Publications by authors named "Naoki Kaneko"

100 Publications

Incidence and risk factor of vocal cord paralysis following slide tracheoplasty for congenital tracheal stenosis: a retrospective observational study.

Cardiol Young 2021 Jul 12:1-5. Epub 2021 Jul 12.

Department of Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan.

Background: Slide tracheoplasty for congenital tracheal stenosis (CTS) has been shown to improve post-operative outcomes, but the incidence and risk factors of vocal cord paralysis (VCP) following slide tracheoplasty remain unclear. This study aimed to review our experience of slide tracheoplasty for CTS with a focus on post-operative VCP.

Methods: Twenty-eight patients, who underwent tracheal reconstruction with or without cardiovascular repair at Kobe Children's Hospital between June, 2016 and March, 2020 were enrolled in this retrospective observational study. They were divided into two groups based on the presence of a pulmonary artery sling (PA sling). Perioperative variables were compared between the two groups.

Results: Twenty-one of the 28 patients underwent concomitant repair for associated cardiovascular anomalies, including 15 patients with PA sling. The overall incidence of VCP following slide tracheoplasty was 28.6%. The incidences of VCP were 46.7% in patients with CTS and PA sling, which were 14.3% in CTS patients without cardiovascular anomalies. The only risk factor associated with VCP following slide tracheoplasty was a concomitant repair for PA sling. Post-operatively, the duration of nasogastric tube feeding in patients with VCP was significantly longer than that in patients without VCP.

Conclusions: The incidence of VCP following slide tracheoplasty for CTS was high, especially in concomitant repair cases for PA sling. Routine screening and evaluation of VCP soon after post-operative extubation is required for its appropriate management.
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http://dx.doi.org/10.1017/S1047951121002663DOI Listing
July 2021

Focused Ultrasound Ablation of an Arteriovenous Malformation Model.

Front Neurol 2021 3;12:671380. Epub 2021 Jun 3.

Department of Radiology, School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Brain AVMs are rare but serious vascular lesions that often pose a management dilemma between the risk of various treatment modalities and uncertain natural history during observation. We describe preliminary data on the use of focused ultrasound as a novel therapeutic strategy. In an AVM model, one session of ultrasound gradually reduced flow through the lesion without inducing rupture. Due to its non-invasive yet immediate ablative effects, focused ultrasound may allow safer treatment of AVMs. However, further studies are needed to clarify its efficacy and side effect profile.
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http://dx.doi.org/10.3389/fneur.2021.671380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209376PMC
June 2021

A new aspiration device equipped with a hydro-separator for acute ischemic stroke due to challenging soft and stiff clots.

Interv Neuroradiol 2021 May 5:15910199211015060. Epub 2021 May 5.

Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

Objective: Fragile soft clots and stiff clots remain challenging in the treatment of acute ischemic stroke. This study aims to investigate the impact of clot stiffness on the efficacy of thrombectomy devices and a new aspiration catheter with a hydro-separator.

Methods: The Neurostar aspiration catheter has a novel hydro-separator technology that macerates clots by a stream of saline inside the catheter. The Neurostar catheter and two commercially available devices, the SOFIA aspiration catheter and Solitaire stent retriever, were tested in this study. We evaluated the efficacy of each device on clots with various stiffness in a simple in vitro model. We also assessed single-pass recanalization performance in challenging situations with large erythrocyte-rich clots and fibrin-rich clots in a realistic vascular model.

Results: We observed an inverse association between the clot stiffness and recanalization rates. The aspiration catheter, SOFIA ingested soft clots but not moderately stiff clots. When removing soft clots with the stent retriever, fragmentation was observed, although relatively stiff clots were well-integrated and removed. The Neurostar ingested soft clots similar to the aspiration catheter, and also aspirated stiff clots by continuous suction with hydro-separator. In the experiments with challenging clots, the Neurostar led to significantly higher recanalization rates than the stent retriever and aspiration catheter.

Conclusions: The stiffness of the clots affected the efficacy of endovascular thrombectomy based on the type of device. The Neurostar catheter with hydro-separator resulted in better success rates than a commercially available aspiration catheter and stent retriever in this experimental model.
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http://dx.doi.org/10.1177/15910199211015060DOI Listing
May 2021

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

In Brief: In severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung.

Highlights: In severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients.

Summary: The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.
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http://dx.doi.org/10.1101/2021.03.23.21253885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010762PMC
March 2021

A case of infant intracranial hemorrhage using an infrared pupillometer.

