Publications by authors named "Motomu Shimaoka"

119 Publications

The Evaluation of Hemostatic Abnormalities Using a CWA-Small Amount Tissue Factor Induced FIX Activation Assay in Major Orthopedic Surgery Patients.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:10760296211012094

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan.

We analyzed the utility for a clot waveform analysis (CWA) of small tissue factor induced FIX activation (sTF/FIXa) assay in patients with major orthopedic surgery (including total hip arthroplasty [THA] and total knee arthroplasty [TKA]) receiving edoxaban for the prevention of venous thromboembolism (VTE). The sTF/FIXa assay using recombinant human TF in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) was performed using a CWA in the above patients to monitor the efficacy of edoxaban administration. Of 147 patients (109 THA and 38 TKA), 21 exhibited deep vein thrombosis (DVT), and 15 had massive bleeding. Increased peak heights of the CWA-sTF/FIX were observed in almost patients after surgery and prolonged peak heights of the CWA-sTF/FIX were observed in almost patients treated with edoxaban. The peak heights and times of the CWA-sTF/FIX were significantly higher and shorter, respectively, in PRP than in PPP. There were no significant differences in parameters of the CWA-sTF/FIXa between the patients with and without DVT or between those with and without massive bleeding. The peak time of CWA-sTF/FIXa were significantly longer in TKA patients than in THA patients on day 1 after surgery. The second derivative peak height of the CWA-sTF/FIXa was significantly lower in TKA patients than in THA patients on day 4. The CWA-sTF/FIX reflected hemostatic abnormalities after surgery and the administration of edoxaban, and the results were better in PRP than PPP. Further studies separately analyzing the THA and TKA subgroups should be conducted.
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http://dx.doi.org/10.1177/10760296211012094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150457PMC
May 2021

Endothelial connexin-integrin crosstalk in vascular inflammation.

Biochim Biophys Acta Mol Basis Dis 2021 May 13;1867(9):166168. Epub 2021 May 13.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan. Electronic address:

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.
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http://dx.doi.org/10.1016/j.bbadis.2021.166168DOI Listing
May 2021

The Spike Glycoprotein of SARS-CoV-2 Binds to β1 Integrins Expressed on the Surface of Lung Epithelial Cells.

Viruses 2021 04 9;13(4). Epub 2021 Apr 9.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City 514-8507, Mie, Japan.

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl-glycyl-aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the β1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular β1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the β1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.
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http://dx.doi.org/10.3390/v13040645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069079PMC
April 2021

Distinct Age-Specific miRegulome Profiling of Isolated Small and Large Intestinal Epithelial Cells in Mice.

Int J Mol Sci 2021 Mar 29;22(7). Epub 2021 Mar 29.

Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

The intestinal epithelium serves as a dynamic barrier to protect the host tissue from exposure to a myriad of inflammatory stimuli in the luminal environment. Intestinal epithelial cells (IECs) encompass differentiated and specialized cell types that are equipped with regulatory genes, which allow for sensing of the luminal environment. Potential inflammatory cues can instruct IECs to undergo a diverse set of phenotypic alterations. Aging is a primary risk factor for a variety of diseases; it is now well-documented that aging itself reduces the barrier function and turnover of the intestinal epithelium, resulting in pathogen translocation and immune priming with increased systemic inflammation. In this study, we aimed to provide an effective epigenetic and regulatory outlook that examines age-associated alterations in the intestines through the profiling of microRNAs (miRNAs) on isolated mouse IECs. Our microarray analysis revealed that with aging, there is dysregulation of distinct clusters of miRNAs that was present to a greater degree in small IECs (22 miRNAs) compared to large IECs (three miRNAs). Further, miRNA-mRNA interaction network and pathway analyses indicated that aging differentially regulates key pathways between small IECs (e.g., toll-like receptor-related cascades) and large IECs (e.g., cell cycle, Notch signaling and small ubiquitin-related modifier pathway). Taken together, current findings suggest novel gene regulation pathways by epithelial miRNAs in aging within the gastrointestinal tissues.
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http://dx.doi.org/10.3390/ijms22073544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036635PMC
March 2021

Irisin supports integrin-mediated cell adhesion of lymphocytes.

Biochem Biophys Rep 2021 Jul 8;26:100977. Epub 2021 Mar 8.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Japan.

