Browsing by Author "Konu, Özlen"
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Item Open Access Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET](Elsevier, 2021-06-24) Fernandez-Checa, J. C.; Bagnaninchi, P.; Ye, H.; Sancho-Bru, P.; Falcon-Perez, J. M.; Royo, F.; Garcia-Ruiz, C.; Konu, Özlen; Miranda, J.; Lunov, O.; Dejneka, A.; Elfick, A.; McDonald, A.; Sullivan, G. J.; Aithal, G. P.; Lucena, M. I.; Andrade, R. J.; Fromenty, B.; Kranendonk, M.; Cubero, F. J.; Nelson, L. J.Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.Item Open Access Convergence between nicotine and leptin signaling in body weight regulation and obesity(Nova Publishers, 2004) Li, M. D.; Konu, Özlen; Ling, P. R.Obesity continues to be one of the major epidemic problems in the U. S. and many other industrialized nations. Although treatment strategies historically targeted small-molecule neurotransmitters, more recently it became evident that neuropeptides such as leptin and NPY also play critical roles in the regulation of appetite and metabolism. Discovery of various obesity models in rodents have shed further light on the importance of leptin signaling and modulation of dopaminergic circuitry in determining the mechanisms behind an obese phenotype. While tobacco smoking has long been used as one strategy to control body weight, nicotine’s adverse associations with addiction and disease prohibits its potential use as an approved antiobesity agent. Pharmacological effects of nicotine on energy homeostasis and weight control may stem partly from the emerging convergence between the nicotine- and leptin-driven receptor signaling in regard to the regulation of dopamine in brain and adrenal chromaffin cells. Resolving the intricacies of the diverse set of the nicotinic acetylcholine receptors (nAChR) on which nicotine acts may reveal yet unknown avenues for addiction, obesity, and neurodegenerative research. Moreover, a better understanding of the regulatory mechanisms underlying the pharmacological effects of nicotine on food intake and body weight will certainly provide novel insights for rapid identification of potential drug targets for the treatment of obesity.Item Open Access CoVrimer: a tool for aligning SARS-CoV-2 primer sequences and selection of conserved/degenerate primers(Academic Press, 2021-07-20) Vural-Özdeniz, Merve; Aktürk, Aslınur; Demirdizen, Mert; Leka, Ronaldo; Acar, Rana; Konu, ÖzlenAs mutations in SARS-CoV-2 virus accumulate rapidly, novel primers that amplify this virus sensitively and specifically are in demand. We have developed a webserver named CoVrimer by which users can search for and align existing or newly designed conserved/degenerate primer pair sequences against the viral genome and assess the mutation load of both primers and amplicons. CoVrimer uses mutation data obtained from an online platform established by NGDC-CNCB (12 May 2021) to identify genomic regions, either conserved or with low levels of mutations, from which potential primer pairs are designed and provided to the user for filtering based on generalized and SARS-CoV-2 specific parameters. Alignments of primers and probes can be visualized with respect to the reference genome, indicating variant details and the level of conservation. Consequently, CoVrimer is likely to help researchers with the challenges posed by viral evolution and is freely available at http://konulabapps.bilkent.edu.tr:3838/CoVrimer/.Item Open Access Cryptic torrent frogs of myanmar: an examination of the amolops marmoratus species complex with the resurrection of amolops afghanus and the identification of a new species(American Society of Ichthyologists and Herpetologists, 2012) Dever, J. A.; Fuiten, A. M.; Konu, Özlen; Wilkinson, J. A.We investigated diversity in the Amolops marmoratus species complex within Myanmar using both molecular and morphological characters from recently collected specimens. Based on congruence between multivariate analyses of quantitative morphological characters and phylogenetic analyses of nucleotide variation in the 16S ribosomal gene conducted on 43 out of 182 frogs examined, we recognize A. marmoratus for specimens from the states of Mon and Shan and northern Tanintharyi Division and designate a neotype for this species; resurrect A. afghanus (Gnther, 1858) from synonymy with A. marmoratus for specimens from the northern state of Kachin and designate a lectotype for this species; recognize A. panhai for specimens from Tanintharyi, a new country record; and