TR Dizin İndeksli Yayınlar Koleksiyonu / TR Dizin Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/20.500.14365/4
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Article Differential Effects of Sertraline and Penfluridol on EMT and ECM Remodeling in Glioblastoma Cell Lines(Dokuz Eylul Univ inst Health Sciences, 2025-01-31) Keleş Bartık, Didem; Oktay, Gulgun; Surer,Seniz Inanc; Sipahi, Murat; Keles, DidemPurpose: Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis due to rapid recurrence, chemoresistance, and limited efficacy of standard therapies. Epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling are critical processes in GBM progression and metastasis. The aim of this study is to examine the potential effects of sertraline and penfluridol on the EMT process and gelatinase activity in human glioblastoma cell lines. Material and Methods: U87 and U251 human glioblastoma cells were treated with sertraline and penfluridol at previously identified IC50 doses. Protein levels of EMT markers, E-cadherin, vimentin, Snail, Slug, Twist1, phospho-Akt (p-Akt), and tissue inhibitor of metalloproteinases-2 (TIMP-2), were evaluated using Western blotting. Additionally, the impact of sertraline and penfluridol on the release and activity of MMP-2 and MMP-9 were assessed through gelatin zymography. Results: Both sertraline and penfluridol significantly reduced vimentin expression in U251 cells, indicating inhibition of the mesenchymal phenotype. Conversely, these drugs increased vimentin levels in U87 cells, highlighting cell line-specific differences. Sertraline and penfluridol also increased TIMP-2 levels in U251 cells but not in U87 cells. Neither drug altered MMP-2 or MMP-9 activity in either cell line, suggesting that their effects on ECM remodeling may be mediated through TIMP-2 upregulation rather than direct modulation of gelatinase activity. Conclusion: These findings suggest that sertraline and penfluridol potentially inhibit EMT and reduce ECM degradation in U251 cells but exert contrasting effects in U87 cells. This highlights the heterogeneity of GBM tumors and the importance of personalized therapeutic approaches.Article Upregulated Acute Systemic Inflammation-Related Genes Based on Endotoxin Exposure Provide ‘Survival Benefit’ or Create ‘High Risk of Death’ in Leukaemia and Colon Cancer(Istanbul University, 2024-07-10) Duran, Gizem Ayna; Duran, Assist. Prof. Dr. Gizem Ayna; Ayna Duran, GizemObjective: Although endotoxin exposure has been shown to trigger innate immune responses and promote cancer, it has also been shown to prevent cancer formation. In our study, survival analysis was performed to determine whether the upregulated genes triggered by endotoxins have hazardous effects on cancers or provide a survival benefit. Materials and Methods: Gene intensity values of control and bacterial endotoxin-administered individuals were obtained from the Gene Expression Omnibus database. Using the R "Linear Models for Microarray Data" package, differentially expressed gene analyses were conducted to determine genes that differ between healthy and bacterial endotoxin-administered samples. "ShinyGo 0.80" web-based tool was used to determine the disease types indicated by these genes. The "Kaplan-Meier Plotter" web-based tool was used to conduct survival analysis. Results: Genes that create an innate immune response to bacterial endotoxin exposure and are upregulated differently than in individuals without exposure were identified. According to gene enrichment analyses, the two main types of cancer identified were leukaemia/lymoma and colon cancer. We detected that MLF1, STAT5B, and BCL3 genes led to poor survival; however, the ARHGAP26 gene was protective for acute myeloid leukaemia patients. In the case of colon cancer, SMAD7 and TLR2 genes were determined as leading to "high risk of death". Conclusion: Once the systemic inflammation-related genes identified in our study are confirmed through laboratory experiments in samples taken from solid tissue in the case of colon cancer and at the level of genes obtained