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Wang L, Xia Z, Singh A, Murarka B, Baumgarth N, Aucott JN, Searson PC. Extravasation of Borrelia burgdorferi Across the Blood-Brain Barrier is an Extremely Rare Event. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413199. [PMID: 40071764 PMCID: PMC12061299 DOI: 10.1002/advs.202413199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/28/2025] [Indexed: 05/10/2025]
Abstract
Lyme disease, the most widespread tick-borne disease in North America, is caused by the bacterium Borrelia burgdorferi (Bb). Approximately 10-15% of infections result in neuroborreliosis, common symptoms of which include headaches, facial palsy, and long-term cognitive impairment. Previous studies of Bb dissemination focus on assessing Bb transmigration at static time points rather than analyzing the complex dynamic process of extravasation. Furthermore, current in vitro models lack crucial physiological factors such as flow, demonstrating a need for more robust models for studying Bb dissemination to understand its dynamics and mechanisms. Here, a 3D tissue-engineered microvessel model is used and fluorescently-labeled Bb is perfused to model vascular dissemination in non-tissue-specific (iEC) and brain-specific (iBMEC) microvessels while acquiring time-lapse images in real time. In iECs, extravasation involves two steps: adhesion to the endothelium and transmigration into the extracellular matrix, which can be modulated through glycocalyx degradation or inflammation. In contrast, Bb extravasation in iBMECs is an extremely rare event regardless of glycocalyx degradation or inflammation. In addition, circulating Bb do not induce endothelial activation in iECs or iBMECs, but induces barrier dysfunction in iECs. These findings provide a further understanding of Bb vascular dissemination.
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Affiliation(s)
- Linus Wang
- Institute for NanobiotechnologyJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
- Department of Biomedical EngineeringJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
| | - Zikai Xia
- Department of Materials Science and EngineeringJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
| | - Anjan Singh
- Institute for NanobiotechnologyJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
- Department of Biomedical EngineeringJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
| | - Bhavna Murarka
- Molecular and Cellular BiologyJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
| | - Nicole Baumgarth
- Department of Molecular Microbiology and ImmunologyJohns Hopkins University615 N Wolfe StBaltimoreMD21205USA
| | - John N. Aucott
- Johns Hopkins Lyme Disease Research CenterJohns Hopkins University2360 Joppa RdTimoniumMD21093USA
| | - Peter C. Searson
- Institute for NanobiotechnologyJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
- Department of Biomedical EngineeringJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
- Department of Materials Science and EngineeringJohns Hopkins University3400 N Charles StBaltimoreMD21218USA
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Huang Y, Xue L, Dou L, Liu Z, Lu X, Tu Z, Chen H, Tu X, Rao J, Wang L, Peng X, Ju W, Wang S, Luo D. Dengue with liver involvement is associated with serum soluble thrombomodulin and P-selectin levels. Trans R Soc Trop Med Hyg 2025:traf034. [PMID: 40197747 DOI: 10.1093/trstmh/traf034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 12/31/2024] [Accepted: 03/14/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The pathogenesis of liver damage in dengue patients has not been clarified. In this study, we sought to identify the factors that are associated with dengue-induced liver damage and evaluate the associations of cytokines/chemokines, including platelets, neutrophils, activated endothelial cells and other inflammatory factors, with liver damage. METHODS We collected and analysed clinical data from 106 hospitalized dengue patients and evaluated the serum levels of platelet (soluble P-selectin [sP-selectin] and soluble CD40 ligand [sCD40L]), neutrophil (neutrophil elastase [NE] and neutrophil myeloperoxidase [MPO]) and endothelial cell (soluble thrombomodulin [sTM]) activation markers, as well as inflammatory mediators, including C-X-C motif chemokine ligand 2 (CXCL2), interleukin (IL)-2, IL-4, IL-6, IL-10, tumour necrosis factor-α and interferon-γ (which are associated with liver damage), in 32 patients. RESULTS In total, 106 dengue patients were included in this study. The patients were categorized into dengue with warning signs (DwWS), dengue without warning signs (DwoWS) and severe dengue (SD). Twenty-four patients (22%) had DwWS and 1 patient (1%) had SD. Compared with the DwoWS group, the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase levels in the DwWS/SD group were significantly greater (p<0.001, p<0.001 and p=0.001, respectively). A long time to onset (odds ratio [OR] 1.495 [95% confidence interval {CI} 1.063 to 2.101], p=0.021), thrombocytopenia (OR 4.166 [95% CI 1.11 to 15.629], p=0.034) and concomitant fatty liver (OR 6.326 [95% CI 1.57 to 25.493], p=0.009) were risk factors for dengue-related liver dysfunction. Compared with patients with normal liver enzyme levels, serum sP-selectin levels were significantly lower (p=0.012), sTM levels were higher (p=0.047), serum ALT and AST levels were positively correlated with sTM (r=0.411, p=0.02 and r=0.419, p=0.039; respectively) and AST levels were negatively correlated with sP-selectin levels (r=-0.441, p=0.011) in dengue patients. CONCLUSIONS Dengue fever with hepatic involvement is related to serum sTM and sP-selectin levels, thus suggesting that platelet and endothelial cell activation may be involved in the pathogenesis of liver damage and can be used as early predictors of dengue liver damage.
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Affiliation(s)
- Yanxia Huang
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Linxuan Xue
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, No. 461, Bayi Road, Nanchang 330006 Jiangxi, China
| | - Longjiao Dou
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Zhuoqi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, No. 461, Bayi Road, Nanchang 330006 Jiangxi, China
| | - Xiaohui Lu
- School of Clinical Medicine, Nanchang University, No. 461, Bayi Road, Nanchang 330006 Jiangxi, China
| | - Zhihui Tu
- School of Clinical Medicine, Nanchang University, No. 461, Bayi Road, Nanchang 330006 Jiangxi, China
| | - Hongyi Chen
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Xianglin Tu
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Jianfeng Rao
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Li Wang
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Xuping Peng
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Weihua Ju
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Shumei Wang
- First Department of Infectious Disease, Affiliated Infection Hospital of Nanchang University, No. 167, Hongdu Central Road, Nanchang 330002 Jiangxi, China
| | - Daya Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, No. 461, Bayi Road, Nanchang 330006 Jiangxi, China
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Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Kersten MJ, Zheng Y, Zhang T, Nater J, Shen R, Miao H, Kim JJ, Miklos DB. Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma. Transplant Cell Ther 2024; 30:1065-1079. [PMID: 39187161 DOI: 10.1016/j.jtct.2024.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/12/2024] [Accepted: 08/22/2024] [Indexed: 08/28/2024]
Abstract
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.
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Affiliation(s)
| | | | | | - Lazaros J Lekakis
- University of Miami Health System, Sylvester Comprehensive Cancer Center, Miami, Florida
| | | | - Ira Braunschweig
- Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | | | - Tanya Siddiqi
- City of Hope National Medical Center, Duarte, California
| | - Yi Lin
- Mayo Clinic, Rochester, Minnesota
| | | | - Marie José Kersten
- Amsterdam UMC, University of Amsterdam, Amsterdam, Cancer Center Amsterdam, Netherlands, on behalf of HOVON/LLPC
| | - Yan Zheng
- Kite, a Gilead Company, Santa Monica, California
| | - Teresa Zhang
- Kite, a Gilead Company, Santa Monica, California
| | - Jenny Nater
- Kite, a Gilead Company, Santa Monica, California
| | - Rhine Shen
- Kite, a Gilead Company, Santa Monica, California
| | - Harry Miao
- Kite, a Gilead Company, Santa Monica, California
| | - Jenny J Kim
- Kite, a Gilead Company, Santa Monica, California
| | - David B Miklos
- Stanford University School of Medicine, Stanford, California
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Ren G, Liu R, Mai H, Yin G, Ding F, Wang C, Chen S, Lan X. GAB1 attenuates lipopolysaccharide‑mediated endothelial dysfunction via regulation of SOCS3. Exp Ther Med 2024; 28:400. [PMID: 39171145 PMCID: PMC11336802 DOI: 10.3892/etm.2024.12689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 07/12/2024] [Indexed: 08/23/2024] Open
Abstract
Endothelial dysfunction is a crucial pathogenetic mechanism for sepsis. GRB2-associated binder 1 (GAB1) alleviates sepsis-induced multi-organ damage; however, to the best of our knowledge, its function in endothelial dysfunction in sepsis remains unclear. HUVECs were induced by lipopolysaccharide (LPS) to simulate endothelial cell injury under sepsis. Cell transfection was conducted to achieve GAB1 overexpression or suppressor of cytokine signaling 3 (SOCS3) knockdown. The expression levels of GAB1 and SOCS3 were detected by reverse transcription-quantitative PCR and western blotting. Cell viability, apoptosis and migration were assessed using Cell Counting Kit-8, TUNEL and wound healing assays, respectively. The production of cytokines and nitric oxide (NO) was detected using commercial kits. The interaction between GAB1 and SOCS3 was confirmed using a co-immunoprecipitation assay. GAB1 was downregulated in LPS-induced HUVECs. However, GAB1 overexpression significantly mitigated LPS-induced cell viability decrease and apoptosis in HUVECs, accompanied by upregulation of Bcl2 expression, and downregulation of Bax and cleaved caspase-3 expression. GAB1 also inhibited the production of pro-inflammatory cytokines and increased NO level, increased the levels of endothelial NO synthase (eNOS) and phosphorylated (p)-eNOS, and promoted migration in LPS-induced HUVECs. However, SOCS3 knockdown partially weakened the effects of GAB1 overexpression on cell viability, apoptosis, inflammation, p-eNOS, eNOS expression and NO levels in LPS-induced HUVECs. In addition, GAB1 and SOCS3 regulated Janus kinase 2 (JAK2)/STAT3 signaling in LPS-induced HUVECs. In conclusion, GAB1 exerted a protective effect against LPS-induced endothelial cell apoptosis, inflammation and dysfunction by modulating the SOCS3/JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Guangdong Ren
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Ran Liu
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Huiqiang Mai
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Gang Yin
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Fulai Ding
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Chunmei Wang
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Shuxin Chen
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Xianqi Lan
- Emergency Department, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
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Feng J, Liu L, Liu J, Wang J. Immunological alterations in the endothelial barrier: a new predictive and therapeutic paradigm for sepsis. Expert Rev Clin Immunol 2024; 20:1205-1217. [PMID: 38850066 DOI: 10.1080/1744666x.2024.2366301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
INTRODUCTION Despite the fact incidence and mortality vary widely among regions, sepsis remains a major cause of morbidity and cost worldwide. The importance of the endothelial barrier in sepsis and infectious diseases is increasingly recognized; however, the underlying pathophysiology of the endothelial barrier in sepsis remains poorly understood. AREAS COVERED Here we review the advances in basic and clinical research for relevant papers in PubMed database. We attempt to provide an updated overview of immunological alterations in endothelial dysfunction, discussing the central role of endothelial barrier involved in sepsis to provide new predictive and therapeutic paradigm for sepsis. EXPERT OPINION Given its physiological and immunological functions in infectious diseases, the endothelial barrier has been dramatically altered in sepsis, suggesting that endothelial dysfunction may play a critical role in the pathogenesis of sepsis. Although many reliable biomarkers have been investigated to monitor endothelial activation and injury in an attempt to find diagnostic and therapeutic tools, there are no specific therapies to treat sepsis due to its complex pathophysiology. Since sepsis is initiated by both hyperinflammation and immunoparalysis occurring simultaneously, a 'one-treatment-fits-all' strategy for sepsis-induced immune injury and immunoparalysis is bound to fail, and an individualized 'precision medicine' approach is required.
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Affiliation(s)
- Jun Feng
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lina Liu
- Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junya Liu
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junshuai Wang
- Department of Emergency Medicine, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ugalde MJ, Caballero A, Martín Fernández M, Tamayo E, de la Varga-Martínez O. [Value of the biomarker soluble tyrosine kinase 1 type fms (sFLT-1) in the diagnosis and prognosis of sepsis: a systematic review]. Med Clin (Barc) 2024; 163:224-231. [PMID: 38851948 DOI: 10.1016/j.medcli.2024.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 06/10/2024]
Abstract
INTRODUCTION The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022. MATERIALS AND METHODS A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry). RESULTS The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction. CONCLUSIONS It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.
