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Author: search.filters.author.Ozbek, Ugur

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    Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study
    (ELSEVIER SCIENCE INC, 2018-01-01) May, Patrick; Girard, Simon; Harrer, Merle; Bobbili, Dheeraj R.; Schubert, Julian; Wolking, Stefan; Becker, Felicitas; Lachance-Touchette, Pamela; Meloche, Caroline; Gravel, Micheline; Niturad, Cristina E.; Knaus, Julia; De Kovel, Carolien; Toliat, Mohamad; Polvi, Anne; Iacomino, Michele; Guerrero-Lopez, Rosa; Baulac, Stephanie; Marini, Carla; Thiele, Holger; Altmueller, Janine; Jabbari, Kamel; Ruppert, Ann-Kathrin; Jurkowski, Wiktor; Lal, Dennis; Rusconi, Raffaella; Cestele, Sandrine; Terragni, Benedetta; Coombs, Ian D.; Reid, Christopher A.; Striano, Pasquale; Caglayan, Hande; Siren, Auli; Everett, Kate; Moller, Rikke S.; Hjalgrim, Helle; Muhle, Hiltrud; Helbig, Ingo; Kunz, Wolfram S.; Weber, Yvonne G.; Weckhuysen, Sarah; De Jonghe, Peter; Sisodiya, Sanjay M.; Nabbout, Rima; Franceschetti, Silvana; Coppola, Antonietta; Vari, Maria S.; Trenite, Dorothee Kasteleijn-Nolst; Baykan, Betul; Ozbek, Ugur; Bebek, Nerses; Klein, Karl M.; Rosenow, Felix; Nguyen, Dang K.; Dubeau, Francois; Carmant, Lionel; Lortie, Anne; Desbiens, Richard; Clement, Jean-Francois; Cieuta-Walti, Cecile; Sills, Graeme J.; Auce, Pauls; Francis, Ben; Johnson, Michael R.; Marson, Anthony G.; Berghuis, Bianca; Sander, Josemir W.; Avbersek, Andreja; McCormack, Mark; Cavalleri, Gianpiero L.; Delanty, Norman; Depondt, Chantal; Krenn, Martin; Zimprich, Fritz; Peter, Sarah; Nikanorova, Marina; Kraaij, Robert; van Rooij, Jeroen; Balling, Rudi; Ikram, M. Arfan; Uitterlinden, Andre G.; Avanzini, Giuliano; Schorge, Stephanie; Petrou, Steven; Mantegazza, Massimo; Sander, Thomas; LeGuern, Eric; Serratosa, Jose M.; Koeleman, Bobby P. C.; Palotie, Aarno; Lehesjoki, Anna-Elina; Nothnagel, Michael; Nuernberg, Peter; Maljevic, Snezana; Zara, Federico; Cossette, Patrick; Krause, Roland; Lerche, Holger; Consortium, Epicure; Consortium, EuroEP.I.N.O.M.I.C.S. C. O. G. I. E.; Consortium, EpiPG. X.
    Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80\% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio {[}OR] 2.40 {[}95\% CI 1.41-4.10]
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    No evidence for a BRD2 promoter hypermethylation inblood leukocytes of Europeans with juvenile myoclonic epilepsy
    (WILEY, 2019-01-01) Schulz, Herbert; Ruppert, Ann-Kathrin; Zara, Federico; Madia, Francesca; Iacomino, Michele; Vari, Maria S.; Balagura, Ganna; Minetti, Carlo; Striano, Pasquale; Blanche, Amedeo; Marini, Carla; Guerrini, Renzo; Weber, Yvonne G.; Becker, Felicitas; Lerche, Holger; Kapser, Claudia; Schankin, Christoph J.; Kunz, Wolfram S.; Moller, Rikke S.; Oliver, Karen L.; Bellows, Susannah T.; Mullen, Saul A.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Caglayan, Hande; Ozbek, Ugur; Hoffmann, Per; Schramm, Sara; Tsortouktzidis, Despina; Becker, Albert J.; Sander, Thomas
    Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5\%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P=0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci {[}meQTL], P=0.29) or 470 German control subjects (meQTL, P=0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.