from blood samples in leukemias, genetically targeted treatments will also be possible.Article The first uniportal VATS sleeve lobectomy in Türkiye: A case report(2024) Hakkı ULUTAŞ; Gülçek, İlham; Kalkan, Muhammed; Ulutas, HakkıIn recent years, video-assisted thoracic surgery (VATS) has become the gold standard approach in the surgical treatment of early-stage non-small cell lung cancer. Especially in cases of central tumors, sleeve lobectomies that preserve parenchyma and respiratory reserves are performed instead of pneumonectomies by experienced clinics. Here, we present the first case of uniportal VATS right bronchial sleeve upper lobectomy for right main bronchial invasion in Turkey, which was successfully performed in August 2022. A patient diagnosed with laryngeal carcinoma who had been in remission for 5 years complained of a cough. Computed thoracic tomography showed hilar peribronchial thickening and an endobronchial lesion (EBL) extending from the right upper lobe bronchus to the main bronchus, almost completely obstructing the upper lobe bronchus. Bronchoscopy revealed that the right upper lobe entrance was obstructed with EBL, and its distance to the carina was 1.6 cm. Bronchoscopic biopsy revealed squamous cell carcinoma. The thorax was entered through an incision of approximately 3 cm in the right fifth intercostal space. First, the right upper lobe pulmonary arteries and superior pulmonary vein were dissected and cut. The main bronchus was divided until the intermediate bronchus. With the help of an endoscissor, the main and intermediate bronchus were incised with appropriate surgical margins, and the lobectomy material was removed. Both macroscopic appearance and frozen and microscopic main and intermediate bronchus surgical margin tumor negativity were confirmed. One suture was passed through the lateral cartilage from the inside out, and the needle was fixed to the posterior pleura. Membranous and cartilage parts were continuously anastomosed with a double-needle 3/0 prolene suture at 2–3 mm intervals. Pathological evaluation confirmed squamous cell carcinoma with a tumor diameter of 1.7 cm, hilar 1/11 lymph node metastasis, and negative surgical margin. Adhering to oncologic principles, sleeve resections, which are difficult even with the currently known open techniques, can be performed effectively and safely with uniportal VATS in experienced centers.Article Citation - WoS: 1Citation - Scopus: 1Differential Effects of Choline on TLR2/4 Mediated Signaling Through Possible Regulation of Toll-Interacting Protein in Hepatocellular Carcinoma Cell Lines(Walter de Gruyter GmbH, 2024-05-30) Barış, Elif; Demir, Ayse BanuObjectives: Toll-like receptor (TLR) mediated inflammatory status plays an important role in development and pro- gression of hepatocellular carcinoma (HCC). Toll-interacting protein (TOLLIP) has an inhibitory effect on TLR-mediated inflammatory signalling and expression profile of TOLLIP varies between malignancies including HCC. Cholinergic anti-inflammatory pathway (CAP) is an endogenous mech- anism that controls inflammatory status via α7nicotinic acetylcholine receptors (α7nAChR). This study aims to investigate the effect of CAP-acting agent choline on TOLLIP and its related TLR-mediated inflammatory response in HCC cells with distinct differentiation stages. Methods: The expression patterns of α7nAChR, TLR2/4, TOLLIP, IL6, NFkB genes were evaluated by RT-PCR and ELISA in the presence of choline, along with the real-time cell proliferation and migration in HEP3B and SNU449 HCC cell lines. The interaction between choline and TOLLIP assessed by using in-silico analyses. Results: Choline downregulated TOLLIP in Hep3B and SNU449 cells. However, the expressions of α7nAChR, NF-κB, IL-6, TLR2 and TLR4 showed a decreased pattern in well differentiated HEP3B cells, while an increased pattern in poorly differentiated SNU449 cells. Conclusions: Choline might exert differential effects in TLR2/4-dependent signalling based on the differentiation stages of the HCC cells, suggesting its potential