Browsing by Author "Durdu, S."

Now showing 1 - 4 of 4

Open Access
Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection
(Blackwell Publishing Ltd, 2012) Durdu, S.; Deniz, G. C.; Balci, D.; Zaim, C.; Dogan, A.; Can, A.; Akcali, K. C.; Akar, A. R.
Aims: This study investigates the expression patterns of BCL2 (B-cell CLL/lymphoma2) family of proteins and the extent of vascular smooth muscle cell (VSMC) apoptosis in thoracic aortic aneurysms (TAA), type-A aortic dissections (TAD), and nondilated ascending aortic samples. Methods: Aortic wall specimens were obtained from patients undergoing surgical repair for TAA (n = 24), TAD (n = 20), and normal aortic tissues from organ donors (n = 6). The expression pattern of BCL2, BCL2L1 (BCL2-like1), BAK1 (BCL2-antagonist/killer1), and BAX (BCL2-associated X protein) proteins was investigated by immunohistochemistry. Furthermore, colocalization of alpha smooth muscle actin (ACTA2) and caspase3 (CASP3) in aortic VSMCs was analyzed by double-immunofluorescence staining. Onset of DNA fragmentation was measured by TUNEL assay. Results: Apoptotic index was significantly increased in both TAD group (31.3 ± 17.2, P < 0.001) and TAA group (21.1 ± 12.7, P = 0.001) relative to control aortas (2.0 ± 1.2). Anti-CASP3 and ACTA2 double-immunostaining confirmed apoptosis in VSMCs in TAA and TAD groups but not in controls. Proapoptotic BAX expression was significantly elevated in VSMCs of TAA patients, compared with that of controls (OR = 20; P = 0.02; 95% CI, 16-250). In contrast, antiapoptotic BCL2L1 expression was higher in controls compared with that of TAA group (OR = 11.2; P = 0.049; 95% CI, 1.0-123.9). Furthermore, BAX/BCL2 ratio was significantly increased in both TAA (1.2 ± 0.7, P < 0.001) and TAD (0.6 ± 0.4, P = 0.05) groups relative to controls (0.2 ± 0.1, P < 0.001). Conclusions: Apoptotic VSMC depletion in human TAA/TAD is associated with disturbance of the balance between proapoptotic and antiapoptotic members of the BCL2 family proteins, which may have a role in the pathogenesis of vascular remodelling in aortic disease. In light of the future studies, targeting apoptotic pathways in TAA and TAD pathogenesis may provide therapeutic benefits to patients by slowing down the progression and even possibly preventing the TAD. © 2012 Blackwell Publishing Ltd.
Open Access
A combined ULBP2 and SEMA5A expression signature as a prognostic and predictive biomarker for colon cancer
(Ivyspring International Publisher, 2017) Demirkol, S.; Gomceli, I.; Isbilen, M.; Dayanc, B. E.; Tez, M.; Bostanci, E. B.; Turhan, N.; Akoglu, M.; Ozyerli, E.; Durdu, S.; Konu, O.; Nissan, A.; Gonen, M.; Gure, A. O.
Background: Prognostic biomarkers for cancer have the power to change the course of disease if they add value beyond known prognostic factors, if they can help shape treatment protocols, and if they are reliable. The aim of this study was to identify such biomarkers for colon cancer and to understand the molecular mechanisms leading to prognostic stratifications based on these biomarkers. Methods and Findings: We used an in house R based script (SSAT) for the in silico discovery of stage-independent prognostic biomarkers using two cohorts, GSE17536 and GSE17537, that include 177 and 55 colon cancer patients, respectively. This identified 2 genes, ULBP2 and SEMA5A, which when used jointly, could distinguish patients with distinct prognosis. We validated our findings using a third cohort of 48 patients ex vivo. We find that in all cohorts, a combined ULBP2/SEMA5A classification (SU-GIB) can stratify distinct prognostic sub-groups with hazard ratios that range from 2.4 to 4.5 (p=0.01) when overall- or cancer-specific survival is used as an end-measure, independent of confounding prognostic parameters. In addition, our preliminary analyses suggest SU-GIB is comparable to Oncotype DX colon(®) in predicting recurrence in two different cohorts (HR: 1.5-2; p=0.02). SU-GIB has potential as a companion diagnostic for several drugs including the PI3K/mTOR inhibitor BEZ235, which are suitable for the treatment of patients within the bad prognosis group. We show that tumors from patients with worse prognosis have low EGFR autophosphorylation rates, but high caspase 7 activity, and show upregulation of pro-inflammatory cytokines that relate to a relatively mesenchymal phenotype. Conclusions: We describe two novel genes that can be used to prognosticate colon cancer and suggest approaches by which such tumors can be treated. We also describe molecular characteristics of tumors stratified by the SU-GIB signature.
