Person: ARĞA, KAZIM YALÇIN
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ARĞA
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KAZIM YALÇIN
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Publication Metadata only Molecular signatures in acute myeloid leukemia: from diagnosis to targeted therapy and drug repositioning(Springer, 2022-01-01) YILMAZ, BETÜL; ARĞA, KAZIM YALÇIN; KELEŞOĞLU N., YILMAZ B., ARĞA K. Y.Publication Open Access Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib(ELSEVIER, 2020-05) YILMAZ GÖLER, AYŞE MİNE; Jannuzzi, Ayse Tarbin; Arslan, Sema; Yilmaz, Ayse Mine; Sari, Gulce; Beklen, Hande; Mendez, Lucia; Fedorova, Maria; Arga, Kazim Yalcin; Yilmaz, Betul Karademir; Alpertunga, BuketProteasome inhibitors have great success for their therapeutic potential against hematologic malignancies. First generation proteasome inhibitor bortezomib induced peripheral neuropathy is considered as a limiting factor in chemotherapy and its second-generation counterpart carfilzomib is associated with lower rates of neurotoxicity. The mitochondrial toxicity (mitotoxicity) hypothesis arises from studies with animal models of bortezomib induced peripheral neuropathy. However, molecular mechanisms are not fully elucidated and the role of mitotoxicity in bortezomib and carfilzomib induced neurotoxicity has not been investigated comparatively. Herein, we characterized the neurotoxic effects of bortezomib and carfilzomib at the molecular level in human neuronal cells using LC-MS/MS analysis, flow cytometry, RT-qPCR, confocal microscopy and western blotting. We showed that bortezomib and carfilzomib affected the human neuronal proteome differently, and bortezomib caused higher proteotoxic stress via protein oxidation, protein K48-ubiquitination, heat shock protein expression up-regulation and reduction of mitochondria membrane potential. Bortezomib and carfilzomib did not affect the gene expression levels related to mitochondrial dynamics (optic atrophy 1; OPA1, mitofusin 1; MFN1, mitofusin 2; MFN2, fission 1; FIS1, dynamin-related protein 1; DRP1) and overall mitophagy rate whereas, PINK1/Parkin mediated mitophagy gene expressions were altered with both drugs. Bortezomib and carfilzomib caused downregulation of the contents of mitochondrial oxidative phosphorylation complexes, voltage-dependent anion channel 1 (VDAC1) and uncoupling protein 2 (UCP2) similarly. Our findings suggest that, both drugs induce mitotoxicity besides proteotoxic stress in human neuronal cells and the higher incidence of neurotoxicity with bortezomib than carfilzomib is not directly related to mitochondrial pathways.Publication Metadata only MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment(KARGER) YILMAZ, BETÜL; Aydin, Busra; Arslan, Sema; Bayrakli, Fatih; Karademir, Betul; Arga, Kazim YalcinIntroduction: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. Methods: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. Results: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. Discussion: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.Publication Metadata only Past, present, and future of therapies for pituitary neuroendocrine tumors: need for omics and drug repositioning guidance(2022-03-01) ERDOĞAN, ONUR; ARĞA, KAZIM YALÇIN; BOZKURT, SÜHEYLA; BAYRAKLI, FATİH; YILMAZ, BETÜL; TURANLI, BESTE; Aydin B., Yildirim E., ERDOĞAN O., ARĞA K. Y., Yilmaz B., BOZKURT S., BAYRAKLI F., TURANLI B.Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs\" treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.Publication Metadata only Transcriptomics-based drug repurposing unravels novel therapeutic strategies in AML(2022-11-16) TURANLI, BESTE; ARĞA, KAZIM YALÇIN; YILMAZ, BETÜL; KELEŞOĞLU N., Korkmaz N. S., TURANLI B., ARĞA K. Y., YILMAZ B., ATEŞ DURU Ö.Acute myeloid leukemia (AML) is a disease of the hematopoietic system in which abnormal cells multiply rapidly, accumulate in the blood and bone marrow, and prevent the production of healthy blood cells. To date, first-line treatment of AML has been based primarily on conventional chemotherapy. Despite progress, the rate of complete remission in AML remains low, especially in older patients, and the relapse rate after complete remission remains high. The combination of clinical and laboratory data has been shown to play an important role in the development of new therapeutic strategies in AML, in addition to features of tumor histopathogenesis and transcriptional regulation. 1 Therefore, we integrated transcriptomics data from relapsed, refractory, and previously untreated AML patients based on their response to therapy using disease-specific signatures with biological and pharmacological data to enable rational identification of the potential of signaling pathways and drugs in AML. Based on the integration of transcriptomics data, we identified eight drug candidates by repurposing and evaluated their potential by in vitro testing in the HL60 and KG -1 cell lines. Six repurposed drugs, including nortriptyline, desipramine, doxepin, estramustine, risedronate, and hydrochlorothiazide, were proposed as potential drug candidates for the treatment of AML. We confirmed possible mechanisms of action of the drugs on cell viability HL -60 and KG -1 by apoptosis assays and Western blotting. Given the beneficial effects of the drugs on the apoptosis pathway, our results are intriguing and suggest that these therapies may prove useful and be potential candidates for the future treatment of AML.Publication Metadata only Acute myeloid leukemia: New multiomics molecular signatures and implications for systems medicine diagnostics and therapeutics innovation(2022-07-01) ARĞA, KAZIM YALÇIN; TURANLI, BESTE; YILMAZ, BETÜL; Kelesoglu N., Kori M., TURANLI B., ARĞA K. Y., Yilmaz B., Duru O. A.Acute myeloid leukemia (AML) is a common, complex, and multifactorial malignancy of the hematopoietic system. AML diagnosis and treatment outcomes display marked heterogeneity