TY  - JOUR
AU  - Mitrović-Ajtić, Olivera
AU  - Đikić, Dragoslava
AU  - Subotički, Tijana
AU  - Bižić-Radulović, Sandra
AU  - Beleslin-Čokić, Bojana
AU  - Dragojević, Teodora
AU  - Živković, Emilija
AU  - Miljatović, Sanja
AU  - Vukotić, Milica
AU  - Stanisavljević, Dejana
AU  - Santibanez, Juan F.
AU  - Čokić, Vladan
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1355
AB  - The severity and mortality of coronavirus disease 2019 (COVID-19) are greater in males than in females, though the infection rate is the same in the two sexes. We investigated sex hormone differences associated with the hyperinflammatory immune response to SARS-CoV-2 on the basis of patients’ cytokine profiles and vaccination statuses. Clinical and laboratory data of 117 patients with COVID-19 were collected to examine sex differences associated with oxidative stress markers, neutrophil extracellular traps (NETs), and plasma cytokine levels up to 5 months from hospital admission. The testosterone and free testosterone levels were low in male patients with COVID-19 and returned to normal values after recovery from the disease. The dihydrotestosterone (DHT) levels were transiently reduced, while the sex hormone-binding globulin levels were decreased in post-COVID-19 male patients. The levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-10 appeared generally increased at diagnosis and decreased in post-COVID-19 patients. In females, the concentration of tumor necrosis factor-alpha was increased by four times at diagnosis. The levels of the coagulation markers intercellular adhesion molecule-1 (ICAM-1) and E-selectin were consistently upregulated in post-COVID-19 female patients, in contrast to those of vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and chemokine IL-8. DHT increased the levels of reactive oxygen species in the neutrophils of male patients, while estradiol decreased them in females. Markers for NET, such as circulating DNA and myeloperoxidase, were significantly more abundant in the patients’ plasma. Sex hormones have a potential protective role during SARS-CoV-2 infection, which is weakened by impaired testosterone synthesis in men.
PB  - Multidisciplinary Digital Publishing Institute (MDPI)
T2  - Vaccines
T2  - Vaccines
T1  - Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males
IS  - 10
SP  - 1560
VL  - 11
DO  - 10.3390/vaccines11101560
ER  - 

@article{
author = "Mitrović-Ajtić, Olivera and Đikić, Dragoslava and Subotički, Tijana and Bižić-Radulović, Sandra and Beleslin-Čokić, Bojana and Dragojević, Teodora and Živković, Emilija and Miljatović, Sanja and Vukotić, Milica and Stanisavljević, Dejana and Santibanez, Juan F. and Čokić, Vladan",
year = "2023",
abstract = "The severity and mortality of coronavirus disease 2019 (COVID-19) are greater in males than in females, though the infection rate is the same in the two sexes. We investigated sex hormone differences associated with the hyperinflammatory immune response to SARS-CoV-2 on the basis of patients’ cytokine profiles and vaccination statuses. Clinical and laboratory data of 117 patients with COVID-19 were collected to examine sex differences associated with oxidative stress markers, neutrophil extracellular traps (NETs), and plasma cytokine levels up to 5 months from hospital admission. The testosterone and free testosterone levels were low in male patients with COVID-19 and returned to normal values after recovery from the disease. The dihydrotestosterone (DHT) levels were transiently reduced, while the sex hormone-binding globulin levels were decreased in post-COVID-19 male patients. The levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-10 appeared generally increased at diagnosis and decreased in post-COVID-19 patients. In females, the concentration of tumor necrosis factor-alpha was increased by four times at diagnosis. The levels of the coagulation markers intercellular adhesion molecule-1 (ICAM-1) and E-selectin were consistently upregulated in post-COVID-19 female patients, in contrast to those of vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and chemokine IL-8. DHT increased the levels of reactive oxygen species in the neutrophils of male patients, while estradiol decreased them in females. Markers for NET, such as circulating DNA and myeloperoxidase, were significantly more abundant in the patients’ plasma. Sex hormones have a potential protective role during SARS-CoV-2 infection, which is weakened by impaired testosterone synthesis in men.",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
journal = "Vaccines, Vaccines",
title = "Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males",
number = "10",
pages = "1560",
volume = "11",
doi = "10.3390/vaccines11101560"
}

Mitrović-Ajtić, O., Đikić, D., Subotički, T., Bižić-Radulović, S., Beleslin-Čokić, B., Dragojević, T., Živković, E., Miljatović, S., Vukotić, M., Stanisavljević, D., Santibanez, J. F.,& Čokić, V.. (2023). Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males. in Vaccines
Multidisciplinary Digital Publishing Institute (MDPI)., 11(10), 1560.
https://doi.org/10.3390/vaccines11101560

Mitrović-Ajtić O, Đikić D, Subotički T, Bižić-Radulović S, Beleslin-Čokić B, Dragojević T, Živković E, Miljatović S, Vukotić M, Stanisavljević D, Santibanez JF, Čokić V. Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males. in Vaccines. 2023;11(10):1560.
doi:10.3390/vaccines11101560 .

Mitrović-Ajtić, Olivera, Đikić, Dragoslava, Subotički, Tijana, Bižić-Radulović, Sandra, Beleslin-Čokić, Bojana, Dragojević, Teodora, Živković, Emilija, Miljatović, Sanja, Vukotić, Milica, Stanisavljević, Dejana, Santibanez, Juan F., Čokić, Vladan, "Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males" in Vaccines, 11, no. 10 (2023):1560,
https://doi.org/10.3390/vaccines11101560 . .

TY  - CONF
AU  - Mitrović-Ajtić, Olivera
AU  - Đikić, Dragoslava
AU  - Dragojević, Teodora
AU  - Otašević, Vladimir
AU  - Živković, Emilija
AU  - Vuković, Vojin
AU  - Vukotić, Milica
AU  - Subotički, Tijana
AU  - Diklić, Miloš
AU  - Suvajdžić-Vuković, Nada
AU  - Mitrović, Mirjana
AU  - Mihaljević, Biljana
AU  - Antić, Darko
AU  - Čokić, Vladan
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1420
AB  - Introduction: Patients with hematological malignancies have an increased risk of thrombotic complications, ranging from 3-5% in patients with lymphoma and acute myeloid leukemia (AML). The presented study observed the onset of thrombus formation to predict risk factors for thrombosis in lymphoid and myeloid malignancies. Methods: Coagulation factors, inflammatory signaling pathways and adhesion molecules have been observed in patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and AML. Their mononuclear cells (MNC) trans-endothelial migration through human microvascular endothelial cells (HMEC-1) monolayer is observed by Boyden chamber.
Results: Thrombin was in positive correlation with tumor necrosis factor alpha (TNF-α) in HL, while with P-selectin (p<0.001), tumor growth factor-beta (TGF-β) and factor VIII (p<0.05) in DLBCL and AML. Transendothelial migration of MNC was increased by TNF-α (p<0.001) in DLBCL regardless of previous thrombosis. Regarding coagulation, factor VIII was increased in HL and AML (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Tissue factor was in positive correlation with adhesion molecule P-selectin and factor VIII (p<0.05). P-selectin was increased in non-Hodgkin lymphomas (p<0.0001), while TGF-β only in FL (p<0.001). Fibrinolytic activity was decreased in plasma of patients with HL, DLBCL, and FL (p<0.05), but largely in AML (p<0.01) as measured by tissue-type plasminogen activator. Inflammatory NF-κB signaling has been activated in HL and DLBCL, while p38 signaling only in HL. Conclusion: Coagulation factors and inflammation are increased in hematological malignancies along with the interaction of the endothelium and circulating cells that predispose to thrombus formation
PB  - Belgrade: Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies
EP  - 134
SP  - 134
UR  - https://hdl.handle.net/21.15107/rcub_rimi_1420
ER  - 

@conference{
author = "Mitrović-Ajtić, Olivera and Đikić, Dragoslava and Dragojević, Teodora and Otašević, Vladimir and Živković, Emilija and Vuković, Vojin and Vukotić, Milica and Subotički, Tijana and Diklić, Miloš and Suvajdžić-Vuković, Nada and Mitrović, Mirjana and Mihaljević, Biljana and Antić, Darko and Čokić, Vladan",
year = "2023",
abstract = "Introduction: Patients with hematological malignancies have an increased risk of thrombotic complications, ranging from 3-5% in patients with lymphoma and acute myeloid leukemia (AML). The presented study observed the onset of thrombus formation to predict risk factors for thrombosis in lymphoid and myeloid malignancies. Methods: Coagulation factors, inflammatory signaling pathways and adhesion molecules have been observed in patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and AML. Their mononuclear cells (MNC) trans-endothelial migration through human microvascular endothelial cells (HMEC-1) monolayer is observed by Boyden chamber.
Results: Thrombin was in positive correlation with tumor necrosis factor alpha (TNF-α) in HL, while with P-selectin (p<0.001), tumor growth factor-beta (TGF-β) and factor VIII (p<0.05) in DLBCL and AML. Transendothelial migration of MNC was increased by TNF-α (p<0.001) in DLBCL regardless of previous thrombosis. Regarding coagulation, factor VIII was increased in HL and AML (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Tissue factor was in positive correlation with adhesion molecule P-selectin and factor VIII (p<0.05). P-selectin was increased in non-Hodgkin lymphomas (p<0.0001), while TGF-β only in FL (p<0.001). Fibrinolytic activity was decreased in plasma of patients with HL, DLBCL, and FL (p<0.05), but largely in AML (p<0.01) as measured by tissue-type plasminogen activator. Inflammatory NF-κB signaling has been activated in HL and DLBCL, while p38 signaling only in HL. Conclusion: Coagulation factors and inflammation are increased in hematological malignancies along with the interaction of the endothelium and circulating cells that predispose to thrombus formation",
publisher = "Belgrade: Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies",
pages = "134-134",
url = "https://hdl.handle.net/21.15107/rcub_rimi_1420"
}

Mitrović-Ajtić, O., Đikić, D., Dragojević, T., Otašević, V., Živković, E., Vuković, V., Vukotić, M., Subotički, T., Diklić, M., Suvajdžić-Vuković, N., Mitrović, M., Mihaljević, B., Antić, D.,& Čokić, V.. (2023). Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Belgrade: Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 134-134.
https://hdl.handle.net/21.15107/rcub_rimi_1420

Mitrović-Ajtić O, Đikić D, Dragojević T, Otašević V, Živković E, Vuković V, Vukotić M, Subotički T, Diklić M, Suvajdžić-Vuković N, Mitrović M, Mihaljević B, Antić D, Čokić V. Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:134-134.
https://hdl.handle.net/21.15107/rcub_rimi_1420 .

Mitrović-Ajtić, Olivera, Đikić, Dragoslava, Dragojević, Teodora, Otašević, Vladimir, Živković, Emilija, Vuković, Vojin, Vukotić, Milica, Subotički, Tijana, Diklić, Miloš, Suvajdžić-Vuković, Nada, Mitrović, Mirjana, Mihaljević, Biljana, Antić, Darko, Čokić, Vladan, "Activation of coagulation factors and prothrombic properties of endothelium in hematological malignancies" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):134-134,
https://hdl.handle.net/21.15107/rcub_rimi_1420 .

TY  - CONF
AU  - Mitrović Ajtić, Olivera
AU  - Đikić, Dragoslava
AU  - Suvajdžić-Vuković, Nada
AU  - Mitrović, Mirjana
AU  - Subotički, Tijana
AU  - Vukotić, Milica
AU  - Dragojević, Teodora
AU  - Diklić, Miloš
AU  - Pantić, Nikola
AU  - Čokić, Vladan
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1425
AB  - Background: Patients with acute myeloid leukemia (AML) have an increased risk of thrombotic complications in the range of 4.2 - 5.2%.
Aims: Our hypothesis is that inflammation is responsible for deterioration of coagulation in AML.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of patients with AML by measurement of circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. Inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity with fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in AML, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with AML (p<0.05) as measured by cfDNA and MPO activity. Regarding coagulation, factor VIII (p<0.05) and adhesion molecule P-selectin (p<0.001) were increased in plasma. Fibrinolytic activity was 3-fold decreased in the plasma of patients with AML (p<0.01) as measured by tPA. In contrast, uPA levels were increased in patients with AML (p<0.05). Tissue factor (CD142+) inflammatory microparticles derived from monocytes (CD14+: 5.1±0.6, p<0.001), activated monocytes (CD14+/CD16+: 2.89±0.4%, p<0.05) and circulating endothelial cells (CD31+/CD144+: 4.08±0.5%, p<0.05) were increased in AML compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in AML in parallel with reduced fibrinolysis and increased coagulation provoking the risk of thrombosis. A panel of the applied inflammatory/ procoagulant biomarkers can be used as a predictor of thrombosis in AML.
PB  - Wolters Kluwer Health, Inc.
C3  - HemaSphere - EHA2023 Hybrid Congress Abstract Book
T1  - PB1832: Inflammation induced coagulation in acute myeloid leukemia
IS  - S3
SP  - 68019.6f
VL  - 7
DO  - 10.1097/01.HS9.0000974172.68019.6f
ER  - 

@conference{
author = "Mitrović Ajtić, Olivera and Đikić, Dragoslava and Suvajdžić-Vuković, Nada and Mitrović, Mirjana and Subotički, Tijana and Vukotić, Milica and Dragojević, Teodora and Diklić, Miloš and Pantić, Nikola and Čokić, Vladan",
year = "2023",
abstract = "Background: Patients with acute myeloid leukemia (AML) have an increased risk of thrombotic complications in the range of 4.2 - 5.2%.
Aims: Our hypothesis is that inflammation is responsible for deterioration of coagulation in AML.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of patients with AML by measurement of circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. Inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity with fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in AML, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with AML (p<0.05) as measured by cfDNA and MPO activity. Regarding coagulation, factor VIII (p<0.05) and adhesion molecule P-selectin (p<0.001) were increased in plasma. Fibrinolytic activity was 3-fold decreased in the plasma of patients with AML (p<0.01) as measured by tPA. In contrast, uPA levels were increased in patients with AML (p<0.05). Tissue factor (CD142+) inflammatory microparticles derived from monocytes (CD14+: 5.1±0.6, p<0.001), activated monocytes (CD14+/CD16+: 2.89±0.4%, p<0.05) and circulating endothelial cells (CD31+/CD144+: 4.08±0.5%, p<0.05) were increased in AML compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in AML in parallel with reduced fibrinolysis and increased coagulation provoking the risk of thrombosis. A panel of the applied inflammatory/ procoagulant biomarkers can be used as a predictor of thrombosis in AML.",
publisher = "Wolters Kluwer Health, Inc.",
journal = "HemaSphere - EHA2023 Hybrid Congress Abstract Book",
title = "PB1832: Inflammation induced coagulation in acute myeloid leukemia",
number = "S3",
pages = "68019.6f",
volume = "7",
doi = "10.1097/01.HS9.0000974172.68019.6f"
}

Mitrović Ajtić, O., Đikić, D., Suvajdžić-Vuković, N., Mitrović, M., Subotički, T., Vukotić, M., Dragojević, T., Diklić, M., Pantić, N.,& Čokić, V.. (2023). PB1832: Inflammation induced coagulation in acute myeloid leukemia. in HemaSphere - EHA2023 Hybrid Congress Abstract Book
Wolters Kluwer Health, Inc.., 7(S3), 68019.6f.
https://doi.org/10.1097/01.HS9.0000974172.68019.6f

Mitrović Ajtić O, Đikić D, Suvajdžić-Vuković N, Mitrović M, Subotički T, Vukotić M, Dragojević T, Diklić M, Pantić N, Čokić V. PB1832: Inflammation induced coagulation in acute myeloid leukemia. in HemaSphere - EHA2023 Hybrid Congress Abstract Book. 2023;7(S3):68019.6f.
doi:10.1097/01.HS9.0000974172.68019.6f .

