TY  - JOUR
AU  - Janić, Dragana
AU  - Perić, Jelena
AU  - Karan-Đurašević, Teodora
AU  - Kostić, Tatjana
AU  - Marjanović, Irena
AU  - Stanić, Bojana
AU  - Pejanović, Nadja
AU  - Dokmanović, Lidija
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Virijević, Marijana
AU  - Tomin, Dragica
AU  - Vidović, Ana
AU  - Suvajdžić-Vuković, Nada
AU  - Pavlović, Sonja
AU  - Tošić, Nataša
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1303
AB  - lt b gt Uvod: lt /b gt  Akutna limfoblastna leukemija (ALL) je najčešće maligno oboljenje kod dece, dok je kod odraslih njena učestalost mnogo niža. U današnjoj kliničkoj praksi kao najvažnije metode stratifikacije pacijenata u određene grupe rizika koriste se metode identifikacije citogenetičkih aberacija i malog broja molekulanih markera. Tehnologija sekvenciranja nove generacije (SNG) obezbeđuje veliku količinu podataka koji doprinose razjašnjavanju mutacionog profila dečje (dALL) i adultne ALL (aALL).  lt b gt Metode: lt /b gt  Uzorci DNK iz 34 dALL i aALL pacijenata analizirani su primenom SNG ciljanog sekvenciranja ("TruSeq Amplicon Cancer Panel - TSACP") kojim se sekvenciraju "hotspot" mutacije u 48 gena povezanih sa kancerom.  lt b gt Rezultati: lt /b gt  Identifikovano je ukupno 330 varijanti u kodirajućim regionima, od kojih je samo 95 njih za posledicu imalo potencijalnu promenu u proteinu. Posmatrano kod pojedinačnih pacijenata, detektovane mutacije su pretežno remetile Ras/RTK signalni put (STK11, KIT, MET, NRAS, KRAS, PTEN). Pored toga, identifikovano je 5 pacijenata sa istom mutacijom u HNF1A genu, koja je uzrokovala poremećaje u Wnt i Notch signalnom putu. Kod dva pa cijenta otkrivene su varijante u NOTCH1 genu. Nije detektovano istovremeno prisustvo varijanti u HNF1A i NOTCH1 genu, dok su geni uključeni u Ras/RTK signalni put pokazali tendenciju ka akumuliranju mutacija.  lt b gt Zaključak: lt /b gt  Naši rezultati pokazuju da ALL sadrži Mali broj mutacija, bez značajnih razlika između dALL i aALL (medijana po pacijentu 2 odnosno 3). Detektovane mutacije izazivaju poremećaje u nekoliko ključnih signalnih puteva, prvenstveno Ras/RTK kaskade. Ova studija doprinosi ukupnom znanju o mutacionom profilu ALL, što vodi ka boljem razumijevanju molekularne osnove ovog oboljenja.
AB  - lt b gt Background: lt /b gt  Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL).  lt b gt Methods: lt /b gt  We analyzed DNA samples from 34 cALL and aALL patients, using NGS targeted sequencing TruSeq Amplicon - Cancer Panel (TSACP) which targets mutational hotspots in 48 cancer related genes.  lt b gt Results: lt /b gt  We identified a total of 330 variants in the coding regions, out of which only 95 were potentially protein-changing. Observed in individual patients, detected mutations predominantly disrupted Ras/RTK pathway (STK11, KIT, MET, NRAS, KRAS, PTEN). Additionally, we identified 5 patients with the same mutation in HNF1A gene, disrupting both Wnt and Notch signaling pathway. In two patients we detected variants in NOTCH1 gene. HNF1A and NOTCH1 variants were mutually exclusive, while genes involved in Ras/RTK pathway exhibit a tendency of mutation accumulation.  lt b gt Conclusions: lt /b gt  Our results showed that ALL contains low number of mutations, without significant differences between cALL and aALL (median per patient 2 and 3, respectively). Detected mutations affect few key signaling pathways, primarily Ras/RTK cascade. This study contributes to knowledge of ALL mutational landscape, leading to better understanding of molecular basis of this disease.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom
T1  - Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia
EP  - 82
IS  - 1
SP  - 72
VL  - 39
DO  - 10.2478/jomb-2019-0017
ER  - 

