Browsing by Author "Jurisic, Vladimir (6603015144)"

Gelatinase A (MMP-2) and gelatinase B (MMP-9) are proteolytic enzymes involved in the process of tumor invasion, and they are considered as possible tumor markers in breast cancer patients. In this study, we examined serum activity of proMMP-2 and proMMP-9 in relation to TNM stage, tumor size, lymph node involvement, grade of differentiation of tumors, as well as steroid and Her2/neu receptor status in breast cancer patients. The activity of gelatinase in the sera of 52 patients was analyzed by SDS-PAGE zymography. The activity of proMMP-2 and proMMP-9 significantly increased with each advancing clinical stage of disease (p=0.02-0.0009) and compared to controls (p=0.015 to p<0.01). We found a positive correlation between the activity of proMMP-2 and proMMP-9 and tumor size (p=0.007; p=0.05). Patients with lymph node-positive cancer have higher proMMP-2 and proMMP-9 activity than those with node-negative cancer. ProMMP-2 and proMMP-9 activity is not associated with the expression of Her2/neu receptors, but patients with Her2/neu overexpression (3+) showed increased proMMP-2 activity. Steroid receptor score is not associated with enhanced gelatinase activity. The relationship between the increase in proMMP-2 and proMMP-9 activity in serum and tumor size and lymph node status suggests the usefulness of these enzymes as staging markers of breast cancer patients. © 2009 Elsevier GmbH.

Gelatinase A (MMP-2) and gelatinase B (MMP-9) are proteolytic enzymes involved in the process of tumor invasion, and they are considered as possible tumor markers in breast cancer patients. In this study, we examined serum activity of proMMP-2 and proMMP-9 in relation to TNM stage, tumor size, lymph node involvement, grade of differentiation of tumors, as well as steroid and Her2/neu receptor status in breast cancer patients. The activity of gelatinase in the sera of 52 patients was analyzed by SDS-PAGE zymography. The activity of proMMP-2 and proMMP-9 significantly increased with each advancing clinical stage of disease (p=0.02-0.0009) and compared to controls (p=0.015 to p<0.01). We found a positive correlation between the activity of proMMP-2 and proMMP-9 and tumor size (p=0.007; p=0.05). Patients with lymph node-positive cancer have higher proMMP-2 and proMMP-9 activity than those with node-negative cancer. ProMMP-2 and proMMP-9 activity is not associated with the expression of Her2/neu receptors, but patients with Her2/neu overexpression (3+) showed increased proMMP-2 activity. Steroid receptor score is not associated with enhanced gelatinase activity. The relationship between the increase in proMMP-2 and proMMP-9 activity in serum and tumor size and lymph node status suggests the usefulness of these enzymes as staging markers of breast cancer patients. © 2009 Elsevier GmbH.

B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P < 0.01) and peripheral blood lymphocyte counts (P < 0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P < 0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P = 0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 × 109/l) and in the advanced stages of disease. © 2008 Humana Press Inc.

B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P < 0.01) and peripheral blood lymphocyte counts (P < 0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P < 0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P = 0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 × 109/l) and in the advanced stages of disease. © 2008 Humana Press Inc.

Retinoic acid (RA), similar to specific growth factors, can induce differentiation of proliferating promyelocytic precursors into terminally differentiated granulocytes, although little is known about effects of its 13-cis isomer on promyelocytic leukemia (PML). In this study we demonstrate that 13-cis-RA has a dose and time-dependant antiproliferative effect on HL-60 PML cell line, that it induces cell accumulation in resting G0/G1 phase of the cell cycle followed by an increase in CD11b granulocyte differentiation antigen expression. The obtained increase in the percentage of HL-60 cells in G0/G1 phase and complementary decrease in S phase of the cell cycle are accompanied by a decrease in the expression of cell cycle regulatory molecule cyclin B1. We also show the induction of interferon regulatory factor-1 (IRF-1) transcription that can, also, to some extent contribute to the antiproliferative effect of 13-cis-RA. Furthermore, down-regulation of Bcl-2 protein expression in 13-cis-RA treated HL-60 cells may contribute to sensitivity to apoptosis of growth arrested HL-60 promyelocytic cells. © 2010 Arányi Lajos Foundation.