describe a new species for specimens from the western states of Chin and Rakhine, and Sagaing Division.Item Open Access Design, synthesis and anticancer/antiestrogenic activities of novel indole-benzimidazoles(Elsevier , 2020-05) Karadayı, F. Z.; Yaman, Murat; Kışla, M. M.; Keşküş, Ayşe G.; Konu, Özlen; Ateş Alagöz, Z.Indole-benzimidazoles have recently gained attention due to their antiproliferative and antiestrogenic effects. However, their structural similarities and molecular mechanisms shared with selective estrogen receptor modulators (SERMs) have not yet been investigated. In this study, we synthesized novel ethylsulfonyl indole-benzimidazole derivatives by substituting the first (R1) and fifth (R2) positions of benzimidazole and indole groups, respectively. Subsequently, we performed 1 H NMR, 13C NMR, and Mass spectral and in silico docking analyses, and anticancer activity screening studies of these novel indole-benzimidazoles. The antiproliferative effects of indolebenzimidazoles were found to be more similar between the estrogen (E2) responsive cell lines MCF-7 and HEPG2 in comparison to the Estrogen Receptor negative (ER-) cell line MDA-MB-231. R1:p-fluorobenzyl group members were selected as lead compounds for their potent anticancer effects and moderate structural affinity to ER. Microarray expression profiling and gene enrichment analyses (GSEA) of the selected compounds (R1:p-fluorobenzyl: 48, 49, 50, 51; R1:3,4-difluorobenzyl: 53) helped determine the similarly modulated cellular signaling pathways among derivatives. Moreover, we identified known compounds that have significantly similar gene signatures to that of 51 via queries performed in LINCS database; and further transcriptomics comparisons were made using public GEO datasets (GSE35428, GSE7765, GSE62673). Our results strongly demonstrate that these novel indole-benzimidazoles can modulate ER target gene expression as well as dioxin-mediated aryl hydrocarbon receptor and amino acid deprivation-mediated integrated stress response signaling in a dose-dependent manner.Item Open Access Design, synthesis, anticancer activity, molecular docking and ADME studies of novel methylsulfonyl indole-benzimidazoles in comparison with ethylsulfonyl counterparts(Royal Society of Chemistry, 2021-04-26) Zengin Karadayı, F.; Yaman, M.; Kışla, M. M.; Konu, Özlen; Ateş-Alagöz, Z.Cancer poses a world-wide healthcare problem, demanding selective and effective therapy protocols. To address that, a vast amount of therapeutic candidates are being investigated in the field of medicinal chemistry. Accordingly, indole-benzimidazole structures have recently gained considerable interest because of their anticancer properties and estrogen receptor (ER) modulatory actions. In this study, novel methylsulfonyl indole-benzimidazole derivatives have been synthesized upon substitution of respectively the first (R1) and fifth (R2) positions of benzimidazole and indole groups. Structure and activity relationships were then studied via1H NMR, 13C NMR, mass spectral and in silico docking analyses, as well as cell viability measurements. We found that the compounds exhibited substantial affinity levels towards ER alpha (ERα). In addition, the correlation analysis of cytotoxicity profiles between ethyl- and methyl-sulfonyl indole-benzimidazoles revealed a collection of effective and consistent R1 and R2 substitutions. However, for some candidate derivatives, distinctive cytotoxicity levels and varying viability versus ERα affinity correlations were observable across the studies, suggesting that the sulfonyl side chain modifications themselves can also influence the ERα binding levels. These results demonstrated that our novel methylsulfonyl indole-benzimidazole derivatives, similar to their ethylsulfonyl counterparts, exhibit anticancer effects with potential estrogen receptor modulatory actions.Item Open Access Development of a novel zebrafish xenograft model in ache mutants using liver cancer cell lines(Nature Publishing Group, 2018) Avcı, M. Ender; Keskus, Ayşe Gökçe; Targen, Seniye; Işılak, M. Efe; Öztürk, Mehmet; Çetin-Atalay, Rengül; Adams, Michelle M.; Konu, ÖzlenAcetylcholinesterase (AChE), an enzyme responsible for degradation of acetylcholine, has been identified as a prognostic marker in liver cancer. Although in vivo Ache tumorigenicity assays in mouse are present, no established liver cancer xenograft model in zebrafish using an ache mutant background exists. Herein, we developed an embryonic