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1.
Biomed Pharmacother ; 147: 112614, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1682939

ABSTRACT

Post-Covid pulmonary fibrosis is evident following severe COVID-19. There is an urgent need to identify the cellular and pathophysiological characteristics of chronic lung squeals of Covid-19 for the development of future preventive and/or therapeutic interventions. Tissue-resident memory T (TRM) cells can mediate local immune protection against infections and cancer. Less beneficially, lung TRM cells cause chronic airway inflammation and fibrosis by stimulating pathologic inflammation. The effects of Janus kinase (JAK), an inducer pathway of cytokine storm, inhibition on acute Covid-19 cases have been previously evaluated. Here, we propose that Tofacitinib by targeting the CD8+ TRM cells could be a potential candidate for the treatment of chronic lung diseases induced by acute SARS-CoV-2 infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Janus Kinase Inhibitors/therapeutic use , Lung Injury/drug therapy , Piperidines/therapeutic use , Pyrimidines/therapeutic use , T-Lymphocyte Subsets/immunology , COVID-19/complications , COVID-19/immunology , Humans , Immunologic Memory/immunology , Lung/immunology , Lung Injury/etiology , Lung Injury/immunology , SARS-CoV-2 , T-Lymphocytes/immunology
2.
Eur Rev Med Pharmacol Sci ; 26(1): 270-277, 2022 01.
Article in English | MEDLINE | ID: covidwho-1631285

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare new syndrome occurring after the ChAdOx1 nCoV-19 vaccine immunization. Patients with VITT are characterized by a variable clinical presentation, likewise also the outcome of these patients is very variable. Here we report the lung ultrastructural findings in the course of VITT of a 58-year-old male patient. Alveoli were mainly dilated, irregular in shape, and occupied by a reticular network of fibrin, while interalveolar septa appeared thickened. The proliferation of small capillaries gave rise to plexiform structures and pulmonary capillary hemangiomatosis-like features. Near the alveoli occupied by a dense fibrin network, the medium-sized arteries showed a modified wall and an intraluminal thrombus. This scenario looks quite similar to that found during COVID-19, where the lungs suffer from the attack of the antigen-antibodies complexes and the virus respectively. In both diseases, the final outcome is a severe inflammation, activation of the haemostatic system and fibrinolysis.


Subject(s)
/adverse effects , Lung Injury/etiology , Lung Injury/pathology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Vaccination/adverse effects , COVID-19/prevention & control , Fibrin , Humans , Lung Injury/diagnostic imaging , Lung Injury/immunology , Male , Microscopy, Electron, Scanning , Middle Aged , Parenchymal Tissue/pathology , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/immunology
3.
Cell Rep ; 37(1): 109798, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1415262

ABSTRACT

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Complement System Proteins/immunology , Eosinophils/immunology , Inflammation/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antigen-Antibody Complex/metabolism , COVID-19/metabolism , COVID-19/virology , Complement Activation , Complement Membrane Attack Complex/metabolism , Eosinophils/virology , Female , Humans , Inflammation/metabolism , Inflammation/virology , Lung Injury/immunology , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged , Pneumonia, Viral/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Severity of Illness Index , Signal Transduction , Th2 Cells/immunology , Viral Load , Young Adult
4.
Signal Transduct Target Ther ; 6(1): 339, 2021 09 08.
Article in English | MEDLINE | ID: covidwho-1402052

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.


Subject(s)
COVID-19/therapy , Lung Injury/therapy , Lung/immunology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , Humans , Lung/pathology , Lung/virology , Lung Injury/immunology , Lung Injury/virology , Mesenchymal Stem Cells/pathology
5.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1166352

ABSTRACT

Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.


Subject(s)
DNA Viruses , Lung Injury , RNA Viruses , Respiratory Tract Infections , Virus Diseases , Adult , Aged , Antiviral Agents/therapeutic use , COVID-19 , Child , Child, Preschool , Female , Humans , Immunologic Factors/therapeutic use , Infant , Infant, Newborn , Interferons/therapeutic use , Lung/immunology , Lung/virology , Lung Injury/diagnosis , Lung Injury/drug therapy , Lung Injury/immunology , Lung Injury/virology , Male , Middle Aged , Pandemics , SARS-CoV-2
6.
Clin Immunol ; 226: 108716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1152310

ABSTRACT

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Complement Pathway, Alternative/immunology , Lung Injury/immunology , Aged , Aged, 80 and over , COVID-19/complications , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Immunohistochemistry , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung Injury/complications , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged
7.
Int J Mol Sci ; 22(2)2021 01 19.
Article in English | MEDLINE | ID: covidwho-1038653

ABSTRACT

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define any possible specific pattern. Histopathologic alterations are principally found within lungs and blood vessels, and these abnormalities also seem to have the highest clinical impact. Nevertheless, many of the morphological data collected so far are non-specific, fickle, and possibly associated with other co-existing factors. The aim of this minireview is to describe the main histopathological features related to COVID-19 and the mechanism known as "cytokine storm".