Mitrović Ajtić, Olivera, Đikić, Dragoslava, Suvajdžić-Vuković, Nada, Mitrović, Mirjana, Subotički, Tijana, Vukotić, Milica, Dragojević, Teodora, Diklić, Miloš, Pantić, Nikola, Čokić, Vladan, "PB1832: Inflammation induced coagulation in acute myeloid leukemia" in HemaSphere - EHA2023 Hybrid Congress Abstract Book, 7, no. S3 (2023):68019.6f,
https://doi.org/10.1097/01.HS9.0000974172.68019.6f . .

TY  - CONF
AU  - Antić, Darko
AU  - Mitrović Ajtić, Olivera
AU  - Đikić, Dragoslava
AU  - Otašević, Vladimir
AU  - Živković, Emilija
AU  - Ivanović, Jelena
AU  - Vuković, Vojin
AU  - Vukotić, Milica
AU  - Šarac, Sofija
AU  - MIhajljević, Biljana
AU  - Čokić, Vladan
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1426
AB  - Background: Patients with lymphomas increased the risk of thrombotic complications, especially in diagnosis and during chemotherapy treatment, in the range of 2.9-4.2%.
Aims: Our hypothesis is that inflammation and provoked immunity are responsible for generation of thrombus due to disturbed balance between coagulation and fibrinolysis.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of 80 patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) measuring circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. The inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity by fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays. Using a Boyden chamber, trans-endothelial migration of mononuclear cells (MNC) across a monolayer of human microvascular endothelial cells (HMEC-1) will be observed.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in DLBCL and HL, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with HL (p<0.05) as measured by cfDNA and MPO activity. In contrast, cfDNA was largely reduced in DLBCL with thrombosis (p<0.001). Trans-endothelial migration of MNC was decreased by IL-6, but increased by TNF-α (p<0.001) in DLBCL with thrombosis. In the absence of thrombosis, MNC of HL demonstrated increased trans-endothelial migration in the presence of pro-inflammatory IL-6 (p<0.01), while MNC of HL and DLBCL in the presence of TNF-α (p<0.05). Regarding coagulation, factor VIII was increased in HL (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Adhesion molecule P-selectin was increased in lymphomas, mostly in non-Hodgkin lymphomas (p<0.0001), while TGF-β is only in FL (p<0.001). Fibrinogen was negatively correlated with cfDNA (p=0.021, r=-0.767) in HL, while in positive correlation with TNF-α (p=0.028, r=0.517), IL-8 (p=0.009, r=0.598) and MCP-1 (p=0.004, r=0.643) in FL and with TGF-β (p=0.007, r=0.748) in HL. In opposite to uPA, fibrinolytic activity was decreased in the plasma of patients with HL, DLBCL, and FL (p<0.05) as measured by tPA. The tPA was in negative correlation with MPO in HL (p=0.017, r=-0.783) and FL (p=0.006, r=-0.818), while positively correlated with cfDNA in DLBCL (p=0.034, r=0.402, Table 1). The uPA was in positive correlation with cfDNA (p=0.009, r=0.692) and fibrinogen (p=0.009, r=0.692) in FL. Tissue factor (CD142+) procoagulant microparticles derived from monocytes (CD14+: 7.49±0.2, p<0.001) and activated monocytes (CD14+/CD16+: 3.75±0.8%, p<0.05) were increased in DLBCL compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in the examined lymphomas where TNF-α, as an activator of the immune response, is linked with the initiation of thrombus formation. Moreover, augmented innate immunity is accompanied by procoagulants that mutually support thrombosis.
F1
PB  - Wolters Kluwer Health, Inc.
C3  - HemaSphere - EHA2023 Hybrid Congress Abstract Book S3
T1  - Inflammation mediated thrombus formation in lymphomas
EP  - 3213
IS  - 7(S)
SP  - 3212
DO  - 10.1097/01.HS9.0000973484.54165.7a
ER  - 

@conference{
author = "Antić, Darko and Mitrović Ajtić, Olivera and Đikić, Dragoslava and Otašević, Vladimir and Živković, Emilija and Ivanović, Jelena and Vuković, Vojin and Vukotić, Milica and Šarac, Sofija and MIhajljević, Biljana and Čokić, Vladan",
year = "2023",
abstract = "Background: Patients with lymphomas increased the risk of thrombotic complications, especially in diagnosis and during chemotherapy treatment, in the range of 2.9-4.2%.
Aims: Our hypothesis is that inflammation and provoked immunity are responsible for generation of thrombus due to disturbed balance between coagulation and fibrinolysis.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of 80 patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) measuring circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. The inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity by fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays. Using a Boyden chamber, trans-endothelial migration of mononuclear cells (MNC) across a monolayer of human microvascular endothelial cells (HMEC-1) will be observed.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in DLBCL and HL, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with HL (p<0.05) as measured by cfDNA and MPO activity. In contrast, cfDNA was largely reduced in DLBCL with thrombosis (p<0.001). Trans-endothelial migration of MNC was decreased by IL-6, but increased by TNF-α (p<0.001) in DLBCL with thrombosis. In the absence of thrombosis, MNC of HL demonstrated increased trans-endothelial migration in the presence of pro-inflammatory IL-6 (p<0.01), while MNC of HL and DLBCL in the presence of TNF-α (p<0.05). Regarding coagulation, factor VIII was increased in HL (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Adhesion molecule P-selectin was increased in lymphomas, mostly in non-Hodgkin lymphomas (p<0.0001), while TGF-β is only in FL (p<0.001). Fibrinogen was negatively correlated with cfDNA (p=0.021, r=-0.767) in HL, while in positive correlation with TNF-α (p=0.028, r=0.517), IL-8 (p=0.009, r=0.598) and MCP-1 (p=0.004, r=0.643) in FL and with TGF-β (p=0.007, r=0.748) in HL. In opposite to uPA, fibrinolytic activity was decreased in the plasma of patients with HL, DLBCL, and FL (p<0.05) as measured by tPA. The tPA was in negative correlation with MPO in HL (p=0.017, r=-0.783) and FL (p=0.006, r=-0.818), while positively correlated with cfDNA in DLBCL (p=0.034, r=0.402, Table 1). The uPA was in positive correlation with cfDNA (p=0.009, r=0.692) and fibrinogen (p=0.009, r=0.692) in FL. Tissue factor (CD142+) procoagulant microparticles derived from monocytes (CD14+: 7.49±0.2, p<0.001) and activated monocytes (CD14+/CD16+: 3.75±0.8%, p<0.05) were increased in DLBCL compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in the examined lymphomas where TNF-α, as an activator of the immune response, is linked with the initiation of thrombus formation. Moreover, augmented innate immunity is accompanied by procoagulants that mutually support thrombosis.
F1",
publisher = "Wolters Kluwer Health, Inc.",
journal = "HemaSphere - EHA2023 Hybrid Congress Abstract Book S3",
title = "Inflammation mediated thrombus formation in lymphomas",
pages = "3213-3212",
number = "7(S)",
doi = "10.1097/01.HS9.0000973484.54165.7a"
}

Antić, D., Mitrović Ajtić, O., Đikić, D., Otašević, V., Živković, E., Ivanović, J., Vuković, V., Vukotić, M., Šarac, S., MIhajljević, B.,& Čokić, V.. (2023). Inflammation mediated thrombus formation in lymphomas. in HemaSphere - EHA2023 Hybrid Congress Abstract Book S3
Wolters Kluwer Health, Inc..(7(S)), 3212-3213.
https://doi.org/10.1097/01.HS9.0000973484.54165.7a

Antić D, Mitrović Ajtić O, Đikić D, Otašević V, Živković E, Ivanović J, Vuković V, Vukotić M, Šarac S, MIhajljević B, Čokić V. Inflammation mediated thrombus formation in lymphomas. in HemaSphere - EHA2023 Hybrid Congress Abstract Book S3. 2023;(7(S)):3212-3213.
doi:10.1097/01.HS9.0000973484.54165.7a .

Antić, Darko, Mitrović Ajtić, Olivera, Đikić, Dragoslava, Otašević, Vladimir, Živković, Emilija, Ivanović, Jelena, Vuković, Vojin, Vukotić, Milica, Šarac, Sofija, MIhajljević, Biljana, Čokić, Vladan, "Inflammation mediated thrombus formation in lymphomas" in HemaSphere - EHA2023 Hybrid Congress Abstract Book S3, no. 7(S) (2023):3212-3213,
https://doi.org/10.1097/01.HS9.0000973484.54165.7a . .

TY  - JOUR
AU  - Đikić, Dragoslava
AU  - Bogdanović, Andrija
AU  - Marković, Dragana
AU  - Mitrović-Ajtić, Olivera
AU  - Subotički, Tijana
AU  - Diklić, Miloš
AU  - Vukotić, Milica
AU  - Dragojević, Teodora
AU  - Živković, Emilija
AU  - Santibanez, Juan F.
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1202
AB  - Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the pro-liferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dis-mutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H2O2 activity compared to healthy subjects. Moreover, phosphorylation of the apoptotic p53 protein was reduced while the activity of the AKT/mTOR signaling pathway was increased, which was further enhanced by oxidative stress (H2O2) in granulocytes and erythroleukemic K562 cells. IL-6 caused oxidative stress and DNA damage that was mitigated using antioxidant or inhibition of inflammatory NFkB transcription factor in K562 cells. We demonstrated the presence of oxidative and ni-trosative stress in CML, with the former mediated by AKT/mTOR signaling and stimulated by in-flammation.
PB  - MDPI
T2  - Biomolecules
T1  - Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia
IS  - 2
SP  - 247
VL  - 12
DO  - 10.3390/biom12020247
ER  - 

@article{
author = "Đikić, Dragoslava and Bogdanović, Andrija and Marković, Dragana and Mitrović-Ajtić, Olivera and Subotički, Tijana and Diklić, Miloš and Vukotić, Milica and Dragojević, Teodora and Živković, Emilija and Santibanez, Juan F. and Čokić, Vladan",
year = "2022",
abstract = "Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the pro-liferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dis-mutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H2O2 activity compared to healthy subjects. Moreover, phosphorylation of the apoptotic p53 protein was reduced while the activity of the AKT/mTOR signaling pathway was increased, which was further enhanced by oxidative stress (H2O2) in granulocytes and erythroleukemic K562 cells. IL-6 caused oxidative stress and DNA damage that was mitigated using antioxidant or inhibition of inflammatory NFkB transcription factor in K562 cells. We demonstrated the presence of oxidative and ni-trosative stress in CML, with the former mediated by AKT/mTOR signaling and stimulated by in-flammation.",
publisher = "MDPI",
journal = "Biomolecules",
title = "Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia",
number = "2",
pages = "247",
volume = "12",
doi = "10.3390/biom12020247"
}

Đikić, D., Bogdanović, A., Marković, D., Mitrović-Ajtić, O., Subotički, T., Diklić, M., Vukotić, M., Dragojević, T., Živković, E., Santibanez, J. F.,& Čokić, V.. (2022). Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia. in Biomolecules
MDPI., 12(2), 247.
https://doi.org/10.3390/biom12020247

Đikić D, Bogdanović A, Marković D, Mitrović-Ajtić O, Subotički T, Diklić M, Vukotić M, Dragojević T, Živković E, Santibanez JF, Čokić V. Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia. in Biomolecules. 2022;12(2):247.
doi:10.3390/biom12020247 .

Đikić, Dragoslava, Bogdanović, Andrija, Marković, Dragana, Mitrović-Ajtić, Olivera, Subotički, Tijana, Diklić, Miloš, Vukotić, Milica, Dragojević, Teodora, Živković, Emilija, Santibanez, Juan F., Čokić, Vladan, "Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia" in Biomolecules, 12, no. 2 (2022):247,
https://doi.org/10.3390/biom12020247 . .