zebrafish xenograft model using epithelial (Hep3B) and mesenchymal (SKHep1) liver cancer cell lines in wild-type and ache sb55 sibling mutant larvae after characterization of cholinesterase expression and activity in cell lines and zebrafish larvae. The comparison of fluorescent signal reflecting tumor size at 3-days post-injection (dpi) revealed an enhanced tumorigenic potential and a reduced migration capacity in cancer cells injected into homozygous ache sb55 mutants when compared with the wild-type. Increased tumor load was confirmed using an ALU based tumor DNA quantification method modified for use in genotyped xenotransplanted zebrafish embryos. Confocal microscopy using the Huh7 cells stably expressing GFP helped identify the distribution of tumor cells in larvae. Our results imply that acetylcholine accumulation in the microenvironment directly or indirectly supports tumor growth in liver cancer. Use of this model system for drug screening studies holds potential in discovering new cholinergic targets for treatment of liver cancers.Item Open Access Discovery of cancer-specific and independent prognostic gene subsets of the slit-robo family using TCGA-PANCAN datasets(Mary Ann Liebert, 2021-12-08) Özhan, Ayşe; Tombaz, Melike; Konu, ÖzlenThe Slit-Robo family of axon guidance molecules works in concert, playing important roles in organ devel opment and cancer. Expressions of individual Slit-Robo genes have been used in calculating univariable hazard ratios (HRuni) for predicting cancer prognosis in the literature. However, Slit-Robo members do not act in dependently; hence, hazard ratios from multivariable Cox regression (HRmulti) on the whole gene set can further lead to identification of cancer-specific, novel, and independent prognostic gene pairs or modules. Herein, we obtained mRNA expressions of the Slit-Robo family consisting of four Robos (ROBO1/2/3/4) and three Slits (SLIT1/2/3), along with four types of survival outcome across cancers found in the Cancer Genome Atlas (TCGA). We used cluster heat maps to visualize closely associated pairs/modules of prognostic genes across 33 different cancers. We found a smaller number of significant genes in HRmulti than in HRuni, suggesting that the former analysis was less redundant. High ROBO4 expression emerged as relatively protective within the family, in both types of HR analyses. Multivariable Cox regression, on the other hand, revealed significantly more HR signatures containing Slit-Robo pairs acting in opposing directions than those containing Slit-Slit or Robo-Robo pairs for disease-specific survival. Furthermore, we discovered, through the online app SmulTCan’s lasso regression, Slit-Robo gene subsets that significantly differentiated between high- versus low-risk prog nosis patient groups, particularly for renal cancers and low-grade glioma. The statistical pipeline reported herein can help test independent and significant pairs/modules within a codependent gene family for cancer prog nostication, and thus should also prove useful in personalized/precision medicine research.Item Open Access Doxorubicin induces prolonged DNA damage signal in cells overexpressing DEK isoform-2(Public Library of Science, 2022-10-03) Özçelik, Emrah; Kalaycı, Ahmet; Çelik, Büşra; Avcı, Açelya; Akyol, Hasan; Kılıç, İrfan Baki; Güzel, Türkan; Çetin, Metin; Öztürk, Merve Tuzlakoğlu; Çalışkaner, Zihni Onur; Tombaz, Melike; Yoleri, Dilan; Konu, Özlen; Kandilci, AytenDEK has a short isoform (DEK isoform-2; DEK2) that lacks amino acid residues between 49–82. The full-length DEK (DEK isoform-1; DEK1) is ubiquitously expressed and plays a role in different cellular processes but whether DEK2 is involved in these processes remains elusive. We stably overexpressed DEK2 in human bone marrow stromal cell line HS-27A, in which endogenous DEKs were intact or suppressed via short hairpin RNA (sh-RNA). We have found that contrary to ectopic DEK1, DEK2 locates in the nucleus and nucleolus, causes persistent үH2AX signal upon doxorubicin treatment, and couldn’t functionally compensate for the loss of DEK1. In addition, DEK2 overexpressing cells were more sensitive to doxorubicin than DEK1-cells. Expressions of DEK1 and DEK2 in cell lines and primary tumors exhibit tissue specificity. DEK1 is upregulated in cancers of the colon, liver, and lung compared to normal tissues while both DEK1 and DEK2 are downregulated in subsets of kidney, prostate, and thyroid carcinomas. Interestingly, only DEK2 was downregulated in a