Browsing by Author "Perovic, Vladimir (57197980665)"

Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research. ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.

Background: Hereditary C1q deficiency is associated with early-onset autoimmunity causing SLE or SLE-like disease as well as increased risk for infections with encapsulated bacteria. It is a rare genetic condition inherited in an autosomal recessive manner, caused by mutations in C1q genes. Treatment and management of this rare disease are very complex and include prophylactic vaccination, antibiotics, and immunosuppressive drugs. There are two possible modalities for the replacement of the missing protein: regular fresh frozen plasma (FFP) administration and allogeneic hematopoietic stem cell transplant because the protein is derived from monocytes. Replacing C1q with FFP is being attempted in some patients with success in controlling the disease and in avoiding flare. Case Report: We report a case of sixteen-month-old girl with ulcerations in her mouth, skin erythema, and elevated liver enzymes. ANAs were positive, antibodies against dsDNA were negative, but she had positive anti-Smith antibodies. Complement complements C3 and C4 levels were normal. Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency. The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T). The initial response to corticosteroid therapy was good. Regular fresh frozen plasma infusions keep her disease under control, and we were able to reduce the dose of corticosteroids. Conclusion: Young patients with cutaneous lesions resembling SLE, early onset of autoimmunity, with normal C3, C4, elevated ANAs, and negative anti-dsDNA, C1q deficiency should be suspected and complement screening tests should be done. It is important to exclude secondary C1q deficiency. FFP in our patient seems to be well tolerated, without any side effects, able to control the disease. Copyright © 2021 Zecevic, Minic, Pasic, Perovic and Prohászka.

Background and Aims: Transplantation is the best treatment option for end stage kidney disease. The most common early complications in post-transplant period are acute rejection (AR) of the graft and delayed graft function (DGF). The underlying mechanisms in these events are heterogeneous and at least in part involve cytokine genes which regulate immune response to allograft. We have investigated whether functional single nucleotide polymorphisms (SNP) in the genes encoding IFN-γ (IFNG), TNF (TNFA), IL-10 (IL10) and p40 subunit of IL-12/IL-23 (IL12B) could predict risk of AR and DGF in kidney allograft recipients. Methods: Our study involved 152 kidney transplant recipients on standard immunosuppressive regimen which included calcineurin inhibitors, mycophenolic acid derivatives and corticosteroids. Genotyping of IFNG, TNFA, IL10 and IL12B was performed using commercial TaqMan assays. Results: We found association between the carriers of AA genotype of IL12B +1188A/C polymorphism (rs3212227) and a lower rate of DGF (p = 0.037, OR = 0.45, 95% CI = 0.21–0.96), implying protective role of A allele in the pathogenesis of DGF in kidney transplant recipients, whereas no such association was observed with AR. None of the analyzed SNPs in TNFA (−308G/A), IFNG (+874T/A), IL10 (−1082G/A, −819T/C, −592C/A) were associated with AR or DGF in our patients. Conclusions: Our study shows a preliminary evidence that the AA genotype of rs3212227 SNP in the IL12B gene might be associated with a lower risk for DGF after kidney transplantation. In the future, additional well-designed large studies are required for the validation of our results. © 2018 IMSS

Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (−308G/A), IFNG (+874 T/A), IL10 (−1082G/A, −819T/C and −592A/C), and IL6 (−174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p = 0.006; OR = 2.27; 95%CI = 1.24-4.17 and p = 0.038, OR = 15.64; 95%CI = 1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p = 0.019, OR = 0.43, 95%CI = 0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p = 0.037, OR = 1.78, 95% CI = 1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p = 0.032; OR = 2.86; 95% CI = 1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms −308 G/A TNF and −174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings. © 2016 European Federation of Immunological Societies

Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (−308G/A), IFNG (+874 T/A), IL10 (−1082G/A, −819T/C and −592A/C), and IL6 (−174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p = 0.006; OR = 2.27; 95%CI = 1.24-4.17 and p = 0.038, OR = 15.64; 95%CI = 1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p = 0.019, OR = 0.43, 95%CI = 0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p = 0.037, OR = 1.78, 95% CI = 1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p = 0.032; OR = 2.86; 95% CI = 1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms −308 G/A TNF and −174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings. © 2016 European Federation of Immunological Societies

Objective: This study was aimed at analyzing alterations in K-ras gene and SMAD4 gene promoter in endometrial carcinoma tissue in Serbian patients. Methods/Materials: The study has encompassed 36 patients whose endometrial cancer tissue samples and peripheral blood samples were analyzed for the presence of alterations in the K-ras gene and the SMAD4 gene promoter. The detection of K-ras codon 12 mutation was performed by polymerase chain reaction restriction fragment length polymorphism technique. Analysis of mononucleotide repeat variants at -462T(15) and -4T(12) of the SMAD4 gene promoter was performed by capillary electrophoresis analysis of DNA fragments fluorescently labeled by polymerase chain reaction. Results: Mutation in codon 12 of the K-ras gene was detected with relatively high frequency of 75.0% (27 of 36 cases). Analysis of 2 mononucleotide repeats in the SMAD4 gene promoter showed that in most cases, haplotypes -462T(15)/-4T(12) and -462T(16)/-4T(12) were present; whereas in one case, a novel haplotype -462T(15)/-4T(10) was detected. Conclusions: Findings on the role and potential significance of the K-ras codon 12 mutation and SMAD4 gene promoter variants in patients with endometrial carcinoma remain controversial, and their occurrence in this type of cancer should be further investigated. Copyright © 2012 by IGCS and ESGO.

[No abstract available]

Complement plays a central role in organ ischemia/reperfusion injury (IRI) and allograft rejection. A retrospective observational study included a cohort of 73 non-diabetic deceased donor kidney allograft recipients. We collected data on donor and recipient demographic, clinical and laboratory parameters. The main outcomes of our study were delayed graft function (DGF) and kidney allograft function during five years posttransplant. Gene single nucleotide polymorphisms (SNPs) for complement components C3 (rs2230199, G_C) and FH (rs800292, G_A) were determined. The genotyping results for FH polymorphism (184G > A) showed a distribution of GG (71.2%) and GA (28.8%) genotypes, with the AA genotype not detected in the cohort. The genotype frequencies of the C3 polymorphism (304 C > G) were CC (71.2%), CG (26.0%) and GG (2.8%). Analysis of FH SNP demonstrated that patients with the GG genotype had a statistically higher frequency of DGF compared to those with the GA genotype (67.3% vs. 38.1%, p = 0.022). Univariate linear regression analysis confirmed that the FH GG genotype was the only significant determinant of DGF (p = 0.025). Analysis of C3 SNP showed that patients with the GC/GG genotype demonstrated significantly lower levels of creatinine clearance compared to those with the CC genotype at 1 year (p = 0.002), 3 years (p = 0.001) and 5 years (p = 0.010) posttransplant. These findings underscore the importance of genetic factors in influencing renal outcomes post-transplant. © The Author(s) 2025.

[No abstract available]

Background: Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds. Hypothesis/Purpose: The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1—derived from untransformed roots, E2—derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3—derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined. Methods: The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting. Results: E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (β-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress. Conclusion: These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma. © 2018 Elsevier GmbH

Background: Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds. Hypothesis/Purpose: The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1—derived from untransformed roots, E2—derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3—derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined. Methods: The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting. Results: E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (β-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress. Conclusion: These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma. © 2018 Elsevier GmbH