Browsing by Author "Malkan, Ü. Y."

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Open Access
Ankaferd Hemostat affects etoposide resistance of the malignant melanoma cells
(Akademi Doktorlar Yayınevi, 2020) Ghasemi, M.; Okay, M.; Malkan, Ü. Y.; Türk, S.; Jabbar, Javaid; Hocaoğlu, H.; Haznedaroğlu, İ. C.
The development of resistance towards chemotherapeutic drugs has become an obstacle in treatment of cancer. Ankaferd Hemostat [ABS] has shown to suppress the proliferation of melanoma cells, but little is known about its’ mechanism. In this study, we demon¬strate that ABS can make some melanoma cell lines such as A2058 more sensitive towards etoposide by altering the genes involved in oxidative phosphorylation [OXPHOS] pathway. ABS treatment has shown to increase the sensitivity of A2058 towards etoposide and showed no effect for SK-MEL-5. Previously known to be more resistant to etoposide, SK-MEL-30 showed least amount of sen¬sitivity to ABS. We found mitochondrion cluster to be the most relevant to genes altered by ABS. To validate our claim, we compared two sets of melanoma cell lines; A375 with A2058 and A375 with SK-MEL-2. The clusters that we obtained from A375 and A2058 comparison did contain mitochondrial related clusters, their corresponding p value was not significant. Whereas, the clusters from A375 and SK-MEL-2 comparison contain 72 genes in ‘oxidoreductase’ cluster with enrichment score of 2.52. To get insight of the oxidoreductase cluster, we put the genes in that cluster to Enrichr. We found that majority of the genes among oxidoreductase cluster participate in oxidative phosphorylation and electron transport chain. Our study suggests that the use of ABS prior to etoposide treat¬ment can increase the response of melanoma cell lines because of the alteration of OXPHOS genes.
Open Access
Current community transmission and future perspectives on the COVID-19 process
(TÜBİTAK, 2021-03) Türk, S.; Türk, C.; Malkan, Ü. Y.; Temirci, Elif Sena; Peker, M. Ç.; Haznedaroĝlu, İ. C.
Background/aim: COVID-19 syndrome due to the SARS-CoV-2 virus is a currently challenging situation ongoing worldwide. Since the current pandemic of the SARS-CoV-2 virus is a great concern for everybody in the World, the frequently asked question is how and when the COVID-19 process will be concluded. The aim of this paper is to propose hypotheses in order to answer this essential question. As recently demonstrated, SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome. Our main hypothesis is that the ultimate aim of the SARS-CoV-2 virus is the incorporation to human genome and being an element of the intestinal virobiota. Materials and methods: We propose that the SARS-CoV-2 genomic incorporation to be a part of human virobiota is essentially based on three pathobiological phases which are called as the ‘induction’, ‘consolidation’, and ‘maintenance phases’. The phase of ‘recurrence’ complicates any of these three disease phases based on the viral load, exposure time, and more contagious strains and/or mutants. We have performed the ‘random walk model’ in order to predict the community transmission kinetics of the virus. Results: Chimerism-mediated immunotherapy at the individual and community level with the help of vaccination seems to be the only option for ending the COVID-19 process. After the integration of SARS-CoV-2 virus into the human genome via the induction, consolidation, and maintenance phases as an element of intestinal virobiota, the chimerism would be concluded. The ‘viral load’, the ‘genomic strain of the SARS-CoV-2’, and ‘host immune reaction against the SARS-CoV-2’ are the hallmarks of this long journey. Conclusion: Elucidation of the functional viral dynamics will be helpful for disease management at the individual- and community based long-term management strategies.
Open Access
Expression profiles of the individual genes corresponding to the genes generated by cytotoxicity experiments with bortezomib in multiple myeloma
(Turkish Society of Hematology, 2016) Ghasemi M.; Alpsoy, S.; Türk, S.; Malkan, Ü. Y.; Atakan, Ş.; Haznedaroğlu, İ. C.; Güneş, G.; Gündüz, M.; Yılmaz, B.; Etgül, S.; Aydın, S.; Aslan, T.; Sayınalp, N.; Aksu S.; Demiroğlu, H.; Özcebe, O, İ.; Büyükaşık, Y.; Göker, H.
Objective: Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. Materials and Methods: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. Results: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. Conclusion: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of the targeted anti-myeloma therapies, such as bortezomib. ï¿½ 2016, Turkish Society of Hematology. All rights reserved.
