​Davor Galušić

Ime i prezime: dr. sc. DAVOR GALUŠIĆ, dr. med.
 
Naslov disertacije: „ANALIZA AURORA KINAZA A / POLO KINAZA 1 SIGNALNOG PUTA U OBOLJELIH OD MIJELOFIBROZE“
 
Mentor: prof. dr. sc. RAJKO KUŠEC
 
Datum obrane: 10. ožujka 2021.
 
Poveznica: https://library.foi.hr/lib/knjiga.php?B=419&H=&E=&V=&lok=&zbi=&item=3546&nivo=&upit=galu%9Ai%E6


Kvalifikacijski znanstveni radovi za doktorsku disertaciju:


Galusic D, Lucijanic M, Livun A, Radman M, Blaslov V, Cutura LV, Petric M, Miljak A, Lucijanic J, Hofman, ID, Kusec R. Higher AURKA and PLK1 expression are associated with inferior overall T survival in patients with myelofibrosis. Blood Cells Mol Dis. 2020;81:102396.
 
Galusic D, Lucijanic M, Livun A, Radman M, Lucijanic J, Hofman ID, Kusec R. CDC25c expression in patients with myelofibrosis is associated with stronger myeloproliferation and shorter overall survival. Wien Klin Wochenschr Suppl. 2020;10.1007/s00508-020-01738-2.
 
SAŽETAK:
 
Aurora kinaza A (AURKA), protein Aurora borealis (BORA), Polo-like kinaza 1 (PLK1) i Cell-division-cycle 25c (CDC25c) kontroliraju stanični ciklus i ulazak stanice u mitozu, a njihova disregulacija opisana je u brojnim malignim bolestima. Cilj rada bio je ispitati do sad nedovoljno istražen izražaj njihovih mRNA u mijeloproliferativnoj bolesti, mijelofibrozi (MF). Iz citoloških punktata koštane srži urađena je PCR mRNA analiza navedenih gena u 43 bolesnika s mijelofibrozom, i to 28 s primarnom (PMF) i 15 sa sekundarnom mijelofibrozom (SMF). U kontrolnim skupinama bilo je 12 ispitanika s agresivnim ne-Hodginovim limfom bez infiltracije koštane srži i 6 ispitanika s reaktivnom promjenom koštane srži bez zloćudne bolesti. Optimalne granične vrijednosti izražaja mRNA za diskriminaciju preživljenja odabrane su korištenjem analize ROC krivulje. Nije bilo značajne razlike u izražaju AURKA mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.466). Viša vrijednost izražaja AURKA mRNA značajno je povezana s većim apsolutnim brojem monocita (P=0.024) i kraćim ukupnim preživljenjem (HR=3.77; P=0.012). U bolesnika s PMF i SMF značajno je niži izražaj BORA mRNA u odnosu na kontrolne ispitanike (P=0.009). Viša vrijednost izražaja BORA mRNA značajno je povezana s povoljnim prognostičkim pokazateljima: odsutnošću konstitucijskih simptoma (P=0.049) i cirkulirajućih blasta (P=0.047), ali bez značajne povezanosti s ukupnim preživljenjem (P>0.05). Nije bilo značajne razlike u izražaju PLK1 mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.103). Viša vrijednost izražaja PLK1 mRNA značajno je povezana s većim ukupnim brojem leukocita (P=0.042) i kraćim ukupnim preživljenjem (HR=5.87; P=0.003). Nije bilo značajne razlike u izražaju CDC25c mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.162). Viša vrijednost izražaja CDC25c mRNA značajno je povezana s nepovoljnim prognostičkim pokazateljima: većom jetrom (P=0.022), većim ukupnim brojem leukocita (P=0.017), većim apsolutnim brojem neutrofila (P=0.010), monocita (P=0.050), bazofila (P=0.012) i eozinofila (P=0.013) te kraćim ukupnim preživljenjem (HR=2.99; P=0.049). Izražaj ovih gena ima utjecaj na ukupno preživljenje u mijelofibrozi te istraživanje treba proširiti na druge hematološke zloćudne bolesti i one s reaktivnim i prolaznim promjenama hematopoeze.
 
SUMMARY:
 
“AURORA KINASE A / POLO-LIKE KINASE 1 SIGNALING PATHWAY ANALYSIS IN PATIENTS WITH MYELOFIBROSIS”
 
Aurora kinase A (AURKA), Aurora borealis protein (BORA), Polo-like kinase 1 (PLK1) and Cell-division-cycle 25c (CDC25c) are required for cell cycle control and promotion of mitosis entry. Their dysregulation has been described in a number of malignant diseases. However, their role in pathogenesis of myelofibrosis is less known. We investigated AURKA, BORA, PLK1 and CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary - PMF, 15 secondary myelofibrosis - SMF) and 18 controls (the first control group of 12 with limited stage of aggressive non Hodgkin lymphoma without bone marrow involvement and the second group of 6 with nonmalignant reactive bone marrow). Optimal cut-off values for dichotomization of expression levels of investigated genes for the purpose of survival analysis were done using the ROC curve analysis with survival status as a classification variable. AURKA mRNA expression did not significantly differ between myelofibrosis and controls (P=0.466). Higher AURKA expression was significantly associated with higher absolute monocyte count (P=0.024) and shorter overall survival (HR=3.77; P=0.012). Patients with both PMF and SMF had lower BORA mRNA expression than controls (P=0.009). Higher BORA expression was significantly associated with favourable prognostic factors: absence of constitutional symptoms (P=0.049) and absence of circulatory blasts (P=0.047), but with neutral effect on survival (P>0.05). PLK1 mRNA expression did not significantly differ between myelofibrosis and controls (P=0.103). Higher PLK1 expression was significantly associated with higher white blood cell count (P=0.042) and inferior overall survival (HR=5.87; P=0.003). CDC25c mRNA expression did not significantly differ between myelofibrosis and controls (P=0.162). Higher CDC25c mRNA was significantly associated with unfavourable prognostic factors: higher white blood cells count (P=0.017), larger liver size (P=0.022), higher absolute neutrophil (P=0.010), monocyte (P=0.050), basophil (P=0.012) and eosinophil counts (P=0.013) and inferior overall survival (HR=2.99; P=0.049). In conclusion, these genes effects survival and seem to be involved in pathogenesis of myelofibrosis. Future studies investigating these genes in hematological malignancies, as well as in reactive disorders, are warranted.
 
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