TY  - JOUR
AU  - Vukotić, Milica
AU  - Kapor, Sunčica
AU  - Simon, Felipe
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2024
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1458
AB  - Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells, including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic cells affect the proliferation and dif- ferentiation of other hematopoietic lineages in the bone marrow and peripheral blood, leading to severe and life-threatening complications. Mesenchymal stromal cells (MSCs) residing in the bone marrow exert immunosuppressive functions by suppressing innate and adaptive immune systems, thus creating a supportive and tolerant microenvironment for myeloid malignancy progression. This review summarizes the significant features of MSCs in myeloid malignancies, including their role in regulating cell growth, cell death, and antineoplastic resistance, in addition to their immunosuppressive contributions. Understanding the implications of MSCs in myeloid malig- nancies could pave the path for potential use in immunotherapy.
PB  - Elsevier
T2  - Heliyon
T1  - Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities
IS  - 3
SP  - e25081
VL  - 10
DO  - 10.1016/j.heliyon.2024.e25081
ER  - 

@article{
author = "Vukotić, Milica and Kapor, Sunčica and Simon, Felipe and Čokić, Vladan and Santibanez, Juan F.",
year = "2024",
abstract = "Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells, including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic cells affect the proliferation and dif- ferentiation of other hematopoietic lineages in the bone marrow and peripheral blood, leading to severe and life-threatening complications. Mesenchymal stromal cells (MSCs) residing in the bone marrow exert immunosuppressive functions by suppressing innate and adaptive immune systems, thus creating a supportive and tolerant microenvironment for myeloid malignancy progression. This review summarizes the significant features of MSCs in myeloid malignancies, including their role in regulating cell growth, cell death, and antineoplastic resistance, in addition to their immunosuppressive contributions. Understanding the implications of MSCs in myeloid malig- nancies could pave the path for potential use in immunotherapy.",
publisher = "Elsevier",
journal = "Heliyon",
title = "Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities",
number = "3",
pages = "e25081",
volume = "10",
doi = "10.1016/j.heliyon.2024.e25081"
}

Vukotić, M., Kapor, S., Simon, F., Čokić, V.,& Santibanez, J. F.. (2024). Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities. in Heliyon
Elsevier., 10(3), e25081.
https://doi.org/10.1016/j.heliyon.2024.e25081

Vukotić M, Kapor S, Simon F, Čokić V, Santibanez JF. Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities. in Heliyon. 2024;10(3):e25081.
doi:10.1016/j.heliyon.2024.e25081 .

Vukotić, Milica, Kapor, Sunčica, Simon, Felipe, Čokić, Vladan, Santibanez, Juan F., "Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities" in Heliyon, 10, no. 3 (2024):e25081,
https://doi.org/10.1016/j.heliyon.2024.e25081 . .

TY  - CHAP
AU  - Kapor, Sunčica
AU  - Momčilović, Sanja
AU  - Kapor, Slobodan
AU  - Mojsilović, Slavko
AU  - Radojković, Milica
AU  - Apostolović, Milica
AU  - Filipović, Branka
AU  - Gotić, Mirjana
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
AU  - Simon, Felipe
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1391
AB  - The Philadelphia-negative myeloproliferative neoplasms (MPNs), defined as clonal disorders of the hematopoietic stem cells, are characterized by the proliferation of mature myeloid cells in the bone marrow and a chronic inflammatory status impacting the initiation, progression, and symptomatology of the malignancies. There are three main entities defined as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), and genetically classified by JAK2V617F, CALR, or MPL mutations. In MPNs, due to the overproduction of inflammatory cytokines by the neoplastic cells and non-transformed immune cells, chronic inflammation may provoke the generation and expansion of myeloid-derived suppressors cells (MDSCs) that highly influence the adaptive immune response. Although peripheral blood MDSC levels are elevated, their frequency in the bone marrow of MPNs patients is not well elucidated yet. Our results indicated increased levels of total (T)-MDSCs (CD33+HLA-DR−/low) and polymorphonuclear (PMN)-MDSCs (CD33+/HLA-DRlow/CD15+/CD14−) in the bone marrow and peripheral blood of all three types of MPNs malignancies. However, these bone marrow MDSCs-increased frequencies did not correlate with the clinical parameters, such as hepatomegaly, leukocytes, hemoglobin, or platelet levels, or with JAK2 and CALR mutations. Besides, bone marrow MDSCs, from ET, PV, and PMF patients, exhibited immunosuppressive function, determined as T-cell proliferation inhibition. Notably, the highest T-MDSCs and PMN-MDSC levels were found in PMF samples, and the increased MDSCs frequency strongly correlated with the degree of myelofibrosis. Thus, these data together indicate that the immunosuppressive MDSCs population is increased in the bone marrow of MPNs patients and may be implicated in generating a fibrotic microenvironment.
PB  - Springer Nature
T2  - Advances in Molecular Pathology
T1  - Increase in Frequency of Myeloid-Derived Suppressor Cells in the Bone Marrow of Myeloproliferative Neoplasm: Potential Implications in Myelofibrosis
EP  - 290
SP  - 273
VL  - 1408
DO  - 10.1007/978-3-031-26163-3_15
ER  - 

