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1.  Serum Angiogenesis Markers and Their Correlation with Ultrasound-Detected Synovitis in Juvenile Idiopathic Arthritis 
Journal of Immunology Research  2015;2015:741457.
Synovial angiogenesis is considered to be an important early step in the pathogenesis of juvenile idiopathic arthritis (JIA). In this study we assessed levels of angiogenic markers in serum or synovial fluid and their possible relevance to disease activity or degree of ultrasound signs of synovial inflammation and angiogenesis in early JIA. The concentration of vascular endothelial growth factor (VEGF), its soluble receptors 1 and 2 (sVEGF-R1, sVEGF-R2), and angiopoietins 1 and 2 (ANG-1, ANG-2) were evaluated in 43 JIA patients and 23 healthy controls. Synovial angiogenesis was assessed by means of Power-Doppler Ultrasonography (PDUS), according to the fourth-grade vascularity scale. VEGF and its receptors' (sVEGF-R1, sVEGF-R2) serum levels were significantly higher in JIA patients (p = 0.002). We found large variation in serum ANG-1 and ANG-2 levels. The PDUS imaging identified increased synovial microvascular blood flow in 15 (35.7%) examined JIA children. Intensity of joint vascularization correlated with higher serum VEGF and its levels was lowest in grade 0 and highest in grade 3 (p < 0.007 and p < 0.001, resp.). In conclusion, the high correlation between synovial microvascular blood flow, serum angiogenic proteins, and symptoms of synovitis may indicate its important role in pathogenesis of JIA.
PMCID: PMC4434192  PMID: 26065004
2.  The Role of Radiotherapy in Hodgkin's Lymphoma: What Has Been Achieved during the Last 50 Years? 
BioMed Research International  2015;2015:485071.
Currently, Hodgkin's lymphoma (HL) has an excellent clinical outcome, with overall survival of approximately 90% in early stages of the disease. Based on young age of the majority of patients at the time of diagnosis and their long survival time, increased attention has been focused on long-term toxicity of therapy. While novel, directly targeting antitumor agents, with an excellent safety profile, have been developed for HL treatment, the role of radiotherapy is still debated. Radiotherapy may induce cardiovascular disease and impairment of thyroid or pulmonary function and, most importantly, may lead to development of secondary cancers. As a consequence, the current radiation therapy planning paradigm is mainly focused on a reduction of field size. As it was investigated in clinical trials regional therapy is as effective as extended field radiotherapy, but less toxic. Although chemotherapy is the mainstay of HL treatment, consolidative involved field radiation therapy is still considered to be the standard of care in both early and advanced stages. Recently, further field reduction has been investigated to further decrease the late radiation-induced toxicity. In this paper we describe the role and safety profile of radiotherapy in the past and present and hope for the novel techniques in the future.
PMCID: PMC4331316  PMID: 25705661
3.  Angiopoietins in haematopoietic stem cell mobilisation in patients with haematological malignancies 
Blood Transfusion  2015;13(1):102-108.
The bone marrow niche contains different types of cells including osteoblasts and endothelial progenitors, all of which interact and take part in the process of mobilisation. The aim of our study was to evaluate the levels of cytokines (osteopontin and angiopoietins 1 and 2) active in the bone marrow niche during the mobilisation of haematopoietic stem cells for autologous transplantation.
Materials and methods
Forty-eight patients (24 females, 24 males), median age 56.5 years, entered the study. The group consisted of patients with multiple myeloma (n=34), lymphoma (n=13) and acute myeloid leukaemia (n=1). Blood samples were collected before chemotherapy and on the day of the first apheresis. Cytokines were evaluated by enzyme-linked immunosorbent assays. Additionally, circulating endothelial cells were assessed by flow cytometry.
