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Publication Open Access Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations(2010) Bilgüvar, Kaya; Öztürk, Ali Kemal; Louvi, Angeliki; Kwan, Kenneth Y.; Choi, Murim; Tatlí, Burak; Yalnizoǧlu, Dilek; Tüysüz, Beyhan; Caglayan, Ahmet Okay; Gökben, Sarenur; Bilgüvar, Kaya, Department of Neurosurgery, Yale School of Medicine, New Haven, United States, Department of Neurobiology, Yale School of Medicine, New Haven, United States, Department of Genetics, Yale School of Medicine, New Haven, United States; Öztürk, Ali Kemal, Department of Neurosurgery, Yale School of Medicine, New Haven, United States, Department of Neurobiology, Yale School of Medicine, New Haven, United States, Department of Genetics, Yale School of Medicine, New Haven, United States; Louvi, Angeliki, Department of Neurosurgery, Yale School of Medicine, New Haven, United States, Department of Neurobiology, Yale School of Medicine, New Haven, United States, Department of Genetics, Yale School of Medicine, New Haven, United States; Kwan, Kenneth Y., Department of Neurobiology, Yale School of Medicine, New Haven, United States, Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, United States; Choi, Murim, Department of Genetics, Yale School of Medicine, New Haven, United States; Tatlí, Burak, Department of Pediatrics, İstanbul Tıp Fakültesi, Istanbul, Turkey; Yalnizoǧlu, Dilek, Department of Pediatrics, Hacettepe Üniversitesi, Ankara, Turkey; Tüysüz, Beyhan, Department of Pediatrics, İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine, Istanbul, Turkey; Caglayan, Ahmet Okay,; Gökben, Sarenur, Department of Pediatrics, Ege University Medical School, Izmir, TurkeyThe development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers1,2. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development3-6. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging. © 2010 Macmillan Publishers Limited. All rights reserved. © 2012 Elsevier B.V., All rights reserved., MEDLINE® is the source for the MeSH terms of this document.Publication Open Access Recessive LAMC3 mutations cause malformations of occipital cortical development(2011) Barak, Tanyeri; Kwan, Kenneth Y.; Louvi, Angeliki; Demirbilek, Veysi; Sütçü Saygı, Serap; Tüysüz, Beyhan; Choi, Murim; Boyacı, Hüseyin; Doerschner, Katja; Zhu, Ying; Barak, Tanyeri, Department of Neurosurgery, Yale School of Medicine, New Haven, United States, Department of Neurobiology, Yale School of Medicine, New Haven, United States, Department of Genetics, Yale School of Medicine, New Haven, United States; Kwan, Kenneth Y., Department of Neurobiology, Yale School of Medicine, New Haven, United States, Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, United States; Louvi, Angeliki, Department of Neurosurgery, Yale School of Medicine, New Haven, United States, Department of Neurobiology, Yale School of Medicine, New Haven, United States; Demirbilek, Veysi, Department of Neurology, Istanbul University-Cerrahpasa, Istanbul, Turkey; Saygı, Serap Sütçü, Department of Neurology, Hacettepe Üniversitesi, Ankara, Turkey; Tüysüz, Beyhan, Department of Pediatrics, Istanbul University-Cerrahpasa, Istanbul, Turkey; Choi, Murim, Department of Genetics, Yale School of Medicine, New Haven, United States; Boyaci, Huseyin, Department of Psychology, Bilkent Üniversitesi, Ankara, Turkey, National Magnetic Resonance Research Center, Bilkent Üniversitesi, Ankara, Turkey; Doerschner, Katja, Department of Psychology, Bilkent Üniversitesi, Ankara, Turkey, National Magnetic Resonance Research Center, Bilkent Üniversitesi, Ankara, Turkey; Zhu, Ying, Department of Neurobiology, Yale School of Medicine, New Haven, United States, Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, United StatesThe biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin 33 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations. © 2011 Nature America, Inc. All rights reserved. © 2011 Elsevier B.V., All rights reserved., MEDLINE® is the source for the MeSH terms of this document.Publication Open Access A reference finding rarely seen in primary hyperparathyroidism: Brown tumor(Hindawi Limited, 2012) Mantar, Ferhan; Gündüz, Şeyda Gülenay; Gündüz, Umut Rıza; Mantar, Ferhan, Department of Endocrinology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Gündüz, Şeyda Gulenay, Department of Medical Oncology, Akdeniz Üniversitesi, Antalya, Turkey; Gündüz, Umut Riza, Department of Surgery, Antalya Education and Research Hospital, Antakya, TurkeyPrimary hyperparathyroidism is an endocrinopathy which is characterized with the hypersecretion of parathormone. During the progress of the disease bone loss takes place due to resorption on the subperiosteal and endosteal surfaces. Brown tumor is a localized form of osteitis fibrosa cystica, being part of the hyperparathyroid bone disease. It is rarely the first symptom of hyperparathyroidism. Nowadays, the diagnosis is made at an asymptomatic or minimally symptomatic stage. We