@inbook{
author = "Kapor, Sunčica and Momčilović, Sanja and Kapor, Slobodan and Mojsilović, Slavko and Radojković, Milica and Apostolović, Milica and Filipović, Branka and Gotić, Mirjana and Čokić, Vladan and Santibanez, Juan F. and Simon, Felipe",
year = "2023",
abstract = "The Philadelphia-negative myeloproliferative neoplasms (MPNs), defined as clonal disorders of the hematopoietic stem cells, are characterized by the proliferation of mature myeloid cells in the bone marrow and a chronic inflammatory status impacting the initiation, progression, and symptomatology of the malignancies. There are three main entities defined as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), and genetically classified by JAK2V617F, CALR, or MPL mutations. In MPNs, due to the overproduction of inflammatory cytokines by the neoplastic cells and non-transformed immune cells, chronic inflammation may provoke the generation and expansion of myeloid-derived suppressors cells (MDSCs) that highly influence the adaptive immune response. Although peripheral blood MDSC levels are elevated, their frequency in the bone marrow of MPNs patients is not well elucidated yet. Our results indicated increased levels of total (T)-MDSCs (CD33+HLA-DR−/low) and polymorphonuclear (PMN)-MDSCs (CD33+/HLA-DRlow/CD15+/CD14−) in the bone marrow and peripheral blood of all three types of MPNs malignancies. However, these bone marrow MDSCs-increased frequencies did not correlate with the clinical parameters, such as hepatomegaly, leukocytes, hemoglobin, or platelet levels, or with JAK2 and CALR mutations. Besides, bone marrow MDSCs, from ET, PV, and PMF patients, exhibited immunosuppressive function, determined as T-cell proliferation inhibition. Notably, the highest T-MDSCs and PMN-MDSC levels were found in PMF samples, and the increased MDSCs frequency strongly correlated with the degree of myelofibrosis. Thus, these data together indicate that the immunosuppressive MDSCs population is increased in the bone marrow of MPNs patients and may be implicated in generating a fibrotic microenvironment.",
publisher = "Springer Nature",
journal = "Advances in Molecular Pathology",
booktitle = "Increase in Frequency of Myeloid-Derived Suppressor Cells in the Bone Marrow of Myeloproliferative Neoplasm: Potential Implications in Myelofibrosis",
pages = "290-273",
volume = "1408",
doi = "10.1007/978-3-031-26163-3_15"
}

Kapor, S., Momčilović, S., Kapor, S., Mojsilović, S., Radojković, M., Apostolović, M., Filipović, B., Gotić, M., Čokić, V., Santibanez, J. F.,& Simon, F.. (2023). Increase in Frequency of Myeloid-Derived Suppressor Cells in the Bone Marrow of Myeloproliferative Neoplasm: Potential Implications in Myelofibrosis. in Advances in Molecular Pathology
Springer Nature., 1408, 273-290.
https://doi.org/10.1007/978-3-031-26163-3_15

Kapor S, Momčilović S, Kapor S, Mojsilović S, Radojković M, Apostolović M, Filipović B, Gotić M, Čokić V, Santibanez JF, Simon F. Increase in Frequency of Myeloid-Derived Suppressor Cells in the Bone Marrow of Myeloproliferative Neoplasm: Potential Implications in Myelofibrosis. in Advances in Molecular Pathology. 2023;1408:273-290.
doi:10.1007/978-3-031-26163-3_15 .

Kapor, Sunčica, Momčilović, Sanja, Kapor, Slobodan, Mojsilović, Slavko, Radojković, Milica, Apostolović, Milica, Filipović, Branka, Gotić, Mirjana, Čokić, Vladan, Santibanez, Juan F., Simon, Felipe, "Increase in Frequency of Myeloid-Derived Suppressor Cells in the Bone Marrow of Myeloproliferative Neoplasm: Potential Implications in Myelofibrosis" in Advances in Molecular Pathology, 1408 (2023):273-290,
https://doi.org/10.1007/978-3-031-26163-3_15 . .

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  - JOUR
AU  - Čokić, Vladan
AU  - Popovska, Zorana
AU  - Lijeskić, Olivera
AU  - Šabić, Ljiljana
AU  - Đurković-Đaković, Olgica
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1317
AB  - Older people in nursing homes (NH) have been hit particularly hard by the COVID-19 pandemic. We conducted a retrospective study of three outbreaks of COVID-19, occurring during the waves of the initial pre-Alpha, Delta and Omicron SARS-CoV-2 variants, in one NH in suburban Belgrade, Serbia. All staff and 95% residents were vaccinated in February 2021, mostly with BBIBP-CorV, and two thirds were boosted with a third dose in August 2021. COVID-19 was diagnosed by positive PCR and/or antigen test. After the first outbreak, 80 affected individuals were tested for SARS-CoV-2 specific antibodies. The first outbreak involved 64/126 (50.8%) residents and 45/64 (70.3%) staff, the second 22/75 (29.3%) residents and 3/40 (7.5%) staff, and the third involved 36/110 (32.7%) residents and 19/56 (33.9%) staff. Clinical presentation ranged from asymptomatic to severe, with severe cases referred to hospital ICUs. Deaths occurred only in residents, and the case fatality rate was 31.2%, 9.1% and 0%, respectively in outbreaks 1, 2 and 3. Specific IgG antibodies were detected in all 35 residents and 44 of the 45 staff, and higher IgG levels were detected in the residents (417.3±273.5) than in the staff (201.9±192.9, p<0.0001) despite a double difference in age (79.0±7.4 vs. 40.1±11.5 years). Outbreaks 2 and 3 involved four and 23 breakthrough infections, respectively. Older individuals mounted a good immunological response to SARS-CoV-2 infection and vaccination, which prevented significant mortality and severe morbidity in the subsequent outbreaks, despite a significant number of breakthrough infections.
PB  - International Society on Aging and Disease
T2  - Aging and disease
T1  - Three Outbreaks of COVID-19 in a Single Nursing Home over Two Years of the SARS-CoV-2 Pandemic
EP  - 111
IS  - 1
SP  - 99
VL  - 14
DO  - 10.14336/AD.2022.0624
ER  - 