Pediatr Int 2021 Apr 16;63(4):470-472. Epub 2021 Mar 16.

Pediatric Critical Care Medicine, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.

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http://dx.doi.org/10.1111/ped.14433DOI Listing
April 2021

Endothelial Shear Stress and Platelet FcγRIIa Expression in Intracranial Atherosclerotic Disease.

Front Neurol 2021 25;12:646309. Epub 2021 Feb 25.

Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, VT, United States.

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD.
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http://dx.doi.org/10.3389/fneur.2021.646309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947292PMC
February 2021

Treating life-threatening TAFRO syndrome with interleukin-1 inhibition.

Eur J Intern Med 2021 05 17;87:121-123. Epub 2021 Feb 17.

Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR); IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1016/j.ejim.2021.02.006DOI Listing
May 2021

Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2.

J Cereb Blood Flow Metab 2021 06 2;41(6):1179-1192. Epub 2021 Feb 2.

Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/ATR/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.
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http://dx.doi.org/10.1177/0271678X20985666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142132PMC
June 2021

Mer tyrosine kinase (MerTK) as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.

Rheumatology (Oxford) 2021 Jan 29. Epub 2021 Jan 29.

Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objectives: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand Protein S (ProS1) have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis.

Methods: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively.

Results: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren syndrome and interacted with apoptotic cells and ProS1 expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-β and their numbers declined following rituximab induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD.

Conclusions: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.
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http://dx.doi.org/10.1093/rheumatology/keab096DOI Listing
January 2021

[Future of Cerebral Aneurysm Treatment].

No Shinkei Geka 2021 Jan;49(1):164-169

Ronald Reagan UCLA Medical Center.

There has been an increasing role in the low invasive endovascular treatment of intracranial aneurysms. In addition to the detachable coils, the development of intracranial stents that are capable of repairing the parent artery itself has induced a significant treatment paradigm shift from open surgical to endovascular intervention. Recent evidence suggests that chronic inflammation plays a critical role in the process of intracranial aneurysm formation and rupture. It is, therefore, a natural evolution to seek drug treatments for intracranial aneurysms for growth or rupture prevention rather than any mechanical intervention. The authors review the current preclinical efforts on aneurysm drug treatments and prospective. Also covered is an emerging technology such as robotic endovascular treatment. The robotic system is capable of performing a subset of endovascular procedures such as stent-assisted aneurysm coiling. Although a lot of work needs to be done, remote health care is no longer science fiction.
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http://dx.doi.org/10.11477/mf.1436204372DOI Listing
January 2021

Role of Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke with Large Vessel Occlusion.

World Neurosurg 2021 04 11;148:e321-e325. Epub 2021 Jan 11.

Division of Interventional Neuroradiology, University of California, Los Angeles, Los Angeles, California, USA.

Objective: The goal of the present study was to determine the safety and efficacy of intravenous tissue plasminogen activator (IVT) in patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing mechanical thrombectomy (MT).

Methods: We performed a retrospective analysis of prospectively collected data gathered during a 3-year period for all our patients with AIS and LVO. We analyzed the stroke outcomes and complications between patients who had received a combination of IVT and MT and those who had undergone MT only. Standardized selection criteria, including the uniform use of perfusion imaging, were used for selection for MT, irrespective of IVT administration.

Results: Of the patients who had received IVT, 10% had had successful reperfusion found at initial angiography and did not require MT. A door-to-puncture time within 1 hour of presentation was achieved in 19% of both groups. IVT+MT was not associated with an increased incidence of intracranial hemorrhage (IVT+MT, 47.1%; MT, 49%). Of the 73 patients in IVT+MT group, 8 had developed access-site hematomas compared with 9 of the 95 patients in the MT group (28.6% vs. 26.5%; P = 0.85). The IVT+MT group had a lower proportion of patients with a modified Rankin scale score of 5-6 at 90 days compared with the MT group (36% vs. 56%; P = 0.024). Both groups showed statistically similar proportions of patients with a Thrombolysis in Cerebral Infarction scale score of ≥2c (IVT+MT, 50%; MT, 43%; P = 0.58). The IVT+MT group had a greater proportion of patients with Thrombolysis in Cerebral Infarction scale score of 2c (IVT+MT, 29.6%; MT, 16.8%; P = 0.068).