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    Frontline nilotinib treatment in Turkish patients with Philadelphia chromosome-positive chronic Myeloid Leukemia in chronic phase: updated results with 2 years of follow-up
    (TAYLOR \& FRANCIS LTD, 2018-01-01) Saydam, Guray; Haznedaroglu, Ibrahim Celalettin; Kaynar, Leylagul; Yavuz, Akif S.; Ali, Ridvan; Guvenc, Birol; Akay, Olga M.; Baslar, Zafer; Ozbek, Ugur; Sonmez, Mehmet; Aydin, Demet; Pehlivan, Mustafa; Undar, Bulent; Dagdas, Simten; Ayyildiz, Orhan; Akin, Gulnur; Dag, Ilkiz M.; Ilhan, Osman
    Objectives: This report presents final results (24 months of follow-up) from the first prospective, national study of frontline nilotinib in chronic myeloid leukemia (CML) patients in Turkey. Methods: Patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CML-CP
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    Primary antibody deficiencies in Turkey: molecular and clinical aspects (Oct, 10.1007/s12026-021-09242-z, 2021)
    (HUMANA PRESS INC, 2022-01-01) Firtina, Sinem; Ng, Yuk Yin; Ng, Ozden H.; Kiykim, Ayca; Ozek, Esra Yucel; Kara, Manolya; Aydiner, Elif; Nepesov, Serdar; Camcioglu, Yildiz; Sayar, Esra H.; Gungoren, Ezgi Yalcin; Reisli, Ismail; Torun, Selda H.; Haskologlu, Sule; Cogurlu, Tuba; Kaya, Aysenur; Cekic, Sukru; Baris, Safa; Ozbek, Ugur; Ozen, Ahmet; Sayitoglu, Muge
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    Hydrogen Sulphide and Nitric Oxide Cooperate in Cardioprotection Against Ischemia/Reperfusion Injury in Isolated Rat Heart
    (INT INST ANTICANCER RESEARCH, 2020-01-01) Ustunova, Savas; Takir, Selcuk; Yilmazer, Nadim; Bulut, Huri; Altindirek, Didem; Ng, Ozden Hatirnaz; Tansel, Cihan Demirci; Dogan, B. Sonmez Uydes; Ozbek, Ugur; Armutak, Elif Ilkay; Gurevin, Ebru Gurel
    Background/Aim: This study was designed to provide further evidence for the interactions between hydrogen sulfide (H2S) and nitric oxide (NO) in ischemia/reperfiision (I/R) injury. Materials and Methods: Rat hearts were studied with the Langendorff technique using the H2S donor sodium hydrosulfide (NaHS, 40 mu M) and the cystathionine gamma-lyase (CTH or CSE) inhibitor DL-propargylglycine (PAG, 1 mM). NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 30 mg/kg, 7 days) was administered before the isolation. The hearts were homogenized for biochemical and molecular analysis. Results: NaHS reversed I/R-induced cardiac performance impairment, increased tissue nitric oxide production and decreased tissue markers for cardiac injury, while L-NAME inhibited these effects. The expression of CTH was increased with PAG, which was suppressed by L-NAME. Conclusion: H2S and NO increase each other's production suggesting their interaction and cooperation in cardioprotection against I/R injury.
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    SCREENING SLC2A1 GENE FOR SEQUENCE AND COPY NUMBER VARIATIONS ASSOCIATED WITH GLUT-1 DEFICIENCY SYNDROME
    (ISTANBUL UNIV, FAC MEDICINE, PUBL OFF, 2020-01-01) Ornek Erguzeloglu, Cemre; Kara, Bulent; Karacan, Ilker; Ozdemir, Ozkan; Kesim, Yesim; Bebek, Nerses; Ozbek, Ugur; Ugur Iseri, Sibel Aylin
    Objective: Glucose transporter-1 deficiency syndrome (GLUT1- DS) is defined as a metabolic encephalopathy that is associated with heterozygous and usually de novo pathogenic variations in the SLC2A1 (solute carrier family2 member1) gene. Materials and Methods: In this study, all coding exons and neighboring intronic regions of SLC2A1 were Sanger sequenced in 12 patients with clinically suspected GLUT1-DS. For de novo variations revealed after sequencing and segregation analysis, we also performed genome wide Single Nucleotide Polymor- phism (SNP) genotyping to confirm parental relatedness with the proband. In patients without any sequence variations, real-time quantitative real-time polymerase chain reaction (qPCR) was applied to determine the presence of any copy number variations (CNV). Results: Sanger sequencing followed by bioinformatics analysis, segregation in the family and SNP array genotyping revealed two novel and de novo pathogenic variations associated with the GLUT1-DS phenotype in 2 patients. qPCR results were compatible with one copy loss of SLC2A1 gene in another patient. All variations identified herein are likely to have caused null al-leles and resulted in GLUT1-DS through haplo insufficiency. Disscussion : In this study we used a series of molecular genetic approaches in order to identify all possible variations in SLC2A1 that may be associated with GLUT1-DS. This collective effort fa- cilitated diagnosis in 3 patients.
