141 results on '"Yoko Kojima"'
Search Results
2. Safety and Efficacy of Proefferocytic Nanoparticles to Treat Atherosclerosis in a Porcine Model
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Sharika Bamezai, Tom Alsaigh, Mozhgan Lofti, Yapei Zhang, Gayatri S. Kumar, Fudi Wang, Jianqin Ye, Lingfeng Luo, Lars Maegdefessel, Yoko Kojima, Manisha Kumari, Caitlin Bell, Shaunak Adkar, Bryan R. Smith, and Nick J. Leeper
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2023
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3. Relationship between drainage capacity and foundation settlement at Pre Rup Temple: Basic study on Khmer architecture drainage systems Part 1
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Yoko Kojima, Kousei Mikami, Hiroyoshi Shiokawa, Yutaka Shigeeda, and Hiroki Agatsuma
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Angkor ,drainage capacity ,drainage systems ,foundation settlement ,Pre Rup ,Architecture ,NA1-9428 ,Architectural engineering. Structural engineering of buildings ,TH845-895 - Abstract
Abstract In the ancient city of Angkor, heavy rainfall was common in the rainy season and rapid rainwater drainage was important for maintaining urban functions. This study focuses on the drainage system of an example of Khmer architecture from the Angkor period, the Pre Rup temple built in the year 961. We analyze the relationship between the drainage capacity and foundation settlement, revealing that the foundation settlement was larger near drainage channels with a low drainage capacity. After showing that only a few of the drainage channels function properly, it is possible to have some certainty on the relationship between the drainage capacity and foundation settlement.
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- 2022
- Full Text
- View/download PDF
4. Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion
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Takumi Kishimoto, Yoko Kojima, and Nobukazu Fujimoto
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Medicine ,Science - Abstract
Abstract Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p
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- 2021
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5. Bejel, a Nonvenereal Treponematosis, among Men Who Have Sex with Men, Japan
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Takuya Kawahata, Yoko Kojima, Keiichi Furubayashi, Koh Shinohara, Tsunehiro Shimizu, Jun Komano, Haruyo Mori, and Kazushi Motomura
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Bejel ,nonvenereal treponematoses ,Treponema pallidum subsp. endemicum ,bacteria ,men who have sex with men ,MSM ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Bejel, an endemic treponematosis caused by infection with Treponema pallidum subspecies endemicum, has not been reported in eastern Asia and the Pacific region. We report local spread of bejel among men who have sex with men in Japan. Spread was complicated by venereal syphilis.
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- 2019
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6. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer
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Paola A. Betancur, Brian J. Abraham, Ying Y. Yiu, Stephen B. Willingham, Farnaz Khameneh, Mark Zarnegar, Angera H. Kuo, Kelly McKenna, Yoko Kojima, Nicholas J. Leeper, Po Ho, Phung Gip, Tomek Swigut, Richard I. Sherwood, Michael F. Clarke, George Somlo, Richard A. Young, and Irving L. Weissman
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Science - Abstract
Super-enhancers (SEs) are big DNA regions regulating the transcription of oncogenes. Here the authors identify two SE regions regulating the expression of CD47, a protein expressed by cancer cells to avoid phagocytosis by macrophages, thus suggesting a potential mechanism of immune surveillance escape.
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- 2017
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7. MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation
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Irinna Papangeli, Jongmin Kim, Inna Maier, Saejeong Park, Aram Lee, Yujung Kang, Keiichiro Tanaka, Omar F. Khan, Hyekyung Ju, Yoko Kojima, Kristy Red-Horse, Daniel G. Anderson, Arndt F. Siekmann, and Hyung J. Chun
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Science - Abstract
G protein-coupled receptors APLNR and CXCR4 are crucial for vascular development. Here, the authors show that these two signaling pathways communicate and that in response to blood flow APLNR signaling induces a decrease in CXCR4 expression via miR-139-5p, thereby restricting CXCR4 expression to the non-flow exposed tip cells in the retinal vasculature.
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- 2016
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8. Comparative evaluation of the Geenius HIV 1/2 Confirmatory Assay and the HIV-1 and HIV-2 Western blots in the Japanese population.
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Makiko Kondo, Koji Sudo, Takako Sano, Takuya Kawahata, Ichiro Itoda, Shinya Iwamuro, Yukihiro Yoshimura, Natsuo Tachikawa, Yoko Kojima, Haruyo Mori, Hiroshi Fujiwara, Naoki Hasegawa, and Shingo Kato
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Medicine ,Science - Abstract
Accurate diagnosis of earlier HIV infection is essential for treatment and prevention. Currently, confirmation tests of HIV infection in Japan are performed using Western blot (WB), but WB has several limitations including low sensitivity and cross-reactivity between HIV-1 and HIV-2 antibodies. To address these problems, a new HIV testing algorithm and a more reliable confirmation and HIV-1/2 differentiation assay are required. The Bio-Rad Geenius HIV-1/2 Confirmatory Assay (Geenius) has recently been approved and recommended for use in the revised guidelines for diagnosis of HIV infection by the Center for Disease Control and Prevention (USA). We made comprehensive comparison of the performance of Geenius and the Bio-Rad NEW LAV BLOT 1 and 2 (NLB 1 and 2) which are WB kits for HIV-1 and HIV-2, respectively, to examine if Geenius is a suitable alternative to these WB assays which are now being used in HIV testing in Japan. A total of 166 HIV-1 positive samples (146 from patients with established HIV-1 infection and 20 from patients with acute infection), five HIV-1 seroconversion panels containing 21 samples and 30 HIV-2 positive samples were used. In addition, a total of 140 HIV negative samples containing 10 false-positives on screening tests were examined. The sensitivity of Geenius and NLB 1 for HIV-1 positive samples was 99.3% and 98.6%, respectively. Geenius provided more positive results in the samples from acute infections and detected positivity 0 to 32 days earlier in seroconversion panels than NLB 1. NLB 2 gave positive results in 12.3% of HIV-1 positive samples. The sensitivity of both Geenius and NLB 2 for HIV-2 positive samples was 100%. The specificity of Geenius, NLB 1 and NLB 2 was 98.5%, 81.5% and 90.0%, respectively. Geenius is an attractive alternative to WB for confirmation and differentiation of HIV-1 and HIV-2 infections. The adaptation of Geenius to the HIV testing algorithm may be advantageous for rapid diagnosis and the reduction of testing costs.
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- 2018
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9. A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential - An Implication of Micropapillary Element.
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Mai Matsumura, Koji Okudela, Yoko Kojima, Shigeaki Umeda, Yoko Tateishi, Akimasa Sekine, Hiromasa Arai, Tetsukan Woo, Michihiko Tajiri, and Kenichi Ohashi
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Medicine ,Science - Abstract
The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P
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- 2016
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10. Targeted deletion of endothelial lipase increases HDL particles with anti-inflammatory properties both in vitro and in vivo
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Tetsuya Hara, Tatsuro Ishida, Yoko Kojima, Hanayo Tanaka, Tomoyuki Yasuda, Masakazu Shinohara, Ryuji Toh, and Ken-ichi Hirata
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high density lipoprotein ,inflammation ,lipopolysaccharide ,endotoxin shock ,adhesion molecule ,Biochemistry ,QD415-436 - Abstract
Previous studies have shown that targeted deletion of endothelial lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL−/− and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL−/− and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL−/− mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL−/− mice than that in WT mice. To evaluate the anti-inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL−/− mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL−/− mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good’ cholesterol in the plasma.