TY  - JOUR
AU  - Vukotić, Milica
AU  - Kapor, Sunčica
AU  - Dragojević, Teodora
AU  - Đikić, Dragoslava
AU  - Mitrović-Ajtić, Olivera
AU  - Diklić, Miloš
AU  - Subotički, Tijana
AU  - Živković, Emilija
AU  - Beleslin-Čokić, Bojana
AU  - Vojvodić, Aleksandar
AU  - Santibanez, Juan F.
AU  - Gotić, Mirjana
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1226
AB  - Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been identified as a major cellular source of fibrosis, the exact molecular mechanism and signaling pathways involved have not been identified thus far. Here, we show that BM-MSCs contribute to fibrosis in myeloproliferative neoplasms (MPNs) by differentiating into αSMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGFβ and inflammatory JAK2/STAT3 and NFκB signaling pathway activity is increased in BM-MSCs of MPN patients. Moreover, coculture with mononuclear cells from MPN patients was sufficient to induce fibrosis in healthy BM-MSCs. Inhibition of JAK1/2, SMAD3 or NFκB significantly reduced the fibrotic phenotype of MPN BM-MSCs and was able to prevent the development of fibrosis induced by coculture of healthy BM-MSCs and MPN mononuclear cells with overly active JAK/STAT signaling, underlining their involvement in fibrosis. Combined treatment with JAK1/2 and SMAD3 inhibitors showed synergistic and the most favorable effects on αSMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGFβ and inflammatory signaling to extenuate fibrosis in MPN.
PB  - Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation]
PB  - Springer Nature [Commercial Publisher]
T2  - Experimental & Molecular Medicine
T1  - Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms
EP  - 284
IS  - 3
SP  - 273
VL  - 54
DO  - 10.1038/s12276-022-00742-y
ER  - 

@article{
author = "Vukotić, Milica and Kapor, Sunčica and Dragojević, Teodora and Đikić, Dragoslava and Mitrović-Ajtić, Olivera and Diklić, Miloš and Subotički, Tijana and Živković, Emilija and Beleslin-Čokić, Bojana and Vojvodić, Aleksandar and Santibanez, Juan F. and Gotić, Mirjana and Čokić, Vladan",
year = "2022",
abstract = "Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been identified as a major cellular source of fibrosis, the exact molecular mechanism and signaling pathways involved have not been identified thus far. Here, we show that BM-MSCs contribute to fibrosis in myeloproliferative neoplasms (MPNs) by differentiating into αSMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGFβ and inflammatory JAK2/STAT3 and NFκB signaling pathway activity is increased in BM-MSCs of MPN patients. Moreover, coculture with mononuclear cells from MPN patients was sufficient to induce fibrosis in healthy BM-MSCs. Inhibition of JAK1/2, SMAD3 or NFκB significantly reduced the fibrotic phenotype of MPN BM-MSCs and was able to prevent the development of fibrosis induced by coculture of healthy BM-MSCs and MPN mononuclear cells with overly active JAK/STAT signaling, underlining their involvement in fibrosis. Combined treatment with JAK1/2 and SMAD3 inhibitors showed synergistic and the most favorable effects on αSMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGFβ and inflammatory signaling to extenuate fibrosis in MPN.",
publisher = "Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation], Springer Nature [Commercial Publisher]",
journal = "Experimental & Molecular Medicine",
title = "Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms",
pages = "284-273",
number = "3",
volume = "54",
doi = "10.1038/s12276-022-00742-y"
}

Vukotić, M., Kapor, S., Dragojević, T., Đikić, D., Mitrović-Ajtić, O., Diklić, M., Subotički, T., Živković, E., Beleslin-Čokić, B., Vojvodić, A., Santibanez, J. F., Gotić, M.,& Čokić, V.. (2022). Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms. in Experimental & Molecular Medicine
Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation]., 54(3), 273-284.
https://doi.org/10.1038/s12276-022-00742-y

Vukotić M, Kapor S, Dragojević T, Đikić D, Mitrović-Ajtić O, Diklić M, Subotički T, Živković E, Beleslin-Čokić B, Vojvodić A, Santibanez JF, Gotić M, Čokić V. Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms. in Experimental & Molecular Medicine. 2022;54(3):273-284.
doi:10.1038/s12276-022-00742-y .

Vukotić, Milica, Kapor, Sunčica, Dragojević, Teodora, Đikić, Dragoslava, Mitrović-Ajtić, Olivera, Diklić, Miloš, Subotički, Tijana, Živković, Emilija, Beleslin-Čokić, Bojana, Vojvodić, Aleksandar, Santibanez, Juan F., Gotić, Mirjana, Čokić, Vladan, "Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms" in Experimental & Molecular Medicine, 54, no. 3 (2022):273-284,
https://doi.org/10.1038/s12276-022-00742-y . .

TY  - JOUR
AU  - Mitrović-Ajtić, Olivera
AU  - Subotički, Tijana
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Vukotić, Milica
AU  - Dragojević, Teodora
AU  - Živković, Emilija
AU  - Antić, Darko
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1244
AB  - The calcium-binding proteins S100A4, S100A8, and S100A9 are upregulated in chronic lymphocytic leukemia (CLL), while the S100A9 promotes NF-κB activity during disease progression. The S100-protein family has been involved in several malignancies as mediators of inflammation and proliferation. The hypothesis of our study is that S100A proteins are mediators in signaling pathways associated with inflammation-induced proliferation, such as NF-κB, PI3K/AKT, and JAK/STAT. The mononuclear cells (MNCs) of CLL were treated with proinflammatory IL-6, anti-inflammatory IL-10 cytokines, inhibitors of JAK1/2, NF-κB, and PI3K signaling pathways, to evaluate S100A4, S100A8, S100A9, and S100A12 expression as well as NF-κB activation by qRT-PCR, immunocytochemistry, and immunoblotting. The quantity of S100A4, S100A8, and S100A9 positive cells (p < 0.05) and their protein expression (p < 0.01) were significantly decreased in MNCs of CLL patients compared to healthy controls. The S100A levels were generally increased in CD19+ cells compared to MNCs of CLL. The S100A4 gene expression was significantly stimulated (p < 0.05) by the inhibition of the PI3K/AKT signaling pathway in MNCs. IL-6 stimulated S100A4 and S100A8 protein expression, prevented by the NF-κB and JAK1/2 inhibitors. In contrast, IL-10 reduced S100A8, S100A9, and S100A12 protein expressions in MNCs of CLL. Moreover, IL-10 inhibited activation of NF-κB signaling (4-fold, p < 0.05). In conclusion, inflammation stimulated the S100A protein expression mediated via the proliferation-related signaling and balanced by the cytokines in CLL.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia
IS  - 13
SP  - 6952
VL  - 23
DO  - 10.3390/ijms23136952
ER  - 

@article{
author = "Mitrović-Ajtić, Olivera and Subotički, Tijana and Diklić, Miloš and Đikić, Dragoslava and Vukotić, Milica and Dragojević, Teodora and Živković, Emilija and Antić, Darko and Čokić, Vladan",
year = "2022",
abstract = "The calcium-binding proteins S100A4, S100A8, and S100A9 are upregulated in chronic lymphocytic leukemia (CLL), while the S100A9 promotes NF-κB activity during disease progression. The S100-protein family has been involved in several malignancies as mediators of inflammation and proliferation. The hypothesis of our study is that S100A proteins are mediators in signaling pathways associated with inflammation-induced proliferation, such as NF-κB, PI3K/AKT, and JAK/STAT. The mononuclear cells (MNCs) of CLL were treated with proinflammatory IL-6, anti-inflammatory IL-10 cytokines, inhibitors of JAK1/2, NF-κB, and PI3K signaling pathways, to evaluate S100A4, S100A8, S100A9, and S100A12 expression as well as NF-κB activation by qRT-PCR, immunocytochemistry, and immunoblotting. The quantity of S100A4, S100A8, and S100A9 positive cells (p < 0.05) and their protein expression (p < 0.01) were significantly decreased in MNCs of CLL patients compared to healthy controls. The S100A levels were generally increased in CD19+ cells compared to MNCs of CLL. The S100A4 gene expression was significantly stimulated (p < 0.05) by the inhibition of the PI3K/AKT signaling pathway in MNCs. IL-6 stimulated S100A4 and S100A8 protein expression, prevented by the NF-κB and JAK1/2 inhibitors. In contrast, IL-10 reduced S100A8, S100A9, and S100A12 protein expressions in MNCs of CLL. Moreover, IL-10 inhibited activation of NF-κB signaling (4-fold, p < 0.05). In conclusion, inflammation stimulated the S100A protein expression mediated via the proliferation-related signaling and balanced by the cytokines in CLL.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia",
number = "13",
pages = "6952",
volume = "23",
doi = "10.3390/ijms23136952"
}

Mitrović-Ajtić, O., Subotički, T., Diklić, M., Đikić, D., Vukotić, M., Dragojević, T., Živković, E., Antić, D.,& Čokić, V.. (2022). Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia. in International Journal of Molecular Sciences
MDPI., 23(13), 6952.
https://doi.org/10.3390/ijms23136952

Mitrović-Ajtić O, Subotički T, Diklić M, Đikić D, Vukotić M, Dragojević T, Živković E, Antić D, Čokić V. Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia. in International Journal of Molecular Sciences. 2022;23(13):6952.
doi:10.3390/ijms23136952 .

Mitrović-Ajtić, Olivera, Subotički, Tijana, Diklić, Miloš, Đikić, Dragoslava, Vukotić, Milica, Dragojević, Teodora, Živković, Emilija, Antić, Darko, Čokić, Vladan, "Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia" in International Journal of Molecular Sciences, 23, no. 13 (2022):6952,
https://doi.org/10.3390/ijms23136952 . .

TY  - CONF
AU  - Antić, Darko
AU  - Đikić, Dragoslava
AU  - Otašević, Vladimir
AU  - Mitrović-Ajtić, Olivera
AU  - Vuković, Vojin
AU  - Subotički, Tijana
AU  - Đurašinović, Vladislava
AU  - Tomić, Kristina
AU  - Mihaljević, Biljana
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1428
AB  - Background: Oxidative stress is caused by imbalance between excessive production of reactive oxygen species and decreased capabilities of antioxidant system, and it is recognized as a feature in cancerogenesis, as well in hematologic malignancies. Previous studies have shown increasing expression of oxidative stress markers and antioxidant enzymes in lymph nodes progressing to aggressive lymphomas.
Aims: The aim of our study was to assess the clinical and prognostic significance of oxidative stress markers in patients with untreated diffuse large B-cell lymphoma (DLBCL).
Methods: We analysed 64 patients diagnosed with DLBLC during 2018 and 2019, while 27 healthy volunteers (51.9% males) served as a control group. The plasma sample and laboratory analyses were obtained prior to initiation of specific hematologic treatment. After completion of the therapy, the patients were followed up for up to 4 years and for each of them progression free survival (PFS) and overall survival (OS) were calculated. Malondialdehyde (MDA) and protein carbonyl (PC) were used as markers of oxidative stress in plasma of patients and volunteers, while catalase is used as an antioxidant marker.
Results: The mean patients’ age was 56.2 years (range, 20–87); 51.6% were males. Majority of patients were analysed before 1L therapy (n=61; 95,3%), and had following clinical stages: Ann Arbor stage I 23.4%, stage II 37.5%, stage III 15.6% and stage IV 23.4%. Majority of the patients had satisfactory performance status (73.5% had ECOG PS ≥1), bulky tumorous mass was present in 34.4% of patients, whereas 70.3% had extranodal localisation of lymphoma. MDA (6.66±2.7 nmol/ml) was significantly increased (p<0.001, 2.6-fold), while PC (4.29±2.7 nmol/mg) was also significantly increased (p=0.0027, 5-fold) in patients with DLBCL compared to healthy volunteers. In opposite, antioxidant catalase (0.194±0.06 IU/ml) was significantly reduced (p=0.0034, 1.9-fold) in patients with DLBCL. MDA was in significant (p<0.05) negative correlation with hemoglobin (r2=0.586) and LDH (r2=0.59) levels before chemotherapy. MDA was in significant (p<0.01) positive correlation with the age (r2=0.769) of patients with DLBCL at diagnosis. Moreover, MDA was in significant positive correlation with overall survival (p<0.01, r2=0.736) and progression-free survival (p<0.01, r2=0.736) of patients with DLBCL. PC was in negative correlation with the clinical stage (r2=0.103, p=0.146) and therapy response (r2=0.136, p=0.091) of DLBCL but did not reach significance.
Summary/Conclusion: The elevated oxidative markers and reduced antioxidant support oxidative stress in patients with DLBCL, while MDA can be a prognostic marker of overall survival.
PB  - Wolters Kluwer Health, Inc
C3  - HemaSphere
T1  - Increased oxidative stress in diffuse large B-cell lymphoma
IS  - S3
SP  - 3741
VL  - 6
DO  - 10.1097/01.HS9.0000851476.12536.06
ER  - 