subset of breast tumors suggesting that DEK2 can be modulated differently than DEK1 in specific cancers. In summary, our findings show distinct expression patterns and subcellular location and suggest non-overlapping functions between the two DEK isoforms. © 2022 Ozçelik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Item Open Access Extraction and prioritization of a gene-cancer-by-survival network involved in homeostasis of intracellular calcium concentrations using TCGA PANCAN data(Mary Ann Liebert, Inc. Publishers, 2022-05-26) Tombaz, Melike; Yanyatan, Çağdaş; Keşküş, Ayşe Gökçe; Konu, ÖzlenRegulation of intracellular calcium concentrations, [Ca++]i is important in maintaining the viability of normal as well as cancer cells and can be mediated by tumor microenvironment. Calcium release-activated calcium channel protein (ORAI) calcium channels on the plasma membrane (PM) become physically connected by stromal interaction molecules (STIMs) to the endoplasmic reticulum (ER), on which paralogous receptors of inositol phosphate and of ryanodine are also present along with ATP2A/SERCA (sarco/endoplasmic reticulum calcium ATPases) subunits (also known as PM-ER geneset). Proper expression of this functionally and physically interconnected geneset is essential for the maintenance of [Ca++]i, yet has not been interrogated as a whole for its role in cancer prognosis using multivariable Cox regression. In the present study, we examined whether the expression profile of the PM-ER geneset exhibited prognostic significance across different cancers found in The Cancer Genome Atlas (TCGA) by generating gene-cancer-by-survival networks, in which the nodes represented either genes or cancers and the edges, the logarithmically transformed hazard ratios for overall survival (OS). We then applied network clustering to identify the gene-cancer subnetworks with high connectivity, among which uveal melanoma (UVM) emerged exhibiting the highest degree of genes (k = 10). BAP1, a well-known [Ca++]i regulator and a tumor suppressor, was not found to be significant in predicting OS by PM-ER geneset for UVM, yet it was for several others, including mesothelioma (MESO). Moreover, the best subset of the PM-ER geneset obtained by lasso predicted OS in the TCGA UVM cohort with an area under the receiver operating characteristics (AUC) of 91.4%, comparable to or better than previous prognostic signatures in the literature. Our findings indicate that homeostasis of [Ca++]i is an essential determinant of prognosis in multiple cancers and particularly in UVM. The proposed gene-cancer-by-survival network approach can be extended with other gene sets as well as different survival types.Item Open Access Functional analysis of co-expression networks of zebrafish ace2 reveals enrichment of pathways associated with development and disease(Canadian Science Publishing, 2022-02-02) Keşkuş, Ayşe Gökçe; Tombaz, Melike; Arıcı, Burçin İrem; Dinçaslan, Fatma Betül; Nabi, Afshan; Shehwana, Huma; Konu, ÖzlenHuman Angiotensin I Converting Enzyme 2 (ACE2) plays an essential role in blood pressure regulation and SARS-CoV-2 entry. ACE2 has a highly conserved, one-to-one ortholog (ace2) in zebrafish, which is an important model for human diseases. However, the zebrafish ace2 expression profile has not yet been studied during early development, between genders, across different genotypes, or in disease. Moreover, a network-based meta-analysis for the extraction of functionally enriched pathways associated with differential ace2 expression is lacking in the literature. Herein, we first identified significant development-, tissue-, genotype-, and gender-specific modulations in ace2 expression via meta-analysis of zebrafish Affymetrix transcriptomics datasets (ndatasets = 107); and the correlation analysis of ace2 meta-differential expression profile revealed distinct positively and negatively correlated local functionally enriched gene networks. Moreover, we demonstrated that ace2 expression was significantly modulated under different physiological and pathological conditions related to development, tissue, gender, diet, infection, and inflammation using additional RNA-seq datasets. Our findings implicate a novel translational role for zebrafish ace2 in organ differentiation and pathologies observed in the intestines and liver.Item Open Access Increased SGK1 activity potentiates mineralocorticoid/NaCl-induced kidney injury(American Physiological Society, 2021-04-08) Sierra-Ramos, Catalina; Velazquez-Garcia, Silvia; Keskus, Ayşe