Browsing by Author "Perovic, Dijana (55251514500)"

Purpose: Treatment of Ischemic stroke (IS) in acute phase is based on the use of thrombolytic rt-PA therapy. We aimed to determine whether different alleles and genotypes of I/D ACE gene and 4G/5G PAI-1 gene polymorphisms may influence outcome of rt-PA therapy in patients with IS and the occurrence of haemorrhagic transformation (HT). Methods: Our study included 94 consecutive patients with IS treated with rt-PA. Modified Rankin Scale (mRS) at 3rd month after IS was used to determine the stroke outcome, with scores 0-1 defining the favourable outcome, and scores 2-6 defining poor outcome. Genotypisation of the ACE-1 I/D polymorphism was performed by polymerase chain reaction and of the PAI-1 4G/5G polymorphism by polymerase chain reaction - restriction fragment length analysis. Results: Regarding PAI-I 4G/5G polymorphism, 44 patients (46.8%) were heterozygotes, and the number of 4G/4G and 5G/5G homozygotes was the same – 25 each (26.6%). Number of heterozygotes for the ACE I/D polymorphism was 54 (57.4%), 9 patients (9.6%) had II, and 31 (33%) DD genotypes. A favourable outcome was recorded in 26 (28.0%) and the poor outcome in 67 (72.0%) patients. Favourable and poor outcome groups did not differ significantly in PAI-1 4G/5G and ACE I/D polymorphisms genotype or allele frequencies. There was a statistically significant difference in the occurrence of HT between patients with ACE II and patients with ACE ID or DD genotypes (p=0.035). Conclusion: Results of our study suggest that stroke patients with ACE II genotype, treated with rt-PA, may be at risk of HT. © 2019, MDPI AG. All rights reserved.

Objectives: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1β and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA. Methods: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0–1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1β-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses. Results: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121–4.880), while patients who were G-allele carriers of the Il-6–174 G/C polymorphism and had the AA genotype of the IL-1β-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414–7.1426). Conclusion: GG genotype of the IL-6-174G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy. © 2023 Informa UK Limited, trading as Taylor & Francis Group.

Objectives: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1β and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA. Methods: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0–1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1β-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses. Results: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121–4.880), while patients who were G-allele carriers of the Il-6–174 G/C polymorphism and had the AA genotype of the IL-1β-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414–7.1426). Conclusion: GG genotype of the IL-6-174G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy. © 2023 Informa UK Limited, trading as Taylor & Francis Group.

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: Array-based genomic analysis is a gold standard for the detection of copy number variations (CNVs) as an important source of benign as well as pathogenic variations in humans. The introduction of chromosomal microarray (CMA) has led to a significant leap in diagnostics of genetically caused congenital malformations and neurodevelopmental disorders, with an average diagnostic yield of 15%. Here, we present our experience from a single laboratory perspective in four years’ postnatal clinical CMA application. Methods: DNA samples of 430 patients with congenital anomalies and/or neurodevelopmental disorders were analyzed by comparative genome hybridization using oligonucleotide-based microarray platforms. Interpretation of detected CNVs was performed according to current guidelines. The detection rate (DR) of clinically significant findings (pathogenic/likely pathogenic CNVs) was calculated for the whole cohort and isolated or combined phenotypic categories. Results: A total of 140 non-benign CNVs were detected in 113/430 patients (26.5%). In 70 patients at least one CNV was considered clinically significant thus reaching a diagnostic yield of 16.3%. The more complex the phenotype, including developmental delay/intellectual disability (DD/ID) as a prevailing feature, the higher the DR of clinically significant CNVs is obtained. Isolated congenital anomalies had the lowest, while the “dysmorphism plus” category had the highest diagnostic yield. Conclusion: In our study, CMA proved to be a very useful method in the diagnosis of genetically caused congenital anomalies and neurodevelopmental disorders. DD/ID and dysmorphism stand out as important phenotypic features that significantly increase the diagnostic yield of the analysis. © 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.