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- 2011
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11. Clinical perspectives of Treponema pallidum subsp. Endemicum infection in adults, particularly men who have sex with men in the Kansai area, Japan: A case series
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Haruyo Mori, Jun Komano, Keiichi Furubayashi, Takuya Kawahata, Koh Shinohara, and Yoko Kojima
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Adult ,Male ,Microbiology (medical) ,Pediatrics ,medicine.medical_specialty ,Disease ,Men who have sex with men ,Sexual and Gender Minorities ,Japan ,medicine ,Humans ,Treponema ,Pharmacology (medical) ,Syphilis ,Treponema pallidum ,Homosexuality, Male ,Treponemal Infections ,biology ,Transmission (medicine) ,business.industry ,Treponema pallidum subsp. endemicum ,Middle Aged ,medicine.disease ,biology.organism_classification ,Genital lesions ,Infectious Diseases ,business ,Developed country - Abstract
Bejel, caused by Treponema pallidum subsp. Endemicum (TEN), is a locally transmitted disease among children and juveniles in hot and dry regions. The number of adult cases of TEN infection outside of endemic areas has recently increased. We clinically examined five cases of TEN infection among adult cases previously reported in Japan. TEN infection mainly developed among young to middle-aged men who have sex with men (MSM). The clinical features of cases of TEN infection were similar to those of primary- and secondary-stage T. pallidum subsp. pallidum (TPA) infection. Genital lesions were common as the primary lesion. The clinical features and laboratory parameters of cases of TEN infection were similar to those of TPA infection. Most of the isolated strains had the A2058G mutation in 23S rDNA, which is responsible for resistance to macrolides. We also performed the systemic literature review of the TEN cases outside the endemic countries. The recent reported cases diagnosed with molecular methods shared the clinical features, occurred in young-to middle-aged sexually active persons in urban areas of developed countries and often accompanied with genital lesions, which were distinct from the classic description of bejel. This case series and the literature review provides important clinical insights and will contribute to the clinical detection of this rarely identified disease in developed countries. The surveillance of treponematoses, including TEN infection, using molecular diagnostic techniques is also warranted in developed countries, for the purpose of grasping the epidemic situation and control the local transmission.
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- 2022
12. Relationship between drainage capacity and foundation settlement at Pre Rup Temple: Basic study on Khmer architecture drainage systems Part 1
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Yoko Kojima, Hiroyoshi Shiokawa, Yutaka Shigeeda, Kousei Mikami, and Hiroki Agatsuma
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History ,Settlement (structural) ,Architectural engineering. Structural engineering of buildings ,Foundation (engineering) ,General Medicine ,Pre Rup ,NA1-9428 ,Archaeology ,medicine.anatomical_structure ,Temple ,Architecture ,TH845-895 ,medicine ,drainage systems ,foundation settlement ,Drainage ,drainage capacity ,Angkor - Abstract
In the ancient city of Angkor, heavy rainfall was common in the rainy season and rapid rainwater drainage was important for maintaining urban functions. This study focuses on the drainage system of an example of Khmer architecture from the Angkor period, the Pre Rup temple built in the year 961. We analyze the relationship between the drainage capacity and foundation settlement, revealing that the foundation settlement was larger near drainage channels with a low drainage capacity. After showing that only a few of the drainage channels function properly, it is possible to have some certainty on the relationship between the drainage capacity and foundation settlement.
- Published
- 2021
13. The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis
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Kai-Uwe Jarr, Jianqin Ye, Yoko Kojima, Zhongde Ye, Hua Gao, Sofie Schmid, Lingfeng Luo, Richard A. Baylis, Mozhgan Lotfi, Nicolas Lopez, Anne V. Eberhard, Bryan Ronain Smith, Irving L. Weissman, Lars Maegdefessel, and Nicholas J. Leeper
- Abstract
The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPα inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFκB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect.
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- 2022
14. 2021 Jeffrey M. Hoeg Award Lecture: Defining the Role of Efferocytosis in Cardiovascular Disease: A Focus on the CD47 (Cluster of Differentiation 47) Axis
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Kai-Uwe Jarr, Yoko Kojima, Irving L. Weissman, and Nicholas J. Leeper
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Cardiology and Cardiovascular Medicine - Abstract
A key feature of atherogenesis is the accumulation of diseased and dying cells within the lesional necrotic core. While the burden of intraplaque apoptotic cells may be driven in part by an increase in programmed cell death, mounting evidence suggests that their presence may primarily be dictated by a defect in programmed cell removal, or efferocytosis. In this brief review, we will summarize the evidence suggesting that inflammation-dependent changes within the plaque render target cells inedible and reduce the appetite of lesional phagocytes. We will present the genetic causation studies, which indicate these phenomena promote lesion expansion and plaque vulnerability, and the interventional data which suggest that these processes can be reversed. Particular emphasis is provided related to the antiphagocytic CD47 (cluster of differentiation 47) do not eat me axis, which has emerged as a novel antiatherosclerotic translational target that is predicted to provide benefit independent of traditional cardiovascular risk factors.
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- 2022
15. 18 F-Fluorodeoxyglucose-Positron Emission Tomography Imaging Detects Response to Therapeutic Intervention and Plaque Vulnerability in a Murine Model of Advanced Atherosclerotic Disease—Brief Report
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Alyssa M. Flores, Ying Wang, Anne V. Eberhard, Pavlos Tsantilas, Nicholas J. Leeper, Niloufar Hosseini-Nassab, Yoko Kojima, Jianqin Ye, Kai-Uwe Jarr, Lars Maegdefessel, Vivek Nanda, Mozhgan Lotfi, Max Käller, and Bryan Smith
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Atherosclerotic disease ,Computed tomography ,medicine.disease ,Fluorodeoxyglucose positron emission tomography ,Murine model ,medicine ,Radiology ,Tomography ,Cardiology and Cardiovascular Medicine ,business ,Stroke - Abstract
Objective: This study sought to determine whether 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography could be applied to a murine model of advanced atherosclerotic plaque vulnerability to detect response to therapeutic intervention and changes in lesion stability. Approach and Results: To analyze plaques susceptible to rupture, we fed ApoE −/− mice a high-fat diet and induced vulnerable lesions by cast placement over the carotid artery. After 9 weeks of treatment with orthogonal therapeutic agents (including lipid-lowering and proefferocytic therapies), we assessed vascular inflammation and several features of plaque vulnerability by 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography and histopathology, respectively. We observed that 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography had the capacity to resolve histopathologically proven changes in plaque stability after treatment. Moreover, mean target-to-background ratios correlated with multiple characteristics of lesion instability, including the corrected vulnerability index. Conclusions: These results suggest that the application of noninvasive 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography to a murine model can allow for the identification of vulnerable atherosclerotic plaques and their response to therapeutic intervention. This approach may prove useful as a drug discovery and prioritization method.
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- 2020
16. Macrophage LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Is Required for the Effect of CD47 Blockade on Efferocytosis and Atherogenesis—Brief Report
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Nathalie Pamir, Richard A Maldonado, Hagai Tavori, Jianqin Ye, Paul Mueller, Katherine T. Huynh, Yoko Kojima, Sergio Fazio, and Nicholas J. Leeper
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Chemistry ,Phagocytosis ,LDL receptor ,Cancer research ,medicine ,Macrophage ,Tumor necrosis factor alpha ,Inflammation ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Efferocytosis ,LRP1 ,Blockade - Abstract
Objective: Antibody blockade of the “do not eat me” signal CD47 (cluster of differentiation 47) enhances efferocytosis and reduces lesion size and necrotic core formation in murine atherosclerosis. TNF (Tumor necrosis factor)-α expression directly enhances CD47 expression, and elevated TNF-α is observed in the absence of the proefferocytosis receptor LRP1 (low-density lipoprotein receptor-related protein 1), a regulator of atherogenesis and inflammation. Thus, we tested the hypothesis that CD47 blockade requires the presence of macrophage LRP1 to enhance efferocytosis, temper TNF-α-dependent inflammation, and limit atherosclerosis. Approach and Results: Mice lacking systemic apoE (apoE −/− ), alone or in combination with the loss of macrophage LRP1 (double knockout), were fed a Western-type diet for 12 weeks while receiving anti-CD47 antibody (anti-CD47) or IgG every other day. In apoE −/− mice, treatment with anti-CD47 reduced lesion size by 25.4%, decreased necrotic core area by 34.5%, and decreased the ratio of free:macrophage-associated apoptotic bodies by 47.6% compared with IgG controls ( P −/− phagocytes were incubated with anti-CD47 compared with IgG controls ( P −/− macrophages compared with wild type, but no differences were observed in inflammatory lipopolysaccharide-treated macrophages. Conclusions: The proefferocytosis receptor LRP1 in macrophages is necessary for anti-CD47 blockade to enhance efferocytosis, limit atherogenesis, and decrease necrotic core formation in the apoE −/− model of atherosclerosis.
