sensitivity to intestinal inflammation after dextran sulfate sodium (DSS) treatment. Introduction of an UC-associated Rnf186 mutation led to impaired E3 ligase activity and increased sensitivity to DSS-induced intestinal inflammation in mice. Thus, RNF186 maintains gut homeostasis by controlling ER stress in colonic epithelia.
- Published
- 2017
12. [Emergent Endovascular Treatment of Spontaneous Rupture of the Thoracic Aorta]
- Author
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Hajime, Kinoshita, Mariko, Hori, Atsushi, Tamura, Kei, Kazuno, Hiroshige, Sato, and Seiichiro, Murata
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Aged, 80 and over ,Male ,Blood Vessel Prosthesis Implantation ,Treatment Outcome ,Aortic Aneurysm, Thoracic ,Rupture, Spontaneous ,Endovascular Procedures ,Humans ,Aorta, Thoracic ,Female ,Stents ,Aged ,Retrospective Studies - Abstract
Spontaneous rupture of the thoracic aorta is a rare disease with a poor prognosis without obvious trauma, aortic aneurysm and aortic dissection. We report 2 cases of successful endovascular aortic repair for spontaneous rupture of the thoracic aorta. Case 1:A 79-year-old man was referred to our hospital complaining of general fatigue. He returned home without any obvious abnormalities in blood tests and computed tomography (CT). The patient was aware of dizziness and fluttering in the early morning the next day, and was transported to the hospital by shock vital. CT showed rupture of descending aorta, so we performed emergent thoracic endovascular aortic repair (TEVAR). Postoperatively, the patient progressed without paraplegia and was transferred to other hospital on the 15th day of hospital for the purpose of rehabilitation. Case 2:A 87-year-old woman was admitted to hospital with suspected pyelonephritis, but his respiratory status was gradually exacerbated. CT showed a rupture of the thoracic aorta at the distal arch. Ten days ago, CT showed no findings suggestive of aneurysm and dissection at the same site of aorta. We performed emergency TEVAR. She was removed from mechanical ventilation on the 4th postoperative day. We are continuing rehabilitation treatment now.
- Published
- 2019
13. Reciprocal Association between the Apical Junctional Complex and AMPK: A Promising Therapeutic Target for Epithelial/Endothelial Barrier Function?
- Author
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Kazuto Tsukita, Atsushi Tamura, Sachiko Tsukita, and Tomoki Yano
- Subjects
tight junction ,Regulator ,Review ,paracellular barrier ,AMP-Activated Protein Kinases ,Cell junction ,adherens junction ,Catalysis ,Permeability ,Tight Junctions ,Inorganic Chemistry ,Adherens junction ,AMP-activated protein kinase (AMPK) ,Cell polarity ,Animals ,Humans ,Physical and Theoretical Chemistry ,Protein kinase A ,Molecular Biology ,Spectroscopy ,Tight junction ,Chemistry ,Organic Chemistry ,AMPK ,Cell Polarity ,Endothelial Cells ,Epithelial Cells ,General Medicine ,Adherens Junctions ,Computer Science Applications ,Cell biology ,Paracellular transport ,apical junctional complex ,Energy Metabolism ,Signal Transduction - Abstract
Epithelial/endothelial cells adhere to each other via cell–cell junctions including tight junctions (TJs) and adherens junctions (AJs). TJs and AJs are spatiotemporally and functionally integrated, and are thus often collectively defined as apical junctional complexes (AJCs), regulating a number of spatiotemporal events including paracellular barrier, selective permeability, apicobasal cell polarity, mechano-sensing, intracellular signaling cascades, and epithelial morphogenesis. Over the past 15 years, it has been acknowledged that adenosine monophosphate (AMP)-activated protein kinase (AMPK), a well-known central regulator of energy metabolism, has a reciprocal association with AJCs. Here, we review the current knowledge of this association and show the following evidences: (1) as an upstream regulator, AJs activate the liver kinase B1 (LKB1)–AMPK axis particularly in response to applied junctional tension, and (2) TJ function and apicobasal cell polarization are downstream targets of AMPK and are promoted by AMPK activation. Although molecular mechanisms underlying these phenomena have not yet been completely elucidated, identifications of novel AMPK effectors in AJCs and AMPK-driven epithelial transcription factors have enhanced our knowledge. More intensive studies along this line would eventually lead to the development of AMPK-based therapies, enabling us to manipulate epithelial/endothelial barrier function.
- Published
- 2019
14. Vinculin is critical for the robustness of the epithelial cell sheet paracellular barrier for ions
- Author
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Tomoaki Mizuno, Shimpei Gotoh, Atsushi Tamura, Toyohiro Hirai, Toshinori Namba, Tomoki Yano, Shigenobu Yonemura, Sachiko Tsukita, Kazuto Tsukita, Satoshi Konishi, Hisako Matsumoto, Hatsuho Kanoh, and Hiroo Tanaka
- Subjects
animal structures ,Health, Toxicology and Mutagenesis ,Plant Science ,macromolecular substances ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Heterocyclic Compounds, 4 or More Rings ,Cell Line ,Tight Junctions ,Adherens junction ,03 medical and health sciences ,Gene Knockout Techniques ,0302 clinical medicine ,Myosin ,medicine ,Humans ,Barrier function ,Research Articles ,030304 developmental biology ,Ions ,0303 health sciences ,Stochastic Processes ,Ecology ,biology ,Tight junction ,Chemistry ,urogenital system ,HEK 293 cells ,digestive, oral, and skin physiology ,Epithelial Cells ,Actomyosin ,Vinculin ,musculoskeletal system ,Epithelium ,medicine.anatomical_structure ,HEK293 Cells ,Paracellular transport ,biology.protein ,Biophysics ,030217 neurology & neurosurgery ,Research Article - Abstract
Vinculin in the apical junctional complex maintains the paracellular barrier function specifically for ions, but not for large solutes, by buffering mechanical fluctuations., The paracellular barrier function of tight junctions (TJs) in epithelial cell sheets is robustly maintained against mechanical fluctuations, by molecular mechanisms that are poorly understood. Vinculin is an adaptor of a mechanosensory complex at the adherens junction. Here, we generated vinculin KO Eph4 epithelial cells and analyzed their confluent cell-sheet properties. We found that vinculin is dispensable for the basic TJ structural integrity and the paracellular barrier function for larger solutes. However, vinculin is indispensable for the paracellular barrier function for ions. In addition, TJs stochastically showed dynamically distorted patterns in vinculin KO cell sheets. These KO phenotypes were rescued by transfecting full-length vinculin and by relaxing the actomyosin tension with blebbistatin, a myosin II ATPase activity inhibitor. Our findings indicate that vinculin resists mechanical fluctuations to maintain the TJ paracellular barrier function for ions in epithelial cell sheets.
- Published
- 2019
15. Enhanced autophagy induction via the mitochondrial delivery of methylated beta-cyclodextrin-threaded polyrotaxanes using a MITO-Porter
- Author
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Kei Nishida, Shinnosuke Daikuhara, Yuma Yamada, Nobuhiko Yui, Hideyoshi Harashima, and Atsushi Tamura
- Subjects
Methylated β cyclodextrin ,Abnormal mitochondria ,Rotaxanes ,010402 general chemistry ,01 natural sciences ,Methylation ,Catalysis ,Materials Chemistry ,Autophagy ,Humans ,Nanotechnology ,Nanodevice ,010405 organic chemistry ,Chemistry ,beta-Cyclodextrins ,Metals and Alloys ,General Chemistry ,Polyrotaxane ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Cell biology ,Mitochondria ,Ceramics and Composites ,HeLa Cells - Abstract
Failure of autophagy induction results in the accumulation of abnormal mitochondria to cause neurodegenerative diseases. Artificial autophagy activation via the mitochondrial delivery of polyrotaxane with autophagy induced activity is achieved using a MITO-Porter, a nanodevice for mitochondrial delivery. This strategy can be applied to innovative research and therapy.