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Affiliation(s)
| | - Alberto Caballero
- Department of Anatomy and Radiology, Health Sciences Faculty, GIR: Physical Exercise and Aging, Campus Universitario Los Pajaritos, University of Valladolid Soria, España
| | - Marta Martín Fernández
- Department of Cellular Biology, Genetics, Histology and Pharmacology. University of Valladolid, Valladolid, España; BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, España; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, España
| | - Eduardo Tamayo
- BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, España; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, España; Anestesia y Cuidados intensivos, Hospital Clínico Universitario de Valladolid, Valladolid, España
| | - Olga de la Varga-Martínez
- BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, España; Anestesiología y Reanimación, Hospital Universitario Infanta Leonor, Madrid, España
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Takei Y, Yamada M, Saito K, Kameyama Y, Aihara T, Iwasaki Y, Murakami T, Kaiho Y, Ohkoshi A, Konno D, Shiga T, Takahashi K, Ikumi S, Toyama H, Ejima Y, Yamauchi M. Endothelium-Derived Extracellular Vesicles Expressing Intercellular Adhesion Molecules Reflect Endothelial Permeability and Sepsis Severity. Anesth Analg 2024; 139:385-396. [PMID: 39008867 DOI: 10.1213/ane.0000000000006988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
BACKGROUND Currently, clinical indicators for evaluating endothelial permeability in sepsis are unavailable. Endothelium-derived extracellular vesicles (EDEVs) are emerging as biomarkers of endothelial injury. Platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial (VE)-cadherin are constitutively expressed endothelial intercellular adhesion molecules that regulate intercellular adhesion and permeability. Herein, we investigated the possible association between EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) and endothelial permeability and sepsis severity. METHODS Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor alpha (TNF-α) directly or after pretreatment with permeability-modifying reagents such as angiopoietin-1, prostacyclin, or vascular endothelial growth factor (VEGF) to alter TNF-α-induced endothelial hyperpermeability. Endothelial permeability was measured using the dextran assay or transendothelial electrical resistance. Additionally, a prospective cross-sectional observational study was conducted to analyze circulating EDEV levels in patients with sepsis. EDEVs were examined in HUVEC culture supernatants or patient plasma (nonsepsis, n = 30; sepsis, n = 30; septic shock, n = 42) using flow cytometry. The Wilcoxon rank-sum test was used for comparisons between 2 groups. Comparisons among 3 or more groups were performed using the Steel-Dwass test. Spearman's test was used for correlation analysis. Statistical significance was set at P < .05. RESULTS TNF-α stimulation of HUVECs significantly increased EDEV release and endothelial permeability. Pretreatment with angiopoietin-1 or prostacyclin suppressed the TNF-α-induced increase in endothelial permeability and inhibited the release of PECAM+ and VE-cadherin+ EDEVs. In contrast, pretreatment with VEGF increased TNF-α-induced endothelial permeability and the release of PECAM+ and VE-cadherin+ EDEVs. However, pretreatment with permeability-modifying reagents did not affect the release of EDEVs expressing inflammatory stimulus-inducible endothelial adhesion molecules such as E-selectin, intracellular adhesion molecule-1, or vascular cell adhesion molecule-1. The number of PECAM+ EDEVs on admission in the septic-shock group (232 [124, 590]/μL) was significantly higher (P = .043) than that in the sepsis group (138 [77,267]/μL), with an average treatment effect of 98/μL (95% confidence interval [CI], 2-270/μL), and the number of VE-cadherin+ EDEVs in the septic-shock group (173 [76,339]/μL) was also significantly higher (P = .004) than that in the sepsis group (81 [42,159]/μL), with an average treatment effect (ATE) of 79/μL (95% CI, 19-171/μL); these EDEV levels remained elevated until day 5. CONCLUSIONS EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) may reflect increased endothelial permeability and could be valuable diagnostic and prognostic markers for sepsis.
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Affiliation(s)
- Yusuke Takei
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Saito
- Department of Intensive Care of Medicine, Tohoku University Hospital, Sendai, Japan
| | | | - Takanori Aihara
- Department of Anesthesiology, Osaki Citizen Hospital, Sendai, Japan
| | - Yudai Iwasaki
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Murakami
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yu Kaiho
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Ohkoshi
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Daisuke Konno
- Department of Intensive Care of Medicine, Tohoku University Hospital, Sendai, Japan
| | - Takuya Shiga
- Department of Intensive Care of Medicine, Tohoku University Hospital, Sendai, Japan
| | - Kazuhiro Takahashi
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Saori Ikumi
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Toyama
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yutaka Ejima
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masanori Yamauchi
- From the Department of Anesthesiology and Perioperative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Zhang Q, Zhu X, Xiao Y. The critical role of endothelial cell in the toxicity associated with chimeric antigen receptor T cell therapy and intervention strategies. Ann Hematol 2024; 103:2197-2206. [PMID: 38329486 PMCID: PMC11224091 DOI: 10.1007/s00277-024-05640-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 01/21/2024] [Indexed: 02/09/2024]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown promising results in patients with hematological malignancies. However, many patients still have poor prognoses or even fatal outcomes due to the life-threatening toxicities associated with the therapy. Moreover, even after improving the known influencing factors (such as number or type of CAR-T infusion) related to CAR-T cell infusion, the results remain unsatisfactory. In recent years, it has been found that endothelial cells (ECs), which are key components of the organization, play a crucial role in various aspects of immune system activation and inflammatory response. The levels of typical markers of endothelial activation positively correlated with the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS), suggesting that ECs are important targets for intervention and toxicity prevention. This review focuses on the critical role of ECs in CRS and ICANS and the intervention strategies adopted.
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Affiliation(s)
- Qi Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Engel ER, Le Cras TD, Ricci KW. How we use angiopoietin-2 in the diagnosis and management of vascular anomalies. Pediatr Blood Cancer 2024; 71:e30921. [PMID: 38439088 DOI: 10.1002/pbc.30921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/30/2023] [Accepted: 01/31/2024] [Indexed: 03/06/2024]
Abstract
The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.
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Affiliation(s)
- Elissa R Engel
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Timothy D Le Cras
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Kiersten W Ricci
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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10
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Leng X, Yang H, Zhao L, Feng J, Jin K, Liao L, Zhang F. Dengue encephalopathy in an adult due to dengue virus type 1 infection. BMC Infect Dis 2024; 24:319. [PMID: 38491361 PMCID: PMC10943806 DOI: 10.1186/s12879-024-09198-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/06/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Dengue is an important public health problem, which caused by the dengue virus (DENV), a single-stranded RNA virus consisted of four serotypes. Central nervus system (CNS) impairment in dengue usually results from DENV-2 or DENV-3 infection, which lead to life-threatening outcomes. Furthermore, neurological complications due to DENV-1 was rare especially in adult patients. CASE PRESENTATION A 44-year-old man without comorbidities had lethargy after hyperpyrexia and a positive DENV NS1 antigen was detected for confirming the diagnosis of dengue on day 8 of onset. Then logagnosia, decreased muscle strength, delirium and irritability were occurred even radiographic examination were normal. He was treated with low-dose hormone, sedatives and gamma goblin with a short duration of 6 days. The cerebrospinal fluid (CSF) tests were persistent normal. However, presence of DENV-1 RNA was confirmed both in CSF and serum. Furthermore, the complete sequence of the DENV isolated from the patient's serum was performed (GenBank No.: MW261838). The cytokines as IL-6, IL-10 and sVCAM-1 were increased in critical phase of disease. Finally, the patient was discharged on day 24 of onset without any neurological sequelae. CONCLUSION Encephalopathy caused by a direct CNS invasion due to DENV-1 during viremia was described in an adult patient. Treatment with low-dose hormone and gamma goblin was helpful for admission.
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Affiliation(s)
- Xingyu Leng
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China
| | - Huiqin Yang
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China
| | - Lingzhai Zhao
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Clinical Laboratory, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P. R. China
| | - Jiamin Feng
- Guangzhou Medical Research Institute of Infectious Diseases, Institution of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China
| | - Kanghong Jin
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China
| | - Lu Liao
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China
| | - Fuchun Zhang
- Guangzhou Medical Research Institute of Infectious Diseases, Department of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China.
- Guangzhou Medical Research Institute of Infectious Diseases, Institution of Infectious Disease, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 510000, Guangzhou, P.R. China.
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11
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Sim MM, Mollica MY, Alfar HR, Hollifield M, Chung DW, Fu X, Gandhapudi S, Coenen DM, Prakhya KS, Mahmood DFD, Banerjee M, Peng C, Li X, Thornton AC, Porterfield JZ, Sturgill JL, Sievert GA, Barton-Baxter M, Zheng Z, Campbell KS, Woodward JG, López JA, Whiteheart SW, Garvy BA, Wood JP. Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.08.579463. [PMID: 38370737 PMCID: PMC10871343 DOI: 10.1101/2024.02.08.579463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.
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Affiliation(s)
- Martha M.S. Sim
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
| | - Molly Y. Mollica
- Bloodworks Northwest Research Institute, WA, USA
- Division of Hematology, School of Medicine, University of Washington, WA, USA
- Department of Mechanical Engineering, University of Maryland, Baltimore County, MD, USA
| | - Hammodah R. Alfar
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
| | - Melissa Hollifield
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
| | - Dominic W. Chung
- Bloodworks Northwest Research Institute, WA, USA
- Department of Biochemistry, University of Washington, WA, USA
| | - Xiaoyun Fu
- Bloodworks Northwest Research Institute, WA, USA
- Division of Hematology, School of Medicine, University of Washington, WA, USA
| | - Siva Gandhapudi
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
| | - Daniëlle M. Coenen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
| | | | | | - Meenakshi Banerjee
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
| | - Chi Peng
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, KY, USA
| | - Xian Li
- Saha Cardiovascular Research Center, University of Kentucky, KY, USA
| | | | - James Z. Porterfield
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
- Division of Infectious Disease, University of Kentucky, KY, USA
| | - Jamie L. Sturgill
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
| | - Gail A. Sievert
- Center for Clinical and Translational Science, University of Kentucky, KY, USA
| | | | - Ze Zheng
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- Versiti Blood Research Institute, Milwaukee, WI, USA
| | - Kenneth S. Campbell
- Center for Clinical and Translational Science, University of Kentucky, KY, USA
| | - Jerold G. Woodward
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
| | - José A. López
- Bloodworks Northwest Research Institute, WA, USA
- Division of Hematology, School of Medicine, University of Washington, WA, USA
| | - Sidney W. Whiteheart
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
- Saha Cardiovascular Research Center, University of Kentucky, KY, USA
| | - Beth A. Garvy
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, KY, USA
| | - Jeremy P. Wood
- Department of Molecular and Cellular Biochemistry, University of Kentucky, KY, USA
- Saha Cardiovascular Research Center, University of Kentucky, KY, USA
- Division of Cardiovascular Medicine Gill Heart and Vascular Institute, University of Kentucky, KY, USA
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12
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Ferreira FM, Gomes SV, Carvalho LCF, de Alcantara AC, da Cruz Castro ML, Perucci LO, Pio S, Talvani A, de Abreu Vieira PM, Calsavara AJC, Costa DC. Potential of piperine for neuroprotection in sepsis-associated encephalopathy. Life Sci 2024; 337:122353. [PMID: 38104862 DOI: 10.1016/j.lfs.2023.122353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
AIMS Sepsis-associated encephalopathy (SAE) is a common complication that increases mortality and leads to long-term cognitive impairment in sepsis survivors. However, no specific or effective therapy has been identified for this complication. Piperine is an alkaloid known for its anti-inflammatory, antioxidant, and neuroprotective properties, which are important characteristics for treatment of SAE. The objective of this study was to evaluate the neuroprotective effect of piperine on SAE in C57BL/6 mice that underwent cecum ligation and perforation surgery (CLP). MAIN METHODS C57BL/6 male mice were randomly assigned to groups that underwent SHAM surgery or CLP. Mice in the CLP group were treated with piperine at doses of 20 or 40 mg/kg for short- (5 days) or long-term (10 days) periods after CLP. KEY FINDINGS Our results revealed that untreated septic animals exhibited increased concentrations of IL-6, TNF, VEGF, MMP-9, TBARS, and NLRP3, and decreased levels of BDNF, sulfhydryl groups, and catalase in the short term. Additionally, the levels of carbonylated proteins and degenerated neuronal cells were increased at both time points. Furthermore, short-term and visuospatial memories were impaired. Piperine treatment reduced MMP-9 activity in the short term and decreased the levels of carbonylated proteins and degenerated neuronal cells in the long term. It also lowered IL-6 and TBARS levels at both time points evaluated. Moreover, piperine increased short-term catalase and long-term BDNF factor levels and improved memory at both time points. SIGNIFICANCE In conclusion, our data demonstrate that piperine exerts a neuroprotective effect on SAE in animals that have undergone CLP.
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Affiliation(s)
- Flavia Monteiro Ferreira
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Sttefany Viana Gomes
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Luana Cristina Faria Carvalho
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Ana Carolina de Alcantara
- Laboratory of Cognition and Health (LACOS), School of Medicine, Department of Pediatric and Adult Clinics (DECPA), Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Maria Laura da Cruz Castro
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Luiza Oliveira Perucci
- Laboratory of Immunobiology of Inflammation, Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Sirlaine Pio
- Laboratory of Immunobiology of Inflammation, Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - André Talvani
- Laboratory of Immunobiology of Inflammation, Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Paula Melo de Abreu Vieira
- Morphopathology Laboratory, Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Allan Jefferson Cruz Calsavara
- Laboratory of Cognition and Health (LACOS), School of Medicine, Department of Pediatric and Adult Clinics (DECPA), Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Daniela Caldeira Costa
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil.