present a male patient presented with a massive painless swelling in the left maxilla as the first manifestation of primary hyperparathyroidism due to a parathyroid adenoma. Parathyroidectomy was performed, and there was a regression of the bone lesion, without the need of performing other local surgical procedures. © 2012 F. Mantar et al. © 2017 Elsevier B.V., All rights reserved.Publication Open Access Turkish perspective of Jervell and Lange-Nielsen syndrome(2013) Temel, Şehime Gülsün; Bostan, Özlem Mehtap; Cangül, Hakan; Çil, Ergün; Temel, Şehime Gülsün, Faculty of Medicine, Bursa Uludağ Üniversitesi, Bursa, Turkey, Faculty of Medicine, University of Near East, Nicosia, Cyprus; Bostan, Özlem Mehtap, Faculty of Medicine, Bursa Uludağ Üniversitesi, Bursa, Turkey; Cangül, Hakan, Faculty of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Medical and Molecular Genetics, University of Birmingham, Birmingham, United Kingdom; Çil, Ergün, Faculty of Medicine, Bursa Uludağ Üniversitesi, Bursa, Turkey[No abstract available]Publication Open Access Percutaneous and transurethral lithotripsy for forgotten ureteral stents(Brieflands, 2013) Tefekli, Ahmet Hamdi; Tefekli, Ahmet Hamdi, Department of Urology, Bahçeşehir Üniversitesi, Istanbul, Turkey[No abstract available]Publication Open Access The history of urinary stones: In parallel with civilization(Hindawi Publishing Corporation 410 Park Avenue, 15th Floor, 287 pmb New York NY 10022, 2013) Tefekli, Ahmet Hamdi; Cezayirli, Fatin; Tefekli, Ahmet Hamdi, Bahçeşehir Üniversitesi, Istanbul, Turkey; Cezayirli, Fatin, VKV Amerikan Hastanesi, Istanbul, TurkeyThe roots of modern science and history of urinary stone disease go back to the Ancient Egyptians and Mesopotamia. Hippocrates defined the symptoms of bladder stones. The first recorded details of perineal lithotomy were those of Cornelius Celsus. Ancient Arabic medicine was based mainly on classical Greco-Roman works. Interestingly, the Fourth Lateran Council in 1215 forbade physicians from performing surgical procedures, as contact with blood or body fluids was viewed as contaminating to men. With Renaissance new procedures could be tried on criminals. The first recorded suprapubic lithotomy was carried out by Pierre Franco in 1561. In 1874, Bigelow developed a lithotrite, which was introduced into the bladder under anaesthesia (called as litholopaxy). Young was the first to report ureteroscopy (1929). With advances in intracorporeal lithotripsy techniques, ureteroscopy became the treatment of choice for ureteric stones. In 1976, Fernstrom and Johannson established percutaneous access to remove a renal stone. However, with the introduction of the first extracorporeal shock wave machine in 1980, a dramatic change in stone management was observed. Civilization in parallel with scientific developments has brought us to a point where we try not to cut our patients for stone disease, as Hippocrates admonishes, but rather manage them with minimal invasive alternatives. © 2013 Ahmet Tefekli and Fatin Cezayirli. © 2014 Elsevier B.V., All rights reserved.Publication Open Access The Identification of Pathway Markers in Intracranial Aneurysm Using Genome-Wide Association Data from Two Different Populations(2013) Bakir Güngör, Burcu; Sezerman, Osman Uğur; Bakir-Güngör, Burcu, Department of Genetics and Bioinformatics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Advanced Genomics and Bioinformatics Research Center, UEKAE, Kocaeli, Turkey; Sezerman, Osman Uğur, Biological Sciences and Bioengineering Program, Sabancı Üniversitesi, Tuzla, TurkeyThe identification of significant individual factors causing complex diseases is challenging in genome-wide association studies (GWAS) since each factor has only a modest effect on the disease development mechanism. In this study, we hypothesize that the biological pathways that are targeted by these individual factors show higher conservation within and across populations. To test this hypothesis, we searched for the disease related pathways on two intracranial aneurysm GWAS in European and Japanese case-control cohorts. Even though there were a few significantly conserved SNPs within and between populations, seven of the top ten affected pathways were found significant in both populations. The probability of random occurrence of such an event is 2.44E-36. We therefore claim that even though each individual has a unique combination of factors involved in the mechanism of disease development, most targeted pathways that need to be altered by these factors are, for the most part, the same. These pathways can serve as disease markers. Individuals, for example, can be scanned for factors affecting the genes in marker pathways. Hence, individual factors of disease development can be determined, and this knowledge can be exploited for drug development and personalized therapeutic applications. Here, we discuss the potential avenues of pathway markers in medicine and their translation to preventive and