scholarly journals Small peptide functionalized thiol–ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition

2012 ◽  
Vol 8 (9) ◽  
pp. 3201-3209 ◽  
Author(s):  
Sarah T. Gould ◽  
Nicole J. Darling ◽  
Kristi S. Anseth
Keyword(s):  
Cell Activation ◽  
Interstitial Cell ◽  
De Novo ◽  
Small Peptide

scholarly journals Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Patricia Price ◽  
David M. Murdoch ◽  
Upasna Agarwal ◽  
Sharon R. Lewin ◽  
Julian H. Elliott ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Granulomatous Inflammation ◽  
T Cell Response ◽  
Immune Restoration ◽  
Immunological Parameters ◽  
Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

scholarly journals Effect of biodegradation and de novo matrix synthesis on the mechanical properties of valvular interstitial cell-seeded polyglycerol sebacate–polycaprolactone scaffolds

2013 ◽  
Vol 9 (4) ◽  
pp. 5963-5973 ◽  
Author(s):  
Shilpa Sant ◽  
Dharini Iyer ◽  
Akhilesh K. Gaharwar ◽  
Alpesh Patel ◽  
Ali Khademhosseini
Keyword(s):  
Mechanical Properties ◽  
Interstitial Cell ◽  
De Novo ◽  
Matrix Synthesis

scholarly journals Hemagglutinin-Dependent Tropism of H5N1 Avian Influenza Virus for Human Endothelial Cells

2009 ◽  
Vol 83 (24) ◽  
pp. 12947-12955 ◽  
Author(s):  
Manuela Ocaña-Macchi ◽  
Michael Bel ◽  
Laurence Guzylack-Piriou ◽  
Nicolas Ruggli ◽  
Matthias Liniger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Avian Influenza ◽  
Cell Activation ◽  
De Novo ◽  
Binding Capacity ◽  
Multiorgan Failure ◽  
Influenza Viruses ◽  
Human Influenza ◽  
Receptor Specificity ◽  
Activation Markers

ABSTRACT Although current H5N1 highly pathogenic avian influenza viruses (HPAIV) are inefficiently transmitted to humans, infected individuals can suffer from severe disease, often progressing rapidly to acute respiratory distress syndrome and multiorgan failure. This is in contrast with the situation with human influenza viruses, which in immunocompetent individuals usually cause only a respiratory disease which is less aggressive than that observed with avian H5N1 viruses. While the biological basis of inefficient transmission is well documented, the mechanisms by which the H5N1 viruses cause fatal disease remain unclear. In the present study, we demonstrate that human pulmonary microvascular endothelial cells (hPMEC) had a clearly higher susceptibility to infection by H5N1 HPAIV than to infection by human influenza viruses. This was measurable by de novo intracellular nucleoprotein production and virus replication. It was also related to a relatively higher binding capacity to cellular receptors. After infection of hPMEC, cell activation markers E-selectin and P-selectin were upregulated, and the proinflammatory cytokines interleukin-6 and beta interferon were secreted. H5N1 virus infection was also associated with an elevated rate of cell death. Reverse genetics analyses demonstrated a major role for the viral hemagglutinin in this cell tropism. Overall, avian H5N1 viruses have a particular receptor specificity targeting endothelial cells that is different from human influenza viruses, and this H5N1 receptor specificity could contribute to disease pathogenesis.

scholarly journals B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Benjamin G. Barwick ◽  
Christopher D. Scharer ◽  
Ryan J. Martinez ◽  
Madeline J. Price ◽  
Alexander N. Wein ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Differentiation ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
De Novo ◽  
B Cell Activation ◽  
Plasma Cell Differentiation

scholarly journals PD-L1 and tumor-associated macrophages in de novo DLBCL

2019 ◽  
Vol 3 (4) ◽  
pp. 531-540 ◽  
Author(s):  
Ronald McCord ◽  
Christopher R. Bolen ◽  
Hartmut Koeppen ◽  
Edward E. Kadel ◽  
Mikkel Z. Oestergaard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Activation ◽  
Immune Cell ◽  
De Novo ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Staining Procedure ◽  
Immune Cell Activation ◽  
Improved Outcomes ◽  
Risk Patients

Abstract Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.

scholarly journals The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

2018 ◽  
Vol 46 (11) ◽  
pp. 5547-5560 ◽  
Author(s):  
Kuo-Hsuan Hung ◽  
Yong H Woo ◽  
I-Ying Lin ◽  
Chin-Hsiu Liu ◽  
Li-Chieh Wang ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
De Novo ◽  
Epigenetic Mechanism ◽  
B Cell Activation ◽  
Motif Analysis ◽  
Follicular Helper

Abstract T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.

scholarly journals Regulation of CXCR6 Expression on Adipocytes and Osteoblasts Differentiated from Human Adipose Tissue-Derived Mesenchymal Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Seung-Cheol Lee ◽  
Yoo-Jung Lee ◽  
Min Kyoung Shin ◽  
Jung-Suk Sung
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Human Mesenchymal Stem Cells ◽  
De Novo Synthesis ◽  
Differentiation Potential ◽  
Differentiated Cells

