The objective of this study was to assess indirectly the existence of X imprinting and its potent... more The objective of this study was to assess indirectly the existence of X imprinting and its potential role in a number of clinical characteristics of Turner syndrome patients. Highly polymorphic X linked microsatellite markers were used to determine the origin of the single X chromosome in 13 patients with Turner syndrome. Ten (77%) patients retained the maternal X chromosome (X m ), while only three patients (23%) retained the paternal X chromosome (X p ). Fisher exact statistical test was used for the association of X chromosome origin with the clinical phenotype. No significant difference was found between the two groups of patients regarding the following phenotype characteristics: lymphoedema at birth, short neck, low posterior hairline, eye anomalies (ptosis, epicanthal folds, hypertelorism, strabismus), multiple pigmented naevi, cardiac and renal anomalies. Absence of association between the X chromosome origin and Turner phenotype was confirmed by a meta-analysis combining fi...
(BET) family protein was reported to be a potential therapeutic target by inhibiting epigenetics ... more (BET) family protein was reported to be a potential therapeutic target by inhibiting epigenetics interaction between bromodomains and acetylated histones. Objectives: We aimed to investigate the effects of bromodomain-containing protein 4 (BRD4) inhibition on tumor necrosis factor (TNF)-α-stimulated rheumatoid arthritis fibroblast-like synoviocyte (RA-FLS) using BRD4 inhibitor, I-BET762. Methods: We examined the effects of BET protein inhibitor on cytokine production and cellular proliferation in RA-FLS. RA-FLSs were treated with TNF-α (10 ng/ml) in the presence of I-BET762 for 48 h. The cell viability and proliferation were measured after 24, 48, and 72 h in I-BET762-treated RA-FLS using CCK-8 colorimetric assay. We then screened pro-inflammatory mediators by using the human inflammation antibody array (Abcam). The levels of interleukin (IL)-6 and IL-8 in culture supernatants of TNF-α-stimulated RA-FLS were measured by enzyme-linked immunosorbent assays (ELISA). Results: I-BET762 had no significant effect on cytotoxicity and proliferation of RA-FLS. I-BET762 reduced the secretion of CXCL-10 and regulated upon activation, normal T cell expressed, and secreted (RANTES) from RA-FLS while increased the secretion of tissue inhibitor of metalloproteinase 2 (TIMP-2) in the antibody array. In addition, ELISA showed significantly decreased level of IL-6 and IL-8 in culture supernatant after treatment with I-BET762. Conclusion: Inhibition of BRD4 by I-BET762 leads to down-regulation of proinflammatory cytokines and chemokines in RA-FLS. I-BET762 may have antiinflammatory properties and provide a therapeutic target molecule in RA.
Febrile seizures (FS) are the most common neurological disorder in childhood and are a great stre... more Febrile seizures (FS) are the most common neurological disorder in childhood and are a great stress for parents due to their dramatic clinical appearance. Using test for determination of homozygously recessive characteristics in humans (HRC test) we analyzed presence, distribution, and individual combination of 20 selected genetically controlled morphophysiological traits among FS patients (N=121) and control (N=121) to determine a possible deviation in the homozygosity level and genetic loads in the group of affected children and whether there is a predisposition to the occurrence of FS. The results of our study show a statistically significant difference in the mean values of the HRC tested (x¯HRC/20 CN = 3.2 ± 0.2; x¯HRC/20 FS = 4.6 ± 0.2, t= 5.74 , p< 0.0001), as well as in the distribution and variability of two studied samples (VC=55,3%, VFS= 39,6%), which indicates a complex polygenic difference among the tested groups of subjects. The differences in the degree of genetic ...
Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is th... more Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is the major cause of morbidity and mortality among preterm infants. Genetic predisposition may have an impact on EOS susceptibility and outcome. The aim of our study was to explore the association between TNF-α-308 G/A or IL-6-174 G/C gene polymorphism and the susceptibility and outcome of EOS in preterm infants. The study included 471 preterm infants: 282 with EOS (151 with culture proven sepsis and 131 with clinical sepsis) and 189 without infection (control group). TNF-α-308 G/A and IL-6-174 G/C were genotyped using Real-time RCR method. We observed significantly higher frequency of A allele of TNF-α-308 G/A polymorphism in blood culture proven EOS (p = 0.017) or clinical EOS (p = 0.025) compared with the control group. Logistic regression confirmed significant association between TNF-α-308 GA+AA genotypes and development of culture proven EOS (B =-0.718, p = 0.013) or clinical EOS (B =-0.602, p = 0.027). No significant differences in IL6-174G/C alleles or genotypes distribution have been observed between culture proven EOS group, clinical EOS group and the control group. An association between TNF-α-308 G/A or IL-6-174 G/C genotypes and EOS lethal outcome was not observed (p = 0.652 and p = 0.384, respectively). According to our analysis of large cohort of preterm infants with clearly defined EOS groups, the TNF-α-308 A allele may be a risk factor for the EOS occurrence.
gestational age under 30 weeks (p=0.032), but multivariate linear regression analysis does not sh... more gestational age under 30 weeks (p=0.032), but multivariate linear regression analysis does not show association of 4a/b genotypes with gestational age of premature infants. According to results of the present study T-786C and 4a/b polymorphisms of the eNOS gene may not be the risk factors for the manifestation of severe ROP in Serbian infants.
Aim: Our aim was to explore the influence of 9-bp insertion/deletion and variable number of 9 bp ... more Aim: Our aim was to explore the influence of 9-bp insertion/deletion and variable number of 9 bp elements (63/91) length polymorphism in noncoding interfering RNA and major promoter of DHFR gene on methotrexate (MTX) efficacy and toxicity in patients with rheumatoid arthritis (RA). Patients & methods: Response to the MTX therapy and adverse effects were estimated in 243 RA patients genotyped for the selected polymorphism. Results: The presence of allele 1 of analyzed polymorphism had significant protective effect against MTX toxicity (odds ratio: 0.37 [95% CI: 0.19–0.70]; p = 0.002). Results remained significant in multiple logistic regression analysis with the inclusion of disease and treatment features in the model (p = 0.03). Conclusion: Polymorphism 63/91 in DHFR gene promoter can modulate the onset of MTX-related adverse effects in RA patients.
Developmental delay and intellectual disabilities (DD/ID) are significant health problems affecti... more Developmental delay and intellectual disabilities (DD/ID) are significant health problems affecting 3% of the human population. Submicroscopic chromosomal rearrangements involving subtelomeric regions are often considered to be the cause of unexplained DD/ID. Screening of subtelomeric regions was performed in 80 unrelated patients with DD/ID and normal GTG-banded chromosomes using the MLPA method with two kits (SALSA P070-B1 and P036-E1). The MLPA screening revealed subtelomeric chromosome aberrations in four cases (5%). The aberrations detected were: 1p deletion, 1p deletion combined with 12q duplication, 4p deletion, and 9p deletion combined with 15q duplication. The deletions detected were classified as causative for the patients' observed phenotypes. This study confirms the high frequency of subtelomeric rearrangements in unexplained DD/ID and reinforces the argument for routine subtelomeric screening in order to get a correct diagnosis, establish genotype-phenotype correlat...
Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of ... more Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction-restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course.
BACKGROUND. For patients with two or more primary cancers a correct diagnosis is critically impor... more BACKGROUND. For patients with two or more primary cancers a correct diagnosis is critically important because prognosis and treatment vary considerably between multiple primary cancers and metastatic disease. Two bilateral synchronous primary lung malignancies of different histological types were diagnosed and immunohistochemically confirmed in a 60-year-old woman. In biopsy specimens of the right lung pure squamous cell carcinoma was detected (stage IIIa). The tumor expressed AE1/AE3, cytokeratin 5 and 34βE12. In biopsy specimens of the left lung small cell carcinoma was detected (stage IIIa). The small cells expressed synaptophysin, chromogranin A and CD56. DNA was extracted from paraffin-embedded tissue of both tumors. Exons 5-9 of the TP53 gene were examined for genetic mutations by polymerase chain reaction and DNA sequencing analysis. Direct sequencing of DNA isolated from the small cell carcinoma revealed a TGC to TTC mutation at codon 404 of TP53 exon 5. In DNA isolated from...
Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumato... more Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects. The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX. According to the EULAR response criteria, 96 RA patients (76.8%) were classifi...
INTRODUCTION Our study of genetic homozygosity degree includes an analysis of the presence, distr... more INTRODUCTION Our study of genetic homozygosity degree includes an analysis of the presence, distribution and individual combination of 15 selected genetically controlled morphophysiological traits in the sample of patients with spinal dysraphia (N=35) and in the control-healthy group (N=50). OBJECTIVE Assuming that spinal dysraphia is a genetically controlled disease, we made a hypothesis that an increased homozygosity level, as well as the changed variability among patients, could be a population-genetic parameter for the prediction of the illness. METHOD Taking into consideration our experience, as well as the experience of numerous scientists who studied the nature of the inheritance of monoand oligo-genically controlled qualitative traits, we applied a methodology to estimate the proportion of such homozygously recessive characters (HRC-test,). RESULTS This population-genetic study did not only show a statistically significant difference of the mean values of genetic homozygosit...
Your article is protected by copyright and all rights are held exclusively by Arányi Lajos Founda... more Your article is protected by copyright and all rights are held exclusively by Arányi Lajos Foundation. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to selfarchive your work, please use the accepted author's version for posting to your own website or your institution's repository. You may further deposit the accepted author's version on a funder's repository at a funder's request, provided it is not made publicly available until 12 months after publication.
International Journal of Oral and Maxillofacial Surgery, 2010
The aim of this study was to gain a better understanding of cancer genes contributing to oral squ... more The aim of this study was to gain a better understanding of cancer genes contributing to oral squamous cell (OSCC) development and progression and correlate genetic changes to clinical parameters. Human papilloma virus (HPV) 16 detection is also included in the study. 60 samples of OSCC were analysed for c-erbB2 and c-myc amplification by dPCR, H-ras and p53 point mutations by PCR/ SSCP. HPV was detected via amplification of its E1 and E6 genes. c-erbB2 was altered in 45%, c-myc in 35%, H-ras in 22% and p53 in 60% of samples. HPV was detected in 10% of cases. The frequency of p53 gene mutations showed a statistically significant association with tumour stage. Patients with c-erbB2 and Hras alterations had lower survival than patients without these alterations. The number of detected genetic changes was remarkable but statistical association with tumour natural history was poor, indicating high clonal heterogeneity and multiple pathways of carcinogenesis.
The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on serum l... more The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on serum lipid profiles is controversial. We randomly selected 530 healthy schoolchildren that were included in the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD). The detected frequencies of MTHFR 677TT genotypes and MTHFR 677T allele were 13.4% and 35.5%, respectively. The mean levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides were higher and high-density lipoprotein cholesterol was lower in the group of children with TT genotype compared with remaining genotypes. All differences were without statistical significance. Our findings suggest that there is no influence of MTHFR C677T gene variants on the lipid parameters in the population of Serbian children.
Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders with an as yet unknown... more Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders with an as yet unknown molecular pathology. Genetic instability has been proposed as a cause of MDS. Mutations in the NBS1 gene, whose product nibrin (p95) is involved in DNA damage repair and cell-cycle control, might be associated with an elevated predisposition to the development of MDS. The aim of the study was to examine truncating 5 bp deletion (657del5), the most frequent NBS1 gene mutation in Slavic populations, in MDS patients. Among 71 MDS patients, we found one case that was heterozygous for the NBS1 657del5 mutation. To the best of our knowledge, this is the first report of a NBS1 mutation in MDS.