The median concentration of angiopoietin 1 at the time of apheresis was lower than that at baseline (2.7 vs 7.8 ng/mL, p<0.001). In contrast, the median level of angiopoietin 2 increased during the mobilisation procedure (3.6 vs 2.8 ng/mL, p=0.001). The patients were divided according to the number of days of granulocyte colony-stimulating factor treatment before the first apheresis into “early” (median) mobilisers. The group of “early mobilisers” had higher baseline angiopoietin 1 levels (median=11.6 ng/mL) than those of the “late mobilisers” (median=6.0 ng/mL, p=0.05). An adverse correlation was observed between duration of granulocyte colony-stimulating factor treatment and baseline angiopoietin 1 level. Baseline angiopoietin 1 levels correlated with numbers of circulating endothelial cells. Low angiopoietin 2 level increased the chance of poor mobilisation.
The angiogenic processes can influence the timing of mobilisation. Angiopoietins 1 and 2 need further evaluation in the context of mobilisation.
PMCID: PMC4317096  PMID: 25369606
angiopoietin; osteopontin; mobilisation of haematopoietic stem cells
4.  Expression of Toll-Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus 
Mediators of Inflammation  2014;2014:381418.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. The results of experimental studies point to the involvement of innate immunity receptors—toll-like receptors (TLR)—in the pathogenesis of the disease. The aim of the study was to assess the expression of TLR3, 7, and 9 in the population of peripheral blood mononuclear cells (PBMC) and in B lymphocytes (CD19+), T lymphocytes (CD4+ and CD8+) using flow cytometry. The study group included 35 patients with SLE and 15 healthy controls. The patient group presented a significantly higher percentage of TLR3- and TLR9-positive cells among all PBMCs and their subpopulations (CD3+, CD4+, CD8+, and CD19+ lymphocytes) as well as TLR7 in CD19+ B-lymphocytes, compared to the control group. There was no correlation between the expression of all studied TLRs and the disease activity according to the SLAM scale, and the degree of organ damage according to the SLICC/ACR Damage Index. However, a correlation was observed between the percentage of various TLR-positive cells and some clinical (joint lesions) and laboratory (lymphopenia, hypogammaglobulinemia, anaemia, and higher ESR) features and menopause in women. The results of the study suggest that TLR3, 7, and 9 play a role in the pathogenesis of SLE and have an impact on organ involvement in SLE.
PMCID: PMC3955595  PMID: 24692849
5.  Imbalance of Th17 and T-regulatory cells in peripheral blood and synovial fluid in treatment naïve children with juvenile idiopathic arthritis 
The imbalance between Th17 and T regulatory cells (Tregs) may be a key event in development of autoimmunity. The problem is poorly explored in juvenile idiopathic arthritis (JIA) so far. In this study, peripheral blood (PB) and synovial fluid (SF) Tregs and Th17 cells from were assessed in untreated JIA children.
Material and methods
In 50 children with JIA the PB or SF percentages of Tregs and Th17 cells were assessed by flow cytometry, in comparison with PB Tregs and Th17 cells from 28 healthy controls. Additionally, in both groups the levels of proinfammatory cytokines, such as interleukin (IL)-1β, IL -6, IL -17, IL -21, IL -23 and tumor necrosis factor α (TN F-α) were assessed using ELI SA method.
The proportion of JIA PB Th17 cells was significantly higher than in the controls (p = 0.01). Serum levels of IL -1β, IL -6, IL -17, IL -23 were also significantly higher in JIA (p = 0.011, p = 0.007, p = 0.008 and p = 0.023, respectively). The highest serum IL -6 levels were observed in oligoarthritis JIA (p = 0.031). Synovial fluid IL -21 concentration was distinctly higher in polyarticular JIA. Synovial fluid levels of TN F-α, IL -1β and IL -6 were significantly higher than in JIA PB (p = 0.038, p = 0.013 and p < 0.001, respectively). There was a significant correlation between IL -6 and PB Tregs (p = 0.02).
The results of this comprehensive analysis indicate a role of Th17 cell activation in the pathogenesis of JIA.