Gökçe; Vastola-Mascolo, Arianna; Rodríguez-Rodríguez, Ana E.; Luis-Lima, Sergio; Hernández, Guadalberto; Navarro-González, Juan F.; Porrini, Esteban; Konu, Özlen; Alvarez de la Rosa, DiegoSerum and glucocorticoid-regulated kinase 1 (SGK1) stimulates aldosterone-dependent renal Na reabsorption and modulates blood pressure. In addition, genetic ablation or pharmacological inhibition of SGK1 limits the development of kidney inflammation and fibrosis in response to excess mineralocorticoid signaling. In this work, we tested the hypothesis that a systemic increase in SGK1 activity would potentiate mineralocorticoid/salt-induced hypertension and kidney injury. To that end, we used a transgenic mouse model with increased SGK1 activity. Mineralocorticoid/salt-induced hypertension and kidney damage was induced by unilateral nephrectomy and treatment with deoxycorticosterone acetate and NaCl in the drinking water for 6 wk. Our results show that although SGK1 activation did not induce significantly higher blood pressure, it produced a mild increase in glomerular filtration rate, increased albuminuria, and exacerbated glomerular hypertrophy and fibrosis. Transcriptomic analysis showed that extracellular matrix-and immune response-related terms were enriched in the downregulated and upregulated genes, respectively, in transgenic mice. In conclusion, we propose that systemically increased SGK1 activity is a risk factor for the development of mineralocorticoid-dependent kidney injury in the context of low renal mass and independently of blood pressure. NEW and NOTEWORTHY Increased activity of the protein kinase serum and glucocorticoid-regulated kinase 1 may be a risk factor for accelerated renal damage. Serum and glucocorticoid-regulated kinase 1 expression could be a marker for the rapid progression toward chronic kidney disease and a potential therapeutic target to slow down the process. © 2021 American Physiological Society. All rights reserved.Item Open Access Investigation and comparison of the preprocessing algorithms for microarray analysis for robust gene expression calculation and performance analysis of technical replicates(IEEE, 2006) İlk, H. G.; İlk, Ö.; Konu, Özlen; Özdağ, H.Preprocessing of microarray data involves the necessary steps of background correction, normalization and summarization of the raw intensity data obtained from cDNA or oligo-arrays before statistical analysis. Several algorithms, namely RMA, dChip, and MAS5 exist for the preprocessing of Affymetrix microarray data. Previous studies have identified RMA as one of most accurate algorithms while MAS5 was characterized with lower accuracy and sensitivity levels. In this study, performance of different preprocessing algorithms have been compared in terms of ROC characteristics of pairwise intensity differences of microarray replicates. Our findings indicated that all three algorithms predicted in similar order the quality of the technical replicates obtained from a selected set of latin square experiments [1]. On the other hand, RMA exhibited higher performance in terms of accuracy by maximizing the area under the receiver operating curve. The proposed method also is useful for detection of global and/or local artifacts associated within the technical replicas of a microarray experiment. Therefore this study is unique in the sense that it provides an extensive investigation and comparison of preprocessing algorithms and proposes a novel method for the detection and identification of fine technical replicate pair.Item Open Access Long-term acetylcholinesterase depletion alters the levels of key synaptic proteins while maintaining neuronal markers in the aging zebrafish (Danio rerio) Brain(S. Karger AG, 2023-10-04) Karoğlu-Eravsar, Elif Tuğçe; Tüz-Şaşik, Melek Umay; Karaduman, Ayşenur; Keşküş, Ayse Gökçe; Arslan-Ergul, Ayça; Konu, Özlen; Kafalıgönül, Hulusi; Adams, Michelle M.Introduction: Interventions targeting cholinergic neurotransmission like acetylcholinesterase (AChE) inhibition distinguish potential mechanisms to delay age-related impairments and attenuate deficits related to neurodegenerative diseases. However, the chronic effects of these interventions are not well described. Methods: In the current study, global levels of cholinergic, cellular, synaptic, and inflammation-mediating proteins were assessed within the context of aging and chronic reduction of AChE activity. Long-term depletion of AChE activity was induced by using a