@conference{
author = "Antić, Darko and Đikić, Dragoslava and Otašević, Vladimir and Mitrović-Ajtić, Olivera and Vuković, Vojin and Subotički, Tijana and Đurašinović, Vladislava and Tomić, Kristina and Mihaljević, Biljana and Čokić, Vladan",
year = "2022",
abstract = "Background: Oxidative stress is caused by imbalance between excessive production of reactive oxygen species and decreased capabilities of antioxidant system, and it is recognized as a feature in cancerogenesis, as well in hematologic malignancies. Previous studies have shown increasing expression of oxidative stress markers and antioxidant enzymes in lymph nodes progressing to aggressive lymphomas.
Aims: The aim of our study was to assess the clinical and prognostic significance of oxidative stress markers in patients with untreated diffuse large B-cell lymphoma (DLBCL).
Methods: We analysed 64 patients diagnosed with DLBLC during 2018 and 2019, while 27 healthy volunteers (51.9% males) served as a control group. The plasma sample and laboratory analyses were obtained prior to initiation of specific hematologic treatment. After completion of the therapy, the patients were followed up for up to 4 years and for each of them progression free survival (PFS) and overall survival (OS) were calculated. Malondialdehyde (MDA) and protein carbonyl (PC) were used as markers of oxidative stress in plasma of patients and volunteers, while catalase is used as an antioxidant marker.
Results: The mean patients’ age was 56.2 years (range, 20–87); 51.6% were males. Majority of patients were analysed before 1L therapy (n=61; 95,3%), and had following clinical stages: Ann Arbor stage I 23.4%, stage II 37.5%, stage III 15.6% and stage IV 23.4%. Majority of the patients had satisfactory performance status (73.5% had ECOG PS ≥1), bulky tumorous mass was present in 34.4% of patients, whereas 70.3% had extranodal localisation of lymphoma. MDA (6.66±2.7 nmol/ml) was significantly increased (p<0.001, 2.6-fold), while PC (4.29±2.7 nmol/mg) was also significantly increased (p=0.0027, 5-fold) in patients with DLBCL compared to healthy volunteers. In opposite, antioxidant catalase (0.194±0.06 IU/ml) was significantly reduced (p=0.0034, 1.9-fold) in patients with DLBCL. MDA was in significant (p<0.05) negative correlation with hemoglobin (r2=0.586) and LDH (r2=0.59) levels before chemotherapy. MDA was in significant (p<0.01) positive correlation with the age (r2=0.769) of patients with DLBCL at diagnosis. Moreover, MDA was in significant positive correlation with overall survival (p<0.01, r2=0.736) and progression-free survival (p<0.01, r2=0.736) of patients with DLBCL. PC was in negative correlation with the clinical stage (r2=0.103, p=0.146) and therapy response (r2=0.136, p=0.091) of DLBCL but did not reach significance.
Summary/Conclusion: The elevated oxidative markers and reduced antioxidant support oxidative stress in patients with DLBCL, while MDA can be a prognostic marker of overall survival.",
publisher = "Wolters Kluwer Health, Inc",
journal = "HemaSphere",
title = "Increased oxidative stress in diffuse large B-cell lymphoma",
number = "S3",
pages = "3741",
volume = "6",
doi = "10.1097/01.HS9.0000851476.12536.06"
}

Antić, D., Đikić, D., Otašević, V., Mitrović-Ajtić, O., Vuković, V., Subotički, T., Đurašinović, V., Tomić, K., Mihaljević, B.,& Čokić, V.. (2022). Increased oxidative stress in diffuse large B-cell lymphoma. in HemaSphere
Wolters Kluwer Health, Inc., 6(S3), 3741.
https://doi.org/10.1097/01.HS9.0000851476.12536.06

Antić D, Đikić D, Otašević V, Mitrović-Ajtić O, Vuković V, Subotički T, Đurašinović V, Tomić K, Mihaljević B, Čokić V. Increased oxidative stress in diffuse large B-cell lymphoma. in HemaSphere. 2022;6(S3):3741.
doi:10.1097/01.HS9.0000851476.12536.06 .

Antić, Darko, Đikić, Dragoslava, Otašević, Vladimir, Mitrović-Ajtić, Olivera, Vuković, Vojin, Subotički, Tijana, Đurašinović, Vladislava, Tomić, Kristina, Mihaljević, Biljana, Čokić, Vladan, "Increased oxidative stress in diffuse large B-cell lymphoma" in HemaSphere, 6, no. S3 (2022):3741,
https://doi.org/10.1097/01.HS9.0000851476.12536.06 . .

TY  - CONF
AU  - Miljatović, Sanja
AU  - Dragojević, Teodora
AU  - Đikić, Dragoslava
AU  - Živković, Emilija
AU  - Stevanović, Goran
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1457
AB  - Background. A vascular system inflammation is a risk of venous thromboembolism
and can result in widespread microangiopathy with microvascular thrombosis.
Methods. We performed laboratory clinical follow-up of patients with COVID-19 to
compare gender differences. To study the sex difference in COVID-19 outcome we
will measure estradiol and androgens: dihydrotestosterone (DHT) and sex hormone
binding globulin (SHBP) in plasma of 63 COVID-19 patients, analyzed by ELISA. Their
levels will be correlated to the adhesion molecules: soluble intercellular adhesion
molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), sE-selectin,
and sP-selectin as biomarkers for inflammation and thrombosis.
Results. DHT was increased (1.9 fold) in male COVID-19 patients compared to healthy
male volunteers. SHBP was significantly increased in COVID-19 patients compared
to healthy volunteers (p<0.05) as well as female vs. male COVID-19 patients (p<0.001,
2.5 fold). sVCAM-1 and sICAM-1 were increased in female COVID-19 patients compared
to male COVID-19 patients and female volunteers, respectively (p<0.05). The
sP-selection was significantly (p<0.01) increased in male vs. female COVID-19 patients.
SHBP was in negative correlation with sP-selectin (p<0.05). DHT was in positive
correlation with sVCAM-1 (p<0.05). Ferritin had 3-fold higher levels in male than
female COVID-19 patients (p<0.001).
Conclusions. Upregulation of androgen hormones and thrombotic biomarkers in
COVID-19 patients demonstrate sex dependence.
PB  - Belgrade: MEDAPP Association
C3  - The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book, 2022
T1  - Androgen Dependence in Thrombosis of Patients With COVID-19
EP  - 391
SP  - 391
UR  - https://hdl.handle.net/21.15107/rcub_rimi_1457
ER  - 

@conference{
author = "Miljatović, Sanja and Dragojević, Teodora and Đikić, Dragoslava and Živković, Emilija and Stevanović, Goran and Čokić, Vladan",
year = "2022",
abstract = "Background. A vascular system inflammation is a risk of venous thromboembolism
and can result in widespread microangiopathy with microvascular thrombosis.
Methods. We performed laboratory clinical follow-up of patients with COVID-19 to
compare gender differences. To study the sex difference in COVID-19 outcome we
will measure estradiol and androgens: dihydrotestosterone (DHT) and sex hormone
binding globulin (SHBP) in plasma of 63 COVID-19 patients, analyzed by ELISA. Their
levels will be correlated to the adhesion molecules: soluble intercellular adhesion
molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), sE-selectin,
and sP-selectin as biomarkers for inflammation and thrombosis.
Results. DHT was increased (1.9 fold) in male COVID-19 patients compared to healthy
male volunteers. SHBP was significantly increased in COVID-19 patients compared
to healthy volunteers (p<0.05) as well as female vs. male COVID-19 patients (p<0.001,
2.5 fold). sVCAM-1 and sICAM-1 were increased in female COVID-19 patients compared
to male COVID-19 patients and female volunteers, respectively (p<0.05). The
sP-selection was significantly (p<0.01) increased in male vs. female COVID-19 patients.
SHBP was in negative correlation with sP-selectin (p<0.05). DHT was in positive
correlation with sVCAM-1 (p<0.05). Ferritin had 3-fold higher levels in male than
female COVID-19 patients (p<0.001).
Conclusions. Upregulation of androgen hormones and thrombotic biomarkers in
COVID-19 patients demonstrate sex dependence.",
publisher = "Belgrade: MEDAPP Association",
journal = "The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book, 2022",
title = "Androgen Dependence in Thrombosis of Patients With COVID-19",
pages = "391-391",
url = "https://hdl.handle.net/21.15107/rcub_rimi_1457"
}

Miljatović, S., Dragojević, T., Đikić, D., Živković, E., Stevanović, G.,& Čokić, V.. (2022). Androgen Dependence in Thrombosis of Patients With COVID-19. in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book, 2022
Belgrade: MEDAPP Association., 391-391.
https://hdl.handle.net/21.15107/rcub_rimi_1457

Miljatović S, Dragojević T, Đikić D, Živković E, Stevanović G, Čokić V. Androgen Dependence in Thrombosis of Patients With COVID-19. in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book, 2022. 2022;:391-391.
https://hdl.handle.net/21.15107/rcub_rimi_1457 .

Miljatović, Sanja, Dragojević, Teodora, Đikić, Dragoslava, Živković, Emilija, Stevanović, Goran, Čokić, Vladan, "Androgen Dependence in Thrombosis of Patients With COVID-19" in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book, 2022 (2022):391-391,
https://hdl.handle.net/21.15107/rcub_rimi_1457 .

TY  - CONF
AU  - Dragojević, Teodora
AU  - Mitrović Ajtić, Olivera
AU  - Diklić, Miloš
AU  - Subotički, Tijana
AU  - Đikić, Dragoslava
AU  - Živković, Emilija
AU  - Čokić, Vladan
AU  - Vukotić, Milica
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1427
AB  - Background:: Hydroxyurea (HU) is a chemotherapeutic agent that reduces ribonucleotide reductase, stops DNA synthesis and repar, and therefore causes cell proliferation inhibition and apoptosis. Due to its cytostatic properties, HU is frequently used for treatment of myeloproliferative neoplasms, ovarian cancer, and sickle cell anemia. Nitric oxide (NO), produced by nitric oxide synthase (NOS) enzymes is a potent signaling molecule involved in blood flow regulation, neutrotransmission, and immunity. Although HU treatment increases NO levels, up to date it is not clear whether it originates from activation of NOS enzymes or HU degradation.

Aims: The aim of this study was to determine the involvement of NOS2 enzyme in the cytostatic effect of HU.
Methods: To examine the involvement of the NOS2 enzyme in the molecular mechanism of HU, we treated erythroleukemic HEL92.7.1 cells with pan-selective NOS inhibitor L-NAME (200µM, 1mM, and 5mM), NOS2 specific inhibitor 1400W (1, 10, and 100µM), or NOS2/NOS3 inhibitor DPI (1, 5, and 10µM), in combination with hydroxyurea (200µM), and monitored their effect on proliferation and cell cycle. Immunocytochemistry for the proliferation marker Ki67 was performed to assess proliferation, while cell distribution in cell cycle phases was determined by flow cytometry after propidium iodide staining. Colony forming assay have been performed with the bone marrow cells of Nos2 null mice after oral HU treatment to corroborate the data obtained by enzymatic inhibition.
Results: In this study, we demonstrated that treatment of HEL92.7.1 cells with HU induces a dose-dependent increase in NOS2 protein levels and two products of the enzyme NOS - NO and citrulline. HU-induced citrulline levels can be reduced by treatment with the NOS inhibitor L-NAME, indicating that NO is produced de novo by the NOS enzyme rather than HU degradation. Inhibition of the NOS2 enzyme by L-NAME, 1400W, or DPI was sufficient to abolish HU-mediated inhibition of proliferation. While HU increased the number of cells in S-phase of the cycle at the expanse of the G0/G1 due to blocked DNA synthesis, combined treatment with HU and L-NAME or DPI inhibitor resulted in decreased G0/G1 phase and increased S and G2/M phases pointing to increased proliferation. These data indicate that the cytostatic properties of HU are mediated by the NOS2 enzyme. A colony formation assay showed that Nos2 deficient bone marrow cells isolated from mice treated orally with HU (200mg/kg) formed significantly more erythroid colonies (BFU-E and CFU-E) and granulocyte/macrophage progenitors (CFU-GM) compared to HU treated wild-type and untreated Nos2 null mice showing the involvement of Nos2 in the molecular mechanism of HU in vivo.
Summary/Conclusion: Our results show that HU induces the enzymatic activity of the NOS2 protein which in turn is involved in the HU regulation of proliferation and cell cycle. Comprehensive knowledge of the molecular mechanism of HU might help to improve its beneficial properties and decrease adverse effects.
PB  - Wolters Kluwer Health, Inc.
C3  - HemaSphere - EHA2022 Hybrid Congress Abstract Book S3
T1  - Molecural mechanism of chemotherapeutic hydroxyurea is mediated by NOS2
EP  - 2584
IS  - S3
SP  - 2584
VL  - 6
DO  - 10.1097/01.HS9.0000848752.48359.16
ER  - 

@conference{
author = "Dragojević, Teodora and Mitrović Ajtić, Olivera and Diklić, Miloš and Subotički, Tijana and Đikić, Dragoslava and Živković, Emilija and Čokić, Vladan and Vukotić, Milica",
year = "2022",
abstract = "Background:: Hydroxyurea (HU) is a chemotherapeutic agent that reduces ribonucleotide reductase, stops DNA synthesis and repar, and therefore causes cell proliferation inhibition and apoptosis. Due to its cytostatic properties, HU is frequently used for treatment of myeloproliferative neoplasms, ovarian cancer, and sickle cell anemia. Nitric oxide (NO), produced by nitric oxide synthase (NOS) enzymes is a potent signaling molecule involved in blood flow regulation, neutrotransmission, and immunity. Although HU treatment increases NO levels, up to date it is not clear whether it originates from activation of NOS enzymes or HU degradation.

Aims: The aim of this study was to determine the involvement of NOS2 enzyme in the cytostatic effect of HU.
Methods: To examine the involvement of the NOS2 enzyme in the molecular mechanism of HU, we treated erythroleukemic HEL92.7.1 cells with pan-selective NOS inhibitor L-NAME (200µM, 1mM, and 5mM), NOS2 specific inhibitor 1400W (1, 10, and 100µM), or NOS2/NOS3 inhibitor DPI (1, 5, and 10µM), in combination with hydroxyurea (200µM), and monitored their effect on proliferation and cell cycle. Immunocytochemistry for the proliferation marker Ki67 was performed to assess proliferation, while cell distribution in cell cycle phases was determined by flow cytometry after propidium iodide staining. Colony forming assay have been performed with the bone marrow cells of Nos2 null mice after oral HU treatment to corroborate the data obtained by enzymatic inhibition.
Results: In this study, we demonstrated that treatment of HEL92.7.1 cells with HU induces a dose-dependent increase in NOS2 protein levels and two products of the enzyme NOS - NO and citrulline. HU-induced citrulline levels can be reduced by treatment with the NOS inhibitor L-NAME, indicating that NO is produced de novo by the NOS enzyme rather than HU degradation. Inhibition of the NOS2 enzyme by L-NAME, 1400W, or DPI was sufficient to abolish HU-mediated inhibition of proliferation. While HU increased the number of cells in S-phase of the cycle at the expanse of the G0/G1 due to blocked DNA synthesis, combined treatment with HU and L-NAME or DPI inhibitor resulted in decreased G0/G1 phase and increased S and G2/M phases pointing to increased proliferation. These data indicate that the cytostatic properties of HU are mediated by the NOS2 enzyme. A colony formation assay showed that Nos2 deficient bone marrow cells isolated from mice treated orally with HU (200mg/kg) formed significantly more erythroid colonies (BFU-E and CFU-E) and granulocyte/macrophage progenitors (CFU-GM) compared to HU treated wild-type and untreated Nos2 null mice showing the involvement of Nos2 in the molecular mechanism of HU in vivo.
Summary/Conclusion: Our results show that HU induces the enzymatic activity of the NOS2 protein which in turn is involved in the HU regulation of proliferation and cell cycle. Comprehensive knowledge of the molecular mechanism of HU might help to improve its beneficial properties and decrease adverse effects.",
publisher = "Wolters Kluwer Health, Inc.",
journal = "HemaSphere - EHA2022 Hybrid Congress Abstract Book S3",
title = "Molecural mechanism of chemotherapeutic hydroxyurea is mediated by NOS2",
pages = "2584-2584",
number = "S3",
volume = "6",
doi = "10.1097/01.HS9.0000848752.48359.16"
}

Dragojević, T., Mitrović Ajtić, O., Diklić, M., Subotički, T., Đikić, D., Živković, E., Čokić, V.,& Vukotić, M.. (2022). Molecural mechanism of chemotherapeutic hydroxyurea is mediated by NOS2. in HemaSphere - EHA2022 Hybrid Congress Abstract Book S3
Wolters Kluwer Health, Inc.., 6(S3), 2584-2584.
https://doi.org/10.1097/01.HS9.0000848752.48359.16

Dragojević T, Mitrović Ajtić O, Diklić M, Subotički T, Đikić D, Živković E, Čokić V, Vukotić M. Molecural mechanism of chemotherapeutic hydroxyurea is mediated by NOS2. in HemaSphere - EHA2022 Hybrid Congress Abstract Book S3. 2022;6(S3):2584-2584.
doi:10.1097/01.HS9.0000848752.48359.16 .