Irisin, a myokine released from skeletal muscle, has recently been found to act as a ligand for the integrins αVβ5, αVβ1, and α5β1 expressed on mesenchymal cells, thereby playing an important role in the metabolic remodeling of the bone, skeletal muscle and adipose tissues. Although the immune-modulatory effects of irisin in chronic inflammation have been documented, its interactions with lymphocytic integrins have yet to be elucidated. Here, we show that irisin supports the cell adhesion of human and mouse lymphocytes. Cell adhesion assays using a panel of inhibitory antibodies to integrins have shown that irisin-mediated lymphocyte adhesion involves multiple integrins including not only α4β1 and α5β1, but also leukocyte-specific αLβ2 and α4β7. Importantly, mouse lymphocytic TK-1 cells that lack the expression of β1 integrins have exhibited αLβ2- and α4β7-mediated cell adhesion to irisin. Irisin has also been demonstrated to bind to purified recombinant integrin αLβ2 and α4β7 proteins. Thus, irisin represents a novel ligand for integrin αLβ2 and α4β7, capable of supporting lymphocyte cell adhesion independently of β1 integrins. These results suggest that irisin may play an important role in regulating lymphocyte adhesion and migration in the inflamed vasculature.
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http://dx.doi.org/10.1016/j.bbrep.2021.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944048PMC
July 2021

Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway.

Front Immunol 2020 17;11:624279. Epub 2021 Feb 17.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie, Japan.

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.
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http://dx.doi.org/10.3389/fimmu.2020.624279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925640PMC
February 2021

Integrin Regulation in Immunological and Cancerous Cells and Exosomes.

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City 514-8507, Mie, Japan.

Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. It has recently emerged that integrins are expressed not only in cells but also in exosomes, important entities of extracellular vesicles secreted from cells. Exosomal integrins have received considerable attention in recent years, and they are clearly involved in determining the tissue distribution of exosomes, forming premetastatic niches, supporting internalization of exosomes by target cells and mediating exosome-mediated transfer of the membrane proteins and associated kinases to target cells. A growing body of evidence shows that tumor and immune cell exosomes have the ability to alter endothelial characteristics (proliferation, migration) and gene expression, some of these effects being facilitated by vesicle-bound integrins. As endothelial metabolism is now thought to play a key role in tumor angiogenesis, we also discuss how tumor cells and their exosomes pleiotropically modulate endothelial functions in the tumor microenvironment.
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http://dx.doi.org/10.3390/ijms22042193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926977PMC
February 2021

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan.

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.
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http://dx.doi.org/10.3390/ijms22041881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918833PMC
February 2021

Internet-Based Individualized Cognitive Behavioral Therapy for Shift Work Sleep Disorder Empowered by Well-Being Prediction: Protocol for a Pilot Study.

JMIR Res Protoc 2021 Mar 18;10(3):e24799. Epub 2021 Mar 18.

Departments of Molecular and Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

Background: Shift work sleep disorders (SWSDs) are associated with the high turnover rates of nurses, and are considered a major medical safety issue. However, initial management can be hampered by insufficient awareness. In recent years, it has become possible to visualize, collect, and analyze the work-life balance of health care workers with irregular sleeping and working habits using wearable sensors that can continuously monitor biometric data under real-life settings. In addition, internet-based cognitive behavioral therapy for psychiatric disorders has been shown to be effective. Application of wearable sensors and machine learning may potentially enhance the beneficial effects of internet-based cognitive behavioral therapy.

Objective: In this study, we aim to develop and evaluate the effect of a new internet-based cognitive behavioral therapy for SWSD (iCBTS). This system includes current methods such as medical sleep advice, as well as machine learning well-being prediction to improve the sleep durations of shift workers and prevent declines in their well-being.

Methods: This study consists of two phases: (1) preliminary data collection and machine learning for well-being prediction; (2) intervention and evaluation of iCBTS for SWSD. Shift workers in the intensive care unit at Mie University Hospital will wear a wearable sensor that collects biometric data and answer daily questionnaires regarding their well-being. They will subsequently be provided with an iCBTS app for 4 weeks. Sleep and well-being measurements between baseline and the intervention period will be compared.

Results: Recruitment for phase 1 ended in October 2019. Recruitment for phase 2 has started in October 2020. Preliminary results are expected to be available by summer 2021.