Subject(s)
COVID-19/immunology , COVID-19/pathology , Lung Injury/immunology , Lung Injury/virology , Angiotensin-Converting Enzyme 2/metabolism , Autopsy , COVID-19/diagnostic imaging , Cytokine Release Syndrome , Cytokines/blood , Humans , Lung Injury/diagnostic imaging , Lung Injury/pathology , SARS-CoV-2/isolation & purification
8.
Curr Mol Med ; 21(6): 441-456, 2021.
Article in English | MEDLINE | ID: covidwho-934391

ABSTRACT

Severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) is an extremely pathogenic virus belonging to the family of Coronaviridae. First identified in Wuhan, China in December 2019 after an epidemiological investigation of an emerging cluster of pneumonia of unknown etiology, SARS-CoV-2 was declared the cause of a pandemic on March 11 by the World Health Organization (WHO), pointing to the over 118000 cases of Coronavirus disease 2019 (COVID-19) in over 110 countries. Despite the promising results of drug repositioning studies in the treatment of COVID-19, the evidence of their safety and efficacy remains inconclusive. Cell based therapy has been proven safe and possibly effective in treating multiple lung injuries and diseases, but its potential use in the treatment of COVID-19 has not been yet elucidated. Our aim in this review is to provide an overview of the immunomodulatory effect and the regenerative capacity of stem cells and their secretome in the treatment of many diseases including lung injuries. Those findings may contribute to a better understanding of the potential of stem cell therapy in SARS-CoV-2 infection and its potential use in order to find a solution for this healthcare crisis.


Subject(s)
COVID-19/drug therapy , COVID-19/etiology , Cell- and Tissue-Based Therapy/methods , Stem Cells/physiology , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/therapy , Host-Pathogen Interactions , Humans , Immunomodulation , Lung Injury/immunology , Lung Injury/therapy , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Stem Cell Transplantation
9.
Med Sci Monit ; 26: e928996, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-921300

ABSTRACT

Since the initial reports of coronavirus disease 2019 (COVID-19) in China in late 2019, infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have spread rapidly, resulting in a global pandemic that has caused millions of deaths. Initially, the large number of infected people required the direction of global healthcare resources to provide supportive care for the acutely ill population in an attempt to reduce mortality. While clinical trials for safe and effective antiviral agents are ongoing, and vaccine development programs are being accelerated, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized and concerning. Although the upper and lower respiratory tracts are the main sites of entry of SARS-CoV-2 into the body, resulting in COVID-19 pneumonia as the most common presentation, acute lung damage may be followed by pulmonary fibrosis and chronic impairment of lung function, with impaired quality of life. Also, increasing reports have shown that SARS-CoV-2 infection involves the central nervous system (CNS) and the peripheral nervous system (PNS) and directly or indirectly damages neurons, leading to long-term neurological sequelae. This review aims to provide an update on the mechanisms involved in the development of the long-term sequelae of SARS-CoV-2 infection in the 3 main areas of lung injury, neuronal injury, and neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis, and highlights the need for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide a rationale for the prevention, diagnosis, and management of these potential long-term sequelae.


Subject(s)
COVID-19/complications , Lung Injury/epidemiology , Neurodegenerative Diseases/epidemiology , Pulmonary Fibrosis/epidemiology , SARS-CoV-2/pathogenicity , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Disease Progression , Humans , Lung Injury/diagnosis , Lung Injury/immunology , Lung Injury/prevention & control , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/prevention & control , Pandemics , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/prevention & control , Quality of Life , SARS-CoV-2/immunology , Time Factors
10.
Front Immunol ; 11: 2063, 2020.
Article in English | MEDLINE | ID: covidwho-868947

ABSTRACT

Background: Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19. Methods: A retrospective analysis was performed on 55 COVID-19 patients classified as mild (n = 22), moderate (n = 25), and severe (n = 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF. Results: Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis. Conclusion: Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/immunology , Extracellular Traps/genetics , Neutrophil Activation/genetics , Neutrophils/immunology , Pneumonia, Viral/immunology , Adult , Aged , Bayes Theorem , COVID-19 , Coronavirus Infections/virology , Female , Humans , Leukocyte Count , Lung Injury/immunology , Lung Injury/pathology , Male , Middle Aged , Neutrophil Infiltration/immunology , Pandemics , Pneumonia, Viral/virology , Protein Interaction Maps/immunology , RNA, Viral/genetics , Retrospective Studies , SARS-CoV-2 , Transcriptome
11.
Cell Transplant ; 29: 963689720952089, 2020.
Article in English | MEDLINE | ID: covidwho-729480

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical trials have treated COVID-19 patients with DPSCs, this therapy has not been approved. Here, we review the potential use of DPSCs and their significance in the development of a therapy for COVID-19.