- Published
- 2019
16. [Intracellularly Degradable Polyrotaxanes for Therapeutic Applications]
- Author
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Atsushi Tamura
- Subjects
Rotaxanes ,Macromolecular Substances ,PH reduction ,Pharmaceutical Science ,Poloxamer ,Cleavage (embryo) ,Methylation ,chemistry.chemical_compound ,Mice ,Extracellular ,Autophagy ,Animals ,Humans ,Pharmacology ,chemistry.chemical_classification ,Niemann-Pick Diseases ,Cyclodextrins ,Drug Carriers ,Cyclodextrin ,Chemistry ,Cholesterol ,beta-Cyclodextrins ,Fibroblasts ,Hydrogen-Ion Concentration ,Cell biology ,Supramolecular polymers ,Disease Models, Animal ,Drug Design ,Lysosomes ,Intracellular - Abstract
Recently, the application of β-cyclodextrins (β-CDs) as therapeutic agents has received considerable attention. β-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of β-CDs, the use of β-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of β-CDs for NPC disease. PRXs are supramolecular polymers composed of many CDs threaded onto a linear polymer chain and capped with bulky stopper molecules. In this review, the design of PRXs and their therapeutic applications are described. To achieve the intracellular release of threaded β-CDs from PRXs, stimuli-cleavable linkers are introduced in an axle polymer of PRXs. The stimuli-labile PRXs can dissociate into their constituent molecules by a cleavage reaction under specific stimuli, such as pH reduction in lysosomes. The release of the threaded β-CDs from acid-labile PRXs in acidic lysosomes leads to the formation of an inclusion complex with the cholesterol that has accumulated in NPC disease patient-derived fibroblasts, thus promoting the extracellular excretion of the excess cholesterol. Moreover, the administration of PRXs to a mouse model of NPC disease caused significant suppression of the tissue accumulation of cholesterol, resulting in a prolonged life span in the model mice. Additionally, the induction of autophagy by the methylated β-CD-threaded PRXs (Me-PRXs) is described. Accordingly, the stimuli-labile PRXs are expected to be effective carriers of CDs for therapeutic applications.
- Published
- 2019
17. Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection
- Author
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Naoki Shimizu, Rebecca S. Cook, Aida G. Walker, Shannon E. Ronca, Kelly T. Dineley, Takaaki Koma, Tomoko Makishima, Slobodan Paessler, Atsushi Tamura, Nadia Wauquier, Bayon Bockarie, Sheik Humarr Khan, Jeanon N. Smith, Joseph N. Fair, Alexey Seregin, Milagros Miller, and Nadezhda E. Yun
- Subjects
0301 basic medicine ,Hearing loss ,Hearing Loss, Sensorineural ,media_common.quotation_subject ,Immunology ,Disease ,Biology ,medicine.disease_cause ,Microbiology ,Disease Outbreaks ,Sierra Leone ,Sierra leone ,Mice ,03 medical and health sciences ,Lassa Fever ,0302 clinical medicine ,Virology ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Lassa virus ,Lassa fever ,Cochlear Nerve ,Spiral ganglion ,media_common ,Microscopy ,Virulence ,Histocytochemistry ,Convalescence ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Ear, Inner ,Insect Science ,Pathogenesis and Immunity ,Sensorineural hearing loss ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss. IMPORTANCE Sensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.
- Published
- 2016
18. Correlation of climbing perception and eye movements during daytime and nighttime takeoffs using a flight simulator
- Author
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Yoshiro Wada, Takuo Inui, Atsushi Tamura, Naoki Shimizu, and Akihiro Shiotani
- Subjects
Adult ,Male ,medicine.medical_specialty ,Eye Movements ,genetic structures ,media_common.quotation_subject ,Illusion ,Flight simulator ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,Perception ,medicine ,Humans ,Takeoff ,030223 otorhinolaryngology ,Simulation Training ,media_common ,Eye movement ,General Medicine ,Darkness ,Middle Aged ,Vestibular Function Tests ,Otorhinolaryngology ,Spatial disorientation ,Space Perception ,Climbing ,Aerospace Medicine ,Reflex ,sense organs ,Psychology ,human activities ,030217 neurology & neurosurgery - Abstract
This study suggests that the subjective climbing perception can be quantitatively evaluated using values calculated from induced eye movements, and the findings may aid in the detection of pilots who are susceptible to spatial disorientation in a screening test.The climbing perception experienced by a pilot during takeoff at night is stronger than that experienced during the day. To investigate this illusion, this study assessed eye movements and analyzed their correlation with subjective climbing perception during daytime and nighttime takeoffs.Eight male volunteers participated in this study. A simulated aircraft takeoff environment was created using a flight simulator and the maximum slow-phase velocities and vestibulo-ocular reflex gain of vertical eye movements were calculated during takeoff simulation.Four of the eight participants reported that their perception of climbing at night was stronger, while the other four reported that there was no difference between day and night. These perceptions were correlated with eye movements; participants with a small difference in the maximum slow-phase velocities of their downward eye movements between daytime and nighttime takeoffs indicated that their perception of climbing was the same under the two conditions.
- Published
- 2016
19. Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori Infection
- Author
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Kazuhiro Sentani, Atsushi Tamura, Masanobu Oshima, Sachiko Tsukita, Wataru Yasui, Kazuo Suzuki, Koya Suzuki, Tomoki Yano, and Hiroo Tanaka
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Wnt1 Protein ,medicine.disease_cause ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Stomach Neoplasms ,Metaplasia ,Medicine ,Animals ,Humans ,lcsh:RC799-869 ,Claudin ,Wnt Signaling Pathway ,Hepatology ,business.industry ,Stomach ,digestive, oral, and skin physiology ,Gastroenterology ,Wnt signaling pathway ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Editorial ,Gastritis ,Claudins ,Cancer research ,Disease Progression ,Gastric acid ,Cytokines ,030211 gastroenterology & hepatology ,lcsh:Diseases of the digestive system. Gastroenterology ,medicine.symptom ,business ,Carcinogenesis ,Signal Transduction - Abstract
Background & Aims: Epithelial cells are joined by tight junctions (TJs) to form a cell sheet. In the stomach, epithelial cell sheet forms an essential barrier against gastric material, including gastric acid. Although the decreased expression of stomach-type claudin-18 (stCldn18), a TJ protein, is generally observed in human gastritis and gastric cancer, its pathological roles are not fully understood. We previously reported that mice lacking stCldn18 (stCldn18-/-) exhibit gastric acid leakage through TJs, which induces active gastritis at a young age. Here, we examined the gastric pathologies in mice after long-term stCldn18 deficiency. Methods: The gastric pathologies in stCldn18-/- mice were sequentially analyzed from youth to old age, and compared to those in humans. To examine the relationship between stCldn18 deficiency-induced gastric pathologies and Wnt-dependent tumorigenesis, we generated Wnt1-overexpressing stCldn18-/- mice. Results: StCldn18-/- mice developed chronic active gastritis at middle age, with expression of the chemoattractant CCL28. At old age, 20-30% of these mice developed gastric tumors with CXCL5 expression, indicative of EMT. In this process, spasmolytic polypeptide-expressing metaplasia (SPEM) cells appeared. Increased expressions of CD44-variants, TLR2, and CXCL5 indicated age-dependent changes in cell characteristics. Some features of the stCldn18-/- mouse gastric tumorigenesis resembled H pylori-infection-related human carcinogenesis. The gastric tumorigenesis was accelerated in Wnt1-overexpressing stCldn18-/- mice, indicating that Wnt is involved in the stCldn18-/- mouse gastric tumorigenesis. Conclusions: StCldn18 deficiency induced gastric tumorigenesis in mice without H pylori infection. Our findings revealed that several signaling networks, including the cytokine-, stemness-, and Wnt-signaling pathways, may be activated under the stCldn18-deficiency-induced chronic active gastritis to accelerate the gastric tumorigenesis. Keywords: Epithelial Barrier, Tight Junction, Chronic Active Gastritis, SPEM
- Published
- 2018
20. [Concomitant Atrial Septal Defect Closure and Repair of Pectus Excavatum in a 50-year-old Patient;Report of a Case]
- Author
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Atsushi, Tamura, Hajime, Kinoshita, Kei, Kazuno, Hiroshige, Sato, Seiichiro, Murata, and Hiroshi, Iida
- Subjects
Stroke ,Venous Thrombosis ,Sternum ,Funnel Chest ,Humans ,Female ,Ribs ,Middle Aged ,Thoracic Wall ,Sternotomy ,Heart Septal Defects, Atrial - Abstract
We report a case of atrial septal defect (ASD) with severe pectus excavatum. A 50-year-old female had a stroke due to paradoxical embolism from deep vein thrombosis thorough ASD. Her preoperative computed tomography(CT) revealed a severe pectus excavatum (Haller CT index 28.6). The patient underwent ASD closure and repair of the pectus excavatum concomitantly. Median full sternotomy was performed for ASD closure. And we adopted sterno-costal elevation for pectus excavatum repair. Cartilages of the 3rd to the 7th rib were segmentally resected and the remainders were re-sutured to the sternum. The operation was performed uneventfully. The postoperative echocardiogram revealed no residual shunt. And the deformity of the anterior chest wall was remarkably lessen.