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- 2022
17. Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis
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Robert C. Wirka, Yoko Kojima, Kai-Uwe Jarr, Pavlos Tsantilas, Bryan Ronain Smith, Ai Leen Koh, Jianqin Ye, Robert Sinclair, Xingjun Zhu, Yitian Zeng, Nicholas J. Leeper, Irving L. Weissman, Ying Wang, Vivek Nanda, Erik Ingelsson, Mozhgan Lotfi, Niloufar Hosseini-Nassab, and Alyssa M. Flores
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Male ,Chemokine ,Transgene ,medicine.medical_treatment ,Phagocytosis ,Biomedical Engineering ,Bioengineering ,CD47 Antigen ,Mice, Transgenic ,02 engineering and technology ,Protein tyrosine phosphatase ,010402 general chemistry ,01 natural sciences ,Article ,Medicine ,Animals ,Humans ,General Materials Science ,Electrical and Electronic Engineering ,Receptors, Immunologic ,Receptor ,biology ,business.industry ,Nanotubes, Carbon ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,Macrophages ,Cardiovascular Agents ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Atherosclerosis ,Atomic and Molecular Physics, and Optics ,Plaque, Atherosclerotic ,0104 chemical sciences ,Disease Models, Animal ,Cytokine ,Nanomedicine ,Apoptosis ,biology.protein ,Cancer research ,Nanoparticles ,Female ,Antibody ,0210 nano-technology ,business ,Signal Transduction - Abstract
Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of ‘Trojan horse’ nanoparticles to prevent atherosclerotic cardiovascular disease. Single-walled carbon nanotubes can restore phagocytotic properties of macrophages in artherosclerotic plaques to promote plaque clearance and combat artherosclerosis.
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- 2020
18. Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion
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Nobukazu Fujimoto, Yoko Kojima, and Takumi Kishimoto
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Pathology ,medicine.medical_specialty ,Pleural effusion ,Science ,CCL2 ,Article ,Diagnosis, Differential ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hyaluronic acid ,medicine ,Biomarkers, Tumor ,Humans ,Secretory Leukocyte Peptidase Inhibitor ,Lung cancer ,Multidisciplinary ,business.industry ,Mesothelioma, Malignant ,Area under the curve ,respiratory system ,medicine.disease ,respiratory tract diseases ,Pleural Effusion, Malignant ,Pleural Effusion ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,Oncology ,ROC Curve ,030220 oncology & carcinogenesis ,Area Under Curve ,Asbestosis ,Biomarker (medicine) ,Medicine ,business ,Biomarkers ,Respiratory tract ,SLPI - Abstract
Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p
- Published
- 2021
19. Knockout of the Murine Ortholog to the Human 9p21 Coronary Artery Disease Locus Leads to Smooth Muscle Cell Proliferation, Vascular Calcification, and Advanced Atherosclerosis
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Pavlos Tsantilas, Renu Virmani, Alyssa M. Flores, Jianqin Ye, Kai-Uwe Jarr, Vivek Nanda, Nicholas J. Leeper, Aloke V. Finn, Yoko Kojima, Ying Wang, and Liang Guo
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Male ,Pathology ,medicine.medical_specialty ,business.industry ,Cell growth ,Myocytes, Smooth Muscle ,Locus (genetics) ,Coronary Artery Disease ,Atherosclerosis ,medicine.disease ,Article ,Coronary artery disease ,Mice ,Smooth muscle ,Physiology (medical) ,medicine ,Animals ,Humans ,Female ,Vascular Calcification ,Cardiology and Cardiovascular Medicine ,business ,Vascular calcification ,Cell Proliferation - Published
- 2020
20. ON THE RELATIONSHIP BETWEEN THE DRAINAGE CAPACITY AND THE FOUNDATION SETTLEMENT IN PRE RUP
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Hiroyoshi Shiokawa, Kousei Mikami, Yutaka Shigeeda, Hiroki Agatsuma, and Yoko Kojima
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Settlement (structural) ,Drainage system (geomorphology) ,Foundation (engineering) ,Architecture ,Drainage ,Water resource management ,Geology - Published
- 2019
21. ON THE MEASUREMENTS OF THE FOUNDATION AND TEMPLE LAYOUT OF TA KEV IN ANGKOR PERIOD
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Yutaka Shigeeda and Yoko Kojima
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Engineering ,medicine.anatomical_structure ,Construction method ,business.industry ,Temple ,medicine ,Foundation (engineering) ,Ancient history ,Architecture ,business ,Period (music) - Published
- 2019
22. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade
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Anne V. Eberhard, Nicholas J. Leeper, Lars Lind, Ying Wang, Kathryn L. Howe, Arno Ruusalepp, Alexandra A. C. Newman, Simon Koplev, Yoko Kojima, Erik Ingelsson, Abhiram Rao, Clint L. Miller, Alyssa M. Flores, Irving L. Weissman, James R. Priest, Gerard Pasterkamp, Johan L.M. Björkegren, Jianqin Ye, Vivek Nanda, Daniel Direnzo, Gary K. Owens, Sophia Xiao, Kai-Uwe Jarr, Lars Maegdefessel, Pavlos Tsantilas, and Noah Tsao
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Male ,Vascular smooth muscle ,Mice, Knockout, ApoE ,Cell ,Myocytes, Smooth Muscle ,Inflammation ,CD47 Antigen ,Biology ,Phagocytosis ,medicine ,Animals ,Humans ,Anaphylatoxin ,Cell Lineage ,Cloning, Molecular ,Efferocytosis ,Opsonin ,Complement Activation ,Cell Proliferation ,Multidisciplinary ,Sequence Analysis, RNA ,CD47 ,Macrophages ,Complement C3 ,Biological Sciences ,Atherosclerosis ,Plaque, Atherosclerotic ,Complement system ,Cell biology ,Up-Regulation ,medicine.anatomical_structure ,Female ,medicine.symptom - Abstract
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
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- 2020
23. Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability
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Ying Wang, Nicholas J. Leeper, Philip S. Tsao, Ljubica Perisic Matic, Kai-Uwe Jarr, Lars Maegdefessel, Greg Winski, Shen Lao, Vivek Nanda, Valentina Paloschi, Jianqin Ye, Pavlos Tsantilas, Alyssa M. Flores, Monika Vaerst, Zhiyuan Wu, Yoko Kojima, Hans-Henning Eckstein, Jaroslav Pelisek, Anne V. Eberhard, and Ulf Hedin
- Subjects
Cell physiology ,Carotid Artery Diseases ,Cell type ,Physiology ,Mice, Knockout, ApoE ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Vascular Remodeling ,CHI3L1 ,Muscle, Smooth, Vascular ,Lesion ,Physiology (medical) ,Carotid artery disease ,Neointima ,Medicine ,Animals ,Humans ,Chitinase-3-Like Protein 1 ,Stroke ,Cells, Cultured ,Endarterectomy ,Rupture, Spontaneous ,business.industry ,Fibrous cap ,Editorials ,Cell Differentiation ,medicine.disease ,Fibrosis ,Plaque, Atherosclerotic ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Carotid Arteries ,Phenotype ,Cancer research ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. Methods and results Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. Conclusion CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.
- Published
- 2020
24. Knockout of the Murine Ortholog to the Human 9p21 Coronary Artery Disease Locus Leads to SMC Proliferation, Vascular Calcification, and Advanced Atherosclerosis
- Author
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Kai-Uwe Jarr, Aloke V. Finn, Jianqin Ye, Yoko Kojima, Ying Wang, Nicholas J. Leeper, Pavlos Tsantilas, Vivek Nanda, Liang Guo, Renu Virmani, and Alyssa M. Flores
- Subjects
Coronary artery disease ,Pathology ,medicine.medical_specialty ,SMC proliferation ,business.industry ,cardiology ,Vascular biology ,medicine ,Locus (genetics) ,medicine.disease ,business ,Vascular calcification ,Calcification - Abstract
Background: Genome-wide association studies have identified the chromosome 9p21 locus as one of the most important genetic risk factors for cardiovascular disease. However, the mechanism by which this locus promotes disease remains unclear due to difficulty identifying the causal genes and lack of a suitable animal model. Methods and Results: A total of 180 coronary artery autopsy specimens were analyzed histopathologically. The genotype of 9p21 (rs1333049) was not associated with any coronary risk factors nor the vulnerable plaque phenotype, but carriers of 9p21 risk allele did demonstrate more lesional calcification. To extend these studies into an animal model, mice with a targeted deletion of the orthologous 70-kb non-coding interval on chromosome 4 (chr4D70kb/D70kb) were bred onto ApoE-/- and fed with high fat diet. Targeted deletion of the 9p21 risk interval increased susceptibility to atherosclerotic plaque progression, but did not affect plaque rupture in the tandem stenosis model. Coronary risk factors such as body weight, blood pressure, lipid, and glucose levels did not differ between genotypes. Von Kossa staining revealed that chr4D70kb/D70kb, ApoE-/- developed more calcification in the plaque compared with chr4+/+, ApoE-/- mice, and that this this change was accompanied by increased aortic mRNA expression of Runx2, a key osteogenic transcription factor. Primarily cultured smooth muscle cells from chr4D70kb/D70kb were hyperproliferative, and showed a calcification-prone phenotype after exposure to high-phosphate medium. Treatment with Palbociclib, a selective inhibitor of cyclin-dependent kinase 4/6, reduced mRNA expression of osteogenic genes in smooth muscle cells. Conclusion: Results from human and mouse studies indicate that the 9p21 non coding risk interval is associated with larger atherosclerotic plaque burden, but not with plaque rupture. 9p21 may promote lesion expansion by inducing the proliferation of de-differentiated and osteogenic smooth muscle cells.
