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Öğe 24-year-old Male patient Diagnosed with Intramucosal Signet Ring Cell Gastric Cancer with Molecular Analysis: A Case Report(Kare Publ, 2020) Eroglu, Mehtap; Akin Bali, Dilara Fatma; Aktas, Sedef Hande; Kankilic, TeomanStomach cancer is the third leading cause of death among cancer-related deaths in the world. Signet-ring cell carcinoma (SRCC), a type of gastric adenocarcinoma, is frequently diagnosed in people aged fifty or older, and its incidence increases with age, but SRCC is rare in young age groups. In general, this type of cancer is thought to be more aggressive and has a worse prognosis than other types of gastric cancer. However, there are uncertainties about the characteristics and survival outcomes. Since the diagnostic tools used in patients with SRCC have low sensitivity and specificity in diagnosis and prognosis, it is important to support the diagnosis, follow-up of treatment and relapse with molecular genetic biomarkers. The aim in the current case is to see if TP53, which is the most frequently mutated gene in SRCC and NF1, that is expressed as one of the largest genes in the human genome and classified as a tumor suppressor gene, can be used as a prognostic genetic biomarker in the pathogenesis of early SRCCIt is predicted that P53 may be a determinant factor in the pathogenesis of SRCC due to the mutation burden in this case.Öğe A detailed in-silico analysis of potential gastric cancer molecular marker genes in the literature(Inderscience Enterprises Ltd, 2021) Aktas, Sedef Hande; Akin-Bali, Dilara Fatma; Yazici, OzanGenes found extremely important for the diagnosis and prognosis of Gastric Cancer (GC) in the literature between 2015 and 2020 were analysed in detail by in-silico methods. Thereby, broadly-based analysis of the genes was performed for future studies of GC. For this purpose, expression, pathological stage, Overall Survival (OS) and Disease Free Survival (DFS) plots were carried out with GEPIA web tool. PolyPhen-2 and SNAP tools were used to detect pathogenic impact of the mutations. As a result, COL10A1, SOX9, MTBP, CCL5, PSMB8 and PBK genes were found significant to distinguish individuals with GC from healthy individuals. PCDH9 and HGF genes were found significant for both OS and DFS. METTL3, COL10A1, USP3, CCL5, IMP3, CXCR6, PBK, HGF, MRC1, CD163, SSP1 genes were found correlated with the stage of GC. Effect of the mutations of PCDH9 and HGF genes, especially on the Kringle domain of HGF gene, were found pathogenic.Öğe A detailed understanding of the COL10A1 and SOX9 genes interaction based on potentially damaging mutations in gastric cancer using computational techniques(Taylor & Francis Inc, 2022) Aktas, Sedef Hande; Taskin-Tok, Tugba; Al-Khafaji, Khattab; Akin-Bali, Dilara FatmaGastric cancer (GC) has limited effective treatment options and is followed up with biomarkers that have insufficient sensitivity and specificity. Recent studies on Collagen Type X Alpha 1 Chain (COL10A1) show that the COL10A1 gene may be a diagnostic and/or prognostic biomarker for different cancer types. Moreover, its relationship with the Sex determining Region Y (SRY)-related HighMobility Group (HMG) box (SOX9) gene which is also a transcription factor, was discovered recently, and co-expression of these two genes are associated with the development of GC. However, to the best of our knowledge, there is no study in the literature on how potential damaging mutations in the SOX9 and COL10A1 genes can affect their interactions. The aim of this study is to investigate the interactions of wild-type and potentially damaging mutated structures of COL10A1 and SOX9 genes. Thus, outputs for drug development and therapeutic strategies for GC can be obtained. For this purpose, structure validation and energy minimization analyses as well as docking and binding affinity calculations were performed. As a result, it was found that all investigated mutations (P563S, I588L, T624A, H165R and N110T) increased the binding affinity between the COL10A1-SOX9 complex, especially the N110T and H165R mutants in SOX9. As a conclusion, the N110T and H165R mutants in SOX9 may contribute to tumor progression. Therefore, it is important to consider these mutations for future therapeutic strategies.