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13
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Yang S, Xu J, Dai Y, Jin S, Sun Y, Li J, Liu C, Ma X, Chen Z, Chen L, Hou J, Mi JQ, Chen SJ. Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma. Nat Commun 2024; 15:360. [PMID: 38191582 PMCID: PMC10774397 DOI: 10.1038/s41467-023-44648-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 12/21/2023] [Indexed: 01/10/2024] Open
Abstract
Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor redirected T cells (CAR-T) therapy. CAR-T toxicity management has been greatly improved, but CRS remains a prime safety concern. Here we follow serum cytokine levels and circulating immune cell transcriptomes longitudinally in 26 relapsed/refractory multiple myeloma patients receiving the CAR-T product, ciltacabtagene autoleucel, to understand the immunological kinetics of CRS. We find that although T lymphocytes and monocytes/macrophages are the major overall cytokine source in manifest CRS, neutrophil activation peaks earlier, before the onset of severe symptoms. Intracellularly, signaling activation dominated by JAK/STAT pathway occurred prior to cytokine cascade and displayed regular kinetic changes. CRS severity is accurately described and potentially predicted by temporal cytokine secretion signatures. Notably, CAR-T re-expansion is found in three patients, including a fatal case characterized by somatic TET2-mutation, clonal expanded cytotoxic CAR-T, broadened cytokine profiles and irreversible hepatic toxicity. Together, our findings show that a latent phase with distinct immunological changes precedes manifest CRS, providing an optimal window and potential targets for CRS therapeutic intervention and that CAR-T re-expansion warrants close clinical attention and laboratory investigation to mitigate the lethal risk.
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Affiliation(s)
- Shuangshuang Yang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jie Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuting Dai
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shiwei Jin
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yan Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jianfeng Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chenglin Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaolin Ma
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhu Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lijuan Chen
- Department of Hematology, First affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
| | - Jian Hou
- Department of Hematology, Ren Ji Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jian-Qing Mi
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Sai-Juan Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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14
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Xu J, He J, Zhou YL, Weng Z, Li M, Wang ZX, He Y. Von Willebrand factor promotes radiation-induced intestinal injury (RIII) development and its cleavage enzyme rhADAMTS13 protects against RIII by reducing inflammation and oxidative stress. Free Radic Biol Med 2024; 210:1-12. [PMID: 37956910 DOI: 10.1016/j.freeradbiomed.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/20/2023]
Abstract
Patients with abdominopelvic cancer undergoing radiotherapy commonly develop radiation-induced intestinal injury (RIII); however, its underlying pathogenesis remains elusive. The von Willebrand factor (vWF)/a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in thrombosis, inflammation, and oxidative stress. However, its role in RIII remains unclear. In this study, the effect of radiation on vWF and ADAMTS13 expression was firstly evaluated in patients with cervical cancer undergoing radiotherapy and C57BL/6J mice exposed to different doses of total abdominal irradiation. Then, mice with the specific deletion of vWF in the platelets and endothelium were established to demonstrate the contribution of vWF to RIII. Additionally, the radioprotective effect of recombinant human (rh) ADAMTS13 against RIII was assessed. Results showed that both the patients with cervical cancer undergoing radiotherapy and RIII mouse model exhibited increased vWF levels and decreased ADAMTS13 levels. The knockout of platelet- and endothelium-derived vWF rectified the vWF/ADAMTS13 axis imbalance; improved intestinal structural damage; increased crypt epithelial cell proliferation; and reduced radiation-induced apoptosis, inflammation, and oxidative stress, thereby alleviating RIII. Administration of rhADAMTS13 could equally alleviate RIII. Our results demonstrated that abdominal irradiation affected the balance of the vWF/ADAMTS13 axis. vWF exerted a deleterious role and ADAMTS13 exhibited a protective role in RIII progression. rhADAMTS13 has the potential to be developed into a radioprotective agent.
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Affiliation(s)
- Jie Xu
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Jun He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Ya-Li Zhou
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Zhen Weng
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Ming Li
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, 215123, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
| | - Zhen-Xin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Yang He
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China.
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15
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Tomasik J, Avni B, Grisariu S, Elias S, Zimran E, Stepensky P, Basak GW. Endothelial Activation and Stress Index Score as a Prognostic Factor of Cytokine Release Syndrome in CAR-T Patients - A Retrospective Analysis of Multiple Myeloma and Large B-Cell Lymphoma Cohorts. Arch Immunol Ther Exp (Warsz) 2024; 72:aite-2024-0018. [PMID: 39277881 DOI: 10.2478/aite-2024-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 08/02/2024] [Indexed: 09/17/2024]
Abstract
Endothelial Activation and Stress Index (EASIX) has been proposed as a prognostic factor of adverse events or survival in hematological malignancies. Endothelial dysfunction has been associated with complications following stem cell transplantation and chimeric antigen receptor (CAR)-T therapy. This retrospective cohort study evaluated the utility of the EASIX score as a prognostic factor of cytokine release syndrome (CRS) in multiple myeloma/light-chain amyloidosis (MM/AL amyloidosis; N = 69) and large B-cell lymphoma (LBCL) cohorts (N = 65). Occurrence of CRS grade ≥3 was the primary endpoint. For both cohorts, the EASIX and simplified EASIX (s-EASIX) scores were calculated at four different time points before CAR-T infusion to assess its prognostic value. In the MM/AL amyloidosis cohort, neither EASIX nor s-EASIX scores calculated at any time point were associated with the occurrence of CRS grade ≥3. In the LBCL cohort, EASIX and s-EASIX scores measured before lymphodepletion (EASIX-pre and s-EASIX-pre) showed a significant relationship with CRS grade ≥3 (odds ratio [OR] = 1.06 and OR = 1.05, respectively). The cutoff value of 1.835 for EASIX-pre was associated with 4.59-fold increased OR of CRS grade ≥3 (95% confidence interval [CI]: 1.13-21.84), whereas s-EASIX-pre cutoff equaled 2.134 and was associated with 4.13-fold increased OR of CRS grade ≥3 (95% CI: 1.01-17.93). However, after internal validation with bootstrapping, the significance was lost both for the EASIX-pre and s-EASIX-pre cutoff. The presented findings indicate that the EASIX scores fail to predict CRS in MM/amyloidosis CAR-T patients, whereas they can be implemented as CRS grade ≥3 predictors in LBCL CAR-T patients.
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Affiliation(s)
- Jaromir Tomasik
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Batia Avni
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
| | - Sigal Grisariu
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
| | - Shlomo Elias
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
| | - Eran Zimran
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
| | - Grzegorz W Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
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16
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Asghar MS, Ismail Shah SM, Rani A, Kazmi S, Savul IS, Ukrani J, Khan F, Hasan CA, Rathore N, Syed M, Keswani S, Surkasha FNU, Mal D, Kumar D. Toxicities of CAR T-cell therapy: a review of current literature. Ann Med Surg (Lond) 2023; 85:6013-6020. [PMID: 38098580 PMCID: PMC10718333 DOI: 10.1097/ms9.0000000000001375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/24/2023] [Indexed: 12/17/2023] Open
Abstract
The chimeric antigen receptor (CAR) design, first invented by Zelig Eshhar, paved the way for the use of genetically modified T-cells in targeted therapy against cancer cells. Since then, it has gone through many generations, especially with the integration of co-stimulation in the second and third-generation CARs. However, it also mounts a hyperactive immune response named as cytokine release syndrome with the release of several cytokines eventually resulting in multiple end-organ toxicities. The severity of cytokine release syndrome depends upon certain factors such as the tumor burden, choice of co-stimulation, and degree of lymphodepletion, and can manifest as pulmonary edema, vascular leak, renal dysfunction, cardiac problems, hepatic failure, and coagulopathy. Many grading criteria have been used to define these clinical manifestations but they lack harmonization. Neurotoxicity has also been significantly associated with CAR T-cell therapy but it has not been studied much in previous literature. This review aims to provide a comprehensive account of the clinical manifestations, diagnosis, management, and treatment of CAR T-cell associated neurotoxicity.
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Affiliation(s)
| | | | - Anooja Rani
- Department of Internal Medicine, Dow Medical College, Dow University of Health Sciences
| | - Sana Kazmi
- Department of Internal Medicine, Dow Medical College, Dow University of Health Sciences
| | - Ilma S. Savul
- Department of Internal Medicine, St. Joseph Medical Center, Houston
| | - Janta Ukrani
- Department of Internal Medicine, Mather Hospital-Northwell Health, New York
| | - Farmanullah Khan
- Department of Medicine, Liaquat National Hospital and Medical College
| | - Chaudhary A. Hasan
- Department of Internal Medicine, Dow Medical College, Dow University of Health Sciences
| | - Navin Rathore
- Department of Medicine, Liaquat National Hospital and Medical College
| | - Maria Syed
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
| | - Shiwani Keswani
- Department of Medicine, Ghulam Muhammad Mahar Medical College, Sukkur
| | - FNU Surkasha
- Department of Medicine, Ghulam Muhammad Mahar Medical College, Sukkur
| | - Doongro Mal
- Department of Internal Medicine, Dow Medical College, Dow University of Health Sciences
| | - Dileep Kumar
- Department of Medicine, Liaquat University of Medical and Health Sciences
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Giardini V, Grilli L, Terzaghi A, Todyrenchuk L, Zavettieri C, Mazzoni G, Cozzolino S, Casati M, Vergani P, Locatelli A. sFlt-1 Levels as a Predicting Tool in Placental Dysfunction Complications in Multiple Pregnancies. Biomedicines 2023; 11:2917. [PMID: 38001918 PMCID: PMC10669317 DOI: 10.3390/biomedicines11112917] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND several studies have demonstrated that angiogenic markers can improve the clinical management of hypertensive disorders (HDs) and fetal growth restriction (FGR) in singleton pregnancies, but few studies have evaluated the performance of these tests in multiple pregnancies. Our aim was to investigate the role of soluble fms-like tyrosine kinase 1 (sFlt-1) in predicting adverse obstetric outcomes in hospitalized multiple pregnancies with HD (preeclampsia/gestational hypertension/uncontrolled chronic hypertension) and/or FGR in one or more fetuses. METHODS A retrospective analysis of multiple pregnancies with HD/FGR occurring after the 20th gestational week. Pregnant women were divided into two groups: women with high levels of sFlt-1 and those with low levels of sFlt-1. A value of sFlt-1 greater than or equal to 15,802 pg/mL was considered arbitrarily high, as it is equivalent to two times the 90th percentile expected in an uncomplicated full-term singleton pregnancy based on data from a prospective multicenter study (7901 pg/mL). RESULTS The cohort included 39 multiple pregnancies. There were no cases of birth <34 weeks, HELLP syndrome, ICU admission, and urgent cesarean sections for HD/FGR complications reported among women with low levels of sFlt-1. CONCLUSIONS A cut-off value of sFlt-1 ≥ 15,802 pg/mL could represent a valuable tool for predicting adverse obstetric outcomes in multiple pregnancies hospitalized for HD/FGR disorders, regardless of gestational age and chorionicity.
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Affiliation(s)
- Valentina Giardini
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Leonora Grilli
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Alessandra Terzaghi
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Lyudmyla Todyrenchuk
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Caterina Zavettieri
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Giulia Mazzoni
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Sabrina Cozzolino
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Marco Casati
- Laboratory Medicine, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy
| | - Patrizia Vergani
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
| | - Anna Locatelli
- Department of Obstetrics and Gynecology, IRCCS San Gerardo dei Tintori Foundation, University of Milano-Bicocca, 20900 Monza, Italy; (L.G.); (A.T.); (C.Z.); (A.L.)
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18
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Yang C, Nguyen J, Yen Y. Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. J Biomed Sci 2023; 30:89. [PMID: 37864230 PMCID: PMC10590030 DOI: 10.1186/s12929-023-00982-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapies have been approved by FDA to treat relapsed or refractory hematological malignancies. However, the adverse effects of CAR-T cell therapies are complex and can be challenging to diagnose and treat. In this review, we summarize the major adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR T-cell associated HLH (carHLH), and discuss their pathophysiology, symptoms, grading, and diagnosis systems, as well as management. In a future outlook, we also provide an overview of measures and modifications to CAR-T cells that are currently being explored to limit toxicity.