Open Access
The impact of At1r inhibition via losartan on the anti-leukaemic effects of doxorubicin in acute myeloid leukaemia
(Sage Publications, 2019-05) Ghasemi, M.; Okay, M.; Türk, S.; Naeemaee, Ronak; Güver, Ebru; Malkan, Ü. Y.; Aksu, S.; Sayınalp, N.; Haznedaroğlu, I. C.
Introduction: Bone marrow renin–angiotensin system(RAS) modulates acute myeloid leukaemia(AML).The aim of this study is to clarify the relationships between RAS and AML, and to show the effect of losartan and doxorubicin treatment in AML cell lines. Methods: AML cell lines including CESS, HL-60, MO-1, P31/FUJ, GDM-1 and KASUMI-3 were used as models in this study. Results:After treating the six AML cell lines with a combination of losartan and doxorubicin, they were divided into two groups based on their behaviour: one became more sensitive to drug treatment (Group A) and the other had no change observed in behaviour after drug treatment (Group B). In silico analyses showed that Group A is involved in cellular apoptosis, while Group B is involved in tumour angiogenesis further supporting the in vitro results. Conclusion:The combined treatment of the AML cell lines with losartan and doxorubicin resulted in an increase in sensitivity of some of the cell lines. Those leukaemic cells are modulated via the induction of apoptosis, whereas the other cells resistant to the drug treatment are closely related to tumour angiogenesis indicating that RAS-AT1R seems to be differently expressed in different leukaemic blast cells and tumour microenvironments. Pharmaco-biological actions of RAS inhibitors may be different in distinct leukaemic cells based on the pathological behaviour of AML genomic subtypes.
Open Access
In vitro analysis of the renin–angiotensin system and inflammatory gene transcripts in human bronchial epithelial cells after infection with severe acute respiratory syndrome coronavirus
(SAGE, 2020) Türk, C.; Türk, S.; Temirci, Elif Sena; Malkan, Ü. Y.; Haznedaroğlu, İ. C.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus family member that triggers a respiratory disease similar to severe acute respiratory syndrome coronavirus (SARS-CoV). SARS-CoV and SARS-CoV-2 are very similar to each other in many respects, such as structure, genetics, and pathobiology. We hypothesized that coronaviruses could affect pulmonary tissues via integration with the critical immune genes after their interaction with renin–angiotensin system (RAS) elements. The aim of the present bioinformatics study was to assess expression changes of the RAS and non-RAS genes, particularly immune response genes, in the lung epithelial cells after infection with SARS-CoV. Methods: Linear regression, hierarchical clustering, pathway analysis, and network analysis were performed using the E-GEOD-17400 data set. Results: The whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were analyzed, and a total of 15 RAS family and 29 immune genes were found to be highly correlated with the exposure time to the virus in the studied groups. Conclusion: RAS genes are important at the initiation of the infections caused by coronavirus family members and may have a strong relationship with the exchange of immune genes in due course following the infection.
Open Access
Renin angiotensin system genes are biomarkers for personalized treatment of acute myeloid leukemia with Doxorubicin as well as etoposide
(Public Library of Science, 2020) Türk, S.; Türk, C.; Akbar, Muhammad Waqas; Küçükkaraduman, Barış; İşbilen, Murat; Demirkol-Canlı, S.; Malkan, Ü. Y.; Okay, M.; Uçar, G.; Sayınalp, N.; Haznedaroğlu, İ. C.; Güre, Ali Osmay
Despite the availability of various treatment protocols, response to therapy in patients with Acute Myeloid Leukemia (AML) remains largely unpredictable. Transcriptomic profiling studies have thus far revealed the presence of molecular subtypes of AML that are not accounted for by standard clinical parameters or by routinely used biomarkers. Such molecular subtypes of AML are predicted to vary in response to chemotherapy or targeted therapy. The Renin-Angiotensin System (RAS) is an important group of proteins that play a critical role in regulating blood pressure, vascular resistance and fluid/electrolyte balance. RAS pathway genes are also known to be present locally in tissues such as the bone marrow, where they play an important role in leukemic hematopoiesis. In this study, we asked if the RAS genes could be utilized to predict drug responses in patients with AML. We show that the combined in silico analysis of up to five RAS genes can reliably predict sensitivity to Doxorubicin as well as Etoposide in AML. The same genes could also predict sensitivity to Doxorubicin when tested in vitro. Additionally, gene set enrichment analysis revealed enrichment of TNF-alpha and type-I IFN response genes among sensitive, and TGF-beta and fibronectin related genes in resistant cancer cells. However, this does not seem to reflect an epithelial to mesenchymal transition per se. We also identified that RAS genes can stratify patients with AML into subtypes with distinct prognosis. Together, our results demonstrate that genes present in RAS are biomarkers for drug sensitivity and the prognostication of AML.