Browsing by Author "Çetin-Atalay, R."
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Item Open Access Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles(Taylor and Francis Ltd, 2015) Çikla-Süzgün P.; Kaushik-Basu, N.; Basu, A.; Arora P.; Talele, T.T.; Durmaz I.; Çetin-Atalay, R.; Küçükgüzel, S.G.Arachidonic acid is an unsaturated fatty acid liberated from phospholipids of cell membranes. NSAIDs are known as targets of cyclooxygenase enzyme (COX-1, COX-2 and COX-3) in arachidonic acid metabolism. This mechanism of COX-2 in carcinogenesis causes cancer. In addition, COX-2 plays a role in the early stages of hepatocarcinogenesis. Hepatitis C virus (HCV) infection is cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to improve effective agents against HCV. A novel series of new etodolac 1,2,4-triazoles derivatives (4a-h) have been synthesized and investigated for their activity against HCV NS5B polymerase. Compound 4a was found to be the most active with IC50 value of 14.8 M. In accordance with these results, compound 4a was screened for anti-cancer activity on liver cancer cell lines (Huh7, Mahlavu, HepG2, FOCUS). Compound 4a showed anti-cancer activity against Huh7 human hepatoma cell line with IC50 value of 4.29 M. Therefore, compound 4a could be considered as a new anti-cancer and anti-HCV lead compound. © 2015 Informa UK Ltd.Item Open Access Author correction: CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation (Scientific Reports, (2020), 10, 1, (5971), 10.1038/s41598-020-62912-0)(Nature Research, 2020) Ayaz, G.; Razizadeh, N.; Yaşar, P.; Kars, G.; Kahraman, D. C.; Saatci, Ö.; Şahin, Özgür; Çetin-Atalay, R.; Muyan, M.Item Open Access Automated cancer stem cell recognition in H and E stained tissue using convolutional neural networks and color deconvolution(SPIE, 2017) Aichinger, W.; Krappe, S.; Çetin, A. Enis; Çetin-Atalay, R.; Üner, A.; Benz, M.; Wittenberg, T.; Stamminger, M.; Münzenmayer, C.The analysis and interpretation of histopathological samples and images is an important discipline in the diagnosis of various diseases, especially cancer. An important factor in prognosis and treatment with the aim of a precision medicine is the determination of so-called cancer stem cells (CSC) which are known for their resistance to chemotherapeutic treatment and involvement in tumor recurrence. Using immunohistochemistry with CSC markers like CD13, CD133 and others is one way to identify CSC. In our work we aim at identifying CSC presence on ubiquitous Hematoxilyn and Eosin (HE) staining as an inexpensive tool for routine histopathology based on their distinct morphological features. We present initial results of a new method based on color deconvolution (CD) and convolutional neural networks (CNN). This method performs favorably (accuracy 0.936) in comparison with a state-of-the-art method based on 1DSIFT and eigen-analysis feature sets evaluated on the same image database. We also show that accuracy of the CNN is improved by the CD pre-processing.Item Open Access Çarpmasız yapay sinir ağı(IEEE, 2015-05) Akbaş, Cem Emre; Bozkurt, Alican; Çetin, A. Enis; Çetin-Atalay, R.; Üner, A.Bu bildiride çarpma işlemi kullanmadan oluşturulan bir Yapay Sinir Ağı (YSA) sunulmaktadır. Girdi vektörleri ve YSA katsayılarının iç çarpımları çarpmasız bir vektör işlemiyle hesaplanmıştır. Yapay sinir ağının eğitimi sign-LMS algoritması ile yapılmıştır. Önerilen YSA sistemi, hesap gücü kısıtlı olan veya düşük enerji tüketimine ihtiyaç duyulan mikroişlemcilerde kullanılabilir.Item Open Access Classification of human carcinoma cells using multispectral imagery(SPIE, 2016) Çınar, U.; Çetin, Y. Y.; Çetin-Atalay, R.; Çetin, A. EnisIn this paper, we present a technique for automatically classifying human carcinoma cell images using textural features. An image dataset containing microscopy biopsy images from different patients for 14 distinct cancer cell line type is studied. The images are captured using a RGB camera attached to an inverted microscopy device. Texture based Gabor features are extracted from multispectral input images. SVM classifier is used to generate a descriptive model for the purpose of cell line classification. The experimental results depict satisfactory performance, and the proposed method is versatile for various microscopy magnification options.Item Open Access CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation(Nature Research, 2020) Ayaz, G.; Razizadeh, N.; Yaşar, P.; Kars, G.; Kahraman, D. C.; Saatci, Ö.; Şahin, Özgür; Çetin-Atalay, R.; Muyan, M.Evidence suggests that the CXXC type zinc finger (ZF-CXXC) protein 5 (CXXC5) is a critical regulator/integrator of various signaling pathways that include the estrogen (E2)-estrogen receptor α (ERα). Due