23 results on '"Kostadinova L"'
Search Results
2. Evaluation of salivary flow rate and salivary lactoferrin after radiotherapy of head and neck malignant neoplasms
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Rogoleva-Gjurovski Sonja, Popovski Vladimir, Tošeska-Trajkovska Katerina, Kostadinova Lenče, and Emin Melda
- Subjects
hyposalivation ,malignant neoplasms ,volumetric modulated radiotherapy ,salivary proteins ,lactoferrin ,Dentistry ,RK1-715 - Abstract
Introduction: The most common postradiation complication in patients with head and neck neoplasms resulting from decreased salivary flow rate is xerostomia which affects the quality of life of patients in a negative way. On account of that, the application of volumetric modulated radiation therapy (VMAT) is found to be more precise in dose application, thus the surrounding healthy tissues can be spared from the negative influence of radiation. The aim of this study was to evaluate the salivary flow rate and salivary lactoferrin levels in patients with head and neck malign neoplasms following radiation therapy. Material and Methods: The research sample consisted of 24 patients treated with different radiation techniques, in which the salivary flow rate was measured for one minute. Additionally, the concentration of lactoferrin was quantitatively evaluated using biochemical analyses. Results: Higher average values were obtained in patients treated with a lower dose of radiation with up to 60 Gy, especially in those treated with a volumetric modulated radiotherapy technique. Therefore, from the results of linear correlation between the evaluated variables of lactoferrin and salivary flow volume in ml/min, it can be concluded that the correlation between these two variables is statistically significant whereby the correlation is negative with the coefficient of correlation r (24) = -0.903; (p < 0.01). Conclusion: The salivary flow rate is higher in patients treated with volumetric modulated radiotherapy, whereby the lower the dose of radiation, the higher the values of excreted saliva per minute. Therefore it can also be concluded that the higher values of lactoferrin are considered to have anti-inflammatory characteristics and are indicators of inflammation, which can be used for prevention of the salivary glands from negative effects of the radiation therapy.
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- 2023
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3. Administrative And Legal Analysis Of The Statute Of Directorate 'Border Control' Of Bfsa, Related To Risk Assessment Of Safety Of Food And Feed
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Kostadinova, L.
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opinion ,public health ,epizootic risks ,veterinary border control ,Bulgaria - Abstract
The scientific opinion analyzes the legal and administrative conditions in Republic of Bulgaria concerning the implementation of regulations on border veterinary control. We point out the main risk factors related to animal health and animal welfare and public health, quality and safety of food products for human and non-human consumption, animal by-products in the Republic of Bulgaria and its role as an EU external border. We perform a retrospective analysis of the statute of Directorate "Border control" of BFSA regarding risk management related to the safety of food and feed. We discuss the capacity of veterinary border control authorities to react effectively in a hazardous situation, in cooperation with other border control authorities and state institutions in order to ensure public needs, consistent with the interests of trade operators., BG; bg; EFSAfocalpoint@mzh.government.bg
- Published
- 2016
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4. NON-DESTRUCTIVE TECHNIQUE FOR ON-LINE DETERMINATION OF FRUIT AND VEGETABLE QUALITY
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Damyanov, C., primary, Georgiev, A., additional, and Kostadinova, L., additional
- Published
- 2003
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5. Relationship between the Optical Characteristics of Beans Leaves and the Yield
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Ilieva, V., primary and Raicheva-Kostadinova, L., additional
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- 1996
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6. The optoelectronic systems application for automatic qualification of fruits and vegetables
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Kostadinova, L., primary, Georgiev, A., additional, and Damyanov, C., additional
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7. The optoelectronic systems application for automatic qualification of fruits and vegetables.
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Kostadinova, L., Georgiev, A., and Damyanov, C.
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- 2000
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8. Higher Vitamin D Levels before Methotrexate Therapy Initiation Are Associated with Lower Subsequent Mortality in Patients with Rheumatoid Arthritis.