Conclusions: Administration of IVT before MT to patients with AIS with LVO resulted in reperfusion before MT in 10% of patients, reduced the incidence of mortality and severe disability at 90 days, did not affect the door-to-puncture time, and was associated with a similar incidence of systemic and intracranial hemorrhage compared with MT only.
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http://dx.doi.org/10.1016/j.wneu.2020.12.142DOI Listing
April 2021

CD4CTLs in Fibrosing Mediastinitis Linked to .

J Immunol 2021 02 16;206(3):524-530. Epub 2020 Dec 16.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;

Although fibrotic disorders are frequently assumed to be linked to T cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4CTLs. In both these diseases T cell accumulation was found to be sparse. Fibrosing mediastinitis linked to infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by Ags. T cells are relatively sparse at lesional sites. These studies support a general role for CD4CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.
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http://dx.doi.org/10.4049/jimmunol.2000433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978153PMC
February 2021

Flow-Mediated Susceptibility and Molecular Response of Cerebral Endothelia to SARS-CoV-2 Infection.

Stroke 2021 01 9;52(1):260-270. Epub 2020 Nov 9.

Department of Neurology, David Geffen School of Medicine (Y.K., J.A., D.S.L., J.D.H.), University of California, Los Angeles.

Background And Purpose: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with an increased rate of cerebrovascular events including ischemic stroke and intracerebral hemorrhage. The mechanisms underlying cerebral endothelial susceptibility and response to SARS-CoV-2 are unknown yet critical to understanding the association of SARS-CoV-2 infection with cerebrovascular events.

Methods: Endothelial cells were isolated from human brain and analyzed by RNA sequencing. Human umbilical vein and human brain microvascular cells were used in both monolayer culture and endothelialized within a 3-dimensional printed vascular model of the middle cerebral artery. Gene expression levels were measured by quantitative polymerase chain reaction and direct RNA hybridization. Recombinant SARS-CoV-2 S protein and S protein-containing liposomes were used to measure endothelial binding by immunocytochemistry.

Results: (angiotensin-converting enzyme-2) mRNA levels were low in human brain and monolayer endothelial cell culture. Within the 3-dimensional printed vascular model, gene expression and protein levels were progressively increased by vessel size and flow rates. SARS-CoV-2 S protein-containing liposomes were detected in human umbilical vein endothelial cells and human brain microvascular endothelial cells in 3-dimensional middle cerebral artery models but not in monolayer culture consistent with flow dependency of ACE2 expression. Binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells including upregulation of complement component C3.

Conclusions: Brain endothelial cells are susceptible to direct SARS-CoV-2 infection through flow-dependent expression of ACE2. Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events.
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http://dx.doi.org/10.1161/STROKEAHA.120.032764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769899PMC
January 2021

Plasma Amyloid-β Biomarker Associated with Cognitive Decline in Preclinical Alzheimer's Disease.

J Alzheimers Dis 2020 ;77(3):1057-1065

Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

Background: Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear.

Objective: We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts.

Methods: Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry.

Results: Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures.

Conclusion: Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals.
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http://dx.doi.org/10.3233/JAD-200475DOI Listing
January 2020

B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma.

Oncoimmunology 2020 07 16;9(1):1794359. Epub 2020 Jul 16.

Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19 B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.
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http://dx.doi.org/10.1080/2162402X.2020.1794359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458626PMC
July 2020

Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19.

Cell 2020 10 19;183(1):143-157.e13. Epub 2020 Aug 19.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6 germinal center B cells but preservation of AID B cells. Absence of germinal centers correlated with an early specific block in Bcl-6 T cell differentiation together with an increase in T-bet T cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6 T cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
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http://dx.doi.org/10.1016/j.cell.2020.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437499PMC
October 2020

Catalogue of the type material of Scarabaeoidea (Coleoptera) deposited in the Research Institute of Evolutionary Biology, Tokyo, Japan.

Zookeys 2020 11;958:35-89. Epub 2020 Aug 11.

School of Science and Engineering, Meisei University, 2-1-1 Hodokubo, Hino, Tokyo 191-8506, Japan Meisei University Tokyo Japan.

A detailed catalogue of the type material of the Scarabaeoidea housed in the Research Institute of Evolutionary Biology, Tokyo, Japan is listed. The catalogue includes the data of the type material of four families and 111 species.
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http://dx.doi.org/10.3897/zookeys.958.52799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434809PMC
August 2020

Endovascular Approaches to the Cavernous Sinus in the Setting of Dural Arteriovenous Fistula.

Brain Sci 2020 Aug 14;10(8). Epub 2020 Aug 14.