@article{
author = "Čokić, Vladan and Popovska, Zorana and Lijeskić, Olivera and Šabić, Ljiljana and Đurković-Đaković, Olgica",
year = "2023",
abstract = "Older people in nursing homes (NH) have been hit particularly hard by the COVID-19 pandemic. We conducted a retrospective study of three outbreaks of COVID-19, occurring during the waves of the initial pre-Alpha, Delta and Omicron SARS-CoV-2 variants, in one NH in suburban Belgrade, Serbia. All staff and 95% residents were vaccinated in February 2021, mostly with BBIBP-CorV, and two thirds were boosted with a third dose in August 2021. COVID-19 was diagnosed by positive PCR and/or antigen test. After the first outbreak, 80 affected individuals were tested for SARS-CoV-2 specific antibodies. The first outbreak involved 64/126 (50.8%) residents and 45/64 (70.3%) staff, the second 22/75 (29.3%) residents and 3/40 (7.5%) staff, and the third involved 36/110 (32.7%) residents and 19/56 (33.9%) staff. Clinical presentation ranged from asymptomatic to severe, with severe cases referred to hospital ICUs. Deaths occurred only in residents, and the case fatality rate was 31.2%, 9.1% and 0%, respectively in outbreaks 1, 2 and 3. Specific IgG antibodies were detected in all 35 residents and 44 of the 45 staff, and higher IgG levels were detected in the residents (417.3±273.5) than in the staff (201.9±192.9, p<0.0001) despite a double difference in age (79.0±7.4 vs. 40.1±11.5 years). Outbreaks 2 and 3 involved four and 23 breakthrough infections, respectively. Older individuals mounted a good immunological response to SARS-CoV-2 infection and vaccination, which prevented significant mortality and severe morbidity in the subsequent outbreaks, despite a significant number of breakthrough infections.",
publisher = "International Society on Aging and Disease",
journal = "Aging and disease",
title = "Three Outbreaks of COVID-19 in a Single Nursing Home over Two Years of the SARS-CoV-2 Pandemic",
pages = "111-99",
number = "1",
volume = "14",
doi = "10.14336/AD.2022.0624"
}

Čokić, V., Popovska, Z., Lijeskić, O., Šabić, L.,& Đurković-Đaković, O.. (2023). Three Outbreaks of COVID-19 in a Single Nursing Home over Two Years of the SARS-CoV-2 Pandemic. in Aging and disease
International Society on Aging and Disease., 14(1), 99-111.
https://doi.org/10.14336/AD.2022.0624

Čokić V, Popovska Z, Lijeskić O, Šabić L, Đurković-Đaković O. Three Outbreaks of COVID-19 in a Single Nursing Home over Two Years of the SARS-CoV-2 Pandemic. in Aging and disease. 2023;14(1):99-111.
doi:10.14336/AD.2022.0624 .

Čokić, Vladan, Popovska, Zorana, Lijeskić, Olivera, Šabić, Ljiljana, Đurković-Đaković, Olgica, "Three Outbreaks of COVID-19 in a Single Nursing Home over Two Years of the SARS-CoV-2 Pandemic" in Aging and disease, 14, no. 1 (2023):99-111,
https://doi.org/10.14336/AD.2022.0624 . .

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  - Leković, Danijela
AU  - Bogdanović, Andrija
AU  - Sobas, Marta
AU  - Arsenović, Isidora
AU  - Smiljanić, Mihailo
AU  - Ivanović, Jelena
AU  - Bodrožić, Jelena
AU  - Čokić, Vladan
AU  - Milić, Nataša
PY  - 2023
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1344
AB  - Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments.
PB  - Multidisciplinary Digital Publishing Institute (MDPI)
T2  - Cancers
T2  - Cancers
T1  - Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia
IS  - 16
SP  - 4180
VL  - 15
DO  - 10.3390/cancers15164180
ER  - 

@article{
author = "Leković, Danijela and Bogdanović, Andrija and Sobas, Marta and Arsenović, Isidora and Smiljanić, Mihailo and Ivanović, Jelena and Bodrožić, Jelena and Čokić, Vladan and Milić, Nataša",
year = "2023",
abstract = "Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments.",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
journal = "Cancers, Cancers",
title = "Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia",
number = "16",
pages = "4180",
volume = "15",
doi = "10.3390/cancers15164180"
}

Leković, D., Bogdanović, A., Sobas, M., Arsenović, I., Smiljanić, M., Ivanović, J., Bodrožić, J., Čokić, V.,& Milić, N.. (2023). Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia. in Cancers
Multidisciplinary Digital Publishing Institute (MDPI)., 15(16), 4180.
https://doi.org/10.3390/cancers15164180

Leković D, Bogdanović A, Sobas M, Arsenović I, Smiljanić M, Ivanović J, Bodrožić J, Čokić V, Milić N. Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia. in Cancers. 2023;15(16):4180.
doi:10.3390/cancers15164180 .

Leković, Danijela, Bogdanović, Andrija, Sobas, Marta, Arsenović, Isidora, Smiljanić, Mihailo, Ivanović, Jelena, Bodrožić, Jelena, Čokić, Vladan, Milić, Nataša, "Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia" in Cancers, 15, no. 16 (2023):4180,
https://doi.org/10.3390/cancers15164180 . .

