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Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-Cov-2 Infection
Journal of Autoimmunity 121 (2021) 102662 Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection Dennis McGonagle a,b, Gabriele De Marco a, Charles Bridgewood a,* a Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK b National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK ARTICLE INFO ABSTRACT Keywords: Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA COVID-19 pneumonia related thrombosis vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate Vaccine induced thrombotic thrombocytopenia immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including (VITT) venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the Heparin induced thrombocytopenia (HIT) ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed DNA-PF4 interactions. VITT model Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin- Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent in teractions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extra cellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone inter actons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. -
Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: a Canonical Pathway
Lipid related genes altered in NASH connect inflammation in liver pathogenesis progression to HCC: a canonical pathway Christophe Desterke1, Franck Chiappini2* 1 Inserm, U935, Villejuif, F-94800, France 2 Cell Growth and Tissue Repair (CRRET) Laboratory, Université Paris-Est Créteil (UPEC), EA 4397 / ERL CNRS 9215, F-94010, Créteil, France. Corresponding author: *Franck Chiappini. Laboratoire du CRRET (Croissance, Réparation et Régénération Tissulaires), Université Paris-Est Créteil, 61 avenue du Général de Gaulle F- 94010, Créteil Cedex, Val de Marne, France. Email address: [email protected]; Tel: +33(0)145177080; Fax: +33(0)145171816 Supplementary Information Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Supplementary Datasets Table S2: Expression fold change of lipid related genes found differentially expressed between NASH and healthy obese liver samples. Supplementary Datasets Table S3: Liver as principal filter for prioritization of lipid related genes found differentially expressed in NASH. Supplementary Datasets Table S4: Gene prioritization secondary filters (immunological, inflammation, liver pathogenesis progression) table found with lipid related genes differentially expressed in NASH. Supplementary Datasets Table S5: Identification of protein partners of YWHAZ gene using InnateDB database. Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Ranking of "lipidic" textmining Gene symbol -
Critical Role of CXCL4 in the Lung Pathogenesis of Influenza (H1N1) Respiratory Infection
ARTICLES Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection L Guo1,3, K Feng1,3, YC Wang1,3, JJ Mei1,2, RT Ning1, HW Zheng1, JJ Wang1, GS Worthen2, X Wang1, J Song1,QHLi1 and LD Liu1 Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung. INTRODUCTION necrosis factor (TNF)-a, interleukin (IL)-6, and IL-1b, to exert Influenza A virus (IAV) infections cause respiratory diseases in further antiviral innate immune effects.2 Meanwhile, the innate large populations worldwide every year and result in seasonal immune cells act as antigen-presenting cells and release influenza epidemics and unexpected pandemic. -
Pathogenesis of Coronary Artery Disease: Focus on Genetic Risk Factors and Identification of Genetic Variants
The Application of Clinical Genetics Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants Sergi Sayols-Baixeras Abstract: Coronary artery disease (CAD) is the leading cause of death and disability worldwide, Carla Lluís-Ganella and its prevalence is expected to increase in the coming years. CAD events are caused by the Gavin Lucas interplay of genetic and environmental factors, the effects of which are mainly mediated through Roberto Elosua cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Cardiovascular Epidemiology and Genetics Research Group, Institut Linkage studies have been able to identify genetic variants associated with monogenic diseases, Hospital del Mar d’Investigacions whereas genome-wide association studies have been more successful in determining genetic Mèdiques, Barcelona, Spain variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility. Keywords: coronary artery disease, pathogenesis, genetic risk factors, genetic variants Introduction Coronary artery disease (CAD) is the principal individual cause of mortality and morbidity worldwide. -
Inflammatory Modulation of Hematopoietic Stem Cells by Magnetic Resonance Imaging
