TR Dizin İndeksli Yayınlar Koleksiyonu / TR Dizin Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/20.500.14365/4
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Article Effect of CTLA-4 and TNF-α Gene Polymorphisms on Inhibitor Development in a Turkish Cohort of Severe Hemophilia A Cases with Intron 22 Inversion Mutation: An Analytical Study(Türkiye Klinikleri, 2022) Ozbek, Namik Yasar; Akgun, Bilcag; Mehdiyeva, Humay; Onay, Huseyin; İsik, Esra; Özen, Başak Durmuş; Atık, Tahır; Durmuş, Başak; Alpay, Araz; Köse, Melis; Ozkinay, Ferda; Evim, Melike SezginAmaç: Hemofili A (HA) hastalarında faktör VIII’e karşı inhibitör adı ve- rilen nötralizan antikorların gelişmesi en önemli tedavi komplikasyonudur. İnhi- bitör gelişimi ile ili şkili faktörler 2 gruba (genetik ve genetik olmayan) ayr ılır. F8 geni mutasyon tipi d ışındaki genetik faktörler aras ında aile öyküsü, etnik köken, insan lökosit antijen haplotipi ve immün sistemde rol oynayan genlerdeki birtakım polimorfizmler bulunur. Bu çalışmada, intron 22 inversiyon (inv22) mu- tasyonu taşıyan ağır HA hastalarından oluşan bir kohortta CTLA-4 (c.-318C> T; rs5742909 ve c.49A>G; rs231775) ve tümör nekrozis faktör alfa ( TNF-α) (c.-308G>A; rs1800629) gen polimorfizimleri ile inhibitör geli şimi arasındaki ilişkinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmaya, inv22 mutasyonu taşıyan 94 ağır HA hastası dâhil edildi. Hastalar, inhibitör varl ığına göre 2 gruba ayrıldı: İnhibitör pozitif ve inhibitör negatif. Her iki grupta da San- ger dizi analizi yöntemi kullanılarak CTLA-4 geninde c.-318C>T; rs5742909 ve c.49A>G; rs231775 ve TNF-α geninde de c.-308G>A; rs1800629 polimorfizim- leri araştırıldı. Bulgular: Bu çalışmada, inv22 mutasyonu ta şıyan ağır HA has- talarında CTLA-4 polimorfizmleri ile inhibitör gelişimi arasında anlamlı bir ilişki saptanmamıştır. Bununla birlikte, TNF-α genindeki c.-308G>A varyantının A al- lelinin, bu hastalarda inhibitör gelişimi için artmış risk ile ilişkili olduğu bulun- muştur. Sonuç: İnv22 mutasyonu ta şıyan a ğır HA hastalar ında, CTLA-4 genindeki c.-318C>T ve c.49A>G varyantları inhibitör gelişimi ile ilişkili değil- dir, oysa TNF-α genindeki c.-308G>A varyantı, A alleli, inhibitör gelişme riski ile ilgilidir.Article A Novel Molecular Indicator for Inhibitor Development in Haemophilia A(Galenos Publishing House, 2021-05-25) Işık, E.; Mehdiyeva, H.; Akgün, B.; Köse, T.; Kavaklı, K.; Özkınay, F.; Atik, T.Aim: Previous studies have reported inhibitor development (ID) risk in those patients who have hemophilia A (HA) with missense mutations to be 3-10%. We investigated the association between ID risk and various features of missense mutations; including the impact directly related to amino acid group change. Materials and Methods: Missense mutations in the F8 gene, clinical findings of the patients including severity of HA, and ID status were obtained from the F8 gene variant database (http://www.factorviii-db.org/). Twenty amino acids were then classified into groups according to their side chains. All information regarding each specific mutation, as well as any impact of the mutation on the amino acid group change, was recorded. Additionally, localization (at which domain) of any changed amino acid in the F8 protein was noted. Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), Mendelian Clinically Applicable Pathogenicity and Deleterious Annotation using Neural Networks scores were applied to identify a significant cut-off value indicative of ID. Results: Three variations were identified that could be considered as useful in the prediction of ID in mild HA. The first being that among mild HA patients, 7.9% (n=70/883) with mutations causing no amino acid group changes showed ID. This rate, however, was only 2.9% in patients with mutations leading to amino acid group changes. Secondly; in patients with mutations causing no amino acid group changes affecting A2, A3 and C2 domains, ID risk was found to be higher than in patients with mutations leading to amino acid group changes. Thirdly; an association between ID and CADD and REVEL scores was observed. Conclusion: In mild HA patients, the characteristics of missense mutations in terms of amino acid group changes, and CADD and REVEL scores could be of considerable utility in the prediction of ID risk. © Copyright 2021 by Ege University Faculty of Medicine, Department of Pediatrics and Ege Children’s FoundationArticle Citation - Scopus: 1Effects of 1-(2 (trim) on Receptor-Independent And-Dependent Contractile Responses in Rat Aorta(Tubitak Scientific & Technical Research Council Turkey, 2016) Selli, Cigdem; Erac, Yasemin; Tosun, MetinerBackground/aim: This study investigates whether 1-(2-trifluoromethylphenyl)-imidazole (TRIM), originally proposed as a nitric oxide synthase inhibitor and also suggested to be an inhibitor of store-operated calcium entry in mouse anococcygeal muscle, inhibits receptor-independent and -dependent responses in rat thoracic aorta. Materials and methods: Cyclopiazonic acid-and serotonin-induced vascular responses were investigated in aortic segments isolated from male Sprague Dawley rats using isolated tissue experiments. Changes in intracellular calcium levels were also monitored via front surface fluorescence measurements in fura-2-loaded embryonic rat vascular smooth muscle cell line A7r5. Results: TRIM inhibited serotonin-mediated vascular contractions without affecting cyclopiazonic acid-induced responses. In addition, TRIM caused a nonlinear rightward shift in the serotonin concentration-response curve, possibly via serotonin receptor modulation. Conclusion: TRIM may have an impact on investigation of tissue-specific receptor-independent and -dependent vascular responses. It may also be used as a lead compound in the development of selective serotonin receptor modulators.