individualized health care. © 2013 Bakir-Gungor, Sezerman. © 2013 Elsevier B.V., All rights reserved., MEDLINE® is the source for the MeSH terms of this document.Publication Open Access Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities(2013) Radmanesh, Farid; Çağlayan, Ahmet Okay; Silhavy, Jennifer L.; Yılmaz, Cahide; Cantagrel, Vincent; Omar, Tarek E.I.; Rosti, Başak; Kaymakçalan, Hande; Gabriel, Stacey Bolk; Li, Mingfeng; Radmanesh, Farid, Department of Neurosciences, La Jolla, United States, Howard Hughes Medical Institute, Chevy Chase, United States; Caglayan, Ahmet Okay, Department of Neurosurgery, Yale School of Medicine, New Haven, United States; Silhavy, Jennifer L., Department of Neurosciences, La Jolla, United States, Howard Hughes Medical Institute, Chevy Chase, United States; Yilmaz, Cahide, Department of Pediatrics, Mustafa Kemal Üniversitesi, Antakya, Turkey; Cantagrel, Vincent, Department of Neurosciences, La Jolla, United States, Howard Hughes Medical Institute, Chevy Chase, United States; Omar, Tarek E.I., Department of Pediatric Neurology, Faculty of Medicine, Alexandria, Egypt; Rosti, Başak, Department of Neurosciences, La Jolla, United States, Howard Hughes Medical Institute, Chevy Chase, United States; Kaymakçalan, Hande, Department of Genetics and Bioinformatics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Gabriel, Stacey Bolk, Massachusetts Institute of Technology, Cambridge, United States; Li, Mingfeng, Department of Neurobiology, Yale School of Medicine, New Haven, United StatesCobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation. © 2013 The American Society of Human Genetics. © 2013 Elsevier B.V., All rights reserved., MEDLINE® is the source for the MeSH terms of this document.Publication Open Access Kinetic and in silico analysis of thiazolidin-based inhibitors of α-carbonic anhydrase isoenzymes(2013) Ekinci, Deniz; Fidan, Ismail; Durdağı, Serdar; Kaban, Şeniz; Supuran, Claudiu T.; Ekinci, Deniz, Department of Agricultural Biotechnology, Ondokuz Mayis Üniversitesi, Samsun, Turkey; Fidan, Ismail, Institute of Social Sciences, Yıldız Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kaban, Şeniz, Institute of Social Sciences, Yıldız Teknik Üniversitesi, Istanbul, Turkey; Supuran, Claudiu T., Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, ItalyCarbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, inorganic anions, phenols, salicylic acid derivatives (acting as drug or prodrugs). A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I and II (cytosolic) in a different manner, is reported here. Kinetic measurements allowed us to identify thiazolidin-based compounds as submicromolar-low micromolar inhibitors of these two CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II active site allowed us to understand the inhibition mechanism. This new class of inhibitors bind differently compared to other classes of inhibitors known to date: they were found between the phenol-binding site, filling thus the middle of the enzyme cavity. © 2013 Informa UK, Ltd. © 2014 Elsevier B.V., All rights reserved., MEDLINE® is the source for the MeSH terms of this document.Publication Open Access Future prospects in the diagnosis and management of localized prostate cancer(2013) Tefekli, Ahmet Hamdi; Tunç, Murat H.; Tefekli, Ahmet Hamdi, Department of Urology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Tunç, Murat H., Department of Urology, İstanbul Tıp Fakültesi, Istanbul, TurkeyProstate cancer (PCa) is the commonest visceral cancer in men worldwide. Introduction of serum PSA as a highly specific biomarker for prostatic diseases has led to a dramatic increase in the diagnosis of early stage PCa in last decades. Guidelines underline that benefits as well as risks and squeals of early diagnosis and treatment should be discussed with patients. There are several new biomarkers (Pro-PSA, PCA-3 test, and TMPRSS2-ERG) available on the market but new ones are awaited in order to improve specificity and sensitivity. Investigators have also focused on identifying and isolating the gene, or genes, responsible for PCa. Current definitive treatment options for clinically localized PCa with functional and oncological success rates up to 95% include surgery (radical prostatectomy), external-beam radiation therapy, and interstitial radiation therapy (brachytherapy). Potential complications of overdiagnosis and overtreatment have resulted in arguments about screening and introduced a new management approach called active surveillance. Improvements in diagnostic techniques, especially multiparametric magnetic resonance imaging, significantly ameliorated the accuracy of tumor localization and local staging. These advances will further support focal therapies as emerging treatment alternatives for localized PCa. As a conclusion, revolutionary changes in the diagnosis and management of PCa are awaited in the near future. © 2013 Ahmet Tefekli and Murat Tunc. © 2013 Elsevier B.V., All rights reserved.