Conclusions: iCBTS empowered with well-being prediction is expected to improve the sleep durations of shift workers, thereby enhancing their overall well-being. Findings of this study will reveal the potential of this system for improving sleep disorders among shift workers.

Trial Registration: UMIN Clinical Trials Registry UMIN000036122 (phase 1), UMIN000040547 (phase 2); https://tinyurl.com/dkfmmmje, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046284.

International Registered Report Identifier (irrid): DERR1-10.2196/24799.
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http://dx.doi.org/10.2196/24799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088862PMC
March 2021

Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin.

Front Cell Dev Biol 2021 5;9:634853. Epub 2021 Feb 5.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.
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http://dx.doi.org/10.3389/fcell.2021.634853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892973PMC
February 2021

The Evaluation of APTT Reagents in Reference Plasma, Recombinant FVIII Products; Kovaltry® and Jivi® Using CWA, Including sTF/7FIX Assay.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:1076029620976913

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of medicine, Tsu, Japan.

The FVIII activity in patients treated with several extended half-life FVIII (EHL-FVIII) agents different when various activated partial thromboplastin time (APTT) reagents were used. The present study examined the difference in clot waveform analysis (CWA) findings and FVIII activity when various APTT reagents and CWA were used. The CWA including FVIII activity was measured using 12 APTT reagents, and the FIX activation based on a small amount of tissue factor assay (sTF/FIX) were examined in reference plasma (RP), EHL-FVIII (Jivi) and Kovaltry. The 3 APTT reagents were associated with high variation in the peak time and height in the CWA when analyzing low concentrations of FVIII. The peak time and height could not be measured with one APTT reagent, and there were marked differences in the CWA findings between Jivi and Kovaltry among APTT reagents. Several APTT reagents showed a markedly lower FVIII activity with Jivi than with Kovaltry. In the FVIII assay, the peak time measured with sTF/FIX did not differ markedly between Jivi and Kovaltry; however, the FVIII activity in Jivi (as measured by the peak height) tended to be higher than in Kovaltry. The CWA findings for monitoring Jivi varied for monitoring Jivi depending on the APTT reagents used, and sTF/FIX assay may be able to measure the EHL-FVIII.
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http://dx.doi.org/10.1177/1076029620976913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900842PMC
February 2021

The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin.

Biomedicines 2021 Feb 7;9(2). Epub 2021 Feb 7.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan.

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca and Mg but not under strong integrin-activation conditions in the presence of Mg without Ca. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin.
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http://dx.doi.org/10.3390/biomedicines9020162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914543PMC
February 2021

Ligand-competent fractalkine receptor is expressed on exosomes.

Biochem Biophys Rep 2021 Jul 2;26:100932. Epub 2021 Feb 2.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.

Expression of chemokine receptor CX3CR1 is reportedly restricted to several cell types including natural killer cells, cytotoxic T cells, monocytes, and macrophages. However, its expression and function on exosomes, which are nanosized extracellular vesicles known to act as mediators of intercellular communications, remain unclear. Here, we investigated CX3CR1 expression on exosomes isolated from various cell types. Although we found that all the exosomes tested in our study highly expressed CX3CR1, this chemokine receptor was expressed only inside, but barely on, their source cells. Moreover, exosomal CX3CR1 was capable of binding soluble CX3CL1. Therefore, our study suggests that CX3CR1 is a novel and ligand-competent exosome receptor.
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http://dx.doi.org/10.1016/j.bbrep.2021.100932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859287PMC
July 2021

Elevated D-Dimer Levels Predict a Poor Outcome in Critically Ill Patients.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620973084

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

D-dimer is a biomarker of thrombosis and recently been considered to predict a poor outcome in patients with infectious diseases. Plasma D-dimer levels were measured in critically ill patients to examine their relationship with the poor outcome. The plasma D-dimer levels were markedly higher in the patients with various underlying disease especially venous thromboembolism in comparison to those without severe underlying diseases. The plasma D-dimer levels in non-survivors were significantly higher than those in survivors. In a receiver operating characteristic analysis, the area under the curve was high for the disseminated intravascular coagulation (DIC) score, the D-dimer value, and the prothrombin time-international normalize ratio (PT-INR). Adequate cut-off values for predicting the outcome were 3 as follows: DIC score, 3 points; D-dimer, 4.2 mg/L; and PT-INR, 1.08. D-dimer, which is a biomarker for thrombosis, is increased in various underlying diseases and predicts a poor outcome.
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http://dx.doi.org/10.1177/1076029620973084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755937PMC
December 2020

How ICU Patient Severity Affects Communicative Interactions Between Healthcare Professionals: A Study Utilizing Wearable Sociometric Badges.