- Published
- 2020
25. Effect of CD47 Blockade on Vascular Inflammation
- Author
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Kai-Uwe Jarr, Yoko Kojima, Ranjana H. Advani, Andrei Iagaru, Nicholas J. Leeper, Ryusuke Nakamoto, Brandon H. Doan, and Irving L. Weissman
- Subjects
Carotid Artery Diseases ,Male ,Pathology ,medicine.medical_specialty ,CD47 Antigen ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Fluorodeoxyglucose F18 ,Humans ,Medicine ,030212 general & internal medicine ,Immune Checkpoint Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Inflammation ,biology ,medicine.diagnostic_test ,business.industry ,CD47 ,Retrospective cohort study ,General Medicine ,Middle Aged ,Atherosclerosis ,medicine.disease ,Blockade ,Lymphoma ,Positron emission tomography ,Positron-Emission Tomography ,Monoclonal ,biology.protein ,Female ,Radiopharmaceuticals ,Antibody ,business - Abstract
Effect of CD47 Blockade on Vascular Inflammation Patients in a trial of the anti-CD47 antibody magrolimab for treatment of lymphoma underwent 18F-FDG PET–CT. Treatment was found to reduce arterial ...
- Published
- 2021
26. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer
- Author
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Phung Gip, Irving L. Weissman, Yoko Kojima, Richard I. Sherwood, Richard A. Young, Brian J. Abraham, Angera H. Kuo, Michael F. Clarke, Stephen B. Willingham, Mark A. Zarnegar, Po Ho, George Somlo, Mckenna Kelly Marie, Paola Betancur, Ying Y. Yiu, Nicholas J. Leeper, Tomek Swigut, Farnaz Khameneh, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, and Young, Richard A
- Subjects
0301 basic medicine ,Science ,General Physics and Astronomy ,Down-Regulation ,Breast Neoplasms ,CD47 Antigen ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,Super-enhancer ,Immune system ,Phagocytosis ,Animals ,Humans ,Enhancer ,Regulation of gene expression ,Inflammation ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,CD47 ,NF-kappa B p50 Subunit ,General Chemistry ,Hedgehog signaling pathway ,3. Good health ,Cell biology ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Enhancer Elements, Genetic ,Editorial ,Cancer cell ,Immunology ,Female ,Signal transduction ,Inflammation Mediators ,Protein Binding ,Signal Transduction - Abstract
CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels by neoplastic and normal cells. Here, to reveal mechanisms by which different neoplastic cells generate this dominant ‘don’t eat me’ signal, we analyse the CD47 regulatory genomic landscape. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47-associated SE specific to breast cancer. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance.
- Published
- 2017
27. The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas
- Author
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Takehisa Suzuki, Akimasa Sekine, Mai Matsumura, Yoko Tateishi, Koji Okudela, Hideaki Mitsui, Takahiro Omori, Tetsukan Woo, Tamiko Takemura, Yoichi Kameda, Takashi Ogura, Yoko Kojima, Tae Iwasawa, Michihiko Tajiri, Hiromasa Arai, Munetaka Masuda, Tomohisa Baba, Kenich Ohashi, and Shigeaki Umeda
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Histology ,Bronchiole ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Adenocarcinoma ,Biology ,medicine.disease_cause ,Disease-Free Survival ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,Metaplasia ,medicine ,Humans ,Idiopathic Interstitial Pneumonias ,Pathological ,Idiopathic interstitial pneumonia ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Thyroid ,General Medicine ,Middle Aged ,respiratory system ,medicine.disease ,Immunohistochemistry ,ErbB Receptors ,medicine.anatomical_structure ,030228 respiratory system ,Hepatocyte nuclear factor 4 alpha ,030220 oncology & carcinogenesis ,Female ,KRAS ,medicine.symptom - Abstract
Aims To investigate the pathological features of idiopathic interstitial pneumonia (IIP) - associated pulmonary adenocarcinoma. Methods Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected. We here further focused on adenocarcinomas that developed in the honeycomb lesions. Adenocarcinomas in the IIP group were subdivided into two groups, one group included tumors connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group) and the other included tumors unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance, immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Results Most of tumor cells in the H-IIP group showed tall columnar shape that displayed similar features to proximal bronchial epithelium, while tumors in the NH-IIP group and the non-IIP group showed club-like shape that displayed similar features to respiratory bronchiole /alveolar epithelium. The cell differentiation markers, thyroid transcription factor-1 (TTF-1) and Hepatocyte nuclear factor 4 alpha (HNF- 4α), tended to be negative for TTF-1 and positive for HNF- 4α in adenocarcinomas in the H-IIP group. The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequency of KRAS and ALK mutations did not differ among the three groups. Conclusions The IIP-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features. This article is protected by copyright. All rights reserved.
- Published
- 2016
28. Chitinase-3-Like Protein 1 is an Inhibitor of Vascular Smooth Muscle Cell Dedifferentiation in Advanced Atherosclerosis
- Author
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Yuhuang Li, Jianqin Ye, Shen Lao, Monika Vaerst, Nicholas J. Leeper, Pavlos Tsantilas, Hans-Henning Eckstein, Kai-Uwe Jarr, Yoko Kojima, Alyssa M. Flores, Ying Wang, Vivek Nanda, Lars Maegdefessel, and Jaroslav Pelisek
- Subjects
Vascular smooth muscle cell dedifferentiation ,business.industry ,Medicine ,Surgery ,Cardiology and Cardiovascular Medicine ,Chitinase-3-Like Protein 1 ,business ,Cell biology - Published
- 2019
29. Resolvin D1 promotes the targeting and clearance of necroptotic cells
- Author
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Justin Heinz, Gabrielle Fredman, Margarida Barroso, Katey J. Rayner, Zeinab F. Hosseini, Colin O. Riley, Sudeshna Sadhu, Dale D. Tang, Brian E. Sansbury, Brennan D. Gerlach, Matthew Spite, Nicholas Rymut, Yoko Kojima, Nicholas J. Leeper, and Michael Marinello
- Subjects
0301 basic medicine ,RHOA ,Dependent manner ,Docosahexaenoic Acids ,CDC42 ,behavioral disciplines and activities ,Article ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Blocking antibody ,mental disorders ,Animals ,Humans ,Efferocytosis ,Molecular Biology ,Mice, Knockout ,biology ,Chemistry ,CD47 ,Macrophages ,Cell Biology ,Resolvin d1 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Necroptosis ,biology.protein ,Calreticulin - Abstract
Inflammation-resolution is a protective response that is mediated by specialized pro-resolving mediators (SPMs). The clearance of dead cells or efferocytosis is a critical cellular program of inflammation-resolution. Impaired efferocytosis can lead to tissue damage in prevalent human diseases, like atherosclerosis. Therefore understanding mechanisms associated with swift clearance of dead cells is of utmost clinical importance. Recently, the accumulation of necroptotic cells (NCs) was observed in human plaques and we postulated that this is due to defective clearance programs. Here we present evidence that NCs are inefficiently taken up by macrophages because they have increased surface expression of a well-known “don’t eat me” signal called CD47. High levels of CD47 on NCs stimulated RhoA-pMLC signaling in macrophages that promoted “nibbling”, rather than whole-cell engulfment of NCs. Anti-CD47 blocking antibodies limited RhoA-p-MLC signaling and promoted whole-cell NC engulfment. Treatment with anti-CD47 blocking antibodies to Ldlr(−/−) mice with established atherosclerosis decreased necrotic cores, limited the accumulation of plaque NCs and increased lesional SPMs, including Resolvin D1 (RvD1) compared with IgG controls. Mechanistically, RvD1 promoted whole-cell engulfment of NCs by decreasing RhoA signaling and activating CDC42. RvD1 specifically targeted NCs for engulfment by facilitating the release of the well-known “eat me signal” called calreticulin from macrophages in a CDC42 dependent manner. Lastly, RvD1 enhanced the clearance of NCs in advanced murine plaques. Together, these results suggest new molecules and signaling associated with the clearance of NCs, provide a new paradigm for the regulation of inflammation-resolution, and offer a potential treatment strategy for diseases where NCs underpin the pathology.