Background: Array-based genomic analysis is a gold standard for the detection of copy number variations (CNVs) as an important source of benign as well as pathogenic variations in humans. The introduction of chromosomal microarray (CMA) has led to a significant leap in diagnostics of genetically caused congenital malformations and neurodevelopmental disorders, with an average diagnostic yield of 15%. Here, we present our experience from a single laboratory perspective in four years’ postnatal clinical CMA application. Methods: DNA samples of 430 patients with congenital anomalies and/or neurodevelopmental disorders were analyzed by comparative genome hybridization using oligonucleotide-based microarray platforms. Interpretation of detected CNVs was performed according to current guidelines. The detection rate (DR) of clinically significant findings (pathogenic/likely pathogenic CNVs) was calculated for the whole cohort and isolated or combined phenotypic categories. Results: A total of 140 non-benign CNVs were detected in 113/430 patients (26.5%). In 70 patients at least one CNV was considered clinically significant thus reaching a diagnostic yield of 16.3%. The more complex the phenotype, including developmental delay/intellectual disability (DD/ID) as a prevailing feature, the higher the DR of clinically significant CNVs is obtained. Isolated congenital anomalies had the lowest, while the “dysmorphism plus” category had the highest diagnostic yield. Conclusion: In our study, CMA proved to be a very useful method in the diagnosis of genetically caused congenital anomalies and neurodevelopmental disorders. DD/ID and dysmorphism stand out as important phenotypic features that significantly increase the diagnostic yield of the analysis. © 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.

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

In the context of rheumatoid arthritis (RA) treatment, Methotrexate (MTX) plays a crucial role in preventing joint damage and bone erosion (BE). RA is characterized by elevated levels of matrix metalloproteinase 2 (MMP2), an enzyme responsible for extracellular matrix degradation, which contributes to joint damage and inflammation. Tissue inhibitor of metalloproteinase 2 (TIMP2) counteracts MMP2, and an imbalance between the two can exacerbate BE. Inosine triphosphatase (ITPA) is an enzyme involved in regulating inosine triphosphate levels, potentially linked to RA susceptibility. Genetic variations in ITPA, MMP2, and TIMP2 genes can influence MTX's efficacy. A study of 122 RA patients on MTX monotherapy assessed its effectiveness using Disease Activity Score (DAS28) changes over 6 months following EULAR response criteria. Genotyping, including MMP2 (rs243866, rs2285053), TIMP2 (rs2277698), and ITPA (rs1127354) polymorphisms, was performed. Among the patients, 87.7% were responders, 63.9% experienced BE, and 24.6% encountered adverse events. Notably, patients with the MMP2 (rs243866) GG genotype were the only ones reporting nausea (p=0.025). Patients with both the MMP2 (rs2285053) CC and TIMP2 (rs2277698) CT genotypes had a lower incidence of BE compared to those lacking this combination (p=0.048). The TIMP2 (rs2277698) CC genotype was associated with a higher baseline DAS28 score (p=0.035). In summary, this study suggests that specific MMP2/TIMP2 genotype combinations may serve as predictors for BE development in RA patients undergoing MTX monotherapy. © 2024 Marmara University Press.

In the context of rheumatoid arthritis (RA) treatment, Methotrexate (MTX) plays a crucial role in preventing joint damage and bone erosion (BE). RA is characterized by elevated levels of matrix metalloproteinase 2 (MMP2), an enzyme responsible for extracellular matrix degradation, which contributes to joint damage and inflammation. Tissue inhibitor of metalloproteinase 2 (TIMP2) counteracts MMP2, and an imbalance between the two can exacerbate BE. Inosine triphosphatase (ITPA) is an enzyme involved in regulating inosine triphosphate levels, potentially linked to RA susceptibility. Genetic variations in ITPA, MMP2, and TIMP2 genes can influence MTX's efficacy. A study of 122 RA patients on MTX monotherapy assessed its effectiveness using Disease Activity Score (DAS28) changes over 6 months following EULAR response criteria. Genotyping, including MMP2 (rs243866, rs2285053), TIMP2 (rs2277698), and ITPA (rs1127354) polymorphisms, was performed. Among the patients, 87.7% were responders, 63.9% experienced BE, and 24.6% encountered adverse events. Notably, patients with the MMP2 (rs243866) GG genotype were the only ones reporting nausea (p=0.025). Patients with both the MMP2 (rs2285053) CC and TIMP2 (rs2277698) CT genotypes had a lower incidence of BE compared to those lacking this combination (p=0.048). The TIMP2 (rs2277698) CC genotype was associated with a higher baseline DAS28 score (p=0.035). In summary, this study suggests that specific MMP2/TIMP2 genotype combinations may serve as predictors for BE development in RA patients undergoing MTX monotherapy. © 2024 Marmara University Press.