@article{
author = "Janić, Dragana and Perić, Jelena and Karan-Đurašević, Teodora and Kostić, Tatjana and Marjanović, Irena and Stanić, Bojana and Pejanović, Nadja and Dokmanović, Lidija and Lazić, Jelena and Krstovski, Nada and Virijević, Marijana and Tomin, Dragica and Vidović, Ana and Suvajdžić-Vuković, Nada and Pavlović, Sonja and Tošić, Nataša",
year = "2020",
abstract = "lt b gt Uvod: lt /b gt  Akutna limfoblastna leukemija (ALL) je najčešće maligno oboljenje kod dece, dok je kod odraslih njena učestalost mnogo niža. U današnjoj kliničkoj praksi kao najvažnije metode stratifikacije pacijenata u određene grupe rizika koriste se metode identifikacije citogenetičkih aberacija i malog broja molekulanih markera. Tehnologija sekvenciranja nove generacije (SNG) obezbeđuje veliku količinu podataka koji doprinose razjašnjavanju mutacionog profila dečje (dALL) i adultne ALL (aALL).  lt b gt Metode: lt /b gt  Uzorci DNK iz 34 dALL i aALL pacijenata analizirani su primenom SNG ciljanog sekvenciranja ("TruSeq Amplicon Cancer Panel - TSACP") kojim se sekvenciraju "hotspot" mutacije u 48 gena povezanih sa kancerom.  lt b gt Rezultati: lt /b gt  Identifikovano je ukupno 330 varijanti u kodirajućim regionima, od kojih je samo 95 njih za posledicu imalo potencijalnu promenu u proteinu. Posmatrano kod pojedinačnih pacijenata, detektovane mutacije su pretežno remetile Ras/RTK signalni put (STK11, KIT, MET, NRAS, KRAS, PTEN). Pored toga, identifikovano je 5 pacijenata sa istom mutacijom u HNF1A genu, koja je uzrokovala poremećaje u Wnt i Notch signalnom putu. Kod dva pa cijenta otkrivene su varijante u NOTCH1 genu. Nije detektovano istovremeno prisustvo varijanti u HNF1A i NOTCH1 genu, dok su geni uključeni u Ras/RTK signalni put pokazali tendenciju ka akumuliranju mutacija.  lt b gt Zaključak: lt /b gt  Naši rezultati pokazuju da ALL sadrži Mali broj mutacija, bez značajnih razlika između dALL i aALL (medijana po pacijentu 2 odnosno 3). Detektovane mutacije izazivaju poremećaje u nekoliko ključnih signalnih puteva, prvenstveno Ras/RTK kaskade. Ova studija doprinosi ukupnom znanju o mutacionom profilu ALL, što vodi ka boljem razumijevanju molekularne osnove ovog oboljenja., lt b gt Background: lt /b gt  Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL).  lt b gt Methods: lt /b gt  We analyzed DNA samples from 34 cALL and aALL patients, using NGS targeted sequencing TruSeq Amplicon - Cancer Panel (TSACP) which targets mutational hotspots in 48 cancer related genes.  lt b gt Results: lt /b gt  We identified a total of 330 variants in the coding regions, out of which only 95 were potentially protein-changing. Observed in individual patients, detected mutations predominantly disrupted Ras/RTK pathway (STK11, KIT, MET, NRAS, KRAS, PTEN). Additionally, we identified 5 patients with the same mutation in HNF1A gene, disrupting both Wnt and Notch signaling pathway. In two patients we detected variants in NOTCH1 gene. HNF1A and NOTCH1 variants were mutually exclusive, while genes involved in Ras/RTK pathway exhibit a tendency of mutation accumulation.  lt b gt Conclusions: lt /b gt  Our results showed that ALL contains low number of mutations, without significant differences between cALL and aALL (median per patient 2 and 3, respectively). Detected mutations affect few key signaling pathways, primarily Ras/RTK cascade. This study contributes to knowledge of ALL mutational landscape, leading to better understanding of molecular basis of this disease.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom, Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia",
pages = "82-72",
number = "1",
volume = "39",
doi = "10.2478/jomb-2019-0017"
}

Janić, D., Perić, J., Karan-Đurašević, T., Kostić, T., Marjanović, I., Stanić, B., Pejanović, N., Dokmanović, L., Lazić, J., Krstovski, N., Virijević, M., Tomin, D., Vidović, A., Suvajdžić-Vuković, N., Pavlović, S.,& Tošić, N.. (2020). Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 39(1), 72-82.
https://doi.org/10.2478/jomb-2019-0017

Janić D, Perić J, Karan-Đurašević T, Kostić T, Marjanović I, Stanić B, Pejanović N, Dokmanović L, Lazić J, Krstovski N, Virijević M, Tomin D, Vidović A, Suvajdžić-Vuković N, Pavlović S, Tošić N. Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom. in Journal of Medical Biochemistry. 2020;39(1):72-82.
doi:10.2478/jomb-2019-0017 .

Janić, Dragana, Perić, Jelena, Karan-Đurašević, Teodora, Kostić, Tatjana, Marjanović, Irena, Stanić, Bojana, Pejanović, Nadja, Dokmanović, Lidija, Lazić, Jelena, Krstovski, Nada, Virijević, Marijana, Tomin, Dragica, Vidović, Ana, Suvajdžić-Vuković, Nada, Pavlović, Sonja, Tošić, Nataša, "Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom" in Journal of Medical Biochemistry, 39, no. 1 (2020):72-82,
https://doi.org/10.2478/jomb-2019-0017 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Lazić, Jelena
AU  - Ristivojević, Bojan
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Milosević, Goran
AU  - Janić, Dragana
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1322
AB  - Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
PB  - MDPI, Basel
T2  - Genes
T1  - Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment
IS  - 4
VL  - 11
DO  - 10.3390/genes11040468
ER  - 

@article{
author = "Kotur, Nikola and Lazić, Jelena and Ristivojević, Bojan and Stanković, Biljana and Gašić, Vladimir and Dokmanović, Lidija and Krstovski, Nada and Milosević, Goran and Janić, Dragana and Zukić, Branka and Pavlović, Sonja",
year = "2020",
abstract = "Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.",
publisher = "MDPI, Basel",
journal = "Genes",
title = "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment",
number = "4",
volume = "11",
doi = "10.3390/genes11040468"
}

Kotur, N., Lazić, J., Ristivojević, B., Stanković, B., Gašić, V., Dokmanović, L., Krstovski, N., Milosević, G., Janić, D., Zukić, B.,& Pavlović, S.. (2020). Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes
MDPI, Basel., 11(4).
https://doi.org/10.3390/genes11040468

Kotur N, Lazić J, Ristivojević B, Stanković B, Gašić V, Dokmanović L, Krstovski N, Milosević G, Janić D, Zukić B, Pavlović S. Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes. 2020;11(4).
doi:10.3390/genes11040468 .

Kotur, Nikola, Lazić, Jelena, Ristivojević, Bojan, Stanković, Biljana, Gašić, Vladimir, Dokmanović, Lidija, Krstovski, Nada, Milosević, Goran, Janić, Dragana, Zukić, Branka, Pavlović, Sonja, "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment" in Genes, 11, no. 4 (2020),
https://doi.org/10.3390/genes11040468 . .

TY  - JOUR
AU  - Gašić, Vladimir
AU  - Stanković, Biljana
AU  - Zukić, Branka
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Milošević, Goran
AU  - Lucafò, Marianna
AU  - Stocco, Gabriele
AU  - Decorti, Giuliana
AU  - Pavlović, Sonja
AU  - Kotur, Nikola
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1269
AB  - Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL.
AB  - Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije
T1  - Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia
EP  - 298
IS  - 3
SP  - 292
VL  - 38
DO  - 10.2478/jomb-2018-0038
ER  - 

@article{
author = "Gašić, Vladimir and Stanković, Biljana and Zukić, Branka and Janić, Dragana and Dokmanović, Lidija and Krstovski, Nada and Lazić, Jelena and Milošević, Goran and Lucafò, Marianna and Stocco, Gabriele and Decorti, Giuliana and Pavlović, Sonja and Kotur, Nikola",
year = "2019",
abstract = "Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL., Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije, Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia",
pages = "298-292",
number = "3",
volume = "38",
doi = "10.2478/jomb-2018-0038"
}

Gašić, V., Stanković, B., Zukić, B., Janić, D., Dokmanović, L., Krstovski, N., Lazić, J., Milošević, G., Lucafò, M., Stocco, G., Decorti, G., Pavlović, S.,& Kotur, N.. (2019). Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 38(3), 292-298.
https://doi.org/10.2478/jomb-2018-0038

Gašić V, Stanković B, Zukić B, Janić D, Dokmanović L, Krstovski N, Lazić J, Milošević G, Lucafò M, Stocco G, Decorti G, Pavlović S, Kotur N. Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2019;38(3):292-298.
doi:10.2478/jomb-2018-0038 .