Electronic Supplementary Material (ESI) for RSC Advances. This journal is © The Royal Society of Chemistry 2014 Inflammatory modulation of hematopoietic stem cells by Magnetic Resonance Imaging (MRI)-detectable nanoparticles Sezin Aday1,2*, Jose Paiva1,2*, Susana Sousa2, Renata S.M. Gomes3, Susana Pedreiro4, Po-Wah So5, Carolyn Ann Carr6, Lowri Cochlin7, Ana Catarina Gomes2, Artur Paiva4, Lino Ferreira1,2 1CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal, 2Biocant, Biotechnology Innovation Center, Cantanhede, Portugal, 3King’s BHF Centre of Excellence, Cardiovascular Proteomics, King’s College London, London, UK, 4Centro de Histocompatibilidade do Centro, Coimbra, Portugal, 5Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK, 6Cardiac Metabolism Research Group, Department of Physiology, Anatomy & Genetics, University of Oxford, UK, 7PulseTeq Limited, Chobham, Surrey, UK. *These authors contributed equally to this work. #Correspondence to Lino Ferreira ([email protected]). Experimental Section Preparation and characterization of NP210-PFCE. PLGA (Resomers 502 H; 50:50 lactic acid: glycolic acid) (Boehringer Ingelheim) was covalently conjugated to fluoresceinamine (Sigma- Aldrich) according to a protocol reported elsewhere1. NPs were prepared by dissolving PLGA (100 mg) in a solution of propylene carbonate (5 mL, Sigma). PLGA solution was mixed with perfluoro- 15-crown-5-ether (PFCE) (178 mg) (Fluorochem, UK) dissolved in trifluoroethanol (1 mL, Sigma). This solution was then added to a PVA solution (10 mL, 1% w/v in water) dropwise and stirred for 3 h. The NPs were then transferred to a dialysis membrane and dialysed (MWCO of 50 kDa, Spectrum Labs) against distilled water before freeze-drying. Then, NPs were coated with protamine sulfate (PS). -
Effects of in Utero Exposure to Di-N-Butyl Phthalate on Testicular
Article Effects of In Utero Exposure to Di‐n‐Butyl Phthalate on Testicular Development in Rat Tan Ma 1,2,†, Xiaoqin Yin 1,2,†, Ruitong Han 1,2, Jie Ding 1,2, Huan Zhang 3,*, Xiaodong Han 1,2,* and Dongmei Li 1,2,* 1 Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; [email protected] (T.M.); [email protected] (X.Y.); [email protected] (R.H.); [email protected] (J.D.) 2 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China 3 Department of Clinical and Experimental Medicine, Linköping University, SE‐581 83 Linköping, Sweden * Correspondence: [email protected] (H.Z.); [email protected] (X.H.); [email protected] (D.L.) † These authors contributed equally to this work. Received: 17 October 2017; Accepted: 20 October 2017; Published: 24 October 2017 Abstract: Humans are inevitably exposed to ubiquitous phthalate esters (PAEs). In utero exposure to di‐n‐butyl phthalate (DBP) induces abnormal development of the testis and reproductive tract in male offspring, which correspond closely with the human condition of testicular dysgenesis syndrome (TDS)‐like syndrome. However, the underlying mechanisms have not been elucidated in detail. In this study, pregnant rats were orally exposed to either corn oil (controls) or DBP at three different doses by gavage during Gestational Days 12.5–21.5. Pathological examinations were performed for toxicity evaluation. Proliferation and apoptosis related proteins (ras related dexamethasone induced 1 (Rasd1), mitogen‐activated protein kinase kinases1/2 (MEK1/2), Bcl‐2, and Bax) were measured for mechanisms exploration. -
Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................ -
Role of Estrogen and RAS Signaling in Repeated Implantation Failure
BMB Rep. 2018; 51(5): 225-229 BMB www.bmbreports.org Reports Invited Mini Review Role of estrogen and RAS signaling in repeated implantation failure Kwonho Hong1 & Youngsok Choi2,* 1Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, 2Department of Biomedical Science, CHA University, Seongnam 13488, Korea In humans, hormonal regulation is crucial for the preparation RAS signal as well as the implications for patient with repeated of uterine environment leading to either successful implantation failure. implantation or menstrual cycle. Estrogen is a pivotal female steroid hormone that regulates the uterine dynamics along ESTROGEN SIGNALING with progesterone in the estrous and menstrual cycles in humans. Estrogen signals act via nuclear estrogen receptor or Estrogen production from the ovary during the estrous or membrane-bound receptor. The membrane-bound estrogen menstrual cycle receptor plays a crucial role in the rapid response of estrogen Estrogen exists in three forms such as estrone, estradiol, and in the uterine epithelium. Recently, RASD1 has received estriol (1, 2). Estrogen is produced in various tissues including attention as a novel signal transducer of estrogen in various the ovary, placenta, fat, and the liver in females (3, 4). It is the systems including female reproductive organs. In this review, primary source of estrogen production. Two different somatic we discuss the regulation of estrogen and RASD1 signaling in cells known as theca and granulosa cells surround the oocyte the uterus and also provide insights into RAS as a novel in the ovarian follicles (3-5). Estrogen biosynthesis depends on signaling molecule in repeated implantation failure. [BMB P450 aromatase enzyme activity, which catalyzes the Reports 2018; 51(5): 225-229] hydroxylation of estrogen precursors, adrostenedione or testosterone (Fig. -
Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead
cells Review Chimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead Tahereh Soltantoyeh 1,†, Behnia Akbari 1,† , Amirali Karimi 2, Ghanbar Mahmoodi Chalbatani 1 , Navid Ghahri-Saremi 1, Jamshid Hadjati 1, Michael R. Hamblin 3,4 and Hamid Reza Mirzaei 1,* 1 Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; [email protected] (T.S.); [email protected] (B.A.); [email protected] (G.M.C.); [email protected] (N.G.-S.); [email protected] (J.H.) 2 School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran; [email protected] 3 Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa; [email protected] 4 Radiation Biology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran * Correspondence: [email protected]; Tel.: +98-21-64053268; Fax: +98-21-66419536 † Equally contributed as first author. Abstract: Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. Citation: Soltantoyeh, T.; Akbari, B.; These include targeted molecular therapy and novel immune-based approaches such as immune Karimi, A.; Mahmoodi Chalbatani, G.; checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T- Ghahri-Saremi, N.; Hadjati, J.; lymphocytes such as chimeric antigen receptor (CAR) T cells. -
Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury
BASIC RESEARCH www.jasn.org Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury Jun-Jae Chung ,1 Leonard Goldstein ,2 Ying-Jiun J. Chen,2 Jiyeon Lee ,1 Joshua D. Webster,3 Merone Roose-Girma,2 Sharad C. Paudyal,4 Zora Modrusan,2 Anwesha Dey,5 and Andrey S. Shaw1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background The glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability. Methods Single-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxo- rubicin toxicity, and CD2AP deficiency). Results Allcelltypesintheglomeruluswereidentified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arteri- oles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type–specific and injury type–specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis. -
Up-Regulating of RASD1 and Apoptosis of DU-145 Human Prostate Cancer Cells Induced by Formononetin in Vitro
DOI:http://dx.doi.org/10.7314/APJCP.2014.15.6.2835 Up-regulating of RASD1 and Apoptosis of DU-145 Human Prostate Cancer Cells Induced by Formononetin in Vitro RESEARCH ARTICLE Up-regulating of RASD1 and Apoptosis of DU-145 Human Prostate Cancer Cells Induced by Formononetin in Vitro Xiao-Jia Liu&, Yun-Qian Li&, Qiu-Yue Chen, Sheng-Jun Xiao, Si-En Zeng* Abstract Prostate cancer is one of the most prevalent malignant cancers in men. The isoflavone formononetin is a main active component of red clover plants. In the present study, we assessed the effect of formononetin on human prostate cancer DU-145 cells in vitro, and elucidated posssible mechanisms. DU-145 cells were treated with different concentrations of formononetin and cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 and flow cytometry, and protein levels of RASD1, Bcl-2 and Bax by Western blotting. The results showed that formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax. The level of RASD1 reached its maximum at 48h post-treatment, and rapidly decreased thereafter. Together, we present evidence that formononetin triggered cell apoptosis through the mitochondrial apoptotic pathway by up-regulating RASD1. Keywords: Formononetin - prostate cancer cells - apoptosis - RASD1 Asian Pac J Cancer Prev, 15 (6), 2835-2839 Introduction which has been wildly used for centuries. -
Biomarkers, Master Regulators and Genomic Fabric Remodeling in a Case of Papillary Thyroid Carcinoma
G C A T T A C G G C A T genes Article Biomarkers, Master Regulators and Genomic Fabric Remodeling in a Case of Papillary Thyroid Carcinoma Dumitru A. Iacobas Personalized Genomics Laboratory, CRI Center for Computational Systems Biology, Roy G Perry College of Engineering, Prairie View A&M University, Prairie View, TX 77446, USA; [email protected]; Tel.: +1-936-261-9926 Received: 1 August 2020; Accepted: 1 September 2020; Published: 2 September 2020 Abstract: Publicly available (own) transcriptomic data have been analyzed to quantify the alteration in functional pathways in thyroid cancer, establish the gene hierarchy, identify potential gene targets and predict the effects of their manipulation. The expression data have been generated by profiling one case of papillary thyroid carcinoma (PTC) and genetically manipulated BCPAP (papillary) and 8505C (anaplastic) human thyroid cancer cell lines. The study used the genomic fabric paradigm that considers the transcriptome as a multi-dimensional mathematical object based on the three independent characteristics that can be derived for each gene from the expression data. We found remarkable remodeling of the thyroid hormone synthesis, cell cycle, oxidative phosphorylation and apoptosis pathways. Serine peptidase inhibitor, Kunitz type, 2 (SPINT2) was identified as the Gene Master Regulator of the investigated PTC. The substantial increase in the expression synergism of SPINT2 with apoptosis genes in the cancer nodule with respect to the surrounding normal tissue (NOR) suggests that SPINT2 experimental overexpression may force the PTC cells into apoptosis with a negligible effect on the NOR cells. The predictive value of the expression coordination for the expression regulation was validated with data from 8505C and BCPAP cell lines before and after lentiviral transfection with DDX19B.