Open Access
Timing of induction of cardiomyocyte differentiation for in vitro cultured mesenchymal stem cells: a perspective for emergencies
(NRC Research Press, 2009) Tokçaer-Keskin, Zeynep; Akar, A. R.; Ayaloğlu-Bütün, Fatma; Terzioğlu-Kara, Ece; Durdu, S.; Özyurda, U.; Uğur, M.; Akçalı, Kamil C.
Mesenchymal stem cells (MSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes, and cardiomyocytes. Several established methods are presently available for in vitro isolation of MSCs from bone marrow. However, the duration necessary to culture them can be a major handicap to cell-based therapies needed for such urgent cardiovascular conditions as acute myocardial infarction and acute hindlimb ischemia. The best timing of car- diomyocyte differentiation induction after MCS isolation and expansion is still an unresolved issue. Our goal was to investigate the possibility of obtaining functional cardiomyocytes from rat MSC within a shorter time period. We examined MSCs' colony-forming capacity, CD90 and CD34 immunoreactivity during the 14 days of culturing. Cardiomyocyte differentiation was induced by 5-azacytidine. Immunohistochemic staining, together with intracellular Ca2+ measurement experiments, revealed that MSCs do not differentiate into any specific cell lineage but show the characteristics of MSCs on both the 9th and 14th days of the culture. To check the potential for differentiation into cardiomyocytes, experiments with caffeine application and depolarization with KCl were performed. The cells possessed some of the specific biochemical features of contracting cells, with slightly higher capacities on the 14th day. Cells from 9th and 14th days of the culture that were treated with 5-azacytidine had a higher expression of cardiac-specific markers such as troponin I, α-sarcomeric actin, and MEF2D compared with the control groups. This study illustrates that it is possible to get functional cardiomyocytes from in vitro MSC culture in a shorter time period than previously achieved. This reduction in time may provide emergency cases with access to cell-based therapies that may have previously been unavailable.
Open Access
Validation of the EuroSCORE risk models in Turkish adult cardiac surgical population
(Oxford University Press, 2011) Akar, A. R.; Kurtcephe, M.; Sener, E.; Alhan, C.; Durdu, S.; Kunt, A. G.; Güvenir, H. A.
Objective: The aim of this study was to validate additive and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) models on Turkish adult cardiac surgical population. Methods: TurkoSCORE project involves a reliable web-based database to build up Turkish risk stratification models. Current patient population consisted of 9443 adult patients who underwent cardiac surgery between 2005 and 2010. However, the additive and logistic EuroSCORE models were applied to only 8018 patients whose EuroSCORE determinants were complete. Observed and predicted mortalities were compared for low-, medium-, and high-risk groups. Results: The mean patient age was 59.5 years (±12.1 years) at the time of surgery, and 28.6% were female. There were significant differences (all p< 0.001) in the prevalence of recent myocardial infarction (23.5% vs 9.7%), moderate left ventricular function (29.9% vs 25.6%), unstable angina (9.8% vs 8.0%), chronic pulmonary disease (13.4% vs 3.9%), active endocarditis (3.2% vs 1.1%), critical preoperative state (9.0% vs 4.1%), surgery on thoracic aorta (3.7% vs 2.4%), extracardiac arteriopathy (8.6% vs 11.3%), previous cardiac surgery (4.1% vs 7.3%), and other than isolated coronary artery bypass graft (CABG; 23.0% vs 36.4%) between Turkish and European cardiac surgical populations, respectively. For the entire cohort, actual hospital mortality was 1.96% (n = 157; 95% confidence interval (CI), 1.70-2.32). However, additive predicted mortality was 2.98% (p< 0.001 vs observed; 95%CI, 2.90-3.00), and logistic predicted mortality was 3.17% (p< 0.001 vs observed; 95%CI, 3.03-3.21). The predictive performance of EuroSCORE models for the entire cohort was fair with 0.757 (95%CI, 0.717-0.797) AUC value (area under the receiver operating characteristic, AUC) for additive EuroSCORE, and 0.760 (95%CI, 0.721-0.800) AUC value for logistic EuroSCORE. Observed hospital mortality for isolated CABG was 1.23% (n = 75; 95%CI, 0.95-1.51) while additive and logistic predicted mortalities were 2.87% (95%CI, 2.82-2.93) and 2.89% (95%CI, 2.80-2.98), respectively. AUC values for the isolated CABG subset were 0.768 (95%CI, 0.707-0.830) and 0.766 (95%CI, 0.705-0.828) for additive and logistic EuroSCORE models. Conclusion: The original EuroSCORE risk models overestimated mortality at all risk subgroups in Turkish population. Remodeling strategies for EuroSCORE or creation of a new model is warranted for future studies in Turkey. © 2011 European Association for Cardio-Thoracic Surgery.