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    <ns1:title language="sr">Analiza genetskih biomarkera redoks homeostaze kao faktora rizika za nastanak i progresiju svetloćelijskog karcinoma bubrežnog parenhima</ns1:title>
    <ns2:subtitle language="sr">doktorska disertacija</ns2:subtitle>
    <ns2:alt_title language="en">The analysis of redox homeostasis genetic biomarkers as risk factors for clear cell renal cell carcinoma development and progression : doctoral dissertation</ns2:alt_title>
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    <ns1:description language="sr">Uvod: Hemijske reakcije koje se kontinuirano odvijaju na ćelijskom nivou, praćene sunepotpunom redukcijom kiseonika čime nastaju kiseonični slobodni radikali (engl. reactiveoxygen species, ROS). Njihovo prisustvo aktivira niz antioksidantnih sistema koji će raditi nauklanjanju ROS. Aktivacija nuklearnog faktora povezanog sa eritroid 2-faktorom 2 (engl. nuclearfactor erythroid 2-related factor 2, Nrf2), dovodi do ekspresije enzima, poput superoksiddizmutaza (SOD), glutation peroksidaza (GPX) i glutation S-transferaza (GST), koji učestvuju uantioksidantnom odgovoru. Tumorska mikrosredina sa prooksidantnom aktivnošću ima velikiznačaj u nastanku i daljoj progresiji svetloćelijskog karcinoma bubrežnog parenhima. Cilj ovogispitivanja bio je da se ispita da li najčešći genetski polimorfizmi za gene Nrf2, SOD2, GPX1 iGSTP1 mogu imati uticaj na nastanak sKBP.Materijal i metode: Sprovedena je genotipizacija polimorfizama Nrf2 (rs6721961), SOD2(rs4880), GPX1 (rs1050450) kao i GSTP1 (rs1695, rs1138272) kod 223 pacijenta sa dijagnozomsKBP i 336 pripadnika kontrolne grupe, odgovarajućim metodama reakcije lančanog umnožavanja(engl. PCR). Ispitivana je povezanost pomenutih polimorfizama sa rizikom za nastanak sKBP, kaoi sa fenotipskim karakteristikama tumora i postojanje udruženog efekta sa poznatim faktorimarizika za nastanak KBP. Takođe je praćeno preživljavanje pacijenata nakon učinjene hirurškeresekcije tumora u periodu od 13 godina, i mogući prognostički značaj ispitivanih polimorfizama.Rezultati: Osobe nosioci varijantnih genotipova za SOD2 polimorfizam imaju 4,5 puta većirizik za nastanak sKBP u odnosu na nosioce referentnog genotipa (p&lt;0,001). Osobe nosiocivarijantnih genotipova za GSTP1 rs1695 polimorfizam, koje su istovremeno nosioci referentnoggenotipa za rs1138272, imaju 3,2 puta veći rizik za nastanak sKBP (p=0,001), dok je ispitivanjemhaplotipa za navedene polimorfizme pokazano da su u 3,5 puta većem riziku osobe nosioci Val105i Val114 genotipa u odnosu na nosioce referentne kombinacije Ile105 i Ala114 (p=0,004).Hipertenzivni ispitanici, koji su uz to nosioci varijantnih genotipova za SOD2, imaju čak 12 putaveći rizik za nastanak sKBP u odnosu na referentnu grupu (p&lt;0,001). Ispitivani polimorfizmi nisupredstavljali značajan prognostički faktor među pacijentima obolelim od sKBP. Međutim, nosiocivarijantnih kombinacija ispitivanih GSTP1 rs1695 i rs1138272 polimorfizama imali su kraćiperiod preživljavanja nakon nerfrektomije.Zaključak: Pojedini polimorfizmi gena koji kodiraju antiokioksidantne enzime mogu bitipovezani sa nastankom sKBP, posebno varijantni genotipovi SOD2 rs4880 i varijantni genotipoviGSTP1 rs1695 i rs1138272 polimorfizama. Rizik za nastanak sKBP se dodatno povećava kada suovi rizični genotipovi prisutni u kombinaciji. Takođe, nosioci kombinovanih varijantnihgenotipova rs1695 i rs1138272 GSTP1, imali su kraći period preživljavanja u odnosu na nosiocekombinacije referentnih genotipova.</ns1:description>
    <ns1:description language="en">Introduction: Continuous cellular chemical reactions result in incomplete oxygen reactionwhich produce reactive oxygen species (ROS). Their accumultation stimulates activation ofantioxidative systems as resistance mechanisms. Activated nuclear factor erythroid 2-related factor2 (Nrf2) further causes antioxidant enzymes expression, such as superoxide dismutases (SOD),glutathione peroxidases (GPX), as well as glutathione S-transferases (GST). Prooxidant tumorenvironment is of great significance for promoting development and progression of clear cell renalcell carcinoma (ccRCC). The aim of this study was to evaluate importance of geneticpolymorphisms of Nrf2, GSTP1, SOD2 and GPX1 genes in case of ccRCC.Material and methods: Genotyping of Nrf2 (rs6721961), SOD2 (rs4880), GPX1(rs1050450) and GSTP1 (rs1695, rs1138272) polymorphisms was performed in 223 cases ofccRCC and 336 matched controls by polymerase chain reaction. The connection betweeninvestigated polmorphysms and risk for ccRCC development, as well as their relation to tumorfenotype characteristics with or without contributing factors, were examined. Furthermore, overallsurvival after surgical resection in relation to beformentioned genotypes, was studied during thecourse of 13 years.Results: Carriers of SOD2 variant genotypes expressed 4.5 fold increased risk for ccRCCin comparison to referent genotype carriers (p&lt;0.001). Similarly, variant genotypes carriers ofGSTP1 rs1695 also carrying referent rs1138272 genotype, exhibited 3.2 fold increased risk(p=0.001), while haplotype analysis for two GSTP1 polymorphisms showed 3.5 fold increased riskfor Val105 and Val114 carriers in comparison to referent combination consisting of Ile105 andAla114 (p=0.004). Hypertension as risk factor in combination with variant SOD2 genotype had 12fold increased risk for ccRCC compared to referent group (p&lt;0.001). Examined polymorphismswere not shown to be of significant prognostic importance for patients with ccRCC, althoughvariant genotype carriers of examined GSTP1 polymorphisms did have shorter overall survival.Conclusions: Certain gene polymorphisms encoding antioxidant enzymes might beassociated with the risk for ccRCC, with emphasis on variant genotype of SOD2 rs4880polymorphism and variant genotypes of rs1695 and rs1138272 GSTP1 polymorphisms.Combination of these genotypes may even further significantly increase the risk. Furthermore,carriers of variant genotypes of rs1695 and rs1138272 GSTP1 polymorphisms had shorter survivalperiod in comparison to individuals with referent combination of these genotypes.</ns1:description>
    <ns1:description language="sr">Medicina - Biologija tumora i oksidativna oboljenja / Medicine - Biology of tumors and oxidative diseases  
Datum odbrane: 15.07.2024.</ns1:description>
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