Publications by authors named "Julia Kzhyshkowska"

94 Publications

Modification of PCL Scaffolds by Reactive Magnetron Sputtering: A Possibility for Modulating Macrophage Responses.

ACS Biomater Sci Eng 2020 07 5;6(7):3967-3974. Epub 2020 Jun 5.

National Research Tomsk Polytechnic University, 30 Lenin Avenue, Tomsk 634050, Russian Federation.

Direct current (DC) reactive magnetron sputtering is as an efficient method for enhancing the biocompatibility of poly(ε-caprolactone) (PCL) scaffolds. However, the PCL chemical bonding state, the composition of the deposited coating, and their interaction with immune cells remain unknown. Herein, we demonstrated that the DC reactive magnetron sputtering of the titanium target in a nitrogen atmosphere leads to the formation of nitrogen-containing moieties and the titanium dioxide coating on the scaffold surface. We have provided the possible mechanism of PCL fragmentation and coating formation supported by XPS results and DFT calculations. Our preliminary biological studies suggest that DC reactive magnetron sputtering of the titanium target could be an effective tool to control macrophage functional responses toward PCL scaffolds as it allows to inhibit respiratory burst while retaining cell viability and scavenging activity.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00440DOI Listing
July 2020

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers.

Front Oncol 2020 22;10:566511. Epub 2020 Oct 22.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia.

Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
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http://dx.doi.org/10.3389/fonc.2020.566511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642726PMC
October 2020

Serum Levels of Bone Morphogenetic Proteins 2 and 4 in Patients with Acute Myocardial Infarction.

Cells 2020 09 27;9(10). Epub 2020 Sep 27.

Siberian State Medical University, 634055 Tomsk, Russia.

Background: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics.

Methods: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients ( = 31) during the six-month follow-up period after myocardial infarction (MI).

Results: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR.

Conclusions: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further.
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http://dx.doi.org/10.3390/cells9102179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601292PMC
September 2020

Epigenetic Regulation of S100A9 and S100A12 Expression in Monocyte-Macrophage System in Hyperglycemic Conditions.

Front Immunol 2020 2;11:1071. Epub 2020 Jun 2.

Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Heidelberg University, Mannheim, Germany.

The number of diabetic patients in Europe and world-wide is growing. Diabetes confers a 2-fold higher risk for vascular disease. Lack of insulin production (Type 1 diabetes, T1D) or lack of insulin responsiveness (Type 2 diabetes, T2D) causes systemic metabolic changes such as hyperglycemia (HG) which contribute to the pathology of diabetes. Monocytes and macrophages are key innate immune cells that control inflammatory reactions associated with diabetic vascular complications. Inflammatory programming of macrophages is regulated and maintained by epigenetic mechanisms, in particular histone modifications. The aim of our study was to identify the epigenetic mechanisms involved in the hyperglycemia-mediated macrophage activation. Using Affymetrix microarray profiling and RT-qPCR we identified that hyperglycemia increased the expression of and in primary human macrophages. Expression of was sustained after glucose levels were normalized. Glucose augmented the response of macrophages to Toll-like receptor (TLR)-ligands Palmatic acid (PA) and Lipopolysaccharide (LPS) i.e., pro-inflammatory stimulation. The abundance of activating histone Histone 3 Lysine 4 methylation marks (H3K4me1, H3K4me3) and general acetylation on histone 3 (AceH3) with the promoters of these genes was analyzed by chromatin immunoprecipitation. Hyperglycemia increased acetylation of histones bound to the promoters of and in M1 macrophages. In contrast, hyperglycemia caused a reduction in total H3 which correlated with the increased expression of both S100 genes. The inhibition of histone methyltransferases SET domain-containing protein (SET)7/9 and SET and MYND domain-containing protein (SMYD)3 showed that these specifically regulated expression. We conclude that hyperglycemia upregulates expression of via epigenetic regulation and induces an activating histone code on the respective gene promoters in M1 macrophages. Mechanistically, this regulation relies on action of histone methyltransferases SMYD3 and SET7/9. The results define an important role for epigenetic regulation in macrophage mediated inflammation in diabetic conditions.
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http://dx.doi.org/10.3389/fimmu.2020.01071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280556PMC
March 2021

Editorial: Targeting Angiogenesis to Treat Autoimmune Diseases and Cancer.

Front Immunol 2020 21;11:1005. Epub 2020 May 21.

Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL, United States.

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http://dx.doi.org/10.3389/fimmu.2020.01005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253682PMC
May 2021

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages.

