Julia Kzhyshkowska - Academia.edu (original) (raw)
Papers by Julia Kzhyshkowska
European Heart Journal, Nov 1, 2020
Introduction Molecular biomarkers of monocytes/macrophages identified to date have provided advan... more Introduction Molecular biomarkers of monocytes/macrophages identified to date have provided advanced diagnostic capabilities. We have accumulated a large amount of knowledge related to the role of innate immune response in the development of postinfarction cardiac remodeling. However, there is no significant advancement in clinical studies. Purpose The purpose was to assess prospects of macrophage biomarkers in diagnostics of postinfarction tissue inflammation associated with adverse cardiac remodeling in patients with myocardial infarction (MI). Methods The study included 41 patients with MI type 1, died in 2013–2014. We used a biobank of tissue samples for analysis. Group 1 (n=24) comprised patients who died within 72 hours of MI (the inflammatory phase), group 2 (n=17) comprised patients who died 4–28 days after MI (the regenerative phase). Macrophage infiltration in the heart was assessed by double immunofluorescence. We used stabilin-1 as a marker of M2 macrophages, while α-smooth muscle actin (α-SMA) was considered as a marker of cell transdifferentiation. Cells were counted in the infarct (IA) and non-infarct area (NIA). Morphological determination of adverse cardiac remodeling was based on the ratio of heart size, in particular, length/width ratio that was <1.1. Results We identified subpopulations of stabilin-1+/α-SMA− and stabilin-1+/α-SMA+ macrophages. In the IA the number of stabilin-1+/α-SMA− macrophages was lower during the inflammatory phase than during the regenerative phase (Table 1). The calculation of sensitivity and specificity of stabilin-1+/α-SMA− macrophages in the NIA for predicting of adverse cardiac remodeling has shown following: AUC=0.96, p<0.001. The cut-off value was 18 cells/mm2. The ROC curve is presented in Figure 1. Conclusions We identified that number of stabilin-1+/α-SMA− macrophages in the NIA ranged from 0 to 18 cells/mm2 was associated with adverse cardiac remodeling. The presence of stabilin-1+/α-SMA+ macrophages could indicate persistent tissue inflammation and possibility of macrophage transdifferentiation and plasticity. Our study supports prospects for implementation of macrophage biomarkers in clinical practice that might become a breakthrough in the development of new methods for management of MI and following complications. Figure 1 Funding Acknowledgement Type of funding source: None
Sibirskij žurnal kliničeskoj i èksperimentalʹnoj mediciny, Jul 7, 2023
The spleen is one of the main reservoirs of monocytes, the leading cells of the post-infarction i... more The spleen is one of the main reservoirs of monocytes, the leading cells of the post-infarction inflammatory response.Aim: To assess features of splenic macrophage infiltration, its dynamics and correlations with myocardial macrophage infiltration and an adverse course of the myocardial infarction (MI)Material and Methods. The macrophage composition of spleen and myocardium sections of patients (n = 30) with fatal MI and persons from the control group without cardiovascular disease (n = 5) was assessed by immunohistochemistry.Results and conclusion. All investigated cells, as CD68+, CD163+, CD206+, and stabilin-1+ were represented in the spleen regardless of the presence of MI. Their number in spleen in patients with MI remained consistently high regardless of the period of MI, and was accompanied by an increased number of such cells in the infarction area of myocardium. CD68+, CD163+ and stabilin-1+ cells predominated in the red pulp in patients with fatal MI, its number many fold exceeded that in the control group and that in the white pulp and in the infarction area of myocardium. In the white pulp of patients with fatal MI, the number of CD68+ cells predominated, in persons from the control group – CD163+. We revealed only one cell types whose content in the spleen in the control group was higher than in individuals with fatal MI – CD206+in the red pulp. Low content of CD206+ cells in the red and white pulp of the spleen characterized patients with a fatal outcome of MI.