Gašić, Vladimir, Stanković, Biljana, Zukić, Branka, Janić, Dragana, Dokmanović, Lidija, Krstovski, Nada, Lazić, Jelena, Milošević, Goran, Lucafò, Marianna, Stocco, Gabriele, Decorti, Giuliana, Pavlović, Sonja, Kotur, Nikola, "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 38, no. 3 (2019):292-298,
https://doi.org/10.2478/jomb-2018-0038 . .

TY  - JOUR
AU  - Milosević, Goran
AU  - Kotur, Nikola
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Stanković, Biljana
AU  - Zukić, Branka
AU  - Janić, Dragana
AU  - Jurisić, Vladimir
AU  - Pavlović, Sonja
AU  - Dokmanović, Lidija
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1235
AB  - 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.
PB  - Balkan Union of Oncology (B.U.ON.)
T2  - Journal of Buon
T1  - Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia
EP  - 2083
IS  - 5
SP  - 2075
VL  - 24
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1235
ER  - 

@article{
author = "Milosević, Goran and Kotur, Nikola and Lazić, Jelena and Krstovski, Nada and Stanković, Biljana and Zukić, Branka and Janić, Dragana and Jurisić, Vladimir and Pavlović, Sonja and Dokmanović, Lidija",
year = "2019",
abstract = "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.",
publisher = "Balkan Union of Oncology (B.U.ON.)",
journal = "Journal of Buon",
title = "Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia",
pages = "2083-2075",
number = "5",
volume = "24",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1235"
}

Milosević, G., Kotur, N., Lazić, J., Krstovski, N., Stanković, B., Zukić, B., Janić, D., Jurisić, V., Pavlović, S.,& Dokmanović, L.. (2019). Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia. in Journal of Buon
Balkan Union of Oncology (B.U.ON.)., 24(5), 2075-2083.
https://hdl.handle.net/21.15107/rcub_imagine_1235

Milosević G, Kotur N, Lazić J, Krstovski N, Stanković B, Zukić B, Janić D, Jurisić V, Pavlović S, Dokmanović L. Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia. in Journal of Buon. 2019;24(5):2075-2083.
https://hdl.handle.net/21.15107/rcub_imagine_1235 .

Milosević, Goran, Kotur, Nikola, Lazić, Jelena, Krstovski, Nada, Stanković, Biljana, Zukić, Branka, Janić, Dragana, Jurisić, Vladimir, Pavlović, Sonja, Dokmanović, Lidija, "Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia" in Journal of Buon, 24, no. 5 (2019):2075-2083,
https://hdl.handle.net/21.15107/rcub_imagine_1235 .

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Milošević, Goran
AU  - Perić, Jelena
AU  - Tošić, Nataša
AU  - Krstovski, Nada
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1131
AB  - Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL.
AB  - Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece
T1  - Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia
EP  - 411
IS  - 7-8
SP  - 407
VL  - 146
DO  - 10.2298/SARH171003194D
ER  - 

@article{
author = "Dokmanović, Lidija and Milošević, Goran and Perić, Jelena and Tošić, Nataša and Krstovski, Nada and Janić, Dragana and Pavlović, Sonja",
year = "2018",
abstract = "Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL., Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece, Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia",
pages = "411-407",
number = "7-8",
volume = "146",
doi = "10.2298/SARH171003194D"
}

Dokmanović, L., Milošević, G., Perić, J., Tošić, N., Krstovski, N., Janić, D.,& Pavlović, S.. (2018). Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 146(7-8), 407-411.
https://doi.org/10.2298/SARH171003194D

Dokmanović L, Milošević G, Perić J, Tošić N, Krstovski N, Janić D, Pavlović S. Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo. 2018;146(7-8):407-411.
doi:10.2298/SARH171003194D .

Dokmanović, Lidija, Milošević, Goran, Perić, Jelena, Tošić, Nataša, Krstovski, Nada, Janić, Dragana, Pavlović, Sonja, "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece" in Srpski arhiv za celokupno lekarstvo, 146, no. 7-8 (2018):407-411,
https://doi.org/10.2298/SARH171003194D . .

TY  - JOUR
AU  - Milošević, Goran
AU  - Kotur, Nikola
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Janić, Dragana
AU  - Katsila, Theodora
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
AU  - Dokmanović, Lidija
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1116
AB  - Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije.
AB  - Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije
T1  - Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia
EP  - 327
IS  - 3
SP  - 320
VL  - 37
DO  - 10.1515/jomb-2017-0060
ER  - 

@article{
author = "Milošević, Goran and Kotur, Nikola and Krstovski, Nada and Lazić, Jelena and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Katsila, Theodora and Patrinos, George P. and Pavlović, Sonja and Dokmanović, Lidija",
year = "2018",
abstract = "Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije., Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije, Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia",
pages = "327-320",
number = "3",
volume = "37",
doi = "10.1515/jomb-2017-0060"
}

Milošević, G., Kotur, N., Krstovski, N., Lazić, J., Zukić, B., Stanković, B., Janić, D., Katsila, T., Patrinos, G. P., Pavlović, S.,& Dokmanović, L.. (2018). Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 37(3), 320-327.
https://doi.org/10.1515/jomb-2017-0060

Milošević G, Kotur N, Krstovski N, Lazić J, Zukić B, Stanković B, Janić D, Katsila T, Patrinos GP, Pavlović S, Dokmanović L. Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2018;37(3):320-327.
doi:10.1515/jomb-2017-0060 .