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Affiliation(s)
- Chieh Yang
- Department of Internal Medicine, School of Medicine, University of California Riverside, Riverside, CA USA
| | - John Nguyen
- Covina Discovery Center, Theragent Inc., Covina, CA USA
| | - Yun Yen
- College of Medical Technology, Taipei Medical University, Taipei City, Taiwan
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19
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Tsai PS, Du PX, Keskin BB, Lee NY, Wan SW, Lin YL, Su WY, Lin PC, Lin WH, Shih HC, Ho TS, Syu GD. Antibody Profiling of Dengue Severities Using Flavivirus Protein Microarrays. Anal Chem 2023; 95:15217-15226. [PMID: 37800729 DOI: 10.1021/acs.analchem.3c02165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Dengue is a viral disease transmitted by Aedes aegypti mosquitoes. According to the World Health Organization, about half of the world's population is at risk of dengue. There are four serotypes of the dengue virus. After infection with one serotype, it will be immune to such a serotype. However, subsequent infection with other serotypes will increase the risk of severe outcomes, e.g., dengue hemorrhagic fever, dengue shock syndrome, and even death. Since severe dengue is challenging to predict and lacks molecular markers, we aim to build a multiplexed Flavivirus protein microarray (Flaviarray) that includes all of the common Flaviviruses to profile the humoral immunity and cross-reactivity in the dengue patients with different outcomes. The Flaviarrays we fabricated contained 17 Flavivirus antigens with high reproducibility (R-square = 0.96) and low detection limits (172-214 pg). We collected serums from healthy subjects (n = 36) and dengue patients within 7 days after symptom onset (mild dengue (n = 21), hospitalized nonsevere dengue (n = 29), and severe dengue (n = 36)). After profiling the serum antibodies using Flaviarrays, we found that patients with severe dengue showed higher IgG levels against multiple Flavivirus antigens. With logistic regression, we found groups of markers with high performance in distinguishing dengue patients from healthy controls as well as hospitalized from mild cases (AUC > 0.9). We further reported some single markers that were suitable to separate dengue patients from healthy controls (AUC > 0.9) and hospitalized from mild outcomes (AUC > 0.8). Together, Flaviarray is a valuable tool to profile antibody specificities, uncover novel markers for decision-making, and shed some light on early preventions and treatments.
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Affiliation(s)
- Pei-Shan Tsai
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Pin-Xian Du
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Batuhan Birol Keskin
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Nan-Yao Lee
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Center for Infection Control, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Shu-Wen Wan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan
| | - Ya-Lan Lin
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Wen-Yu Su
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Pei-Chun Lin
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Wei-Hsun Lin
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Hsi-Chang Shih
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Tzong-Shiann Ho
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Pediatrics, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan R.O.C
- Department of Pediatrics, National Cheng Kung University Hospital Dou-Liou Branch, College of Medicine, National Cheng Kung University, Yunlin 640, Taiwan
| | - Guan-Da Syu
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 701, Taiwan
- Center for Infection Control, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 701, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan 701, Taiwan
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20
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Liu W, Huang J, He S, Du R, Shi W, Wang Y, Du D, Du Y, Liu Q, Wang Y, Wang G, Yin T. Senescent endothelial cells' response to the degradation of bioresorbable scaffold induces intimal dysfunction accelerating in-stent restenosis. Acta Biomater 2023; 166:266-277. [PMID: 37211308 DOI: 10.1016/j.actbio.2023.05.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/16/2023] [Accepted: 05/16/2023] [Indexed: 05/23/2023]
Abstract
Atherosclerotic cardiovascular disease is a typical age-related disease accompanied by stiffening arteries. We aimed to elucidate the influence of aged arteries on in-stent restenosis (ISR) after the implantation of bioresorbable scaffolds (BRS). Histology and optical coherence tomography showed increased lumen loss and ISR in the aged abdominal aorta of Sprague-Dawley rats, with apparent scaffold degradation and deformation, which induce lower wall shear stress (WSS). This was also the case at the distal end of BRS, where the scaffolds degraded faster, and significant lumen loss was followed by a lower WSS. In addition, early thrombosis, inflammation, and delayed re-endothelialization were presented in the aged arteries. Degradation of BRS causes more senescent cells in the aged vasculature, increasing endothelial cell dysfunction and the risk of ISR. Thus, profoundly understanding the mechanism between BRS and senescent cells may give a meaningful guide for the age-related scaffold design. STATEMENT OF SIGNIFICANCE: The degradation of bioresorbable scaffolds aggravates senescent endothelial cells and a much lower wall shear stress areas in the aged vasculature, lead to intimal dysfunction and increasing in-stent restenosis risk. Early thrombosis and inflammation, as well as delayed re-endothelialization, are presented in the aged vasculature after bioresorbable scaffolds implantation. Age stratification during the clinical evaluation and senolytics in the design of new bioresorbable scaffolds should be considered, especially for old patients.
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Affiliation(s)
- Wanling Liu
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China
| | - Junyang Huang
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China
| | - Shicheng He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Ruolin Du
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China
| | - Wen Shi
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China
| | - Yang Wang
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China
| | - Dingyuan Du
- Department of Traumatology, and Department of Cardiothoracic Surgery, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Yan Du
- Ultrasonography Department, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400014, China
| | - Qing Liu
- Beijing Advanced Medical Technologies Inc., Beijing 102609, China
| | - Yazhou Wang
- School of Medicine, Chongqing University, Chongqing 400044, PR China.
| | - Guixue Wang
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China.
| | - Tieying Yin
- Key Laboratory of Biorheological and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Modern Life Science Experiment Teaching Center, Bioengineering College of Chongqing University, Chongqing 400030, PR China.
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21
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Stins MF, Mtaja A, Mulendele E, Mwimbe DW, Pinilla G, Mutengo M, Pardo CA, Chipeta J. Elevated brain derived neurotrophic factor in plasma and interleukin-6 levels in cerebrospinal fluid in meningitis compared to cerebral malaria. J Neurol Sci 2023; 450:120663. [PMID: 37182424 PMCID: PMC10330544 DOI: 10.1016/j.jns.2023.120663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 03/11/2023] [Accepted: 04/22/2023] [Indexed: 05/16/2023]
Abstract
Neurological infections, such as Cerebral malaria (CM) and meningitis are associated with high mortality and in survivors, particularly young children, persistent neurologic deficits often remain. As brain inflammation plays a role in the development of these neurological sequelae, multiplex assays were used to assess a select set of immune mediators in both plasma and cerebrospinal fluid (CSF) from Zambian children with neurological infections. Both CM and meningitis patients showed high levels of markers for vascular inflammation, such as soluble ICAM-1 and angiopoietins. Although high levels of angiopoietin 1 and angiopoietin 2 were found in the meningitis group, their levels in the CSF were low and did not differ. As expected, there were high levels of cytokines and notably a significantly elevated IL-6 level in the CSF of the meningitis group. Interestingly, although elevated levels BDNF were found, BDNF levels were significantly higher in plasma of the meningitis group but similar in the CSF. The striking differences in plasma BDNF and IL-6 levels in the CSF point to markedly different neuro-pathological processes. Therefore, further investigations in the role of both IL-6 and BDNF in the neurological outcomes are needed.
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Affiliation(s)
- Monique F Stins
- Johns Hopkins School of Public Health, Malaria Research Institute, 615N Wolfe Street, SPH E45141, Baltimore, MD 21205, United States of America.
| | - Agnes Mtaja
- University of Zambia School of Medicine, Department of Paediatrics and Child Health, The School of Medicine, University Teaching Hospital Malaria Research Unit (SMUTH-MRU), P.O. Box 50110, Lusaka, Zambia
| | - Evan Mulendele
- University of Zambia School of Medicine, Department of Paediatrics and Child Health, The School of Medicine, University Teaching Hospital Malaria Research Unit (SMUTH-MRU), P.O. Box 50110, Lusaka, Zambia
| | - Daniel W Mwimbe
- University of Zambia School of Medicine, Department of Paediatrics and Child Health, The School of Medicine, University Teaching Hospital Malaria Research Unit (SMUTH-MRU), P.O. Box 50110, Lusaka, Zambia
| | - Gabriel Pinilla
- Johns Hopkins School of Medicine, Department of Neurology, Division of Neuroimmunology and Neuroinfectious Diseases, 600 N Wolfe Street, Baltimore, MD 21285, United States of America; Icesi University, Department of Clinical Sciences, Calle 18 No. 122-135, Cali 760031, Colombia
| | - Mable Mutengo
- University of Zambia School of Medicine, Department of Paediatrics and Child Health, The School of Medicine, University Teaching Hospital Malaria Research Unit (SMUTH-MRU), P.O. Box 50110, Lusaka, Zambia
| | - Carlos A Pardo
- Johns Hopkins School of Medicine, Department of Neurology, Division of Neuroimmunology and Neuroinfectious Diseases, 600 N Wolfe Street, Baltimore, MD 21285, United States of America
| | - James Chipeta
- University of Zambia School of Medicine, Department of Paediatrics and Child Health, The School of Medicine, University Teaching Hospital Malaria Research Unit (SMUTH-MRU), P.O. Box 50110, Lusaka, Zambia
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22
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Jess J, Yates B, Dulau-Florea A, Parker K, Inglefield J, Lichtenstein D, Schischlik F, Ongkeko M, Wang Y, Shahani S, Cullinane A, Smith H, Kane E, Little L, Chen D, Fry TJ, Shalabi H, Wang HW, Satpathy A, Lozier J, Shah NN. CD22 CAR T-cell associated hematologic toxicities, endothelial activation and relationship to neurotoxicity. J Immunother Cancer 2023; 11:e005898. [PMID: 37295816 PMCID: PMC10277551 DOI: 10.1136/jitc-2022-005898] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. METHODS We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. RESULTS Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3-4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. CONCLUSION With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. TRIAL REGISTRATION NUMBER NCT02315612.
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Affiliation(s)
- Jennifer Jess
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Bonnie Yates
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Alina Dulau-Florea
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Kevin Parker
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Jon Inglefield
- Applied Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Dan Lichtenstein
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Fiorella Schischlik
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, Maryland, USA
| | - Martin Ongkeko
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Yanyu Wang
- Applied Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Shilpa Shahani
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ann Cullinane
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Hannah Smith
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Eli Kane
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Lauren Little
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Dong Chen
- Mayo Clinic, Rochester, Minnesota, USA
| | - Terry J Fry
- University of Colorado Denver Children's Hospital Colorado Research Institute, Aurora, Colorado, USA
| | - Haneen Shalabi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Hao-Wei Wang
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Ansuman Satpathy
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Jay Lozier
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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23
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Chopra M, Bhagwani A, Kumar H. The Provenance, Providence, and Position of Endothelial Cells in Injured Spinal Cord Vascular Pathology. Cell Mol Neurobiol 2023; 43:1519-1535. [PMID: 35945301 PMCID: PMC11412425 DOI: 10.1007/s10571-022-01266-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 07/21/2022] [Indexed: 11/03/2022]
Abstract
Endothelial cells (ECs) and pericytes are present in all blood vessels. Their position confers an important role in controlling oxygen and nutrient transportation to the different organs. ECs can adopt different morphologies based on their need and functions. Both ECs and pericytes express different surface markers that help in their identification, but heterogeneity and overlapping between markers among different cells pose a challenge for their precise identification. Spatiotemporal association of ECs and pericytes have great importance in sprout formation and vessel stabilization. Any traumatic injury in CNS may lead to vascular damage along with neuronal damage. Hence, ECs-pericyte interaction by physical contact and paracrine molecules is crucial in recovering the epicenter region by promoting angiogenesis. ECs can transform into other types of cells through endothelial-mesenchymal transition (EndMT), promoting wound healing in the epicenter region. Various signaling pathways mediate the interaction of ECs with pericytes that have an extensive role in angiogenesis. In this review, we discussed ECs and pericytes surface markers, the spatiotemporal association and interaction of ECs-pericytes, and signaling associated with the pathology of traumatic SCI. Linking the brain or spinal cord-specific pathologies and human vascular pathology will pave the way toward identifying new therapeutic targets and developing innovative preventive strategies. Endothelial-pericyte interaction strategic for formation of functional neo-vessels that are crucial for neurological recovery.
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Affiliation(s)
- Manjeet Chopra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ankita Bhagwani
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India.
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24
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Rejeski K, Blumenberg V, Iacoboni G, Lopez-Corral L, Kharboutli S, Hernani R, Petrera A, Müller N, Hildebrand F, Frölich L, Karschnia P, Schmidt C, Cordas dos Santos DM, Piñana JL, Müller F, Martin AA, Dreyling M, von Bergwelt-Baildon M, Barba P, Subklewe M, Bücklein VL. Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL. Hemasphere 2023; 7:e858. [PMID: 37038465 PMCID: PMC10082278 DOI: 10.1097/hs9.0000000000000858] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 02/06/2023] [Indexed: 04/08/2023] Open
Abstract
Early fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0-30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use.