mutant zebrafish line, and they were compared with the wildtype group at young and old ages. Results: Results demonstrated that AChE activity was lower in both young and old mutants, and this decrease coincided with a reduction in ACh content. Additionally, an overall age-related reduction in AChE activity and the AChE/ACh ratio was observed, and this decline was more prominent in wildtype groups. The levels of an immature neuronal marker were upregulated in mutants, while a glial marker showed an overall reduction. Mutants had preserved levels of inhibitory and presynaptic elements with aging, whereas glutamate receptor subunit levels declined. Conclusion: Long-term AChE activity depletion induces synaptic and cellular alterations. These data provide further insights into molecular targets and adaptive responses following the long-term reduction of AChE activity that was also targeted pharmacologically to treat neurodegenerative diseases in human subjects.Item Open Access Lower connectivity of tumor coexpression networks is not specific to cancer(IOP, 2019-05) Dalgıç, E.; Konu, Özlen; Safi Öz, Z.; Chan, C.Global level network analysis of molecular links is necessary for systems level view of complex diseases like cancer. Using genome-wide expression datasets, we constructed and compared gene co-expression based specific networks of pre-cancerous tumors (adenoma) and cancerous tumors (carcinoma) with paired normal networks to assess for any possible changes in network connectivity. Previously, loss of connectivity was reported as a characteristic of cancer samples. Here, we observed that pre-cancerous conditions also had significantly less connections than paired normal samples. We observed a loss of connectivity trend for colorectal adenoma, aldosterone producing adenoma and uterine leiomyoma. We also showed that the loss of connectivity trend is not specific to positive or negative correlation based networks. Differential hub genes, which were the most highly differentially less connected genes in tumor, were mostly different between different datasets. No common gene list could be defined which underlies the lower connectivity of tumor specific networks. Connectivity of colorectal cancer methylation targets was different from other genes. Extracellular space related terms were enriched in negative correlation based differential hubs and common methylation targets of colorectal carcinoma. Our results indicate a systems level change of lower connectivity as cells transform to not only cancer but also pre-cancerous conditions. This systems level behavior could not be attributed to a group of genes.Item Open Access mESAdb: microRNA expression and sequence analysis database(Oxford University Press, 2011) Kaya, Koray D.; Karakülah, G.; Yakıcıer, Cengiz M.; Acar, Aybar C.; Konu, ÖzlenMicroRNA expression and sequence analysis database (http://konulab.fen. bilkent.edu.tr/mirna/) (mESAdb) is a regularly updated database for the multivariate analysis of sequences and expression of microRNAs from multiple taxa. mESAdb is modular and has a user interface implemented in PHP and JavaScript and coupled with statistical analysis and visualization packages written for the R language. The database primarily comprises mature microRNA sequences and their target data, along with selected human, mouse and zebrafish expression data sets. mESAdb analysis modules allow (i) mining of microRNA expression data sets for subsets of microRNAs selected manually or by motif; (ii) pair-wise multivariate analysis of expression data sets within and between taxa; and (iii) association of microRNA subsets with annotation databases, HUGE Navigator, KEGG and GO. The use of existing and customized R packages facilitates future addition of data sets and analysis tools. Furthermore, the ability to upload and analyze user-specified data sets makes mESAdb an interactive and expandable analysis tool for microRNA sequence and expression data.Item Open Access PKNOX2 expression and regulation in the bone marrow mesenchymal stem cells of Fanconi anemia patients and healthy donors(Springer, 2019) Çağnan, I.; Coşgun, E.; Konu, Özlen; Uçkan, D.; Günel-Özcan, A.HOX and TALE transcription factors are important regulators of development and homeostasis in determining cellular identity. Deregulation of this process may drive cancer progression. The aim of this study was to investigate the expression of these transcription factors in the bone marrow derived mesenchymal stem cells (BM-MSCs) of