Milošević, Goran, Kotur, Nikola, Krstovski, Nada, Lazić, Jelena, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Katsila, Theodora, Patrinos, George P., Pavlović, Sonja, Dokmanović, Lidija, "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 37, no. 3 (2018):320-327,
https://doi.org/10.1515/jomb-2017-0060 . .

TY  - JOUR
AU  - Gašić, Vladimir
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Dolzan, Vita
AU  - Jazbec, Janez
AU  - Pavlović, Sonja
AU  - Kotur, Nikola
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1099
AB  - Background. Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods. Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTPI (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results. Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the noncarriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rsl 138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions. Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.
PB  - Walter De Gruyter Gmbh, Berlin
T2  - Radiology and Oncology
T1  - Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia
EP  - 306
IS  - 3
SP  - 296
VL  - 52
DO  - 10.2478/raon-2018-0034
ER  - 

@article{
author = "Gašić, Vladimir and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Dokmanović, Lidija and Lazić, Jelena and Krstovski, Nada and Dolzan, Vita and Jazbec, Janez and Pavlović, Sonja and Kotur, Nikola",
year = "2018",
abstract = "Background. Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods. Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTPI (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results. Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the noncarriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rsl 138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions. Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.",
publisher = "Walter De Gruyter Gmbh, Berlin",
journal = "Radiology and Oncology",
title = "Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia",
pages = "306-296",
number = "3",
volume = "52",
doi = "10.2478/raon-2018-0034"
}

Gašić, V., Zukić, B., Stanković, B., Janić, D., Dokmanović, L., Lazić, J., Krstovski, N., Dolzan, V., Jazbec, J., Pavlović, S.,& Kotur, N.. (2018). Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia. in Radiology and Oncology
Walter De Gruyter Gmbh, Berlin., 52(3), 296-306.
https://doi.org/10.2478/raon-2018-0034

Gašić V, Zukić B, Stanković B, Janić D, Dokmanović L, Lazić J, Krstovski N, Dolzan V, Jazbec J, Pavlović S, Kotur N. Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia. in Radiology and Oncology. 2018;52(3):296-306.
doi:10.2478/raon-2018-0034 .

Gašić, Vladimir, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Dokmanović, Lidija, Lazić, Jelena, Krstovski, Nada, Dolzan, Vita, Jazbec, Janez, Pavlović, Sonja, Kotur, Nikola, "Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia" in Radiology and Oncology, 52, no. 3 (2018):296-306,
https://doi.org/10.2478/raon-2018-0034 . .

TY  - JOUR
AU  - Lazić, Jelena
AU  - Kotur, Nikola
AU  - Krstovski, Nada
AU  - Dokmanović, Lidija
AU  - Zukić, Branka
AU  - Predojević-Samardzić, Jelica
AU  - Zivotić, Maja
AU  - Milosević, Goran
AU  - Dorić, Milica
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1080
AB  - Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.
PB  - Srpsko biološko društvo, Beograd, i dr.
T2  - Archives of Biological Sciences
T1  - Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia
EP  - 246
IS  - 2
SP  - 239
VL  - 69
DO  - 10.2298/ABS160325091L
ER  - 

@article{
author = "Lazić, Jelena and Kotur, Nikola and Krstovski, Nada and Dokmanović, Lidija and Zukić, Branka and Predojević-Samardzić, Jelica and Zivotić, Maja and Milosević, Goran and Dorić, Milica and Janić, Dragana and Pavlović, Sonja",
year = "2017",
abstract = "Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.",
publisher = "Srpsko biološko društvo, Beograd, i dr.",
journal = "Archives of Biological Sciences",
title = "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia",
pages = "246-239",
number = "2",
volume = "69",
doi = "10.2298/ABS160325091L"
}

Lazić, J., Kotur, N., Krstovski, N., Dokmanović, L., Zukić, B., Predojević-Samardzić, J., Zivotić, M., Milosević, G., Dorić, M., Janić, D.,& Pavlović, S.. (2017). Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences
Srpsko biološko društvo, Beograd, i dr.., 69(2), 239-246.
https://doi.org/10.2298/ABS160325091L

Lazić J, Kotur N, Krstovski N, Dokmanović L, Zukić B, Predojević-Samardzić J, Zivotić M, Milosević G, Dorić M, Janić D, Pavlović S. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences. 2017;69(2):239-246.
doi:10.2298/ABS160325091L .

Lazić, Jelena, Kotur, Nikola, Krstovski, Nada, Dokmanović, Lidija, Zukić, Branka, Predojević-Samardzić, Jelica, Zivotić, Maja, Milosević, Goran, Dorić, Milica, Janić, Dragana, Pavlović, Sonja, "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia" in Archives of Biological Sciences, 69, no. 2 (2017):239-246,
https://doi.org/10.2298/ABS160325091L . .

TY  - JOUR
AU  - Janković, Srdja
AU  - Marjanović, Irena
AU  - Tošić, Nataša
AU  - Kotur, Nikola
AU  - Dokmanović, Lidija
AU  - Skorić, Dejan
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Rodić, Predrag
AU  - Pavlović, Sonja
AU  - Janić, Dragana
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/946
AB  - Acute leukemias constitute the most common malignancy in childhood, accounting for 25-35% of all cancer in children. They are divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Genetic susceptibility is known to play a major role in childhood leukemias. Wilms tumor (WT)1 is a zinc finger transcription factor involved in regulating the process of cell differentiation; it has been implicated in a wide range of human neoplasms. WT1 overexpression in the bone marrow at diagnosis is reported to be an independent negative prognostic factor in adults and children with AML. The aim of the present investigation was to determine the expression of WT1 in the bone marrow of children with AML and ALL in Serbia and its possible impact on patient survival. We determined bone marrow WT1 expression levels by reverse -transcription polymerase chain reaction (RT-PCR) at diagnosis in 20 children with AML and 20 children with ALL (16 B-ALL and 4 T-ALL), as well as 15 age- and sex-matched controls who were evaluated for immune thrombocytopenic purpura (ITP). For children with AML, follow-up samples were also analyzed one month after treatment initiation and at variable later timepoints of control punctures. The results were normalized based on WT1 expression in controls. We found that children with AML had significantly higher WT1 expression at diagnosis (median SD: 139.42 244.03) than those with ALL (1.18 54.37; Mann -Whitney U=82; p lt 0.01) and ITP (0.76 1.01; U=32; p lt 0.01). Patients with T-ALL had higher WT1 expression than those with B-ALL, though significance was not reached due to subgroup size; differences between AML subgroups according to the French-American-British (FAB) classification were also below the level of significance, though a tendency toward higher values in M3 and M4 leukemias was notable. There was also a tendency toward higher values in 14 children with AML who were still alive after a median follow-up of 1.5 years (181.42 192.52) than in 6 who succumbed to the disease (104.29 354.87). All children with AML who had WT1 expression 1 month after diagnosis below the fourth quartile (10 of 10) were still alive, while only 2 of 5 with 1 -month WT1 expression in the fourth quartile survived (Fisher's exact test: p=0.0952). Taken together, our results support a role for WT1 in the diagnostic workup in children with acute leukemia, although it needs to be considered in view of a complex and indvidualized context.
PB  - Društvo genetičara Srbije, Beograd
T2  - Genetika-Belgrade
T1  - Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia
EP  - 421
IS  - 1
SP  - 409
VL  - 48
DO  - 10.2298/GENSR1601409J
ER  - 