Cancers (Basel) 2020 May 29;12(6). Epub 2020 May 29.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia.

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.
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http://dx.doi.org/10.3390/cancers12061411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352439PMC
May 2020

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer.

Front Immunol 2019 22;10:2930. Epub 2020 Jan 22.

Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, University of Heidelberg, Mannheim, Germany.

YKL-39 belongs to the evolutionarily conserved family of Glyco_18-containing proteins composed of chitinases and chitinase-like proteins. Chitinase-like proteins (CLPs) are secreted lectins that lack hydrolytic activity due to the amino acid substitutions in their catalytic domain and combine the functions of cytokines and growth factors. One of the major cellular sources that produce CLPs in various pathologies, including cancer, are macrophages. Monocytes recruited to the tumor site and programmed by tumor cells differentiate into tumor-associated macrophages (TAMs), which are the primary source of pro-angiogenic factors. Tumor angiogenesis is a crucial process for supplying rapidly growing tumors with essential nutrients and oxygen. We recently determined that YKL-39 is produced by tumor-associated macrophages in breast cancer. YKL-39 acts as a strong chemotactic factor for monocytes and stimulates angiogenesis. Chemotherapy is a common strategy to reduce tumor size and aggressiveness before surgical intervention, but chemoresistance, resulting in the relapse of tumors, is a common clinical problem that is critical for survival in cancer patients. Accumulating evidence indicates that TAMs are essential regulators of chemoresistance. We have recently found that elevated levels of YKL-39 expression are indicative of the efficiency of the metastatic process in patients who undergo neoadjuvant chemotherapy. We suggest YKL-39 as a new target for anti-angiogenic therapy that can be combined with neoadjuvant chemotherapy to reduce chemoresistance and inhibit metastasis in breast cancer patients.
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http://dx.doi.org/10.3389/fimmu.2019.02930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988383PMC
December 2020

Impact of estrogen receptor α on the tamoxifen response and prognosis in luminal-A-like and luminal-B-like breast cancer.

Clin Exp Med 2019 Nov 27;19(4):547-556. Epub 2019 Sep 27.

Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation, 634050.

The luminal-A-like and luminal-B-like breast cancer groups have distinct biological features that lead to differences in the treatment response and clinical outcome. The aim of this study was to examine the value of the distribution pattern of ERα expression, ESR1 SNPs as well as ESR1 mRNA expression in predicting tamoxifen response and survival in patients with luminal-A-like and luminal-B-like breast cancer. A total of 135 patients with both subtypes were stratified into two groups depending on the tamoxifen response: tamoxifen-resistant patients (TR) and tamoxifen-sensitive patients (TS). ESR1 mRNA expression was measured by real-time quantitative reverse transcription-PCR. Three polymorphisms of ESR1 (rs2077647, rs2228480 and rs1801132) were genotyped using a TaqMan assay. The distribution pattern of ERα expression was analyzed immunohistochemically using the visual assessment of staining. The primary endpoint was progression-free survival (PFS). There was a significant decrease in ESR1 mRNA expression level in the TR group when compared to the TS group among patients with luminal-B-like subtype (P = 0.038). ESR1 2014AA mutant genotype of rs2228480 was more prevalent in the TR patients with luminal-B-like subtype than the TS group (P = 0.045). In the luminal-A-like group, tamoxifen-resistant tumors were more frequently heterogeneous for ERα expression than tamoxifen-sensitive tumors (P = 0.016). Multivariate analysis showed a strong association of lymph node status and the distribution pattern of ERα expression with tamoxifen responsiveness in this cohort of patients. In addition, a luminal-A-like patients with the heterogeneous ERα expression had a significantly shorter PFS time than those with the homogeneous ERα (P = 0.013). These results indicate that the heterogeneous expression of ERα is an accurate predictor of tamoxifen response and survival in luminal-A-like breast cancer patients. ESR1 rs2228480 may act as a marker with a high prognostic potential in luminal-B-like tumors.
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http://dx.doi.org/10.1007/s10238-019-00583-6DOI Listing
November 2019

SI-CLP inhibits the growth of mouse mammary adenocarcinoma by preventing recruitment of tumor-associated macrophages.

Int J Cancer 2020 03 4;146(5):1396-1408. Epub 2019 Dec 4.

Medical Faculty Mannheim, Institute for Transfusion Medicine and Immunology, Ruprecht-Karls University of Heidelberg, Mannheim, Germany.