therapeutic effects in earlier stages of HCC which might be result of its partial modulation of TOLLIP.Article Kolanjiyokarsinom ve Hepatoselüler Karsinom Hastalarında Farklı Genler Tarafından Tetiklenen Ortak Biyolojik Yolaklar(2024-03-27) Ayna Duran, Gizem; Duran, Assist. Prof. Dr. Gizem AynaKolanjiyokarsinom (CHOL) erken teşhis edilmesi zor olan ve oldukça yüksek düzeyde öldürücü bir kanser türüdür. CHOL tanısında radyolojik görüntülemede kısıtlılıklar mevcuttur ve biyopsi ile tanı yöntemi gibi invaziv tanı yöntemleri dışında genetik tabanlı ve özgün biyobelirteçlerin belirlenmesi zorunlu hale gelmektedir. Literatürde bu amaçlar gerçekleştirilen çalışmalar çalışmalardan farklı olarak bizim çalışmamızda öncelikle intrahepatik (iCHOL) ve ekstrahepatik (eCHOL) kolanjiyokarsinom hastalarında ortak upregüle olan genler belirlenmiştir. Ayrıca çalışmamızda klinikte CHOL kanserlerinin LIHC kanserinden ayırt edici tanısının zor olması sebebiyle CHOL hastalarında hepatoselüler karsinomdan (LICH) farklı olarak ve LIHC hastaları ile ortak olarak upregüle edilen genlerin tespit edilmesi de amaçlanmıştır. Hastaların gen yoğunluk verileri NCBI Gene Expression Omnibus (GEO) veri tabanından (GSE121248, GSE132305 ve GSE45001) sağlanmıştır. Çalışmada R LIMMA paketinde yer alan lineer modelleme yöntemi kullanılarak kanserli olan ve olmayan örnekler arasında upregüle genler (differentially expressed genes-DEGs) tespit edilmiştir. Tespit edilen genlerin hangi biyolojik yolaklara etki ettiğini belirlemek için Gen seti zenginleştirme analizi (Fonksiyonel zenginleştirme analizi) (GSEA) ShinyGO 0.80 webtool kullanılarak yapılmıştır. Sonuçlarımıza göre CHOL hastalarında LIHC hastalarından farklı olarak upregüle edilen 4 gene (F2R, ITGA11, LAMC2 ve LAMB3) odaklanılmıştır. CHOL ve LIHC hastalarında ise ortak olarak upregüle edilen 2 gen (COL1A1, ITGA2) tespit edilmiştir. Söz konusu genlerinin ortak olarak işaret ettiği biyolojik yolaklar PI3K-Akt sinyal yolağı ve ekstraselüler matriks (ECM)-reseptör etkileşimi süreçleridir. Belirlenen genler ile protein-protein ve ilaç etkileşim çalışmaları sonuçları klinik denemeler ile desteklenip CHOL ile LIHC kanserlerinin ayırt edilmesinde etkin bir şekilde hedeflenebilecektir.Article Virtual Drug Screening for P65/Rela Subunit of Nf-Κb: Promising Repurposable Drugs in the Treatment of Stress-Based Diseases(Istanbul Univ, Fac Pharmacy, 2023-12-28) Portakal, Hüseyin SaygınBackground and Aims: Although NF-kappa B is composed of five subunits, RelA receives much more attention due to fact that its expression level is regulated under various stress conditions, such as exposure to radiation, reactive oxygen species (ROS), hypoxia, pathogens, and inflammatory cytokines, as well as regulating many inflammatory, proliferation, and apoptosis genes. To date, many pieces of evidence have demonstrated that RelA plays a significant role in in the prognosis of various proliferative and inflammatory diseases. Therefore, the design of novel inhibitors and the discovery of repurposable drugs are considered promising approaches in the treatment of RelA-based diseases.Methods: A drug library including a total of 12,111 ligands has been screened for the RelA subunit of NF-kappa B. The sufficiency of the study's strategy has been revealed by analysis of commercially available inhibitors and re-docking applications.Results: Findings demonstrate that ZINC000096928979 (Deleobuvir), ZINC000012503187 (Conivaptan), and ZINC000003974230 ligands have the highest binding affinity to RelA. Furthermore, many ligands with structural similarities to Valstar, Ergotamine drugs and Benzo[a]pyrene-7,8-Diol metabolite have been discovered.Conclusion: While the ligands with the highest binding affinities could be repurposed in the treatment of RelA-based diseases, the structures of the ligands exhibiting similarity with Valstar, Ergotamine, and Benzo[a]pyrene-7, 8-D may be used as a scaffold in structure-based drug design studies. The stability of the interactions between the ligands and the receptor should be analyzed with further Molecular Dynamics