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  - JOUR
AU  - Mitrović-Ajtić, Olivera
AU  - Stanisavljević, Dejana
AU  - Miljatović, Sanja
AU  - Dragojević, Teodora
AU  - Živković, Emilija
AU  - Šabanović, Miloš
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1258
AB  - The COVID-19 pandemic has had a strong impact on people’s quality of life (QoL), which is affected by social and economic changes as well as by mental and physical health. The aim of this study was to determine QoL in post-COVID-19 patients who had required hospitalization, and to identify relevant sociodemographic data. We used questionnaires which considered demographic and socioeconomic data, health and vaccination status, the pandemic situation, and EQ-5D scoring. The interactions of all data and the scores of EQ-5D were analyzed. Multivariate logistic regression analysis was applied to the five dimensions of EQ-5D. In this single-hospital-cohort study, the average times elapsed since initial diagnosis and hospital admission were 2.5 (76.3 ± 18.1 days) and 5 months (155.4 ± 33.9 days), respectively. Post-COVID-19 females were 3–5 times more likely to be affected in terms of anxiety/depression, and in negative impact upon their usual activities, at 5 months after diagnosis. At the same time, reductions in mobility were 3–4 times more likely in elderly post-COVID-19 patients, whose levels of pain and discomfort increased. Single patients, those with low incomes, and those with severe clinical outcomes were 2–4 times more likely to experience a reduction in their usual activities, while the presence of co-morbidities and lower levels of education were associated with increased pain and discomfort. Aging-induced pain/discomfort and anxiety/depression were significantly exacerbated in elderly patients with widespread vaccination. Our study revealed effects of demographic and socioeconomic factors upon lower QoL in post-COVID-19 patients in four dimensions of EQ-5D: mobility, usual activity, pain/discomfort, and anxiety/depression, 5 months after first diagnosis and hospitalization.
PB  - MDPI
T2  - Healthcare
T1  - Quality of Life in Post-COVID-19 Patients after Hospitalization
IS  - 9
SP  - 1666
VL  - 10
DO  - 10.3390/healthcare10091666
ER  - 

@article{
author = "Mitrović-Ajtić, Olivera and Stanisavljević, Dejana and Miljatović, Sanja and Dragojević, Teodora and Živković, Emilija and Šabanović, Miloš and Čokić, Vladan",
year = "2022",
abstract = "The COVID-19 pandemic has had a strong impact on people’s quality of life (QoL), which is affected by social and economic changes as well as by mental and physical health. The aim of this study was to determine QoL in post-COVID-19 patients who had required hospitalization, and to identify relevant sociodemographic data. We used questionnaires which considered demographic and socioeconomic data, health and vaccination status, the pandemic situation, and EQ-5D scoring. The interactions of all data and the scores of EQ-5D were analyzed. Multivariate logistic regression analysis was applied to the five dimensions of EQ-5D. In this single-hospital-cohort study, the average times elapsed since initial diagnosis and hospital admission were 2.5 (76.3 ± 18.1 days) and 5 months (155.4 ± 33.9 days), respectively. Post-COVID-19 females were 3–5 times more likely to be affected in terms of anxiety/depression, and in negative impact upon their usual activities, at 5 months after diagnosis. At the same time, reductions in mobility were 3–4 times more likely in elderly post-COVID-19 patients, whose levels of pain and discomfort increased. Single patients, those with low incomes, and those with severe clinical outcomes were 2–4 times more likely to experience a reduction in their usual activities, while the presence of co-morbidities and lower levels of education were associated with increased pain and discomfort. Aging-induced pain/discomfort and anxiety/depression were significantly exacerbated in elderly patients with widespread vaccination. Our study revealed effects of demographic and socioeconomic factors upon lower QoL in post-COVID-19 patients in four dimensions of EQ-5D: mobility, usual activity, pain/discomfort, and anxiety/depression, 5 months after first diagnosis and hospitalization.",
publisher = "MDPI",
journal = "Healthcare",
title = "Quality of Life in Post-COVID-19 Patients after Hospitalization",
number = "9",
pages = "1666",
volume = "10",
doi = "10.3390/healthcare10091666"
}

Mitrović-Ajtić, O., Stanisavljević, D., Miljatović, S., Dragojević, T., Živković, E., Šabanović, M.,& Čokić, V.. (2022). Quality of Life in Post-COVID-19 Patients after Hospitalization. in Healthcare
MDPI., 10(9), 1666.
https://doi.org/10.3390/healthcare10091666

Mitrović-Ajtić O, Stanisavljević D, Miljatović S, Dragojević T, Živković E, Šabanović M, Čokić V. Quality of Life in Post-COVID-19 Patients after Hospitalization. in Healthcare. 2022;10(9):1666.
doi:10.3390/healthcare10091666 .

Mitrović-Ajtić, Olivera, Stanisavljević, Dejana, Miljatović, Sanja, Dragojević, Teodora, Živković, Emilija, Šabanović, Miloš, Čokić, Vladan, "Quality of Life in Post-COVID-19 Patients after Hospitalization" in Healthcare, 10, no. 9 (2022):1666,
https://doi.org/10.3390/healthcare10091666 . .