Retinoic acid (RA), similar to specific growth factors, can induce differentiation of proliferating promyelocytic precursors into terminally differentiated granulocytes, although little is known about effects of its 13-cis isomer on promyelocytic leukemia (PML). In this study we demonstrate that 13-cis-RA has a dose and time-dependant antiproliferative effect on HL-60 PML cell line, that it induces cell accumulation in resting G0/G1 phase of the cell cycle followed by an increase in CD11b granulocyte differentiation antigen expression. The obtained increase in the percentage of HL-60 cells in G0/G1 phase and complementary decrease in S phase of the cell cycle are accompanied by a decrease in the expression of cell cycle regulatory molecule cyclin B1. We also show the induction of interferon regulatory factor-1 (IRF-1) transcription that can, also, to some extent contribute to the antiproliferative effect of 13-cis-RA. Furthermore, down-regulation of Bcl-2 protein expression in 13-cis-RA treated HL-60 cells may contribute to sensitivity to apoptosis of growth arrested HL-60 promyelocytic cells. © 2010 Arányi Lajos Foundation.

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-α (TNF-α). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-α and lactate dehydrogenase (LDH). Parathormone was not disturbed. © 2007 Elsevier GmbH. All rights reserved.

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-α (TNF-α). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-α and lactate dehydrogenase (LDH). Parathormone was not disturbed. © 2007 Elsevier GmbH. All rights reserved.

Purpose: Considering that cyclin D1 had a prognostic and clinical value for breast cancer patients, adequate measurement of cyclin D1 is necessary. Methods: In this investigation, we detect cyclin D1 expression in tumour and peritumoral tissue of breast cancer patients by Western blotting method and by immunohistochemistry. Results: Cyclin D1 expression decreased significantly with each advanced clinical stage of disease and tumour size. Also, patients without lymph node involvement, with positive hormone receptors and Luminal A type of tumours had significantly increased the expression of cyclin D1. We show that cyclin D1 expression correlates with longer RFS in the entire group of patients, in the group of ER-positive and in the group of HER2-negative patients. Patients who were both ER and cyclin D1 positive had a better prognosis. Conclusion: Taken together, our results showing correlation of cyclin D1 with clinical stage, tumour size and lymph nodes, suggest that cyclin D1 expression detected by Western blotting could be considered as an additional marker for the staging of breast cancer, as well as a marker for longer RFS and survival in ER-positive breast cancer patients. © 2021 Zerbinis Publications. All rights reserved.

Purpose: Considering that cyclin D1 had a prognostic and clinical value for breast cancer patients, adequate measurement of cyclin D1 is necessary. Methods: In this investigation, we detect cyclin D1 expression in tumour and peritumoral tissue of breast cancer patients by Western blotting method and by immunohistochemistry. Results: Cyclin D1 expression decreased significantly with each advanced clinical stage of disease and tumour size. Also, patients without lymph node involvement, with positive hormone receptors and Luminal A type of tumours had significantly increased the expression of cyclin D1. We show that cyclin D1 expression correlates with longer RFS in the entire group of patients, in the group of ER-positive and in the group of HER2-negative patients. Patients who were both ER and cyclin D1 positive had a better prognosis. Conclusion: Taken together, our results showing correlation of cyclin D1 with clinical stage, tumour size and lymph nodes, suggest that cyclin D1 expression detected by Western blotting could be considered as an additional marker for the staging of breast cancer, as well as a marker for longer RFS and survival in ER-positive breast cancer patients. © 2021 Zerbinis Publications. All rights reserved.

Dysregulation of apoptosis is a distinctive feature of chronic lymphocytic leukemia (CLL), although a unique mechanism underlying apoptosis resistance of CLL B lymphocytes has not been identified yet. Aberrant expression as well as genetic and epigenetic alterations of numerous genes involved in different pathways of apoptosis regulation has been described in CLL. Here, we report the expression analysis of Bcl2L12 (Bcl2-like 12), a novel apoptotic gene belonging to Bcl2 family, in 58 Serbian CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2L12 mRNA in CLL samples compared to non-leukemic samples, implying its role in the pathogenesis of the disease. Receiver operating characteristic (ROC) analysis showed that Bcl2L12 expression efficiently discriminates CLL cases from healthy controls. However, relatively homogenous Bcl2L12 mRNA expression among patients did not reflect their clinical characteristics (with the exception of lactate dehydrogenase status and time from diagnosis to treatment) and failed to show association with the most informative prognostic markers, namely the mutational status of rearranged immunoglobulin heavy chain variable region genes, CD38 and lipoprotein lipase gene (LPL) expression. © 2013 Springer Science+Business Media New York.