Chitinase-like proteins (CLP) are chitin-binding proteins that lack chitin hydrolyzing activity, but possess cytokine-like and growth factor-like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL-40 and stabilin-1 interacting chitinase-like protein (SI-CLP). Despite numerous reports indicating the role of YKL-40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI-CLP in cancer was not reported. Using gain-of-function approach, we demonstrate in the current study that the expression of recombinant SI-CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor-associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI-CLP expressing tumors. Gene expression analysis in TAM isolated from SI-CLP-expressing and control tumors demonstrated that SI-CLP does not affect macrophage phenotype. However, SI-CLP significantly inhibited migration of murine bone-marrow derived macrophages and human primary monocytes toward monocyte-recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI-CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI-CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine-induced TAM recruitment. Taking into consideration weak to absent expression of SI-CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM-mediated support of breast tumor growth.
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http://dx.doi.org/10.1002/ijc.32685DOI Listing
March 2020

Interaction of tumor-associated macrophages and cancer chemotherapy.

Oncoimmunology 2019;8(7):1596004. Epub 2019 Apr 13.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia.

It has been recently recognized that the tumor microenvironment (TME) is an essential factor that defines the efficiency of chemotherapy. The local TME, consisting of immune cells with diverse phenotypes and functions, can strongly modulate the response to chemotherapy. Tumor-associated macrophages (TAMs) that display pronounced heterogeneity and phenotypic plasticity are the major innate immune component in the microenvironment of solid tumors. In our review, we elucidate the complex role of TAMs in the progression of different types of solid tumors, summarize the current knowledge about the effects of different anticancer chemotherapeutic agents on monocytes/macrophages, and describe the mechanisms of chemotherapy resistance mediated by TAMs.
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http://dx.doi.org/10.1080/2162402X.2019.1596004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527283PMC
April 2019

Reactive oxygen species (ROS) in macrophage activation and function in diabetes.

Immunobiology 2019 03 1;224(2):242-253. Epub 2018 Dec 1.

The Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Germany; Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia; Red Cross Blood Service Baden-Württemberg-Hessen, Germany. Electronic address:

In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular complications of diabetes. Recent studies have shown that ROS formation is exacerbated in diabetic monocytes and macrophages due to a glycolytic metabolic shift. Macrophages are important players in the progression of diabetes and promote inflammation through the release of pro-inflammatory cytokines and proteases. Because ROS is an important mediator for the activation of pro-inflammatory signaling pathways, obesity and hyperglycemia-induced ROS production may favor induction of M1-like pro-inflammatory macrophages during diabetes onset and progression. ROS induces MAPK, STAT1, STAT6 and NFκB signaling, and interferes with macrophage differentiation via epigenetic (re)programming. Therefore, a comprehensive understanding of the impact of ROS on macrophage phenotype and function is needed in order to improve treatment of diabetes and its vascular complications. In the current comprehensive review, we dissect the role of ROS in macrophage polarization, and analyze how ROS production links metabolism and inflammation in diabetes and its complications. Finally, we discuss the contribution of ROS to the crosstalk between macrophages and endothelial cells in diabetic complications.
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http://dx.doi.org/10.1016/j.imbio.2018.11.010DOI Listing
March 2019

Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease.

Gene 2019 Apr 12;692:102-112. Epub 2019 Jan 12.

Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences (IBG UFRC RAS), Pr. Oktybry 71, Ufa 450054, Russian Federation; Bashkir State Medical University, Department of Biology, Department of Internal Diseases, Lenina Str, 3, Ufa 450008, Russian Federation.

Background And Objective: Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This work was designed as a case-control study aimed at investigating the association of the NRF2/KEAP1 signaling system, and antioxidant defense gene polymorphisms with COPD in population from Russia.

Methods: Ten SNPs: NFE2L2 (rs35652124), KEAP1 (rs1048290), MPO (rs2333227), PRNP (rs1799990), PTGR1 (rs2273788), HSPA1A (rs1008438), TXNRD2 (rs1139793), GSR (rs1002149), SIRT2 (rs10410544), and PTGS1 (rs1330344) were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (425 COPD patients and 457 controls, from the same region of Russia, representatives of Tatar population). Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years.