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Malakooti SK, Siddiqui H, Wilson B, Bej T, O'Mara M, Desotelle A, Lange A, Shive CL, Singer NG, McComsey GA, Kostadinova L, Mattar M, Zidar DA, and Anthony DD
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- Humans, Methotrexate therapeutic use, Retrospective Studies, Vitamin D, Vitamins, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid complications, Vitamin D Deficiency epidemiology
- Abstract
(1) Vitamin D deficiency is associated with mortality in the general population and has been observed in one rheumatoid arthritis (RA) cohort. Here, we investigate the relationship between 25-hydroxyvitamin D (25(OH)D) levels before methotrexate (MTX) therapy initiation in patients with RA and the subsequent all-cause mortality in a national Veterans Affairs (VA) cohort. (2) This is a retrospective study on RA patients time-oriented around the initial MTX prescription and 25(OH)D levels before starting MTX. We examined survival in patients with 25(OH)D levels > 50 nmol/L and ≤50 nmol/L using the Cox Proportional Hazard Model and fully adjusted for risk factors. (3) In total, 15,109 RA patients were included in the nationwide cohort. RA patients with 25(OH)D levels > 50 nmol/L before starting MTX had a 28% reduced risk of mortality when compared to those with levels ≤ 50 nmol/L (HR: 0.72, CI: 0.64-0.80, p < 0.001) after adjusting for traditional risk factors. (4) In this national RA cohort receiving standard-of-care MTX, patients with 25(OH)D levels > 50 nmol/L have a lower subsequent mortality when compared to those with 25(OH)D levels ≤ 50 nmol/L. It remains to be determined whether increasing Vitamin D levels in RA patients initially found to be Vitamin D deficient impacts their all-cause mortality.
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- 2024
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9. Dr. Kostadinova et al reply.
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Kostadinova L, Lange A, Damjanovska S, Gad I, Syed S, Siddiqui H, Yousif P, Kowal CM, Shive C, Burant C, Singer N, Bej T, Al-Kindi S, Wilson B, Mattar M, Zidar DA, and Anthony DD
- Published
- 2023
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10. Rheumatoid arthritis and older age are associated with lower humoral and cellular immune response to primary series COVID-19 mRNA vaccine.
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Dudley HM, O'Mara M, Auma A, Gong J, Ross Y, Gurevich N, Carbone S, Reihs A, Nguyen Y, McComsey GA, Cao Y, Balazs AB, Gordesky L, Payne M, Singer N, Kostadinova L, Wilson B, Zidar DA, King CL, Canaday DH, Shive CL, Mattar MM, and Anthony DD
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- Humans, Aged, COVID-19 Vaccines, Leukocytes, Mononuclear, Interleukin-2, Antibodies, Neutralizing, Immunity, Cellular, Immunoglobulin G, COVID-19 prevention & control, Arthritis, Rheumatoid
- Abstract
Objective: People with autoimmune disease have worse COVID-19 infection-related outcomes, lower antibody responses to COVID-19 vaccine, and higher rates of breakthrough infection. Immunosuppressive medications used to treat rheumatoid arthritis (RA) are associated with lower COVID-19 vaccine responses, though independent contributions of comorbidities, T-cell immunity, and age are less clear. We sought to test the hypothesis that RA, immunosuppressive medications used to treat RA, and older age, contribute to reduced B and T cell response to COVID-19 vaccine., Methods: We evaluated serum samples, taken the day of 1st vaccine dose, the day of 2nd dose, 2-6 weeks after 2nd dose, 7-12 weeks after 2nd dose, 13-24 weeks after 2nd dose, and 2-6 weeks after the 3rd dose, for anti-spike IgG and neutralizing antibody levels to Wuhan and Omicron BA.1 and peripheral blood mononuclear cells (PBMC) for spike-specific IFN-γ and IL-2 production by ELISPOT assay in 46 RA and 101 non-autoimmune control participants before and after the primary series COVID-19 mRNA vaccination., Results: RA participants had lower spike-specific IgG and Wuhan-strain neutralizing antibody levels 2-6 weeks compared to controls after the second dose of primary vaccine series. Neutralizing antibody levels against Omicron BA.1 were low in both groups. IFN-γ production correlated with Wuhan neutralizing antibody levels, while older age negatively correlated with spike-specific IL-2, IFN-γ and IgG. Lower antibody levels were associated with older age, RA status, and medication usage, while lower T cell responses were associated primarily with older age., Conclusions: These data indicate lower COVID-19 mRNA vaccine-induced antibody levels in persons with RA compared to individuals without RA, likely partially attributable to immune suppressive medications. At the same time, older age is associated with lower antibody and cellular immune response to COVID-19 vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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11. Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.