Front Med (Lausanne) 2020 3;7:606987. Epub 2020 Dec 3.

Departments of Molecular and Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

Numerous factors affecting the interactions between healthcare professionals in the workplace demand a comprehensive understanding if the quality of patient healthcare is to be improved. Our previous cross-sectional analysis showed that patient severity scores [i.e., Acute Physiology and Chronic Health Evaluation (APACHE) II] in the 24 h following admission positively correlated with the length of the face-to-face interactions among ICU healthcare professionals. The present study aims to address how the relationships between patient severity and interaction lengths can change over a period of time during both admission and treatment in the ICU. We retrospectively analyzed data prospectively collected between 19 February to 17 March 2016 from an open ICU in a University Hospital in Japan. We used wearable sensors to collect a spatiotemporal distribution dataset documenting the face-to-face interactions between ICU healthcare professionals, which involved 76 ICU staff members, each of whom worked for 160 h, on average, during the 4-week period of data collection. We studied the longitudinal relationships among these interactions, which occurred at the patient bedside, vis-à-vis the severity of the patient's condition [i.e., the Sequential Organ Failure Assessment (SOFA) score] assessed every 24 h. On Day 1, during which a total of 117 patients stayed in the ICU, we found statistically significant positive associations between the interaction lengths and their SOFA scores, as shown by the Spearman's correlation coefficient value (R) of 0.447 ( < 0.01). During the course of our observation from Day 1 to Day 10, the number of patients () who stayed in the ICU gradually decreased ( = 117, Day1; = 10, Day 10), as they either were discharged or died. The statistically significant positive associations of the interaction lengths with the SOFA scores disappeared from Days 2 to 6, but re-emerged on Day 7 ( = 0.620, < 0.05) and Day 8 ( = 0.625, < 0.05), then disappearing again on Days 9 and 10. Whereas all 6 SOFA sub-scores correlated well with the interaction lengths on Day 1, only a few of the sub-scores (coagulation, cardiovascular, and central nervous system scores) did so; specifically, those on Days 7 and 8. The results suggest that patient severity may play an important role in affecting the interactions between ICU healthcare professionals in a time-related manner on ICU Day 1 and on Days 7/8.
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http://dx.doi.org/10.3389/fmed.2020.606987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744931PMC
December 2020

Social Network Analysis of Intensive Care Unit Health Care Professionals Measured by Wearable Sociometric Badges: Longitudinal Observational Study.

J Med Internet Res 2020 12 31;22(12):e23184. Epub 2020 Dec 31.

Department of Molecular Pathobiology and Cell Adhesion Biology, Graduate School of Medicine, Mie University, Tsu-City, Japan.

Background: Use of wearable sensor technology for studying human teamwork behavior is expected to generate a better understanding of the interprofessional interactions between health care professionals.

Objective: We used wearable sociometric sensor badges to study how intensive care unit (ICU) health care professionals interact and are socially connected.

Methods: We studied the face-to-face interaction data of 76 healthcare professionals in the ICU at Mie University Hospital collected over 4 weeks via wearable sensors.

Results: We detail the spatiotemporal distributions of staff members' inter- and intraprofessional active face-to-face interactions, thereby generating a comprehensive visualization of who met whom, when, where, and for how long in the ICU. Social network analysis of these active interactions, concomitant with centrality measurements, revealed that nurses constitute the core members of the network, while doctors remain in the periphery.

Conclusions: Our social network analysis using the comprehensive ICU interaction data obtained by wearable sensors has revealed the leading roles played by nurses within the professional communication network.
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http://dx.doi.org/10.2196/23184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808885PMC
December 2020

Methods to Study Integrin Functions on Exosomes.

Methods Mol Biol 2021 ;2217:265-281

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.