Introduction. p53 gene is the most common tumor suppressor gene involved in pathogenesis oral squ... more Introduction. p53 gene is the most common tumor suppressor gene involved in pathogenesis oral squamous cell carcinoma (OSCC). Protein product of p53 gene contributes to cell cycle control and apoptosis. p53 gene mutations may lead to uncontrolled cell growth. The aim of this study was to determine the incidence of mutation in DNA-binding domain of p53 gene. Materials and Methods. In the 60 specimens, the presence of point mutation in exons 5, 6, 7 and 8 was detected using PCR-SSCP method. To confirm the presence of p53 mutation found by SSCP method, five samples were analyzed by sequencing of exon 5. Results. Point mutation affecting exons 5, 6, 7 and 8 were found in 60% of analyzed samples. A higher incidence of mutation was detected in exon 7 and 8 (60%), than in exon 5 and 6. Sequencing of exon 5, confirmed the presence of mutations revealed by SSCP method. Study of associations showed an increase of p53 mutations in poor differentiated and carcinoma of higher clinical stages. Co...
Aim: The aim of this study was to analyze the presence of the anti-apoptotic protein bcl-2 in ora... more Aim: The aim of this study was to analyze the presence of the anti-apoptotic protein bcl-2 in oral squamous cell carcinoma and determine its potential role in the development and progression of this type of tumor. Materials and methods: The expression of bcl-2 was determined in 28 paraffin blocks of oral squamous cell carcinoma using the immunohistochemical method. The percentage of the immuno-reactive cells in positively stained tumor regions was determined using the microscopic analysis and Ozaria software. Results: Positive immunohistochemical test was observed in 19 out of 28 samples (68%) as follows: in 11 samples there was a low (+), in four a moderate (++) and in the last four a high percentage (+++) of stained cells. In the group of patients at the low stage of the disease (T2), 50% of tumor samples showed bcl-2 protein expression whereas in the higher stages (T3 and T4) of positively stained samples, this percentage was 67%. There was a trend of an increasing number of cell...
The objective of this study was to assess indirectly the existence of X imprinting and its potent... more The objective of this study was to assess indirectly the existence of X imprinting and its potential role in a number of clinical characteristics of Turner syndrome patients. Highly polymorphic X linked microsatellite markers were used to determine the origin of the single X chromosome in 13 patients with Turner syndrome. Ten (77%) patients retained the maternal X chromosome (X m ), while only three patients (23%) retained the paternal X chromosome (X p ). Fisher exact statistical test was used for the association of X chromosome origin with the clinical phenotype. No significant difference was found between the two groups of patients regarding the following phenotype characteristics: lymphoedema at birth, short neck, low posterior hairline, eye anomalies (ptosis, epicanthal folds, hypertelorism, strabismus), multiple pigmented naevi, cardiac and renal anomalies. Absence of association between the X chromosome origin and Turner phenotype was confirmed by a meta-analysis combining fi...
(BET) family protein was reported to be a potential therapeutic target by inhibiting epigenetics ... more (BET) family protein was reported to be a potential therapeutic target by inhibiting epigenetics interaction between bromodomains and acetylated histones. Objectives: We aimed to investigate the effects of bromodomain-containing protein 4 (BRD4) inhibition on tumor necrosis factor (TNF)-α-stimulated rheumatoid arthritis fibroblast-like synoviocyte (RA-FLS) using BRD4 inhibitor, I-BET762. Methods: We examined the effects of BET protein inhibitor on cytokine production and cellular proliferation in RA-FLS. RA-FLSs were treated with TNF-α (10 ng/ml) in the presence of I-BET762 for 48 h. The cell viability and proliferation were measured after 24, 48, and 72 h in I-BET762-treated RA-FLS using CCK-8 colorimetric assay. We then screened pro-inflammatory mediators by using the human inflammation antibody array (Abcam). The levels of interleukin (IL)-6 and IL-8 in culture supernatants of TNF-α-stimulated RA-FLS were measured by enzyme-linked immunosorbent assays (ELISA). Results: I-BET762 had no significant effect on cytotoxicity and proliferation of RA-FLS. I-BET762 reduced the secretion of CXCL-10 and regulated upon activation, normal T cell expressed, and secreted (RANTES) from RA-FLS while increased the secretion of tissue inhibitor of metalloproteinase 2 (TIMP-2) in the antibody array. In addition, ELISA showed significantly decreased level of IL-6 and IL-8 in culture supernatant after treatment with I-BET762. Conclusion: Inhibition of BRD4 by I-BET762 leads to down-regulation of proinflammatory cytokines and chemokines in RA-FLS. I-BET762 may have antiinflammatory properties and provide a therapeutic target molecule in RA.