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Shive CL, Kowal CM, Desotelle AF, Nguyen Y, Carbone S, Kostadinova L, Davitkov P, O'Mara M, Reihs A, Siddiqui H, Wilson BM, and Anthony DD
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- Humans, Hepacivirus, Chemokine CXCL10, Interleukin-6, Programmed Cell Death 1 Receptor, T-Cell Exhaustion, Inflammation, CD3 Complex, Antiviral Agents, Endotoxemia complications, Hepatitis C, Chronic complications, Hepatitis C
- Abstract
Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.
- Published
- 2023
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12. Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.
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Lange A, Kostadinova L, Damjanovska S, Gad I, Syed S, Siddiqui H, Yousif P, Kowal CM, Shive C, Burant C, Singer N, Bej T, Al-Kindi S, Wilson B, Mattar M, Zidar DA, and Anthony DD
- Subjects
- Humans, Erythrocyte Indices, Retrospective Studies, Inflammation drug therapy, Methotrexate therapeutic use, Biomarkers, Lymphocyte Count, Arthritis, Rheumatoid, Antirheumatic Agents therapeutic use
- Abstract
Objective: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated., Methods: In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers., Results: In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC., Conclusion: RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation., (Copyright © 2023 by the Journal of Rheumatology.)
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- 2023
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13. During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study.
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Damjanovska S, Alao H, Zebrowski E, Kowal C, Kostadinova L, Davitkov P, Falck-Ytter Y, Shive CL, Cartwright M, Richardson B, Wald D, Cameron M, Valadkhan S, and Anthony DD
- Abstract
Background: Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease. We investigated plasma levels of these RNAs and select serum markers before, during, and after HCV therapy, preceding HCC. Methods: Of 187 DAA treated HCV patients where therapy oriented longitudinal sampling was performed at a time without HCC diagnosis, 9 were subsequently diagnosed with HCC within 2 years of therapy. They were matched with 7 patients not diagnosed with HCC over the same time period. RNASeq was performed on plasma, and serum was assessed for biomarkers of inflammation by ELISA. Results: HCC diagnosis was 19 months (6-28) after therapy start in the HCC group. 73 and 63 miRs were differentially expressed at baseline (before DAA therapy) and 12 weeks after DAA therapy comparing HCC and non-HCC groups. Several lncRNA- showed differential expression as well. Several miRNA suppressors of cancer-related pathways, lncRNA- and mRNA-derived stabilized short RNAs were consistently absent in the plasma of patients who developed HCC. Serum IP10, and MCP-1 level was higher in the HCC group 12 weeks after therapy, and distinct miRNAs correlated with IP10 and MCP-1. Finally, in a focused analysis of 8 miRNAs best associated with HCC we observed expression of mi576 and mi-5189 correlation with expression of a select group of PBMC mRNA. Conclusions: These results are consistent with complex interplay between RNA-mediated host immune regulation and cancer suppression, strikingly skewed 12 weeks following therapy, prior to HCC diagnosis.
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- 2022
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14. Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.
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Auma AWN, Kowal C, Shive CL, Lange A, Damjanovska S, Zebrowski E, Reyes E, Calabrese L, Kostadinova L, Falck-Ytter Y, Mattar M, and Anthony DD
- Subjects
- Antiviral Agents therapeutic use, Biomarkers, Humans, Inflammation drug therapy, Longitudinal Studies, RNA, Rheumatoid Factor, Elasticity Imaging Techniques, Hepatitis C, Chronic complications
- Abstract
Background: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here., Methods: In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants., Results: Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy., Conclusion: During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA., Competing Interests: The authors have declared no competing interests exist.
- Published
- 2022
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15. Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection.
- Author
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Auma AWN, Shive CL, Kostadinova L, and Anthony DD
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- Apoptosis, Coinfection drug therapy, HIV Infections drug therapy, Hepacivirus, Hepatitis C drug therapy, Hepatitis C, Chronic immunology, Homeostasis, Humans, Liver Cirrhosis immunology, Lymphopenia, Sustained Virologic Response, Antiviral Agents therapeutic use, Biomarkers, CD4-Positive T-Lymphocytes immunology, Hepatitis C, Chronic drug therapy, Lymphocyte Activation, Monocytes immunology
- Abstract
Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently reported that accelerated peripheral cell death may contribute to naïve CD4+ T cell loss and that mechanistic relationships between monocyte activation, T cell activation, and soluble inflammatory mediators may also contribute. Chronic HCV infection can be cured by direct-acting anti-viral (DAA) therapy, and success is defined as sustained virological response (SVR, undetectable HCV RNA (ribonucleic acid) at 12 weeks after DAA treatment completion). However, there is no general consensus on the short-term and long-term immunological outcomes of DAA therapy. Here, we consolidate previous reports on the partial normalization of naïve CD4+ lymphopenia and T cell immune activation and the apparent irreversibility of monocyte activation following DAA therapy in HCV infected and HCV/HIV co-infected individuals. Further, advanced age and cirrhosis are associated with delayed or abrogation of immune reconstitution after DAA therapy, an indication that non-viral factors also likely contribute to host immune dysregulation in HCV infection.