The Results: In our population, a significant associations of KEAP1 (rs1048290) (P = 0.0015, OR = 0.72 in additive model), HSPA1A (rs1008438) (P = 0.006, OR = 2.26 in recessive model), GSR (rs1002149) (P = 0.037, OR = 1.31 in additive model) with COPD were revealed. NFE2L2 (rs35652124), PRNP (rs1799990), and HSPA1A (rs1008438) were significantly associated with COPD only in smokers. In nonsmokers, significant association was established for GSR (rs1002149). KEAP1 (rs1048290) was associated with COPD in both groups. The relationship between KEAP1 (rs1048290), NFE2L2 (rs35652124), and HSPA1A (rs1008438) and smoking pack-years was found (P = 0.005, P = 0.0028, P = 0.015). A significant genotype-dependent variation of forced vital capacity and forced expiratory volume in 1 s was observed for SIRT2 (rs10410544) (P = 0.04), NFE2L2 (rs35652124) (P = 0.028), and PRNP (rs1799990) (P = 0.044).
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http://dx.doi.org/10.1016/j.gene.2018.12.061DOI Listing
April 2019

Infliximab ameliorates tumor necrosis factor-alpha-induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro.

Scand J Immunol 2018 Nov 10;88(5):e12716. Epub 2018 Oct 10.

Laboratory for Proteomics and Metabolomics, Research Division, General Hospital of Mexico "Dr. Eduardo Liceaga", Mexico City, Mexico.

Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L 2-deoxy-D-glucose- H and stimulated twice with 2 μmol L insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients.
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http://dx.doi.org/10.1111/sji.12716DOI Listing
November 2018

A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability.

Am J Med Genet A 2018 11 23;176(11):2395-2403. Epub 2018 Sep 23.

Laboratory of Cytogenetics, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia.

The application of array-based comparative genomic hybridization and next-generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation.
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http://dx.doi.org/10.1002/ajmg.a.40478DOI Listing
November 2018

Monocytes and Macrophages as Viral Targets and Reservoirs.

Int J Mol Sci 2018 Sep 18;19(9). Epub 2018 Sep 18.

Department of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.

Viruses manipulate cell biology to utilize monocytes/macrophages as vessels for dissemination, long-term persistence within tissues and virus replication. Viruses enter cells through endocytosis, phagocytosis, macropinocytosis or membrane fusion. These processes play important roles in the mechanisms contributing to the pathogenesis of these agents and in establishing viral genome persistence and latency. Upon viral infection, monocytes respond with an elevated expression of proinflammatory signalling molecules and antiviral responses, as is shown in the case of the influenza, Chikungunya, human herpes and Zika viruses. Human immunodeficiency virus initiates acute inflammation on site during the early stages of infection but there is a shift of M1 to M2 at the later stages of infection. Cytomegalovirus creates a balance between pro- and anti-inflammatory processes by inducing a specific phenotype within the M1/M2 continuum. Despite facilitating inflammation, infected macrophages generally display abolished apoptosis and restricted cytopathic effect, which sustains the virus production. The majority of viruses discussed in this review employ monocytes/macrophages as a repository but certain viruses use these cells for productive replication. This review focuses on viral adaptations to enter monocytes/macrophages, immune escape, reprogramming of infected cells and the response of the host cells.
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http://dx.doi.org/10.3390/ijms19092821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163364PMC
September 2018

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity.

J Clin Invest 2018 08 20;128(9):4057-4073. Epub 2018 Aug 20.

Department of Pathology and Molecular Medicine and.

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.
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http://dx.doi.org/10.1172/JCI96400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118640PMC
August 2018

Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy.

Oncoimmunology 2018;7(6):e1436922. Epub 2018 Mar 13.

Department of Innate Immunity and Tolerance, University of Heidelberg, Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Mannheim, Germany.

In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is a chitinase-like protein found in human and absent in rodents, and its expression in TAMs and role in breast cancer progression was not studied to date. Here for the first time we demonstrate that YKL-39 is expressed on TAMs, predominantly positive for stabilin-1, but not by malignant cells or other stromal cells in human breast cancer. TGF-beta in combination with IL-4, but not IL-4 alone was responsible of the stimulation of the production of YKL-39 in human primary macrophages. Mechanistically, stabilin-1 directly interacted with YKL-39 and acted as sorting receptor for targeting YKL-39 into the secretory pathway. Functionally, purified YKL-39 acted as a strong chemotactic factor for primary human monocytes, and induced angiogenesis in vitro. Elevated levels of YKL-39 expression in tumors after neoadjuvant chemotherapy (NAC) were predictive for increased risk of distant metastasis and for poor response to NAC in patients with nonspecific invasive breast carcinoma. Our findings suggest YKL-39 as a novel therapeutic target, and blocking of its activity can be combined with NAC in order to reduce the risk of metastasis in breast cancer patients.
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http://dx.doi.org/10.1080/2162402X.2018.1436922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980380PMC
March 2018

Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy.