Subject(s)
Coronavirus Infections/therapy , Dental Pulp/cytology , Immunomodulation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , Pneumonia, Viral/therapy , Betacoronavirus/immunology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/immunology , Cytokines/immunology , Dental Pulp/immunology , Humans , Immunotherapy/methods , Inflammation/immunology , Inflammation/therapy , Lung/immunology , Lung/physiology , Lung Injury/immunology , Lung Injury/therapy , Mesenchymal Stem Cells/cytology , Pandemics , Pneumonia, Viral/immunology , Regeneration , SARS-CoV-2
13.
Stem Cells Transl Med ; 9(10): 1163-1173, 2020 10.
Article in English | MEDLINE | ID: covidwho-623777

ABSTRACT

The broad immunomodulatory properties of human mesenchymal stem cells (MSCs) have allowed for wide application in regenerative medicine as well as immune/inflammatory diseases, including unmatched allogeneic use. The novel coronavirus disease COVID-19 has unleashed a pandemic in record time accompanied by an alarming mortality rate mainly due to pulmonary injury and acute respiratory distress syndrome. Because there are no effective preventive or curative therapies currently, MSC therapy (MSCT) has emerged as a possible candidate despite the lack of preclinical data of MSCs for COVID-19. Interestingly, MSCT preclinical data specifically on immune/inflammatory disorders of the lungs were among the earliest to be reported in 2003, with the first clinical use of MSCT for graft-vs-host disease reported in 2004. Since these first reports, preclinical data showing beneficial effects of MSC immunomodulation have accumulated substantially, and as a consequence, over a third of MSCT clinical trials now target immune/inflammatory diseases. There is much preclinical evidence for MSCT in noninfectious-including chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis-as well as infectious bacterial immune/inflammatory lung disorders, with data generally demonstrating therapeutic effects; however, for infectious viral pulmonary conditions, the preclinical evidence is more scarce with some inconsistent outcomes. In this article, we review the mechanistic evidence for clinical use of MSCs in pulmonary immune/inflammatory disorders, and survey the ongoing clinical trials-including for COVID-19-of MSCT for these diseases, with some perspectives and comment on MSCT for COVID-19.


Subject(s)
COVID-19/therapy , Inflammation/therapy , Lung Injury/therapy , Respiratory Distress Syndrome/therapy , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell- and Tissue-Based Therapy/methods , Humans , Inflammation/immunology , Inflammation/pathology , Inflammation/virology , Lung/immunology , Lung/pathology , Lung/virology , Lung Injury/immunology , Lung Injury/pathology , Lung Injury/virology , Mesenchymal Stem Cells/cytology , Pandemics , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology
14.
Cell Res ; 30(9): 794-809, 2020 09.
Article in English | MEDLINE | ID: covidwho-601806

ABSTRACT

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.


Subject(s)
Human Embryonic Stem Cells/immunology , Lung Injury/therapy , Lung/pathology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , Animals , Cells, Cultured , Female , Fibrosis , Haplorhini , Human Embryonic Stem Cells/cytology , Humans , Immunity , Immunomodulation , Lung/immunology , Lung Injury/immunology , Lung Injury/pathology , Male , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred C57BL
15.
Cardiorenal Med ; 10(5): 277-287, 2020.
Article in English | MEDLINE | ID: covidwho-619624

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.


Subject(s)
Coronavirus Infections/therapy , Cytokine Release Syndrome/therapy , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/therapy , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , CCR5 Receptor Antagonists/therapeutic use , COVID-19 , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Enzyme Inhibitors/therapeutic use , Extracorporeal Membrane Oxygenation , HIV Antibodies/therapeutic use , Hemoperfusion , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Immunomodulation , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Lung Injury/immunology , Lung Injury/therapy , Mesenchymal Stem Cell Transplantation , Multiple Organ Failure , Pandemics , Plasma Exchange , Plasmapheresis , Pneumonia, Viral/immunology , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome/immunology , SARS-CoV-2 , Tumor Necrosis Factor Inhibitors/therapeutic use
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