Papers by Kazim Yalcin Arga
OMICS: A Journal of Integrative Biology
Frontiers in Oncology
IntroductionIntegrating interaction data with biological knowledge can be a critical approach for... more IntroductionIntegrating interaction data with biological knowledge can be a critical approach for drug development or drug repurposing. In this context, host-pathogen-protein-protein interaction (HP-PPI) networks are useful instrument to uncover the phenomena underlying therapeutic effects in infectious diseases, including cervical cancer, which is almost exclusively due to human papillomavirus (HPV) infections. Cervical cancer is one of the second leading causes of death, and HPV16 and HPV18 are the most common subtypes worldwide. Given the limitations of traditionally used virus-directed drug therapies for infectious diseases and, at the same time, recent cancer statistics for cervical cancer cases, the need for innovative treatments becomes clear.MethodsAccordingly, in this study, we emphasize the potential of host proteins as drug targets and identify promising host protein candidates for cervical cancer by considering potential differences between HPV subtypes (i.e., HPV16 and ...
Aims Diabetes is a chronic disease that limits the quality and duration of life. We aimed to esti... more Aims Diabetes is a chronic disease that limits the quality and duration of life. We aimed to estimate the trends in prediabetes and diabetes between 2010-2020, and the projections to 2023 and 2045 in Turkey. Materials and methods Prediabetes and diabetes estimates were calculated by direct standardization using age/sex-specific data from the previous TURDEP-II survey as reference. The 2010-2020 population demographics were obtained from TurkStat. Comparative age-adjusted diabetes rates were estimated using standard population models of world and Europe. ResultsEstimates depicted that the population (20-84 years) of any degree of glucose intolerance in Turkey increased by approximately 5.3 million (diabetes: 2.2 million and prediabetes: 3.1 million) from 2010 to 2020. While the increase in prediabetes and diabetes rates was 22% and 31.6% in overall population, corresponding increase were 45.2% and 45.6% in the elderly. Notably, diabetes awareness was comparable (54% and 58%). Age-spe...
European Journal of Pharmacology, 2020
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has ... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR<0.05 and logFC ≥ 1). The DEGs were significantly involved in the immune and inflammatory response. The pathway analysis revealed the DEGs were found in influenza A, measles, cytokine signaling in the immune system, interleukin-4, interleukin − 13, interleukin − 17 signaling, and TNF signaling pathways. Protein-protein interaction analysis showed 10 hub genes (BIRC3,
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2020
Oncogenic viruses are among the apparent causes of cancer-associated mortality. It was estimated ... more Oncogenic viruses are among the apparent causes of cancer-associated mortality. It was estimated that 12% to 15% of human malignancies are linked to oncoviruses. Although modernist strategies and traditional genetic studies have defined host-pathogen interactions of the oncoviruses, their host functions which are critical for the establishment of infection still remain mysterious. However, over the last few years, it has become clear that infections hijack and modify cellular pathways for their benefit. In this context, we constructed the virus-host protein interaction networks of seven oncoviruses (EBV, HBV, HCV, HTLV-1, HHV8, HPV16, and HPV18), and revealed cellular pathways hijacking as a result of oncogenic virus infection. Several signaling pathways/processes such as TGF-β signaling, cell cycle, retinoblastoma tumor suppressor protein, and androgen receptor signaling were mutually targeted by viruses to induce oncogenesis. Besides, cellular pathways specific to a certain virus were detected. By this study, we believe that we improve the understanding of the molecular pathogenesis of viral oncogenesis and provide information in setting new targets for treatment, prognosis, and diagnosis.
Frontiers in Physiology, 2018
Drug repositioning has gained attention from both academia and pharmaceutical companies as an aux... more Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved noncancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time-and cost-efficiency comparing to conventional drug discovery and development process.
Computational Biology and Chemistry, 2018
Alzheimer's disease (AD) is a dynamic degeneration of the brain with progressive dementia. Consid... more Alzheimer's disease (AD) is a dynamic degeneration of the brain with progressive dementia. Considering the uncertainties in its molecular mechanism, in the present study, we employed network-based integrative analyses, and aimed to explore the key molecules and their associations with small drugs to identify potential biomarkers and therapeutic agents for the AD. First of all, we studied a transcriptome dataset (n=20) and identified 1521 differentially expressed genes (DEGs). Integration of transcriptome data with protein-protein and transcriptional regulatory interactions resulted with central (hub) proteins (UBA52,
Omics : a journal of integrative biology, 2018
The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world,... more The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independen...
Journal of Personalized Medicine
Cancer hallmark genes and proteins orchestrate and drive carcinogenesis to a large extent, theref... more Cancer hallmark genes and proteins orchestrate and drive carcinogenesis to a large extent, therefore, it is important to study these features in different cancer types to understand the process of tumorigenesis and discover measurable indicators. We performed a pan-cancer analysis to map differentially interacting hallmarks of cancer proteins (DIHCP). The TCGA transcriptome data associated with 12 common cancers were analyzed and the differential interactome algorithm was applied to determine DIHCPs and DIHCP-centric modules (i.e., DIHCPs and their interacting partners) that exhibit significant changes in their interaction patterns between the tumor and control phenotypes. The diagnostic and prognostic capabilities of the identified modules were assessed to determine the ability of the modules to function as system biomarkers. In addition, the druggability of the prognostic and diagnostic DIHCPs was investigated. As a result, we found a total of 30 DIHCP-centric modules that showed ...