- Published
- 2019
30. Circulation of Distinct Treponema pallidum Strains in Individuals with Heterosexual Orientation and Men Who Have Sex with Men
- Author
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Haruyo Mori, Yoko Kojima, Takuya Kawahata, Keiichi Furubayashi, and Jun Komano
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Treponema ,biology ,business.industry ,030106 microbiology ,Treponema carateum ,Prevalence ,Physiology ,medicine.disease ,biology.organism_classification ,Men who have sex with men ,03 medical and health sciences ,0302 clinical medicine ,Epidemiology ,Genotype ,medicine ,Syphilis ,030212 general & internal medicine ,business ,Treponematosis - Abstract
Human treponematosis is caused by various pathogenic Treponema pallidum subspecies, including T. pallidum subsp. pallidum, T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and Treponema carateum. The global prevalence of syphilis has been increasing since the 2000s. Men account for more than 90% of the cases, with the majority being men who have sex with men (MSM). In Japan, the increase in the number of syphilis patients began in 2011, a 10-year delay from the global trend. In 2017, a total of 5,829 syphilis cases (3,934 men and 1,895 women) were reported, with an outstanding increase in cases among young adult women; the number reported for women age 15 to 20 years was 1,100. Hence, a molecular epidemiological study was conducted on circulating T. pallidum strains using two strain typing methods, the enhanced CDC method and sequencing-based molecular typing. Clinical specimens from 95 adults suspected of syphilis were collected from September 2013 to August 2017 in Osaka, Japan. T. pallidum DNA was detected in specimens from 25 males and 11 females, including seven MSM. The majority of the heterosexual patients (66.7% and 90.9% of males and females, respectively) were positive for 14d/f-SSR8. In contrast, the genotypes identified in the MSM group were significantly divergent. T. pallidum subsp. endemicum was notably identified in two MSM patients. Macrolide-sensitive or Nichols-like strains were significantly associated with the MSM group. These data suggest that distinct T. pallidum strains were circulating in the heterosexual and MSM groups. Our findings imply that independent factors may contribute to the increased syphilis prevalence in heterosexual and MSM populations.
- Published
- 2019
31. Alterations in cathepsin L expression in lung cancers
- Author
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Takehisa Suzuki, Shigeaki Umeda, Yoko Kojima, Hiromasa Arai, Munetaka Masuda, Yoko Tateishi, Kenichi Ohashi, Hideaki Mitsui, Tetsukan Woo, Koji Okudela, and Mai Matsumura
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Lung ,General Medicine ,respiratory system ,Biology ,medicine.disease_cause ,medicine.disease ,Protein expression ,Pathology and Forensic Medicine ,Cathepsin L ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Lung cancer cell ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Adenocarcinoma ,Carcinogenesis ,Lung cancer - Abstract
We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P
- Published
- 2016
32. MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation
- Author
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Hyekyung Ju, Omar F. Khan, Yujung Kang, Arndt F. Siekmann, Aram Lee, Saejeong Park, Irinna Papangeli, Keiichiro Tanaka, Hyung J. Chun, Inna Maier, Kristy Red-Horse, Daniel G. Anderson, Jongmin Kim, Yoko Kojima, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Khan, Omar Fizal, and Anderson, Daniel Griffith
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Receptors, CXCR4 ,Science ,General Physics and Astronomy ,Down-Regulation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Downregulation and upregulation ,Adipokines ,Internal medicine ,microRNA ,medicine ,Atorvastatin ,Animals ,Receptor ,G protein-coupled receptor ,Apelin receptor ,Apelin Receptors ,Multidisciplinary ,Endothelial Cells ,Retinal Vessels ,General Chemistry ,Receptor Cross-Talk ,Phenotype ,Cell biology ,Apelin ,Mice, Inbred C57BL ,Crosstalk (biology) ,MicroRNAs ,030104 developmental biology ,Endocrinology ,Hemorheology ,Intercellular Signaling Peptides and Proteins - Abstract
G protein-coupled receptor (GPCR) signalling, including that involving apelin (APLN) and its receptor APLNR, is known to be important in vascular development. How this ligand–receptor pair regulates the downstream signalling cascades in this context remains poorly understood. Here, we show that mice with Apln, Aplnr or endothelial-specific Aplnr deletion develop profound retinal vascular defects, which are at least in part due to dysregulated increase in endothelial CXCR4 expression. Endothelial CXCR4 is negatively regulated by miR-139-5p, whose transcription is in turn induced by laminar flow and APLN/APLNR signalling. Inhibition of miR-139-5p in vivo partially phenocopies the retinal vascular defects of APLN/APLNR deficiency. Pharmacological inhibition of CXCR4 signalling or augmentation of the miR-139-5p-CXCR4 axis can ameliorate the vascular phenotype of APLN/APLNR deficient state. Overall, we identify an important microRNA-mediated GPCR crosstalk, which plays a key role in vascular development., G protein-coupled receptors APLNR and CXCR4 are crucial for vascular development. Here, the authors show that these two signaling pathways communicate and that in response to blood flow APLNR signaling induces a decrease in CXCR4 expression via miR-139-5p, thereby restricting CXCR4 expression to the non-flow exposed tip cells in the retinal vasculature.
- Published
- 2016
33. CDKN2B Regulates TGF β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels
- Author
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Andrew J. Connolly, Lars Maegdefessel, Xiaoqing Zhao, Harry R. Davis, Jianqin Ye, Ljubica Perisic, Vivek Nanda, Kevin T. Nead, Daniel Direnzo, Joshua M. Spin, Sonny Dandona, Liang Guo, Kelly P. Downing, Frank D. Kolodgie, Sophia Xiao, Renu Virmani, Jessie Dalman, Ulf Hedin, Nicholas J. Leeper, and Yoko Kojima
- Subjects
Male ,0301 basic medicine ,Aging ,Time Factors ,Physiology ,Angiogenesis ,Cell ,cyclin-dependent kinase inhibitor p15 ,Cardiorespiratory Medicine and Haematology ,030204 cardiovascular system & hematology ,Inbred C57BL ,Cardiovascular ,Muscle, Smooth, Vascular ,Mice ,0302 clinical medicine ,Smooth Muscle ,CDKN2B ,2.1 Biological and endogenous factors ,Aetiology ,Cultured ,Skeletal ,Coronary Vessels ,Cell Hypoxia ,Hindlimb ,smooth muscle cells ,Endothelial stem cell ,Carotid Arteries ,Phenotype ,medicine.anatomical_structure ,Muscle ,RNA Interference ,Female ,Smooth ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Human ,Pair 9 ,Signal Transduction ,Cells ,Knockout ,Myocytes, Smooth Muscle ,Clinical Sciences ,Neovascularization, Physiologic ,Biology ,Transfection ,peripheral artery disease ,Article ,Chromosomes ,Smad7 Protein ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Downregulation and upregulation ,Vascular ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Muscle, Skeletal ,Physiologic ,Neovascularization ,Cyclin-Dependent Kinase Inhibitor p15 ,Pathologic ,Myocytes ,pathologic angiogenesis ,Animal ,Endoglin ,Atherosclerosis ,030104 developmental biology ,Cardiovascular System & Hematology ,Disease Models ,genetic variation ,Immunology ,Cancer research ,Transforming growth factor - Abstract
Rationale: Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown. Objective: To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism. Methods and Results: Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b . These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b -deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor β ( TGF β) signaling in cultured cyclin-dependent kinase inhibitor 2B ( CDKN2B )–deficient cells, as well as TGF β 1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7 , which promotes downstream TGF β activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGF β 1-induced-1 , which is a TGF β-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro. Conclusions: These results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGF β signaling and hypoxic neovessel maturation.