Dragojević, Teodora, Mitrović Ajtić, Olivera, Diklić, Miloš, Subotički, Tijana, Đikić, Dragoslava, Živković, Emilija, Čokić, Vladan, Vukotić, Milica, "Molecural mechanism of chemotherapeutic hydroxyurea is mediated by NOS2" in HemaSphere - EHA2022 Hybrid Congress Abstract Book S3, 6, no. S3 (2022):2584-2584,
https://doi.org/10.1097/01.HS9.0000848752.48359.16 . .

TY  - JOUR
AU  - Marković, Dragana
AU  - Maslovarić, Irina
AU  - Đikić, Dragoslava
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1205
AB  - Neutrophils are an essential component of the innate immune response, but their prolonged activation can lead to chronic inflammation. Consequently, neutrophil homeostasis is tightly regulated through balance between granulopoiesis and clearance of dying cells. The bone marrow is both a site of neutrophil production and the place they return to and die. Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by the mutations in three types of molecular markers, with emphasis on Janus kinase 2 gene mutation (JAK2V617F). The MPN bone marrow stem cell niche is a site of chronic inflammation, with commonly increased cells of myeloid lineage, including neutrophils. The MPN neutrophils are characterized by the upregulation of JAK target genes. Additionally, MPN neutrophils display malignant nature, they are in a state of activation, and with deregulated apoptotic machinery. In other words, neutrophils deserve to be placed in the midst of major events in MPN. Our crucial interest in this review is better understanding of how neutrophils die in MPN mirrored by defects in apoptosis and to what possible extent they can contribute to MPN pathophysiology. We tend to expect that reduced neutrophil apoptosis will establish a pathogenic link to chronic inflammation in MPN.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation
IS  - 3
SP  - 1490
VL  - 23
DO  - 10.3390/ijms23031490
ER  - 

@article{
author = "Marković, Dragana and Maslovarić, Irina and Đikić, Dragoslava and Čokić, Vladan",
year = "2022",
abstract = "Neutrophils are an essential component of the innate immune response, but their prolonged activation can lead to chronic inflammation. Consequently, neutrophil homeostasis is tightly regulated through balance between granulopoiesis and clearance of dying cells. The bone marrow is both a site of neutrophil production and the place they return to and die. Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by the mutations in three types of molecular markers, with emphasis on Janus kinase 2 gene mutation (JAK2V617F). The MPN bone marrow stem cell niche is a site of chronic inflammation, with commonly increased cells of myeloid lineage, including neutrophils. The MPN neutrophils are characterized by the upregulation of JAK target genes. Additionally, MPN neutrophils display malignant nature, they are in a state of activation, and with deregulated apoptotic machinery. In other words, neutrophils deserve to be placed in the midst of major events in MPN. Our crucial interest in this review is better understanding of how neutrophils die in MPN mirrored by defects in apoptosis and to what possible extent they can contribute to MPN pathophysiology. We tend to expect that reduced neutrophil apoptosis will establish a pathogenic link to chronic inflammation in MPN.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation",
number = "3",
pages = "1490",
volume = "23",
doi = "10.3390/ijms23031490"
}

Marković, D., Maslovarić, I., Đikić, D.,& Čokić, V.. (2022). Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation. in International Journal of Molecular Sciences
MDPI., 23(3), 1490.
https://doi.org/10.3390/ijms23031490

Marković D, Maslovarić I, Đikić D, Čokić V. Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation. in International Journal of Molecular Sciences. 2022;23(3):1490.
doi:10.3390/ijms23031490 .

Marković, Dragana, Maslovarić, Irina, Đikić, Dragoslava, Čokić, Vladan, "Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation" in International Journal of Molecular Sciences, 23, no. 3 (2022):1490,
https://doi.org/10.3390/ijms23031490 . .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Živković, Emilija
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Tošić, Milica
AU  - Beleslin-Čokić, Bojana
AU  - Dragojević, Teodora
AU  - Gotić, Mirjana
AU  - Santibanez, Juan F.
AU  - Čokić, Vladan
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1136
AB  - Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
IS  - 13
SP  - 6671
VL  - 22
DO  - 10.3390/ijms22136671
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Živković, Emilija and Diklić, Miloš and Đikić, Dragoslava and Tošić, Milica and Beleslin-Čokić, Bojana and Dragojević, Teodora and Gotić, Mirjana and Santibanez, Juan F. and Čokić, Vladan",
year = "2021",
abstract = "Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms",
number = "13",
pages = "6671",
volume = "22",
doi = "10.3390/ijms22136671"
}

Subotički, T., Mitrović-Ajtić, O., Živković, E., Diklić, M., Đikić, D., Tošić, M., Beleslin-Čokić, B., Dragojević, T., Gotić, M., Santibanez, J. F.,& Čokić, V.. (2021). VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms. in International Journal of Molecular Sciences
MDPI., 22(13), 6671.
https://doi.org/10.3390/ijms22136671

Subotički T, Mitrović-Ajtić O, Živković E, Diklić M, Đikić D, Tošić M, Beleslin-Čokić B, Dragojević T, Gotić M, Santibanez JF, Čokić V. VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms. in International Journal of Molecular Sciences. 2021;22(13):6671.
doi:10.3390/ijms22136671 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Živković, Emilija, Diklić, Miloš, Đikić, Dragoslava, Tošić, Milica, Beleslin-Čokić, Bojana, Dragojević, Teodora, Gotić, Mirjana, Santibanez, Juan F., Čokić, Vladan, "VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms" in International Journal of Molecular Sciences, 22, no. 13 (2021):6671,
https://doi.org/10.3390/ijms22136671 . .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera 
AU  - Đikić, Dragoslava
AU  - Santibanez, Juan F.
AU  - Tošić, Milica
AU  - Čokić, Vladan
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1151
AB  - Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ-and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.
PB  - Multidisciplinary Digital Publishing Institute (MDPI)
T2  - Genes
T1  - Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth
IS  - 8
SP  - 1145
VL  - 12
DO  - 10.3390/genes12081145
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera  and Đikić, Dragoslava and Santibanez, Juan F. and Tošić, Milica and Čokić, Vladan",
year = "2021",
abstract = "Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ-and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
journal = "Genes",
title = "Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth",
number = "8",
pages = "1145",
volume = "12",
doi = "10.3390/genes12081145"
}

Subotički, T., Mitrović-Ajtić, O., Đikić, D., Santibanez, J. F., Tošić, M.,& Čokić, V.. (2021). Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth. in Genes
Multidisciplinary Digital Publishing Institute (MDPI)., 12(8), 1145.
https://doi.org/10.3390/genes12081145

Subotički T, Mitrović-Ajtić O, Đikić D, Santibanez JF, Tošić M, Čokić V. Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth. in Genes. 2021;12(8):1145.
doi:10.3390/genes12081145 .

Subotički, Tijana, Mitrović-Ajtić, Olivera , Đikić, Dragoslava, Santibanez, Juan F., Tošić, Milica, Čokić, Vladan, "Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth" in Genes, 12, no. 8 (2021):1145,
https://doi.org/10.3390/genes12081145 . .

TY  - JOUR
AU  - Kapor, Sunčica
AU  - Vukotić, Milica
AU  - Subotički, Tijana
AU  - Đikić, Dragoslava
AU  - Mitrović-Ajtić, Olivera
AU  - Radojković, Milica
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1172
AB  - Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.
PB  - MDPI
T2  - Journal of Personalized Medicine
T1  - Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro
IS  - 11
SP  - 1048
VL  - 11
DO  - 10.3390/jpm11111048
ER  - 

@article{
author = "Kapor, Sunčica and Vukotić, Milica and Subotički, Tijana and Đikić, Dragoslava and Mitrović-Ajtić, Olivera and Radojković, Milica and Čokić, Vladan and Santibanez, Juan F.",
year = "2021",
abstract = "Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.",
publisher = "MDPI",
journal = "Journal of Personalized Medicine",
title = "Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro",
number = "11",
pages = "1048",
volume = "11",
doi = "10.3390/jpm11111048"
}

Kapor, S., Vukotić, M., Subotički, T., Đikić, D., Mitrović-Ajtić, O., Radojković, M., Čokić, V.,& Santibanez, J. F.. (2021). Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro. in Journal of Personalized Medicine
MDPI., 11(11), 1048.
https://doi.org/10.3390/jpm11111048

Kapor S, Vukotić M, Subotički T, Đikić D, Mitrović-Ajtić O, Radojković M, Čokić V, Santibanez JF. Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro. in Journal of Personalized Medicine. 2021;11(11):1048.
doi:10.3390/jpm11111048 .

Kapor, Sunčica, Vukotić, Milica, Subotički, Tijana, Đikić, Dragoslava, Mitrović-Ajtić, Olivera, Radojković, Milica, Čokić, Vladan, Santibanez, Juan F., "Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro" in Journal of Personalized Medicine, 11, no. 11 (2021):1048,
https://doi.org/10.3390/jpm11111048 . .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Đikić, Dragoslava
AU  - Kovačić, Marijana
AU  - Santibanez, Juan F.
AU  - Tošić, Milica
AU  - Čokić, Vladan
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1196
AB  - In several systems, hydroxyurea has been shown to trigger nitric oxide (NO) release or activation of NO synthase (NOS). To elucidate this duality in its pharmacological effects, during myelosuppression, we individually examined hydroxyurea’s (NO releasing agent) and NO metabolites’ (stable NO degradation products) effects on erythroid colony growth and NOS/NO levels in mice using NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Hydroxyurea and nitrite/nitrate decreased the bone marrow cellularity that was blocked by PTIO only for the NO metabolites. Hydroxyurea inhibition of colony-forming unit-erythroid (CFU-E) formation and reticulocytes was reversed by PTIO. Moreover, hydroxyurea, through a negative feedback mechanism, reduced inducible NOS (iNOS) expressing cells in CFU-E, also prevented by PTIO. Nitrate inhibition of burst-forming units-erythroid (BFU-E) colony growth was blocked by PTIO, but not in mature CFU-E. The presented results reveal that NO release and/or production mediates the hydroxyurea inhibition of mature erythroid colony growth and the frequency of iNOS immunoreactive CFU-E.
PB  - MDPI
T2  - Biomolecules
T1  - Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth
IS  - 11
SP  - 1562
VL  - 11
DO  - 10.3390/biom11111562
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Đikić, Dragoslava and Kovačić, Marijana and Santibanez, Juan F. and Tošić, Milica and Čokić, Vladan",
year = "2021",
abstract = "In several systems, hydroxyurea has been shown to trigger nitric oxide (NO) release or activation of NO synthase (NOS). To elucidate this duality in its pharmacological effects, during myelosuppression, we individually examined hydroxyurea’s (NO releasing agent) and NO metabolites’ (stable NO degradation products) effects on erythroid colony growth and NOS/NO levels in mice using NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Hydroxyurea and nitrite/nitrate decreased the bone marrow cellularity that was blocked by PTIO only for the NO metabolites. Hydroxyurea inhibition of colony-forming unit-erythroid (CFU-E) formation and reticulocytes was reversed by PTIO. Moreover, hydroxyurea, through a negative feedback mechanism, reduced inducible NOS (iNOS) expressing cells in CFU-E, also prevented by PTIO. Nitrate inhibition of burst-forming units-erythroid (BFU-E) colony growth was blocked by PTIO, but not in mature CFU-E. The presented results reveal that NO release and/or production mediates the hydroxyurea inhibition of mature erythroid colony growth and the frequency of iNOS immunoreactive CFU-E.",
publisher = "MDPI",
journal = "Biomolecules",
title = "Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth",
number = "11",
pages = "1562",
volume = "11",
doi = "10.3390/biom11111562"
}

Subotički, T., Mitrović-Ajtić, O., Đikić, D., Kovačić, M., Santibanez, J. F., Tošić, M.,& Čokić, V.. (2021). Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth. in Biomolecules
MDPI., 11(11), 1562.
https://doi.org/10.3390/biom11111562

Subotički T, Mitrović-Ajtić O, Đikić D, Kovačić M, Santibanez JF, Tošić M, Čokić V. Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth. in Biomolecules. 2021;11(11):1562.
doi:10.3390/biom11111562 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Đikić, Dragoslava, Kovačić, Marijana, Santibanez, Juan F., Tošić, Milica, Čokić, Vladan, "Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth" in Biomolecules, 11, no. 11 (2021):1562,
https://doi.org/10.3390/biom11111562 . .