@article{
author = "Janković, Srdja and Marjanović, Irena and Tošić, Nataša and Kotur, Nikola and Dokmanović, Lidija and Skorić, Dejan and Krstovski, Nada and Lazić, Jelena and Rodić, Predrag and Pavlović, Sonja and Janić, Dragana",
year = "2016",
abstract = "Acute leukemias constitute the most common malignancy in childhood, accounting for 25-35% of all cancer in children. They are divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Genetic susceptibility is known to play a major role in childhood leukemias. Wilms tumor (WT)1 is a zinc finger transcription factor involved in regulating the process of cell differentiation; it has been implicated in a wide range of human neoplasms. WT1 overexpression in the bone marrow at diagnosis is reported to be an independent negative prognostic factor in adults and children with AML. The aim of the present investigation was to determine the expression of WT1 in the bone marrow of children with AML and ALL in Serbia and its possible impact on patient survival. We determined bone marrow WT1 expression levels by reverse -transcription polymerase chain reaction (RT-PCR) at diagnosis in 20 children with AML and 20 children with ALL (16 B-ALL and 4 T-ALL), as well as 15 age- and sex-matched controls who were evaluated for immune thrombocytopenic purpura (ITP). For children with AML, follow-up samples were also analyzed one month after treatment initiation and at variable later timepoints of control punctures. The results were normalized based on WT1 expression in controls. We found that children with AML had significantly higher WT1 expression at diagnosis (median SD: 139.42 244.03) than those with ALL (1.18 54.37; Mann -Whitney U=82; p lt 0.01) and ITP (0.76 1.01; U=32; p lt 0.01). Patients with T-ALL had higher WT1 expression than those with B-ALL, though significance was not reached due to subgroup size; differences between AML subgroups according to the French-American-British (FAB) classification were also below the level of significance, though a tendency toward higher values in M3 and M4 leukemias was notable. There was also a tendency toward higher values in 14 children with AML who were still alive after a median follow-up of 1.5 years (181.42 192.52) than in 6 who succumbed to the disease (104.29 354.87). All children with AML who had WT1 expression 1 month after diagnosis below the fourth quartile (10 of 10) were still alive, while only 2 of 5 with 1 -month WT1 expression in the fourth quartile survived (Fisher's exact test: p=0.0952). Taken together, our results support a role for WT1 in the diagnostic workup in children with acute leukemia, although it needs to be considered in view of a complex and indvidualized context.",
publisher = "Društvo genetičara Srbije, Beograd",
journal = "Genetika-Belgrade",
title = "Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia",
pages = "421-409",
number = "1",
volume = "48",
doi = "10.2298/GENSR1601409J"
}

Janković, S., Marjanović, I., Tošić, N., Kotur, N., Dokmanović, L., Skorić, D., Krstovski, N., Lazić, J., Rodić, P., Pavlović, S.,& Janić, D.. (2016). Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia. in Genetika-Belgrade
Društvo genetičara Srbije, Beograd., 48(1), 409-421.
https://doi.org/10.2298/GENSR1601409J

Janković S, Marjanović I, Tošić N, Kotur N, Dokmanović L, Skorić D, Krstovski N, Lazić J, Rodić P, Pavlović S, Janić D. Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia. in Genetika-Belgrade. 2016;48(1):409-421.
doi:10.2298/GENSR1601409J .

Janković, Srdja, Marjanović, Irena, Tošić, Nataša, Kotur, Nikola, Dokmanović, Lidija, Skorić, Dejan, Krstovski, Nada, Lazić, Jelena, Rodić, Predrag, Pavlović, Sonja, Janić, Dragana, "Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia" in Genetika-Belgrade, 48, no. 1 (2016):409-421,
https://doi.org/10.2298/GENSR1601409J . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Stanković, Biljana
AU  - Krstovski, Nada
AU  - Tošić, Nataša
AU  - Katsila, Theodora
AU  - Patrinos, George P.
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/842
AB  - Aims: 6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture. Materials & methods:TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27). Results: A threefold increase of TPMT gene expression was obtained during maintenance therapy, modulated by the architecture of the VNTR region. Conclusion: The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner
EP  - 1712
IS  - 15
SP  - 1701
VL  - 16
DO  - 10.2217/pgs.15.109
ER  - 

@article{
author = "Kotur, Nikola and Dokmanović, Lidija and Janić, Dragana and Stanković, Biljana and Krstovski, Nada and Tošić, Nataša and Katsila, Theodora and Patrinos, George P. and Zukić, Branka and Pavlović, Sonja",
year = "2015",
abstract = "Aims: 6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture. Materials & methods:TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27). Results: A threefold increase of TPMT gene expression was obtained during maintenance therapy, modulated by the architecture of the VNTR region. Conclusion: The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner",
pages = "1712-1701",
number = "15",
volume = "16",
doi = "10.2217/pgs.15.109"
}

Kotur, N., Dokmanović, L., Janić, D., Stanković, B., Krstovski, N., Tošić, N., Katsila, T., Patrinos, G. P., Zukić, B.,& Pavlović, S.. (2015). TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner. in Pharmacogenomics
Future Medicine Ltd, London., 16(15), 1701-1712.
https://doi.org/10.2217/pgs.15.109

Kotur N, Dokmanović L, Janić D, Stanković B, Krstovski N, Tošić N, Katsila T, Patrinos GP, Zukić B, Pavlović S. TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner. in Pharmacogenomics. 2015;16(15):1701-1712.
doi:10.2217/pgs.15.109 .