Febrile seizures (FS) are the most common neurological disorder in childhood and are a great stre... more Febrile seizures (FS) are the most common neurological disorder in childhood and are a great stress for parents due to their dramatic clinical appearance. Using test for determination of homozygously recessive characteristics in humans (HRC test) we analyzed presence, distribution, and individual combination of 20 selected genetically controlled morphophysiological traits among FS patients (N=121) and control (N=121) to determine a possible deviation in the homozygosity level and genetic loads in the group of affected children and whether there is a predisposition to the occurrence of FS. The results of our study show a statistically significant difference in the mean values of the HRC tested (x¯HRC/20 CN = 3.2 ± 0.2; x¯HRC/20 FS = 4.6 ± 0.2, t= 5.74 , p< 0.0001), as well as in the distribution and variability of two studied samples (VC=55,3%, VFS= 39,6%), which indicates a complex polygenic difference among the tested groups of subjects. The differences in the degree of genetic ...
Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is th... more Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is the major cause of morbidity and mortality among preterm infants. Genetic predisposition may have an impact on EOS susceptibility and outcome. The aim of our study was to explore the association between TNF-α-308 G/A or IL-6-174 G/C gene polymorphism and the susceptibility and outcome of EOS in preterm infants. The study included 471 preterm infants: 282 with EOS (151 with culture proven sepsis and 131 with clinical sepsis) and 189 without infection (control group). TNF-α-308 G/A and IL-6-174 G/C were genotyped using Real-time RCR method. We observed significantly higher frequency of A allele of TNF-α-308 G/A polymorphism in blood culture proven EOS (p = 0.017) or clinical EOS (p = 0.025) compared with the control group. Logistic regression confirmed significant association between TNF-α-308 GA+AA genotypes and development of culture proven EOS (B =-0.718, p = 0.013) or clinical EOS (B =-0.602, p = 0.027). No significant differences in IL6-174G/C alleles or genotypes distribution have been observed between culture proven EOS group, clinical EOS group and the control group. An association between TNF-α-308 G/A or IL-6-174 G/C genotypes and EOS lethal outcome was not observed (p = 0.652 and p = 0.384, respectively). According to our analysis of large cohort of preterm infants with clearly defined EOS groups, the TNF-α-308 A allele may be a risk factor for the EOS occurrence.
gestational age under 30 weeks (p=0.032), but multivariate linear regression analysis does not sh... more gestational age under 30 weeks (p=0.032), but multivariate linear regression analysis does not show association of 4a/b genotypes with gestational age of premature infants. According to results of the present study T-786C and 4a/b polymorphisms of the eNOS gene may not be the risk factors for the manifestation of severe ROP in Serbian infants.
Aim: Our aim was to explore the influence of 9-bp insertion/deletion and variable number of 9 bp ... more Aim: Our aim was to explore the influence of 9-bp insertion/deletion and variable number of 9 bp elements (63/91) length polymorphism in noncoding interfering RNA and major promoter of DHFR gene on methotrexate (MTX) efficacy and toxicity in patients with rheumatoid arthritis (RA). Patients & methods: Response to the MTX therapy and adverse effects were estimated in 243 RA patients genotyped for the selected polymorphism. Results: The presence of allele 1 of analyzed polymorphism had significant protective effect against MTX toxicity (odds ratio: 0.37 [95% CI: 0.19–0.70]; p = 0.002). Results remained significant in multiple logistic regression analysis with the inclusion of disease and treatment features in the model (p = 0.03). Conclusion: Polymorphism 63/91 in DHFR gene promoter can modulate the onset of MTX-related adverse effects in RA patients.