Objectives The aim of this study is to determine the connection of gross motor skills (locomotor skills and object control) and the degree of associated intellectual disability (ID) in children with cerebral palsy (CP). Participants and methods The study sample included 54 children with CP and associated ID age 5 years to 6 years and 11 months. For the assessment of tested skills, The Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R), Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) and Test of Gross Motor Development Second Edition (TGMD-2) were used. Results The results of this study indicate better quality of locomotor skills than object control skills in children with CP and associated ID. Children with CP and mild ID have better quality of locomotor skills and object control, than children with CP and moderate ID. Differences between these 2 groups of children are presented relative to GMFCS-E&R levels. Conclusion This study has determined significant interconnection of the quality of gross motor functions and intellectual capacity in preschool children with CP. This should be considered when creating more detailed individual developmental rehabilitation plan in children with CP and associated ID and predict adequate measures of developmental stimulation. © 2021 Georg Thieme Verlag. All rights reserved.

Objectives The aim of this study is to determine the connection of gross motor skills (locomotor skills and object control) and the degree of associated intellectual disability (ID) in children with cerebral palsy (CP). Participants and methods The study sample included 54 children with CP and associated ID age 5 years to 6 years and 11 months. For the assessment of tested skills, The Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R), Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) and Test of Gross Motor Development Second Edition (TGMD-2) were used. Results The results of this study indicate better quality of locomotor skills than object control skills in children with CP and associated ID. Children with CP and mild ID have better quality of locomotor skills and object control, than children with CP and moderate ID. Differences between these 2 groups of children are presented relative to GMFCS-E&R levels. Conclusion This study has determined significant interconnection of the quality of gross motor functions and intellectual capacity in preschool children with CP. This should be considered when creating more detailed individual developmental rehabilitation plan in children with CP and associated ID and predict adequate measures of developmental stimulation. © 2021 Georg Thieme Verlag. All rights reserved.

The influence of chromosomal sex on human diseases is recognized but underresearched, particularly in diseases with early developmental origins. Copy number variations (CNVs) from sex chromosomes or autosomes, which cause different gene expressions, may influence the disease preferences in females and males. Chromosomal microarray is a standard method for detecting CNVs, with a diagnostic yield of approximately 15 % among patients with congenital anomalies and neurodevelopmental disorders, the primary indications for the analysis. Here, we explore sex disparities in phenotype prevalence and CNV detection rates in patients referred for chromosomal microarray to identify sex-biased traits and CNVs. Our cohort comprises 1412 patients, with a male-to-female ratio of 1.6 to 1. Despite being outnumbered, females are significantly more likely to receive a genetic diagnosis through this type of molecular karyotyping. Most of the patients have neurodevelopmental disorders with other comorbidities. Females have a higher frequency of comorbidities, but the difference in diagnostic yield is significant only in the groups with simpler phenotypes (≤2 comorbidities). Higher diagnostic yield is revealed for congenital heart disease, urogenital anomalies, and the autism spectrum group. All three categories show populational preponderance in males, supporting a higher threshold liability model in females. © 2025 Elsevier B.V.