- Published
- 2021
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16. High Red Cell Distribution Width and Low Absolute Lymphocyte Count Associate With Subsequent Mortality in HCV Infection.
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Damjanovska S, Davitkov P, Gopal S, Kostadinova L, Kowal C, Lange A, Moreland A, Shive CL, Wilson B, Bej T, Al-Kindi S, Falck-Ytter Y, Zidar DA, and Anthony DD
- Abstract
Background: Hepatitis-C virus (HCV) chronic infection can lead to cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, cardiovascular disease (CVD), and mortality. Transient Elastography (TE) is used to non-invasively assess fibrosis. Whether immune monitoring provides additive prognostic value is not established. Increased red-cell distribution width (RDW) and decreased absolute lymphocyte count (ALC) predict mortality in those without liver disease. Whether these relationships remain during HCV infection is unknown., Materials and Methods: A retrospective cohort of 1,715 single-site VA Liver Clinic patients receiving Transient Elastography (TE) 2014-2019 to evaluate HCV-associated liver damage were evaluated for RDW and ALC in relation to traditional parameters of cardiovascular risk, liver health, development of HCC, and mortality., Results: The cohort was 97% male, 55% African American, 26% with diabetes mellitus, 67% with hypertension, and 66% with tobacco use. After TE, 3% were subsequently diagnosed with HCC, and 12% (n=208) died. Most deaths (n=189) were due to non-liver causes. The TE score associated with prevalent CVD, positively correlated with atherosclerotic cardiovascular disease (ASCVD) 10-Year Risk Score, age, RDW, and negatively correlated with ALC. Patients with anisocytosis (RDW above 14%) or lymphopenia (ALC level under 1.2×10
9 /L) had greater subsequent all-cause mortality, even after adjusting for age, TE score, and comorbidities. TE score, and to a modest degree RDW, were associated with subsequent liver-associated mortality, while TE score, RDW, and ALC were each independently associated with non-liver cause of death., Conclusion: Widely available mortality calculators generally require multiple pieces of clinical information. RDW and ALC, parameters collected on a single laboratory test that is commonly performed, prior to HCV therapy may be pragmatic markers of long-term risk of mortality., Competing Interests: The authors report no relevant conflicts of interest., (Copyright © Pathogens and Immunity 2021.)- Published
- 2021
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17. Elevated Autotaxin and LPA Levels During Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation.
- Author
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Kostadinova L, Shive CL, and Anthony DD
- Abstract
Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC)., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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18. Soluble Markers of Immune Activation Differentially Normalize and Selectively Associate with Improvement in AST, ALT, Albumin, and Transient Elastography During IFN-Free HCV Therapy.
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Kostadinova L, Shive CL, Zebrowski E, Fuller B, Rife K, Hirsch A, Compan A, Moreland A, Falck-Ytter Y, Popkin DL, and Anthony DD
- Abstract
Background: During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear., Methods: We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window., Results: Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy., Conclusions: Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy., Competing Interests: POTENTIAL CONFLICT OF INTEREST The authors have no known conflicts of interest.
- Published
- 2018
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19. CD56 bright NK IL-7Rα expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections.