Simulations (MD) studies and the possible ligands should be investigated by both in vitro and in vivo applications.Article Classification of Colon Cancer Patients Into Consensus Molecular Subtypes Using Support Vector Machines(2023-12-28) Koçhan, Necla; Dayanç, Barış EmreBackground/aim: The molecular heterogeneity of colon cancer has made classification of tumors a requirement for effective treatment. One of the approaches for molecular subtyping of colon cancer patients is the consensus molecular subtypes (CMS), developed by the Colorectal Cancer Subtyping Consortium. CMS-specific RNA-Seq-dependent classification approaches are recent, with relatively low sensitivity and specificity. In this study, we aimed to classify patients into CMS groups using their RNA-seq profiles. Materials and methods: We first identified subtype-specific and survival-associated genes using the Fuzzy C-Means algorithm and log- rank test. We then classified patients using support vector machines with backward elimination methodology. Results: We optimized RNA-seq-based classification using 25 genes with a minimum classification error rate. In this study, we reported the classification performance using precision, sensitivity, specificity, false discovery rate, and balanced accuracy metrics. Conclusion: We present a gene list for colon cancer classification with minimum classification error rates and observed the lowest sensitivity but the highest specificity with CMS3-associated genes, which significantly differed due to the low number of patients in the clinic for this group.Article Evaluation of Oxidative/Nitrosative Stress Parameters and Histopathological, Immunohistochemical Effects on Cisplatin-Induced Lung Toxicity in Rats(2023-12-01) Yıldız Dalgınlı, Kezban; Öztürkler, Melek; Beşeren, Hatice; Adalı, Yasemen; Atakişi, Onur; Dalgınlı, Kezban YıldızThe main focus of this study is to investigate oxidative/nitrosative stress and antioxidant effects and immunohistochemical effects in cisplatin-induced lung toxicity. In the study, 12 male Sprague Dawley rats, 2 months old, were divided into two groups: control (n=6) and cisplatin (n=6). Isotonic solution was administered to control and cisplatin 10 mg/kg single dose intraperitoneal to cisplatin group. Reducte glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) levels were determined by spectrophotometricmethod in the lung tissues taken. Paraffin blocks were made from lung tissues and stained with hematoxylin-eosin (HE) staining. Immunohistochemically, p53, CD3, CD20, Bcl-2 ve Ki67 were evaluated. It was found that cisplatin administration alone had no effect on MDA and GSH values in the lung tissue of rats, and NO levels were significantly increased (P<0.005). In the histopathological evaluation of the lung tissue, congestion-bleeding findings, intense inflammation areas, lymphoid follicles around the bronchi and bronchioles were seen with HE staining. Concentric fibrous and fibrinous plugs consisting of blood-fibrin and inflammatory cells and fibroblasts in the airways were observed, with low- density edema between the alveoli. Reactive pan B cell markers CD20, T-cell marker CD3 in the interstitial component and desmin in sub-epithelial cells were stainedpositively by immunohistochemical staining, while reactive germinal centers Bcl-2 and p53 applied to the bronchioles and alveolarducts were immunohistochemically stained negative. In addition, low-intensity nuclear staining was found with Ki67 immunohistochemical staining.In conclusion, significant increase in NO level and immunohistochemically intense inflammation, lymphoid follicles, fibrous and fibrinous plugs are an expression of the onset of cisplatin-induced lung injury..Article Exploring Pi3k Pathway Inhibitors for Acute Myeloid Leukemia: a Drug-Repurposing Approach(Istanbul University Press, 2023-12-28) Ergun, Cansu; Kiremitci, Buse Zeren; Arslantas, Gizem; Bozkurt, Busenur; Duran, Gizem Ayna; Kiraz, YağmurObjective: Acute myeloid leukemia (AML) is a malignant disease characterized by the uncontrolled growth, differentiation, and