- Published
- 2016
34. Circulation of Distinct
- Author
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Yoko, Kojima, Keiichi, Furubayashi, Takuya, Kawahata, Haruyo, Mori, and Jun, Komano
- Subjects
Adult ,Aged, 80 and over ,Male ,Molecular Epidemiology ,Genotype ,Epidemiology ,Genetic Variation ,Middle Aged ,Molecular Typing ,Sexual and Gender Minorities ,Young Adult ,Japan ,Drug Resistance, Bacterial ,Prevalence ,Humans ,Female ,Macrolides ,Syphilis ,Treponema pallidum ,Heterosexuality ,Aged - Abstract
Human treponematosis is caused by various pathogenic Treponema pallidum subspecies, including T. pallidum subsp. pallidum, T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and Treponema carateum. The global prevalence of syphilis has been increasing since the 2000s. Men account for more than 90% of the cases, with the majority being men who have sex with men (MSM). In Japan, the increase in the number of syphilis patients began in 2011, a 10-year delay from the global trend. In 2017, a total of 5,829 syphilis cases (3,934 men and 1,895 women) were reported, with an outstanding increase in cases among young adult women; the number reported for women age 15 to 20 years was 1,100. Hence, a molecular epidemiological study was conducted on circulating T. pallidum strains using two strain typing methods, the enhanced CDC method and sequencing-based molecular typing. Clinical specimens from 95 adults suspected of syphilis were collected from September 2013 to August 2017 in Osaka, Japan. T. pallidum DNA was detected in specimens from 25 males and 11 females, including seven MSM. The majority of the heterosexual patients (66.7% and 90.9% of males and females, respectively) were positive for 14d/f-SSR8. In contrast, the genotypes identified in the MSM group were significantly divergent. T. pallidum subsp. endemicum was notably identified in two MSM patients. Macrolide-sensitive or Nichols-like strains were significantly associated with the MSM group. These data suggest that distinct T. pallidum strains were circulating in the heterosexual and MSM groups. Our findings imply that independent factors may contribute to the increased syphilis prevalence in heterosexual and MSM populations.
- Published
- 2018
35. Relationship between non-TRU lung adenocarcinomas and bronchiolar metaplasia - potential implication in their histogenesis
- Author
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Koji, Okudela, Yoko, Kojima, Mai, Matsumura, Hiromasa, Arai, Shigeaki, Umeda, Yoko, Tateishi, Hideaki, Mitsui, Takehisa, Suzuki, Michihiko, Tajiri, Takashi, Ogura, and Kenichi, Ohashi
- Subjects
Adult ,Male ,Metaplasia ,Lung Neoplasms ,Humans ,Adenocarcinoma of Lung ,Female ,Adenocarcinoma ,Middle Aged ,Bronchioles ,Aged - Abstract
Lung adenocarcinomas (ADCs) have been roughly divided into two groups: the terminal respiratory unit (TRU) type and non-TRU type. These ADCs appear to develop through exclusive carcinogenetic pathways because of differences in their cellular morphologies and the profiles of protein expression and genetic alterations. The TRU type develops from atypical adenomatous hyperplasia as a precursor. On the other hand, the histogenesis of the non-TRU type has not yet been defined in detail. We herein investigated histopathological changes in the non-tumor lung tissues of patients with non-TRU-type ADCs in order to define their potential histogenesis. The non-TRU type preferentially occurs in patients with interstitial pneumonia, in whom tumors are located in honeycomb lesions and are associated with bronchiolar metaplasia (BM). Among patients without interstitial pneumonia, non-tumor lung tissues from non-TRU-type ADCs were often affected by multiple BM. In these cases, tumors often were associated with BM. Metaplastic cells adjacent to non-TRU-type ADCs ectopically expressed HNF-4α, a marker for non-TRU-type ADCs. These results suggest that the non-TRU type develops through distinct histogenesis, in which BM is implicated.
- Published
- 2017
36. The potential role of microRNA-31 expression in early colorectal cancer
- Author
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Naomi Kawano, Takehisa Suzuki, Shigeaki Umeda, Hideaki Mitsui, Yoko Kojima, Yoko Tateishi, Kenichi Ohashi, Kazuteru Watanabe, Koji Okudela, and Itaru Endo
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,Colorectal cancer ,Host gene ,Locus (genetics) ,General Medicine ,Mouse model of colorectal and intestinal cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Pathology and Forensic Medicine ,Internal medicine ,microRNA ,medicine ,Clinical significance ,Carcinogenesis ,Fluorescence in situ hybridization - Abstract
The expression of microRNA-31 (miR-31) has been implicated in the progression of some human malignancies including colorectal cancer. However, the clinical significance of the expression of miR-31 in submucosally invasive (T1) colorectal cancer remains unclear. The aim of the present study was to delineate the relationship between clinicopathological features and the oncogenic modulator miR-31 in submucosally invasive colorectal cancer. We investigated the expression of miR-31 in 50 submucosally invasive colorectal cancer specimens, along with the corresponding non-tumoral mucosa specimens, using a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The relationships between miR-31 expression levels and clinicopathological characteristics were assessed. The miR-31 host gene locus was investigated using fluorescence in situ hybridization. qRT-PCR revealed that the expression of miR-31 was higher in colorectal cancer tissue than in non-tumoral tissue (P = 0.0002). The up-regulated expression of miR-31 may play an oncogenic role in the early stage of carcinogenesis in colorectal cancers.
- Published
- 2015
37. The Role of Efferocytosis in Atherosclerosis
- Author
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Nicholas J. Leeper, Irving L. Weissman, and Yoko Kojima
- Subjects
0301 basic medicine ,Programmed cell death ,Necrotic core ,business.industry ,Macrophages ,Apoptosis ,Atherosclerosis ,Article ,Lesion ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Phagocytosis ,Physiology (medical) ,Immunology ,medicine ,Macrophage ,Humans ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Efferocytosis ,business ,Clearance ,Blood vessel - Abstract
The necrotic core has long been a hallmark of the vulnerable atherosclerotic plaque. Although apoptotic cells are cleared quickly in almost all other tissue beds, their removal appears to be significantly impaired in the diseased blood vessel. Emerging evidence indicates that this phenomenon is caused by a defect in efferocytosis, the process by which apoptotic tissue is recognized for engulfment by phagocytic cells such as macrophages. Genetic and experimental data suggest that efferocytosis is impaired during atherogenesis caused by dysregulation of so-called eat me ligands, which govern the edibility of cells undergoing programmed cell death. The following is a summary of recent data indicating that efferocytosis is a major unappreciated driver of lesion expansion but also a reversible defect that can potentially be targeted as a means to prevent plaque progression.
- Published
- 2017
38. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis
- Author
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Frederick E. Dewey, Uwe Raaz, Ramendra K. Kundu, Eric E. Schadt, Yoko Kojima, Kelly P. Downing, Nicholas J. Leeper, Thomas Quertermous, Ulf Hedin, Hope L. Lancero, Clint L. Miller, Lars Maegdefessel, and Ljubica Perisic
- Subjects
Male ,Phagocytosis ,Myocytes, Smooth Muscle ,Quantitative Trait Loci ,Down-Regulation ,Gene Expression ,Apoptosis ,E2F4 Transcription Factor ,Retinoblastoma Protein ,Mice ,Necrosis ,Cyclin-dependent kinase ,CDKN2B ,Animals ,Humans ,Efferocytosis ,Receptor ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p15 ,Foam cell ,Mice, Knockout ,biology ,Macrophages ,General Medicine ,Atherosclerosis ,Coronary Vessels ,Coculture Techniques ,Plaque, Atherosclerotic ,Mice, Inbred C57BL ,Carotid Arteries ,biology.protein ,Cancer research ,Female ,Corrigendum ,Calreticulin ,Research Article - Abstract
Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2b-deficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis.
