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Öğe A Novel FOXN1 Variant Is Identified in Two Siblings with Nude Severe Combined Immunodeficiency(Springer/Plenum Publishers, 2019) Firtina, Sinem; Cipe, Funda; Ng, Yuk Yin; Kiykim, Ayca; Ng, Ozden Hatirnaz; Sudutan, Tugce; Aydogmus, Cigdem[Abstract Not Available]Öğe A novel pathogenic frameshift variant of CD3E gene in two T-B plus NK plus SCID patients from Turkey(Springer, 2017) Firtina, Sinem; Ng, Yuk Yin; Ng, Ozden Hatirnaz; Nepesov, Serdar; Yesilbas, Osman; Kilercik, Meltem; Burtecene, NihanSevere combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.Öğe Correction to: Primary antibody deficiencies in Turkey: molecular and clinical aspects(Springer, 2022-02) Ng, Yuk YinAbstract: The original published version of this article contained a mistake in one of the affiliations. The correct affiliation of author Manolya Kara (7) should read: Istinye University Faculty of Medicine, VM MedicalPark Pendik Hospital, Pediatric Infectious Diseases Clinic, Istanbul, Turkey The original article has been corrected. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.Öğe Design and synthesis of novel 1,2,3,4-tetrazines as new anti-leukemia cancer agents(WILEY, 2023-09-29) Eyilcim, Özgür; Günay, Fulya; Günkara, Ömer Tahir; Ng, Yuk Yin; Ulucan, Özlem; Erden, İhsanA series of novel 1,2,3,4-tetrazines were designed and synthesized. 1H-NMR spectroscopy, 13C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm-6, Reh, K562, and Molt-4) and one non-leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm-6, K562, Jurkat, and Molt-4 cell lines, IC50 values were found to be 15.98, 19.12, 23.15, and 25.80 & mu;M, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4-tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents. Eleven novel 1,2,3,4-tetrazine derivatives were synthesized via [3 + 3] cycloaddition reaction between in situ formed aza-oxyallyl cations and azides and their anticancer activities were evaluated against five different leukemia cell lines and one non-leukemic cell line. Compound 3a showed the best activity in all cell lines except the Reh cell line. Docking studies showed that DHFR could be a potential target protein for these new compounds and the binding structures of some compounds were investigated.imageÖğe Determining T and B Cell development by TREC/KREC analysis in primary immunodeficiency patients and healthy controls(Wiley, 2022) Senturk, Gizem; Ng, Yuk Yin; Eltan, Sevgi Bilgic; Baser, Dilek; Ogulur, Ismail; Altindirek, Didem; Firtina, SinemT cell receptor excision circles (TRECs) and kappa-deleting excision circles (KRECs) are DNA fragments potentially indicative of T and B cell development, respectively. Recent thymic emigrants (RTEs) are a subset of peripheral cells that may also represent thymic function. Here, we investigated TREC/KREC copy numbers by quantitative real-time PCR in the peripheral blood of patients with primary immunodeficiencies (PIDs, n = 145) and that of healthy controls (HCs, n = 86) and assessed the correlation between RTEs and TREC copy numbers. We found that TREC copy numbers were significantly lower in children and adults with PIDs (P < .0001 and P < .002, respectively) as compared with their respective age-matched HCs. A moderate correlation was observed between TREC copies and RTE numbers among children with PID (r = .5114, P < .01), whereas no significant correlation was detected between RTE values and TREC content in the HCs (r = .0205, P = .9208). Additionally, we determined TREC and KREC copy numbers in DNA isolated from the Guthrie cards of 200 newborns and showed that this method is applicable to DNA isolated from both peripheral blood samples and dried blood spots, with the two sample types showing comparable TREC and KREC values. We further showed that RTE values are not always reliable markers of T cell output. Although additional confirmatory studies with larger cohorts are needed, our results provide thresholds for TREC/KREC copy numbers for different age groups.