Cancer Chemother Pharmacol 2018 07 4;82(1):99-109. Epub 2018 May 4.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Pr. Lenina, 36, 634050, Tomsk, Russia.

Purpose: High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC.

Methods: Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed.

Results: We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39CCL18 or YKL-39CCL18) and only one patient had M2- macrophage phenotype (YKL-39CCL18). In DOX-Res group, out of 14 patients who clinically responded to NAC 9 patients had M2- phenotype and only 5 patients had M2+ macrophage phenotype. Among pathological non-responders in DOX-Sense group, 19 (82%) patients had M2+ tumor phenotype and only 4 (18%) patients had M2- phenotype. In DOX-Res group, all 5 patients who pathologically responded to NAC had M2 phenotype (YKL-39CCL18). Unlike the clinical response to NAC, the differences in the frequency of M2+ and M2- phenotypes between pathologically responding and non-responding patients within DOX-Sense and DOX-Res groups were statistically significant.

Conclusions: Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.
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http://dx.doi.org/10.1007/s00280-018-3594-8DOI Listing
July 2018

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant mice.

Oncoimmunology 2018;7(5):e1423168. Epub 2018 Feb 1.

Dept. of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

To identify novel hubs for cancer immunotherapy, we generated J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.
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http://dx.doi.org/10.1080/2162402X.2017.1423168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927516PMC
February 2018

The effect of neoadjuvant chemotherapy on the correlation of tumor-associated macrophages with CD31 and LYVE-1.

Immunobiology 2018 Jun - Jul;223(6-7):449-459. Epub 2017 Oct 31.

Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050, Tomsk, Russia; Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany; German Red Cross Blood Service Baden-Württemberg - Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany. Electronic address:

Angiogenesis and lymphangiogenesis play a crucial role in tumor growth, invasion and metastasis. Tumor-associated macrophages (TAM) induce both angiogenesis and lymphangiogenesis in mouse breast cancer models and positively correlate with these processes in human breast cancer patients. Neoadjuvant chemotherapy (NAC) is a widely used therapeutic option for cancer treatment. However, the effect of NAC on the distribution of TAM within intratumoral compartments and their correlation with angiogenesis and lymphangiogenesis remained unknown. In the present study we analyzed the effect of NAC on the distribution of CD68+ and stabilin-1+ TAM in five functionally distinct areas of human breast cancer and their correlations with microvessel density (MVD) and lymphatic microvessel density (LMVD), identified by CD31 and LYVE1, respectively. We found that NAC enhances blood vessel density in soft fibrous stroma and in coarse fibrous stroma. Without NAC the amount of CD68+ TAM in gaps of ductal tumor structures positively correlate with CD31+ microvessel density in soft fibrous stroma. NAC had enhancing effect on the amount of CD68+ TAM but not stabilin-1+ TAM in soft fibrous stroma. However, no correlation between TAM and CD31+ microvessel density was identified after NAC. NAC did not enhance the lymphatic microvessel density. But after NAC stabilin-1 expressing subpopulation of TAM positively correlated with expression of LYVE-1. We hypothesized that CD68+ TAM can support tumor angiogenesis primarily before NAC, while stabilin-1+ TAM can contribute to the maintenance of lymphatic microvessel density after NAC.
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http://dx.doi.org/10.1016/j.imbio.2017.10.050DOI Listing
April 2019

Editorial: Targeting of Cancer Cells and Tumor Microenvironment: Perspectives for Personalized Therapy.

Curr Pharm Des 2017 ;23(32):4703-4704

Tomsk State University and Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk. Russian Federation.

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http://dx.doi.org/10.2174/138161282332171221165319DOI Listing
March 2019

Predictive value of vascular endothelial growth factor receptor type 2 in triple-negative breast cancer patients treated with neoadjuvant chemotherapy.

Mol Cell Biochem 2018 Jul 11;444(1-2):197-206. Epub 2017 Dec 11.

Department of Molecular Oncology and Immunology, Federal State Budgetary Scientific Institution "Саncеr Research Institute", Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk, 634050, Russian Federation.