Division of Interventional Neuroradiology, Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

Dural arteriovenous fistulas involving the cavernous sinus can lead to orbital pain, vision loss and, in the setting of associated cortical venous reflux, intracranial hemorrhage. The treatment of dural arteriovenous fistulas has primarily become the role of the endovascular surgeon. The venous anatomy surrounding the cavernous sinus and venous sinus thrombosis that is often associated with these fistulas contributes to the complexity of these interventions. The current report gives a detailed description of the alternate endovascular routes to the cavernous sinus based on a single center's experience as well as a literature review supporting each approach. A comprehensive understanding of the anatomy and approaches to the cavernous sinus available to the endovascular surgeon is vital to the successful treatment of this condition.
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http://dx.doi.org/10.3390/brainsci10080554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464669PMC
August 2020

Targeted Radiation Therapy Can Treat Myxomatous Cerebral Aneurysms.

World Neurosurg 2020 11 8;143:332-335. Epub 2020 Aug 8.

Department of Radiological Sciences, Division of Interventional Neuroradiology, University of California Los Angeles, Los Angeles, California, USA.

Background: Neoplastic cerebral aneurysms are rare presentations of cardiac myxomas. The natural history of such aneurysms is not well understood, and the optimal treatment strategy remains unclear. Clipping and coiling are effective, although can carry significant morbidity. Chemotherapy and radiation can theoretically be effective, although their clinical efficacy remains to be proven.

Case Description: Here we describe a patient with cardiac myxoma presenting with multiple progressively fusiform aneurysms. These aneurysms were noted to be growing during conservative monitoring given the eloquent location. Subsequently, the patient underwent multiple sessions of targeted radiation therapy, which lead to obliteration, shrinkage, or halting in growth of these aneurysms.

Conclusions: Low-dose targeted radiation therapy can be safe and effective in treatment of neoplastic myxomatous aneurysms.
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http://dx.doi.org/10.1016/j.wneu.2020.08.022DOI Listing
November 2020

The Loss of Bcl-6 Expressing T Follicular Helper Cells and the Absence of Germinal Centers in COVID-19.

SSRN 2020 Jul 16:3652322. Epub 2020 Jul 16.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.

Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+TFH cell differentiation together with an increase in T-bet+TH1 cells and aberrant extra-follicular TNF-a accumulation.  Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult. Funding: This work was supported by NIH U19 AI110495 to SP, NIH R01 AI146779 to AGS, NIH R01AI137057 and DP2DA042422 to DL, BMH was supported by NIGMS T32 GM007753, TMC was supported by T32 AI007245. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged. Conflict of Interest: None. Ethical Approval: This study was performed with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women's Hospital.
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http://dx.doi.org/10.2139/ssrn.3652322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385482PMC
July 2020

Mercury concentrations in the tissues of blue shark (Prionace glauca) from Sagami Bay and cephalopods from East China Sea.

Environ Pollut 2020 Nov 9;266(Pt 1):115192. Epub 2020 Jul 9.

Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, 4-5-7 Konan, Minato-ku, Tokyo, 108-8277, Japan. Electronic address:

The toxicity of mercury (Hg), is generally known, and around 90% of Hg exist as methylmercury (CHHg) in marine organism. Mercury concentrates in sharks and whales, which are at the top of the food chain as predators to cephalopods. The concentrations of Hg in liver and muscle of blue shark, caught in Sagami Bay, and in digestive gland and mantles of Todarodes pacificus, Sepia madokai, and Uroteuthis edulis caught in East China Sea were measured and analyzed. The Hg concentrations in the sharks, squids, and cuttlefishes determined in this study were almost same as those in the other sea regions. In addition, the Hg concentration in the blue shark was higher in the muscle than in the liver. In S. madokai and U. edulis, Hg accumulated in the digestive gland but not in the mantle. Although the Hg concentration in the digestive gland of T. pacificus is lower than those of S. madkai and U edulis, Hg concentration in the mantle is critically higher. More than 90% of Hg is present as CHHg in muscle of blue shark and mantle of T. pacificus. This feature is explained due to amino acids with the thiol groups and chain genes in the muscle of blue shark as well as in the mantle of T. pacificus. Myosin in the mantle of T. pacificus and blue shark enhances the stability of CHHg. The amount of Hg in the digestive gland of T. pacificus could be too large to store; thus, Hg is released to the mantle, whereas the nutrients in the digestive gland of T. pacificus are supplied to other tissues. It is considered that the muscle fiber of T. pacificus is strong; therefore, large amounts of myosin levels may be present in T. pacificus than in S. madokai and U. edulis.
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http://dx.doi.org/10.1016/j.envpol.2020.115192DOI Listing
November 2020

In Vitro Modeling of Human Brain Arteriovenous Malformation for Endovascular Simulation and Flow Analysis.