Kotur, Nikola, Dokmanović, Lidija, Janić, Dragana, Stanković, Biljana, Krstovski, Nada, Tošić, Nataša, Katsila, Theodora, Patrinos, George P., Zukić, Branka, Pavlović, Sonja, "TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner" in Pharmacogenomics, 16, no. 15 (2015):1701-1712,
https://doi.org/10.2217/pgs.15.109 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Stanković, Biljana
AU  - Klaassen, Kristel
AU  - Georgitsi, Marianthi
AU  - Vicha, Anna
AU  - Leontari, Iliana
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Karan-Đurašević, Teodora
AU  - Ugrin, Milena
AU  - Stojiljković, Maja
AU  - Nikčević, Gordana
AU  - Simeonidis, Argiris
AU  - Sivolapenko, Gregory
AU  - Pavlović, Sonja
AU  - Partinos, George P.
AU  - Zukić, Branka
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/554
AB  - Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP. Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner
EP  - 295
IS  - 3
SP  - 283
VL  - 13
DO  - 10.2217/PGS.11.153
ER  - 

@article{
author = "Kotur, Nikola and Stanković, Biljana and Klaassen, Kristel and Georgitsi, Marianthi and Vicha, Anna and Leontari, Iliana and Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Karan-Đurašević, Teodora and Ugrin, Milena and Stojiljković, Maja and Nikčević, Gordana and Simeonidis, Argiris and Sivolapenko, Gregory and Pavlović, Sonja and Partinos, George P. and Zukić, Branka",
year = "2012",
abstract = "Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP. Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner",
pages = "295-283",
number = "3",
volume = "13",
doi = "10.2217/PGS.11.153"
}

Kotur, N., Stanković, B., Klaassen, K., Georgitsi, M., Vicha, A., Leontari, I., Dokmanović, L., Janić, D., Krstovski, N., Karan-Đurašević, T., Ugrin, M., Stojiljković, M., Nikčević, G., Simeonidis, A., Sivolapenko, G., Pavlović, S., Partinos, G. P.,& Zukić, B.. (2012). 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner. in Pharmacogenomics
Future Medicine Ltd, London., 13(3), 283-295.
https://doi.org/10.2217/PGS.11.153

Kotur N, Stanković B, Klaassen K, Georgitsi M, Vicha A, Leontari I, Dokmanović L, Janić D, Krstovski N, Karan-Đurašević T, Ugrin M, Stojiljković M, Nikčević G, Simeonidis A, Sivolapenko G, Pavlović S, Partinos GP, Zukić B. 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner. in Pharmacogenomics. 2012;13(3):283-295.
doi:10.2217/PGS.11.153 .

Kotur, Nikola, Stanković, Biljana, Klaassen, Kristel, Georgitsi, Marianthi, Vicha, Anna, Leontari, Iliana, Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Karan-Đurašević, Teodora, Ugrin, Milena, Stojiljković, Maja, Nikčević, Gordana, Simeonidis, Argiris, Sivolapenko, Gregory, Pavlović, Sonja, Partinos, George P., Zukić, Branka, "6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner" in Pharmacogenomics, 13, no. 3 (2012):283-295,
https://doi.org/10.2217/PGS.11.153 . .

TY  - JOUR
AU  - Krstovski, Nada
AU  - Tošić, Nataša
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Kuzmanović, Milos
AU  - Spasovski, Vesna
AU  - Pavlović, Sonja
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/446
AB  - Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing.FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.
PB  - Humana Press Inc, Totowa
T2  - Medical Oncology
T1  - Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature
EP  - 645
IS  - 3
SP  - 640
VL  - 27
DO  - 10.1007/s12032-009-9261-5
ER  - 

@article{
author = "Krstovski, Nada and Tošić, Nataša and Janić, Dragana and Dokmanović, Lidija and Kuzmanović, Milos and Spasovski, Vesna and Pavlović, Sonja",
year = "2010",
abstract = "Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing.FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.",
publisher = "Humana Press Inc, Totowa",
journal = "Medical Oncology",
title = "Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature",
pages = "645-640",
number = "3",
volume = "27",
doi = "10.1007/s12032-009-9261-5"
}

Krstovski, N., Tošić, N., Janić, D., Dokmanović, L., Kuzmanović, M., Spasovski, V.,& Pavlović, S.. (2010). Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. in Medical Oncology
Humana Press Inc, Totowa., 27(3), 640-645.
https://doi.org/10.1007/s12032-009-9261-5

Krstovski N, Tošić N, Janić D, Dokmanović L, Kuzmanović M, Spasovski V, Pavlović S. Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. in Medical Oncology. 2010;27(3):640-645.
doi:10.1007/s12032-009-9261-5 .

Krstovski, Nada, Tošić, Nataša, Janić, Dragana, Dokmanović, Lidija, Kuzmanović, Milos, Spasovski, Vesna, Pavlović, Sonja, "Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature" in Medical Oncology, 27, no. 3 (2010):640-645,
https://doi.org/10.1007/s12032-009-9261-5 . .