Dysregulation of apoptosis is a distinctive feature of chronic lymphocytic leukemia (CLL), although a unique mechanism underlying apoptosis resistance of CLL B lymphocytes has not been identified yet. Aberrant expression as well as genetic and epigenetic alterations of numerous genes involved in different pathways of apoptosis regulation has been described in CLL. Here, we report the expression analysis of Bcl2L12 (Bcl2-like 12), a novel apoptotic gene belonging to Bcl2 family, in 58 Serbian CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2L12 mRNA in CLL samples compared to non-leukemic samples, implying its role in the pathogenesis of the disease. Receiver operating characteristic (ROC) analysis showed that Bcl2L12 expression efficiently discriminates CLL cases from healthy controls. However, relatively homogenous Bcl2L12 mRNA expression among patients did not reflect their clinical characteristics (with the exception of lactate dehydrogenase status and time from diagnosis to treatment) and failed to show association with the most informative prognostic markers, namely the mutational status of rearranged immunoglobulin heavy chain variable region genes, CD38 and lipoprotein lipase gene (LPL) expression. © 2013 Springer Science+Business Media New York.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers represent a highly aggressive breast cancer subtype and are associated with a worse prognosis. This study was designed to investigate the mammography finding of HER2-positive breast cancer and to compare the results with the characteristics of HER2-negative breast cancer patients. From January 2010 to October 2011, mammography findings of 65 patients with pathologically confirmed HER2-positive breast cancers (n 5 22) or HER2-negative breast cancers (n 5 43) were retrospectively reviewed. The authors also reviewed pathological reports for information on the histological type and differentiation grade. Among the two types of breast cancer patients, estrogen receptornegative/PR-negative/HER2-positive breast cancer patients most commonly had associated calcifications (18 of 22) on mammography. On mammography, cases with a cluster of calcifications usually were presented as pleomorphic calcifications (12 of 20) and branching calcifications (4 of 20). Patients with HER2-positive breast cancers showed a histological grade II. HER2-positive breast cancer patients usually had ductal invasive carcinoma (17 of 22). Moreover, postmenopausal patients showed a significantly higher frequency of HER2-positive tumours. Our results suggest that the imaging findings might be useful in diagnosing HER2-positive breast cancer patients. © The Author 2014.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers represent a highly aggressive breast cancer subtype and are associated with a worse prognosis. This study was designed to investigate the mammography finding of HER2-positive breast cancer and to compare the results with the characteristics of HER2-negative breast cancer patients. From January 2010 to October 2011, mammography findings of 65 patients with pathologically confirmed HER2-positive breast cancers (n 5 22) or HER2-negative breast cancers (n 5 43) were retrospectively reviewed. The authors also reviewed pathological reports for information on the histological type and differentiation grade. Among the two types of breast cancer patients, estrogen receptornegative/PR-negative/HER2-positive breast cancer patients most commonly had associated calcifications (18 of 22) on mammography. On mammography, cases with a cluster of calcifications usually were presented as pleomorphic calcifications (12 of 20) and branching calcifications (4 of 20). Patients with HER2-positive breast cancers showed a histological grade II. HER2-positive breast cancer patients usually had ductal invasive carcinoma (17 of 22). Moreover, postmenopausal patients showed a significantly higher frequency of HER2-positive tumours. Our results suggest that the imaging findings might be useful in diagnosing HER2-positive breast cancer patients. © The Author 2014.

The neonatal type of coarctation is characterized by the presence of the ductal sling and coarctational shelf placed proximally in relation to the ductal orifice. Those morphological features are not described in detail yet from immunohistochemical and transmission electron microscopy (TEM) aspects, so the aim of this study was to investigate the smooth muscle cells (SMCs) phenotype in aortic intimal thickening, presence of inflammatory cells and contents of intimal and medial, and adventitial connective tissue. We examined samples of coarctation segments excised at surgery after end-to-end anastomosis from 30 patients, ages from 14 days to three months, histochemicaly, immunocytochemically and by TEM. In all samples, it is noticed focal intimal thickening on the posterior aortic wall, with accumulation of SMCs, which show immunoreactivity on alpha-smooth muscle actin (α-SMA) and vimentin (but not on desmin) and also expressed proliferating cell nuclear antigen (PCNA) and S-100 protein. At TEM analysis, those SMCs show a fibroblast-like morphology, so their functions could be to proliferate and secrete extracellular matrix (ECM) components (a synthetic phenotype). In all studied samples of the coarctation, on the posterior wall, the immunocytochemical and TEM examination revealed the presence of SMCs of the synthetic phenotype. Results also showed an increase of the cell number in intima of this part of aortic wall, followed by proliferated SMCs in inner media and absence of inflammatory cells. This finding suggests that proliferation of the SMCs, their synthetic activity and increase of the cell number could lead to formation of the intimal thickening on the posterior wall. © 2019, Editura Academiei Romane. All rights reserved.