TY  - JOUR
AU  - Diklić, Miloš
AU  - Mitrović-Ajtić, Olivera
AU  - Subotički, Tijana
AU  - Đikić, Dragoslava
AU  - Kovačić, Marijana
AU  - Bjelica, Sunčica
AU  - Beleslin-Čokić, Bojana
AU  - Tošić, Milica
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Santibanez, Juan F.
AU  - Čokić, Vladan
PY  - 2020
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1024
AB  - This study has been performed to determine the mechanism of activation of the myeloid related S100A proteins by inflammatory cytokines in myeloproliferative neoplasm (MPN). Besides microarray analysis of MPN-derived CD34(+) cells, we analysed the pro-inflammatory IL6 and anti-inflammatory IL10 dependence of NF-kappa B, PI3K-AKT, and JAK-STAT signalling during induction of S100A proteins in mononuclear cells of MPN, by immunoblotting and flow cytometry. We observed the reduced gene expression linked to NF-kappa B and inflammation signalling in MPN-derived CD34(+) cells. Both IL6 and IL10 reduced S100A8 and 100A9 protein levels mediated via NF-kappa B and PI3K signalling, respectively, in mononuclear cells of essential thrombocythemia (ET). We also determined the increased percentage of S100A8 and S100A9 positive granulocytes in ET and primary myelofibrosis, upgraded by the JAK2V617F mutant allele burden. S100A8/9 heterodimer induced JAK1/2-dependent mitotic arrest of the ET-derived granulocytes. Significance of the study We demonstrated that inflammation reduced the myeloid related S100A8/9 proteins by negative feedback mechanism in ET. S100A8/9 can be a diagnostic marker of inflammation in MPN, supported by the concomitant NF-kappa B and JAK1/2 signalling inhibition in regulation of myeloproliferation and therapy of MPN.
PB  - Wiley, Hoboken
T2  - Cell Biochemistry & Function
T1  - IL6 inhibition of inflammatory S100A8/9 proteins is NF-kappa B mediated in essential thrombocythemia
EP  - 372
IS  - 4
SP  - 362
VL  - 38
DO  - 10.1002/cbf.3482
ER  - 

@article{
author = "Diklić, Miloš and Mitrović-Ajtić, Olivera and Subotički, Tijana and Đikić, Dragoslava and Kovačić, Marijana and Bjelica, Sunčica and Beleslin-Čokić, Bojana and Tošić, Milica and Leković, Danijela and Gotić, Mirjana and Santibanez, Juan F. and Čokić, Vladan",
year = "2020",
abstract = "This study has been performed to determine the mechanism of activation of the myeloid related S100A proteins by inflammatory cytokines in myeloproliferative neoplasm (MPN). Besides microarray analysis of MPN-derived CD34(+) cells, we analysed the pro-inflammatory IL6 and anti-inflammatory IL10 dependence of NF-kappa B, PI3K-AKT, and JAK-STAT signalling during induction of S100A proteins in mononuclear cells of MPN, by immunoblotting and flow cytometry. We observed the reduced gene expression linked to NF-kappa B and inflammation signalling in MPN-derived CD34(+) cells. Both IL6 and IL10 reduced S100A8 and 100A9 protein levels mediated via NF-kappa B and PI3K signalling, respectively, in mononuclear cells of essential thrombocythemia (ET). We also determined the increased percentage of S100A8 and S100A9 positive granulocytes in ET and primary myelofibrosis, upgraded by the JAK2V617F mutant allele burden. S100A8/9 heterodimer induced JAK1/2-dependent mitotic arrest of the ET-derived granulocytes. Significance of the study We demonstrated that inflammation reduced the myeloid related S100A8/9 proteins by negative feedback mechanism in ET. S100A8/9 can be a diagnostic marker of inflammation in MPN, supported by the concomitant NF-kappa B and JAK1/2 signalling inhibition in regulation of myeloproliferation and therapy of MPN.",
publisher = "Wiley, Hoboken",
journal = "Cell Biochemistry & Function",
title = "IL6 inhibition of inflammatory S100A8/9 proteins is NF-kappa B mediated in essential thrombocythemia",
pages = "372-362",
number = "4",
volume = "38",
doi = "10.1002/cbf.3482"
}

Diklić, M., Mitrović-Ajtić, O., Subotički, T., Đikić, D., Kovačić, M., Bjelica, S., Beleslin-Čokić, B., Tošić, M., Leković, D., Gotić, M., Santibanez, J. F.,& Čokić, V.. (2020). IL6 inhibition of inflammatory S100A8/9 proteins is NF-kappa B mediated in essential thrombocythemia. in Cell Biochemistry & Function
Wiley, Hoboken., 38(4), 362-372.
https://doi.org/10.1002/cbf.3482

Diklić M, Mitrović-Ajtić O, Subotički T, Đikić D, Kovačić M, Bjelica S, Beleslin-Čokić B, Tošić M, Leković D, Gotić M, Santibanez JF, Čokić V. IL6 inhibition of inflammatory S100A8/9 proteins is NF-kappa B mediated in essential thrombocythemia. in Cell Biochemistry & Function. 2020;38(4):362-372.
doi:10.1002/cbf.3482 .

Diklić, Miloš, Mitrović-Ajtić, Olivera, Subotički, Tijana, Đikić, Dragoslava, Kovačić, Marijana, Bjelica, Sunčica, Beleslin-Čokić, Bojana, Tošić, Milica, Leković, Danijela, Gotić, Mirjana, Santibanez, Juan F., Čokić, Vladan, "IL6 inhibition of inflammatory S100A8/9 proteins is NF-kappa B mediated in essential thrombocythemia" in Cell Biochemistry & Function, 38, no. 4 (2020):362-372,
https://doi.org/10.1002/cbf.3482 . .

TY  - JOUR
AU  - Bjelica, Sunčica
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Kovačić, Marijana
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Radojković, Milica
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2019
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/907
AB  - Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence-like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence-related phenotypical changes. HU-treated PBMSC display increased senescence-associated beta-galactosidase levels and p16(INK4) expression, as well as DNA damage response and genotoxic effects, evidenced by expression of gamma H2A.X and micronuclei. Moreover, HU-induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N-acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU-induced bystander effect, we used the JAK2V617F-positive human erythroleukemia 92.1.7 (HEL) cells. Co-culture with HU-induced senescent PBMSC (HU-S-PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)-beta expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU-induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.
PB  - Wiley, Hoboken
T2  - FEBS Journal
T1  - Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells
EP  - 3663
IS  - 18
SP  - 3647
VL  - 286
DO  - 10.1111/febs.14927
ER  - 

@article{
author = "Bjelica, Sunčica and Diklić, Miloš and Đikić, Dragoslava and Kovačić, Marijana and Subotički, Tijana and Mitrović-Ajtić, Olivera and Radojković, Milica and Čokić, Vladan and Santibanez, Juan F.",
year = "2019",
abstract = "Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence-like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence-related phenotypical changes. HU-treated PBMSC display increased senescence-associated beta-galactosidase levels and p16(INK4) expression, as well as DNA damage response and genotoxic effects, evidenced by expression of gamma H2A.X and micronuclei. Moreover, HU-induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N-acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU-induced bystander effect, we used the JAK2V617F-positive human erythroleukemia 92.1.7 (HEL) cells. Co-culture with HU-induced senescent PBMSC (HU-S-PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)-beta expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU-induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.",
publisher = "Wiley, Hoboken",
journal = "FEBS Journal",
title = "Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells",
pages = "3663-3647",
number = "18",
volume = "286",
doi = "10.1111/febs.14927"
}

Bjelica, S., Diklić, M., Đikić, D., Kovačić, M., Subotički, T., Mitrović-Ajtić, O., Radojković, M., Čokić, V.,& Santibanez, J. F.. (2019). Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells. in FEBS Journal
Wiley, Hoboken., 286(18), 3647-3663.
https://doi.org/10.1111/febs.14927

Bjelica S, Diklić M, Đikić D, Kovačić M, Subotički T, Mitrović-Ajtić O, Radojković M, Čokić V, Santibanez JF. Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells. in FEBS Journal. 2019;286(18):3647-3663.
doi:10.1111/febs.14927 .

Bjelica, Sunčica, Diklić, Miloš, Đikić, Dragoslava, Kovačić, Marijana, Subotički, Tijana, Mitrović-Ajtić, Olivera, Radojković, Milica, Čokić, Vladan, Santibanez, Juan F., "Hydroxyurea-induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F-positive human erythroleukemia cells" in FEBS Journal, 286, no. 18 (2019):3647-3663,
https://doi.org/10.1111/febs.14927 . .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Bjelica, Sunčica
AU  - Đikić, Dragoslava
AU  - Diklić, Miloš
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Santibanez, Juan F.
AU  - Noguchi, Constance T.
AU  - Čokić, Vladan
PY  - 2019
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/952
AB  - Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.
PB  - Wiley, Hoboken
T2  - Cell Biology International
T1  - IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling
EP  - 206
IS  - 2
SP  - 192
VL  - 43
DO  - 10.1002/cbin.11084
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Bjelica, Sunčica and Đikić, Dragoslava and Diklić, Miloš and Leković, Danijela and Gotić, Mirjana and Santibanez, Juan F. and Noguchi, Constance T. and Čokić, Vladan",
year = "2019",
abstract = "Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.",
publisher = "Wiley, Hoboken",
journal = "Cell Biology International",
title = "IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling",
pages = "206-192",
number = "2",
volume = "43",
doi = "10.1002/cbin.11084"
}

Subotički, T., Mitrović-Ajtić, O., Beleslin-Čokić, B., Bjelica, S., Đikić, D., Diklić, M., Leković, D., Gotić, M., Santibanez, J. F., Noguchi, C. T.,& Čokić, V.. (2019). IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling. in Cell Biology International
Wiley, Hoboken., 43(2), 192-206.
https://doi.org/10.1002/cbin.11084

Subotički T, Mitrović-Ajtić O, Beleslin-Čokić B, Bjelica S, Đikić D, Diklić M, Leković D, Gotić M, Santibanez JF, Noguchi CT, Čokić V. IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling. in Cell Biology International. 2019;43(2):192-206.
doi:10.1002/cbin.11084 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Bjelica, Sunčica, Đikić, Dragoslava, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Santibanez, Juan F., Noguchi, Constance T., Čokić, Vladan, "IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling" in Cell Biology International, 43, no. 2 (2019):192-206,
https://doi.org/10.1002/cbin.11084 . .

TY  - JOUR
AU  - Kovačić, Marijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Đikić, Dragoslava
AU  - Subotički, Tijana
AU  - Diklić, Miloš
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Mossuz, Pascal
AU  - Čokić, Vladan
PY  - 2018
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/834
AB  - Purpose Previously, the family of S 100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins Si 00A4, S 100A8, S 100A9 and S100Al2 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. Methods We analyzed the S100A4, S100A8, S100A9 and S100Al2 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. Results We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34(+ )cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These 5100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. Conclusions From our data we conclude that the 5100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that SIO0A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutationdependent TLR4 blocking and increased by RAGE inhibition in MPN.
PB  - Springer, Dordrecht
T2  - Cellular Oncology
T1  - TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms
EP  - 553
IS  - 5
SP  - 541
VL  - 41
DO  - 10.1007/s13402-018-0392-6
ER  - 

@article{
author = "Kovačić, Marijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Đikić, Dragoslava and Subotički, Tijana and Diklić, Miloš and Leković, Danijela and Gotić, Mirjana and Mossuz, Pascal and Čokić, Vladan",
year = "2018",
abstract = "Purpose Previously, the family of S 100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins Si 00A4, S 100A8, S 100A9 and S100Al2 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. Methods We analyzed the S100A4, S100A8, S100A9 and S100Al2 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. Results We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34(+ )cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These 5100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. Conclusions From our data we conclude that the 5100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that SIO0A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutationdependent TLR4 blocking and increased by RAGE inhibition in MPN.",
publisher = "Springer, Dordrecht",
journal = "Cellular Oncology",
title = "TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms",
pages = "553-541",
number = "5",
volume = "41",
doi = "10.1007/s13402-018-0392-6"
}

Kovačić, M., Mitrović-Ajtić, O., Beleslin-Čokić, B., Đikić, D., Subotički, T., Diklić, M., Leković, D., Gotić, M., Mossuz, P.,& Čokić, V.. (2018). TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms. in Cellular Oncology
Springer, Dordrecht., 41(5), 541-553.
https://doi.org/10.1007/s13402-018-0392-6

Kovačić M, Mitrović-Ajtić O, Beleslin-Čokić B, Đikić D, Subotički T, Diklić M, Leković D, Gotić M, Mossuz P, Čokić V. TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms. in Cellular Oncology. 2018;41(5):541-553.
doi:10.1007/s13402-018-0392-6 .

Kovačić, Marijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Đikić, Dragoslava, Subotički, Tijana, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Mossuz, Pascal, Čokić, Vladan, "TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms" in Cellular Oncology, 41, no. 5 (2018):541-553,
https://doi.org/10.1007/s13402-018-0392-6 . .

