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Results: 1 to 10 of 49

Publication Record


At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.
Barnado A, Crofford LJ, Oates JC
(2016) J Leukoc Biol 99: 265-78
MeSH Terms: Acetylcysteine, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Antibodies, Monoclonal, Antimalarials, Apoptosis, Atherosclerosis, Autoantigens, Autoimmune Diseases, Biomarkers, Deoxyribonuclease I, Extracellular Traps, Female, Humans, Hydrolases, Immunosuppressive Agents, Interferon-alpha, Lupus Erythematosus, Systemic, Molecular Targeted Therapy, Neutrophils, Pregnancy, Pregnancy Complications, Protein Processing, Post-Translational, Protein-Arginine Deiminase Type 4, Protein-Arginine Deiminases, Thrombophilia, Thrombosis, Translational Medical Research, Vitamin D
Show Abstract · Added March 25, 2020
Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN-α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN-α production, measuring neutrophil extracellular traps may estimate IFN-α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti-IFN-α therapies. In addition to anti-IFN-α therapies, other novel agents, such as N-acetyl-cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.
© Society for Leukocyte Biology.
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MeSH Terms
Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
Chaum E, Winborn CS, Bhattacharya S
(2015) Mamm Genome 26: 210-21
MeSH Terms: Adult, Aged, 80 and over, Aging, Animals, Apoptosis, Caspases, Caspases, Initiator, Cell Line, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Gene Expression Regulation, Humans, Immunity, Innate, Interferon-alpha, Interferon-gamma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Primary Cell Culture, Quantitative Trait Loci, Retinal Pigment Epithelium, Signal Transduction, Toll-Like Receptor 4, Tumor Suppressor Protein p53
Show Abstract · Added June 11, 2018
The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset ( www.genenetwork.org ) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172-177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.
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25 MeSH Terms
Addition of nitazoxanide to PEG-IFN and ribavirin to improve HCV treatment response in HIV-1 and HCV genotype 1 coinfected persons naïve to HCV therapy: results of the ACTG A5269 trial.
Amorosa VK, Luetkemeyer A, Kang M, Johnson VA, Umbleja T, Haas DW, Yesmin S, Bardin MC, Chung RT, Alston-Smith B, Tebas P, Peters MG
(2013) HIV Clin Trials 14: 274-83
MeSH Terms: Adult, Animals, Antiviral Agents, Drug Therapy, Combination, Female, HIV Infections, HIV-1, Hepacivirus, Hepatitis C, Humans, Interferon-alpha, Male, Middle Aged, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Ribavirin, Thiazoles
Show Abstract · Added March 13, 2015
BACKGROUND - We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons.
METHODS - Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR).
RESULTS - Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated.
CONCLUSION - Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
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18 MeSH Terms
Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma.
Uchino K, Obi S, Tateishi R, Sato S, Kanda M, Sato T, Arano T, Enooku K, Goto E, Masuzaki R, Nakagawa H, Asaoka Y, Kondo Y, Yamashiki N, Goto T, Shiina S, Omata M, Yoshida H, Koike K
(2012) J Gastroenterol 47: 1152-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Antiviral Agents, Carcinoma, Hepatocellular, Cohort Studies, Female, Fluorouracil, Humans, Infusions, Intravenous, Injections, Subcutaneous, Interferon-alpha, Japan, Liver Neoplasms, Male, Middle Aged, Polyethylene Glycols, Recombinant Proteins, Retrospective Studies, Survival Rate, Treatment Outcome
Show Abstract · Added May 2, 2014
BACKGROUND - In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5-fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan.
METHODS - Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 μg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1-5 and 8-12). We assessed their response to treatment and survival, and treatment safety.
RESULTS - The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child-Pugh class A: 9.2 months vs. Child-Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child-Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3-4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred.
CONCLUSIONS - This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment.
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23 MeSH Terms
A single-amino-acid polymorphism in reovirus protein μ2 determines repression of interferon signaling and modulates myocarditis.