Öğe First Steps of the Genetic Monitorization in Primary Immune Deficiencies in the Lead of Prof. Dr. Isil Barlan in Turkey(Turkish Soc Immunology, 2015) Ng, Yuk Yin; Sisko, Sinem; Ng, Ozden Hatirnaz; Tatonyan, Suzin Catal; Kaya, Dilek Sever; Firtina, Sinem; Sayitoglu, Muge[Abstract Not Available]Öğe High TUBB2A expression in childhood T-ALL is correlated with the clinical outcome(Wiley, 2020) Khodzhaev, Khusan; Ng, Ozden Hatirnaz; Tugcu, Deniz; Erbilgin, Yucel; Ng, Yuk Yin; Celkan, Tiraje; Timur, CetinIntroduction Microtubules are polymers that perform functions such as mitosis, intracellular transport, cell morphology, and ciliary and flagellar motility. Since microtubules are taking active part in cell division, they are among direct targets of several antimitotic drugs. Methods Expression levels of tubulin isotypes were analyzed in microarray data of childhood diagnostic T-ALL samples (n = 31) and healthy thymocytes (n = 7). Findings were validated with qPCR in separate T-ALL cohort (n = 48), and clinical correlation analyses were performed.TUBB2A's effects were tested with siRNA-mediated knockdown in MOLT4 cell line, and apoptosis assay was carried out at 24, 48, and 72 hours time points. Results In microarray data,TUBB2Awas found to be the only differentially expressed tubulin isotype (adj.Pvalue = .01), which was validated by qPCR (P = .02). Samples representing differentiation stages of T cell showed an increasing trend ofTUBB2Atoward mature T-cell stage.TUBB2Aexpression was significantly higher in high-risk group patients (P = .026) and in a group with WBC counts >100 (x10(9)cells/L) (P = .029). HighTUBB2Awas also found to be a predictor of shorter OS (P = .029) and RFS (P = .042). Conclusion Aberrant expression of TUBB isotypes can affect the balance of microtubules or microtubule-associated proteins, which might lead to drug resistance/relapse. Contribution of cytoskeleton proteins to drug resistance needs further investigation, and understanding aberrant expression and mode of action of microtubules will improve therapy strategies.Öğe Lymphocyte Subgroups and KREC Numbers in Common Variable Immunodeficiency: A Single Center Study(Springer/Plenum Publishers, 2020) Yaz, Ismail; Ozbek, Begum; Ng, Yuk Yin; Cetinkaya, Pinar Gur; Halacli, Sevil Oskay; Tan, Cagman; Kasikci, MerveCommon variable immunodeficiency (CVID) results in defective B cell differentiation and impaired antibody production and is the most common symptomatic primary immunodeficiency. Our aim was to evaluate the correlation among B cell subgroups, kappa-deleting recombination excision circle (KREC) copy numbers, and clinical and immunological data of the patients with CVID, and evaluate the patients according to classifications currently available to define the role of KREC copy numbers in the diagnosis of CVID. KREC analysis was performed using a quantitative real-time polymerase chain reaction assay, and B cell subgroups were measured by flow cytometry. The median age of the patients (n = 30) was 25 (6-69) years. Parental consanguinity ratio was 33%. The median age at diagnosis was 15 (4-59), and follow-up period was 6 (1-37) years. CD19(+) and CD4(+) cell counts at the time of diagnosis were low in 66.7% and 46.7% of the patients, respectively. CD19(+) cell counts were positively correlated with KREC copy numbers in patients and healthy controls. CD19(+) cell counts and KREC copy numbers were significantly reduced in CVID patients compared to healthy controls as expected. KRECs are quantitative markers for B cell defects. We found low CD4(+) cell numbers, recent thymic emigrants, and lymphopenia in some of the patients at diagnosis, which reminds the heterogeneity of CVID's etiology. In this study, a positive correlation was shown between CD19(+) cell counts and KREC copy numbers. Low KREC copy numbers indicated B cell deficiency; however, high KREC copy numbers were not sufficient to rule out CVID.Öğe Mutational landscape of severe combined immunodeficiency patients from Turkey(Wiley, 2020) Firtina, Sinem; Ng, Yuk Yin; Ng, Ozden Hatirnaz; Kiykim, Ayca; Aydiner, Elif; Nepesov, Serdar; Camcioglu, YildizSevere combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.Öğe Primary antibody deficiencies in Turkey: molecular and clinical aspects(Springer, 2022) Firtina, Sinem; Ng, Yuk Yin; Ng, Ozden H.; Kiykim, Ayca; Ozek, Esra Yucel; Kara, Manolya; Aydiner, ElifPrimary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.