Russian Journal of Cardiology, Mar 28, 2023
Сибирский медицинский журнал, Jul 14, 2018
Biomedicines, Jun 27, 2023
European Heart Journal, Aug 1, 2017
Journal of Personalized Medicine, Jan 18, 2022
Key Engineering Materials, Feb 1, 2016
Endomyocardial biopsy is the gold standard in the diagnosis of myocardial pathology. Intravital s... more Endomyocardial biopsy is the gold standard in the diagnosis of myocardial pathology. Intravital study of endomyocardial samples offers the possibility to determine the morphological substrate and etiology of disease, to monitor the effectiveness of treatment. We studied morphological features, viral antigens, macrophages and specifically alternatively activated macrophages in endomyocardial biopsies of 25 patients with idiopathic arrhythmias and heart failure. Immunohistological study was performed to identify type of lymphocytes, macrophages and antigens of cardiotropic viruses. We observed the presence of alternatively activated macrophages in myocardium of patients with myocarditis and without it. We detected the presence of viral antigens in the myocardium of patients with myocardial fibrosis without of histological criteria myocarditis. Small focal infiltration of the myocardial CD68+ macrophages associated with heart failure and ventricular arrhythmias. The presence of virus antigens in myocardium associated with fewer myocardial stabilin-1+ macrophages [negative correlation]. On the other side small focal infiltration of stabilin-1+ macrophages correlated with severity of myocardial interstitial fibrosis [positive correlation]
European Heart Journal. Acute Cardiovascular Care, 2021
Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reporte... more Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reported study was funded by RFBR. Project number 19-315-60005. Introduction Heart-kidney axis is an active participant of the formation and progression of chronic heart and renal failure in patients with myocardial infarction (MI). Innate immunity play a great role in this collaboration between the heart and kidney according to the experimental data. However, there is not enough data about clinical studies. Purpose to assess the dynamics of kidney CD68+, CD80+, CD206+, CD163+ and stabilin-1+ macrophages in patients with fatal MI. Methods and results: 30 patients with fatal MI type 1 were included. STEMI was in 87% (n = 26), in 53% (n = 16) it was recurrent MI. Chronic kidney disease was diagnosed in 33% (n = 10). They were divided according to the timeline of MI histopathology into 2 groups: early phase – inflammatory and reparative periods (to the 3d day after MI), late phase - regenerative a...
European Heart Journal. Acute Cardiovascular Care, 2021
Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) ... more Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) and following heart failure (HF) have various clinical scenarios. However, despite the clinical heterogeneity, the management of MI lacks effective personalized approaches. The response to ischemic injury in the infarct zone and remote myocardium has a definite spatio-temporal sequence and underlies the mechanism of adverse cardiac remodeling. Understanding its myocardial biology remains unclear due to insufficiency of heart tissue molecular and genetic analysis. Although animal models play an important role in data accumulation, they failure to reflect all the compounds of response to ischemic injury and following HF syndrome. Purpose. The purpose of the study was to investigate myocardial expression profile in the infarct zone in comparison to remote myocardium in patients with MI. Methods. The study included 4 patients with fatal MI type 1. All patients died within 48 hours of MI. The...
Journal of Leukocyte Biology
![Research paper thumbnail of Corrigendum to 'Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose' [Immunol. Lett. 176 (2016) 81-89]](https://attachments.academia-assets.com/105517851/thumbnails/1.jpg)
](Immunology letters, Jan 17, 2017
Epidemiological data highlight prostate cancer as a significant global health issue, with high in... more Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of ...
Frontiers in Immunology
IntroductionTumor resistance to chemotherapy and metastatic relapse account for more than 90% of ... more IntroductionTumor resistance to chemotherapy and metastatic relapse account for more than 90% of cancer specific mortality. Tumor-associated macrophages (TAMs) can process chemotherapeutic agents and impair their action. Little is known about the direct effects of chemotherapy on TAMs.MethodsThe effect of chemotherapeutic platinum agent cisplatin was assessed in the model system of human ex vivo TAMs. Whole-transcriptome sequencing for paired TAMs stimulated and not stimulated by cisplatin was analysed by NGS. Endocytic uptake of EGF was quantified by flow cytometry. Confocal microscopy was used to visualize stabilin-1-mediated internalization and endocytic trafficking of EGF in CHO cells expressing ectopically recombinant stabilin-1 and in stabilin-1+ TAMs. In cohort of patients with breast cancer, the effect of platinum therapy on the transcriptome of TAMs was validated, and differential expression of regulators of endocytosis was identified.ResultsHere we show that chemotherapeut...
Frontiers in Immunology
IntroductionCirculating monocytes are main source for tumor-associated macrophages (TAMs) that co... more IntroductionCirculating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation.MethodsPatients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS.ResultsIn patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN me...
