Browsing by Author "Dalgic, Buket"

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Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease
(2021) Ozen, Ahmet; Kasap, Nurhan; Vujkovic-Cvijin, Ivan; Apps, Richard; Cheung, Foo; Karakoc-Aydiner, Elif; Akkelle, Bilge; Sari, Sinan; Tutar, Engin; Uygun, Dilara Kocacik; Islek, Ali; Akgun, Gamze; Selcuk, Merve; Sezer, Oya Balci; Ozcay, Figen; Zhang, Yu; Kutluk, Gunsel; Topal, Erdem; Sayar, Ersin; Celikel, Cigdem; Houwen, Roderick H.J.; Bingol, Aysen; Ogulur, Ismail; Eltan, Sevgi Bilgic; Snow, Andrew L.; Lake, Camille; Fantoni, Giovanna; Alba, Camille; Sellers, Brian; Chauvin, Samuel D.; Dalgard, Clifton L.; Harari, Olivier; Ni, Yan G.; Wang, Ming-Dauh; Devalaraja-Narashimha, Kishor; Subramanian, Poorani; Ergelen, Rabia; Artan, Reha; Guner, Sukru Nail; Dalgic, Buket; Tsang, John; Belkaid, Yasmine; Ertem, Deniz; Baris, Safa; Lenardo, Michael J.; https://orcid.org/0000-0002-8402-8208; https://orcid.org/0000-0002-5214-516X; 33398182; AAI-9346-2021; ABG-5684-2020
CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth. Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.
Emergence of rotavirus G9 in 2012, as the dominant genotype in Turkish children with diarrhea, in a university hospital in Ankara
(2019) Kocak, Aylin Altay; Aydin, Merve; Matsumoto, Takashi; Yahiro, Takaaki; Dalgic, Buket; Bozdayi, Gulendam; Ahmed, Kamruddin
Introduction: Rotavirus infection is a major cause of morbidity and mortality in infants and young children with diarrhea throughout the world. Material and Methods: In this study, we aimed to determine the detection rate of rotavirus infection in 181 children less than 5 years of age presenting with acute gastroenteritis and admitted to a tertiary care hospital in Ankara, Turkey, from April to November 2012. We documented the epidemiological data by elucidating the prevalent genotypes. Stool specimens were collected, and rotavirus antigen in the samples was detected using ELISA. G and P genotypes were determined by RT-PCR via type specific primers. The nucleotide sequence of the concerned genes was determined by Sanger sequencing and phylogenetic analysis was performed by neighbor-joining method. Results: Of the 181 samples, 28 (15.5%) were positive for the rotavirus antigen. Twenty-seven samples were positive for G genotypes and 21 were positive for P genotypes. Genotypes G1 (7.1%), G2 (7.1%), G3 (7.1%), G4 (3.6%), G9 (71.5%) and P4 (3.6%), P8 (71.4%) were identified. Genotype G9P[8] (50%) was predominant in the combination of G and P genotypes. Most of the G9 strains of this study formed an independent cluster in Lineage III, except two strains which clustered with an Ethiopian G9 strain of 2012. Conclusions: It seems that during 2012 season, genotype G9P[8] increased significantly in Ankara due to a new circulating strain of G9.
Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency
(2018) Ozcay, Figen; Baris, Zeren; van Rijn, Jorik M.; Ardy, Rico Chandra; Kuloglu, Zarife; Haerter, Bettina; van Haaften-Visser, Desiree Y.; van der Doef, Hubert P. J.; van Hoesel, Marliek; Kansu, Aydan; van Vugt, Anke H. M.; Thian, Marini; Kokke, Freddy T. M.; Krolo, Ana; Basaran, Meryem Keceli; Kaya, Neslihan Gurcan; Aksu, Aysel Unlusoy; Dalgic, Buket; Kain, Renate; Stigter, Edwin C. A.; Lichtenbelt, Klaske D.; Massink, Maarten P. G.; Duran, Karen J.; Verheij, Joke B. G. M.; Lugtenberg, Dorien; Nikkels, Peter G. J.; Brouwer, Henricus G. F.; Verkade, Henkjan J.; Scheenstra, Rene; Spee, Bart; Nieuwenhuis, Edward E. S.; Coffer, Paul J.; Janecke, Andreas R.; van Haaften, Gijs; Houwen, Roderick H. J.; Mueller, Thomas; Middendorp, Sabine; Boztug, Kaan
BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.
Investigation of Group A Rotavirus G10, G12 Genotypes Emerging in Patients with Acute Gastroenteritis in a Tertiary Care Hospital
(2021) Kahraman, Hande; Kocak, Aylin Altay; Albakkour, Katren; Muftah, Hager; Dalgic, Buket; Caglar, Kayhan; Ahmed, Kamruddin; Bozdayi, Gulendam; 34666655
Rotaviruses are the most common cause of viral gastroenteritis with the highest mortality and morbidity rates in children aged 0-5 years. The aim of this study was to determine the frequency of rotavirus infection in patients whose stool samples were sent to microbiology laboratory to investigate the etiology of diarrhea, to investigate the rotavirus genotypes that are common in our region and G10, G12 genotypes that have recently become common in the world. Fecal samples of 476 patients aged between 0-92 years who applied between November 2016 and February 2018 were studied via immunochromatographic rapid test and enzyme-linked immunosorbent assay (ELISA) methods. ELISA positive samples were studied by nested reverse transcriptase chain reaction (RT-PCR) and genotyped by agarose gel electrophoresis. Rotavirus was found positive in 18.3% and 17% of stool samples by immunochromatographic test and ELISA, respectively. All ELISA positive samples were also detected as positive by RT-PCR. 18.5% of female patients and 15.7% of male patients were found to be positive and rotavirus positivity was not statistically significant between genders. The frequency of rotavirus in different age groups was 23.5% (6-12 years), 17.3% (13-24 months) and 16% (25-36 months). It was determined that rotavirus cases were most common in the spring. G1, G2, G3, G4, G9, G10, and G12 were detected in 37%, 7.4%, 16.1%, 6.2%, 9.9%, 2.5%, 26% of the samples, respectively. G12 was the most common genotype after G1. The most common G and P genotype combination was G1P[8] (17.2%). This was followed by G12P[8] (11.11%) and G3P[8] (11.11%). P[8] (53%) was found to be the dominant P genotype. In this study, it was observed that rotavirus, which is the cause of childhood diarrhea, can also be encountered in advanced ages and even new genotypes that infect humans worldwide may also be the causative agents. Therefore, we concluded that it is important to investigate new genotypes such as G10 and G12 in molecular epidemiological studies.