Öğe Tanısı Zor Tek Gen Hastalıklarında Hedefe Yönelik Yeni Nesil Dizileme Panel Tasarımı: Primer İmmün Yetersizlik Örneği(İstanbul Üniversitesi, 2020) Fırtına, Sinem; Ng, Özden Hatırnaz; Sayitoğlu, Müge; Ng, Yuk YinAmaç: Yeni nesil dizileme teknolojileri bugün çok sayıda aday genin, genomun tüm kodlayan bölgelerinin hatta tüm genomun analizini tek seferde ve kısa süre içerisinde düşük maliyet ve yüksek hassasiyette, güvenilir bir şekilde mümkün kılmaktadır. Hedefe yönelik yeni nesil dizileme sistemleri genomda sadece belirli bölgenin dizilenmesine imkan veren, tüm genom dizilemelere göre uygulaması ve analizi daha kolay, hızlı ve yüksek güvenirlilikte bir yöntem olarak pek çok rutin genetik tanı uygulamalarında yerini bulmuştur. Gereç ve Yöntem: Çalışmamızda primer immün yetersizliklerin en yaygın grubu olan primer antikor yetersizlikleri (PAY) ve en ağır seyirli grubu ağır kombine immün yetersizlikler (AKİY) için hastalık ile ilişkili olduğu bilinen genleri kapsayan PZR temelli genetik tanı panelleri geliştirilmiş ve ortaya çıkan yüksek verinin yorumlanması için bir analiz akışı oluşturulmuştur. Bulgular: Tasarlanan paneller ile toplam 112 hasta (PAY:64, AKİY:48) dizilenmiş ve AKİY hastalarının %58’i ve PAY hastalarının %14,2’sinde hastalık ile ilişkili varyantlar tespit edilmiştir. Tüm varyantlar Sanger dizileme ile doğrulanarak oluşturulan moleküler tanı panellerinin ve analiz algoritmasının doğruluğu kontrol edilmiştir. Sonuç: Hedefe yönelik yeni nesil dizileme panellerinin hedeflenen bölgeye uygun olarak doğru yöntemle tasarlanması ve çıkan ham datanın doğru iş akışı ile analiz edilmesi panelin başarısını arttırmaktadır.|Objective: Next-generation sequencing technologies can generate an analysis of a large number of candidate genes, all the coding regions of a genome, or whole genomes with a high degree of accuracy and within a short amount of time. Targeted next generation sequencing systems have been found in many routine genetic diagnosis applications that allow the sequencing of only the candidate regions of the genome. Materials and Methods: In this study, we designed PCR-based targeted next generation sequencing (NGS) panels for severe combined immunodeficiency (SCID) and primary antibody deficiency (PAD) and created an algorithm for analysing high-throughput data. Results: We screened 112 patients (48 SCID and 64 PAD) and we detected genetic variations in 58% of the SCID and in 14.2% of the PAD patients. All variants were validated by Sanger sequencing to validate the accuracy of the NGS panel and analysis algorithm. Conclusion: Designing targeted next generation sequencing panels with an appropriate method, in accordance with the targeted region, and analysing the raw data with a suitable workflow, increases the success of the panel.Öğe TNFRSF13B VARYANTLARI, YAYGIN DEĞİŞKEN İMMÜN YETMEZLİK KLİNİK FENOTİPİNİN DÜZENLENMESİNDE ROL OYNAR(Istanbul University, 2023) Fırtına, Sinem; Kutlu, Aslı; Işıkgil, Begüm; Yozlu, Medinenur; Çepeci, Beyza Nur; Yılmaz, Hülya; Ng, Yuk YinAmaç: TNF reseptör üst ailesi üyesi 13B (TNFSRF13B), B hücre olgunlaşması, plazma hücresi farklılaşması ve antikor yanıtı için kritik olan TNF üst ailesinin bir üyesidir. TNFRSF13B geninin bozulmuş ifadesi, yaygın değişken immün yetmezlik (YDİY), otoimmünite ve lenfoproliferasyon bozuklukları ile ilişkilendirilir. Bu genin hastalığa neden olan varyantlarının yanı sıra bazı farklı izoformlarınında B hücre yanıtını değiştirdiği gösterilmiştir. Gereç ve Yöntemler: Bu çalışmada, 68 YDİY hastası yeni nesil dizileme yöntemi ile taranarak TNFRSF13B geninde 26 varyant (üç sinonim, beş yanlış anlamlı, on bir UTR ve yedi intronik varyant) saptanmıştır. Tespit edilen varyantlar etkilerine göre biyoinformatik araçlar ile modellenmiş, etkili olduğu gösterilen varyantların klinik bulgular ile ilişkisi araştırılmıştır. Bulgular: Saptanan varyantların (15/26) %58’i, transkripsiyon faktörü ya da miRNA bağlama bölgeleri, kırpılma bölgeleri veya protein üzerinde termodinamik etkisi olabileceği gösterilen varyantlardır. Biyoinformatik olarak kırpılma bölgesini değiştirdiği düşünülen varyantlara sahip hastalarda, diğer hastalara göre anlamlı derecede düşük IgA düzeylerinin (p=0,009), otoimmünite varlığının (p=0,02) ve gastrointestinal bulgular (p=0,05) gibi YDİY fenotipinde görülen bulguların olduğunu gözlemledik. Ayrıca c.*79A>G 3-UTR varyantının düşük IgA ve IgE seviyeleri ile ilişkili olduğu bulunmuştur. Global veritabanlarına kıyasla on üç varyantın en az on kat artmış alel frekanslarına sahip olduğu bulundu. Bu fark potansiyel düzenleyici etkiye sahip TNFRSF13B varyantlarının YDİY hastalarında daha yaygın olduğunu göstermektedir. Sonuçlar: Bu bulgular, TNFRSF13B’deki varyantların YDİY fenotipini açıklamasa da, kırpılma bölgesini değiştirme potansiyeli olan varyantların YDİY’in altında yatan genetik arka plandan bağımsız olarak hastaların patogenezine katkıda bulunabileceğini göstermiştir.|Objective: The TNF receptor gene 13B (TNFSRF13B) is a member of the TNF superfamily which is crucial for B cell maturation, plasma cell differentiation, and antibody response. Impaired expression of the TNFRSF13B gene is associated with common variable immune deficiency (CVID), autoimmunity, and lymphoproliferation disorders. Besides the disease-causing variants of this gene, its different isoforms are associated with strong and weak TNFRSF13B expression that leads to an unbalanced B cell response. Materials and Methods: The study detected 26 variants (three synonymous, five missenses, eleven UTR, and seven intronic variants) in the TNFRSF13B gene by screening 68 CVID patients with targeted next generation sequencing. An integrative bioinformatics approach was utilized to provide a plausible explanation for CVID associations from different perspectives and to investigate the associations from the clinical findings. Results: Fifty-eight percent (15/26) of the detected variants were altered regulatory elements, such as transcription factor binding, miRNA binding sites, splice site regions or the thermodynamic impact on protein. We observed that patients who suffered from the potential splicing variants had significantly low IgA levels (p=0.009), autoimmunity (p=0.02) and gastrointestinal findings (p=0.05). In addition, the c.*79A>G 3-UTR variant was found with the low IgA and IgE levels. Thirteen variants found to have at least tenfold increased allele frequencies as compared to global databases indicating that the TNFRSF13B variants, which have a potential regulatory effect, are more common in CVID patients. Conclusions: All findings suggested that these variants may not be the causative variant for the CVID phenotype but the unbalanced TNFRSF13B alternative splices could contribute to the pathogenesis of patients independent from the underlying genetic background of CVID.Öğe Using embossing ice particulate method to prepare polyvinyl alcohol/ pullulan hydrogels with surface open pores loaded with microspheres for breast cancer treatment(Elsevier, 2024) Barer, Neslihan; Tunc, Bugse; Yilmaz, Bengi; Ng, Yuk Yin; Dalgic, Ali DenizIn the post -operative treatment of breast cancer, early prevention of locoregional recurrence is crucial to avoid metastasis of cells from leftover microtumor tissues. The limitations in conventional drug delivery systems show a growing clinical demand for disease -specific drug -releasing systems. This study explores a novel poly(vinyl alcohol)/pullulan (PVA/PUL) hydrogel system for local drug delivery in post -operative breast cancer treatment. Hydrogel was produced by combination of lyophilization and embossing ice particulate techniques to create microspheres loaded open pores on the hydrogel surface for localized release of doxorubicin-loaded polycaprolactone microspheres (DOX-PCL-MSs). PVA/PUL hydrogel was successfully crosslinked with glutaraldehyde and stabilized hydrogel structure has possessed slow degradation rate and increasing water retention through 12 days. Release of DOX after 7 and 16 days from DOX-PCL-MSs loaded hydrogels were slower with a 6.2 +/- 8.9 % and 56.6 +/- 4.5 % release compared to 60.9 +/- 14.6 % and 76.8 +/- 19.7 % release from free DOX loaded hydrogel since DOX release was controlled by PCL microspheres. When interacted with human breast cancer cell line (MCF-7), DOX-PCL-MSs were able to disrupt cell and spheroid morphology after 7 days at concentrations as low as 12 mu g/mL loaded DOX. In vitro cytotoxicity study has showed that, DOX-PCL-MSs loaded hydrogel was able to decrease MCF-7 viability after 7 days of incubation with controlled release of DOX. While free DOX releasing hydrogel has lost cytotoxic activity even after 4 days of incubation. Furthermore, ability of PVA/PUL hydrogel to support L929 cell attachment was shown in the study, suggesting hydrogels potential for promoting tissue regeneration after anti -cancer treatment. The study reveals that PVA/PUL hybrid hydrogels loaded with DOXPCL-MSs has impactful potential in post -surgical treatment of breast cancer.