Fanconi anemia (FA) patients, which is a cancer-predisposing disease. Expression levels of HOX and TALE genes in BM-MSCs were obtained from FA patients and healthy donors by RT-qPCR and highly conserved expression levels were observed between patient and donor cells, except PKNOX2, which is a member of TALE class. PKNOX2 was significantly downregulated in FA cells compared to donors (P < 0.05). PKNOX2 expression levels did not change with diepoxybutane (DEB), a DNA crosslinking agent, in either donor or FA cells except one patient’s with a truncation mutation of FANCA. A difference of PKNOX2 protein level was not obtained between FA patient and donor BM-MSCs by western blot analysis. When human TGF-β1 (rTGF-β1) recombinant protein was provided to the cultures, PKNOX2 as well as TGF-β1 expression increased both in FA and donor BM-MSCs in a dose dependent manner. 5 ng/mL rTGF-β stimulation had more dominant effect on the gene expression of donor BM-MSCs compared to FA cells. Decreased PKNOX2 expression in FA BM-MSCs may provide new insights into the molecular pathophysiology of the disease and TGF-β1 levels of the microenvironment may be the cause of PKNOX2 downregulation.Item Open Access Transcriptome profiles associated with selenium-deficiency-dependent oxidative stress identify potential diagnostic and therapeutic targets in liver cancer cells(Scientific and Technical Research Council of Turkey - TUBITAK,Turkiye Bilimsel ve Teknik Arastirma Kurumu, 2021-04-20) Gözen, D.; Kahraman, D. C.; Narcı, K.; Shehwana, H.; Konu, Özlen; Çetin-Atalay, RengülHepatocellular carcinoma (HCC) is one of the most common cancer types with high mortality rates and displays increased resistance to various stress conditions such as oxidative stress. Conventional therapies have low efficacies due to resistance and off-target effects in HCC. Here we aimed to analyze oxidative stress-related gene expression profiles of HCC cells and identify genes that could be crucial for novel diagnostic and therapeutic strategies. To identify important genes that cause resistance to reactive oxygen species (ROS), a model of oxidative stress upon selenium (Se) deficiency was utilized. The results of transcriptome-wide gene expression data were analyzed in which the differentially expressed genes (DEGs) were identified between HCC cell lines that are either resistant or sensitive to Se-deficiency-dependent oxidative stress. These DEGs were further investigated for their importance in oxidative stress resistance by network analysis methods, and 27 genes were defined to have key roles; 16 of which were previously shown to have impact on liver cancer patient survival. These genes might have Se-deficiency-dependent roles in hepatocarcinogenesis and could be further exploited for their potentials as novel targets for diagnostic and therapeutic approaches.Item Open Access ZenoFishDb v1.1: a database for xenotransplantation studies in zebrafish(Mary Ann Liebert, 2020) Targen, Seniye; Kaya, Tuğberk; Avcı, M. E.; Güneş, Damla; Keşküş, Ayşe Gökçe; Konu, ÖzlenRapidly accumulating literature has proven feasibility of the zebrafish xenograft models in cancer research. Nevertheless, online databases for searching the current zebrafish xenograft literature are in great demand. Herein, we have developed a manually curated database, called ZenoFishDb v1.1 (https://konulab.shinyapps.io/zenofishdb), based on R Shiny platform aiming to provide searchable information on ever increasing collection of zebrafish studies for cancer cell line transplantation and patient-derived xenografts (PDXs). ZenoFishDb v1.1 user interface contains four modules: DataTable, Visualization, PDX Details, and PDX Charts. The DataTable and Visualization pages represent xenograft study details, including injected cell lines, PDX injections, molecular modifications of cell lines, zebrafish strains, as well as technical aspects of the xenotransplantation procedures in table, bar, and/or pie chart formats. The PDX Details module provides comprehensive information on the patient details in table format and can be searched and visualized. Overall, ZenoFishDb v1.1 enables researchers to effectively search, list, and visualize different technical and biological attributes of zebrafish xenotransplantation studies particularly focusing on the new trends that make use of reporters, RNA interference, overexpression, or mutant gene constructs of transplanted cancer cells, stem cells, and PDXs, as well as distinguished host modifications.