TY  - JOUR
AU  - Lazić, Jelena
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Predojević, Jelica
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
AU  - Janić, Dragana
PY  - 2009
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/387
AB  - Uvod. Akutna limfoblastna leukemija (ALL) je maligna klonalna bolest i jedna od najčešćih neoplazmi dečjeg uzrasta. Primenom savremenih protokola postižu se visok stepen remisije i dugogodišnja stopa preživljavanja. Uvođenjem metoda molekularne genetike omogućeni su submikroskopska klasifikacija i praćenje minimalne rezidualne bolesti (MRB), odgovorne za nastanak recidiva. Cilj rada. Cilj rada je bilo ispitivanje učestalosti rearanžmana genskih lokusa za teške lance imunoglobulina (IgH) i T-ćelijski receptor (TCR) i njihova korelacija s kliničkim parametrima. Metode rada. Ispitano je 41 dete obolelo od ALL kojima je na dijagnozi rađena molekularna detekcija rearanžmana genskih lokusa za IgH i TCR metodom lančanog umnožavanja DNK (PCR). Posmatranje razvoja MRB je rađeno u indukcionoj fazi lečenja, kada se očekuje morfološki odgovor na terapiju. Rezultati. Rearanžman genskog lokusa za IgH zabeležen je kod 82,9%, a za TCR kod 56,1% ispitanika. Posle 33 dana indukcione terapije rearanžmani za IgH genski lokus su zabeleženi kod 39%, a za TCR kod 36,5% dece. Zaključak. Otkrivanje genetskih aberacija na molekularnom nivou i njihova korelacija sa standardnim prognostičkim parametrima ukazala je na značaj nove stratifikacije rizičnih grupa, koje zahtevaju promenu intenziteta hemioterapije. Praćenje MRB se pokazalo preciznim prediktivnim faktorom u nastanku recidiva bolesti. PR Projekat Ministarstva nauke Republike Srbije, br. 143051.
AB  - Introduction. Acute lymphoblastic leukaemia (ALL) is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD) follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR). MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom
T1  - Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia
EP  - 390
IS  - 7-8
SP  - 384
VL  - 137
DO  - 10.2298/SARH0908384L
ER  - 

@article{
author = "Lazić, Jelena and Dokmanović, Lidija and Krstovski, Nada and Predojević, Jelica and Tošić, Nataša and Pavlović, Sonja and Janić, Dragana",
year = "2009",
abstract = "Uvod. Akutna limfoblastna leukemija (ALL) je maligna klonalna bolest i jedna od najčešćih neoplazmi dečjeg uzrasta. Primenom savremenih protokola postižu se visok stepen remisije i dugogodišnja stopa preživljavanja. Uvođenjem metoda molekularne genetike omogućeni su submikroskopska klasifikacija i praćenje minimalne rezidualne bolesti (MRB), odgovorne za nastanak recidiva. Cilj rada. Cilj rada je bilo ispitivanje učestalosti rearanžmana genskih lokusa za teške lance imunoglobulina (IgH) i T-ćelijski receptor (TCR) i njihova korelacija s kliničkim parametrima. Metode rada. Ispitano je 41 dete obolelo od ALL kojima je na dijagnozi rađena molekularna detekcija rearanžmana genskih lokusa za IgH i TCR metodom lančanog umnožavanja DNK (PCR). Posmatranje razvoja MRB je rađeno u indukcionoj fazi lečenja, kada se očekuje morfološki odgovor na terapiju. Rezultati. Rearanžman genskog lokusa za IgH zabeležen je kod 82,9%, a za TCR kod 56,1% ispitanika. Posle 33 dana indukcione terapije rearanžmani za IgH genski lokus su zabeleženi kod 39%, a za TCR kod 36,5% dece. Zaključak. Otkrivanje genetskih aberacija na molekularnom nivou i njihova korelacija sa standardnim prognostičkim parametrima ukazala je na značaj nove stratifikacije rizičnih grupa, koje zahtevaju promenu intenziteta hemioterapije. Praćenje MRB se pokazalo preciznim prediktivnim faktorom u nastanku recidiva bolesti. PR Projekat Ministarstva nauke Republike Srbije, br. 143051., Introduction. Acute lymphoblastic leukaemia (ALL) is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD) follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR). MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom, Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia",
pages = "390-384",
number = "7-8",
volume = "137",
doi = "10.2298/SARH0908384L"
}

Lazić, J., Dokmanović, L., Krstovski, N., Predojević, J., Tošić, N., Pavlović, S.,& Janić, D.. (2009). Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 137(7-8), 384-390.
https://doi.org/10.2298/SARH0908384L

Lazić J, Dokmanović L, Krstovski N, Predojević J, Tošić N, Pavlović S, Janić D. Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom. in Srpski arhiv za celokupno lekarstvo. 2009;137(7-8):384-390.
doi:10.2298/SARH0908384L .

Lazić, Jelena, Dokmanović, Lidija, Krstovski, Nada, Predojević, Jelica, Tošić, Nataša, Pavlović, Sonja, Janić, Dragana, "Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom" in Srpski arhiv za celokupno lekarstvo, 137, no. 7-8 (2009):384-390,
https://doi.org/10.2298/SARH0908384L . .

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Zukić, Branka
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
PY  - 2008
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/309
AB  - Uvod. Tiopurin-S-metiltransferaza (TPMT ) je enzim koji katalizuje inaktivaciju merkaptopurina, leka koji se široko primenjuje u lečenju akutne limfoblastne leukemije (ALL) kod dece. Kada se osobe s nedostatkom TPMT leče standardnim dozama merkaptopurina, kod njih se razvija teška i po život opasna mijelotoksičnost. Cilj rada. Cilj rada je bio da se utvrdi da li kod dece s ALL koji su nosioci mutacije u genu za TPMT individualizovanjem doziranja merkaptopurina može da se smanji mijelotoksičnost terapije, te da li broj tandemskih ponovaka (engl. variable number of tandem repeats - VNTR) u promotoru gena za TPMT ima uticaja na efekte terapije merkaptopurinom. Metod rada Metodima lančane reakcije umnožavanja DNK (engl. polymerase chain reaction - PCR) ispitano je 50 nasumično odabrane dece lečene ALL IC-BFM 2002 protokolom na najčešće mutacije u genu za TPMT. Za 20 dece je PCR metodima određen VNTR genotip. Ispitanicima je tokom faze održavanja beležen broj nedelja kada su terapiju dobijali u punim ili smanjenim dozama, kao i broj nedelja bez terapije. Rezultati Među 50 dece bilo je 29 dečaka (58%) i 21 (42%) devojčica, uzrasta od 1,8 do 17,3 godine (medijana 6,2 godine). Utvrđeno je četvoro (8%) heterozigotnih nosilaca mutacija, kod kojih je otkrivena TPMT*3A varijanta. Posle 12, 14, 16 i 19 nedelja lečenja smanjenim dozama merkaptopurina bolesnici su, zbog dobrog podnošenja terapije, postepeno počeli da primaju punu dozu leka. Nije bilo odlaganja terapije. Smanjenje kumulativne doze merkaptopurina za bolesnike sa TPMT mutacijama bilo je 7,8%, 7,4%, 11,2% i 16,6%. Između dece bez TPMT mutacija i heterozigota nije za- beležena statistički značajna razlika u trajanju lečenja punim (53,6 nasuprot 55,7 nedelja) i smanjenim dozama merkaptopurina (19,9 nasuprot 15,2 nedelje). Otkrivenih VNTR bilo je između četiri i sedam. Većina bolesnika imala je različit broj VNTR na homolognim hromozomima. Najčešće uočen polimorfizam bio je VNTR*5. Nije zabeležena korelacija između nasleđivanja TPMT i VNTR genotipa. Zaključak Farmakogenetskim principima u lečenju ALL dece može se postići napredak u podnošenju lečenja merkaptopurinom.
AB  - INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja
T1  - Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy
EP  - 616
IS  - 11-12
SP  - 609
VL  - 136
DO  - 10.2298/SARH0812609D
ER  - 