The identification of informative biomarkers that could predict the treatment response is particularly important in the triple-negative (TN) breast cancer, which is characterized by biological diversity. The aim of this study was to investigate the impact of vascular endothelial growth factor receptor (VEGFR2) expression and its gene polymorphisms on pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in Russian patients with TN breast cancer. We performed a retrospective analysis of 70 women with operable TN breast cancer, who underwent NCT with 5-fluorouracil, adriamycin, and cyclophosphamide (FAC) or cyclophosphamide, adriamycin, and capecitabine (CAX) between 2007 and 2013. VEGFR2 expression was evaluated before NCT by immunohistochemistry. TaqMan SNP assays were used for genotyping KDR - 604T>C (rs2071559) and KDR 1192G>A (rs2305948) polymorphisms. The pCR was used as an end-point in the treatment efficacy analysis. In the univariate analysis, the pCR rate was strongly associated with young age (P = 0.004), high Ki67 expression (P = 0.012), lymph node negativity (P = 0.023) as well as with positive VEGFR2 expression (P = 0.019) and the CAX regimen (P = 0.005). In the multivariate analysis, only patient's age (P = 0.005) and pre-NCT VEGFR2 expression (P = 0.048) remained significant predictors of pCR. The pCR rate was higher in the CAX-treated patients than that in the FAC-treated patients (P = 0.005). Our results revealed that - 604TT genotype of rs2071559 and age < 50 years were correlated with a pCR in the CAX-treated patients. VEGFR2 expression in pre-NCT tumors and KDR gene polymorphism can be considered as additional predictive molecular markers of pCR in Russian TN breast cancer patients treated with NCT.
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http://dx.doi.org/10.1007/s11010-017-3244-1DOI Listing
July 2018

IL-4 driven transcription factor FoxQ1 is expressed by monocytes in atopic dermatitis and stimulates monocyte migration.

Sci Rep 2017 12 4;7(1):16847. Epub 2017 Dec 4.

Department of Dermatology, Venerology and Allergology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Monocytes are actively recruited at sites of chronic inflammation. However, molecular factors involved in this process are not fully elucidated. Here, we show that cytokine IL-4 which is implicated in the development of chronic inflammatory disease atopic dermatitis (AD) induces expression of transcription factor FoxQ1 in human monocytes and macrophages. FoxQ1 mRNA levels were elevated in monocytes of AD patients compared to healthy donors. Overexpression of FoxQ1 in RAW 264.7 monocytic cells facilitated their migration towards MCP-1 and was associated with decreased expression of migration-regulating genes (claudin 11 and plexin C1). Furthermore, FoxQ1 overexpression in RAW cells accelerated TNFα secretion after LPS challenge. Overall, our results indicate that FoxQ1 stimulates monocyte motility, increases pro-inflammatory potential, and directs monocyte migration towards MCP-1 that is crucial for monocyte influx into inflammatory sites. This mechanism could contribute to the pathogenesis of chronic inflammatory disorders such as AD.
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http://dx.doi.org/10.1038/s41598-017-17307-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715145PMC
December 2017

Cardiac CD68+ and stabilin-1+ macrophages in wound healing following myocardial infarction: From experiment to clinic.

Immunobiology 2018 Apr - May;223(4-5):413-421. Epub 2017 Nov 22.

Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 111a Kievskaya Street, Tomsk, 634012, Russian Federation; Siberian State Medical University, 2 Moskovsky Trakt, Tomsk, 634055, Russian Federation. Electronic address:

Myocardial infarction (MI) remains the leading cause of mortality and morbidity throughout the world. Macrophages are key innate immune cells that play a significant role in transition from the inflammatory to the regenerative phase during wound healing following MI. The scavenger receptor stabilin-1 is one of the most interesting macrophage biomarkers. This receptor contributes to wound healing, angiogenesis, and tissue remodeling. We suggested a research protocol using macrophage biomarkers to study the cellular basis of cardiac remodeling and healing in patients with acute MI. The purpose of the research was to translate experimental knowledge regarding macrophage subsets and their biomarkers in post-infarction myocardial regeneration into results observed in clinical settings. The study included 41 patients with fatal MI type 1. All patients were divided into four groups according to the timeline of MI histopathology. In addition to routine histopathological analysis, macrophage infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage and stabilin-1 as an M2-like macrophage biomarker. The number of CD68+ and stabilin-1+ macrophages in the infarct area increased and peaked in the regenerative phase and did not decrease in the late stage of MI. In the peri-infarct area, the number of CD68+ macrophages increased in the inflammatory phase, peaked during the reparative phase, and did not decrease in the late phase, while the number of stabilin-1+ macrophages increased in the regenerative phase and remained unchanged. Additionally, in the reparative phase, we observed increase in the number of CD68+ and stabilin-1+ macrophages in the non-infarct area. The research protocol suggested allowed us to translate experimental knowledge regarding macrophage subsets and their biomarkers in post-infarction myocardial regeneration into clinical data. Taken together, these results demonstrated biphasic cardiac macrophage response following acute MI somewhat similar to that in a murine model. The increase in stabilin-1+ macrophage infiltration noticed in the myocardium during the regenerative phase and the strong positive correlation between the number of these cells and timeline of MI histopathology enabled us to propose stabilin-1 as a diagnostic macrophage biomarker in myocardium wound healing in patients with acute MI.
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http://dx.doi.org/10.1016/j.imbio.2017.11.006DOI Listing
February 2019

Review: the potential impact of surface crystalline states of titanium for biomedical applications.

Crit Rev Biotechnol 2018 May 7;38(3):423-437. Epub 2017 Sep 7.

a Fundamental Research Unit , Protip Medical , Strasbourg , France.

In many biomedical applications, titanium forms an interface with tissues, which is crucial to ensure its long-term stability and safety. In order to exert control over this process, titanium implants have been treated with various methods that induce physicochemical changes at nano and microscales. In the past 20 years, most of the studies have been conducted to see the effect of topographical and physicochemical changes of titanium surface after surface treatments on cells behavior and bacteria adhesion. In this review, we will first briefly present some of these surface treatments either chemical or physical and we explain the biological responses to titanium with a specific focus on adverse immune reactions. More recently, a new trend has emerged in titanium surface science with a focus on the crystalline phase of titanium dioxide and the associated biological responses. In these recent studies, rutile and anatase are the major two polymorphs used for biomedical applications. In the second part of this review, we consider this emerging topic of the control of the crystalline phase of titanium and discuss its potential biological impacts. More in-depth analysis of treatment-related surface crystalline changes can significantly improve the control over titanium/host tissue interface and can result in considerable decreases in implant-related complications, which is currently a big burden on the healthcare system.
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http://dx.doi.org/10.1080/07388551.2017.1363707DOI Listing
May 2018

Corrigendum to 'Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose' [Immunol. Lett. 176 (2016) 81-89].

Immunol Lett 2017 12 18;192:106. Epub 2017 Aug 18.

Laboratory of Liver, Pancreas and Motility, Unit of Experimental Medicine, School of Medicine, National Autonomous University of Mexico, General Hospital of Mexico, 06726 Mexico City, Mexico. Electronic address:

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http://dx.doi.org/10.1016/j.imlet.2017.08.013DOI Listing
December 2017

Role of the Immune Component of Tumor Microenvironment in the Efficiency of Cancer Treatment: Perspectives for the Personalized Therapy.

Curr Pharm Des 2017 ;23(32):4807-4826

Laboratory for translational cellular and molecular biomedicine, Tomsk State University, Tomsk. Russian Federation.

Despite significant progress in cancer diagnostics and development of novel therapeutic regimens, successful treatment of advanced forms of cancer is still a challenge and may require personalized therapeutic approaches. In this review, we analyzed major mechanisms responsible for tumor cells chemoresistance and emphasized that intratumor heterogeneity is a critical factor that limits efficiency of cancer treatment. Intratumor heterogeneity is caused by genomic instability in cancer cells, resulting in the selection of resistant clones. Moreover, cancer cells in solid tumors are surrounded by cellular and molecular microenvironment that actively influences tumor cell behavior. Local tumor microenvironment (TME) consisting of immune cells with diverse phenotypes and functions strongly contributes to intratumor heterogeneity and modulates responses to treatment. Thus, targeting specific components of TME is a novel treatment strategy that can improve the outcome of conventional anti-cancer therapy. Here, we discuss modern immunotherapeutic approaches based on targeting tumorinfiltrating immune cells including neutrophils, dendritic cells, NK cells, T cells, B cells and macrophages. Among those, tumor-associated macrophages (TAM) that display a pronounced heterogeneity and phenotypic plasticity appear to be a major component in the TME of solid tumors, and emerge as perspective targets for cancer immunotherapy. TAM intratumor heterogeneity and the possible existence of patient-specific phenotype signature generate the basis for the development of individualized TAM-based therapeutic approaches.
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http://dx.doi.org/10.2174/1381612823666170714161703DOI Listing
March 2019

Development of Novel Monoclonal Antibodies for Evaluation of Transmembrane Prostate Androgen-Induced Protein 1 (TMEPAI) Expression Patterns in Gastric Cancer.

Pathol Oncol Res 2018 Apr 5;24(2):427-438. Epub 2017 Jun 5.

Department of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, Russian Federation, 634050.