- Published
- 2018
21. Claudin-3 Loss Causes Leakage of Sweat from the Sweat Gland to Contribute to the Pathogenesis of Atopic Dermatitis
- Author
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Masaru Ishii, Atsushi Tamura, Hirofumi Miyata, Ichiro Katayama, Masato Ohmi, Sachiko Tsukita, Kosuke Yamaga, Hiroyuki Murota, and Junichi Kikuta
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,endocrine system diseases ,Sweating ,Dermatology ,urologic and male genital diseases ,digestive system ,Biochemistry ,Dermatitis, Atopic ,Tight Junctions ,SWEAT ,Pathogenesis ,03 medical and health sciences ,Mice ,Young Adult ,Internal medicine ,Sweat gland ,medicine ,Animals ,Claudin-3 ,Humans ,Claudin ,Sweat ,Molecular Biology ,Mice, Knockout ,integumentary system ,Tight junction ,Chemistry ,CLDN3 ,Cell Biology ,Atopic dermatitis ,medicine.disease ,Water Loss, Insensible ,digestive system diseases ,Acetylcholine ,Healthy Volunteers ,Sweat Glands ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Female ,Homeostasis - Abstract
The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3-/- and Cldn3+/- mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin-3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3.
- Published
- 2017
22. [Valve Replacement for Severe Aortic Stenosis in a Patient with Tangier Disease]
- Author
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Atsushi, Tamura, Takamichi, Yoshizaki, and Sho, Kusadokoro
- Subjects
Heart Valve Prosthesis ,Humans ,Female ,Aortic Valve Stenosis ,Middle Aged ,Tomography, X-Ray Computed ,Vascular Calcification ,Tangier Disease ,ATP Binding Cassette Transporter 1 - Abstract
We report a case of severe aortic valve stenosis in a patient with Tangier disease. A 64-year-old female was diagnosed with Tangier disease on the basis of gene mutation. The serum levels of total cholesterol and high-density lipoprotein were 124 mg/dl and 4.3 mg/dl, respectively. She had a symptom of dyspnea and echocardiography revealed severe aortic valve stenosis with the maximum gradient of 60.5 mmHg. Chest computed tomography showed severe calcification of the ascending aorta and the aortic root. Aortic valve replacement using a bioprosthetic valve was performed. Several reports have been made on coronary artery revascularization in Tangier disease patients, but one on surgical treatment for aortic valve stenosis is extremely rare.
- Published
- 2017
23. [Early Structural Valve Deterioration of Trifecta Biological Prosthesis;Report of a Case]
- Author
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Atsushi, Tamura, Takamichi, Yoshizaki, and Sho, Kusadokoro
- Subjects
Aged, 80 and over ,Bioprosthesis ,Heart Valve Prosthesis Implantation ,Male ,Reoperation ,Treatment Outcome ,Heart Valve Prosthesis ,Aortic Valve Insufficiency ,Humans ,Aortic Valve Stenosis - Abstract
Trifecta valve is a 3rd-generation, stented bioprosthesis which is made from one bovine pericardial sheet. A 77-years-old male patient had undergone combine aortic valve replacement (AVR) using a 23-mm Trifecta valve and ascending aorta replacement for severe aortic valve regurgitation and ascending aorta aneurysm. The postoperative period was uneventful. However, he presented with dyspnea on effort and severe aortic valve regurgitation 31 months after operation. Re-do AVR with a new bioprosthetic valve was performed via 2nd sternotomy. Surgical inspection revealed that the Trifecta valve had a parastent tear in the left-coronary cusp without any calcification or vegetation. We report our experience with a case of early structural valve deterioration of Trifecta biological prosthesis and review relevant literatures.
- Published
- 2017
24. Perceived direction of gravity and the body-axis during static whole body roll-tilt in healthy subjects
- Author
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Atsushi Tamura, Takuo Inui, Akihiro Shiotani, and Yoshiro Wada
- Subjects
Adult ,Male ,medicine.medical_specialty ,Gravity (chemistry) ,media_common.quotation_subject ,Posture ,Flight simulator ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Physical medicine and rehabilitation ,Body axis ,Reference Values ,Perception ,medicine ,Humans ,030223 otorhinolaryngology ,Orientation, Spatial ,media_common ,Dark room ,Healthy subjects ,General Medicine ,Middle Aged ,Proprioception ,Tilt (optics) ,Otorhinolaryngology ,Head Movements ,Space Perception ,Whole body ,Psychology ,030217 neurology & neurosurgery ,Gravitation - Abstract
Objective: We used the subjective visual vertical (SVV) and two different subjective visual body axis (SVBA) methods to quantify roll-tilt perception under gravity, and investigated the characteristics of these methods during static roll-tilt. In addition, we independently developed a compact device to facilitate evaluation of SVBA in different gravitational environments.Methods: Ten male volunteers participated in this study. We created a roll-tilt environment using a flight simulator in a dark room. The cockpit of the simulator was tilted leftward or rightward (−30°, −20°, −10°, 0°, 10°, 20° and 30°) in each randomly ordered trial. We quantified roll-tilt perception such that the experiment was conducted under 21 different conditions per participant.Results: We found no significant differences among the SVV error and the two types of SVBA error.Conclusions: The SVV and the SVBA methods may be useful for evaluating subjective roll-tilt perception.
- Published
- 2017
25. Site-specific distribution of claudin-based paracellular channels with roles in biological fluid flow and metabolism
- Author
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Atsushi Tamura, Koya Suzuki, Sachiko Tsukita, and Hiroo Tanaka
- Subjects
0301 basic medicine ,endocrine system diseases ,digestive system ,Cell junction ,General Biochemistry, Genetics and Molecular Biology ,Tight Junctions ,03 medical and health sciences ,Mice ,0302 clinical medicine ,History and Philosophy of Science ,medicine ,Extracellular ,Animals ,Humans ,Transcellular ,Claudin ,Mice, Knockout ,Ion Transport ,Tight junction ,urogenital system ,Reabsorption ,Chemistry ,General Neuroscience ,digestive, oral, and skin physiology ,Membrane Proteins ,Epithelial Cells ,Epithelium ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Intestinal Absorption ,Paracellular transport ,Claudins ,tissues ,030217 neurology & neurosurgery - Abstract
The claudins are a family of membrane proteins with at least 27 members in humans and mice. The extracellular regions of claudin proteins play essential roles in cell-cell adhesion and the paracellular barrier functions of tight junctions (TJs) in epithelial cell sheets. Furthermore, the extracellular regions of some claudins function as paracellular channels in the paracellular barrier that allow the selective passage of water, ions, and/or small organic solutes across the TJ in the extracellular space. Structural analyses have revealed a common framework of transmembrane, cytoplasmic, and extracellular regions among the claudin-based paracellular barriers and paracellular channels; however, differences in the claudins' extracellular regions, such as their charges and conformations, determine their properties. Among the biological systems that involve fluid flow and metabolism, it is noted that hepatic bile flow, renal Na+ reabsorption, and intestinal nutrient absorption are dynamically regulated via site-specific distributions of paracellular channel-forming claudins in tissue. Here, we focus on how site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine.
- Published
- 2017
26. Apical cytoskeletons and junctional complexes as a combined system in epithelial cell sheets
- Author
-
Tomoki, Yano, Hatsuho, Kanoh, Atsushi, Tamura, and Sachiko, Tsukita
- Subjects
Cell Membrane ,Animals ,Humans ,Epithelial Cells ,Microtubules ,Actins ,Cytoskeleton ,Epithelium ,Tight Junctions - Abstract
Epithelial cell sheet formation is central to many aspects of vertebrate development and function. For example, it is a major principle of differentiation in embryogenesis and regeneration, enables the compartmentalization of tissues, and is the basis for the maintenance of homeostasis throughout the body. A key characteristic of biologically functional epithelial cell sheets is a clear difference between the top and bottom sides owing to the apicobasal polarity of the cells in the sheet, as seen in the simple polar epithelia. Epithelial cell sheets are formed by cell-cell adhesion conferred by junctional complexes, in particular via tight junctions (TJs), which thus create a paracellular barrier. This review focuses on the apical side of the sheet, which serves as the front line. The apical membranes and TJs of the various tissues have specific characteristics that enable them to function and adapt to their biological context: each system must be robust, but also dynamic and flexible to maintain homeostasis. Here, we describe various apical cytoskeletal structures that are critical to the integrity of epithelial cell sheets. We also discuss the association of apical cytoskeletal networks with TJs, which thus forms a combined system, tentatively termed the TJ-apical complex.