@article{
author = "Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Zukić, Branka and Tošić, Nataša and Pavlović, Sonja",
year = "2008",
abstract = "Uvod. Tiopurin-S-metiltransferaza (TPMT ) je enzim koji katalizuje inaktivaciju merkaptopurina, leka koji se široko primenjuje u lečenju akutne limfoblastne leukemije (ALL) kod dece. Kada se osobe s nedostatkom TPMT leče standardnim dozama merkaptopurina, kod njih se razvija teška i po život opasna mijelotoksičnost. Cilj rada. Cilj rada je bio da se utvrdi da li kod dece s ALL koji su nosioci mutacije u genu za TPMT individualizovanjem doziranja merkaptopurina može da se smanji mijelotoksičnost terapije, te da li broj tandemskih ponovaka (engl. variable number of tandem repeats - VNTR) u promotoru gena za TPMT ima uticaja na efekte terapije merkaptopurinom. Metod rada Metodima lančane reakcije umnožavanja DNK (engl. polymerase chain reaction - PCR) ispitano je 50 nasumično odabrane dece lečene ALL IC-BFM 2002 protokolom na najčešće mutacije u genu za TPMT. Za 20 dece je PCR metodima određen VNTR genotip. Ispitanicima je tokom faze održavanja beležen broj nedelja kada su terapiju dobijali u punim ili smanjenim dozama, kao i broj nedelja bez terapije. Rezultati Među 50 dece bilo je 29 dečaka (58%) i 21 (42%) devojčica, uzrasta od 1,8 do 17,3 godine (medijana 6,2 godine). Utvrđeno je četvoro (8%) heterozigotnih nosilaca mutacija, kod kojih je otkrivena TPMT*3A varijanta. Posle 12, 14, 16 i 19 nedelja lečenja smanjenim dozama merkaptopurina bolesnici su, zbog dobrog podnošenja terapije, postepeno počeli da primaju punu dozu leka. Nije bilo odlaganja terapije. Smanjenje kumulativne doze merkaptopurina za bolesnike sa TPMT mutacijama bilo je 7,8%, 7,4%, 11,2% i 16,6%. Između dece bez TPMT mutacija i heterozigota nije za- beležena statistički značajna razlika u trajanju lečenja punim (53,6 nasuprot 55,7 nedelja) i smanjenim dozama merkaptopurina (19,9 nasuprot 15,2 nedelje). Otkrivenih VNTR bilo je između četiri i sedam. Većina bolesnika imala je različit broj VNTR na homolognim hromozomima. Najčešće uočen polimorfizam bio je VNTR*5. Nije zabeležena korelacija između nasleđivanja TPMT i VNTR genotipa. Zaključak Farmakogenetskim principima u lečenju ALL dece može se postići napredak u podnošenju lečenja merkaptopurinom., INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja, Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy",
pages = "616-609",
number = "11-12",
volume = "136",
doi = "10.2298/SARH0812609D"
}

Dokmanović, L., Janić, D., Krstovski, N., Zukić, B., Tošić, N.,& Pavlović, S.. (2008). Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 136(11-12), 609-616.
https://doi.org/10.2298/SARH0812609D

Dokmanović L, Janić D, Krstovski N, Zukić B, Tošić N, Pavlović S. Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja. in Srpski arhiv za celokupno lekarstvo. 2008;136(11-12):609-616.
doi:10.2298/SARH0812609D .

Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Zukić, Branka, Tošić, Nataša, Pavlović, Sonja, "Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja" in Srpski arhiv za celokupno lekarstvo, 136, no. 11-12 (2008):609-616,
https://doi.org/10.2298/SARH0812609D . .

TY  - CONF
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Rodić, Predrag
AU  - Pavlović, Sonja
PY  - 2007
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/274
PB  - Wiley-Liss, Hoboken
C3  - Pediatric Blood & Cancer
T1  - Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia
EP  - 424
IS  - 4
SP  - 424
VL  - 49
UR  - https://hdl.handle.net/21.15107/rcub_imagine_274
ER  - 

@conference{
author = "Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Lazić, Jelena and Rodić, Predrag and Pavlović, Sonja",
year = "2007",
publisher = "Wiley-Liss, Hoboken",
journal = "Pediatric Blood & Cancer",
title = "Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia",
pages = "424-424",
number = "4",
volume = "49",
url = "https://hdl.handle.net/21.15107/rcub_imagine_274"
}

Dokmanović, L., Janić, D., Krstovski, N., Lazić, J., Rodić, P.,& Pavlović, S.. (2007). Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia. in Pediatric Blood & Cancer
Wiley-Liss, Hoboken., 49(4), 424-424.
https://hdl.handle.net/21.15107/rcub_imagine_274

Dokmanović L, Janić D, Krstovski N, Lazić J, Rodić P, Pavlović S. Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia. in Pediatric Blood & Cancer. 2007;49(4):424-424.
https://hdl.handle.net/21.15107/rcub_imagine_274 .

Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Lazić, Jelena, Rodić, Predrag, Pavlović, Sonja, "Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia" in Pediatric Blood & Cancer, 49, no. 4 (2007):424-424,
https://hdl.handle.net/21.15107/rcub_imagine_274 .