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  - Mitrović-Ajtić, Olivera
AU  - Subotički, Tijana
AU  - Miljatović, Sanja
AU  - Beleslin-Čokić, Bojana
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1456
AB  - Background: Although women and men have the same prevalence, men with
COVID-19 are more at risk for worse outcomes and death, independent of age.
Methods: To observe the hyperinflammatory response regarding sex, we will measure
the levels of inflammatory cytokines: interleukin-6 (IL-6), IL-1β, tumor necrosis
factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-10, interferon-
gamma (IFN-γ), IL-8, transforming growth factor-beta 1 (TGF-β1), analyzed by
ELISA, in plasma of 130 COVID-19 patients at diagnosis and correlate them with clinical
parameters. Besides, we checked the quality of life of patients up to 3 months
after hospitalization.
Results: Pro-inflammatory IL-6 was significantly (p<0.01) increased in male COVID-19
patients compared to healthy male volunteers (4.7-fold) and female COVID-19 patients
(1.75-fold). IL-6 was positively correlated to INR, aPTT (p<0.001), and ferritin (p<0.05),
while INR with CRP (p<0.05). IL-8 was significantly increased in female COVID-19 patients
compared to healthy female volunteers (p<0.01, 2.5-fold) and male COVID-19 patients
(p<0.05). TNF-α was significantly (p<0.05) increased in male COVID-19 patients
compared to healthy male volunteers. MCP-1 and IFN-γ were significantly increased
in female COVID-19 patients compared to healthy female volunteers (p<0.01). Anti-inflammatory
TGF-β1 was decreased in COVID-19 patients regardless of gender. Most
patients were men (75%) with chronic disorders (59%, mostly hypertension). COVID-19
reduced their social (32%) and physical activities (34%) after 6 weeks of diagnosis, but
further on reduced in additional 3 months (social 55%) with depression (22%).
Conclusions: Inflammatory response is generally increased in COVID-19 patients
with specific cytokines in accordance with gender.
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  - Gender Difference in SARS-CoV-2 Stimulation of Hyperinflammatory Response in Patients with COVID-19
EP  - 95
SP  - 95
UR  - https://hdl.handle.net/21.15107/rcub_rimi_1456
ER  - 

@conference{
author = "Mitrović-Ajtić, Olivera and Subotički, Tijana and Miljatović, Sanja and Beleslin-Čokić, Bojana and Čokić, Vladan",
year = "2022",
abstract = "Background: Although women and men have the same prevalence, men with
COVID-19 are more at risk for worse outcomes and death, independent of age.
Methods: To observe the hyperinflammatory response regarding sex, we will measure
the levels of inflammatory cytokines: interleukin-6 (IL-6), IL-1β, tumor necrosis
factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-10, interferon-
gamma (IFN-γ), IL-8, transforming growth factor-beta 1 (TGF-β1), analyzed by
ELISA, in plasma of 130 COVID-19 patients at diagnosis and correlate them with clinical
parameters. Besides, we checked the quality of life of patients up to 3 months
after hospitalization.
Results: Pro-inflammatory IL-6 was significantly (p<0.01) increased in male COVID-19
patients compared to healthy male volunteers (4.7-fold) and female COVID-19 patients
(1.75-fold). IL-6 was positively correlated to INR, aPTT (p<0.001), and ferritin (p<0.05),
while INR with CRP (p<0.05). IL-8 was significantly increased in female COVID-19 patients
compared to healthy female volunteers (p<0.01, 2.5-fold) and male COVID-19 patients
(p<0.05). TNF-α was significantly (p<0.05) increased in male COVID-19 patients
compared to healthy male volunteers. MCP-1 and IFN-γ were significantly increased
in female COVID-19 patients compared to healthy female volunteers (p<0.01). Anti-inflammatory
TGF-β1 was decreased in COVID-19 patients regardless of gender. Most
patients were men (75%) with chronic disorders (59%, mostly hypertension). COVID-19
reduced their social (32%) and physical activities (34%) after 6 weeks of diagnosis, but
further on reduced in additional 3 months (social 55%) with depression (22%).
Conclusions: Inflammatory response is generally increased in COVID-19 patients
with specific cytokines in accordance with gender.",
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 = "Gender Difference in SARS-CoV-2 Stimulation of Hyperinflammatory Response in Patients with COVID-19",
pages = "95-95",
url = "https://hdl.handle.net/21.15107/rcub_rimi_1456"
}

Mitrović-Ajtić, O., Subotički, T., Miljatović, S., Beleslin-Čokić, B.,& Čokić, V.. (2022). Gender Difference in SARS-CoV-2 Stimulation of Hyperinflammatory Response in 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., 95-95.
https://hdl.handle.net/21.15107/rcub_rimi_1456

Mitrović-Ajtić O, Subotički T, Miljatović S, Beleslin-Čokić B, Čokić V. Gender Difference in SARS-CoV-2 Stimulation of Hyperinflammatory Response in 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;:95-95.
https://hdl.handle.net/21.15107/rcub_rimi_1456 .

Mitrović-Ajtić, Olivera, Subotički, Tijana, Miljatović, Sanja, Beleslin-Čokić, Bojana, Čokić, Vladan, "Gender Difference in SARS-CoV-2 Stimulation of Hyperinflammatory Response in 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):95-95,
https://hdl.handle.net/21.15107/rcub_rimi_1456 .