TY  - JOUR
AU  - Đikić, Dragoslava
AU  - Marković, Dragana
AU  - Bogdanović, Andrija
AU  - Mitrović-Ajtić, Olivera
AU  - Subotički, Tijana
AU  - Diklić, Miloš
AU  - Beleslin-Čokić, Bojana
AU  - Bjelica, Sunčica
AU  - Kovačić, Marijana
AU  - Čokić, Vladan
PY  - 2018
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/836
AB  - Purpose: A common feature of malignancies is increased reactive oxygen species (ROS) and reactive nitrogen species (RNS). We analyzed the influence of oxidative and nitrosative stress on the activation of AKT/mTOR signaling pathway in myeloproliferative neoplasms (MPN). Methods: Oxidative stress-induced gene expression in circulatory CD34(+) cells of MPN patients was studied by microarray analysis. Biomarkers of oxidative and nitrosative stress were determined using spectrophotometry in plasma and erythrocyte lysate. The levels of nitrotyrosine, inducible NO synthase (iNOS) and AKT/mTOR/p70S6K phosphorylation were determined by immunocytochemistry and immunoblotting in granulocytes of MPN patients. Results: Antioxidants superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1) gene expression were increased in circulatory CD34(+) cells, while SODI and GPx enzymes were reduced in the erythrocytes of MPN. Plasma malonyl-dialdehyde and protein carbonyl levels were elevated in MPN. The total antioxidant capacity in plasma and erythrocyte catalase (CT) activities was the most prominent in primary myelofibrosis (PMF) with JAK2V617F heterozygosity. The total nitrite/ nitrate (NOx) level was augmented in the plasma of PMF patients (p  lt 0.001), while nitrotyrosine and iNOS were generally increased in the granulocytes of MPN patients. Activation of AKT/m TOR signaling was the most significant in PMF (p lt 0.01), but demonstrated JAK2V617F dependence and consequent p70S6K phosphorylation in the granulocytes of essential thrombocytemia (ET) and polycythemia vera (PV) patients. Hydrogen peroxide stimulated mTOR pathway, iNOS and nitrotyrosine quantities, the last one prevented by the antioxidant nacetyl-cysteine (NAC) in the granulocytes of MPN. Conclusion: Our study showed increased levels of oxidative and nitrosative stress parameters in MPN with JAK2V617F dependence. The ROS enhanced the constitutive activation of AKT/mTOR signaling and nitrosative parameters in MPN.
PB  - Balkan Union of Oncology (B.U.ON.)
T2  - Journal of BUON
T1  - Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT/mTOR signaling pathway
EP  - 1491
IS  - 5
SP  - 1481
VL  - 23
UR  - https://hdl.handle.net/21.15107/rcub_rimi_836
ER  - 

@article{
author = "Đikić, Dragoslava and Marković, Dragana and Bogdanović, Andrija and Mitrović-Ajtić, Olivera and Subotički, Tijana and Diklić, Miloš and Beleslin-Čokić, Bojana and Bjelica, Sunčica and Kovačić, Marijana and Čokić, Vladan",
year = "2018",
abstract = "Purpose: A common feature of malignancies is increased reactive oxygen species (ROS) and reactive nitrogen species (RNS). We analyzed the influence of oxidative and nitrosative stress on the activation of AKT/mTOR signaling pathway in myeloproliferative neoplasms (MPN). Methods: Oxidative stress-induced gene expression in circulatory CD34(+) cells of MPN patients was studied by microarray analysis. Biomarkers of oxidative and nitrosative stress were determined using spectrophotometry in plasma and erythrocyte lysate. The levels of nitrotyrosine, inducible NO synthase (iNOS) and AKT/mTOR/p70S6K phosphorylation were determined by immunocytochemistry and immunoblotting in granulocytes of MPN patients. Results: Antioxidants superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1) gene expression were increased in circulatory CD34(+) cells, while SODI and GPx enzymes were reduced in the erythrocytes of MPN. Plasma malonyl-dialdehyde and protein carbonyl levels were elevated in MPN. The total antioxidant capacity in plasma and erythrocyte catalase (CT) activities was the most prominent in primary myelofibrosis (PMF) with JAK2V617F heterozygosity. The total nitrite/ nitrate (NOx) level was augmented in the plasma of PMF patients (p  lt 0.001), while nitrotyrosine and iNOS were generally increased in the granulocytes of MPN patients. Activation of AKT/m TOR signaling was the most significant in PMF (p lt 0.01), but demonstrated JAK2V617F dependence and consequent p70S6K phosphorylation in the granulocytes of essential thrombocytemia (ET) and polycythemia vera (PV) patients. Hydrogen peroxide stimulated mTOR pathway, iNOS and nitrotyrosine quantities, the last one prevented by the antioxidant nacetyl-cysteine (NAC) in the granulocytes of MPN. Conclusion: Our study showed increased levels of oxidative and nitrosative stress parameters in MPN with JAK2V617F dependence. The ROS enhanced the constitutive activation of AKT/mTOR signaling and nitrosative parameters in MPN.",
publisher = "Balkan Union of Oncology (B.U.ON.)",
journal = "Journal of BUON",
title = "Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT/mTOR signaling pathway",
pages = "1491-1481",
number = "5",
volume = "23",
url = "https://hdl.handle.net/21.15107/rcub_rimi_836"
}

Đikić, D., Marković, D., Bogdanović, A., Mitrović-Ajtić, O., Subotički, T., Diklić, M., Beleslin-Čokić, B., Bjelica, S., Kovačić, M.,& Čokić, V.. (2018). Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT/mTOR signaling pathway. in Journal of BUON
Balkan Union of Oncology (B.U.ON.)., 23(5), 1481-1491.
https://hdl.handle.net/21.15107/rcub_rimi_836

Đikić D, Marković D, Bogdanović A, Mitrović-Ajtić O, Subotički T, Diklić M, Beleslin-Čokić B, Bjelica S, Kovačić M, Čokić V. Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT/mTOR signaling pathway. in Journal of BUON. 2018;23(5):1481-1491.
https://hdl.handle.net/21.15107/rcub_rimi_836 .

Đikić, Dragoslava, Marković, Dragana, Bogdanović, Andrija, Mitrović-Ajtić, Olivera, Subotički, Tijana, Diklić, Miloš, Beleslin-Čokić, Bojana, Bjelica, Sunčica, Kovačić, Marijana, Čokić, Vladan, "Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT/mTOR signaling pathway" in Journal of BUON, 23, no. 5 (2018):1481-1491,
https://hdl.handle.net/21.15107/rcub_rimi_836 .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Mićić, Mileva
AU  - Kravic-Stevović, Tamara
AU  - Đikić, Dragoslava
AU  - Diklić, Miloš
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Čokić, Vladan
PY  - 2018
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/853
AB  - In accordance with increased proliferation in myeloproliferative neoplasm (MPN), the goal is to evaluate the immunoexpression of: beta-catenin, PPAR-gamma and Ki67 protein, to compare them with bone marrow ultrastructural characteristics in patients with MPN. Immunoexpression and electron microscopy of bone marrow was analyzed in 30 Ph-negative MPN patients, including per 10 patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The quantity of beta-catenin immunoreactive cells was significantly higher in PV then in ET (p  lt  0.01) or PMF group of patients (p  lt  0.01) and also in ET versus PMF group of patients (p  lt  0.01). Erythroid lineage showed absent beta-catenin staining without immunoreactivity in nucleus. In contrast, immunoreactivity for PPAR-gamma was localized mostly in megakaryocytes and the highest number of PPAR-gamma immunopositive cells was detected in PMF group of patients. In addition, the proliferative Ki67 index was significantly increased in the PMF and PV patients compared to patients with ET. Also, the megakaryocytes showed abnormal maturation in PMF group of patients as determined by ultrastructural analysis. These results indicated that PV dominantly expressed beta-catenin and proliferation marker Ki67 in bone marrow, while PMF is linked preferentially to PPAR-gamma immunopositive megakaryocytes characterized by abnormal maturation.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Ultrastructural Pathology
T1  - beta-catenin and PPAR-gamma levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study
EP  - 507
IS  - 6
SP  - 498
VL  - 42
DO  - 10.1080/01913123.2018.1558323
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Mićić, Mileva and Kravic-Stevović, Tamara and Đikić, Dragoslava and Diklić, Miloš and Leković, Danijela and Gotić, Mirjana and Čokić, Vladan",
year = "2018",
abstract = "In accordance with increased proliferation in myeloproliferative neoplasm (MPN), the goal is to evaluate the immunoexpression of: beta-catenin, PPAR-gamma and Ki67 protein, to compare them with bone marrow ultrastructural characteristics in patients with MPN. Immunoexpression and electron microscopy of bone marrow was analyzed in 30 Ph-negative MPN patients, including per 10 patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The quantity of beta-catenin immunoreactive cells was significantly higher in PV then in ET (p  lt  0.01) or PMF group of patients (p  lt  0.01) and also in ET versus PMF group of patients (p  lt  0.01). Erythroid lineage showed absent beta-catenin staining without immunoreactivity in nucleus. In contrast, immunoreactivity for PPAR-gamma was localized mostly in megakaryocytes and the highest number of PPAR-gamma immunopositive cells was detected in PMF group of patients. In addition, the proliferative Ki67 index was significantly increased in the PMF and PV patients compared to patients with ET. Also, the megakaryocytes showed abnormal maturation in PMF group of patients as determined by ultrastructural analysis. These results indicated that PV dominantly expressed beta-catenin and proliferation marker Ki67 in bone marrow, while PMF is linked preferentially to PPAR-gamma immunopositive megakaryocytes characterized by abnormal maturation.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Ultrastructural Pathology",
title = "beta-catenin and PPAR-gamma levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study",
pages = "507-498",
number = "6",
volume = "42",
doi = "10.1080/01913123.2018.1558323"
}

Subotički, T., Mitrović-Ajtić, O., Mićić, M., Kravic-Stevović, T., Đikić, D., Diklić, M., Leković, D., Gotić, M.,& Čokić, V.. (2018). beta-catenin and PPAR-gamma levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study. in Ultrastructural Pathology
Taylor & Francis Inc, Philadelphia., 42(6), 498-507.
https://doi.org/10.1080/01913123.2018.1558323

Subotički T, Mitrović-Ajtić O, Mićić M, Kravic-Stevović T, Đikić D, Diklić M, Leković D, Gotić M, Čokić V. beta-catenin and PPAR-gamma levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study. in Ultrastructural Pathology. 2018;42(6):498-507.
doi:10.1080/01913123.2018.1558323 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Mićić, Mileva, Kravic-Stevović, Tamara, Đikić, Dragoslava, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Čokić, Vladan, "beta-catenin and PPAR-gamma levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study" in Ultrastructural Pathology, 42, no. 6 (2018):498-507,
https://doi.org/10.1080/01913123.2018.1558323 . .

TY  - THES
AU  - Đikić, Dragoslava
PY  - 2018
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=6174
UR  - http://nardus.mpn.gov.rs/handle/123456789/10169
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:18734/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50655247
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1114
AB  - common characteristic of malignancies is an increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In such circumstances macromolecules are damaged and the cell structure and function are disrupted. The oxidative DNA damage is considered to be the initial event in the developement of carcinogenesis. ROS affects the function of hematopoietic stem cells, changes the cell cycle progression, accelerаtes aging and induces hematological malignancies. The BCR/ABL oncogene and JAK2V617F mutation induces the formation of ROS in hematopoietic stem cells that leads to genomic instability and DNA damage. In the myeloproliferative neoplasm (MPN) patients, JAK2V617F mutation and BCR/ABL oncogene are associated with the constitutive activation of the PI3K/AKT/mTOR signaling pathway, which stimulates the growth and proliferation of cells. As ROS and RNS may affect the activity of mTOR, we have examined the parameters of antioxidant protection and oxidative damage of lipids and proteins in circulation as well as the AKT/mTOR signaling pathway activity in the MPN granulocytes and human erythroleukemia (HEL) cell line with JAK2V617F mutation. Methods: The study includes 110 de novo MPN patients: 30 polycythemia vera (PV), 24 essential thrombocythemia (ET), 34 primary myelofibrosis (PMF) as well as 22 patients with the diagnosis of chronic myeloid leukemia (CML) and 10 healthy subjects. Markers of oxidative and nitrosative stress in plasma and erythrocyte lysates were determined by the colorimetric method. The intracellular production of ROS was determined by fluorogenic reagent H2DCF-DA. The levels of nitrotyrosine, inducible NO synthase (iNOS) and the activation rate of AKT/mTOR/p70S6K kinases were determined in granulocytes of MPN patients using immunocytochemistry and immunoblotting methods. The influence of hydrogen peroxide (H2O2) and 2, 2'-Azobis (2-amidinopropane) dihydrochloride (AAPH) oxidants on AKT/mTOR signal pathway, cell cycle and survival were tested by Western blot, FACS and MTT test in HEL cells...
AB  - Zajednička karakteristika maligniteta je povećana koncentracija reaktivnih vrsta kiseonika (ROS) i reaktivnih vrsta azota (RNS) koje mogu da prouzrokuju oštećenja makromolekula u ćeliji i dovedu do narušavanja njene strukture i funkcije. Oksidativno oštećenje DNK smatra se inicijalnim događajem u razvoju kancerogeneze. ROS utiču na funkciju hematopoetskih matičnih ćelija, dovode do promena ćelijskog ciklusa, ubrzanog starenja ćelija ili do nastanka hematoloških maligniteta. BCR/ABL onkogen i JAK2V617F mutacija indukuju stvaranje ROS u hematopoetskim matičnim ćelijama što vodi genomskoj nestabilnosti i oštećenju DNK. Pod uticajem JAK2V617F mutacije i BCR/ABL onkogena kod hroničnih mijeloproliferativnih neoplazmi (HMN) dolazi do konstitutivne aktivacije PI3K/AKT/mTOR signalnog puta, koji reguliše metabolizam i stimuliše rast i proliferaciju ćelija. S obzirom da ROS i RNS mogu uticati na aktivnost mTOR kinaze, ispitani su parametri antioksidativne zaštite i oksidativno izmenjenih lipida i proteina u cirkulaciji, kao i stepen aktivacije AKT/mTOR signalnog puta u granulocitima bolesnika sa HMN i humanoj eritroleukemijskoj ćelijskoj liniji (eng. Human erythroleukemia cell line, HEL) sa JAK2V617F mutacijom. Metode: U studiju je uključeno 110 de novo HMN bolesnika: 30 sa policitemijom verom (PV), 24 sa esencijalnom trombocitemijom (ET), 34 sa primarnom mijelofibrozom (PMF), 22 bolesnika sa dijagnozom hronične mijeloidne leukemije (HML) i 10 zdravih ispitanika. Markeri oksidativnog i nitrozativnog stresa u plazmi i lizatima eritrocita određeni su kolorimetrijskom metodom. Količina intracelularne produkcije ROS određena je upotrebom fluorogenog reagensa H2DCF-DA. Nivo nitrotirozina, inducibilne NO sintaze (iNOS) i stepen aktivacije AKT/mTOR/p70S6K kinaza određeni su u granulocitima bolesnika sa HMN imunocitohemijskom metodom i metodom imunoblota. U in vitro uslovima ispitan je uticaj vodonik peroksida (H2O2) i N- acetil cisteina na aktivaciju mTOR i ekspresiju iNOS i nitrotirozina. Uticaj dva različita oksidansa, H2O2 i 2,2'-azobis(2-amidinopropan) dihidrohlorida (AAPH), na aktivaciju AKT/mTOR signalnog puta, preživljavanje i ćelijski ciklus HEL ćelija, u in vitro uslovima, ispitan je metodom imunoblota, FACS metodom i MTT testom...
PB  - Univerzitet u Beogradu, Medicinski fakultet
T1  - The impact of reactive oxygen species on the mTOR signaling pathway activity in patients with myeloproliferative neoplasms
T1  - Uticaj reaktivnih vrsta kiseonika na aktivnost mTOR signalnog puta kod pacijenata sa mijeloproliferativnim neoplazmama
UR  - https://hdl.handle.net/21.15107/rcub_nardus_10169
ER  - 