- Published
- 2017
27. The role of the Pharmaceuticals and Medical Devices Agency and healthcare professionals in post-marketing safety
- Author
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Meguru Watanabe, Naoya Horiuchi, Atsushi Tamura, Kazuhiko Mori, and Hiromu Kutsumi
- Subjects
Risk management plan ,Health Personnel ,Population ,Electronic mail ,Patient safety ,Japan ,Environmental health ,Agency (sociology) ,Product Surveillance, Postmarketing ,Humans ,Medicine ,education ,Adverse effect ,Service (business) ,Organizations ,education.field_of_study ,Equipment Safety ,business.industry ,Gastroenterology ,General Medicine ,medicine.disease ,Clinical trial ,Drug Information Services ,Patient Safety ,Medical emergency ,business - Abstract
The development of drugs and medical devices is necessary for medical progress; however, safety measures need to be put in place to protect the health of the population. In order to ensure the safety of drugs and medical devices, it is important to determine measures for appropriate management of risks at any time during the development phase, the regulatory review and the post-marketing phase. Adverse events detected in clinical trials are limited due to the restricted numbers of patients enrolled in the trials. Therefore, it is almost impossible to predict rare serious adverse events during the post-marketing phase. The revised Pharmaceutical Affairs Act was established in Japan in November 20, 2013. The new act focuses on increased safety of drugs and medical devices. The Pharmaceuticals and Medical Devices Agency (PMDA) is the regulatory authority in Japan that promotes safety measures from the development phase through to the post-marketing phase. In the post-marketing phase, the PMDA collects information from the medical product companies and healthcare professionals, as well as instructing and advising them with regard to post-marketing safety measures for each drug and medical device. Since Japan has a national health insurance system, a new drug or a medical device is available throughout the country when the drug price or medical fee is listed in the National Health Insurance price list. Healthcare professionals in medical institutions must learn about the drugs and medical devices they handle, and should make an effort to maintain patient safety. The PMDA medi-navi is a very useful electronic mail delivery service that provides critical information for protecting patients from health hazards caused by adverse events. The 'risk management plan' is also important as it contains important information about safety profile and post-marketing measures of a new drug.
- Published
- 2014
28. The association of microtubules with tight junctions is promoted by cingulin phosphorylation by AMPK
- Author
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Atsushi Tamura, Tomoki Yano, Masami Uji, Takeshi Matsui, and Sachiko Tsukita
- Subjects
Molecular Sequence Data ,Sus scrofa ,Fluorescent Antibody Technique ,macromolecular substances ,AMP-Activated Protein Kinases ,Biology ,Microtubules ,Models, Biological ,Cell junction ,Epithelium ,Tight Junctions ,Mice ,Phosphoserine ,Tubulin ,Microtubule ,Report ,Cell polarity ,Fluorescence Resonance Energy Transfer ,Morphogenesis ,Animals ,Humans ,Amino Acid Sequence ,Phosphorylation ,Research Articles ,Centrosome ,Tight junction ,Cell Polarity ,Membrane Proteins ,AMPK ,Epithelial Cells ,Cell Biology ,Protein Structure, Tertiary ,Cell biology ,Cingulin ,HEK293 Cells ,Intercellular Junctions ,Gene Knockdown Techniques ,biology.protein ,Calcium - Abstract
Cingulin phosphorylation by AMPK promotes its binding to α-tubulin and is required for the association of planar apical microtubules with epithelial tight junctions., Epithelial cells characteristically have noncentrosomal microtubules that are arranged in the apicobasal direction. In this paper, we examined cell sheets formed by an epithelial (Eph4) cell line by structure illumination microscopy and found a previously not clearly described planar apical network of noncentrosomal microtubules (MTs) in which the sides of the MT bundles were associated with tight junctions (TJs). In a gel overlay assay with taxol-stabilized MTs, cingulin showed strong binding to MTs, and a domain analysis showed that this binding occurred through cingulin’s N-terminal region. The association of planar apical MTs with TJs was compromised by cingulin knockdown (KD) or the expression of dephosphomimetic mutants of cingulin at its adenosine monophosphate–activated protein kinase (AMPK) target sites, whereas phosphorylation at these sites facilitated cingulin–tubulin binding. In addition, although wild-type colonies formed spheres in 3D culture, the cingulin KD cells had anisotropic shapes. These findings collectively suggest that the regulated cingulin–MT association has a specific role in TJ-related epithelial morphogenesis that is sensitive to metabolic homeostasis-related AMPK activity.
- Published
- 2013
29. Reduction of Mitral Valve Leaflet Tethering by Procedures Targeting the Subvalvular Apparatus in Addition to Mitral Annuloplasty
- Author
-
Koichi Adachi, Hideo Adachi, Atsushi Tamura, Koichi Yuri, Atsushi Yamaguchi, Naoyuki Kimura, and Chieri Kimura
- Subjects
Male ,medicine.medical_specialty ,Mitral Valve Annuloplasty ,medicine.medical_treatment ,Myocardial Ischemia ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,Coronary Artery Bypass ,Papillary muscle ,Reduction (orthopedic surgery) ,Aged ,Retrospective Studies ,Mitral valve repair ,Ejection fraction ,Ischemic cardiomyopathy ,Tethering ,business.industry ,Mitral Valve Insufficiency ,General Medicine ,Middle Aged ,medicine.anatomical_structure ,Cardiology ,Mitral Valve ,Female ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,business ,Artery ,Mitral valve leaflet - Abstract
Background Ischemic mitral regurgitation (IMR) with ischemic cardiomyopathy (ICM) was treated with surgical procedures, and mitral leaflet tethering was assessed. Twenty-two patients with both ICM (left ventricular ejection fraction 2) underwent coronary artery bypass grafting (CABG), mitral annuloplasty (MAP) with or without surgical ventricular restoration (SVR) and procedures targeting the subvalvular apparatus. Methods and results Fourteen patients (group 1) underwent CABG and MAP, and the remaining 8 (group 2) underwent CABG, MAP, SVR, papillary muscle approximation (PMA), and papillary muscle suspension (PMS). PMA joined the entire papillary muscles with 3 mattress sutures. For PMS, 2 ePTFE sutures were placed between papillary muscle tips and fibrous annuli. Anterior and posterior mitral leaflet tethering angles (ALA and PLA) relative to the line connecting annuli, posterior and apical displacement of coaptation, and IMR grade were measured on echocardiography. Although preoperative ALA and PLA in group 2 were significantly larger than in group 1, there was no significant difference between groups at 1 month after surgery. At 1 year after surgery, however, the situation reversed: ALA and PLA in group 1 were significantly larger than in group 2. Conclusions In addition to MAP, procedures targeting the subvalvular apparatus including PMA and PMS achieved persistent reduction of mitral valve leaflet tethering, which might lead to the improvement of long-term outcome.
- Published
- 2013
30. Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis
- Author
-
Atsushi Tamura, Yuji Yamazaki, Sachiko Tsukita, Hiroyuki Murota, Ichiro Katayama, Kana Bando, Yasuhide Furuta, Reitaro Tokumasu, Kosuke Yamaga, and Koya Suzuki
- Subjects
0301 basic medicine ,Adult ,Male ,endocrine system diseases ,Adolescent ,Eczema ,Biology ,digestive system ,Permeability ,Tight Junctions ,Dermatitis, Atopic ,Pathogenesis ,03 medical and health sciences ,Mice ,Young Adult ,0302 clinical medicine ,In vivo ,Claudin-1 ,medicine ,Animals ,Humans ,Claudin ,Aged ,Multidisciplinary ,Innate immune system ,Tight junction ,Epidermis (botany) ,urogenital system ,Age Factors ,Atopic dermatitis ,Middle Aged ,medicine.disease ,Phenotype ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,PNAS Plus ,030220 oncology & carcinogenesis ,Claudins ,Immunology ,Commentary ,Female ,Epidermis ,tissues - Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1 Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.