Human mesenchymal stem cells derived from adipose tissue (hADMSCs) are a desirable candidate in regenerative medicine. hADMSCs secrete growth factors, cytokines, and chemokines and also express various receptors that are important in cell activation, differentiation, and migration to injured tissue. We showed that the expression level of chemokine receptor CXCR6 was significantly increased by ~2.5-fold in adipogenic-differentiated cells (Ad), but not in osteogenic-differentiated cells (Os) when compared with hADMSCs. However, regulation of CXCR6 expression on hADMSCs by using lentiviral particles did not affect the differentiation potential of hADMSCs. Increased expression of CXCR6 on Ad was mediated by both receptor recycling, which was in turn regulated by secretion of CXCL16, and de novo synthesis. The level of soluble CXCL16 was highly increased in both Ad and Os in particular, which inversely correlates with the expression on a transmembrane-bound form of CXCL16 that is cleaved by disintegrin and metalloproteinase. We concluded that the expression of CXCR6 is regulated by receptor degradation or recycling when it is internalized by interaction with CXCL16 and by de novo synthesis of CXCR6. Overall, our study may provide an insight into the molecular mechanisms of the CXCR6 reciprocally expressed on differentiated cells from hADMSCs.

scholarly journals A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse

2020 ◽  
Vol 127 (3) ◽  
Author(s):  
Jaime Ibarrola ◽  
Amaia Garcia-Peña ◽  
Lara Matilla ◽  
Benjamin Bonnard ◽  
Rafael Sádaba ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Mineralocorticoid Receptor ◽  
Cell Activation ◽  
Cardiac Fibrosis ◽  
Interstitial Cell ◽  
Activation Markers ◽  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

Rationale: Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. Objective: We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. Methods and Results: Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. Conclusions: These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.

Enhanced B7-2 Gene Expression by Interferon-γ in Human Monocytic Cells Is Controlled Through Transcriptional and Posttranscriptional Mechanisms

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1782-1789 ◽  
Author(s):  
R.E. Curiel ◽  
C.S. Garcia ◽  
S. Rottschafer ◽  
M.C. Bosco ◽  
I. Espinoza-Delgado
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Costimulatory Molecule ◽  
Interferon Γ ◽  
Monocytic Cell ◽  
Monocytic Cells ◽  
Enhanced Expression ◽  
Ifn Γ

B7-2 is a costimulatory molecule expressed on professional antigen-presenting cells that provides T cells with a critical signal resulting in T-cell activation. Interferon-γ (IFN-γ) enhances B7-2 protein expression in monocytic cells. However, the molecular mechanisms controlling the enhanced expression of B7-2 are poorly understood. Northern blot and flow cytometry analysis revealed that human monocytes and the human monocytic cell line MonoMac6 (MM6) constitutively expressed B7-2 mRNA and protein and IFN-γ treatment further enhanced the expression of both molecules. The ability of IFN-γ to enhance B7-2 mRNA was evident at the dose of 31 U/mL and reached plateau levels at 500 U/mL. The effects of IFN-γ on B7-2 mRNA expression were time dependent and occurred within 3 hours of treatment and increased through 24 hours. In vitro transcription assays and mRNA stability experiments showed that IFN-γ increases both transcriptional activity and the stability of B7-2 mRNA. Treatment of MM6 cells with cycloheximide showed that de novo protein synthesis was not required for the IFN-γ–enhanced expression of B7-2 mRNA. Overall, these studies show for the first time that IFN-γ–enhanced expression of B7-2 protein in human monocytic cells is controlled at the gene level through a dual mechanism involving transcriptional and posttranscriptional mechanisms.

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9091-9091
Author(s):  
Deborah Jean Lee Wong ◽  
Jeffrey Gary Schneider ◽  
Raid Aljumaily ◽  
Wolfgang Michael Korn ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Advanced Nsclc ◽  
De Novo ◽  
Cd8 T Cell ◽  
Outcome Data ◽  
Low Grade

9091 Background: Although IL-10 has anti-inflammatory properties, it stimulates cytotoxicity and proliferation of intratumoral antigen activated CD8+ T cell at higher concentrations. AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. Methods: We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]. Tumor responses were assessed by irRC every 8 weeks. Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor PD-L1 expression was confirmed by IHC (22C3). Results: Pts had a median of 2 prior therapies. Median follow-up is 9.6 mo (range 0.5-77.3) in this fully enrolled cohort. AM0010 plus anti-PD-1 was well-tolerated. TrAEs were reversible and transient, with most being low grade, most commonly fatigue and pyrexia. G3/4 TrAEs were thrombocytopenia (7), anemia (6), fatigue (4), rash (3), pyrexia (2), hypertriglyceridemia (1) and pneumonitis (1). As of Jan. 31 2017, 22 pts had at least 1 tumor assessment. Partial responses (PRs) were observed in 8 pts (36.4%). 17 of these 22 pts had tissue for analysis of percent of tumor cells with PD-L1 expression (22C3): 58.8% had <1%, 17.7% had 1-49% and 23.5% had >50%. Best response data stratified for PD-L1 are shown in the table. Median PFS and OS for the entire cohort have not been reached. Updated outcome data that includes all enrolled pts will be available at the meeting. AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising. Clinical trial information: NCT02009449. [Table: see text]

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