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Affiliation(s)
- Kai Rejeski
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
| | - Viktoria Blumenberg
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
| | - Gloria Iacoboni
- Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain
- Department of Medicine, Universitat Autònoma of Barcelona (UAB), Bellaterra, Spain
| | - Lucia Lopez-Corral
- Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
- Centro de Investigación del Cáncer-IBMCC, Salamanca, Spain
| | - Soraya Kharboutli
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
- Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Germany
| | - Rafael Hernani
- Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain
| | - Agnese Petrera
- Metabolomics and Proteomics Core Facility, Helmholtz Zentrum Munich – German Research Center for Environmental Health, Munich, Germany
| | - Niklas Müller
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
| | - Friederike Hildebrand
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
| | - Lisa Frölich
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
| | - Philipp Karschnia
- Department of Neurosurgery, University Hospital, LMU Munich, Germany
| | - Christian Schmidt
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
| | - David M. Cordas dos Santos
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
| | - José Luis Piñana
- Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain
| | - Fabian Müller
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
- Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Germany
| | - Ana Africa Martin
- Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
- Centro de Investigación del Cáncer-IBMCC, Salamanca, Spain
| | - Martin Dreyling
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
| | - Pere Barba
- Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain
- Department of Medicine, Universitat Autònoma of Barcelona (UAB), Bellaterra, Spain
| | - Marion Subklewe
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
| | - Veit L. Bücklein
- Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany
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25
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Pang R, Dong L, Liu J, Ji X, Zhuang H, Duan M. The study on role of endothelial cell autophagy in rats with sepsis-induced acute kidney injury. Heliyon 2023; 9:e13796. [PMID: 36873534 PMCID: PMC9976300 DOI: 10.1016/j.heliyon.2023.e13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Sepsis often causes acute kidney injury (AKI). Autophagy of renal tubular epithelial cells is considered a cytoprotective mechanism in septic AKI; however, the role of autophagy of renal endothelial cells is uninvestigated. The current study examined whether autophagy was induced by sepsis in renal endothelial cells and whether induction of autophagy in these cells attenuated the degree of AKI. Cecal ligation and puncture (CLP) was used as a model of sepsis in rats. Four experimental groups included: sham, CLP alone, CLP + rapamycin (RAPA), and CLP + dimethyl sulfoxide (DMSO), where RAPA was used as an activator of autophagy. CLP increased renal LC3-II protein levels with an additional transient increase by RAPA at 18 h. In addition, CLP induced autophagosome formation in renal endothelial cells had an additional increase induced by RAPA. Interestingly, the levels of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), an endothelial cell-specific protein in the kidney, were also increased by CLP, albeit it was transiently downregulated by RAPA at 18 h. Serum thrombomodulin increased and renal vascular endothelial (VE)-cadherin decreased following CLP, and these changes were attenuated by RAPA. The renal cortex exhibited and inflammatory tissue damage after CLP, and RAPA alleviated these histopathological injuries. The current findings indicate that autophagy was induced by sepsis in renal endothelial cells, and upregulation of autophagy in these cells alleviated endothelial injury and AKI. In addition, BAMBI was induced by sepsis in the kidney, which may play a role in regulating endothelial stability in septic AKI.
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Affiliation(s)
- Ran Pang
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lei Dong
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jingfeng Liu
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojun Ji
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Haizhou Zhuang
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meili Duan
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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26
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Balanza N, Erice C, Ngai M, McDonald CR, Weckman AM, Wright J, Richard-Greenblatt M, Varo R, López-Varela E, Sitoe A, Vitorino P, Bramugy J, Lanaspa M, Acácio S, Madrid L, Baro B, Kain KC, Bassat Q. Prognostic accuracy of biomarkers of immune and endothelial activation in Mozambican children hospitalized with pneumonia. PLOS GLOBAL PUBLIC HEALTH 2023; 3:e0001553. [PMID: 36963048 PMCID: PMC10021812 DOI: 10.1371/journal.pgph.0001553] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/24/2023] [Indexed: 02/25/2023]
Abstract
Pneumonia is a leading cause of child mortality. However, currently we lack simple, objective, and accurate risk-stratification tools for pediatric pneumonia. Here we test the hypothesis that measuring biomarkers of immune and endothelial activation in children with pneumonia may facilitate the identification of those at risk of death. We recruited children <10 years old fulfilling WHO criteria for pneumonia and admitted to the Manhiça District Hospital (Mozambique) from 2010 to 2014. We measured plasma levels of IL-6, IL-8, Angpt-2, sTREM-1, sFlt-1, sTNFR1, PCT, and CRP at admission, and assessed their prognostic accuracy for in-hospital, 28-day, and 90-day mortality. Healthy community controls, within same age strata and location, were also assessed. All biomarkers were significantly elevated in 472 pneumonia cases versus 80 controls (p<0.001). IL-8, sFlt-1, and sTREM-1 were associated with in-hospital mortality (p<0.001) and showed the best discrimination with AUROCs of 0.877 (95% CI: 0.782 to 0.972), 0.832 (95% CI: 0.729 to 0.935) and 0.822 (95% CI: 0.735 to 0.908), respectively. Their performance was superior to CRP, PCT, oxygen saturation, and clinical severity scores. IL-8, sFlt-1, and sTREM-1 remained good predictors of 28-day and 90-day mortality. These findings suggest that measuring IL-8, sFlt-1, or sTREM-1 at hospital presentation can guide risk-stratification of children with pneumonia, which could enable prioritized care to improve survival and resource allocation.
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Affiliation(s)
- Núria Balanza
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Clara Erice
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
| | - Michelle Ngai
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
- Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Chloe R. McDonald
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
| | - Andrea M. Weckman
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
- Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Julie Wright
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
- Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Melissa Richard-Greenblatt
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Rosauro Varo
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Elisa López-Varela
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
- Desmond Tutu TB Centre, Department of Pediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Antonio Sitoe
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Pio Vitorino
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Justina Bramugy
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Miguel Lanaspa
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Sozinho Acácio
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
| | - Lola Madrid
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Bàrbara Baro
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Kevin C. Kain
- Sandra-Rotman Centre for Global Health, Toronto General Research Institute, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada
- Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Quique Bassat
- ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
- ICREA, Barcelona, Spain
- Pediatrics Department, Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
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Muppidi P, Wright E, Wassmer SC, Gupta H. Diagnosis of cerebral malaria: Tools to reduce Plasmodium falciparum associated mortality. Front Cell Infect Microbiol 2023; 13:1090013. [PMID: 36844403 PMCID: PMC9947298 DOI: 10.3389/fcimb.2023.1090013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023] Open
Abstract
Cerebral malaria (CM) is a major cause of mortality in Plasmodium falciparum (Pf) infection and is associated with the sequestration of parasitised erythrocytes in the microvasculature of the host's vital organs. Prompt diagnosis and treatment are key to a positive outcome in CM. However, current diagnostic tools remain inadequate to assess the degree of brain dysfunction associated with CM before the window for effective treatment closes. Several host and parasite factor-based biomarkers have been suggested as rapid diagnostic tools with potential for early CM diagnosis, however, no specific biomarker signature has been validated. Here, we provide an updated review on promising CM biomarker candidates and evaluate their applicability as point-of-care tools in malaria-endemic areas.
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Affiliation(s)
- Pranavi Muppidi
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Emily Wright
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Samuel C. Wassmer
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Himanshu Gupta
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, UP, India
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28
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Sootichote R, Puangmanee W, Benjathummarak S, Kowaboot S, Yamanaka A, Boonnak K, Ampawong S, Chatchen S, Ramasoota P, Pitaksajjakul P. Potential Protective Effect of Dengue NS1 Human Monoclonal Antibodies against Dengue and Zika Virus Infections. Biomedicines 2023; 11:biomedicines11010227. [PMID: 36672734 PMCID: PMC9855337 DOI: 10.3390/biomedicines11010227] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/01/2023] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
Due to the lack of an effective therapeutic treatment to flavivirus, dengue virus (DENV) nonstructural protein 1 (NS1) has been considered to develop a vaccine owing to its lack of a role in antibody-dependent enhancement (ADE). However, both NS1 and its antibody have shown cross-reactivity to host molecules and have stimulated anti-DENV NS1 antibody-mediated endothelial damage and platelet dysfunction. To overcome the pathogenic events and reactogenicity, human monoclonal antibodies (HuMAbs) against DENV NS1 were generated from DENV-infected patients. Herein, the four DENV NS1-specific HuMAbs revealed the therapeutic effects in viral neutralization, reduction of viral replication, and enhancement of cell cytolysis of DENV and zika virus (ZIKV) via complement pathway. Furthermore, we demonstrate that DENV and ZIKV NS1 trigger endothelial dysfunction, leading to vascular permeability in vitro. Nevertheless, the pathogenic effects from NS1 were impeded by 2 HuMAbs (D25-4D4C3 and D25-2B11E7) and also protected the massive cytokines stimulation (interleukin [IL-]-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-13, IL-17, eotaxin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1 α, MIP-1β, tumor necrosis factor-α, platelet-derived growth factor, and RANTES). Collectively, our findings suggest that the novel protective NS1 monoclonal antibodies generated from humans has multiple therapeutic benefits against DENV and ZIKV infections.
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Affiliation(s)
- Rochanawan Sootichote
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Wilarat Puangmanee
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Surachet Benjathummarak
- Center of Excellence for Antibody Research, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Siriporn Kowaboot
- Faculty of Medical Technology, Rangsit University, Pathumthani 12000, Thailand
| | - Atsushi Yamanaka
- Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Korbporn Boonnak
- Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Sumate Ampawong
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Supawat Chatchen
- Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pongrama Ramasoota
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Center of Excellence for Antibody Research, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Pannamthip Pitaksajjakul
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Center of Excellence for Antibody Research, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Correspondence: ; Tel.: +66-023069186 or +66-0899858305
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29
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Liles WC. MICROVASCULAR ENDOTHELIAL ACTIVATION/DYSFUNCTION AND DYSREGULATION OF THE ANGIOPOIETIN-TIE2 SYSTEM IN THE PATHOGENESIS OF LIFE-THREATENING INFECTIONS. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2023; 133:234-246. [PMID: 37701588 PMCID: PMC10493726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
Microvascular endothelial activation/dysfunction has emerged as an important mechanistic pathophysiological process in the development of morbidity and mortality in life-threatening infections. The angiopoietin-Tie2 system plays an integral role in the regulation of microvascular endothelial integrity. Angiopoietin-1 (Ang-1), produced by platelets and pericytes, is the cognate agonistic ligand for Tie2, promoting endothelial quiescence and inhibiting microvascular leak. Angiopoietin-2 (Ang-2), released from activated endothelial cells in Weibel-Palade bodies, competes with Ang-1 for binding to Tie-2, thereby promoting endothelial activation/dysfunction and microvascular leak. In healthy homeostasis, levels of Ang-1 far exceed Ang-2 in circulating serum/plasma. In diseases associated with systemic inflammation, Ang-1 falls and Ang-2 rises (i.e., Ang-1/2 dysregulation). Our research has shown that Ang-1/2 dysregulation is a prominent feature in a number of life-threatening infections and critical illnesses, including sepsis, cerebral malaria, COVID-19, streptococcal toxic shock syndrome (STSS), hemolytic-uremic syndrome (HUS), dengue, and CAR T-cell-associated neurotoxicity. Further work has implicated Ang-1/2 dysregulation in the development of end-organ injury, including acute lung injury/ARDS, acute kidney injury (AKI), and blood-brain-barrier (BBB) breakdown. Current studies are focused in three areas: (a) translation of Ang-1 and -2 as clinically informative prognostic and "theranostic" biomarkers in critically ill individuals; (b) incorporation of Ang-1/2 assays in a point of care device for clinical triage decision making; and (c) development of an engineered Ang-1 super agonist nanoparticle as a novel pathogen-agnostic therapeutic to prevent and/or mitigate end-organ dysfunction in individuals with life-threatening infections and critical illnesses associated with systemic inflammation.
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30
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Moraes CRP, Borba-Junior IT, De Lima F, Silva JRA, Bombassaro B, Palma AC, Mansour E, Velloso LA, Orsi FA, Costa FTM, De Paula EV. Association of Ang/Tie2 pathway mediators with endothelial barrier integrity and disease severity in COVID-19. Front Physiol 2023; 14:1113968. [PMID: 36895630 PMCID: PMC9988918 DOI: 10.3389/fphys.2023.1113968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Endothelial barrier (EB) disruption contributes to acute lung injury in COVID-19, and levels of both VEGF-A and Ang-2, which are mediators of EB integrity, have been associated with COVID-19 severity. Here we explored the participation of additional mediators of barrier integrity in this process, as well as the potential of serum from COVID-19 patients to induce EB disruption in cell monolayers. In a cohort from a clinical trial consisting of thirty patients with COVID-19 that required hospital admission due to hypoxia we demonstrate that i) levels of soluble Tie2 were increase, and of soluble VE-cadherin were decreased when compared to healthy individuals; ii) sera from these patients induce barrier disruption in monolayers of endothelial cells; and iii) that the magnitude of this effect is proportional to disease severity and to circulating levels of VEGF-A and Ang-2. Our study confirms and extends previous findings on the pathogenesis of acute lung injury in COVID-19, reinforcing the concept that EB is a relevant component of this disease. Our results pave the way for future studies that can refine our understanding of the pathogenesis of acute lung injury in viral respiratory disorders, and contribute to the identification of new biomarkers and therapeutic targets for these conditions.