The neonatal type of coarctation is characterized by the presence of the ductal sling and coarctational shelf placed proximally in relation to the ductal orifice. Those morphological features are not described in detail yet from immunohistochemical and transmission electron microscopy (TEM) aspects, so the aim of this study was to investigate the smooth muscle cells (SMCs) phenotype in aortic intimal thickening, presence of inflammatory cells and contents of intimal and medial, and adventitial connective tissue. We examined samples of coarctation segments excised at surgery after end-to-end anastomosis from 30 patients, ages from 14 days to three months, histochemicaly, immunocytochemically and by TEM. In all samples, it is noticed focal intimal thickening on the posterior aortic wall, with accumulation of SMCs, which show immunoreactivity on alpha-smooth muscle actin (α-SMA) and vimentin (but not on desmin) and also expressed proliferating cell nuclear antigen (PCNA) and S-100 protein. At TEM analysis, those SMCs show a fibroblast-like morphology, so their functions could be to proliferate and secrete extracellular matrix (ECM) components (a synthetic phenotype). In all studied samples of the coarctation, on the posterior wall, the immunocytochemical and TEM examination revealed the presence of SMCs of the synthetic phenotype. Results also showed an increase of the cell number in intima of this part of aortic wall, followed by proliferated SMCs in inner media and absence of inflammatory cells. This finding suggests that proliferation of the SMCs, their synthetic activity and increase of the cell number could lead to formation of the intimal thickening on the posterior wall. © 2019, Editura Academiei Romane. All rights reserved.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680,-675,-556,-464,-317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants. © 2019 Zerbinis Publications. All rights reserved.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680,-675,-556,-464,-317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants. © 2019 Zerbinis Publications. All rights reserved.

Renal dysfunction as a sequel to extended interferon alfa (IFNα) treatment in chronic myeloid leukaemia (CML) has been reported previously in six patients. An additional patient is presented with Philadelphia chromosome positive (Ph+) CML and nephrotic syndrome in whom initial renal insufficiency developed after only one month of low dose IFNα therapy. The renal biopsy showed a focal segmental mononuclear cell infiltration, basal membrane thickening, and deposits of immunoglobulins (IgG; IgAGM IC3). In spite of discontinuation of IFNα, renal function deteriorated and the patient died six months later. This case represents an instance of fatal kidney insufficiency as an untoward effect of sensitisation to the IFNα, confirmed by modified Coombs assay.

Malignant histiocytosis is a rare neoplasm of the reticuloendothelial system characterized by neoplastic proliferation of tissue histiocytes. We report a case of malignant histiocytosis in a 64-year-old female initially operated on for a mucinous cystadenoma of her liver. Four months after the operation, skin induration on the neck and anterior thoracic wall and systemic lymphadenopathy were noted. Histology and immunohistochemistry of the lymph node and bone marrow specimens showed extensive infiltration with atypical cells, resembling malignant histiocytes (CD45, CD45RO, CD11c, CD68, lysozyme, antitrypsin and α1-antichymotrypsin positive; CD1, CD35, B-cell and T-cells markers negative). She was treated with vinblastine, methotrexate and dexamethasone (3 cycles) without response. The therapy was switched to CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) with disappearance of lymphadenopathy. Bone marrow infiltration by histiocytes was reduced to 20%. Two months after completion of 8 cycles of CHOP she experienced severe headaches, vomiting, loss of consciousness, and developed paraparesis. A CT scan of the brain was normal but the cerebrospinal fluid cytology showed presence of histiocytes. The patient was then treated with intrathecal methotrexate, prednisolone and cytosine-arabinoside and systemic chemotherapy with etoposide and cyclophosphamide. Her condition improved, she became conscious, her headache diminished, she became mobile but skin and nodal lesions reappeared along with extensive marrow histiocytic infiltration. She finally died 22 months after diagnosis. © 2007 Zerbinis Medical Publications.