Interdisciplinary Cancer Research
Expert Review of Anticancer Therapy
Journal of Molecular Neuroscience
<p>(A) Venn diagram representing the distribution of the down-regulated transcripts in the ... more <p>(A) Venn diagram representing the distribution of the down-regulated transcripts in the datasets, where 113 transcripts were mutually down-regulated in all datasets (i.e., down-regulated core genes). (B) Venn diagram representing the distribution of the up-regulated transcripts in datasets, where 199 transcripts were mutually up-regulated in all datasets (i.e., up-regulated core genes). (C) The clustering of the proteins encoded by the down-regulated core genes of cervical cancer according to their molecular activities. (D) The clustering of the proteins encoded by the up-regulated core genes of cervical cancer according to their molecular activities (DEGs: differentially expressed genes).The gene set overrepresentation analysis of the core genes based on the annotations stored in KEGG and GAD databases resulted in (particularly cancers), p53 signaling, and pyrimidine metabolism (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200717#pone.0200717.g002" target="_blank">Fig 2</a>). Periodontitis, hypospadias, and arterial blood pressure pathways were down-regulated, whereas up-regulated core genes were enriched in those associated with the cell cycle, DNA replication, oocyte meiosis, several cancers (colorectal, bladder, breast, ovarian, lung, stomach, and prostate), autoimmune disorders (including rheumatoid arthritis and systemic lupus erythematosus), Alzheimer's disease, p53 signaling pathway, and pyrimidine metabolism.</p
OMICS: A Journal of Integrative Biology
Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nona... more 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.
1. p-values of the genes and the significantly expressed genes with their directions of regulatio... more 1. p-values of the genes and the significantly expressed genes with their directions of regulations in response to rapamycin and caffeine 2. Core proteins of the constructed TOR signaling network 3. Annotation Collection Table (ACT) of the core proteins of TOR Signaling protein interaction network 4. Interactions of the constructed TOR signaling protein interaction network 5. Modules found by MCODE plugin of Cytoscape 6. GO Term enrichment results of the 25 modules identified by MCODE plugin of Cytoscape 7. S. Cerevisiae Receptor List 8. Yeast Transcriptional Regulatory Network 9. Key Transcription Factors that regulates a common set of significantly expressed genes in response to rapamycin and caffeine
OMICS: A Journal of Integrative Biology, 2021
Esophageal squamous cell carcinoma (ESCC) is among the most dangerous cancers with high mortality... more Esophageal squamous cell carcinoma (ESCC) is among the most dangerous cancers with high mortality and lack of robust diagnostics and personalized/precision therapeutics. To achieve a systems-level understanding of tumorigenesis, unraveling of variations in the protein interactome and determination of key proteins exhibiting significant alterations in their interaction patterns during tumorigenesis are crucial. To this end, we have described differential protein-protein interactions and differentially interacting proteins (DIPs) in ESCC by utilizing the human protein interactome and transcriptome. Furthermore, DIP-centered modules were analyzed according to their potential in elucidation of disease mechanisms and improvement of efficient diagnostic, prognostic, and treatment strategies. Seven modules were presented as potential diagnostic, and 16 modules were presented as potential prognostic biomarker candidates. Importantly, our findings also suggest that 30 out of the 53 repurposed drugs were noncancer drugs, which could be used in the treatment of ESCC. Interestingly, 25 of these, proposed as novel drug candidates here, have not been previously associated in a context of esophageal cancer. In this context, risperidone and clozapine were validated for their growth inhibitory potential in three ESCC lines. Our findings offer a high potential for the development of innovative diagnostic, prognostic, and therapeutic strategies for further experimental studies in line with predictive diagnostics, targeted prevention, and personalization of medical services in ESCC specifically, and personalized cancer care broadly.
OMICS: A Journal of Integrative Biology, 2020
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). In a subgroup o... more Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). In a subgroup of patients with PTC, the disease progresses to an invasive stage or in some cases to distant organ metastasis. At present, there is an unmet clinical and diagnostic need for early identification of patients with PTC who are at risk of disease progression or metastasis. In this study, we report several molecular leads and potential biomarker candidates of PTC metastasis for further translational research. The study design was based on comparisons of PTC in three different groups using cross-sectional sampling: Group 1, PTC localized to the thyroid (n = 20); Group 2, PTC with extrathyroidal progression (n = 22); and Group 3, PTC with distant organ metastasis (n = 20). Global transcriptome and microRNAs (miRNA) analyses were conducted using an initial screening set comprising nine formalin-fixed paraffin-embedded PTC samples obtained from three independent patients per study group. The findings were subsequently validated by quantitative real-time polymerase chain reaction (qRT-PCR) using the abovementioned independent patient sample set (n = 62). Comparative analyses of differentially expressed miRNAs showed that miR-193-3p, miR-182-5p, and miR-3607-3p were novel miRNAs associated with PTC metastasis. These potential miRNA biomarkers were associated with TC metastasis and miRNA-target gene associations, which may provide important clinicopathological information on metastasis. Our findings provide new molecular leads for further translational biomarker research, which could facilitate the identification of patients at risk of PTC disease progression or metastasis.
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Papers by Kazim Yalcin Arga