World Neurosurg 2020 09 18;141:e873-e879. Epub 2020 Jun 18.

Department of Radiological Sciences, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.

Background: Current in vitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed in vitro AVM model for embolic material testing, preclinical training, and flow analysis.

Methods: Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI.

Results: The manufacture of 3D in vitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the in vitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis.

Conclusions: An in vitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials.
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http://dx.doi.org/10.1016/j.wneu.2020.06.084DOI Listing
September 2020

CD4 and CD8 cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG-related disease.

J Allergy Clin Immunol 2021 01 30;147(1):368-382. Epub 2020 May 30.

Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass. Electronic address:

Background: IgG-related disease (IgG-RD) is an immune-mediated fibrotic disorder that has been linked to CD4 cytotoxic T lymphocytes (CD4CTLs). The effector phenotype of CD4CTLs and the relevance of both CD8 cytotoxic T lymphocytes (CD8CTLs) and apoptotic cell death remain undefined in IgG-RD.

Objective: We sought to define CD4CTL heterogeneity, characterize the CD8CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG-RD.

Methods: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data.

Results: We establish that among circulating CD4CTLs in IgG-RD, CD27CD28CD57 cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8 T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.

Conclusions: CD4CTLs and CD8CTLs may induce apoptotic cell death in tissues of patients with IgG-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.
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http://dx.doi.org/10.1016/j.jaci.2020.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704943PMC
January 2021

Increased Rate of Successful First Passage Recanalization During Mechanical Thrombectomy for M2 Occlusion.

World Neurosurg 2020 07 1;139:e792-e799. Epub 2020 May 1.

Department of Neurosurgery, University of California, Los Angeles, California, USA.

Background: Mechanical thrombectomy (MT) is the standard of care for the treatment of acute ischemic stroke (AIS) caused by anterior circulation large-vessel occlusion. However, the true safety and efficacy of MT in medium-size vessel occlusions such as the M2 segment of the middle cerebral artery have yet to be completely defined. In this study, we analyze the safety and efficacy of MT in M2 occlusions compared with M1 occlusions.

Methods: A retrospective analysis was performed of patients with AIS secondary to M1 and M2 occlusions between 2011 and 2018. The inclusion criteria were 1) AIS secondary to M1 or M2 occlusion, 2) MT performed by stentrieval technique alone, aspiration technique, or combined stentrieval-aspiration techniques. Basic patient characteristics, number of passages, first passage recanalization success (≥TICI [Thrombolysis in Cerebral Ischemia] grade 2b), total recanalization success, hemorrhagic complications (including intracerebral hemorrhage [ICH] and subarachnoid hemorrhage), and clinical outcomes were compared between both groups.

Results: Two hundred and sixty patients met the inclusion criteria; 171 patients had M1 occlusion versus 89 with M2 occlusion. First passage recanalization success rate was significantly higher in the M2 group (55.1% vs. 39.2%; P = 0.015). Total recanalization success rate was higher in the M2 group but did not reach significance (83% vs. 75%; P = 0.128). Subarachnoid hemorrhage rate was significantly higher in the M2 group (25% vs. 12%; P = 0.010) but there was no difference for ICH complications (14.6% vs. 16.4%; P = 0.711).

Conclusions: MT for M2 occlusions has similar overall efficacy to that for M1 occlusions, but with higher first-pass successful recanalization rates. MT for M2 occlusions has a higher risk of associated subarachnoid hemorrhage.
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http://dx.doi.org/10.1016/j.wneu.2020.04.159DOI Listing
July 2020

Development of Human Hair Reference Material Supporting the Biomonitoring of Methylmercury.

Anal Sci 2020 May 6;36(5):561-567. Epub 2020 Mar 6.

International Mercury Laboratory Inc.