Irvin SC, Zurney J, Ooms LS, Chappell JD, Dermody TS, Sherry B
(2012) J Virol 86: 2302-11
MeSH Terms: Animals, Cell Line, Cells, Cultured, Down-Regulation, Humans, Interferon-alpha, Interferon-beta, Mammalian orthoreovirus 3, Mice, Myocarditis, Myocytes, Cardiac, Orthoreovirus, Mammalian, Polymorphism, Single Nucleotide, Reoviridae Infections, Signal Transduction, Viral Proteins
Show Abstract · Added December 5, 2013
Myocarditis is indicated as the second leading cause of sudden death in young adults. Reovirus induces myocarditis in neonatal mice, providing a tractable model system for investigation of this important disease. Alpha/beta-interferon (IFN-α/β) treatment improves cardiac function and inhibits viral replication in patients with chronic myocarditis, and the host IFN-α/β response is a determinant of reovirus strain-specific differences in induction of myocarditis. Virus-induced IFN-β stimulates a signaling cascade that establishes an antiviral state and further induces IFN-α/β through an amplification loop. Reovirus strain-specific differences in induction of and sensitivity to IFN-α/β are associated with the viral M1, L2, and S2 genes. The reovirus M1 gene-encoded μ2 protein is a strain-specific repressor of IFN-β signaling, providing one possible mechanism for the variation in resistance to IFN and induction of myocarditis between different reovirus strains. We report here that μ2 amino acid 208 determines repression of IFN-β signaling and modulates reovirus induction of IFN-β in cardiac myocytes. Moreover, μ2 amino acid 208 determines reovirus replication, both in initially infected cardiac myocytes and after viral spread, by regulating the IFN-β response. Amino acid 208 of μ2 also influences the cytopathic effect in cardiac myocytes after spread. Finally, μ2 amino acid 208 modulates myocarditis in neonatal mice. Thus, repression of IFN-β signaling mediated by reovirus μ2 amino acid 208 is a determinant of the IFN-β response, viral replication and damage in cardiac myocytes, and myocarditis. These results demonstrate that a single amino acid difference between viruses can dictate virus strain-specific differences in suppression of the host IFN-β response and, consequently, damage to the heart.
1 Communities
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16 MeSH Terms
Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response.
Li HS, Gelbard A, Martinez GJ, Esashi E, Zhang H, Nguyen-Jackson H, Liu YJ, Overwijk WW, Watowich SS
(2011) Blood 118: 3879-89
MeSH Terms: Animals, Cell Differentiation, Dendritic Cells, Interferon-alpha, Mice, Mice, Inbred C57BL, Peyer's Patches, STAT1 Transcription Factor, Stem Cells, Th17 Cells, fms-Like Tyrosine Kinase 3
Show Abstract · Added April 11, 2014
Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. Type I IFN signaling via STAT1 has a cell-autonomous role in accrual of PP pDCs in vivo. Moreover, IFN-α enhances pDC generation from DC progenitors by a STAT1-dependent mechanism. pDCs that have been developed in the presence of IFN-α resemble PP pDCs, produce inflammatory cytokines, stimulate Th17 cell generation, and fail to secrete IFN-α on Toll-like receptor engagement. These results indicate that IFN-α influences the development and function of pDCs by inducing emergence of an inflammatory (Th17-inducing) antigen-presenting subset, and simultaneously regulating accumulation of pDCs in the intestinal microenvironment.
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11 MeSH Terms
Pitavastatin enhances antiviral efficacy of standard pegylated interferon plus ribavirin in patients with chronic hepatitis C: a prospective randomized pilot study.
Shimada M, Yoshida S, Masuzaki R, Schuppan D
(2012) J Hepatol 56: 299-300
MeSH Terms: Antiviral Agents, Drug Synergism, Hepatitis C, Chronic, Humans, Interferon-alpha, Pilot Projects, Prospective Studies, Quinolines, Random Allocation, Ribavirin, Viral Load
Added May 2, 2014
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11 MeSH Terms
Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.
Monsalvo AC, Batalle JP, Lopez MF, Krause JC, Klemenc J, Hernandez JZ, Maskin B, Bugna J, Rubinstein C, Aguilar L, Dalurzo L, Libster R, Savy V, Baumeister E, Aguilar L, Cabral G, Font J, Solari L, Weller KP, Johnson J, Echavarria M, Edwards KM, Chappell JD, Crowe JE, Williams JV, Melendi GA, Polack FP
(2011) Nat Med 17: 195-9
MeSH Terms: Adolescent, Adult, Age Factors, Antibodies, Viral, Antigen-Antibody Complex, Antigens, Viral, Complement C3, Cross Reactions, Cytokines, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Interferon-alpha, Interferon-beta, Lung, Middle Aged, Young Adult
Show Abstract · Added November 14, 2013
Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.