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Affiliation(s)
| | | | - Franciele De Lima
- School of Medical Sciences, University of Campinas, Campinas, Brazil
| | | | - Bruna Bombassaro
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - André C Palma
- School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Eli Mansour
- School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Lício Augusto Velloso
- School of Medical Sciences, University of Campinas, Campinas, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | | | | | - Erich Vinicius De Paula
- School of Medical Sciences, University of Campinas, Campinas, Brazil.,Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
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31
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Genoud V, Migliorini D. Novel pathophysiological insights into CAR-T cell associated neurotoxicity. Front Neurol 2023; 14:1108297. [PMID: 36970518 PMCID: PMC10031128 DOI: 10.3389/fneur.2023.1108297] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/03/2023] [Indexed: 03/29/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy represents a scientific breakthrough in the treatment of advanced hematological malignancies. It relies on cell engineering to direct the powerful cytotoxic T-cell activity toward tumor cells. Nevertheless, these highly powerful cell therapies can trigger substantial toxicities such as cytokine release syndrome (CRS) and immune cell-associated neurological syndrome (ICANS). These potentially fatal side effects are now better understood and managed in the clinic but still require intensive patient follow-up and management. Some specific mechanisms seem associated with the development of ICANS, such as cytokine surge caused by activated CAR-T cells, off-tumor targeting of CD19, and vascular leak. Therapeutic tools are being developed aiming at obtaining better control of toxicity. In this review, we focus on the current understanding of ICANS, novel findings, and current gaps.
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Affiliation(s)
- Vassilis Genoud
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
- Center for Translational Research in Onco-Haematology, University of Geneva, Geneva, Switzerland
| | - Denis Migliorini
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
- Center for Translational Research in Onco-Haematology, University of Geneva, Geneva, Switzerland
- Brain Tumor and Immune Cell Engineering Laboratory, AGORA Cancer Research Center, Lausanne, Switzerland
- Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland
- *Correspondence: Denis Migliorini
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32
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Adams JA, Uryash A, Lopez JR. Non-Invasive Pulsatile Shear Stress Modifies Endothelial Activation; A Narrative Review. Biomedicines 2022; 10:biomedicines10123050. [PMID: 36551807 PMCID: PMC9775985 DOI: 10.3390/biomedicines10123050] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022] Open
Abstract
The monolayer of cells that line both the heart and the entire vasculature is the endothelial cell (EC). These cells respond to external and internal signals, producing a wide array of primary or secondary messengers involved in coagulation, vascular tone, inflammation, and cell-to-cell signaling. Endothelial cell activation is the process by which EC changes from a quiescent cell phenotype, which maintains cellular integrity, antithrombotic, and anti-inflammatory properties, to a phenotype that is prothrombotic, pro-inflammatory, and permeable, in addition to repair and leukocyte trafficking at the site of injury or infection. Pathological activation of EC leads to increased vascular permeability, thrombosis, and an uncontrolled inflammatory response that leads to endothelial dysfunction. This pathological activation can be observed during ischemia reperfusion injury (IRI) and sepsis. Shear stress (SS) and pulsatile shear stress (PSS) are produced by mechanical frictional forces of blood flow and contraction of the heart, respectively, and are well-known mechanical signals that affect EC function, morphology, and gene expression. PSS promotes EC homeostasis and cardiovascular health. The archetype of inducing PSS is exercise (i.e., jogging, which introduces pulsations to the body as a function of the foot striking the pavement), or mechanical devices which induce external pulsations to the body (Enhanced External Pulsation (EECP), Whole-body vibration (WBV), and Whole-body periodic acceleration (WBPA aka pGz)). The purpose of this narrative review is to focus on the aforementioned noninvasive methods to increase PSS, review how each of these modify specific diseases that have been shown to induce endothelial activation and microcirculatory dysfunction (Ischemia reperfusion injury-myocardial infarction and cardiac arrest and resuscitation), sepsis, and lipopolysaccharide-induced sepsis syndrome (LPS)), and review current evidence and insight into how each may modify endothelial activation and how these may be beneficial in the acute and chronic setting of endothelial activation and microvascular dysfunction.
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Affiliation(s)
- Jose A. Adams
- Division of Neonatology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Correspondence:
| | - Arkady Uryash
- Division of Neonatology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Jose R. Lopez
- Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
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33
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Li Y, Huang Q, Fang M, Liu M, Guo J, Wang Z. Prognostic value of serum levels of multiple adhesion factors in patients with sepsis-induced acute kidney injury. Int Urol Nephrol 2022; 55:1229-1237. [PMID: 36333626 PMCID: PMC10105682 DOI: 10.1007/s11255-022-03394-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022]
Abstract
Abstract
Background
Acute kidney injury (AKI) is common in patients with sepsis and septic shock. Urine output and serum creatinine (SCr) levels are the criteria for diagnosing AKI. However, the application of these levels in the diagnosis of AKI has limitations.
Objective
To detect the expression of various adhesion factors in different stages of AKI as defined by Kidney Disease: Improving Global Outcomes (KDIGO) and to analyse their relationship with the prognosis of patients with sepsis-induced AKI (S-AKI).
Methods
Adult patients with sepsis who were admitted to the hospital between June 2019 and May 2020 were included. Of 90 adult patients with sepsis, 58 had S-AKI. Sixty-seven subjects without sepsis were used as controls. Enzyme-linked immunosorbent assay kits were used to measure E-selectin (CD62E), L-selectin (CD62L), P-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their relationship with the prognosis of patients with S-AKI patients was analysed. Receiver operating characteristic curves were used to analyse the predictive value of different adhesion factors on renal resistance index and renal function recovery. Multivariate logistic regression analysis was used to identify factors associated with renal recovery.
Results
The expression of CD62L was significantly higher in S-AKI patients than in non-AKI patients with sepsis. Compared with the non-AKI group, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were significantly higher in the AKI group than in the non-AKI group (P < 0.05). Mean blood pressure, SCr levels and procalcitonin levels were higher in the AKI group than in the non-AKI group (P < 0.05 for all). The CD62L levels decreased with increasing S-AKI stage. The CD62E levels were highest in S-AKI stage 2, and the VCAM-1 levels were highest in S-AKI stage 3. All patients with S-AKI were followed up with for 28 days. The results found that VCAM-1 was the best predictor of renal recovery in patients with S-AKI.
Conclusion
CD62L is an indicator of S-AKI stage1, and CD62E is an indicator of S-AKI stage 2. In addition, VCAM-I demonstrated satisfactory performance in predicting early recovery of renal function in patients with S-AKI.
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Affiliation(s)
- Yan Li
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China
| | - Qingsheng Huang
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China.
| | - Mingxing Fang
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China
| | - Mengyao Liu
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China
| | - Jianying Guo
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China
| | - Zhiyong Wang
- Department of Critical Care Medicine, Third Hospital of HeBei Medical University, The 139rd of ZiQiang Road, ShiJiaZhuang, 050051, China.
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The utility of inflammatory and endothelial factors in the prognosis of severe dengue. Immunobiology 2022; 227:152289. [DOI: 10.1016/j.imbio.2022.152289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 09/19/2022] [Accepted: 10/06/2022] [Indexed: 11/18/2022]
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McDonald CR, Weckman AM, Richardson E, Hawkes MT, Leligdowicz A, Namasopo S, Opoka RO, Conroy AL, Kain KC. Sex as a determinant of disease severity and clinical outcome in febrile children under five presenting to a regional referral hospital in Uganda. PLoS One 2022; 17:e0276234. [PMID: 36269702 PMCID: PMC9586386 DOI: 10.1371/journal.pone.0276234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 10/03/2022] [Indexed: 11/20/2022] Open
Abstract
Sex and gender are well-established determinants of health in adult and adolescent populations in low resource settings. There are limited data on sex as a determinant of host response to disease and clinical outcome in febrile children in sub-Saharan Africa, where the risk of infection-related mortality is greatest. We examined sex differences and gender biases in health-seeking behavior, clinical care, biological response to infection, or outcome in a prospective observational cohort of febrile children under 5 years of age presenting to a regional referral hospital in Jinja, Uganda. Main outcomes (stratified by sex) were disease severity at presentation measured by clinical and biological parameters, clinical management (e.g., time to see a physician, treatment by diagnosis), and disease outcome (e.g., mortality). Clinical measures of disease severity included Lambaréné Organ Dysfunction Score (LODS), Signs of Inflammation in Children that Kill (SICK), and the Pediatric Early Death Index for Africa (PEDIA). Biological measures of disease severity were assessed using circulating markers of immune and endothelial activation associated with severe and fatal infections. Differences in outcome by sex were analyzed using bivariate analyses with Bonferroni correction for multiple comparisons. In this cohort of febrile patients admitted to hospital (n = 2049), malaria infection was common (59.2%). 15.9% of children presented with severe disease (LODS score ≥ 2). 97 children (4.7%) died, and most deaths (n = 83) occurred within 48 hours of hospital admission. Clinical measures of disease severity at presentation, clinical management, and outcome (e.g., mortality) did not differ by sex in children under five years of age. Host response to infection, as determined by endothelial and inflammatory mediators (e.g., sTREM1, Ang-2) quantified at hospital presentation, did not differ by sex. In this cohort of children under the age of five, sex was not a principal determinant of disease severity at hospital presentation, clinical management, disease outcome, or biological response to infection (p-values not significant for all comparisons, after Bonferroni correction). The results suggest that health seeking behavior by caregivers and clinical care in the hospital setting did not reflect a gender bias in this cohort.
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Affiliation(s)
- Chloe R. McDonald
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Andrea M. Weckman
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Emma Richardson
- Clinical Epidemiology & Biostatistics Department, Faculty of Health Sciences, McMaster University, Hamilton, Canada
| | - Michael T. Hawkes
- Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada
| | - Aleksandra Leligdowicz
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada,Interdepartmental Division of Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, Canada
| | - Sophie Namasopo
- Department of Paediatrics, Kabale Regional Referral Hospital, Kabale, Uganda
| | - Robert O. Opoka
- Department of Paediatrics and Child Health, Mulago Hospital and Makerere University, Kawempe, Kampala, Uganda
| | - Andrea L. Conroy
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America
| | - Kevin C. Kain
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada,Toronto General Hospital Research Institute, University Health Network, Toronto, Canada,Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada,* E-mail:
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Moras E, Achappa B, Murlimanju BV, Raj GMN, Holla R, Madi D, D’Souza NV, Mahalingam S. Early diagnostic markers in predicting the severity of dengue disease. 3 Biotech 2022; 12:268. [PMID: 36091089 PMCID: PMC9461388 DOI: 10.1007/s13205-022-03334-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/26/2022] [Indexed: 11/01/2022] Open
Abstract
AbstractThe aim of the present study was to determine whether the serum ferritin, the biomarker of an acute phase reactant and the gall bladder wall edema, an early indicator of capillary leakage can predict the severity of dengue fever. This study included 131 patients, who were between the age group of 18–80 years. The patients presented to our department with an acute illness, within the first four days of high temperature. The statistical analysis of this study was performed by using the Chi-square and independent Student’s t tests. The diagnostic markers are considered statistically significant, if the serum ferritin level is higher than 500 ng/ml and the gall bladder wall thickness is more than 3 mm. The present study observed that, 39 patients (89%) who had severe dengue (n = 44) revealed a significant gall bladder wall thickening, and this correlation was significant statistically (p < 0.000). It was also observed that, the ferritin levels have a highly significant positive correlation with the severity of dengue. The severe dengue patients had a mean ferritin level of 9125.34 μg/l, whereas the non-severe group had 4271 μg/l. This comparison was also statistically significant, as the p value was 0.003. We report that the serum ferritin levels have a highly significant positive correlation with the severity of dengue. The gall bladder wall edema during the third and fourth day of the illness was also associated with severe dengue. However, diffuse gall bladder wall thickening and high serum ferritin levels are also reported in various other conditions and their exact cause have to be determined by the correlation of associated clinical findings and imaging features.