and patient-to-patient variations. To date, AML-related biomarker discovery research has employed single omics inquiries. Multiomics analyses that reconcile and integrate the data streams from multiple levels of the cellular hierarchy, from genes to proteins to metabolites, offer much promise for innovation in AML diagnostics and therapeutics. We report, in this study, a systems medicine and multiomics approach to integrate the AML transcriptome data and reporter biomolecules at the RNA, protein, and metabolite levels using genome-scale biological networks. We utilized two independent transcriptome datasets (GSE5122, GSE8970) in the Gene Expression Omnibus database. We identified new multiomics molecular signatures of relevance to AML: miRNAs (e.g., mir-484 and miR-519d-3p), receptors (ACVR1 and PTPRG), transcription factors (PRDM14 and GATA3), and metabolites (in particular, amino acid derivatives). The differential expression profiles of all reporter biomolecules were crossvalidated in independent RNA-Seq and miRNA-Seq datasets. Notably, we found that PTPRG holds important prognostication potential as evaluated by Kaplan-Meier survival analyses. The multiomics relationships unraveled in this analysis point toward the genomic pathogenesis of AML. These multiomics molecular leads warrant further research and development as potential diagnostic and therapeutic targets.Publication Metadata only Differential interactome based drug repositioning unraveled potential therapeutics for colorectal cancers(2022-01-19) TURANLI, BESTE; ÖZBEK SARICA, PEMRA; YILMAZ, BETÜL; ARĞA, KAZIM YALÇIN; BEKLEN H., Arslan S., GULFİDAN G., TURANLI B., ÖZBEK SARICA P., YILMAZ B., ARĞA K. Y.Publication Metadata only Driving precision oncology to clinical practice: The road ahead from biomarker validation to clinical decision systems(2022-06-01) ARĞA, KAZIM YALÇIN; YILMAZ, BETÜL; Yilmaz B., ARĞA K. Y.Publication Metadata only The Repertoire of Glycan Alterations and Glycoproteins in Human Cancers(MARY ANN LIEBERT, INC, 2021) TURANLI, BESTE; Kori, Medi; Aydin, Busra; Gulfidan, Gizem; Beklen, Hande; Kelesoglu, Nurdan; Caliskan Iscan, Aysegul; Turanli, Beste; Erzik, Can; Karademir, Betul; Arga, Kazim YalcinCancer as the leading cause of death worldwide has many issues that still need to be addressed. Since the alterations on the glycan compositions or/and structures (i.e., glycosylation, sialylation, and fucosylation) are common features of tumorigenesis, glycomics becomes an emerging field examining the structure and function of glycans. In the past, cancer studies heavily relied on genomics and transcriptomics with relatively little exploration of the glycan alterations and glycoprotein biomarkers among individuals and populations. Since glycosylation of proteins increases their structural complexity by several orders of magnitude, glycome studies resulted in highly dynamic biomarkers that can be evaluated for cancer diagnosis, prognosis, and therapy. Glycome not only integrates our genetic background with past and present environmental factors but also offers a promise of more efficient patient stratification compared with genetic variations. Therefore, studying glycans holds great potential for better diagnostic markers as well as developing more efficient treatment strategies in human cancers. While recent developments in glycomics and associated technologies now offer new possibilities to achieve a high-throughput profiling of glycan diversity, we aim to give an overview of the current status of glycan research and the potential applications of the glycans in the scope of the personalized medicine strategies for cancer.Publication Metadata only Determination of candidate biomarkers through differential interactome in colorectal adenocarcinoma(2019-10-17) TURANLI, BESTE; ÖZBEK SARICA, PEMRA; YILMAZ, BETÜL; ARĞA, KAZIM YALÇIN; BEKLEN H., GULFİDAN G., TURANLI B., ÖZBEK SARICA P., YILMAZ B., ARĞA K. Y.Colorectal cancer is one of the most lethal types of cancers common in both men and women. According to the data base published by the International Agency for Research on Cancer, colorectal cancer is the third most common type of cancer found in Turkey and worldwide [1]. The high heterogeneity of colorectal cancer leads to difficulties explaining the biology and behavior of this cancer. The aim of this study is to identify prognostic biomarkers and potential therapeutics for colorectal cancer using the protein interactions differentiated among healthy and tumor groups. Among this purpose at first stage, the differential protein-protein interactions (dPPIs) were identified by using “Differential Interactome” algorithm[2] which is published by our research group. Two independent data sets were obtained from “The Cancer Genome Atlas (TCGA)” containing 644 tumor samples and 51 normal samples and “Gene Expression Omnibus (GEO)” containing 32 tumor samples and 32 normal samples. As a result of differential interactome analysis, significant dPPIs were determined (2434 dPPIs in GEO data set, 1619 dPPIs in TCGA data set) and highly interacting protein modules were identified. Principal Component Analysis for diagnostic purpose and Kaplan-Meier analysis for prognostic purpose were performed for each module. 16 modules were determined significant having diagnostic potential while 6 modules were found having prognostic potential. In addition common significant dPPIs in both data sets were observed in point of drug repositioning and 6 dPPIs and 13 drug targets for these interactions were identified. By using molecular dynamics simulations root mean square deviation (RMSD) and root mean square fluctuation were taken as performance metrics to perform further investigation in vitro cell culture. This study will shed light on the identification of specific biomarkers and drug targets for early detection, disease progression, and accurate treatment, helping to understand some systems of colorectal cancer by preventing high mortality.