Exosomes represent an important group of extracellular vesicles. They are formed in endosomal compartments and are actively secreted to extracellular spaces. Several membrane proteins, including integrins, are present on the surface of exosomes. As exosomal integrins are competent for binding to ligand, they can play important roles in directing the tissue distribution of exosomes. Integrin-directed exosomal trafficking in vivo is involved in regulating the remodeling of cell homing niches for metastatic cancers and migrating lymphocytes. This chapter describes the methods used to study integrin functions on exosomes including: isolation and biophysical characterization of exosomes, exosomal integrin-ligand binding assays, and in vivo competitive exosome homing assays.
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http://dx.doi.org/10.1007/978-1-0716-0962-0_15DOI Listing
March 2021

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin.

Front Cell Dev Biol 2020 26;8:588066. Epub 2020 Oct 26.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

Integrins are transmembrane proteins that mediate cellular adhesion and migration to neighboring cells or the extracellular matrix, which is essential for cells to undertake diverse physiological and pathological pathways. For integrin activation and ligand binding, bidirectional signaling across the cell membrane is needed. Integrins aberrantly activated under pathologic conditions facilitate cellular infiltration into tissues, thereby causing inflammatory or tumorigenic progressions. Thus, integrins have emerged to the forefront as promising targets for developing therapeutics to treat autoimmune and cancer diseases. In contrast, it remains a fact that integrin-ligand interactions are beneficial for improving the health status of different tissues. Among these ligands, irisin, a myokine produced mainly by skeletal muscles in an exercise-dependent manner, has been shown to bind to integrin αVβ5, alleviating symptoms under unfavorable conditions. These findings may provide insights into some of the underlying mechanisms by which exercise improves quality of life. This review will discuss the current understanding of integrin-ligand interactions in both health and disease. Likewise, we not only explain how diverse ligands play different roles in mediating cellular functions under both conditions via their interactions with integrins, but also specifically highlight the potential roles of the emerging ligand irisin in inflammation, cancer, and metabolic disease.
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http://dx.doi.org/10.3389/fcell.2020.588066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649757PMC
October 2020

Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-a and IL-17A Expression in Mucosal Inflammation.

Int J Mol Sci 2020 Nov 10;21(22). Epub 2020 Nov 10.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-a and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target and . These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.
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http://dx.doi.org/10.3390/ijms21228445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696152PMC
November 2020

The Role of Innate Lymphoid Cells in the Regulation of Immune Homeostasis in Sepsis-Mediated Lung Inflammation.

Diagnostics (Basel) 2020 Oct 12;10(10). Epub 2020 Oct 12.

Department of Molecular Pathobiology and Cell Adhesion Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu City, Mie 514-8507, Japan.

Septic shock/severe sepsis is a deregulated host immune system response to infection that leads to life-threatening organ dysfunction. Lung inflammation as a form of acute lung injury (ALI) is often induced in septic shock. Whereas macrophages and neutrophils have been implicated as the principal immune cells regulating lung inflammation, group two innate lymphoid cells (ILC2s) have recently been identified as a new player regulating immune homeostasis. ILC2 is one of the three major ILC subsets (ILC1s, ILC2s, and ILC3s) comprised of newly identified innate immune cells. These cells are characterized by their ability to rapidly produce type 2 cytokines. ILC2s are predominant resident ILCs and, thereby, have the ability to respond to signals from damaged tissues. ILC2s regulate the immune response, and ILC2-derived type 2 cytokines may exert protective roles against sepsis-induced lung injury. This focused review not only provides readers with new insights into the signaling mechanisms by which ILC2s modulate sepsis-induced lung inflammation, but also proposes ILC2 as a novel therapeutic target for sepsis-induced ALI.
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http://dx.doi.org/10.3390/diagnostics10100808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600279PMC
October 2020

Update on the Clot Waveform Analysis.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620912027

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

The activated partial thromboplastin time (APTT)-clot waveform analysis (CWA) was previously reported to be associated with the early detection of disseminated intravascular coagulation and was also reported to be able to measure very low levels of coagulation factor VIII activity. The software program for the analysis for the APTT-CWA allows the associated first and second derivative curves (first and second DCs) to be displayed. The first and second DC reflect the velocity and acceleration, respectively. The height of the first DC reflects the "thrombin burst" and bleeding risk, while that of the second DC is useful for detecting any coagulation factor deficiency and abnormal enhancement of coagulation by phospholipids. Activated partial thromboplastin time-CWA aids in making a differential diagnosis which is difficult to do using only the routine APTT. The CWA is currently used for many applications in the clinical setting, including the monitoring of hemophilia patients and patients receiving anticoagulant therapy and the differential diagnosis of diseases.
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http://dx.doi.org/10.1177/1076029620912027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466886PMC
September 2020

Sepsis Induces Deregulation of IL-13 Production and PD-1 Expression in Lung Group 2 Innate Lymphoid Cells.