Developmental delay and intellectual disabilities (DD/ID) are significant health problems affecti... more Developmental delay and intellectual disabilities (DD/ID) are significant health problems affecting 3% of the human population. Submicroscopic chromosomal rearrangements involving subtelomeric regions are often considered to be the cause of unexplained DD/ID. Screening of subtelomeric regions was performed in 80 unrelated patients with DD/ID and normal GTG-banded chromosomes using the MLPA method with two kits (SALSA P070-B1 and P036-E1). The MLPA screening revealed subtelomeric chromosome aberrations in four cases (5%). The aberrations detected were: 1p deletion, 1p deletion combined with 12q duplication, 4p deletion, and 9p deletion combined with 15q duplication. The deletions detected were classified as causative for the patients' observed phenotypes. This study confirms the high frequency of subtelomeric rearrangements in unexplained DD/ID and reinforces the argument for routine subtelomeric screening in order to get a correct diagnosis, establish genotype-phenotype correlat...
Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of ... more Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction-restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course.
BACKGROUND. For patients with two or more primary cancers a correct diagnosis is critically impor... more BACKGROUND. For patients with two or more primary cancers a correct diagnosis is critically important because prognosis and treatment vary considerably between multiple primary cancers and metastatic disease. Two bilateral synchronous primary lung malignancies of different histological types were diagnosed and immunohistochemically confirmed in a 60-year-old woman. In biopsy specimens of the right lung pure squamous cell carcinoma was detected (stage IIIa). The tumor expressed AE1/AE3, cytokeratin 5 and 34βE12. In biopsy specimens of the left lung small cell carcinoma was detected (stage IIIa). The small cells expressed synaptophysin, chromogranin A and CD56. DNA was extracted from paraffin-embedded tissue of both tumors. Exons 5-9 of the TP53 gene were examined for genetic mutations by polymerase chain reaction and DNA sequencing analysis. Direct sequencing of DNA isolated from the small cell carcinoma revealed a TGC to TTC mutation at codon 404 of TP53 exon 5. In DNA isolated from...
Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumato... more Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects. The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX. According to the EULAR response criteria, 96 RA patients (76.8%) were classifi...
INTRODUCTION Our study of genetic homozygosity degree includes an analysis of the presence, distr... more INTRODUCTION Our study of genetic homozygosity degree includes an analysis of the presence, distribution and individual combination of 15 selected genetically controlled morphophysiological traits in the sample of patients with spinal dysraphia (N=35) and in the control-healthy group (N=50). OBJECTIVE Assuming that spinal dysraphia is a genetically controlled disease, we made a hypothesis that an increased homozygosity level, as well as the changed variability among patients, could be a population-genetic parameter for the prediction of the illness. METHOD Taking into consideration our experience, as well as the experience of numerous scientists who studied the nature of the inheritance of monoand oligo-genically controlled qualitative traits, we applied a methodology to estimate the proportion of such homozygously recessive characters (HRC-test,). RESULTS This population-genetic study did not only show a statistically significant difference of the mean values of genetic homozygosit...
Your article is protected by copyright and all rights are held exclusively by Arányi Lajos Founda... more Your article is protected by copyright and all rights are held exclusively by Arányi Lajos Foundation. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to selfarchive your work, please use the accepted author's version for posting to your own website or your institution's repository. You may further deposit the accepted author's version on a funder's repository at a funder's request, provided it is not made publicly available until 12 months after publication.