A certified reference material, NIMD-01, was developed for the analysis of mercury speciation in human hair. We collected the hair of Vietnamese males from a barbershop in Hanoi in 2016 and prepared 1200 bottles containing 3 g of sieved and blended hair powder. The certified value was given on a dry-mass basis, with the moisture content obtained by drying at 85°C for 4 h. Certified values with the expanded uncertainties (coverage factor, k = 2) were as follows: methylmercury, 0.634 ± 0.071 mg kg as mercury; total mercury, 0.794 ± 0.050 mg kg; copper, 12.8 ± 1.4 mg kg; zinc, 234 ± 29 mg kg; selenium, 1.52 ± 0.29 mg kg. An indicative arsenic concentration of 0.17 ± 0.03 mg kg was measured. Extended uncertainties were estimated by sample homogeneity, long- and short-term stabilities, and a characterization from measurements made by collaborating laboratories.
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http://dx.doi.org/10.2116/analsci.19SBP07DOI Listing
May 2020

Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis.

J Clin Invest 2020 05;130(5):2451-2464

Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.
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http://dx.doi.org/10.1172/JCI131700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190971PMC
May 2020

Naquotinib exerts antitumor activity in activated B-cell-like diffuse large B-cell lymphoma.

Leuk Res 2020 01 10;88:106286. Epub 2019 Dec 10.

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.

Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (NHL), is categorized into two major subtypes, activated B-cell-like (ABC) and germinal center B-cell-like (GCB). The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy. The B-cell receptor (BCR) pathway is activated in ABC DLBCL, suggesting that inhibition of this pathway could provide an alternative strategy for treatment. Naquotinib is an irreversible tyrosine kinase inhibitor (TKI) originally designed to target the epidermal growth factor receptor (EGFR). As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib. Naquotinib inhibited BTK kinase activity with similar potency to that for EGFR activating mutations. In vivo, naquotinib induced tumor regression and suppressed tumor recurrence in TMD8 and OCI-Ly10, ABC DLBCL cell line xenograft models, at a lower dose than the clinically relevant dose. Compared to other BTK inhibitors, naquotinib showed faster onset and comparable inhibition of BTK following incubation with cell lines for 3 and 20 h. In addition, naquotinib showed longer continuous inhibition of BTK following removal of the compound, lasting for at least 26 h after removal. Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients.
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http://dx.doi.org/10.1016/j.leukres.2019.106286DOI Listing
January 2020

Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura disease: A case report.

Medicine (Baltimore) 2019 Dec;98(50):e18300

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences.

Rationale: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD.

Patient Concerns: A 56-year-old Japanese man who exhibited painless swelling in the left parotid region.

Diagnoses: Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels.

Interventions: The patient underwent corticosteroid therapy and had been followed for 2 years.

Outcomes: We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches.

Lessons: The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.
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http://dx.doi.org/10.1097/MD.0000000000018300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922356PMC
December 2019

Immune mechanisms of fibrosis and inflammation in IgG4-related disease.

Curr Opin Rheumatol 2020 03;32(2):146-151

Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge.

Purpose Of Review: To summarize recent advances in the understanding of the pathogenesis of IgG4-related disease.

Recent Findings: Limited data exist to explain genetic susceptibility to IgG4-related disease and the underlying triggers for this disease have not yet been identified. Cytotoxic CD4 T cells and activated B cells infiltrate affected organs and express proinflammatory and profibrotic molecules. Antigen presented by activated B cells likely reactivates cytotoxic CD4 T cells in disease tissues and these T cells in turn induce the targeted apoptotic death of host cells in certain organs - which presumably present the same antigenic peptide on human leukocyte antigen class II molecules of relevance that was also presented on B cells during reactivation. A subsequent exaggerated tissue remodeling process is orchestrated by cytokines, chemokines, and enzymes secreted by both activated B cells and CD4CTLs. These molecules induce an overexuberant repair process resulting in fibrosis and loss of target organ function.

Summary: In IgG4-related disease, presumably self-reactive cytotoxic CD4 T cells infiltrate tissues, are reactivated by T cells and induce apoptotic death. Molecules secreted by activated B cells and by CD4CTLs drive an exaggerated wound healing response resulting in fibrosis and compromised tissue function.
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http://dx.doi.org/10.1097/BOR.0000000000000686DOI Listing
March 2020

CD206 tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production.

Sci Rep 2019 10 10;9(1):14611. Epub 2019 Oct 10.

Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.

Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163 cells were detected diffusely all over the tumor and connective tissue area, while CD204 and CD206 cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206 TAMs strongly produced EGF compared with CD163 and CD204 TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206 TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206 TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206 TAMs might play a critical role in the proliferation of OSCC via EGF production.
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http://dx.doi.org/10.1038/s41598-019-51149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787225PMC
October 2019