Shock 2021 Mar;55(3):357-370

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu City, Mie, Japan.

Abstract: Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expression. Furthermore, using IL-33 knockout mice, we have shown that IL-33 regulates the capacity of ILC2s to produce IL-13, possibly through the modulation of ST2 and PD-1 expression and signaling in the septic lung. To the best of our knowledge, this is the first report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.
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http://dx.doi.org/10.1097/SHK.0000000000001647DOI Listing
March 2021

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening.

Cells 2020 07 30;9(8). Epub 2020 Jul 30.

Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane 693-8501, Japan.

Endothelial cellular stiffening has been observed not only in inflamed cultured endothelial cells but also in the endothelium of atherosclerotic regions, which is an underlying cause of monocyte adhesion and accumulation. Although recombinant soluble thrombomodulin (rsTM) has been reported to suppress the inflammatory response of endothelial cells, its role in regulating endothelial cellular stiffness remains unclear. The purpose of this study was to investigate the impact of anticoagulant rsTM on lipopolysaccharide (LPS)-induced endothelial cellular stiffening. We show that LPS increases endothelial cellular stiffness by using atomic force microscopy and that rsTM reduces LPS-induced cellular stiffening not only through the attenuation of actin fiber and focal adhesion formation but also via the improvement of gap junction functionality. Moreover, post-administration of rsTM, after LPS stimulation, attenuated LPS-induced cellular stiffening. We also found that endothelial cells regulate leukocyte adhesion in a substrate- and cellular stiffness-dependent manner. Our result show that LPS-induced cellular stiffening enhances monocytic THP-1 cell line adhesion, whereas rsTM suppresses THP-1 cell adhesion to inflamed endothelial cells by reducing cellular stiffness. Endothelial cells increase cellular stiffness in reaction to inflammation, thereby promoting monocyte adhesion. Treatment of rsTM reduced LPS-induced cellular stiffening and suppressed monocyte adhesion in a cellular stiffness-dependent manner.
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http://dx.doi.org/10.3390/cells9081811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463703PMC
July 2020

Errors in the diagnosis for DIC due to a statistical misunderstanding.

J Thromb Haemost 2020 07;18(7):1791-1792

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

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http://dx.doi.org/10.1111/jth.14833DOI Listing
July 2020

Effects of platelet and phospholipids on clot formation activated by a small amount of tissue factor.

Thromb Res 2020 09 10;193:146-153. Epub 2020 Jun 10.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of medicine, Tsu, Japan.

Introduction: Physiological coagulation is considered to activate coagulation factor IX (FIX) by a small amount of tissue factor (TF) and activated coagulation factor VII (FVIIa) with the presence of platelets. A Clot waveform analysis (CWA) may be useful for evaluating physiological coagulation.

Material And Methods: A CWA using a small amount of TF (CWA/sTF) was performed in platelet-rich plasma (PRP), platelet-poor plasma (PPP), several phospholipids (PLs) and patients with lupus anticoagulant (LA), idiopathic thrombocytopenic purpura (ITP) or inhibitor for FVIII.

Results: The CWA/sTF without PLs showed a shorter peak time and higher peak height in PRP than in PPP. The effect of PRP on the CWA/sTF depended on the platelet count, and PLs showed a similar effect on the CWA/sTF results in PPP. The peak time of the CWA/sTF in PRP was prolonged in patient with ITP. The CWA/sTF in PRP showed a prolonged peak time and decreased peak height of the second derivative in patient with LA. Both a shortened peak time and elevated peak height were observed in the CWA/sTF of patient with inhibitor after treatment with activated recombinant human FVII.

Conclusion: A CWA can be conducted using a small amount of TF and platelets or PL without contact activation and may be able to detect not only hemostatic abnormalities but also changes in platelet counts.
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http://dx.doi.org/10.1016/j.thromres.2020.06.018DOI Listing
September 2020

The prothrombin time ratio is not a more effective marker for evaluating sepsis-induced coagulopathy than fibrin-related markers.

J Thromb Haemost 2020 06;18(6):1506-1507

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.

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http://dx.doi.org/10.1111/jth.14766DOI Listing
June 2020

Targeted remodeling of breast cancer and immune cell homing niches by exosomal integrins.

Diagn Pathol 2020 Apr 18;15(1):38. Epub 2020 Apr 18.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Exosomes represent an important subset of extracellular vesicles involved in inter-cellular communications in health and diseases. Exosomes secreted from cancer and immune cells travel to the specific tissues containing homing niches. The exosomes reaching the niches dynamically modify the gene expression and molecular architectures of the homing niche micro-environments. Cell adhesion molecule integrins regulate the tissue-specific homing patterns of not only cancer and immune cells, but also of the exosomes secreted from those cells. The exosome-mediated remodeling of the homing niches would affect immune lymphocyte migration and host defense, as well as cancer metastasis, thereby representing a potential therapeutic target.
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http://dx.doi.org/10.1186/s13000-020-00959-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165434PMC
April 2020

Virtual reality as a non-pharmacologic analgesic for fasciotomy wound infections in acute compartment syndrome: a case report.

J Med Case Rep 2020 Apr 14;14(1):46. Epub 2020 Apr 14.

Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Background: Fasciotomy is a life-saving procedure to treat acute compartment syndrome, a surgical emergency. As fasciotomy dramatically improves wound pain, it should be performed as soon as possible. Moreover, delays in the use of fasciotomy can increase the rate of wound infections. Once the fasciotomy wound is infected, pain control is achieved via the long-term use of opioids or anti-inflammatory analgesics. However, the administration of high doses of opioids may cause complications, such as respiratory depression, over-sedation, and constipation. Therefore, treatment methods other than narcotic administration should be established to better manage the pain caused by fasciotomy wound infections. Virtual reality has recently been introduced in analgesic therapy as a replacement, or complement, to conventional pharmacological treatments. Its use has been extensively studied in the pain management of patients with burns. An increasing number of painful conditions are being successfully treated with virtual reality. Here, we report a case of acute compartment syndrome complicated by fasciotomy wound infection.

Case Presentation: A 40-year-old Japanese man suffering from acute compartment syndrome of his leg due to a car accident trauma was treated with a fasciotomy to decompress intra-compartmental pressure and restore tissue perfusion, and admitted to an intensive care unit. Unfortunately, as the open fasciotomy wound was complicated by infection, he complained of hyperalgesia and severe pain during wound debridement. He was therefore given acetaminophen and high-dose intravenous patient-controlled analgesic fentanyl (35 μg/kg per day) to reduce the pain. Despite these efforts, the pain was poorly controlled and opioid-induced side effects such as respiratory depression were observed. An immersive virtual reality analgesic therapy aimed at distraction and relaxation was used and effectively alleviated the pain. Three sessions of virtual reality analgesic therapy over 2 days produced sustainable analgesic effects, which led to a 25-75% dose reduction in fentanyl administration and the concomitant alleviation of respiratory depression.

Conclusions: This case suggests the feasibility of virtual reality analgesic therapy for pain management of fasciotomy wound complications in acute compartment syndromes. Virtual reality represents a treatment option that would reduce analgesic consumption and eliminate opioid-induced respiratory depression to treat fasciotomy wound infection.
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http://dx.doi.org/10.1186/s13256-020-02370-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158090PMC
April 2020

Exosomes in Sepsis and Inflammatory Tissue Injury.

Curr Pharm Des 2019 ;25(42):4486-4495

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Mie 514- 8507, Japan.

Sepsis is the leading cause of death in medical intensive care units, and thus represents a serious healthcare problem worldwide. Sepsis is often caused by the aberrant host responses to infection, which induce dysregulated inflammation that leads to life-threatening multiple organ failures. Mediators such as proinflammatory cytokines that drive the sepsis pathogenesis have been extensively studied. Exosomes, biological lipid bilayer nanoparticles secreted via the endosomal pathway of cells, have recently emerged as important cargos that carry multiple mediators critical for the pathogenesis of sepsis-associated organ dysfunctions. Here we will review current knowledge on the exosomes in sepsis and relevant inflammatory tissue injuries.
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http://dx.doi.org/10.2174/1381612825666191116125525DOI Listing
June 2020