Person: ARĞA, KAZIM YALÇIN
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ARĞA
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KAZIM YALÇIN
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Publication Metadata only Toward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing(2023-09-01) ERDOĞAN, ONUR; ERZİK, CAN; ARĞA, KAZIM YALÇIN; BAYRAKLI, FATİH; ERDOĞAN O., Özkaya Ş. Ç., ERZİK C., Bilguvar K., ARGA K. Y., BAYRAKLI F.Precision/personalized medicine in oncology has two key pillars: molecular profiling of the tumors and personalized reporting of the results in ways that are clinically contextualized and triangulated. Moreover, neurosurgery as a field stands to benefit from precision/personalized medicine and new tools for reporting of the molecular findings. In this context, glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Precision/personalized medicine has emerged as a promising approach for personalized therapy in GBM. In this study, we performed whole exome sequencing of tumor tissue samples from six newly diagnosed GBM patients and matched nontumor control samples. We report here the genetic alterations identified in the tumors, including single nucleotide variations, insertions or deletions (indels), and copy number variations, and attendant mutational signatures. Additionally, using a personalized cancer genome-reporting tool, we linked genomic information to potential therapeutic targets and treatment options for each patient. Our findings revealed heterogeneity in genetic alterations and identified targetable pathways, such as the PI3K/AKT/mTOR pathway. This study demonstrates the prospects of precision/personalized medicine in GBM specifically, and neurosurgical oncology more generally, including the potential for genomic profiling coupled with personalized cancer genome reporting. Further research and larger studies are warranted to validate these findings and advance the treatment options and outcomes for patients with GBM.Publication Open Access Repositioning of anti-inflammatory drugs for the treatment of cervical cancer sub-types(2022-06-01) TURANLI, BESTE; ARĞA, KAZIM YALÇIN; Kori M., ARĞA K. Y., Mardinoglu A., TURANLI B.Cervical cancer is the fourth most commonly diagnosed cancer worldwide and, in almost all cases is caused by infection with highly oncogenic Human Papillomaviruses (HPVs). On the other hand, inflammation is one of the hallmarks of cancer research. Here, we focused on inflammatory proteins that classify cervical cancer patients by considering individual differences between cancer patients in contrast to conventional treatments. We repurposed anti-inflammatory drugs for therapy of HPV-16 and HPV-18 infected groups, separately. In this study, we employed systems biology approaches to unveil the diagnostic and treatment options from a precision medicine perspective by delineating differential inflammation-associated biomarkers associated with carcinogenesis for both subtypes. We performed a meta-analysis of cervical cancer-associated transcriptomic datasets considering subtype differences of samples and identified the differentially expressed genes (DEGs). Using gene signature reversal on HPV-16 and HPV-18, we performed both signature- and network-based drug reversal to identify anti-inflammatory drug candidates against inflammation-associated nodes. The anti-inflammatory drug candidates were evaluated using molecular docking to determine the potential of physical interactions between the anti-inflammatory drug and inflammation-associated nodes as drug targets. We proposed 4 novels anti-inflammatory drugs (AS-601245, betamethasone, narciclasin, and methylprednisolone) for the treatment of HPV-16, 3 novel drugs for the treatment of HPV-18 (daphnetin, phenylbutazone, and tiaprofenoic acid), and 5 novel drugs (aldosterone, BMS-345541, etodolac, hydrocortisone, and prednisolone) for the treatment of both subtypes. We proposed anti-inflammatory drug candidates that have the potential to be therapeutic agents for the prevention and/or treatment of cervical cancer.Publication Open Access Editorial: Omics integration and network medicine to decipher human complex diseases(2023-01-01) ARĞA, KAZIM YALÇIN; Zanfardino M., Babbi G., ARĞA K. Y., Pane K.Publication Metadata only The versatility of plectin in cancer: A pan-cancer analysis on potential diagnostic and prognostic impacts of plectin isoforms(2023-06-01) ARĞA, KAZIM YALÇIN; Gundesli H., Kori M., ARGA K. Y.Plectin, encoded by PLEC, is a cytoskeletal and scaffold protein with a number of unique isoforms that act on various cellular functions such as cell adhesion, signal transduction, cancer cell invasion, and migration. While plectin has been shown to display high expression and mislocalization in tumor cells, our knowledge of the biological significance of plectin and its isoforms in tumorigenesis remain limited. In this study, we first performed pathway enrichment analysis to identify cancer hallmark proteins associated with plectin. Then, a pan-cancer analysis was performed using RNA-seq data collected from the Cancer Genome Atlas (TCGA) to detect the mRNA expression levels of PLEC and its transcript isoforms, and the prognostic as well as diagnostic significance of the transcript isoforms was evaluated considering cancer stages. We show here that several tissue specific PLEC isoforms are dysregulated in different cancer types and stages but not the expression of PLEC. Among them, PLEC 1d and PLEC 1f are potential biomarker candidates and call for further translational and personalized medicine research. This study makes a contribution as a stride to unravel the molecular mechanisms underpinning plectin isoforms in cancer development and progression by revealing the potent plectin isoforms in different stages of cancer as potential early cancer detection biomarkers. Importantly, uncovering how plectin isoforms guide malignancy and particular cancer types by comprehensive functional studies might open new avenues toward novel cancer therapeutics.Publication Metadata only Predicting antimicrobial resistance in Pseudomonas aeruginosa with transcriptome-based molecular signatures(2022-10-20) KULA, CEYDA; ARĞA, KAZIM YALÇIN; Erdoğan E. E., Kula C., Gülfidan G., Arğa K. Y.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 Systems Biomarkers, Artificial Intelligence, and One Health Vision Can Help Fight Antimicrobial Resistance(2023-02-01) KULA, CEYDA; ARĞA, KAZIM YALÇIN; KULA C., ARĞA K. Y.Publication Metadata only RNA-based Screening of Antimicrobial Resistance: A Case Study on Pseudomonas aeruginosa(2022-11-04) ARĞA, KAZIM YALÇIN; KULA, CEYDA; Kula C., Erdoğan E. E., Özçelik B., Gülfidan G., Arğa K. Y.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 Precision diagnosis of maturity-onset diabetes of the young with next-generation sequencing: Findings from the MODY-IST study in adult patients(2022-04-01) ARĞA, KAZIM YALÇIN; Aydogan H. Y., Gul N., Demirci D. K., Mutlu U., Gulfidan G., ARĞA K. Y., ÖZDER A., ÇAMLI A. A., Tutuncu Y., Ozturk O., et al.Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as \"deleterious\" as well as those predicted as \"benign.\" Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.