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17 MeSH Terms
TRAIL and interferon-alpha act synergistically to induce renal cell carcinoma apoptosis.
Clark PE, Polosukhina DA, Gyabaah K, Moses HL, Thorburn A, Zent R
(2010) J Urol 184: 1166-74
MeSH Terms: Apoptosis, Carcinoma, Renal Cell, Cell Line, Tumor, Drug Synergism, Humans, Interferon-alpha, Kidney Neoplasms, TNF-Related Apoptosis-Inducing Ligand
Show Abstract · Added February 17, 2014
PURPOSE - Despite modern targeted therapy metastatic renal cell carcinoma remains a deadly disease. Interferon-alpha (Calbiochem(R)) is currently used to treat this condition, mainly combined with the targeted anti-vascular endothelial growth factor antibody bevacizumab. TRAIL (Apo2 ligand/tumor necrosis factor related apoptosis inducing ligand) (Calbiochem) is a novel antineoplastic agent now in early phase clinical trials. Interferon-alpha and TRAIL can act synergistically to kill cancer cells but to our knowledge this has never been tested in the context of renal cell carcinoma. We hypothesized that TRAIL and interferon-alpha could synergistically induce apoptosis in renal cell carcinoma cells.
MATERIALS AND METHODS - We treated renal cell carcinoma cell lines with recombinant TRAIL and/or interferon-alpha. Viability and apoptosis were assessed by MTS assay, flow cytometry and Western blot. Synergy was confirmed by isobologram. Interferon-alpha induced changes in renal cell carcinoma cell signaling were assessed by Western blot, flow cytometry and enzyme-linked immunosorbent assay.
RESULTS - TRAIL and interferon-alpha acted synergistically to increase apoptotic cell death in renal cell carcinoma cells. Interferon-alpha treatment altered the ability of cells to activate extracellular signal-regulated kinase while inhibiting extracellular signal-regulated kinase with UO126 abrogated TRAIL and interferon-alpha apoptotic synergy. Interferon-alpha did not induce changes in TRAIL or death receptor expression, or change other known mediators of the intrinsic and extrinsic apoptotic cascade in the cells.
CONCLUSIONS - TRAIL plus interferon-alpha synergistically induces apoptosis in renal cell carcinoma cells, which is due at least in part to interferon-alpha mediated changes in extracellular signal-regulated kinase activation. TRAIL and interferon-alpha combination therapy may be a novel approach to advanced renal cell carcinoma that warrants further testing in vivo.
2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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8 MeSH Terms
Does chemotherapy prevent HCV-related hepatocellular carcinoma? Pros.
Masuzaki R, Yoshida H, Omata M
(2010) Dig Liver Dis 42 Suppl 3: S281-6
MeSH Terms: Antiviral Agents, Carcinoma, Hepatocellular, Chemoprevention, Hepatitis C, Chronic, Humans, Interferon alpha-2, Interferon-alpha, Liver Neoplasms, Patient Selection, Polyethylene Glycols, Primary Prevention, Recombinant Proteins, Retinoids
Show Abstract · Added May 2, 2014
Hepatitis C virus (HCV) infection, which seems to have spread worldwide recently, is now the leading cause of hepatocellular carcinoma (HCC) development in various geographic areas. The primary prevention of HCV-related HCC includes strategies for the prevention of HCV infection and those for viral eradication. Even after HCC development, short-term prognosis of patients has been much improved recently due to advances in early diagnosis and treatment. However, long-term prognosis is as yet far from satisfactory due to frequent recurrence of HCC even after apparently curative treatment, either local ablation or surgical resection. At least theoretically, strategies similar to those of primary prevention may be applicable to HCC recurrence. In this review, we summarized the reported favorable effects of chemotherapy on primary and tertiary prevention of HCC.
Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.
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13 MeSH Terms