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Judge CJ, Kostadinova L, Sherman KE, Butt AA, Falck-Ytter Y, Funderburg NT, Landay AL, Lederman MM, Sieg SF, Sandberg JK, and Anthony DD
- Subjects
- Adult, Aged, Aged, 80 and over, Antigens, CD immunology, Female, HIV Infections pathology, HIV Infections therapy, HIV-1 immunology, Hepatitis C, Chronic pathology, Hepatitis C, Chronic therapy, Humans, Killer Cells, Natural, Male, Middle Aged, STAT5 Transcription Factor immunology, CD56 Antigen immunology, Gene Expression Regulation immunology, HIV Infections immunology, Hepatitis C, Chronic immunology, Interleukin-7 immunology, Interleukin-7 Receptor alpha Subunit immunology, Signal Transduction immunology
- Abstract
Several lines of evidence support the concept that NK cells play an important role in control of hepatitis C virus (HCV) infection via cytokine secretion and cytotoxicity. IL-7 is a homeostatic cytokine with a role in T cell development, activation, proliferation, and cytokine secretion. The IL-7Rα chain [cluster of differentiation (CD)127] is expressed on NK cells, with greatest abundance on the CD56
bright CD16dim/- (CD56bright ) subset. Here, we measured CD127 expression on CD56bright , CD56dim CD16+ (CD56dim ), or CD56neg CD16+ (CD56neg ) NK cell subsets of 25 uninfected donors (UD); 34 chronic HCV-infected, treatment-naïve; 25 HIV-infected, virally suppressed on antiretroviral therapy (ART); and 42 HCV-HIV-coinfected subjects on ART. Interestingly, CD127 expression on CD56bright NK cells negatively correlated with HCV plasma levels in HCV monoinfection and HCV-HIV coinfection. IL-7 induced CD69 expression, as well as IFN-γ production, in CD56bright NK cells and also enhanced the IFN-α-induced CD69 expression on these cells. The latter was impaired in HIV infection. Furthermore, IL-7 induced B cell lymphoma 2 (BCL-2) expression and cell cycling of CD56bright NK cells, and this effect was impaired in HCV- and HIV-infected subjects. Whereas IL-7-stimulated CD56bright NK cell degranulation appeared intact in all cohorts, we observed impaired IL-7-activated NK cell cytolytic function in HCV- and HIV-infected subjects. Finally, IL-7-induced phosphorylation of STAT-5 (pSTAT-5) signaling was impaired in NK cells of subjects with chronic viral infection, and this was reversible upon 6 mo of viral suppression with IFN-free HCV therapy. These results implicate that IL-7-dependent NK cell activation and effector function may be other host immune surveillance mechanisms that are impaired in viral infections., (© Society for Leukocyte Biology.)- Published
- 2017
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20. During Hepatitis C Virus (HCV) Infection and HCV-HIV Coinfection, an Elevated Plasma Level of Autotaxin Is Associated With Lysophosphatidic Acid and Markers of Immune Activation That Normalize During Interferon-Free HCV Therapy.
- Author
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Kostadinova L, Shive CL, Judge C, Zebrowski E, Compan A, Rife K, Hirsch A, Falck-Ytter Y, Schlatzer DM, Li X, Chance MR, Rodriguez B, Popkin DL, and Anthony DD
- Subjects
- Adult, Aged, Anti-HIV Agents therapeutic use, Antigens, CD immunology, Antigens, Differentiation, Myelomonocytic immunology, Biomarkers blood, Coinfection drug therapy, Coinfection virology, Female, HIV Infections drug therapy, HIV Infections virology, Hepatitis C drug therapy, Hepatitis C virology, Humans, Interferons therapeutic use, Interleukin-6 immunology, Lipopolysaccharide Receptors immunology, Lipopolysaccharide Receptors metabolism, Lysophospholipids immunology, Male, Middle Aged, Monocytes immunology, Monocytes virology, Receptors, Cell Surface immunology, Coinfection immunology, HIV immunology, HIV Infections immunology, Hepacivirus immunology, Hepatitis C immunology, Phosphoric Diester Hydrolases blood, Plasma immunology
- Abstract
Background: Immune activation predicts morbidity during hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection, although mechanisms underlying immune activation are unclear. Plasma levels of autotaxin and its enzymatic product, lysophosphatidic acid (LPA), are elevated during HCV infection, and LPA activates immunocytes, but whether this contributes to immune activation is unknown., Methods: We evaluated plasma levels of autotaxin, interleukin 6 (IL-6), soluble CD14 (sCD14), soluble CD163 (sCD163), and Mac2 binding protein (Mac2BP) during HCV infection, HIV infection, and HCV-HIV coinfection, as well as in uninfected controls, before and after HIV antiretroviral therapy (ART) initiation and during interferon-free HCV therapy., Results: We observed greater plasma autotaxin levels in HCV-infected and HCV-HIV-coinfected participants, compared with uninfected participants, primarily those with a higher ratio of aspartate aminotransferase level to platelet count. Autotaxin levels correlated with IL-6, sCD14, sCD163, Mac2BP, and LPA levels in HCV-infected participants and with Mac2BP levels in HCV-HIV-coinfected participants, while in HIV-infected individuals, sCD14 levels correlated with Mac2BP levels. Autotaxin, LPA, and sCD14 levels normalized, while sCD163 and Mac2BP levels partially normalized within 6 months of starting interferon-free HCV therapy. sCD163 and IL-6 levels normalized within 6 months of starting ART for HIV infection. In vitro, LPA activated monocytes., Conclusions: These data indicate that elevated levels of autotaxin and soluble markers of immune activation during HCV infection are partially reversible within 6 months of initiating interferon-free HCV treatment and that autotaxin may be causally linked to immune activation during HCV infection and HCV-HIV coinfection., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
- Published
- 2016
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21. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy.