TY  - CONF
AU  - Čokić, Vladan
AU  - Popovska, Zorana
AU  - Lijeskić, Olivera
AU  - Šabić, Ljiljana
AU  - Đurković-Đaković, Olgica
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1455
AB  - Background: Over the two years of the COVID-19 pandemic, the elderly in nursing
homes (NH) have been hit particularly hard.
Methods: We conducted a retrospective study of 3 episodes of COVID-19 in one NH in
suburban Belgrade, Serbia, at the time of pre-alpha (Nov 2020), delta (Nov 2021) and
omicron (Jan 2022) variants of SARS-CoV-2. All staff and 95% of residents were vaccinated
in the early spring of 2021, with BBIBP-CorV, Gam-COVID-Vac and BNT162b2
vaccines. COVID-19 was diagnosed by positive PCR and/or antigen test. Specific IgG
antibodies against SARS-CoV-2 S glycoprotein RBD were assessed by ELISA.
Results: The 3 episodes involved a total of 188 infections. The first involved 65/126
(51.9%) residents and 44/64 (68.7%) staff, the second 22/75 (29.3%) residents and 3/40
(7.5%) staff, and the third 36/110 (32.7%) residents and 18/56 (32.1%) staff. Clinical presentation
ranged from asymptomatic to severe, with severe cases being referred to
hospital ICUs. Mortality per episode was 19.8%, 2.7% and 0%, respectively, and involved
residents only. After the first episode, all 36 examined residents and 43 of the
44 staff had specific antibodies. Interestingly, higher levels (20.45±13.27) were detected
in the residents than in the staff (9.74±9.52) (p<0.001) despite a double difference
in age (79.6±7.48 vs. 40.8±11.43) (p<0.001). Episodes 2 and 3 involved 4 (1 resident, 3
staff) and 22 (13 residents, 9 staff) breakthrough infections.
Conclusions: Elderly individuals mounted a good immunological response to the
vaccines, which prevented significant mortality in the next episodes, despite a significant
number of omicron-induced breakthrough infections.
PB  - Belgrade: MEDAPP Association
C3  - The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book
T1  - Three Episodes of COVID-19 in a Nursing Home in Belgrade, Serbia
EP  - 94
SP  - 94
UR  - https://hdl.handle.net/21.15107/rcub_rimi_1455
ER  - 

@conference{
author = "Čokić, Vladan and Popovska, Zorana and Lijeskić, Olivera and Šabić, Ljiljana and Đurković-Đaković, Olgica",
year = "2022",
abstract = "Background: Over the two years of the COVID-19 pandemic, the elderly in nursing
homes (NH) have been hit particularly hard.
Methods: We conducted a retrospective study of 3 episodes of COVID-19 in one NH in
suburban Belgrade, Serbia, at the time of pre-alpha (Nov 2020), delta (Nov 2021) and
omicron (Jan 2022) variants of SARS-CoV-2. All staff and 95% of residents were vaccinated
in the early spring of 2021, with BBIBP-CorV, Gam-COVID-Vac and BNT162b2
vaccines. COVID-19 was diagnosed by positive PCR and/or antigen test. Specific IgG
antibodies against SARS-CoV-2 S glycoprotein RBD were assessed by ELISA.
Results: The 3 episodes involved a total of 188 infections. The first involved 65/126
(51.9%) residents and 44/64 (68.7%) staff, the second 22/75 (29.3%) residents and 3/40
(7.5%) staff, and the third 36/110 (32.7%) residents and 18/56 (32.1%) staff. Clinical presentation
ranged from asymptomatic to severe, with severe cases being referred to
hospital ICUs. Mortality per episode was 19.8%, 2.7% and 0%, respectively, and involved
residents only. After the first episode, all 36 examined residents and 43 of the
44 staff had specific antibodies. Interestingly, higher levels (20.45±13.27) were detected
in the residents than in the staff (9.74±9.52) (p<0.001) despite a double difference
in age (79.6±7.48 vs. 40.8±11.43) (p<0.001). Episodes 2 and 3 involved 4 (1 resident, 3
staff) and 22 (13 residents, 9 staff) breakthrough infections.
Conclusions: Elderly individuals mounted a good immunological response to the
vaccines, which prevented significant mortality in the next episodes, despite a significant
number of omicron-induced breakthrough infections.",
publisher = "Belgrade: MEDAPP Association",
journal = "The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book",
title = "Three Episodes of COVID-19 in a Nursing Home in Belgrade, Serbia",
pages = "94-94",
url = "https://hdl.handle.net/21.15107/rcub_rimi_1455"
}

Čokić, V., Popovska, Z., Lijeskić, O., Šabić, L.,& Đurković-Đaković, O.. (2022). Three Episodes of COVID-19 in a Nursing Home in Belgrade, Serbia. in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book
Belgrade: MEDAPP Association., 94-94.
https://hdl.handle.net/21.15107/rcub_rimi_1455

Čokić V, Popovska Z, Lijeskić O, Šabić L, Đurković-Đaković O. Three Episodes of COVID-19 in a Nursing Home in Belgrade, Serbia. in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book. 2022;:94-94.
https://hdl.handle.net/21.15107/rcub_rimi_1455 .

Čokić, Vladan, Popovska, Zorana, Lijeskić, Olivera, Šabić, Ljiljana, Đurković-Đaković, Olgica, "Three Episodes of COVID-19 in a Nursing Home in Belgrade, Serbia" in The First World Conference Fighting COVID-19 Pandemic - Health Challenges, 26-28 March 2022, Belgrade, Serbia -Abstract book (2022):94-94,
https://hdl.handle.net/21.15107/rcub_rimi_1455 .