- Published
- 2014
39. Comparative evaluation of the Geenius HIV 1/2 Confirmatory Assay and the HIV-1 and HIV-2 Western blots in the Japanese population
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Takako Sano, Shingo Kato, Koji Sudo, Naoki Hasegawa, Natsuo Tachikawa, Yukihiro Yoshimura, Shinya Iwamuro, Haruyo Mori, Takuya Kawahata, Makiko Kondo, Ichiro Itoda, Yoko Kojima, and Hiroshi Fujiwara
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RNA viruses ,0301 basic medicine ,Physiology ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,Acute infection ,HIV Infections ,HIV Antibodies ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Biochemistry ,Chromatography, Affinity ,Geographical Locations ,0302 clinical medicine ,Immunodeficiency Viruses ,Japan ,Immune Physiology ,HIV Seropositivity ,Medicine and Health Sciences ,Mass Screening ,Medicine ,030212 general & internal medicine ,lcsh:Science ,Cross Reactivity ,Immune System Proteins ,Multidisciplinary ,biology ,virus diseases ,HIV diagnosis and management ,Japanese population ,Disease control ,Blot ,Medical Microbiology ,Viral Pathogens ,Viruses ,Infectious diseases ,Pathogens ,Antibody ,Algorithms ,Research Article ,Asia ,Immunology ,Blotting, Western ,030106 microbiology ,Viral diseases ,Hiv testing ,Microbiology ,Sensitivity and Specificity ,Antibodies ,Comparative evaluation ,03 medical and health sciences ,Retroviruses ,Humans ,False Positive Reactions ,Seroconversion ,Microbial Pathogens ,Mass screening ,business.industry ,Lentivirus ,lcsh:R ,Organisms ,Biology and Life Sciences ,HIV ,Proteins ,Reproducibility of Results ,Virology ,Diagnostic medicine ,HIV-2 ,People and Places ,HIV-1 ,biology.protein ,lcsh:Q ,business - Abstract
Accurate diagnosis of earlier HIV infection is essential for treatment and prevention. Currently, confirmation tests of HIV infection in Japan are performed using Western blot (WB), but WB has several limitations including low sensitivity and cross-reactivity between HIV-1 and HIV-2 antibodies. To address these problems, a new HIV testing algorithm and a more reliable confirmation and HIV-1/2 differentiation assay are required. The Bio-Rad Geenius™ HIV-1/2 Confirmatory Assay (Geenius) has recently been approved and recommended for use in the revised guidelines for diagnosis of HIV infection by the Center for Disease Control and Prevention (USA). We made comprehensive comparison of the performance of Geenius and the Bio-Rad NEW LAV BLOT 1 and 2 (NLB 1 and 2) which are WB kits for HIV-1 and HIV-2, respectively, to examine if Geenius is a suitable alternative to these WB assays which are now being used in HIV testing in Japan. A total of 166 HIV-1 positive samples (146 from patients with established HIV-1 infection and 20 from patients with acute infection), five HIV-1 seroconversion panels containing 21 samples and 30 HIV-2 positive samples were used. In addition, a total of 140 HIV negative samples containing 10 false-positives on screening tests were examined. The sensitivity of Geenius and NLB 1 for HIV-1 positive samples was 99.3% and 98.6%, respectively. Geenius provided more positive results in the samples from acute infections and detected positivity 0 to 32 days earlier in seroconversion panels than NLB 1. NLB 2 gave positive results in 12.3% of HIV-1 positive samples. The sensitivity of both Geenius and NLB 2 for HIV-2 positive samples was 100%. The specificity of Geenius, NLB 1 and NLB 2 was 98.5%, 81.5% and 90.0%, respectively. Geenius is an attractive alternative to WB for confirmation and differentiation of HIV-1 and HIV-2 infections. The adaptation of Geenius to the HIV testing algorithm may be advantageous for rapid diagnosis and the reduction of testing costs.
- Published
- 2018
40. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.
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Ying Wang, Nanda, Vivek, Direnzo, Daniel, Jianqin Ye, Sophia Xiao, Yoko Kojima, Howe, Kathryn L., Jarr, Kai-Uwe, Flores, Alyssa M., Tsantilas, Pavlos, Noah Tsao, Rao, Abhiram, Newman, Alexandra A. C., Eberhard, Anne V., Priest, James R., Ruusalepp, Arno, Pasterkamp, Gerard, Maegdefessel, Lars, Miller, Clint L., and Lind, Lars
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MUSCLE cells ,SMOOTH muscle ,VASCULAR smooth muscle ,ATHEROSCLEROSIS ,ATHEROSCLEROTIC plaque - Abstract
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated†vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the matureSMCcangive riseto a hyperproliferativecellwhich appearsto promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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41. Rapid enlargement of a mesothelial cyst in a short period
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Michihiko Tajiri, Joji Samejima, Yoko Kojima, Takuya Nagashima, Munetaka Masuda, and Takahiro Omori
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business.industry ,Period (gene) ,Mesothelial cyst ,Medicine ,Anatomy ,business - Published
- 2013
42. ON THE MEASUREMENTS OF THE FOUNDATION AND TEMPLE LAYOUT OF PRE RUP IN ANGKOR PERIOD
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Masao Katagiri, Yutaka Shigeeda, and Yoko Kojima
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Engineering ,business.industry ,business - Published
- 2013
43. Evaluation of an Immunochromatographic Fourth Generation Test for the Rapid Diagnosis of Acute HIV Infection
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Yoko Kojima, Haruyo Mori, Takuya Kawahata, Mami Nagashima, and Kenji Sadamasu
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Acute HIV infection ,Rapid diagnostic test ,biology ,Transmission (medicine) ,business.industry ,HIV Infections ,General Medicine ,Window period ,Virology ,Chromatography, Affinity ,Virus ,Immune system ,Acute Disease ,biology.protein ,Humans ,Medicine ,Reagent Kits, Diagnostic ,Antibody ,business ,Viral load - Abstract
The early diagnosis of human immunodeficiency virus (HIV) infection is important to provide effective antiviral treatment and to prevent transmission of HIV. One of the key issues to achieve this goal is to shorten the so-called "diagnostic window period" when the humoral immune response toward the virus is not fully developed during the acute phase of HIV-1 infection. In 2008, the Espline HIV Ag/Ab test kit (E4G, Fujirebio Inc. Japan) was marketed in Japan belonging to the fourth generation of HIV test kits characterized by its ability to detect both viral antigens (Ag) and anti-HIV-1/2 antibodies (Ab). E4G is the first and only fourth generation immunochromatographic HIV test kit approved in Japan at present. To evaluate its performance to diagnose acute HIV infection (AHI), E4G was compared with fourth generation Ag/Ab ELISA test kits, a third generation PA test kit, WB and real-time PCR for the testing of 25 AHI clinical specimens. E4G detected HIV infection in 18/25 specimens (sensitivity : 72.0%), of which the viral Ag was detected in only 2 specimens (8.0%) bearing a viral load > 10 million copies/mL. No spesimens were simultaneously reactive to both Ag and Ab against HIV. The third generation PA achieved a positive score of 17/ 25 specimens (68.0%), which was almost the same as the E4G figure. In contrast the fourth generation Ag/ Ab ELISA scored all the 25 AHI specimens positive (sensitivity : 100%). Overall, although having the merit of offering a rapid diagnostic test for HIV infection, E4G does not provide a sensitivity in AHI diagnosis superior to test kits currently available.
- Published
- 2013
44. A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity
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Kosuke Miyauchi, Jun Komano, Yoko Kojima, Satoshi Fudo, Tyuji Hoshino, Makiko Hamatake, Sherimay D. Ablan, Eric O. Freed, and Emiko Urano
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0301 basic medicine ,Efavirenz ,Anti-HIV Agents ,030106 microbiology ,Drug resistance ,Microbial Sensitivity Tests ,Biology ,Virus Replication ,Biochemistry ,Virus ,Article ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,law ,Drug Discovery ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Binding site ,Cell Line, Transformed ,Pharmacology ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,Triazines ,Organic Chemistry ,virus diseases ,Virology ,Reverse transcriptase ,HIV Reverse Transcriptase ,030104 developmental biology ,chemistry ,Docking (molecular) ,Recombinant DNA ,HIV-1 ,Leukocytes, Mononuclear ,Molecular Medicine ,Reverse Transcriptase Inhibitors - Abstract
A novel HIV-1 inhibitor, 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (compound 1), was identified from a compound library screened for the ability to inhibit HIV-1 replication. EC(50) values of compound 1 were found to range from 107.9 to 145.4 nm against primary HIV-1 clinical isolates. In in vitro assays, HIV-1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC(50) of 4.3 μm. An assay for resistance to compound 1 selected a variant of HIV-1 with a RT mutation (RT(L100I)); this frequently identified mutation confers mild resistance to non-nucleoside RT inhibitors (NNRTIs). A recombinant HIV-1 bearing RT(L100I) exhibited a 41-fold greater resistance to compound 1 than the wild-type virus. Compound 1 was also effective against HIV-1 with RT(K103N), one of the major mutations that confers substantial resistance to NNRTIs. Computer-assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RT(K103) than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile.