Frontiers in Oncology
Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitu... more Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME...
European Heart Journal, Nov 1, 2020
Introduction Molecular biomarkers of monocytes/macrophages identified to date have provided advan... more Introduction Molecular biomarkers of monocytes/macrophages identified to date have provided advanced diagnostic capabilities. We have accumulated a large amount of knowledge related to the role of innate immune response in the development of postinfarction cardiac remodeling. However, there is no significant advancement in clinical studies. Purpose The purpose was to assess prospects of macrophage biomarkers in diagnostics of postinfarction tissue inflammation associated with adverse cardiac remodeling in patients with myocardial infarction (MI). Methods The study included 41 patients with MI type 1, died in 2013–2014. We used a biobank of tissue samples for analysis. Group 1 (n=24) comprised patients who died within 72 hours of MI (the inflammatory phase), group 2 (n=17) comprised patients who died 4–28 days after MI (the regenerative phase). Macrophage infiltration in the heart was assessed by double immunofluorescence. We used stabilin-1 as a marker of M2 macrophages, while α-smooth muscle actin (α-SMA) was considered as a marker of cell transdifferentiation. Cells were counted in the infarct (IA) and non-infarct area (NIA). Morphological determination of adverse cardiac remodeling was based on the ratio of heart size, in particular, length/width ratio that was <1.1. Results We identified subpopulations of stabilin-1+/α-SMA− and stabilin-1+/α-SMA+ macrophages. In the IA the number of stabilin-1+/α-SMA− macrophages was lower during the inflammatory phase than during the regenerative phase (Table 1). The calculation of sensitivity and specificity of stabilin-1+/α-SMA− macrophages in the NIA for predicting of adverse cardiac remodeling has shown following: AUC=0.96, p<0.001. The cut-off value was 18 cells/mm2. The ROC curve is presented in Figure 1. Conclusions We identified that number of stabilin-1+/α-SMA− macrophages in the NIA ranged from 0 to 18 cells/mm2 was associated with adverse cardiac remodeling. The presence of stabilin-1+/α-SMA+ macrophages could indicate persistent tissue inflammation and possibility of macrophage transdifferentiation and plasticity. Our study supports prospects for implementation of macrophage biomarkers in clinical practice that might become a breakthrough in the development of new methods for management of MI and following complications. Figure 1 Funding Acknowledgement Type of funding source: None
Sibirskij žurnal kliničeskoj i èksperimentalʹnoj mediciny, Jul 7, 2023
The spleen is one of the main reservoirs of monocytes, the leading cells of the post-infarction i... more The spleen is one of the main reservoirs of monocytes, the leading cells of the post-infarction inflammatory response.Aim: To assess features of splenic macrophage infiltration, its dynamics and correlations with myocardial macrophage infiltration and an adverse course of the myocardial infarction (MI)Material and Methods. The macrophage composition of spleen and myocardium sections of patients (n = 30) with fatal MI and persons from the control group without cardiovascular disease (n = 5) was assessed by immunohistochemistry.Results and conclusion. All investigated cells, as CD68+, CD163+, CD206+, and stabilin-1+ were represented in the spleen regardless of the presence of MI. Their number in spleen in patients with MI remained consistently high regardless of the period of MI, and was accompanied by an increased number of such cells in the infarction area of myocardium. CD68+, CD163+ and stabilin-1+ cells predominated in the red pulp in patients with fatal MI, its number many fold exceeded that in the control group and that in the white pulp and in the infarction area of myocardium. In the white pulp of patients with fatal MI, the number of CD68+ cells predominated, in persons from the control group – CD163+. We revealed only one cell types whose content in the spleen in the control group was higher than in individuals with fatal MI – CD206+in the red pulp. Low content of CD206+ cells in the red and white pulp of the spleen characterized patients with a fatal outcome of MI.