to its ZF-CXXC domain, CXXC5 is considered to be a member of the ZF-CXXC family, which binds to unmethylated CpG dinucleotides of DNA and through enzymatic activities for DNA methylation and/or chromatin modifications generates a chromatin state critical for gene expressions. Structural/functional features of CXXC5 remain largely unknown. CXXC5, suggested as transcription and/or epigenetic factor, participates in cellular proliferation, differentiation, and death. To explore the role of CXXC5 in E2-ERα mediated cellular events, we verified by generating a recombinant protein that CXXC5 is indeed an unmethylated CpG binder. We uncovered that CXXC5, although lacks a transcription activation/repression function, participates in E2-driven cellular proliferation by modulating the expression of distinct and mutual genes also regulated by E2. Furthermore, we found that the overexpression of CXXC5, which correlates with mRNA and protein levels of ERα, associates with poor prognosis in ER-positive breast cancer patients. Thus, CXXC5 as an unmethylated CpG binder contributes to E2-mediated gene expressions that result in the regulation of cellular proliferation and may contribute to ER-positive breast cancer progression.Item Open Access EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers(Nature Publishing Group, 2021-10-30) Çiçek, E.; Çırçır, A.; Öyken, M.; Akbulut Çalışkan, Özge; Dioken, D. N.; Güntekin Ergün, S.; Çetin-Atalay, R.; Sapmaz, A.; Ovaa, H.; Şahin, Ö.; Erson-Bensan, A. E.Epidermal growth factor receptor (EGFR) has critical roles in epithelial cell physiology. Over-expression and over-activation of EGFR have been implicated in diverse cancers, including triple-negative breast cancers (TNBCs), prompting anti‐EGFR therapies. Therefore, developing potent therapies and addressing the inevitable drug resistance mechanisms necessitates deciphering of EGFR related networks. Here, we describe Sorting Nexin 3 (SNX3), a member of the recycling retromer complex, as a critical player in the epidermal growth factor (EGF) stimulated EGFR network in TNBCs. We show that SNX3 is an immediate and sustained target of EGF stimulation initially at the protein level and later at the transcriptional level, causing increased SNX3 abundance. Using a proximity labeling approach, we observed increased interaction of SNX3 and EGFR upon EGF stimulation. We also detected colocalization of SNX3 with early endosomes and endocytosed EGF. Moreover, we show that EGFR protein levels are sensitive to SNX3 loss. Transient RNAi models of SNX3 downregulation have a temporary reduction in EGFR levels. In contrast, long-term silencing forces cells to recover and overexpress EGFR mRNA and protein, resulting in increased proliferation, colony formation, migration, invasion in TNBC cells, and increased tumor growth and metastasis in syngeneic models. Consistent with these results, low SNX3 and high EGFR mRNA levels correlate with poor relapse-free survival in breast cancer patients. Overall, our results suggest that SNX3 is a critical player in the EGFR network in TNBCs with implications for other cancers dependent on EGFR activity.Item Open Access Mixture of learners for cancer stem cell detection using CD13 and H and E stained images(SPIE, 2016) Oğuz, Oğuzhan; Akbaş, Cem Emre; Mallah, Maen; Taşdemir, K.; Akhan-Güzelcan, E.; Muenzenmayer, C.; Wittenberg, T.; Üner, A.; Çetin, A. Enis; Çetin-Atalay, R.In this article, algorithms for cancer stem cell (CSC) detection in liver cancer tissue images are developed. Conventionally, a pathologist examines of cancer cell morphologies under microscope. Computer aided diagnosis systems (CAD) aims to help pathologists in this tedious and repetitive work. The first algorithm locates CSCs in CD13 stained liver tissue images. The method has also an online learning algorithm to improve the accuracy of detection. The second family of algorithms classify the cancer tissues stained with H and E which is clinically routine and cost effective than immunohistochemistry (IHC) procedure. The algorithms utilize 1D-SIFT and Eigen-Analysis based feature sets as descriptors. Normal and cancerous tissues can be classified with 92.1% accuracy in H and E stained images. Classification accuracy of low and high-grade cancerous tissue images is 70.4%. Therefore, this study paves the way for diagnosing the cancerous tissue and grading the level of it using H and E stained microscopic tissue images.Item Open Access Targeting PI3K/AKT/mTOR pathway identifies differential expression and functional role of IL8 in liver cancer stem cell enrichment(American Association for Cancer Research, 2019) Kahraman, D. C.; Kahraman, Tamer; Çetin-Atalay, R.Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.