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- 2016
45. Alterations in cathepsin L expression in lung cancers
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Koji, Okudela, Hideaki, Mitsui, Tetsukan, Woo, Hiromasa, Arai, Takehisa, Suzuki, Mai, Matsumura, Yoko, Kojima, Shigeaki, Umeda, Yoko, Tateishi, Munetaka, Masuda, and Kenichi, Ohashi
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Gene Expression Regulation, Neoplastic ,Lung Neoplasms ,Cathepsin L ,Cell Line, Tumor ,Humans ,Adenocarcinoma of Lung ,Epithelial Cells ,Adenocarcinoma ,Lung - Abstract
We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearman's rank-order correlation, P = 0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas.
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- 2016
46. Expression of tropomyosins in lung cancer - a potential role in carcinogenesis and its utility in a histopathological diagnosis
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Koji, Okudela, Hideaki, Mitsui, Tetsukan, Woo, Yoko, Kojima, Mai, Matsumura, Hiromasa, Arai, Takehisa, Suzuki, Shigeaki, Umeda, Yoko, Tateishi, Yuichi, Saito, Michihiko, Tajiri, Munetaka, Masuda, Yoichi, Kameda, and Kenichi, Ohashi
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Lung Neoplasms ,Carcinogenesis ,Blotting, Western ,Carcinoma ,Biomarkers, Tumor ,Humans ,Tropomyosin ,Immunohistochemistry ,Sensitivity and Specificity - Abstract
We herein analyzed the relationships between tropomyosin protein expression levels and clinicopathological factors in order to determine the significance of tropomyosins in lung cancers. Although neoplastic cells expressed different isoforms of tropomyosin, overall expression levels were lower than those in bronchial and alveolar epithelial cells. In adenocarcinomas, tropomyosin levels were markedly reduced in poorly differentiated or solid subtype carcinomas, suggesting that a loss in the expression of tropomyosins is involved in the progression of lung adenocarcinomas. The potential utility of the immunohistochemical expression of tropomyosins for a histopathological diagnosis was also investigated. The sensitivity and specificity of a loss in the expression of tropomyosins were 100% and 50%, respectively, which were superior to those for the strong expression of p53 (sensitivity 100% and specificity 44%), a conventional biomarker. An immunohistochemical examination of tropomyosins may assist in the histopathological detection of lung cancer cells in small biopsy specimens.
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- 2016
47. Surgically removed thoracolithiasis: Report of 4 cases
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Takuya Nagashima, Joji Samejima, Yoko Kojima, Munetaka Masuda, Takahiro Omori, and Michihiko Tajiri
- Abstract
胸腔内結石は稀な疾患で,外科的切除された胸腔内結石の本邦報告例は21例である.今回われわれは胸腔鏡下に摘出した4例を経験したため,報告する.症例1は64歳男性で,検診で胸部異常影を指摘,CTでは右肺下葉S6の胸膜直下に径10 mmの結節を認めた.胸腔鏡下に観察すると,S6とS10の区域間線上に白色平滑な結石がはまり込んでいた.症例2・3・4は右肺下葉の原発性肺癌の手術時に偶然胸腔内に遊離した結石を認め,いずれも摘出し胸腔内結石と診断した.結石の中心の核はすべて脂肪壊死組織を伴っていた.肺野末梢,特に横隔膜上の小結節の鑑別診断として,胸腔内結石を考慮する必要がある.
- Published
- 2012
48. Application of media teaching materials 'e-learning for Anatomy' to measures against national examination for nurses in third year students of Undergraduate Nursing course of Tsukuba International University during spring vacation
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Kazunori, Sato, Eiko, Koyama, Midori, Nagashima, Chiyoko, Seki, Yoko, Kojima, Yuriko, Sasaki, Kazuyuki, Sugino, and Kazuhiko, Sawada
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教育 ,保健医療 ,教材 ,Co-medical ,Teaching classes ,Health science ,Teaching materials ,コメディカル ,授業 ,Education - Published
- 2012
49. Abstract 12518: MicroRNA 139-5p Coordinates APLNR-CXCR4 Crosstalk During Vascular Maturation
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Jongmin Kim, Arndt F. Siekmann, Aram Lee, Yoko Kojima, Keiichiro Tanaka, Irinna Papangeli, Inna Maier, Yujung Kang, Hyekyung Ju, and Hyung J. Chun
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Sprouting angiogenesis ,Crosstalk (biology) ,business.industry ,Angiogenesis ,Physiology (medical) ,microRNA ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,CXCR4 ,Sprouting ,Apelin ,Cell biology - Abstract
Rationale: Sprouting angiogenesis is governed by the concept of tip/stalk cells that guides our understanding of the transition from vascular sprouting to maturation and ultimately quiescence. The VEGF and Notch signaling pathways have been extensively described in regulating the discrimination between these two cell populations. However, several additional tip and stalk cell specific genes have been identified. To date, unresolved questions remain, and our understanding of the mechanisms by which these signaling processes are integrated is incomplete. Objective: We set out to investigate novel mechanisms by which signaling pathways involving two G protein coupled receptors (GPCRs), expressed in a mutually exclusive fashion in the tip/stalk cell populations, are intricately linked in vascular development. Methods/Results: Using a combination of in vivo and in vitro techniques, we demonstrate the critical role of crosstalk between APLNR and CXCR4 in vascular maturation. We show robust flow induced expression of the stalk cell specific APLNR, that leads to marked suppression of CXCR4 expression, a mechanism to achieve tip cell restricted expression of the latter. Retinas from Apln (ligand), Aplnr (receptor) and endothelial specific Aplnr deleted mice show retarded vascular expansion, reduced vascularized area and fewer vascular branch points. These phenotypes are in part due to increased expression of Cxcr4 in Apln-/- and Aplnr-/- retinal vessels as Cxcr4 inhibition through a selective inhibitor can ameliorate the Aplnr phenotype. The crosstalk between the two GPCRs was found to involve a key shear responsive microRNA, miR-139-5p, which is upregulated by APLN/APLNR signaling and directly targets CXCR4 in endothelial cells. In accordance, Apln-/- and Aplnr-/- retinal endothelial cells showed depleted levels of miR-139-5p. Lastly, we demonstrate that atorvastatin, an HMG-CoA reductase inhibitor shown to enhance APLNR signaling, can induce miR-139-5p expression and rescue the vascular phenotypes associated with APLN/APLNR deficiency. Conclusions: These findings provide key mechanistic insights into a critical microRNA based crosstalk between two GPCR signaling cascades, which regulates important steps in vascular maturation.
- Published
- 2015
50. A cluster of rapid disease progressors upon primary HIV-1 infection shared a novel variant with mutations in the p6gag/pol and pol/vif genes
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Motoo Matsuura, Jun Komano, Takuya Kawahata, Mitsuru Konishi, Kenji Uno, Yoko Kojima, and Haruyo Mori
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Immunology ,Molecular Sequence Data ,Human immunodeficiency virus (HIV) ,Mutation, Missense ,HIV Infections ,Disease ,Biology ,Disease cluster ,medicine.disease_cause ,gag Gene Products, Human Immunodeficiency Virus ,Acquired immunodeficiency syndrome (AIDS) ,Japan ,medicine ,vif Gene Products, Human Immunodeficiency Virus ,Immunology and Allergy ,Cluster Analysis ,Humans ,Amino Acid Sequence ,Gene ,Genetics ,Molecular Epidemiology ,Clinical course ,virus diseases ,medicine.disease ,Virology ,Rapid disease progression ,Infectious Diseases ,pol Gene Products, Human Immunodeficiency Virus ,HIV-1 - Abstract
Few studies have described the etiologic factors associated with rapid AIDS onset during primary HIV-1 infection. Our molecular epidemiological study identified a cluster of individuals infected with HIV-1 variants characterized by novel mutations in the p6 and pol/vif genes during 2011 and 2013 in Osaka, Japan. Individuals positive for the novel HIV-1 variant showed rapid disease progression, suggesting a role of viral mutations in the fostering of the clinical course of HIV-1 infection.
- Published
- 2015
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