Russian Journal of Cardiology, Mar 28, 2023
Сибирский медицинский журнал, Jul 14, 2018
Biomedicines, Jun 27, 2023
European Heart Journal, Aug 1, 2017
Journal of Personalized Medicine, Jan 18, 2022
Key Engineering Materials, Feb 1, 2016
Endomyocardial biopsy is the gold standard in the diagnosis of myocardial pathology. Intravital s... more Endomyocardial biopsy is the gold standard in the diagnosis of myocardial pathology. Intravital study of endomyocardial samples offers the possibility to determine the morphological substrate and etiology of disease, to monitor the effectiveness of treatment. We studied morphological features, viral antigens, macrophages and specifically alternatively activated macrophages in endomyocardial biopsies of 25 patients with idiopathic arrhythmias and heart failure. Immunohistological study was performed to identify type of lymphocytes, macrophages and antigens of cardiotropic viruses. We observed the presence of alternatively activated macrophages in myocardium of patients with myocarditis and without it. We detected the presence of viral antigens in the myocardium of patients with myocardial fibrosis without of histological criteria myocarditis. Small focal infiltration of the myocardial CD68+ macrophages associated with heart failure and ventricular arrhythmias. The presence of virus antigens in myocardium associated with fewer myocardial stabilin-1+ macrophages [negative correlation]. On the other side small focal infiltration of stabilin-1+ macrophages correlated with severity of myocardial interstitial fibrosis [positive correlation]
European Heart Journal. Acute Cardiovascular Care, 2021
Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reporte... more Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reported study was funded by RFBR. Project number 19-315-60005. Introduction Heart-kidney axis is an active participant of the formation and progression of chronic heart and renal failure in patients with myocardial infarction (MI). Innate immunity play a great role in this collaboration between the heart and kidney according to the experimental data. However, there is not enough data about clinical studies. Purpose to assess the dynamics of kidney CD68+, CD80+, CD206+, CD163+ and stabilin-1+ macrophages in patients with fatal MI. Methods and results: 30 patients with fatal MI type 1 were included. STEMI was in 87% (n = 26), in 53% (n = 16) it was recurrent MI. Chronic kidney disease was diagnosed in 33% (n = 10). They were divided according to the timeline of MI histopathology into 2 groups: early phase – inflammatory and reparative periods (to the 3d day after MI), late phase - regenerative a...
European Heart Journal. Acute Cardiovascular Care, 2021
Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) ... more Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) and following heart failure (HF) have various clinical scenarios. However, despite the clinical heterogeneity, the management of MI lacks effective personalized approaches. The response to ischemic injury in the infarct zone and remote myocardium has a definite spatio-temporal sequence and underlies the mechanism of adverse cardiac remodeling. Understanding its myocardial biology remains unclear due to insufficiency of heart tissue molecular and genetic analysis. Although animal models play an important role in data accumulation, they failure to reflect all the compounds of response to ischemic injury and following HF syndrome. Purpose. The purpose of the study was to investigate myocardial expression profile in the infarct zone in comparison to remote myocardium in patients with MI. Methods. The study included 4 patients with fatal MI type 1. All patients died within 48 hours of MI. The...
Journal of Leukocyte Biology
Immunology letters, Jan 17, 2017
Epidemiological data highlight prostate cancer as a significant global health issue, with high in... more Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of ...
Frontiers in Immunology
IntroductionTumor resistance to chemotherapy and metastatic relapse account for more than 90% of ... more IntroductionTumor resistance to chemotherapy and metastatic relapse account for more than 90% of cancer specific mortality. Tumor-associated macrophages (TAMs) can process chemotherapeutic agents and impair their action. Little is known about the direct effects of chemotherapy on TAMs.MethodsThe effect of chemotherapeutic platinum agent cisplatin was assessed in the model system of human ex vivo TAMs. Whole-transcriptome sequencing for paired TAMs stimulated and not stimulated by cisplatin was analysed by NGS. Endocytic uptake of EGF was quantified by flow cytometry. Confocal microscopy was used to visualize stabilin-1-mediated internalization and endocytic trafficking of EGF in CHO cells expressing ectopically recombinant stabilin-1 and in stabilin-1+ TAMs. In cohort of patients with breast cancer, the effect of platinum therapy on the transcriptome of TAMs was validated, and differential expression of regulators of endocytosis was identified.ResultsHere we show that chemotherapeut...
Frontiers in Immunology
IntroductionCirculating monocytes are main source for tumor-associated macrophages (TAMs) that co... more IntroductionCirculating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation.MethodsPatients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS.ResultsIn patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN me...
Frontiers in Oncology
Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitu... more Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME...