Scopus İndeksli Yayınlar Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/11727/4809

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Author: search.filters.author.Baris, ZerenHas files: Yes

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    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.
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    A single-center experience of post-transplant lymphoproliferative disorder (PTLD) cases after pediatric liver transplantation: Incidence, outcomes, and association with food allergy
    (2018) Haberal, Mehmet; Haberal, Nihan; Baris, Zeren; Ozcay, Figen; Ozbek, Ozlem Yilmaz; Sarialioglu, Faik; 29755021; AAB-4153-2020
    Background/Aims: We evaluated our 16-year single-center experience of pediatric post-transplant lymphoproliferative disorder (PTLD) cases who underwent liver transplantation between 2001 and 2017. Materials and Methods: Of the 236 pediatric patients who underwent liver transplantation between 2001 and 2017, the clinical and laboratory data of eight patients diagnosed with PTLD were reviewed. The pre-transplant Epstein-Barr virus (EBV) status of 172 patients was also recorded. Results: The total incidence of PTLD was 3.4%. The incidence of PTLD was 10% in pre-transplant EBV immunoglobulin G (IgG)-seronegative patients and 0.8% in pre-transplant EBV IgG-seropositive patients. The mean age of the patients at liver transplantation was 2.71 +/- 3.21 years, and four patients were aged below 1 year at the time of transplantation. PTLD was diagnosed at 21.81 +/- 18.1 months after transplantation. The primary site of involvement was variable among patients: peripheral and mediastinal lymph nodes, stomach and intestine, transplanted graft, bone marrow, and nasopharynx. The eosinophil count varied greatly among patients, with a mean value of 524.62 +/- 679/mm3. Three patients had a food allergy and were administered an elimination diet at the time of PTLD diagnosis. Six patients had PTLD of B-cell origin. One patient died due to neutropenic sepsis during chemotherapy, whereas seven patients were followed up in full remission for 7.75 +/- 4 years. Conclusion: PTLD is a life-threatening complication of solid-organ transplantation with a heterogeneous clinical spectrum. Food allergy had a close association with PTLD. A close follow-up of patients with risk factors and an early diagnosis with appropriate treatment may lead to a better outcome.