
<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/">
  <dc:creator>Milošević, Zorica, 1985-</dc:creator>
  <dc:title xml:lang="srp">Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju : doktorska disertacija</dc:title>
  <dc:description xml:lang="srp">Kаrcinomi štitаste žlezde su nаjčešći mаligniteti endokrinog sistemа.
Klаsifikаcijа ovih mаlignitetа je izvršenа nа osnovu njihovih histopаtoloških
kаrаkteristikа nа pаpilаrni, folikulаrni medulаrni i аnаplаstični kаrcinom (ATC).
Većinа karcinoma štitаste žlezde je dobro diferencirаnа i imа odličnu prognozu
(pаpilаrni i folikulаrni), dok аnаplаstični kаrcinom predstаvljа аgresivni tip sа izrаzito
lošom prognozom uprkos rаzličitim terаpijskim pristupimа u njegovom lečenju.
Promene u PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnim putevima su
karakteristične za nastanak karcinoma štitaste žlezde, koji su urođeno rezistentni na
klasičnu hemioterapiju. Upravo promene u аktivnosti PI3K/AKT/mTOR i
RAS/MAPK/ERK signаlnih putevа mogu dovesti i do rezistencije nа klаsične
hemioterаpeutike. Još jedan od mogućih uzroka neuspehа hemioterаpije je i pojаvа
višestruke (engl. multi-drug, MDR) rezistencije. Najčešći uzrok MDR-a je povišena
ekspresija P-gp i BCRP transportnih pumpi.
Cilj ove studije je bio ispitivanje uloge ključnih komponenti
PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnih putevа u pаtogenezi i rezistenciji
ATC. Analizirane su promene na genskom i proteinskom nivou u uzorcima pаcijenаtа
obolelih od ovog tipa kаrcinomа, kao i efekat inhibicije komponenti signalnih puteva
kod humanih ATC ćelijskih linija. Pored toga, ispitana je i uloga P-gp i BCRP pumpi
u rezistenciji ATC.
Pokazano je da su i PI3K/AKT/mTOR i RAS/MAPK/ERK signаlni putevi
važni za genezu ATC, kao i da se pritom međusobno isključuju. NRAS onkogen i p53
tumor supresor su izmenjeni u ispitivanim tumorskim uzorcima sa visokom
učestalošću. Najčešće je izmenjen NRAS gen što ukazuje na njegovu ključnu ulogu u
razvoju ATC. Sve otkrivene mutacije u NRAS genu i dve mutacije u p53 genu su po
prvi put prijavljene kod ATC.
In vitro studije su pokazale da se inhibicijom komponenti RAS/MAPK/ERK i
PI3K/AKT/mTOR signalnih puteva povećava senzitivnost humanih ATC ćelija na
klasičnu hemioterapiju. Najefikasnijim se pokazao dvostruki mTOR inhibitor
AZD2014, kako u pojedinačnim tretmanima tako i u kombinaciji sa paklitakselom
(PTX) i doksorubicinom (DOX)...</dc:description>
  <dc:description xml:lang="eng">Thyroid carcinoma is the most common malignancy of the endocrine system.
Thyroid malignancies are classified according to their histopathological characteristic
as papillary, follicular, medullary and anaplastic thyroid carcinoma (ATC). Most
thyroid malignancies (papillary thyroid carcinoma and follicular thyroid carcinoma)
are well differentiated and have favorable prognosis. On the other hand, ATC is one
of the most aggressive human cancers, with an intrinsic resistance and dismal
prognosis despite various therapeutic modalities. Changes in components of
RAS/MAPK/ERK and PI3K/AKT/mTORpathways are common in thyroid cancer
genesis which are resistant to classic chemotherapy agents. Changes in the activity of
RAS/MAPK/ERK and PI3K/AKT/mTORsignaling pathways can lead to drug
resistance. Besides these changes, possible cause of chemotherapy resistance is also
multi-drug resistance (MDR). The most common cause of MDR is high expression of
P-gp and BCRP proteins.
The aim of this study was to investigate the role of the key components of
RAS/MAPK/ERK and PI3K/AKT/mTOR pathways in the pathogenesis and
chemoresistance of ATC. We analyzed gene and protein changes in set of ATC
patient samples. We also investigated the role of inhibition of RAS/MAPK/ERK and
PI3K/AKT/mTOR pathways in ATC chemosensitization using human ATC cell lines.
The role of P-gp and BCRP proteins in ATC chemoresistance was also investigated.
Analysis of alterations in RAS/MAPK/ERK and PI3K/AKT/mTOR pathways
in ATC patients indicated that both pathways cooperate in the development of ATC.
Our results revealed a negative correlation between the activity of RAS/MAPK/ERK
and PI3K/AKT/mTOR pathways in the samples of ATC patients. NRAS oncogene and
p53 tumor suppressor are mutated with high frequency in our set of ATC samples.
NRAS is dominantly mutated gene, indicating the importance of this gene in ATC
development. All detected mutations in NRAS gene, and two mutations in p53 gene,
have never been reported in ATC genesis before...</dc:description>
  <dc:description xml:lang="srp">Molekularna onkologija - Kancerogeneza / Molecular oncology - Cancerogenesis  Datum odbrane: 26.12.2014 </dc:description>
  <dc:format>122 lista</dc:format>
  <dc:format>4518840 bytes</dc:format>
  <dc:identifier>https://phaidrabg.bg.ac.rs/o:11053</dc:identifier>
  <dc:identifier>cobiss:1024938162</dc:identifier>
  <dc:identifier>thesis:2847</dc:identifier>
  <dc:language>srp</dc:language>
  <dc:subject xml:lang="srp">OSNO - Opšta sistematizacija naučnih oblasti, Molekularna biologija</dc:subject>
  <dc:subject xml:lang="eng">OSNO - Opšta sistematizacija naučnih oblasti, Molekularna biologija</dc:subject>
  <dc:subject xml:lang="srp">Anaplastični karcinom štitaste žlezde (ATC), PI3K/AKT/mTORsignаlni put, RAS/MAPK/ERK signаlni put, rezistencija ATC, invazivnost ATC,dvostruki mTOR inhibitor, AZD2014, paklitaksel (PTX)</dc:subject>
  <dc:subject xml:lang="eng">Anaplastic thyroid cancer (ATC), RAS/MAPK/ERKpathway,PI3K/AKT/mTOR pathway, ATC chemoresistance, ATC invasiveness, dual mTORinhibitor, AZD2014, paclitaxel (PTX)</dc:subject>
  <dc:subject xml:lang="srp">577.2:616.44-006.6(043.3) </dc:subject>
  <dc:date>2014</dc:date>
  <dc:rights>http://creativecommons.org/licenses/by-nc-nd/2.0/at/legalcode</dc:rights>
  <dc:contributor>Stamenković-Radak, Marina, 1958-</dc:contributor>
  <dc:contributor>Banković, Jasna</dc:contributor>
  <dc:contributor>Tanić, Nikola</dc:contributor>
  <dc:contributor>Pešić, Milica</dc:contributor>
  <dc:contributor>Džodić, Radan, 1952-</dc:contributor>
  <dc:type>info:eu-repo/semantics/bachelorThesis</dc:type>
</oai_dc:dc>