- Published
- 2016
31. Hemophagocytic Syndrome in the Course of Sudden Sensorineural Hearing Loss
- Author
-
Akihiro Shiotani, Atsushi Tamura, Akihiro Kurita, and Takeshi Matsunobu
- Subjects
Male ,medicine.medical_specialty ,business.industry ,Hearing Loss, Sensorineural ,Hearing Loss, Sudden ,Middle Aged ,Audiology ,medicine.disease ,Lymphohistiocytosis, Hemophagocytic ,Cochlea ,Otorhinolaryngology ,Sudden sensorineural hearing loss ,Rare case ,otorhinolaryngologic diseases ,medicine ,Audiometry, Pure-Tone ,Humans ,Sensorineural hearing loss ,business - Abstract
Objective: This paper aims to comprehensively document a rare case of sensorineural hearing loss accompanied by hemophagocytic syndrome which could be one of the causes of cochlear dysfunction. Methods: A 63-year-old man presented with right-sided sudden hearing loss and dizziness and pure-tone audiometry showed a right-sided sensorineural hearing loss. The patient was treated with steroid pulse infusion therapy, ATP and vitamin B12. Results: Bone marrow specimen revealed hemophagocytic cells and the diagnosis of hemophagocytic syndrome was made. A blood culture grew Capnocytophaga. The prognosis for hearing recovery was poor. Conclusion: Although viral infection and cochlear circulatory dysfunction have been suggested to be associated with sudden sensorineural hearing loss, hemophagocytic syndrome due to bacterial infection which produces high cytokine levels might cause dysfunction of the inner ear.
- Published
- 2012
32. In vitro and in vivo characteristics of core–shell type nanogel particles: Optimization of core cross-linking density and surface poly(ethylene glycol) density in PEGylated nanogels
- Author
-
Masato Tamura, Yukio Nagasaki, Satoshi Ichinohe, Atsushi Tamura, and Yutaka Ikeda
- Subjects
Male ,Biodistribution ,Materials science ,Biocompatibility ,Biomedical Engineering ,Biochemistry ,Polyethylene Glycols ,Biomaterials ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Polymer chemistry ,PEG ratio ,Animals ,Humans ,Molecular Biology ,Mice, Inbred ICR ,General Medicine ,Nanostructures ,Nylons ,chemistry ,Methacrylates ,Nanocarriers ,Polyamine ,Gels ,Ethylene glycol ,Biotechnology ,Nanogel ,Nuclear chemistry - Abstract
The biocompatibility and body distribution of PEGylated polyamine nanogels composed of chemically cross-linked poly(2-N,N-(diethylamino)ethyl methacrylate) (PEAMA) gel cores surrounded by poly(ethylene glycol) (PEG) chains were investigated to evaluate their feasibility as drug nanocarriers for systemic administration. PEGylated nanogels with different cross-linking densities (1, 2, and 5 mol.%) were prepared to evaluate their biocompatibilities by in vitro cytotoxicity assay, hemolysis assay, and in vivo acute toxicity assay. The toxic effect of the PEGylated nanogels derived from polyamine gel cores was significantly reduced when the cross-linking density was increased, and those with a cross-linking density of 5 mol.% showed a remarkably high median lethal dose (LD50) value >200 mg kg−1,despite the abundance of amino groups in the core. One hour after intravenous injection the PEGylated nanogels were found to have been eliminated from the systemic circulation, and less than 1% of the injected dose (ID) remained in the bloodstream. To improve the blood circulation time by increasing the surface PEG density of the PEGylated nanogels post-PEGylation of the PEGylated nanogels (via the Menschutkin reaction between tertiary amines of the PEAMA gel core and bromobenzyl-terminated short PEG) was carried out. A biodistribution study of these post-PEGylated nanogels revealed that the blood circulation time of the nanogels was definitely prolonged as the PEG content was increased. Therefore, the precise design of PEGylated nanogels with increased cross-linking densities in their polyamine gel cores and increased surface PEG densities seems promising for systemic applications.
- Published
- 2011
33. Predicted expansion of the claudin multigene family
- Author
-
Hiroo Tanaka, Atsushi Tamura, Michihiro Igarashi, Yasuko Yamamoto, Katsuhiko Mineta, Kuniaki Saito, Kosei Takeuchi, Toshinori Endo, Yukiyo Tada, Sachiko Tsukita, and Yuji Yamazaki
- Subjects
endocrine system diseases ,PSI-BLAST ,Biophysics ,Biology ,digestive system ,Biochemistry ,Protein Structure, Secondary ,Cell Line ,Tight Junctions ,Adherens junction ,Mice ,Dogs ,Structural Biology ,Genetics ,medicine ,Animals ,Humans ,Protein Isoforms ,Amino Acid Sequence ,RNA, Messenger ,Databases, Protein ,Cell adhesion ,Claudin ,Molecular Biology ,Tight junction ,Conserved Sequence ,Phylogeny ,Gene Library ,urogenital system ,Erythropoietin-producing hepatocellular (Eph) receptor ,Gene Expression Regulation, Developmental ,Epithelial Cells ,Cell Biology ,Paracellular barrier ,Molecular biology ,Recombinant Proteins ,digestive system diseases ,Epithelium ,Cell biology ,medicine.anatomical_structure ,Membrane protein ,Organ Specificity ,Paracellular transport ,Claudins ,Sequence Alignment ,tissues - Abstract
Claudins (Cldn) are essential membrane proteins of tight junctions (TJs), which form the paracellular permselective barrier. They are produced by a multi-gene family of 24 reported members in mouse and human. Based on a comprehensive search combined with phylogenetic analyses, we identified three novel claudins (claudin-25, -26, and -27). Quantitative RT-PCR revealed that the three novel claudins were expressed in a tissue- and/or developmental stage-dependent manner. Claudins-25 and -26, but not claudin-27, were immunofluorescently localized to TJs when exogenously expressed in cultured MDCK and Eph epithelial cell lines. These findings expand the claudin family to include at least 27 members.Structured summaryClaudin-25 and ZO-1 colocalize by fluorescence microscopy (View interaction)ZO-1 and Claudin-26 colocalize by fluorescence microscopy (View interaction)
- Published
- 2011
34. Smart siRNA delivery systems based on polymeric nanoassemblies and nanoparticles
- Author
-
Yukio Nagasaki and Atsushi Tamura
- Subjects
Small interfering RNA ,Materials science ,Polymers ,media_common.quotation_subject ,Biomedical Engineering ,Medicine (miscellaneous) ,Nanoparticle ,Bioengineering ,Nanotechnology ,Development ,Synthetic polymer ,Mice ,RNA interference ,PEGylation ,Systemic administration ,Animals ,Humans ,Nanoparticles ,General Materials Science ,Gene Silencing ,RNA, Small Interfering ,Internalization ,Nanogel ,media_common - Abstract
RNA interference is a post-transcriptional gene-silencing pathway induced by double-stranded small interfering RNA (siRNA). The potential use of siRNA as a therapeutic agent has attracted great attention as a novel approach to the treatment of several intractable diseases. Despite the rapid progress in the therapeutic use of siRNA, systemic application is still controversial due to the limitations of siRNA, such as low enzymatic tolerability, cellular internalization and body distribution after systemic administration. This review describes the recent progress and strategies of siRNA delivery systems based on polyion complexes. Numerous siRNA-containing polyion complex systems bound together through electrostatic interactions between the negatively charged siRNA and positively charged components, including synthetic polymers, biopolymers and nanoparticles, have been developed for the therapeutic application of siRNA. Additionally, stimulus-sensitive smart siRNA carrier systems, including bioreducible polycations and hydrophilic polymer–siRNA conjugates, have been developed to enhance the gene-silencing efficacy of siRNAs.
- Published
- 2010
35. Reactive proliferation of endothelial cells and pericytes associated with arteriovenous malformation
- Author
-
Atsushi Tamura, Yayoi Nagai, Osamu Ishikawa, Masahito Yasuda, and Etsuko Okada
- Subjects
Male ,Pathology ,medicine.medical_specialty ,CD34 ,Antigens, CD34 ,Dermatology ,Biology ,Arteriovenous Malformations ,Diagnosis, Differential ,medicine ,Humans ,Sarcoma, Kaposi ,Cell Proliferation ,Cell growth ,Endothelial Cells ,Nodule (medicine) ,Arteriovenous malformation ,General Medicine ,Middle Aged ,medicine.disease ,Actins ,Lip ,VASCULAR ABNORMALITY ,Sarcoma ,medicine.symptom ,Differential diagnosis ,Hemangioma ,Pericytes ,Spindle cell hemangioma - Abstract
Arteriovenous malformation (AVM) is a structural vascular abnormality with no proliferation of cellular components. We report on a 53-year-old man who presented with a 15-year history of a progressively enlarging nodule on his lower lip. A dark-reddish, easy-bleeding nodule diagnosed as AVM was resected to reduce the volume and troublesome bleeding. Histologically, the nodule revealed that the proliferating cellular area was composed of endothelial cells and pericytes in addition to the area of dilated vessels. We speculated that the cell proliferation developed secondary to AVM. We also discuss the histological differential diagnosis of spindle cell hemangioma and pseudo-Kaposi's sarcoma.