- Author
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Reyes-Avilés E, Kostadinova L, Rusterholtz A, Cruz-Lebrón A, Falck-Ytter Y, and Anthony DD
- Subjects
- Adult, Aged, Aged, 80 and over, Antiviral Agents therapeutic use, Cryoglobulinemia etiology, Female, Hepatitis C, Chronic complications, Hepatitis C, Chronic drug therapy, Humans, Male, Middle Aged, Receptors, Antigen, B-Cell metabolism, Rheumatoid Factor metabolism, B-Lymphocytes immunology, Hepatitis C, Chronic immunology
- Abstract
Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.
- Published
- 2015
- Full Text
- View/download PDF
22. Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter.
- Author
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Kambara H, Gunawardane L, Zebrowski E, Kostadinova L, Jobava R, Krokowski D, Hatzoglou M, Anthony DD, and Valadkhan S
- Abstract
Recent genome-wide studies have revealed the presence of thousands of long non-protein-coding RNAs (lncRNAs), some of which may play critical roles in the cell. We have previously shown that a large number of lncRNAs show differential expression in response to interferon (IFN)α stimulation in primary human cells. Here, we show that a subset of IFN-induced lncRNAs are positioned in proximity of protein-coding IFN-stimulated genes (ISGs). The majority of gene pairs originated from bidirectional promoters and showed positively correlated expression. We focused our analysis on a pair consisting of the known protein-coding ISG, BST2, and an un-studied putative lncRNA originating from the promoter region of BST2 in a divergent orientation. We showed that this transcript was a multi-exonic, polyadenylated long RNA that lacked protein-coding capacity. BST2 and the lncRNA were both induced in response to IFNα in diverse cell types. The induction of both genes was mediated through the JAK-STAT pathway, suggesting that IFN-stimulated response elements within the shared promoter activated the transcription of both genes. RNAi-mediated knock-down of the lncRNA resulted in down-regulation of BST2, and we could show that this down-regulation occurred at the level of transcription. Forced overexpression of this lncRNA, which we named BST2 IFN-Stimulated Positive Regulator (BISPR), resulted in up-regulation of BST2, indicating that the regulation of expression of BST2 by BISPR is mediated through interactions involving BISPR RNA itself, rather than the impact of its transcription from an adjacent locus. Importantly, upon IFN stimulation, transcriptional activation of BISPR preceded the induction of BST2, suggesting that expression of BISPR facilitated the initiation of transcription in its paired protein-coding gene. The lncRNA-mediated transcriptional regulation described in this study may help govern the expression of additional protein-coding RNAs involved in IFN response and other cellular processes.
- Published
- 2015
- Full Text
- View/download PDF
23. Negative regulation of the interferon response by an interferon-induced long non-coding RNA.
- Author
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Kambara H, Niazi F, Kostadinova L, Moonka DK, Siegel CT, Post AB, Carnero E, Barriocanal M, Fortes P, Anthony DD, and Valadkhan S
- Subjects
- Animals, Cell Line, Cells, Cultured, Gene Expression Regulation, Hepatitis C genetics, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Interferon-gamma pharmacology, Janus Kinases metabolism, Liver metabolism, Mice, RNA, Long Noncoding biosynthesis, RNA, Long Noncoding genetics, STAT Transcription Factors metabolism, Up-Regulation, Interferon-alpha pharmacology, RNA, Long Noncoding metabolism
- Abstract
Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼ 200 IFN-induced lncRNAs, one transcript showed ∼ 100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2014
- Full Text
- View/download PDF
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