PMCID: PMC4439971  PMID: 26155103
juvenile idiopathic arthritis; Th17 cells; T-regulatory cells; proinflammatory cytokines
6.  New Insights into Biology, Prognostic Factors, and Current Therapeutic Strategies in Chronic Lymphocytic Leukemia 
ISRN Oncology  2013;2013:740615.
Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values seem to be the most biologically relevant. During the last decades, the treatment of CLL has been significantly changed. Different strategies such as monotherapy with chlorambucil and purine nucleoside analogues (PNA) used alone or in combination with cyclophosphamide have been introduced. Most recently, immunochemotherapy with anti-CD20 monoclonal antibody, rituximab, combined with fludarabine and cyclophosphamide, became a gold standard of first-line treatment in eligible CLL patients. Currently, new treatment strategies including new monoclonal antibodies, bendamustine, lenalidomide, or inhibitors of several cell signaling pathways are under clinical studies in resistant/relapsed CLL patients. Moreover, allogeneic stem cell transplantation has to be considered, especially in younger high risk patients, for example, those who are resistant to PNA or those with 17p deletion. In this paper, we present the most important recent advances in CLL biology and treatment.
PMCID: PMC3763269  PMID: 24027642
7.  Helicobacter pylori Infection, Chronic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma 
Mediators of Inflammation  2013;2013:523170.
Nowadays, it is believed that the main role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma plays Helicobacter pylori infection. This world-wide distributed bacteria is in charge of most cases of not only upper gastrointestinal tract disorders but also some of extragastric problems. Constant stimulation of the immune system causes a B-lymphocytes proliferation, which is considered to be responsible for the neoplastic transformation. On the other hand, there are 10%–20% of patients who do not respond to Helicobacter pylori eradication treatment. This group has often a chromosome translocation, which suggests that there is another unknown, so far, pathogenetic mechanism of MALT lymphoma. Majority of genetic abnormalities are connected with nuclear factor-κB (NF-κB) pathway, which activates the uncontrolled proliferation of neoplastic cells. Translocations already described in studies are t(11;18)(q21;q21), which is the most common, t(14;18)(q32;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). This non-Hodgkin's lymphoma is an indolent type originated outside lymph nodes. In more than 50% of cases, it occurs in the stomach. Occasionally, it can be found in salivary and thyroid gland, lung, breast, bladder, skin, or any other place in the human body. This paper is a review of the current knowledge on etiology, pathogenesis, treatment, and follow-up of gastric MALT lymphoma.
PMCID: PMC3625579  PMID: 23606792
8.  Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy 
Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p = <0.05 and p < 0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p = 0.02 and p = 0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET.
PMCID: PMC3466431  PMID: 22418850
Essential thrombocythemia; Apoptosis; Anagrelide; Hydroxyurea; JAK2V617F mutation
9.  Laser scanning cytometry for automation of the micronucleus assay 
Mutagenesis  2011;26(1):153-161.
Laser scanning cytometry (LSC) provides a novel approach for automated scoring of micronuclei (MN) in different types of mammalian cells, serving as a biomarker of genotoxicity and mutagenicity. In this review, we discuss the advances to date in measuring MN in cell lines, buccal cells and erythrocytes, describe the advantages and outline potential challenges of this distinctive approach of analysis of nuclear anomalies. The use of multiple laser wavelengths in LSC and the high dynamic range of fluorescence and absorption detection allow simultaneous measurement of multiple cellular and nuclear features such as cytoplasmic area, nuclear area, DNA content and density of nuclei and MN, protein content and density of cytoplasm as well as other features using molecular probes. This high-content analysis approach allows the cells of interest to be identified (e.g. binucleated cells in cytokinesis-blocked cultures) and MN scored specifically in them. MN assays in cell lines (e.g. the CHO cell MN assay) using LSC are increasingly used in routine toxicology screening. More high-content MN assays and the expansion of MN analysis by LSC to other models (i.e. exfoliated cells, dermal cell models, etc.) hold great promise for robust and exciting developments in MN assay automation as a high-content high-throughput analysis procedure.
PMCID: PMC3107611  PMID: 21164197

Results 1-9 (9)