- Published
- 2010
36. Case of livedoid vasculopathy with extensive dermal capillary thrombi
- Author
-
Atsushi Tamura, Yayoi Nagai, Osamu Ishikawa, Akira Shimizu, Hiroo Amano, and Masayoshi Yamanaka
- Subjects
Pathology ,medicine.medical_specialty ,Adolescent ,business.industry ,Leg Ulcer ,Thrombin ,Thrombosis ,Phosphatidylserines ,Dermatology ,General Medicine ,Capillaries ,Pathogenesis ,Humans ,Medicine ,Female ,Prothrombin ,medicine.symptom ,business ,Livedo Reticularis ,Skin ,Livedo reticularis - Abstract
Livedoid vasculopathy (LV) is thought to be a thrombogenic disorder. Here, we report a case of LV presenting livedo reticularis with leg ulcers clinically and many thrombogenic cutaneous vessels histologically. These features strongly suggested the presence of thrombogenic factors involved with the development of the lesions. After examination of various possible thrombogenic factors including phosphatidylserine-dependent anti-prothrombin antibody, we failed to detect any responsible thrombogenic factors for this case of LV. Recently, diverse thrombogenic factors have been reported to be involved in LV. This case may suggest that unknown thrombogenic factors are additionally related to LV pathogenesis.
- Published
- 2010
37. Enhanced Cytoplasmic Delivery of siRNA Using a Stabilized Polyion Complex Based on PEGylated Nanogels with a Cross-Linked Polyamine Structure
- Author
-
Yukio Nagasaki, Atsushi Tamura, and Motoi Oishi
- Subjects
Cytoplasm ,Small interfering RNA ,Polymers and Plastics ,Polymers ,Bioengineering ,Endosomes ,Cell Line ,Polyethylene Glycols ,Biomaterials ,chemistry.chemical_compound ,Drug Delivery Systems ,PEG ratio ,Polyamines ,Materials Chemistry ,Fluorescence microscope ,Humans ,Gene silencing ,Luciferase ,Gene Silencing ,RNA, Small Interfering ,Drug Carriers ,Polyelectrolytes ,Nanostructures ,Cross-Linking Reagents ,chemistry ,Biochemistry ,Biophysics ,Polyamine ,Drug carrier ,Nanogel - Abstract
A novel siRNA delivery system using a polyion complex (PIC) based on PEGylated polyamine nanogels composed of a chemically cross-linked poly[2-(N,N-diethylaminoethyl)methacrylate] (PDEAMA) core and surrounded by PEG tethered chains is described. The nanogel formed PIC spontaneously through electrostatic interaction upon mixing with siRNA. The nanogel/siRNA complex was characterized by a gel retardation assay, size and ζ-potential measurements, and gene silencing activity using a cultured cell line. The nanogel/siRNA complexes showed higher polyanion exchange tolerability compared with the noncross-linked PEG-b-PDEAMA/siRNA complexes, indicating that the three-dimensionally cross-linked structure of the nanogel enhanced the stability of the PIC. Furthermore, the nanogel/siRNA complex was observed to undergo a remarkable enhancement of the gene silencing activity against the firefly luciferase gene expressed in HuH-7 cells at low N/P ratios (N/P = 2), whereas the noncross-linked PEG-b-PDEAMA/siRNA complexes showed negligible gene silencing activity. Moreover, confocal fluorescence microscopy revealed an efficient endosomal escape capability for the transportation of siRNAs into the cytoplasm, presumably due to the buffering effect of the PDEAMA core. Therefore, the PIC of siRNA with cross-linked polyamine nanogel is a potentially effective siRNA carrier for the development of in vivo therapeutic applications of siRNA.
- Published
- 2009
38. Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current
- Author
-
Yoshie Reien, Toshio Nagai, Takehiko Ogura, Masaru Miyazaki, Haruaki Nakaya, Hiroko Uemura, Issei Komuro, Atsushi Tamura, and Takashi Kishimoto
- Subjects
Pharmacology ,Quinidine ,Patch-Clamp Techniques ,Aprindine ,lcsh:RM1-950 ,Cyclic Nucleotide-Gated Cation Channels ,Kidney ,Amiodarone ,Cell Line ,Electrophysiology ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,lcsh:Therapeutics. Pharmacology ,chemistry ,Cibenzoline ,Mexiletine ,medicine ,Humans ,Molecular Medicine ,Verapamil ,Disopyramide ,Anti-Arrhythmia Agents ,Flecainide ,medicine.drug - Abstract
After the report of the Cardiac Arrhythmia Suppression Trial, a tabular framework of the Sicilian Gambit has been proposed to display actions of antiarrhythmic drugs on ion channels and receptors and to provide more rational pharmacotherapy of arrhythmias. However, because effects of antiarrhythmic drugs on If have not been thoroughly examined, we used patch clamp techniques to determine the effects of various antiarrhythmic drugs on the HCN (hyperpolarization-activated cyclic nucleotide–gated) channel currents. HCN4 channels, a dominant isoform of HCN channels in the heart, were expressed in HEK293 cells. Amiodarone and bepridil potently inhibited the HCN4 channel current with IC50 values of 4.5 and 4.9 μM, respectively, which were close to their therapeutic concentrations. The inhibitory effects of quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil on the HCN4 channel current were weak in their therapeutic concentrations, with IC50 values of 78.3, 249, 46.8, 276, 309, 43.7, 14.3, 1700, 50.5, and 44.9 μM, respectively, suggesting that the inhibitory effects on If would be clinically small. d,l-Sotalol hardly affected the HCN4 channel current. Information about the HCN4-channel effects of many antiarrhythmic drugs may be useful for determining the appropriate drug for treatment of various arrhythmias while minimizing adverse effects. Keywords:: antiarrhythmic drug, hyperpolarization-activated cyclic nucleotide–gated (HCN) channel subtype 4, pacemaker current, amiodarone, bepridil
- Published
- 2009
39. Detection of human papillomavirus type 56 in Bowen’s disease involving the nail matrix
- Author
-
Akira Shimizu, Atsushi Tamura, Hiroshi Uezato, Y. Yamamoto, Masatoshi Abe, Yayoi Nagai, Osamu Ishikawa, Youko Nakatani, Sei-ichiro Motegi, and Hiroo Hoshino
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Bowen's Disease ,Dermatology ,Biology ,Polymerase Chain Reaction ,law.invention ,Nail Diseases ,law ,medicine ,Consensus sequence ,Humans ,Polymerase chain reaction ,Pigmentation disorder ,Aged ,Bowen's disease ,Papillomavirus Infections ,virus diseases ,Middle Aged ,medicine.disease ,Virology ,female genital diseases and pregnancy complications ,medicine.anatomical_structure ,Nails ,Melanonychia ,Nail disease ,DNA, Viral ,Nail (anatomy) ,Female ,Nail matrix - Abstract
Summary Background As Bowen’s disease of the nail apparatus is quite rare, there have been only a few reports on the prevalence of human papillomavirus (HPV) infection in this condition. Objectives The purpose of this study was to clarify the association of HPV with this disease involving the nail apparatus. Methods Five patients with Bowen’s disease of the nail apparatus were investigated clinically, virologically and histologically. Total DNAs extracted from excised skin lesions were analysed using polymerase chain reaction (PCR) for the presence of HPV DNA and the amplified products were subjected to DNA sequence analyses. Histological localization of HPV DNA was examined by in situ hybridization. Results In three of five patients, HPV was detected by PCR amplification, and subsequent sequence analyses of the PCR products showed the sequences of HPV type 56. A common clinical feature of the three HPV-positive patients was longitudinal melanonychia. In contrast, the two HPV-negative patients presented with a convex nail deformity and a periungual ulcerative lesion. In two of three positive cases, there was a silent point mutation in the L1 gene of each HPV. In the remaining one case, the nucleotide sequence was consistent with the consensus sequence of HPV 56. Sequence analyses of the E6 gene revealed the infection of different variants of HPV 56 among the three cases. The viral genomes were located in keratinocyte nuclei upon in situ hybridization. Conclusions HPV 56 may be involved in the carcinogenesis of Bowen’s disease affecting the nail matrix with longitudinal pigmentation.