Objective Taking care of children with autism spectrum disorder (ASD), as of children with other developmental disorders, is associated with greater parental stress. The aim of this study was to determine the prevalence and impact of integrative and co-morbid ASD-related symptoms on parental stress levels during the COVID-19 pandemic at four time points. Testing was performed during significant changes related to the state of the COVID-19 pandemic in Serbia. Methods The research sample included 67 parents of children with ASD 4 to 7 years and 6 months of age. The Autism Parenting Stress Index, Gilliam Autism Rating Scale - Third Edition, diagnostic criteria for ASD from DSM-5 and Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition were used to assess the tested abilities. Results Core behavior (problems of social development and communication skills) as well as co-morbid behaviors related to ASD (tantrums, aggressive behavior, self-injurious behavior and difficulties with transitions) caused the highest degree of parental stress. Post hoc tests that used Bonferroni correction found that parental stress caused by basic and co-morbid behaviors gradually decreased from first to fourth measurement, respectively. Sleep and toilet training problems, as well as comorbid physical problems, caused the greatest degree of parental stress during the first measurement. Measuring total parental stress caused by integrative and co-morbid symptoms related to ASD showed that it was at the highest level during the first measurement, decreased during the second measurement and remained unchanged during the third and fourth measurements. Conclusion Time, as a repeating factor, during the COVID-19 pandemic has an effect on lowering the levels of parental stress caused by all examined ASD-related domains. These results may be useful in creating individual programs to support parents of children with ASD during the COVID-19 pandemic. © 2022. Thieme. All rights reserved.

Objective Taking care of children with autism spectrum disorder (ASD), as of children with other developmental disorders, is associated with greater parental stress. The aim of this study was to determine the prevalence and impact of integrative and co-morbid ASD-related symptoms on parental stress levels during the COVID-19 pandemic at four time points. Testing was performed during significant changes related to the state of the COVID-19 pandemic in Serbia. Methods The research sample included 67 parents of children with ASD 4 to 7 years and 6 months of age. The Autism Parenting Stress Index, Gilliam Autism Rating Scale - Third Edition, diagnostic criteria for ASD from DSM-5 and Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition were used to assess the tested abilities. Results Core behavior (problems of social development and communication skills) as well as co-morbid behaviors related to ASD (tantrums, aggressive behavior, self-injurious behavior and difficulties with transitions) caused the highest degree of parental stress. Post hoc tests that used Bonferroni correction found that parental stress caused by basic and co-morbid behaviors gradually decreased from first to fourth measurement, respectively. Sleep and toilet training problems, as well as comorbid physical problems, caused the greatest degree of parental stress during the first measurement. Measuring total parental stress caused by integrative and co-morbid symptoms related to ASD showed that it was at the highest level during the first measurement, decreased during the second measurement and remained unchanged during the third and fourth measurements. Conclusion Time, as a repeating factor, during the COVID-19 pandemic has an effect on lowering the levels of parental stress caused by all examined ASD-related domains. These results may be useful in creating individual programs to support parents of children with ASD during the COVID-19 pandemic. © 2022. Thieme. All rights reserved.

Objective: Prenatal detection of complex chromosomal rearrangements (CCR) is extremely rare, but is of great clinical importance, since CCR can be causative of different congenital disorders. We present an exceptionally rare case of prenatally diagnosed Saethre-Chotzen syndrome (SCS) rising as a consequence of chromothripsis involving chromosomes 5, 7 and 11 and deletion of TWIST1 gene. Case report: Brachycephaly, hypertelorism, flat face, micrognathia, relative macroglossia and small posterior fossa were noted on ultrasound examination at 28th gestational week. Fetal karyotyping revealed de novo translocation 46,XY,t(7;11)(p15.5;q21)dn. Chromosomal microarray showed presence of three microdeletions on chromosome 7 (7p21.1p15.3 including TWIST1, 7p12.1p11.2 and 7q21.11), and one on chromosome 5p12p11. Conclusion: Use of advanced molecular diagnostic techniques in combination with cytogenetic methods allows for precise characterization of CCRs and detection of molecular mechanisms of their origin. Phenomenon of chromothripsis can be causative of rare genetic syndromes such as SCS. © 2024

[No abstract available]