International Journal of Oral and Maxillofacial Surgery, 2010
The aim of this study was to gain a better understanding of cancer genes contributing to oral squ... more The aim of this study was to gain a better understanding of cancer genes contributing to oral squamous cell (OSCC) development and progression and correlate genetic changes to clinical parameters. Human papilloma virus (HPV) 16 detection is also included in the study. 60 samples of OSCC were analysed for c-erbB2 and c-myc amplification by dPCR, H-ras and p53 point mutations by PCR/ SSCP. HPV was detected via amplification of its E1 and E6 genes. c-erbB2 was altered in 45%, c-myc in 35%, H-ras in 22% and p53 in 60% of samples. HPV was detected in 10% of cases. The frequency of p53 gene mutations showed a statistically significant association with tumour stage. Patients with c-erbB2 and Hras alterations had lower survival than patients without these alterations. The number of detected genetic changes was remarkable but statistical association with tumour natural history was poor, indicating high clonal heterogeneity and multiple pathways of carcinogenesis.
The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on serum l... more The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on serum lipid profiles is controversial. We randomly selected 530 healthy schoolchildren that were included in the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD). The detected frequencies of MTHFR 677TT genotypes and MTHFR 677T allele were 13.4% and 35.5%, respectively. The mean levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides were higher and high-density lipoprotein cholesterol was lower in the group of children with TT genotype compared with remaining genotypes. All differences were without statistical significance. Our findings suggest that there is no influence of MTHFR C677T gene variants on the lipid parameters in the population of Serbian children.
Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders with an as yet unknown... more Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders with an as yet unknown molecular pathology. Genetic instability has been proposed as a cause of MDS. Mutations in the NBS1 gene, whose product nibrin (p95) is involved in DNA damage repair and cell-cycle control, might be associated with an elevated predisposition to the development of MDS. The aim of the study was to examine truncating 5 bp deletion (657del5), the most frequent NBS1 gene mutation in Slavic populations, in MDS patients. Among 71 MDS patients, we found one case that was heterozygous for the NBS1 657del5 mutation. To the best of our knowledge, this is the first report of a NBS1 mutation in MDS.
Introduction. p53 gene is the most common tumor suppressor gene involved in pathogenesis oral squ... more Introduction. p53 gene is the most common tumor suppressor gene involved in pathogenesis oral squamous cell carcinoma (OSCC). Protein product of p53 gene contributes to cell cycle control and apoptosis. p53 gene mutations may lead to uncontrolled cell growth. The aim of this study was to determine the incidence of mutation in DNA-binding domain of p53 gene. Materials and Methods. In the 60 specimens, the presence of point mutation in exons 5, 6, 7 and 8 was detected using PCR-SSCP method. To confirm the presence of p53 mutation found by SSCP method, five samples were analyzed by sequencing of exon 5. Results. Point mutation affecting exons 5, 6, 7 and 8 were found in 60% of analyzed samples. A higher incidence of mutation was detected in exon 7 and 8 (60%), than in exon 5 and 6. Sequencing of exon 5, confirmed the presence of mutations revealed by SSCP method. Study of associations showed an increase of p53 mutations in poor differentiated and carcinoma of higher clinical stages. Co...
Aim: The aim of this study was to analyze the presence of the anti-apoptotic protein bcl-2 in ora... more Aim: The aim of this study was to analyze the presence of the anti-apoptotic protein bcl-2 in oral squamous cell carcinoma and determine its potential role in the development and progression of this type of tumor. Materials and methods: The expression of bcl-2 was determined in 28 paraffin blocks of oral squamous cell carcinoma using the immunohistochemical method. The percentage of the immuno-reactive cells in positively stained tumor regions was determined using the microscopic analysis and Ozaria software. Results: Positive immunohistochemical test was observed in 19 out of 28 samples (68%) as follows: in 11 samples there was a low (+), in four a moderate (++) and in the last four a high percentage (+++) of stained cells. In the group of patients at the low stage of the disease (T2), 50% of tumor samples showed bcl-2 protein expression whereas in the higher stages (T3 and T4) of positively stained samples, this percentage was 67%. There was a trend of an increasing number of cell...
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