proliferation of immature hematopoietic cells. Patients with AML often have poor survival rates, which are associated with specific gene mutations in FLT3, CEBPA, and NPM1. The phosphatidylinositol 3-kinase (PI3K) pathway, a lipase pathway, is activated in many malignancies, including AML. Given the low survival rates in AML, this study identified candidate drugs that could inhibit the PI3K pathway, thereby offering a potential treatment for AML, by using a drug-repurposing approach. Materials and Methods: Online bioinformatics tools were utilized to identify pathway-related genes and FDA-approved drugs. Subsequently, molecular docking was performed to determine the binding affinity values. Important genes were identified by evaluating their impact on survival and their aberrant expression in the tumor. In this study, genes such as VAV1, GSK3B, MTOR, PDPK1, PRR5, TSC2, AKT3, and CREB1 were determined and docked with their potential inhibitors. Particular attention was paid to VAV1 because there were no known potential VAV1 inhibitors used in AML. Results: The docking results were ranked, and the proposed gene–drug pairs were identified as tideglusib and fostamatinib for the inhibition of GSK3B, pimecrolimus and fostamatinib for the inhibition of MTOR, and fostamatinib for the inhibition of PDPK1. Furthermore, nebivolol, darifenacin, dihydroergotamine, libanserin and entereg were identified as potential inhibitors of VAV1 in AML. Conclusion: To sum up, most effective gene–drug pairs according to binding affinities were proposed as candidate inhibitor drugs for AML.Article New Lymph Node Parameters and a Comparison With the American Joint Committee on Cancer N-Stages in Breast Cancer(Galenos Publ House, 2023-08-01) Eliyatkin, Nuket Ozkavruk; Başkır, İnci; İşlek, Akif; Zengel, BahaBACKGROUND/AIMS: The N-stage of TNM systems considers only the number of metastatic lymph nodes (NMLN) in breast cancer (BC). However, new lymph node parameters refer to the number of harvested lymph nodes (NHLN) and negative lymph nodes (NNLN), which have had an increasing significance in the current literature. This study aimed to compare NHLN, NNLN, lymph node ratio (LNR), modified lymph node ratio (mLNR), and log odds of positive lymph nodes (LODDS) against the standard American Joint Committee on Cancer (AJCC) N-stage for the prognosis of BC patients. MATERIALS AND METHODS: This study was designed retrospectively. The socio-demographic data, clinical features, histopathological factors, treatment modalities, receptor status of BC, and lymph node related parameters (AJCC N, LNR, mLNR, LODDS) were identified. Then, lymph node related parameters were compared for cancer-related mortality (CRM), cancer recurrence, disease-free survival (DFS), and overall survival (OS). RESULTS: Eight hundred seven women who underwent surgery for BC were included in this study according to its eligibility criteria. The mean follow-up period was 113.34±74.85 (range: 6-378) months. The NHLN was 21.24±9.22, the NMLN was 4.85±7.38, the NNLN was 16.39±9.48, the LNR was 0.23±0.29, the mLNR was 5.38±7.38 and the LODDS was -0.74±0.80 on average. During the follow-up period, 42 (5.2%) patients had local recurrence, 188 (23.3%) had distant metastases, and 252 (31.2%) patients died due to BC. NMLN, LNR, mLNR, and LODDS were found to be significantly higher, and NNLN was significantly lower in those patients with cancer recurrence and CRM (p<0.001). AJCC N-stages, and also LNR, mLNR, and LODDS groups according to the calculated cut-off values, were significant for DFS and OS according to survival analysis. In Cox regression analysis, only LODDS was a significant independent risk factor for OS [p=0.014, heart rate (HR)=3.78, 95% confidence interval (CI) for HR: 1.30-10.94)]. CONCLUSION: The results indicated that LODDS was more successful compared to other lymph node staging systems, especially for OS. However, randomized prospective controlled studies with larger samples and homogeneous study groups are needed to create standard classification systems as alternatives to AJCC N.