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Chen CY, Huang SH, Chien KJ, Lai TJ, Chang WH, Hsieh KS, Weng KP. Reappraisal of VEGF in the Pathogenesis of Kawasaki Disease. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9091343. [PMID: 36138652 PMCID: PMC9498069 DOI: 10.3390/children9091343] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/15/2022] [Accepted: 08/31/2022] [Indexed: 11/30/2022]
Abstract
Vascular endothelial growth factor (VEGF) is an important factor in mediating the inflammation of Kawasaki disease (KD). The literature regarding the relationship between VEGF and KD is sparse. The purpose of this study was to investigate the correlation of VEGF and KD. In a prospective study of 42 Taiwanese KD patients (18.9 ± 12.2 months, M/F 22/20) treated with intravenous immunoglobulin (IVIG), a series of VEGF levels was measured from the acute to convalescent phases. KD patients were classified into two subgroups with (n =20) and without (n = 22) acute coronary artery lesions (CALs). Control samples were obtained from 30 febrile controls (19.1 ± 13.7 months, M/F 13/17). In KD patients, VEGF levels in the pre-IVIG acute phase were significantly higher than those in the subacute and convalescent phases (both p < 0.001). In KD patients with CALs, VEGF levels significantly increased immediately in the post-IVIG phase (p = 0.039), and then significantly decreased in the subacute phase (p = 0.002). KD patients with acute CALs had higher median VEGF levels than those without acute CALs from acute to convalescent phases. In the subacute phase, KD patients with acute CALs had significantly higher VEGF levels (p = 0.022) than those without acute CALs. Our data show that VEGF did not decrease after IVIG treatment, and increased significantly after IVIG treatment in KD patients with acute CALs in acute phase. VEGF might be related to the complications of CALs in KD patients.
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Affiliation(s)
- Chun-Yu Chen
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
- Department of Pediatrics, Chi Mei Medical Center, Tainan 71004, Taiwan
| | - Shih-Hui Huang
- Department of Nursing, Fooyin University, Kaohsiung 83102, Taiwan
| | - Kuang-Jen Chien
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Tsung-Jen Lai
- Division of Clinical Laboratory, Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Wei-Hsiang Chang
- Department of Food Safety/Hygiene and Risk Management, Medical College, National Cheng Kung University, Tainan 701401, Taiwan
- Research Center of Environmental Trace Toxic Substances, National Cheng Kung University, Tainan 701401, Taiwan
| | - Kai-Sheng Hsieh
- Department of Pediatrics, China Medical University Children’s Hospital, Taichung 40447, Taiwan
| | - Ken-Pen Weng
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Correspondence: ; Tel.: +886-7-3468203; Fax: +886-7-3468207
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Endothelial Dysfunction, HMGB1, and Dengue: An Enigma to Solve. Viruses 2022; 14:v14081765. [PMID: 36016387 PMCID: PMC9414358 DOI: 10.3390/v14081765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Dengue is a viral infection caused by dengue virus (DENV), which has a significant impact on public health worldwide. Although most infections are asymptomatic, a series of severe clinical manifestations such as hemorrhage and plasma leakage can occur during the severe presentation of the disease. This suggests that the virus or host immune response may affect the protective function of endothelial barriers, ultimately being considered the most relevant event in severe and fatal dengue pathogenesis. The mechanisms that induce these alterations are diverse. It has been suggested that the high mobility group box 1 protein (HMGB1) may be involved in endothelial dysfunction. This non-histone nuclear protein has different immunomodulatory activities and belongs to the alarmin group. High concentrations of HMGB1 have been detected in patients with several infectious diseases, including dengue, and it could be considered as a biomarker for the early diagnosis of dengue and a predictor of complications of the disease. This review summarizes the main features of dengue infection and describes the known causes associated with endothelial dysfunction, highlighting the involvement and possible relationship between HMGB1 and DENV.
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Turner CT, Pawluk M, Bolsoni J, Zeglinski MR, Shen Y, Zhao H, Ponomarev T, Richardson KC, West CR, Papp A, Granville DJ. Sulfaphenazole reduces thermal and pressure injury severity through rapid restoration of tissue perfusion. Sci Rep 2022; 12:12622. [PMID: 35871073 PMCID: PMC9308818 DOI: 10.1038/s41598-022-16512-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia-reperfusion (I/R) have a major causative role for tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.
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Affiliation(s)
- Christopher T. Turner
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Megan Pawluk
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Juliana Bolsoni
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Matthew R. Zeglinski
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Yue Shen
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Hongyan Zhao
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Tatjana Ponomarev
- grid.17091.3e0000 0001 2288 9830Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, BC Canada
| | - Katlyn C. Richardson
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
| | - Christopher R. West
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Cell and Physiological Sciences, University of British Columbia, Vancouver, BC Canada
| | - Anthony Papp
- grid.17091.3e0000 0001 2288 9830Department of Surgery, University of British Columbia, Vancouver, BC Canada
| | - David J. Granville
- grid.17091.3e0000 0001 2288 9830International Collaboration on Repair Discoveries (ICORD) Centre, Blusson Spinal Cord Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Rm 4470, 818 West 10th Ave., Vancouver, BC V5Z 1M9 Canada ,grid.17091.3e0000 0001 2288 9830Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada ,grid.417243.70000 0004 0384 4428British Columbia Professional Firefighters’ Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, Vancouver, BC Canada
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Lekpor CE, Botchway F, Kusi KA, Adjei AA, Wilson MD, Stiles JK, Wilson NO. Angiogenic and angiostatic factors present in the saliva of malaria patients. Malar J 2022; 21:220. [PMID: 35836234 PMCID: PMC9284857 DOI: 10.1186/s12936-022-04221-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/14/2022] [Indexed: 11/24/2022] Open
Abstract
Background Malaria related mortality is associated with significant deregulation of host inflammatory factors such as interferon-inducible protein 10, a member of the CXC or α-subfamily (CXCL10), and host angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2). However, detection of these factors in malaria patients requires the drawing of blood, which is invasive and increases the risk of accidental blood-borne infections. There has been an increased interest in the use of saliva as the body fluid of choice for the diagnosis of many infectious diseases including malaria. Here, saliva levels of CXCL10, Ang-1, and Ang-2 previously shown to be predictive of severe malaria in malaria patients in Ghana were assessed in malaria patients. Methods This study was conducted in the Shai-Osudoku District Hospital in Dodowa, Accra, Ghana and the study population comprised 119 malaria patients and 94 non-malaria subjects. The non-malaria subjects are healthy community participants with no malaria infection. Plasma and saliva levels of CXCL10, Ang-1 and Ang-2 of the study participants were measured using an enzyme-linked immunoassay. Complete blood counts of each participant were measured with a haematology autoanalyzer. Pearson correlation was used to evaluate the correlation between plasma and saliva levels of each biomarker in malaria patients. A p-value of < 0.05 was considered significant. Box plots of median biomarker concentrations were plotted. SPSS version 14.2 software was used for statistical analysis. Results The non-malaria subjects had a median age of 29 years compared to 23 years for malaria patients (p = 0.001). Among the malaria patients, there was a strong significant relationship between CXCL10 (R2 = 0.7, p < 0.0001) and Ang-1 (R2 = 0.7, p < 0.0001). Malaria patients had lower saliva levels of Ang-1 (p = 0.009) and higher saliva levels of CXCL10 (p = 0.004) and Ang-2 (p = 0.001) compared to non-malaria subjects. Conclusions This study provides the first evidence of elevated levels of CXCL10 and Ang-2 in the saliva of malaria patients. Detection of CXCL10, Ang-1 and Ang-2 in saliva may have a potential application for non-invasive malaria diagnosis.
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Affiliation(s)
- Cecilia Elorm Lekpor
- Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana.
| | - Felix Botchway
- Department of Chemical Pathology, University of Ghana Medical School, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Kwadwo Asamoah Kusi
- Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.,Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Andrew A Adjei
- Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana
| | - Michael D Wilson
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Jonathan K Stiles
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Nana O Wilson
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, USA.
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Impact of Enhanced Phagocytosis of Glycated Erythrocytes on Human Endothelial Cell Functions. Cells 2022; 11:cells11142200. [PMID: 35883644 PMCID: PMC9351689 DOI: 10.3390/cells11142200] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/21/2022] [Accepted: 07/08/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetes is associated with a high mortality rate due to vascular complications. Chronic hyperglycemia in diabetes leads to enhanced oxidative stress and glycation. Here, we explored the impact of glycation on human erythrocyte characteristics and capacity to affect endothelial cell function following erythrophagocytosis. Native and glucose-mediated glycated erythrocytes were prepared and characterized in terms of structural and deformability modifications. Erythrocyte preparations were tested for their binding and phagocytosis capacity as well as the potential functional consequences on human endothelial cell lines and primary cultures. Oxidative modifications were found to be enhanced in glycated erythrocytes after determination of their deformability, advanced glycation end-product content and eryptosis. Erythrophagocytosis by endothelial cells was significantly increased when incubated in the presence of glycated erythrocytes. In addition, higher iron accumulation, oxidative stress and impaired endothelial cell permeability were evidenced in cells previously incubated with glycated erythrocytes. When cultured under flow conditions, cellular integrity was disrupted by glycated erythrocytes at microvessel bifurcations, areas particularly prone to vascular complications. This study provides important new data on the impact of glycation on the structure of erythrocytes and their ability to alter endothelial cell function. Increased erythrophagocytosis may have a deleterious impact on endothelial cell function with adverse consequences on diabetic vascular complications.
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McDonald CR, Leligdowicz A, Conroy AL, Weckman AM, Richard-Greenblatt M, Ngai M, Erice C, Zhong K, Namasopo S, Opoka RO, Hawkes MT, Kain KC. Immune and endothelial activation markers and risk stratification of childhood pneumonia in Uganda: A secondary analysis of a prospective cohort study. PLoS Med 2022; 19:e1004057. [PMID: 35830474 PMCID: PMC9328519 DOI: 10.1371/journal.pmed.1004057] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/27/2022] [Accepted: 06/23/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Despite the global burden of pneumonia, reliable triage tools to identify children in low-resource settings at risk of severe and fatal respiratory tract infection are lacking. This study assessed the ability of circulating host markers of immune and endothelial activation quantified at presentation, relative to currently used clinical measures of disease severity, to identify children with pneumonia who are at risk of death. METHODS AND FINDINGS We conducted a secondary analysis of a prospective cohort study of children aged 2 to 59 months presenting to the Jinja Regional Hospital in Jinja, Uganda between February 2012 and August 2013, who met the Integrated Management of Childhood Illness (IMCI) diagnostic criteria for pneumonia. Circulating plasma markers of immune (IL-6, IL-8, CXCL-10/IP-10, CHI3L1, sTNFR1, and sTREM-1) and endothelial (sVCAM-1, sICAM-1, Angpt-1, Angpt-2, and sFlt-1) activation measured at hospital presentation were compared to lactate, respiratory rate, oxygen saturation, procalcitonin (PCT), and C-reactive protein (CRP) with a primary outcome of predicting 48-hour mortality. Of 805 children with IMCI pneumonia, 616 had severe pneumonia. Compared to 10 other immune and endothelial activation markers, sTREM-1 levels at presentation had the best predictive accuracy in identifying 48-hour mortality for children with pneumonia (AUROC 0.885, 95% CI 0.841 to 0.928; p = 0.03 to p < 0.001) and severe pneumonia (AUROC 0.870, 95% CI 0.824 to 0.916; p = 0.04 to p < 0.001). sTREM-1 was more strongly associated with 48-hour mortality than lactate (AUROC 0.745, 95% CI 0.664 to 0.826; p < 0.001), respiratory rate (AUROC 0.615, 95% CI 0.528 to 0.702; p < 0.001), oxygen saturation (AUROC 0.685, 95% CI 0.594 to 0.776; p = 0.002), PCT (AUROC 0.650, 95% CI 0.566 to 0.734; p < 0.001), and CRP (AUROC 0.562, 95% CI 0.472 to 0.653; p < 0.001) in cases of pneumonia and severe pneumonia. The main limitation of this study was the unavailability of radiographic imaging. CONCLUSIONS In this cohort of Ugandan children, sTREM-1 measured at hospital presentation was a significantly better indicator of 48-hour mortality risk than other common approaches to risk stratify children with pneumonia. Measuring sTREM-1 at clinical presentation may improve the early triage, management, and outcome of children with pneumonia at risk of death. TRIAL REGISTRATION The trial was registered at clinicaltrial.gov (NCT04726826).
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Affiliation(s)
- Chloe R. McDonald
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Aleksandra Leligdowicz
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
- Department of Medicine, Division of Critical Care Medicine, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Andrea L. Conroy
- Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America
| | - Andrea M. Weckman
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Melissa Richard-Greenblatt
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Public Health Ontario Laboratory, Toronto, Canada
| | - Michelle Ngai
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Clara Erice
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Kathleen Zhong
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Sophie Namasopo
- Department of Paediatrics, Kabale Regional Referral Hospital, Kabale, Uganda
| | - Robert O. Opoka
- Department of Paediatrics and Child Health, Mulago Hospital and Makerere University, Kawempe, Kampala, Uganda
| | - Michael T. Hawkes
- Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada
| | - Kevin C. Kain
- SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
- Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada
- * E-mail:
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43
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Boron M, Hauzer-Martin T, Keil J, Sun XL. Circulating Thrombomodulin: Release Mechanisms, Measurements, and Levels in Diseases and Medical Procedures. TH OPEN 2022; 6:e194-e212. [PMID: 36046203 PMCID: PMC9273331 DOI: 10.1055/a-1801-2055] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/11/2022] [Indexed: 12/02/2022] Open
Abstract
Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with novel coronavirus disease 2019 (COVID-19) recently. In addition, microvesicles (MVs) that contain membrane TM (MV-TM) have been found to be released from activated cells which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and MV-TM have been reported, including enzymatic, chemical, and TM mutation mechanisms. Measurements of sTM and MV-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories as follows: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease.