Öğe Bioinformatic and computational analysis for predominant mutations of the Nrf2/Keap1 complex in pediatric leukemia(Taylor & Francis Inc, 2021) Akin-Bali, Dilara Fatma; Al-Khafaji, Khattab; Aktas, Sedef Hande; Taskin-Tok, TugbaThe levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor, which is the main regulator of antioxidant responses and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Our previous study has identified six novel changes in Nrf2/Keap1 pathway in pediatric ALL, which were described for the first time. These changes in the pathway are likely to alter the evolutionary process of amino acids and cause structural changes in the final products of genes. In this study, we aimed to compare the pathogenicity of eight determined mutations reported in our previous study by utilizing different programs with different algorithms and molecular dynamics simulation. Since it is too difficult to handle each existing mutation in a wet laboratory,in silicomethods may give suggestion to choose the important mutations for further analysis and to establish the appropriate patient population and conduct wet laboratory studies. For this purpose, four different algorithms were used to evaluate the effects of single amino acid mutation. In addition, root-mean-square deviation, root-mean-square fluctuation and free-energy landscape analyses were performed to observe stability, flexibility and energetically favorable conformations, respectively, for each amino acid mutation. As a result, our study emphasizes the importance of Keap1 mutations in pediatric ALL Nrf2/Keap1 pathway, a total of eight mutations, two of which were shown for the first time in our study. Especially the mutations in the Keap1 Broad-Complex, Tramtrack and Bric-a-brac domain are worthy of attention. Communicated by Ramaswamy H. Sarma.Öğe Comparative Analysis of the Mutation and Expression Profile of the Cytoprotective NRF2/KEAP1/P62/SQSTM1 Signaling Pathway in Different Glioma Subtypes: An In Silico Study(Galenos Publ House, 2023) Akin, Dilara Fatma; Aktas, Sedef HandeAim: The NRF2/KEAP1/p62/SQSTM1 pathway is the master regulator of antioxidant enzymes and detoxification proteins, both of which play a critical role in redox homeostasis. It shows that the this structurally active pathway has a crucial role in cancer as it inhibits tumorigenesis and metastatic processes and it induces pro-survival genes that promote chemoresistance. The relationship between the molecular mechanisms causing the pathway to malfunction and the development of brain tumors has yet to be fully clarified. The aim of this study is to analyze the genetic changes and expression level differences of the NRF2/KEAP1 pathway comparatively in low-grade gliomas (LGG) and glioblastoma multiforme (GBM) pathology. Materials and Methods: Gene expression profiles and DNA sequences of GBM (n=591) and LGG (n=511) patients and healthy tissue were downloaded from the TCGA database. Not only were gene expression and mutation patterns determined in this study, but also the impacts of genes on survival were assessed. PolyPhen-2 and SNAP tools were used to estimate the pathogenic properties of the changes identified. Results: A total of 16 mutations and gene amplification were identified in the KEAP1, NRF2, p62/SQSTM1, HMOX-1, and MOAP1 for both cancer groups, and the mutation carrying frequency was 4.6%. IDH1 p.R132H and NRF2 p.S164* mutation association was determined in 1 patient with LGG. KEAP1, NRF2, and HMOX1 expression levels for both LGG and GBM subtypes were determined to be high in patient samples compared to healthy samples (p<0.05). Conclusion: By targeting the NRF2/KEAP1/p62/SQSTM1 pathway anomalies, new therapeutic approaches can be provided in the treatment of glioma, particularly for chemotherapy sensitivity.Öğe Comprehensive mutation analysis of the ras/raf/mek/erk pathway in paediatric leukaemia and significant inferences(Medcom Limited, 2021) Akin-Bali, Dilara Fatma; Aktas, Sedef Hande; Ozcan, Alper; Yilmaz, Ebru; Aydin, Firdevs; Gök, Veysel; Ünal, EkremObjectives: Leukaemia is the most common cancer among paediatric population accounting for about 30% of paediatric cancer. As it's known, germ line mutations increase the risk of development of haematopoietic malignancy in childhood and deregulation of the Rat Sarcoma Viral Proto-Oncogene/ Raf-1 Proto-Oncogene/Mitogen-Activated Protein Kinases/Extracellular Regulated Kinases (RAS/RAF/ MEK/ERK) pathway is often caused by somatic mutations in the genes coding proteins of KRAS, NRAS, FLT3, PTPN11 and BRAF. However, mutations in this pathway in paediatric Acute Lymphoblastic Leukaemia (ALL) have not been thoroughly investigated, yet. Methods: Specific exons of 7 significant genes which were frequently mutated in the RAS/RAF/MEK/ERK pathway were determined inclusively by DNA sequence analysis in 27 children with leukaemia. PolyPhen-2 and SNAP tools were used to verify and estimate the determined changes. Also, evolutionary conservation analysis was performed. Results: Seven changes out of 22 changes were identified for the first time in this study. ERK2 p.P319S (18.5%) mutation and