- Published
- 2008
40. Multiple Skin Cysts in Nevoid Basal Cell Carcinoma Syndrome: A Case Report and Review of the Literature
- Author
-
Atsushi Tamura, Yayoi Nagai, Osamu Ishikawa, and Sei-ichiro Motegi
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Epidermal Cyst ,Skin cysts ,Basal Cell Nevus Syndrome ,Nevoid basal-cell carcinoma syndrome ,Dermatology ,Skin Diseases ,Diagnosis, Differential ,Odontogenic cyst ,parasitic diseases ,medicine ,Humans ,Aged ,integumentary system ,Cysts ,business.industry ,medicine.disease ,Trunk ,stomatognathic diseases ,medicine.anatomical_structure ,Epidermis ,business ,Follow-Up Studies - Abstract
We report a 72-year-old man with nevoid basal cell carcinoma syndrome (NBCCS) who presented with 25 skin cysts on his trunk and extremities. Fourteen of 25 skin cysts (56%) were observed on his hands. Histological examination demonstrated that most of the excised cysts had an epithelial wall with typical epidermal keratinization. However, 4 skin cysts (4/16; 25%) showed a corrugated or festooned inner surface of wall without a granular cell layer, which resembled an odontogenic keratocyst, a characteristic feature of skin cysts in NBCCS. A review of the literature suggested that acral localization of skin cysts is a distinctive feature of NBCCS. In addition, the histological findings of skin cysts resembling an odontogenic keratocyst might be a hallmark of NBCCS.
- Published
- 2008
41. Eosinophilic fasciitis: report of two cases and a systematic review of the literature dealing with clinical variables that predict outcome
- Author
-
Michiko Hasegawa, Tomoko Iwasaki, Yayoi Nagai, Osamu Ishikawa, Youichiro Matsushima, Atsushi Tamura, and Yukie Endo
- Subjects
Adult ,medicine.medical_specialty ,Anti-Inflammatory Agents ,Scleroderma, Localized ,Rheumatology ,Fibrosis ,Internal medicine ,Eosinophilia ,medicine ,Humans ,Fasciitis ,Risk factor ,Pathological ,Aged ,business.industry ,Incidence (epidemiology) ,Remission Induction ,General Medicine ,Prognosis ,medicine.disease ,Confidence interval ,Eosinophilic fasciitis ,Surgery ,Fibrosclerosis ,Female ,Steroids ,business ,Morphea - Abstract
We reported two patients with refractory eosinophilic fasciitis (EF) and provided a systematic review of the literature to determine the clinical variables associated with prognosis of EF. We enrolled 88 cases, whose clinical characteristics were analyzed by separating the patients into two or three groups based on outcome. The incidence of certain clinical and pathological features differed among the groups. In particular, the incidence of morphea-like skin lesions in patients with refractory fibrosis was significantly higher than in patients without refractory fibrosis (p = 0.003). Patients with morphea-like skin lesions were 1.9 times more likely to develop persistent fibrosis than patients without these lesions (95% confidence intervals, 1.5-2.5). A younger age (under 12 years) at onset was associated with a 1.6 times greater risk of residual fibrosis (95% confidence interval, 1.1-2.2). Trunk involvement was associated with a 1.4 times greater risk of residual fibrosis (95% confidence interval, 1.0-2.0). Histopathologically, the presence of dermal fibrosclerosis was associated with a 1.4 times greater risk of refractory fibrosis (95% confidence interval, 1.0-2.1). We consider these clinical characteristics, notably the presence of morphea-like skin lesions may be an important risk factor for developing residual fibrosis in EF patients.
- Published
- 2007
42. Successful Treatment with Lymphaticovenular Anastomosis for Secondary Skin Lesions of Chronic Lymphedema
- Author
-
Etsuko Okada, Atsushi Tamura, Sei-ichiro Motegi, Yayoi Nagai, and Osamu Ishikawa
- Subjects
Male ,medicine.medical_specialty ,Exacerbation ,Secondary lymphedema ,Hyperkeratosis ,Dermatology ,Anastomosis ,Vulva ,Erysipelas ,Postoperative Complications ,Venules ,hemic and lymphatic diseases ,Lymphangioma ,medicine ,Humans ,Elephantiasis ,Lymphedema ,Aged ,Lymphatic Vessels ,business.industry ,Anastomosis, Surgical ,Middle Aged ,medicine.disease ,humanities ,Dyskeratosis ,Surgery ,body regions ,medicine.anatomical_structure ,Lower Extremity ,Chronic Disease ,Female ,Vulvar Diseases ,medicine.symptom ,business ,Vascular Surgical Procedures - Abstract
The treatment of severe lymphedema is a difficult challenge. We performed lymphaticovenular anastomosis on two patients with secondary skin lesions of chronic lymphedema; one patient exhibited acquired lymphangioma circumscriptum of the vulva and the other presented elephantiasis nostras verrucosa of the lower leg. Both patients obtained a remarkable improvement in skin lesions and also in the reduction of lymphedema of the lower extremity. During a 6-month-follow-up period, constant reduction in the circumference of the lower extremities without exacerbation of skin lesions was achieved in both patients. Lymphaticovenular anastomosis is a useful surgical treatment for secondary lymphedema in the lower extremities. In addition, this surgical treatment is effective for secondary lesions of lymphedema, including acquired lymphangioma circumscriptum and elephantiasis nostras verrucosa.
- Published
- 2007
43. Cationic Polyrotaxanes as a Feasible Framework for the Intracellular Delivery and Sustainable Activity of Anionic Enzymes: A Comparison Study with Methacrylate-Based Polycations
- Author
-
Atsushi, Tamura, Go, Ikeda, Kei, Nishida, and Nobuhiko, Yui
- Subjects
Cyclodextrins ,Nylons ,Drug Delivery Systems ,Rotaxanes ,Polyamines ,Humans ,Methacrylates ,beta-Galactosidase ,Polyelectrolytes ,HeLa Cells ,Polyethylene Glycols - Abstract
We have developed cationic polyrotaxanes composed of N,N-dimethylaminoethyl (DMAE) group-modified α-cyclodextrins (α-CDs) threaded along a poly(ethylene glycol) (PEG) chain capped with a terminal bulky stopper (DMAE-PRX) for the intracellular delivery of proteins through the polyelectrolyte complexation. Herein, to ascertain the effect of supramolecular backbone structure of cationic polyrotaxanes, the physicochemical properties and biological activity of polyelectrolyte complex with anionic β-galactosidase (β-gal) were investigated in comparison to a cationic linear polymer, poly[2-(N,N-dimethylaminoethyl) methacrylate] (PDMAEMA). In the cellular experiments, the DMAE-PRX/β-gal complexes exhibited higher intracellular uptake of β-gal and sustainable enzymatic activity of delivered β-gal than the PDMAEMA/β-gal complexes. It is considered that the cationic polyrotaxanes are promising supramolecular backbone structure for the intracellular protein delivery.
- Published
- 2015
44. [A case of Carboplatin and pemetrexed combination chemotherapy for synchronous double cancers of hepatocellular carcinoma and primary lung cancer]
- Author
-
Eiko, Okamoto, Jun, Sato, Manabu, Sema, Junnosuke, Hayasaka, Ayako, Watanabe, Kentaro, Takagi, Akiko, Kusano-Kitazume, Atsushi, Tamura, Mayumi, Kondo, Haruyasu, Sakuranaka, Junichi, Ochi, Satoko, Hanada, Michiko, Tanaka, Hidetaka, Akita, Shikofumi, Tei, Masahiko, Ichioka, and Takao, Shibayama
- Subjects
Male ,Carcinoma, Hepatocellular ,Guanine ,Lung Neoplasms ,Liver Neoplasms ,Adenocarcinoma of Lung ,Pemetrexed ,Adenocarcinoma ,Carboplatin ,Neoplasms, Multiple Primary ,Glutamates ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Tomography, X-Ray Computed ,Aged - Abstract
A 78-year-old man presented to our hospital with lung abnormality on his chest radiograph. Computed tomography (CT) showed a mass and obstructive pneumonia in the right upper lobe of the lung. The mass was diagnosed as a pulmonary adenocarcinoma with a bronchoscopy (cT4N2M0, Stage IIIB). CT also revealed multiple hepatic tumors, which were diagnosed as hepatocellular carcinoma (HCC) by dynamic CT and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging(EOB-MRI). First, we treated the lung cancer with a combination of cisplatin and pemetrexed (PEM), but it caused renal dysfunction. Carboplatin (CBDCA) and PEM combination chemotherapy was administered, and not only the lung cancer but also the HCCs decreased in size. There are few reports of synchronous double cancers of HCC and primary lung cancer, and the treatment is not established. We report that platinum-containing anticancer drugs such as CBDCA may be effective against synchronous double cancers of HCC and lung cancer.