Transmembrane prostate androgen-induced protein 1 (TMEPAI) is a single-span membrane protein, functionally involved in transforming growth factor beta signaling pathway. The particular protein presented in cells in three isoforms, which differs in the length of the soluble N-terminal extracellular domain, making it challenging for the immunochemical recognition. By using quantitative real-time polymerase chain reaction, we identified significant upregulation of PMEPA1 gene expression in malignant tissues of patients with gastric adenocarcinoma. The main part of commercially available anti-TMEPAI antibodies are having polyclonal nature or not suitable for immunocytochemical localization of target protein in tissue specimens. Hence, we decide to generate a set of novel rat monoclonal antibodies (mAb) directed against conservative C-terminal cytoplasmic epitope. Immunoblotting analysis showed that monoclonal antibodies, 2E1, 6C6, and 10A7 were able to recognize specifically target protein in transiently transfected HEK293T and CHO-K1 cells. Especially established mAb, named 10A7, showed the excellent binding ability to target protein in immunohistochemistry. By using developed antibodies, we observed pronounced expression of TMEPAI in normal gastric epithelial cells while tumor cells from gastric adenomas, and adenocarcinoma samples were mostly negative for target protein expression. Also, we found that gastric epithelium cells lose the TMEPAI expression concurrently with severe dysplasia progression, which probably caused by a mechanism involving specific microRNA.
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http://dx.doi.org/10.1007/s12253-017-0247-xDOI Listing
April 2018

Macrophage activation and polarization in post-infarction cardiac remodeling.

J Biomed Sci 2017 Feb 7;24(1):13. Epub 2017 Feb 7.

Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation.

Adverse cardiac remodeling leads to impaired ventricular function and heart failure, remaining a major cause of mortality and morbidity in patients with acute myocardial infarction. It have been shown that, even if all the recommended therapies for ST-segment elevation myocardial infarction are performed, one third of patients undergoes progressive cardiac remodeling that represents morphological basis for following heart failure. The need to extend our knowledge about factors leading to different clinical scenarios of myocardial infarction and following complications has resulted in a research of immuno-inflammatory pathways and molecular activities as the basis for post-infarction remodeling. Recently, macrophages (cells of the innate immune system) have become a subject of scientific interest under both normal and pathological conditions. Macrophages, besides their role in host protection and tissue homeostasis, play an important role in pathophysiological processes induced by myocardial infarction. In this article we summarize data about the function of monocytes and macrophages plasticity in myocardial infarction and outline potential role of these cells as effective targets to control processes of inflammation, cardiac remodeling and healing following acute coronary event.
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http://dx.doi.org/10.1186/s12929-017-0322-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297120PMC
February 2017

NMDA receptor subunit composition controls dendritogenesis of hippocampal neurons through CAMKII, CREB-P, and H3K27ac.

J Cell Physiol 2017 Dec 11;232(12):3677-3692. Epub 2017 May 11.

Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.

Dendrite arbor growth, or dendritogenesis, is choreographed by a diverse set of cues, including the NMDA receptor (NMDAR) subunits NR2A and NR2B. While NR1NR2B receptors are predominantly expressed in immature neurons and promote plasticity, NR1NR2A receptors are mainly expressed in mature neurons and induce circuit stability. How the different subunits regulate these processes is unclear, but this is likely related to the presence of their distinct C-terminal sequences that couple different signaling proteins. Calcium-calmodulin-dependent protein kinase II (CaMKII) is an interesting candidate as this protein can be activated by calcium influx through NMDARs. CaMKII triggers a series of biochemical signaling cascades, involving the phosphorylation of diverse targets. Among them, the activation of cAMP response element-binding protein (CREB-P) pathway triggers a plasticity-specific transcriptional program through unknown epigenetic mechanisms. Here, we found that dendritogenesis in hippocampal neurons is impaired by several well-characterized constructs (i.e., NR2B-RS/QD) and peptides (i.e., tatCN21) that specifically interfere with the recruitment and interaction of CaMKII with the NR2B C-terminal domain. Interestingly, we found that transduction of NR2AΔIN, a mutant NR2A construct with increased interaction to CaMKII, reactivates dendritogenesis in mature hippocampal neurons in vitro and in vivo. To gain insights into the signaling and epigenetic mechanisms underlying NMDAR-mediated dendritogenesis, we used immunofluorescence staining to detect CREB-P and acetylated lysine 27 of histone H3 (H3K27ac), an activation-associated histone tail mark. In contrast to control mature neurons, our data shows that activation of the NMDAR/CaMKII/ERK-P/CREB-P signaling axis in neurons expressing NR2AΔIN is not correlated with increased nuclear H3K27ac levels.
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http://dx.doi.org/10.1002/jcp.25843DOI Listing
December 2017