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    Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice
    (NATURE PORTFOLIO, 2021-01-01) Turan, Raife Dilek; Tastan, Cihan; Kancagi, Derya Dilek; Yurtsever, Bulut; Karakus, Gozde Sir; Ozer, Samed; Abanuz, Selen; Cakirsoy, Didem; Tumentemur, Gamze; Demir, Sevda; Seyis, Utku; Kuzay, Recai; Elek, Muhammer; Kocaoglu, Miyase Ezgi; Ertop, Gurcan; Arbak, Serap; Elmas, Merve Acikel; Hemsinlioglu, Cansu; Ng, Ozden Hatirnaz; Akyoney, Sezer; Sahin, Ilayda; Kayhan, Cavit Kerem; Tokat, Fatma; Akpinar, Gurler; Kasap, Murat; Kocagoz, Ayse Sesin; Ozbek, Ugur; Telci, Dilek; Sahin, Fikrettin; Yalcin, Koray; Ratip, Siret; Ince, Umit; Ovali, Ercument
    The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 10(13) or 10(14) viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.
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    Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype
    (VIA MEDICA, 2019-01-01) Akcakaya, Nihan Hande; Haryanyan, Garen; Mercan, Sevcan; Sozer, Nejla; Ali, Asuman; Tombul, Temel; Ozbek, Ugur; Iseri, Sibel Aylin Ugur; Yapici, Zuhal
    Introduction. Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN)
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    PTEN and AKT1 Variations in Childhood T-Cell Acute Lymphoblastic Leukemia
    (GALENOS YAYINCILIK, 2020-01-01) Kucukcankurt, Fulya; Erbilgin, Yucel; Firtina, Sinem; Ng, Ozden Hatirnaz; Karakas, Zeynep; Celkan, Tiraje; Unuvar, Aysegul; Ozbek, Ugur; Sayitoglu, Muge
    Objective: PTEN/AKT pathway deregulations have been reported to be associated with treatment response in acute leukemia. This study examined pediatric T-cell acute lymphoblastic leukemia (T-ALL) samples for PTEN and AKT1 gene variations and evaluated the clinical findings. Materials and Methods: Fifty diagnostic bone marrow samples of childhood T-ALL cases were investigated for the hotspot regions of the PTEN and AKT1 genes by targeted next-generation sequencing. Results: A total of five PTEN variations were found in three of the 50 T-ALL cases (6\%). Three of the PTEN variations were first reported in this study. Furthermore, one patient clearly had two different mutant clones for PTEN. Two intronic single-nucleotide variations were found in AKT1 and none of the patients carried pathogenic AKT1 variations. Conclusion: Targeted deep sequencing allowed us to detect both low-level variations and clonal diversity. Low-level PTEN/AKT1 variation frequency makes it harder to investigate the clinical associations of the variants. On the other hand, characterization of the PTEN/AKT signaling members is important for improving case-specific therapeutic strategies.
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    Preclinical efficacy and safety analysis of gamma-irradiated inactivated SARS-CoV-2 vaccine candidates
    (NATURE RESEARCH, 2021-01-01) Karakus, Gozde Sir; Tastan, Cihan; Kancagi, Derya Dilek; Yurtsever, Bulut; Tumentemur, Gamze; Demir, Sevda; Turan, Raife Dilek; Abanuz, Selen; Cakirsoy, Didem; Seyis, Utku; Ozer, Samed; Elibol, Omer; Elek, Muhammer; Ertop, Gurcan; Arbale, Serap; Elmas, Merve Acikel; Hermsinlioglu, Canso; Kocagoz, Ayse Sesin; Ng, Ozden Hatirnaz; Akyoney, Sezer; Sahin, Ilayda; Ozbek, Ugur; Telci, Dilek; Sahin, Fikrettin; Yalcin, Koray; Ratip, Siret; Ovali, Ercument
    COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1(V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2+ mice.