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  - Šefer, Dijana
AU  - Miljić, Predrag
AU  - Kraguljac-Kurtović, Nada
AU  - Bižić-Radulović, Sandra
AU  - Bogdanović, Andrija
AU  - Knežević, Vesna
AU  - Marković, Dragana
AU  - Beleslin-Čokić, Bojana
AU  - Novaković, Ivana
AU  - Marinković, Jelena
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Čokić, Vladan
PY  - 2022
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1231
AB  - Introduction: The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics. Methods: Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients. Results: During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P <.05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P =.034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P =.046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P =.006) for thrombosis occurrence. Conclusion: Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA.
T2  - International Journal of Laboratory Hematology
T1  - Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms
EP  - 312
IS  - 2
SP  - 302
VL  - 44
DO  - 10.1111/ijlh.13754
ER  - 

@article{
author = "Šefer, Dijana and Miljić, Predrag and Kraguljac-Kurtović, Nada and Bižić-Radulović, Sandra and Bogdanović, Andrija and Knežević, Vesna and Marković, Dragana and Beleslin-Čokić, Bojana and Novaković, Ivana and Marinković, Jelena and Leković, Danijela and Gotić, Mirjana and Čokić, Vladan",
year = "2022",
abstract = "Introduction: The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics. Methods: Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients. Results: During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P <.05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P =.034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P =.046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P =.006) for thrombosis occurrence. Conclusion: Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA.",
journal = "International Journal of Laboratory Hematology",
title = "Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms",
pages = "312-302",
number = "2",
volume = "44",
doi = "10.1111/ijlh.13754"
}

Šefer, D., Miljić, P., Kraguljac-Kurtović, N., Bižić-Radulović, S., Bogdanović, A., Knežević, V., Marković, D., Beleslin-Čokić, B., Novaković, I., Marinković, J., Leković, D., Gotić, M.,& Čokić, V.. (2022). Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms. in International Journal of Laboratory Hematology, 44(2), 302-312.
https://doi.org/10.1111/ijlh.13754

Šefer D, Miljić P, Kraguljac-Kurtović N, Bižić-Radulović S, Bogdanović A, Knežević V, Marković D, Beleslin-Čokić B, Novaković I, Marinković J, Leković D, Gotić M, Čokić V. Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms. in International Journal of Laboratory Hematology. 2022;44(2):302-312.
doi:10.1111/ijlh.13754 .

Šefer, Dijana, Miljić, Predrag, Kraguljac-Kurtović, Nada, Bižić-Radulović, Sandra, Bogdanović, Andrija, Knežević, Vesna, Marković, Dragana, Beleslin-Čokić, Bojana, Novaković, Ivana, Marinković, Jelena, Leković, Danijela, Gotić, Mirjana, Čokić, Vladan, "Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms" in International Journal of Laboratory Hematology, 44, no. 2 (2022):302-312,
https://doi.org/10.1111/ijlh.13754 . .

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  - CONF
AU  - Mitrović-Ajtić, Olivera
AU  - Diklić, Miloš
AU  - Antić, Darko
AU  - Mihaljević, Biljana
AU  - Vuković, Vojin
AU  - Otašević, Vladimir
AU  - Tomić, Kristina
AU  - Čokić, Vladan
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1429
AB  - Background: S100A proteins possess a broad range of intra- and extracellular functions. The involvement of these proteins in inflammation-mediated responses is of particular interests, considering that inflammation represents one of the landmarks of malignancy. Processes such as inflammation and cellular stress trigger the release of S100A proteins to extracellular space, interacting with their receptors and activating numerous intracellular signaling pathways, for instance NF-κB and AP1. Through them, S100A proteins take part into regulation of some 
of the most essential cellular processes: cell differentiation, apoptosis, 
inflammation, proliferation, etc.
Aims: The aim of the study is to assess the role of inflammation in activation of S100A proteins via proliferation and inflammation related signaling pathways.
Methods: We observed 60 CLL patients’ samples to isolate mononuclear cells (MNC) and CD19+
 cells. MNC of CLL patients were treated with pro-inflammatory IL-6 and anti-inflammatory IL-10 cytokines, and inhibitors of JAK1/2, NF-κB and PI3K signaling pathways, to evaluate 
S100A4, S100A8, S100A9, S100A12 and NF-κB protein expression by immunoblotting. Also, we used immunocytochemistry to analyse the number of the S100As immunopositive MNC of CLL patients.Results: S100A8 showed higher level of protein expression in MNC and 
CD19+cells in comparison to healthy control. The number of immunopositive S100A4 (p<0.05) and S100A9 cells (p<0.001) was signifi cantly decreased in CD19+cells and MNC, respectively of CLL patients in comparison to healthy control. In addition, S100A4 and S100A9 proteins expression had statistically significant lower level of expression in MNC. Also, IL-6 stimulated expression of S100A8 and S100A4 in MNC of CLL, while the expression of latter one was prevented by NF-κB and JAK1/2 inhibitors. IL-10 reduced expression of S100A8 and S100A12 in MNC of CLL.Summary/Conclusion: Pro-inflammatory IL-6 and anti-inflammatory 
IL-10 cytokines have opposite effect on inflammatory S100A8 protein 
in CLL, with a potential to be a prognostic marker.
PB  - Wolters Kluwer Health, Inc.
C3  - HemaSphere - The Abstract Book of the 26th Congress of the European Hematology Association, EHA2021 Virtual Congress
T1  - Influence of inflammatory cytokines on S100A proteins expression in CLL patients
EP  - 280
IS  - S2
SP  - 280
VL  - 5
DO  - 10.1097/HS9.0000000000000566
ER  - 