KRAS splice site mutation (3.7%) were predicted to be pathogenic. ERK2 p.P319S mutations was found to be pathogenic and at the critical point on the aminoacid which is evalutionary conserved. Although the frequency of mutations in ERK2 is very low in cancers (0.88%), the frequency of ERK2 p.P319S missense change was detected in our study at a significant rate such as 18.5%. Conclusion: There is limited knowledge about ERK inhibitors in leukaemia. The low frequency of ERK gene compared to KRAS and NRAS genes does not make ERK mutations less important. Our findings indicate the importance of this pathway mutations in paediatric ALL and associated with high risk leukaemia group characteristics. Hence, it can be evaluated as a signalisation pathway to target pharmacologically. © 2021, Medcom Limited. All rights reserved.Öğe Identification of novel Nrf2/Keap1 pathway mutations in pediatric acute lymphoblastic leukemia(Taylor & Francis Inc, 2020) Akin-Bali, Dilara Fatma; Aktas, Sedef Hande; Unal, Mehmet Altay; Kankilic, TeomanAcute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells, characterized by a wide range of biological and clinical heterogeneity. Oxidative stress is a common problem observed in carcinogenesis and it is involved in developing treatment resistance. Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor is the main regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Recently, many studies have shown that most of the genes in the Nrf2/Keap1/nuclear factor kappa-B (NF-kappa B)/phosphotyrosine-independent ligand for the Lck SH2 domain Of 62 KDa (p62) pathway show abnormally high mutational variations in cancer. However, variations in the Nrf2/Keap1/NF-kappa B1/p62 pathway in pediatric ALL have not been thoroughly investigated, yet. Thirty children, who were diagnosed with pediatirc ALL were included in the study. The Nrf2/Keap1/NF-kappa B1/p62 pathway variants were analyzed by DNA sequencing analysis. The PolyPhen-2 program was used for identifying pathogenic mutations. Our study examined the molecular dynamics (MD) perspectives of the effect of A159T and E121K mutations on protein stability for the first time in the literature by using the GROMACS45 software package utilizing the OPSLAA force field. Of the detected 17 nucleotide changes, 6 were novel. The study predicted the potential pathological effect of two mutations p. A159T and p.E121K in the Keap1 gene. The MD perspectives revealed that the E121K mutant's observed structural behavior accounted for the key role of His-129 and E121K, where E121K exhibited much higher drift compared to His-129. For a future perspective, it would be meaningful to study the protein-small molecule interactions of the Keap1 protein to elaborate on the drug effects in patients carrying these mutations.Öğe Survivin As an Immunohistochemical Prognostic Biomarker in Colorectal Cancer: A Meta-Analysis(Kare Publ, 2022) Aktas, Sedef Hande; Emir, Busra; Akin Bali, Dilara Fatma; Yazici, OzanOBJECTIVE Genome-level research qualities survivin as the fourth-best transcriptorne for colon, lung, brain, breast, and melanoma cancers. To date, it has been stated as a prognostic marker and therapeutic target in colorectal cancer (CRC). However, researchers on survivin expression in CRC are heterogeneous. Our current study aimed to reveal prognostic importance of survivin by investigating all CRC articles up to January 2021 that have performed analysis of survivin by immunohistochernical staining method. METHODS A comprehensive literature search for relevant studies published up to January 2021 was performed using SCOPUS and Pubmed databases. Only articles in which survivin was detected by IHC staining were included in the study. All analyses were conducted by using Comprehensive Meta-Analysis. Eight articles and data of 1535 patients were included in the study. Me hazard Ratio was used to examine the relationship between CRC and survivin protein, for the relative weights of each research article. HR and 95% confidence interval values and general summary HR were calculated and forest plot graph was obtained. RESULTS Statistical heterogeneity Cochrane Q test statistics 24.156; p=0.004 and I-2 value was obtained as 62,742. In line with the assumption that the data consisted of different populations, the HR and 95% CI values were calculated as 1.446 (1.1(13-1.897) using the Dersimonian and Laird random effects model. In order to evaluate the risk of publication bias, funnel plots were obtained, including log HR and standard error values on the x and y axes, respectively. CONCLUSION The lite analyzes obtained suggest that survivin overexpression in CRC is associated with poor prognosis. (HR=1.446; 95% CI: 1.103-1.897).