@phdthesis{
author = "Đikić, Dragoslava",
year = "2018",
abstract = "common characteristic of malignancies is an increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In such circumstances macromolecules are damaged and the cell structure and function are disrupted. The oxidative DNA damage is considered to be the initial event in the developement of carcinogenesis. ROS affects the function of hematopoietic stem cells, changes the cell cycle progression, accelerаtes aging and induces hematological malignancies. The BCR/ABL oncogene and JAK2V617F mutation induces the formation of ROS in hematopoietic stem cells that leads to genomic instability and DNA damage. In the myeloproliferative neoplasm (MPN) patients, JAK2V617F mutation and BCR/ABL oncogene are associated with the constitutive activation of the PI3K/AKT/mTOR signaling pathway, which stimulates the growth and proliferation of cells. As ROS and RNS may affect the activity of mTOR, we have examined the parameters of antioxidant protection and oxidative damage of lipids and proteins in circulation as well as the AKT/mTOR signaling pathway activity in the MPN granulocytes and human erythroleukemia (HEL) cell line with JAK2V617F mutation. Methods: The study includes 110 de novo MPN patients: 30 polycythemia vera (PV), 24 essential thrombocythemia (ET), 34 primary myelofibrosis (PMF) as well as 22 patients with the diagnosis of chronic myeloid leukemia (CML) and 10 healthy subjects. Markers of oxidative and nitrosative stress in plasma and erythrocyte lysates were determined by the colorimetric method. The intracellular production of ROS was determined by fluorogenic reagent H2DCF-DA. The levels of nitrotyrosine, inducible NO synthase (iNOS) and the activation rate of AKT/mTOR/p70S6K kinases were determined in granulocytes of MPN patients using immunocytochemistry and immunoblotting methods. The influence of hydrogen peroxide (H2O2) and 2, 2'-Azobis (2-amidinopropane) dihydrochloride (AAPH) oxidants on AKT/mTOR signal pathway, cell cycle and survival were tested by Western blot, FACS and MTT test in HEL cells..., Zajednička karakteristika maligniteta je povećana koncentracija reaktivnih vrsta kiseonika (ROS) i reaktivnih vrsta azota (RNS) koje mogu da prouzrokuju oštećenja makromolekula u ćeliji i dovedu do narušavanja njene strukture i funkcije. Oksidativno oštećenje DNK smatra se inicijalnim događajem u razvoju kancerogeneze. ROS utiču na funkciju hematopoetskih matičnih ćelija, dovode do promena ćelijskog ciklusa, ubrzanog starenja ćelija ili do nastanka hematoloških maligniteta. BCR/ABL onkogen i JAK2V617F mutacija indukuju stvaranje ROS u hematopoetskim matičnim ćelijama što vodi genomskoj nestabilnosti i oštećenju DNK. Pod uticajem JAK2V617F mutacije i BCR/ABL onkogena kod hroničnih mijeloproliferativnih neoplazmi (HMN) dolazi do konstitutivne aktivacije PI3K/AKT/mTOR signalnog puta, koji reguliše metabolizam i stimuliše rast i proliferaciju ćelija. S obzirom da ROS i RNS mogu uticati na aktivnost mTOR kinaze, ispitani su parametri antioksidativne zaštite i oksidativno izmenjenih lipida i proteina u cirkulaciji, kao i stepen aktivacije AKT/mTOR signalnog puta u granulocitima bolesnika sa HMN i humanoj eritroleukemijskoj ćelijskoj liniji (eng. Human erythroleukemia cell line, HEL) sa JAK2V617F mutacijom. Metode: U studiju je uključeno 110 de novo HMN bolesnika: 30 sa policitemijom verom (PV), 24 sa esencijalnom trombocitemijom (ET), 34 sa primarnom mijelofibrozom (PMF), 22 bolesnika sa dijagnozom hronične mijeloidne leukemije (HML) i 10 zdravih ispitanika. Markeri oksidativnog i nitrozativnog stresa u plazmi i lizatima eritrocita određeni su kolorimetrijskom metodom. Količina intracelularne produkcije ROS određena je upotrebom fluorogenog reagensa H2DCF-DA. Nivo nitrotirozina, inducibilne NO sintaze (iNOS) i stepen aktivacije AKT/mTOR/p70S6K kinaza određeni su u granulocitima bolesnika sa HMN imunocitohemijskom metodom i metodom imunoblota. U in vitro uslovima ispitan je uticaj vodonik peroksida (H2O2) i N- acetil cisteina na aktivaciju mTOR i ekspresiju iNOS i nitrotirozina. Uticaj dva različita oksidansa, H2O2 i 2,2'-azobis(2-amidinopropan) dihidrohlorida (AAPH), na aktivaciju AKT/mTOR signalnog puta, preživljavanje i ćelijski ciklus HEL ćelija, u in vitro uslovima, ispitan je metodom imunoblota, FACS metodom i MTT testom...",
publisher = "Univerzitet u Beogradu, Medicinski fakultet",
title = "The impact of reactive oxygen species on the mTOR signaling pathway activity in patients with myeloproliferative neoplasms, Uticaj reaktivnih vrsta kiseonika na aktivnost mTOR signalnog puta kod pacijenata sa mijeloproliferativnim neoplazmama",
url = "https://hdl.handle.net/21.15107/rcub_nardus_10169"
}

Đikić, D.. (2018). The impact of reactive oxygen species on the mTOR signaling pathway activity in patients with myeloproliferative neoplasms. 
Univerzitet u Beogradu, Medicinski fakultet..
https://hdl.handle.net/21.15107/rcub_nardus_10169

Đikić D. The impact of reactive oxygen species on the mTOR signaling pathway activity in patients with myeloproliferative neoplasms. 2018;.
https://hdl.handle.net/21.15107/rcub_nardus_10169 .

Đikić, Dragoslava, "The impact of reactive oxygen species on the mTOR signaling pathway activity in patients with myeloproliferative neoplasms" (2018),
https://hdl.handle.net/21.15107/rcub_nardus_10169 .

TY  - CONF
AU  - Kovačić, Marijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Diklić, Miloš
AU  - Subotički, Tijana
AU  - Đikić, Dragoslava
AU  - Momčilović, Sanja
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Čokić, Vladan
PY  - 2017
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/780
PB  - Ferrata Storti Foundation, Pavia
C3  - Haematologica
T1  - S100a8/9 activation of mapk pathway is supported by its receptors rage and tlr4 in polycythemia vera
EP  - 540
SP  - 540
VL  - 102
UR  - https://hdl.handle.net/21.15107/rcub_rimi_780
ER  - 

@conference{
author = "Kovačić, Marijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Diklić, Miloš and Subotički, Tijana and Đikić, Dragoslava and Momčilović, Sanja and Leković, Danijela and Gotić, Mirjana and Čokić, Vladan",
year = "2017",
publisher = "Ferrata Storti Foundation, Pavia",
journal = "Haematologica",
title = "S100a8/9 activation of mapk pathway is supported by its receptors rage and tlr4 in polycythemia vera",
pages = "540-540",
volume = "102",
url = "https://hdl.handle.net/21.15107/rcub_rimi_780"
}

Kovačić, M., Mitrović-Ajtić, O., Beleslin-Čokić, B., Diklić, M., Subotički, T., Đikić, D., Momčilović, S., Leković, D., Gotić, M.,& Čokić, V.. (2017). S100a8/9 activation of mapk pathway is supported by its receptors rage and tlr4 in polycythemia vera. in Haematologica
Ferrata Storti Foundation, Pavia., 102, 540-540.
https://hdl.handle.net/21.15107/rcub_rimi_780

Kovačić M, Mitrović-Ajtić O, Beleslin-Čokić B, Diklić M, Subotički T, Đikić D, Momčilović S, Leković D, Gotić M, Čokić V. S100a8/9 activation of mapk pathway is supported by its receptors rage and tlr4 in polycythemia vera. in Haematologica. 2017;102:540-540.
https://hdl.handle.net/21.15107/rcub_rimi_780 .

Kovačić, Marijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Diklić, Miloš, Subotički, Tijana, Đikić, Dragoslava, Momčilović, Sanja, Leković, Danijela, Gotić, Mirjana, Čokić, Vladan, "S100a8/9 activation of mapk pathway is supported by its receptors rage and tlr4 in polycythemia vera" in Haematologica, 102 (2017):540-540,
https://hdl.handle.net/21.15107/rcub_rimi_780 .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Nienhold, Ronny
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Leković, Danijela
AU  - Bulat, Tanja
AU  - Marković, Dragana
AU  - Gotić, Mirjana
AU  - Noguchi, Constance T.
AU  - Schechter, Alan N.
AU  - Skoda, Radek C.
AU  - Čokić, Vladan
PY  - 2017
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/807
AB  - It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1 and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1 levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGF and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors.
PB  - Wiley-Blackwell, Hoboken
T2  - Molecular Carcinogenesis
T1  - Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms
EP  - 579
IS  - 2
SP  - 567
VL  - 56
DO  - 10.1002/mc.22517
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Nienhold, Ronny and Diklić, Miloš and Đikić, Dragoslava and Leković, Danijela and Bulat, Tanja and Marković, Dragana and Gotić, Mirjana and Noguchi, Constance T. and Schechter, Alan N. and Skoda, Radek C. and Čokić, Vladan",
year = "2017",
abstract = "It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1 and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1 levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGF and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors.",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Molecular Carcinogenesis",
title = "Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms",
pages = "579-567",
number = "2",
volume = "56",
doi = "10.1002/mc.22517"
}

Subotički, T., Mitrović-Ajtić, O., Beleslin-Čokić, B., Nienhold, R., Diklić, M., Đikić, D., Leković, D., Bulat, T., Marković, D., Gotić, M., Noguchi, C. T., Schechter, A. N., Skoda, R. C.,& Čokić, V.. (2017). Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. in Molecular Carcinogenesis
Wiley-Blackwell, Hoboken., 56(2), 567-579.
https://doi.org/10.1002/mc.22517

Subotički T, Mitrović-Ajtić O, Beleslin-Čokić B, Nienhold R, Diklić M, Đikić D, Leković D, Bulat T, Marković D, Gotić M, Noguchi CT, Schechter AN, Skoda RC, Čokić V. Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. in Molecular Carcinogenesis. 2017;56(2):567-579.
doi:10.1002/mc.22517 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Nienhold, Ronny, Diklić, Miloš, Đikić, Dragoslava, Leković, Danijela, Bulat, Tanja, Marković, Dragana, Gotić, Mirjana, Noguchi, Constance T., Schechter, Alan N., Skoda, Radek C., Čokić, Vladan, "Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms" in Molecular Carcinogenesis, 56, no. 2 (2017):567-579,
https://doi.org/10.1002/mc.22517 . .

TY  - CONF
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Diklić, Miloš
AU  - Vignjević-Petrinović, Sanja
AU  - Budeč, Mirela
AU  - Đikić, Dragoslava
AU  - Santibanez, Juan F.
AU  - Čokić, Vladan
PY  - 2017
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/815
PB  - Ferrata Storti Foundation, Pavia
C3  - Haematologica
T1  - Hydroxyurea inhibits myeloid differentiation via nitric oxide synthase
EP  - 848
SP  - 848
VL  - 102
UR  - https://hdl.handle.net/21.15107/rcub_rimi_815
ER  - 

@conference{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Diklić, Miloš and Vignjević-Petrinović, Sanja and Budeč, Mirela and Đikić, Dragoslava and Santibanez, Juan F. and Čokić, Vladan",
year = "2017",
publisher = "Ferrata Storti Foundation, Pavia",
journal = "Haematologica",
title = "Hydroxyurea inhibits myeloid differentiation via nitric oxide synthase",
pages = "848-848",
volume = "102",
url = "https://hdl.handle.net/21.15107/rcub_rimi_815"
}

Subotički, T., Mitrović-Ajtić, O., Diklić, M., Vignjević-Petrinović, S., Budeč, M., Đikić, D., Santibanez, J. F.,& Čokić, V.. (2017). Hydroxyurea inhibits myeloid differentiation via nitric oxide synthase. in Haematologica
Ferrata Storti Foundation, Pavia., 102, 848-848.
https://hdl.handle.net/21.15107/rcub_rimi_815

Subotički T, Mitrović-Ajtić O, Diklić M, Vignjević-Petrinović S, Budeč M, Đikić D, Santibanez JF, Čokić V. Hydroxyurea inhibits myeloid differentiation via nitric oxide synthase. in Haematologica. 2017;102:848-848.
https://hdl.handle.net/21.15107/rcub_rimi_815 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Diklić, Miloš, Vignjević-Petrinović, Sanja, Budeč, Mirela, Đikić, Dragoslava, Santibanez, Juan F., Čokić, Vladan, "Hydroxyurea inhibits myeloid differentiation via nitric oxide synthase" in Haematologica, 102 (2017):848-848,
https://hdl.handle.net/21.15107/rcub_rimi_815 .