- Published
- 2015
45. [Efficiency of pre-operative chemoradiotherapy in treating a case of advanced rectal cancer]
- Author
-
Atsushi, Tamura, Katsunori, Ami, Ayako, Watanabe, Junnosuke, Hayasaka, Kentaro, Takagi, Eiko, Okamoto, Akiko, Kitazume, Mayumi, Kondou, Kentaro, Gokita, Kenichiro, Imai, Shikofumi, Tei, Masayuki, Ando, Kuniyuki, Arai, and Takao, Shibayama
- Subjects
Aged, 80 and over ,Male ,Antimetabolites, Antineoplastic ,Ileus ,Rectal Neoplasms ,Humans ,Chemoradiotherapy ,Fluorouracil ,Adenocarcinoma ,Deoxycytidine ,Capecitabine ,Neoplasm Staging - Abstract
There is insufficient evidence for the pre-operative use of chemoradiotherapy (CRT) in treatment of advanced rectal cancers, and its efficiency and safety are unclear. However, it has recently been suggested that a new class of carcinostatic agents are more effective during preoperative CRT. Under the National Comprehensive Cancer Network (NCCN) guidelines, 5-FU and capecitabine have been recommended as the standard drugs for use during combination chemoradiotherapy. The Japanese Society for Cancer of Colon and Rectum (JSCCR) guidelines for 2014 also recommend the use of both drugs during preoperative CRT. We report a case of rectal cancer, which was successfully treated with radical resection and neoadjuvant chemoradiotherapy.
- Published
- 2015
46. [A case of primary peritoneal carcinoma successfully treated using Paclitaxel and Carboplatin chemotherapy]
- Author
-
Kentaro, Takagi, Atsushi, Tamura, Junnosuke, Hayasaka, Ayako, Watanabe, Eiko, Okamoto, Akiko, Kusano-Kitazume, Mayumi, Kondo, Takao, Shibayama, Yutaka, Suenobu, Yoshiko, Ohtaka, Hidetaka, Akita, and Shikofumi, Tei
- Subjects
Aged, 80 and over ,Paclitaxel ,CA-125 Antigen ,Antineoplastic Combined Chemotherapy Protocols ,Ascites ,Humans ,Membrane Proteins ,Female ,Peritoneal Neoplasms ,Carboplatin - Abstract
A standard treatment for primary peritoneal carcinoma has not been established to date. We describe a case in which this cancer was successfully treated by use of paclitaxel and carboplatin chemotherapy.An 80-year-old woman who presented with abdominal distension and right upper abdominal pain was diagnosed with massive ascites and an omentum tumor via abdominal computed tomography and magnetic resonance imaging (MRI); her ovaries were normal-sized. Serum levels of the tumor marker CA125 were above normal (170 U/mL), and aspiration cytology showed the presence of adenocarcinoma cells. Despite several examinations, the primary tumor was not detected. The patient underwent exploratory laparotomy and was diagnosed with primary peritoneal carcinoma. She received combination chemotherapy consisting of paclitaxel and carboplatin. Serum CA125 levels returned to normal, and an MRI showed no evidence ofa tumor.Paclitaxel and carboplatin combination chemotherapy is effective for treatment of primary peritoneal adenocarcinomas.
- Published
- 2015
47. [Self-expanding antireflux stents for malignant esophageal stenosis - a report of three cases]
- Author
-
Akiko, Kusano-Kitazume, Katsunori, Ami, Takeshi, Nagahama, Mayumi, Kondo, Eiko, Okamoto, Atsushi, Tamura, Kentaro, Takagi, Junnosuke, Hayasaka, Ayako, Watanabe, Yosuke, Kawai, Keiichi, Fujiya, Hidetoshi, Amagasa, Hideaki, Ganno, Kenichiro, Imai, Akira, Fukuda, Masayuki, Ando, Kuniyoshi, Arai, and Takao, Shibayama
- Subjects
Aged, 80 and over ,Male ,Fatal Outcome ,Lung Neoplasms ,Esophageal Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Esophageal Stenosis ,Gastroesophageal Reflux ,Humans ,Female ,Stents ,Deglutition Disorders ,Aged - Abstract
Use of a standard open stent or self-expanding metal stent for patients with malignant dysphagia is associated with a risk of gastroesophageal reflux especially when placed across the esophagogastric junction. We report 3 cases of malignant esophageal stenosis treated with a long cover-type Niti-STM stent with an antireflux mechanism. Case 1: A 87-year-old man presented with dysphagia due to esophageal cancer at the middle thoracic esophagus. Two months after surgery using a standard open stent, the dysphagia relapsed because of tissue overgrowth. Case 2: A 73-year-old woman presented with lung cancer and severe dysphagia due to enlarged mediastinal lymph nodes. Case 3: A 66-year-old man presented with dysphagia due to esophageal cancer at the lower thoracic esophagus. All 3 patients received an antireflux stent across the esophagogastric junction. In cases 1 and 2, dysphagia was relieved immediately without complications. In case 3, the patient experienced severe reflux and chest pain associated with stent placement and could not ingest any solid food. We conclude that the antireflux stent may be useful for palliation in patients with severe malignant esophageal obstruction; however, patients should be informed about the risk of failure to prevent reflux.
- Published
- 2015
48. Subungual angiokeratoma presenting as a longitudinal pigmented band in the nail
- Author
-
Michiko Hasegawa and Atsushi Tamura
- Subjects
Male ,medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Hemorrhage ,Dermatology ,General Medicine ,medicine.disease ,Angiokeratoma ,Nail Diseases ,medicine.anatomical_structure ,Nail (anatomy) ,Medicine ,Humans ,business ,Aged - Published
- 2015
49. β-Cyclodextrin-threaded Biocleavable Polyrotaxanes Ameliorate Impaired Autophagic Flux in Niemann-Pick Type C Disease*
- Author
-
Atsushi Tamura and Nobuhiko Yui
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Rotaxanes ,Immunoblotting ,Protein degradation ,Biology ,Biochemistry ,chemistry.chemical_compound ,Niemann-Pick C1 Protein ,Lysosome ,hemic and lymphatic diseases ,Phagosomes ,Lysosomal storage disease ,medicine ,otorhinolaryngologic diseases ,Autophagy ,Humans ,Molecular Biology ,Cells, Cultured ,Reporter gene ,Membrane Glycoproteins ,Microscopy, Confocal ,Cholesterol ,beta-Cyclodextrins ,Intracellular Signaling Peptides and Proteins ,nutritional and metabolic diseases ,Molecular Bases of Disease ,Biological Transport ,Niemann-Pick Disease, Type C ,Cell Biology ,Fibroblasts ,medicine.disease ,Cell biology ,2-Hydroxypropyl-beta-cyclodextrin ,stomatognathic diseases ,medicine.anatomical_structure ,chemistry ,Mutation ,NPC1 ,Carrier Proteins ,Lysosomes ,Intracellular - Abstract
Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed β-cyclodextrin (β-CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded β-CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-β-CD (HP-β-CD). In this study, we investigated the effect of biocleavable PRX and HP-β-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-β-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP-GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the β-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease.
- Published
- 2015
50. Supramolecular Polyelectrolyte Complexes of Bone Morphogenetic Protein-2 with Sulfonated Polyrotaxanes to Induce Enhanced Osteogenic Differentiation
- Author
-
Masahiko, Terauchi, Go, Ikeda, Kei, Nishida, Atsushi, Tamura, Satoshi, Yamaguchi, Kiyoshi, Harada, and Nobuhiko, Yui
- Subjects
alpha-Cyclodextrins ,Bone Regeneration ,Rotaxanes ,Osteogenesis ,Bone Morphogenetic Protein 2 ,Humans - Abstract
Although bone morphogenetic protein-2 (BMP-2) has received considerable attention because of its strong osteoinductivity, the clinical application of BMP-2 is limited due to its degradation and deactivation under physiological conditions. Negatively charged heparin is known to form polyelectrolyte complexes with BMP-2 to prevent deactivation and enhance the osteoinduction capability of BMP-2. Herein, we report the sulfonated polyrotaxanes (S-PRX) composed of α-cyclodextrin threaded onto a linear polymer for the protection of BMP-2 through the polyelectrolyte complex formation. When MC3T3-E1 osteoprogenitor cells were treated with the S-PRX/BMP-2 complexes, significantly high alkaline phosphatase production and mineralized matrix deposition were observed compared with that of free BMP-2 and heparin/BMP-2 complexes. Note that the S-PRXs showed negligible anticoagulant activity and cytotoxicity, whereas heparin showed strong anticoagulant activity. Accordingly, the S-PRXs are promising candidates for enhanced osteoinduction ability of BMP-2 without toxicity and anticoagulant activity and could contribute to clinical bone regeneration.
- Published
- 2015
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