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Affiliation(s)
- Mallorie Boron
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Tiffany Hauzer-Martin
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Joseph Keil
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Xue-Long Sun
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
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44
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Sudarsanam H, Buhmann R, Henschler R. Influence of Culture Conditions on Ex Vivo Expansion of T Lymphocytes and Their Function for Therapy: Current Insights and Open Questions. Front Bioeng Biotechnol 2022; 10:886637. [PMID: 35845425 PMCID: PMC9277485 DOI: 10.3389/fbioe.2022.886637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/16/2022] [Indexed: 01/03/2023] Open
Abstract
Ex vivo expansion of T lymphocytes is a central process in the generation of cellular therapies targeted at tumors and other disease-relevant structures, which currently cannot be reached by established pharmaceuticals. The influence of culture conditions on T cell functions is, however, incompletely understood. In clinical applications of ex vivo expanded T cells, so far, a relatively classical standard cell culture methodology has been established. The expanded cells have been characterized in both preclinical models and clinical studies mainly using a therapeutic endpoint, for example antitumor response and cytotoxic function against cellular targets, whereas the influence of manipulations of T cells ex vivo including transduction and culture expansion has been studied to a much lesser detail, or in many contexts remains unknown. This includes the circulation behavior of expanded T cells after intravenous application, their intracellular metabolism and signal transduction, and their cytoskeletal (re)organization or their adhesion, migration, and subsequent intra-tissue differentiation. This review aims to provide an overview of established T cell expansion methodologies and address unanswered questions relating in vivo interaction of ex vivo expanded T cells for cellular therapy.
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Affiliation(s)
| | | | - Reinhard Henschler
- Institute of Transfusion Medicine, University Hospital Leipzig, Leipzig, Germany
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Cabral N, de Figueiredo V, Gandini M, de Souza CF, Medeiros RA, Lery LMS, Lara FA, de Macedo CS, Pessolani MCV, Pereira GMB. Modulation of the Response to Mycobacterium leprae and Pathogenesis of Leprosy. Front Microbiol 2022; 13:918009. [PMID: 35722339 PMCID: PMC9201476 DOI: 10.3389/fmicb.2022.918009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/16/2022] [Indexed: 12/20/2022] Open
Abstract
The initial infection by the obligate intracellular bacillus Mycobacterium leprae evolves to leprosy in a small subset of the infected individuals. Transmission is believed to occur mainly by exposure to bacilli present in aerosols expelled by infected individuals with high bacillary load. Mycobacterium leprae-specific DNA has been detected in the blood of asymptomatic household contacts of leprosy patients years before active disease onset, suggesting that, following infection, the bacterium reaches the lymphatic drainage and the blood of at least some individuals. The lower temperature and availability of protected microenvironments may provide the initial conditions for the survival of the bacillus in the airways and skin. A subset of skin-resident macrophages and the Schwann cells of peripheral nerves, two M. leprae permissive cells, may protect M. leprae from effector cells in the initial phase of the infection. The interaction of M. leprae with these cells induces metabolic changes, including the formation of lipid droplets, that are associated with macrophage M2 phenotype and the production of mediators that facilitate the differentiation of specific T cells for M. leprae-expressed antigens to a memory regulatory phenotype. Here, we discuss the possible initials steps of M. leprae infection that may lead to active disease onset, mainly focusing on events prior to the manifestation of the established clinical forms of leprosy. We hypothesize that the progressive differentiation of T cells to the Tregs phenotype inhibits effector function against the bacillus, allowing an increase in the bacillary load and evolution of the infection to active disease. Epigenetic and metabolic mechanisms described in other chronic inflammatory diseases are evaluated for potential application to the understanding of leprosy pathogenesis. A potential role for post-exposure prophylaxis of leprosy in reducing M. leprae-induced anti-inflammatory mediators and, in consequence, Treg/T effector ratios is proposed.
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Affiliation(s)
- Natasha Cabral
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Vilma de Figueiredo
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Mariana Gandini
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Cíntia Fernandes de Souza
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Rychelle Affonso Medeiros
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Letícia Miranda Santos Lery
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Flávio Alves Lara
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Cristiana Santos de Macedo
- Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | | | - Geraldo Moura Batista Pereira
- Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
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46
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Chaudhary A, Kataria P, Surela N, Das J. Pathophysiology of Cerebral Malaria: Implications of MSCs as A Regenerative Medicinal Tool. Bioengineering (Basel) 2022; 9:bioengineering9060263. [PMID: 35735506 PMCID: PMC9219920 DOI: 10.3390/bioengineering9060263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
The severe form of malaria, i.e., cerebral malaria caused by Plasmodium falciparum, is a complex neurological syndrome. Surviving persons have a risk of behavioral difficulties, cognitive disorders, and epilepsy. Cerebral malaria is associated with multiple organ dysfunctions. The adhesion and accumulation of infected RBCs, platelets, and leucocytes (macrophages, CD4+ and CD8+ T cells, and monocytes) in the brain microvessels play an essential role in disease progression. Micro-vascular hindrance by coagulation and endothelial dysfunction contributes to neurological damage and the severity of the disease. Recent studies in human cerebral malaria and the murine model of cerebral malaria indicate that different pathogens as well as host-derived factors are involved in brain microvessel adhesion and coagulation that induces changes in vascular permeability and impairment of the blood-brain barrier. Efforts to alleviate blood-brain barrier dysfunction and de-sequestering of RBCs could serve as adjunct therapies. In this review, we briefly summarize the current understanding of the pathogenesis of cerebral malaria, the role of some factors (NK cells, platelet, ANG-2/ANG-1 ratio, and PfEMP1) in disease progression and various functions of Mesenchymal stem cells. This review also highlighted the implications of MSCs as a regenerative medicine.
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Affiliation(s)
- Amrendra Chaudhary
- Parasite-Host Biology, National Institute of Malaria Research, New Delhi 110077, India; (A.C.); (P.K.); (N.S.)
| | - Poonam Kataria
- Parasite-Host Biology, National Institute of Malaria Research, New Delhi 110077, India; (A.C.); (P.K.); (N.S.)
| | - Neha Surela
- Parasite-Host Biology, National Institute of Malaria Research, New Delhi 110077, India; (A.C.); (P.K.); (N.S.)
| | - Jyoti Das
- Parasite-Host Biology, National Institute of Malaria Research, New Delhi 110077, India; (A.C.); (P.K.); (N.S.)
- AcSIR, Ghaziabad 201002, India
- Correspondence: or ; Tel.: +91-25307203; Fax: +91-25307177
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47
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Atkinson BK, Goddard A, Engelbrecht M, Pretorius S, Pazzi P. Circulating markers of endothelial activation in canine parvoviral enteritis. J S Afr Vet Assoc 2022. [DOI: 10.36303/jsava.2022.93.1.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Affiliation(s)
- BK Atkinson
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria,
South Africa
| | - A Goddard
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria,
South Africa
| | - M Engelbrecht
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria,
South Africa
| | - S Pretorius
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria,
South Africa
| | - P Pazzi
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria,
South Africa
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48
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Szeghy RE, Stute NL, Province VM, Augenreich MA, Stickford JL, Stickford ASL, Ratchford SM. Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection. J Appl Physiol (1985) 2022; 132:1297-1309. [PMID: 35439042 PMCID: PMC9126215 DOI: 10.1152/japplphysiol.00793.2021] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can increase arterial stiffness 3–4 wk following infection, even among young, healthy adults. However, the long-term impacts of SARS-CoV-2 infection on cardiovascular health and the duration of recovery remain unknown. The purpose of this study was to elucidate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults during the 6 mo following infection. Assessments were performed at months 1, 2, 3, 4, and ∼6 following SARS-CoV-2 infection. Doppler ultrasound was used to measure carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness, and arterial tonometry was used to measure central blood pressures and aortic augmentation index at a heart rate of 75 beats·min−1 (AIx@HR75). Vascular (VCAM-1) and intracellular (ICAM-1) adhesion molecules were analyzed as circulating markers of arterial stiffness. From months 1–6, a significant reduction in cfPWV was observed (month 1: 5.70 ± 0.73 m·s−1; month 6: 4.88 ± 0.65 m·s−1; P < 0.05) without any change in carotid stiffness measures. Reductions in systolic blood pressure (month 1: 123 ± 8 mmHg; month 6: 112 ± 11 mmHg) and mean arterial pressure (MAP; month 1: 97 ± 6 mmHg; month 6: 86 ± 7 mmHg) were observed (P < 0.05), although AIx@HR75 did not change over time. The month 1–6 change in cfPWV and MAP were correlated (r = 0.894; P < 0.001). A reduction in VCAM-1 was observed at month 3 compared with month 1 (month 1: 5,575 ± 2,242 pg·mL−1; month 3: 4,636 ± 1,621 pg·mL−1; P < 0.05) without a change in ICAM-1. A reduction in cfPWV was related with MAP, and some indicators of arterial stiffness remain elevated for several months following SARS-CoV-2 infection, possibly contributing to prolonged recovery and increased cardiovascular health risks. NEW & NOTEWORTHY We sought to investigate potential long-lasting effects of SARS-CoV-2 infection on markers of arterial stiffness among young adults for 6 mo following infection. Carotid femoral pulse wave velocity was significantly reduced while carotid stiffness measures remained unaltered over the 6-mo period. These findings suggest several months of recovery from infection may be necessary for young adults to improve various markers of arterial stiffness, possibly contributing to cardiovascular health and recovery among those infected with SARS-CoV-2.
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Affiliation(s)
- Rachel E Szeghy
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Nina L Stute
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Valesha M Province
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Marc A Augenreich
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Jonathon L Stickford
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Abigail S L Stickford
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
| | - Stephen M Ratchford
- Department of Health & Exercise Science, Appalachian State University, Boone, North Carolina
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49
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Subsets of Cytokines and Chemokines from DENV-4-Infected Patients Could Regulate the Endothelial Integrity of Cultured Microvascular Endothelial Cells. Pathogens 2022; 11:pathogens11050509. [PMID: 35631030 PMCID: PMC9144803 DOI: 10.3390/pathogens11050509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/14/2022] [Accepted: 04/19/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction: It is a consensus that inflammatory mediators produced by immune cells contribute to changes in endothelial permeability in dengue. We propose to relate inflammatory mediators seen in dengue patients with the in vitro alteration of endothelial cells (ECs) cultured with serum from these patients. Methods: Patients with mild (DF) to moderate and severe dengue (DFWS/Sev) were selected. ELISA quantified inflammatory mediators. Expression of adhesion molecules and CD147 were evaluated in the ECs cultured with the patient’s serum by flow cytometry. We assessed endothelial permeability by measuring transendothelial electrical resistance in cocultures of ECs with patient serum. Results: Dengue infection led to an increase in inflammatory mediators—the IL-10 distinguished DF from DFWS/Sev. There were no changes in CD31, CD54, and CD106 but decreased CD147 expression in ECs. DFWS/Sev sera induced a greater difference in endothelial permeability than DF sera. Correlation statistical test indicated that low IL-10 and IFN-γ and high CCL5 maintain the integrity of ECs in DF patients. In contrast, increased TNF, IFN-γ, CXCL8, and CCL2 maintain EC integrity in DFWS/Sev patients. Conclusions: Our preliminary data suggest that a subset of inflammatory mediators may be related to the maintenance or loss of endothelial integrity, reflecting the clinical prognosis.
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50
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Graça NAG, Joly BS, Voorberg J, Vanhoorelbeke K, Béranger N, Veyradier A, Coppo P. TTP: From empiricism for an enigmatic disease to targeted molecular therapies. Br J Haematol 2022; 197:156-170. [PMID: 35146746 PMCID: PMC9304236 DOI: 10.1111/bjh.18040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/29/2021] [Accepted: 12/31/2021] [Indexed: 12/19/2022]
Abstract
The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized.
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Affiliation(s)
- Nuno A. G. Graça
- Department of Molecular Hematology, Sanquin‐Academic Medical CenterLandsteiner LaboratoryAmsterdamThe Netherlands
| | - Bérangère S. Joly
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Jan Voorberg
- Department of Molecular Hematology, Sanquin‐Academic Medical CenterLandsteiner LaboratoryAmsterdamThe Netherlands
- Department of Experimental Vascular MedicineAmsterdam UMCAmsterdamThe Netherlands
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, IRF Life SciencesKU Leuven Campus Kulak KortrijkKortrijkBelgium
| | - Nicolas Béranger
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Agnès Veyradier
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Paul Coppo
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
- Service d'HématologieHôpital Saint‐Antoine, AP‐HPParisFrance
- Sorbonne UniversitéUPMC Univ ParisParisFrance
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