@conference{
author = "Mitrović-Ajtić, Olivera and Diklić, Miloš and Antić, Darko and Mihaljević, Biljana and Vuković, Vojin and Otašević, Vladimir and Tomić, Kristina and Čokić, Vladan",
year = "2021",
abstract = "Background: S100A proteins possess a broad range of intra- and extracellular functions. The involvement of these proteins in inflammation-mediated responses is of particular interests, considering that inflammation represents one of the landmarks of malignancy. Processes such as inflammation and cellular stress trigger the release of S100A proteins to extracellular space, interacting with their receptors and activating numerous intracellular signaling pathways, for instance NF-κB and AP1. Through them, S100A proteins take part into regulation of some 
of the most essential cellular processes: cell differentiation, apoptosis, 
inflammation, proliferation, etc.
Aims: The aim of the study is to assess the role of inflammation in activation of S100A proteins via proliferation and inflammation related signaling pathways.
Methods: We observed 60 CLL patients’ samples to isolate mononuclear cells (MNC) and CD19+
 cells. MNC of CLL patients were treated with pro-inflammatory IL-6 and anti-inflammatory IL-10 cytokines, and inhibitors of JAK1/2, NF-κB and PI3K signaling pathways, to evaluate 
S100A4, S100A8, S100A9, S100A12 and NF-κB protein expression by immunoblotting. Also, we used immunocytochemistry to analyse the number of the S100As immunopositive MNC of CLL patients.Results: S100A8 showed higher level of protein expression in MNC and 
CD19+cells in comparison to healthy control. The number of immunopositive S100A4 (p<0.05) and S100A9 cells (p<0.001) was signifi cantly decreased in CD19+cells and MNC, respectively of CLL patients in comparison to healthy control. In addition, S100A4 and S100A9 proteins expression had statistically significant lower level of expression in MNC. Also, IL-6 stimulated expression of S100A8 and S100A4 in MNC of CLL, while the expression of latter one was prevented by NF-κB and JAK1/2 inhibitors. IL-10 reduced expression of S100A8 and S100A12 in MNC of CLL.Summary/Conclusion: Pro-inflammatory IL-6 and anti-inflammatory 
IL-10 cytokines have opposite effect on inflammatory S100A8 protein 
in CLL, with a potential to be a prognostic marker.",
publisher = "Wolters Kluwer Health, Inc.",
journal = "HemaSphere - The Abstract Book of the 26th Congress of the European Hematology Association, EHA2021 Virtual Congress",
title = "Influence of inflammatory cytokines on S100A proteins expression in CLL patients",
pages = "280-280",
number = "S2",
volume = "5",
doi = "10.1097/HS9.0000000000000566"
}

Mitrović-Ajtić, O., Diklić, M., Antić, D., Mihaljević, B., Vuković, V., Otašević, V., Tomić, K.,& Čokić, V.. (2021). Influence of inflammatory cytokines on S100A proteins expression in CLL patients. in HemaSphere - The Abstract Book of the 26th Congress of the European Hematology Association, EHA2021 Virtual Congress
Wolters Kluwer Health, Inc.., 5(S2), 280-280.
https://doi.org/10.1097/HS9.0000000000000566

Mitrović-Ajtić O, Diklić M, Antić D, Mihaljević B, Vuković V, Otašević V, Tomić K, Čokić V. Influence of inflammatory cytokines on S100A proteins expression in CLL patients. in HemaSphere - The Abstract Book of the 26th Congress of the European Hematology Association, EHA2021 Virtual Congress. 2021;5(S2):280-280.
doi:10.1097/HS9.0000000000000566 .

Mitrović-Ajtić, Olivera, Diklić, Miloš, Antić, Darko, Mihaljević, Biljana, Vuković, Vojin, Otašević, Vladimir, Tomić, Kristina, Čokić, Vladan, "Influence of inflammatory cytokines on S100A proteins expression in CLL patients" in HemaSphere - The Abstract Book of the 26th Congress of the European Hematology Association, EHA2021 Virtual Congress, 5, no. S2 (2021):280-280,
https://doi.org/10.1097/HS9.0000000000000566 . .

TY  - JOUR
AU  - Kapor, Sunčica
AU  - Čokić, Vladan
AU  - Santibanez, Juan F.
PY  - 2021
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1174
AB  - Hydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU's ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases.
PB  - Hindawi
T2  - Oxidative Medicine and Cellular Longevity
T1  - Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?
SP  - e7753857
VL  - 2021
DO  - 10.1155/2021/7753857
ER  - 

@article{
author = "Kapor, Sunčica and Čokić, Vladan and Santibanez, Juan F.",
year = "2021",
abstract = "Hydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU's ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases.",
publisher = "Hindawi",
journal = "Oxidative Medicine and Cellular Longevity",
title = "Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?",
pages = "e7753857",
volume = "2021",
doi = "10.1155/2021/7753857"
}

Kapor, S., Čokić, V.,& Santibanez, J. F.. (2021). Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?. in Oxidative Medicine and Cellular Longevity
Hindawi., 2021, e7753857.
https://doi.org/10.1155/2021/7753857

Kapor S, Čokić V, Santibanez JF. Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?. in Oxidative Medicine and Cellular Longevity. 2021;2021:e7753857.
doi:10.1155/2021/7753857 .

Kapor, Sunčica, Čokić, Vladan, Santibanez, Juan F., "Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?" in Oxidative Medicine and Cellular Longevity, 2021 (2021):e7753857,
https://doi.org/10.1155/2021/7753857 . .