Browsing by Author "Ekser, Burcin"
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Item A year in review: Highlights of health sciences review in 2022(Elsevier, 2022) Grach, Stephanie L.; Ekser, Burcin; Surgery, School of MedicineItem Assessment of morbidity and mortality after liver transplantation for primary sclerosing cholangitis(AME, 2024) Ekser, Burcin; Mihaylov, Plamen; Mangus, Richard S.; Surgery, School of MedicineItem ATG14 plays a critical role in hepatic lipid droplet homeostasis(Elsevier, 2023) Huang, Menghao; Zhang, Yang; Park, Jimin; Chowdhury, Kushan; Xu, Jiazhi; Lu, Alex; Wang, Lu; Zhang, Wenjun; Ekser, Burcin; Yu, Liqing; Dong, X. Charlie; Biochemistry and Molecular Biology, School of MedicineBackground & aims: Autophagy-related 14 (ATG14) is a key regulator of autophagy. ATG14 is also localized to lipid droplet; however, the function of ATG14 on lipid droplet remains unclear. In this study, we aimed to elucidate the role of ATG14 in lipid droplet homeostasis. Methods: ATG14 loss-of-function and gain-of-function in lipid droplet metabolism were analyzed by fluorescence imaging in ATG14 knockdown or overexpression hepatocytes. Specific domains involved in the ATG14 targeting to lipid droplets were analyzed by deletion or site-specific mutagenesis. ATG14-interacting proteins were analyzed by co-immunoprecipitation. The effect of ATG14 on lipolysis was analyzed in human hepatocytes and mouse livers that were deficient in ATG14, comparative gene identification-58 (CGI-58), or both. Results: Our data show that ATG14 is enriched on lipid droplets in hepatocytes. Mutagenesis analysis reveals that the Barkor/ATG14 autophagosome targeting sequence (BATS) domain of ATG14 is responsible for the ATG14 localization to lipid droplets. Co-immunoprecipitation analysis illustrates that ATG14 interacts with adipose triglyceride lipase (ATGL) and CGI-58. Moreover, ATG14 also enhances the interaction between ATGL and CGI-58. In vitro lipolysis analysis demonstrates that ATG14 deficiency remarkably decreases triglyceride hydrolysis. Conclusions: Our data suggest that ATG14 can directly enhance lipid droplet breakdown through interactions with ATGL and CGI-58.Item Attachment and parental bond: impact on psychopathology, mental health and quality of life of hemodialysis patients: a cross-sectional study(BMC, 2023-07-15) De Pasquale, Concetta; Pistorio, Maria Luisa; Veroux, Massimiliano; Sapienza, Gabriella; Florio, Alberto; Hichy, Zira; Ekser, Burcin; Giaquinta, Alessia; Veroux, Pierfrancesco; Surgery, School of MedicineBackground: Attachment theory represents a reference model for understanding better how pre-existing personality factors can influence the coping with some chronic conditions. The onset of a chronic disease can represent a "threat" to the relationships between the subject and parental figures according to the type of bond that already exists. The aim of our study was to explore attachment styles in a sample of hemodialysis patients, hypothesizing that a secure attachment bond can constitute a protective factor for the quality of life and mental health in this type of patients. Design: We used a cross-sectional design. Methods: Fifty hemodialysis patients were given the following tests: Attachment Style Questionnaire (ASQ) to assess attachment styles, Parental Bonding Instrument (PBI) to assess parental bonding, Short Form Health Survey-36 (SF-36) for perceived quality of life and Middlesex Hospital Questionnaire (MHQ) to detect key psychological symptoms and relevant traits. Results: The results showed that secure attachment style correlated with good general health (r = 0.339; p < 0.05), good mental health (r = 0.547; p < 0.001) and mental component scale (r = 0.373; p < 0.05) of SF-36. Secure attachment was also significantly associated with mental health (B = 1.104; p = .002) of the SF-36. Conclusions: The results confirmed the positive role of a secure attachment style for adequate psychological health. Early identification of patients with dysfunctional attachment styles will make it possible to offer them targeted interventions to improve their ability to accept, adapt and manage the disease and to maintain adequate psychological well-being.Item Bridging to Allotransplantation-Is Pig Liver Xenotransplantation the Best Option?(Wolters Kluwer, 2022) Lamm, Vladimir; Ekser, Burcin; Vagefi, Parsia A.; Cooper, David K. C.; Surgery, School of MedicineIn the past 20 y, the number of patients in the United States who died while waiting for a human donor liver totaled >52 000. The median national wait time for patients with acute liver failure and the most urgent liver transplant listing was 7 d in 2018. The need for a clinical "bridge" to allotransplantation is clear. Current options for supporting patients with acute liver failure include artificial liver support devices, extracorporeal liver perfusion, and hepatocyte transplantation, all of which have shown mixed results with regard to survival benefit and are largely experimental. Progress in the transplantation of genetically engineered pig liver grafts in nonhuman primates has grown steadily, with survival of the pig graft extended to almost 1 mo in 2017. Further advances may justify consideration of a pig liver transplant as a clinical bridge to allotransplantation. We provide a brief history of pig liver xenotransplantation, summarize the most recent progress in pig-to-nonhuman primate liver transplantation models, and suggest criteria that may be considered for patient selection for a clinical trial of bridging by genetically engineered pig liver xenotransplantation to liver allotransplantation.Item A brief history of clinical xenotransplantation(Elsevier, 2015-11) Cooper, David K. C.; Ekser, Burcin; Tector, A. Joseph; Department of Surgery, IU School of MedicineBetween the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century, with grafts from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into elderly men, believing that the hormones produced by the testis would rejuvenate his patients. In 1963-4, when human organs were not available and dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 h. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992 he obtained patient survival for 70 days following a baboon liver transplant. The first clinical pig islet transplant was carried out by Groth in 1993. Today, genetically-modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant.Item Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression(Springer, 2018-02-06) Kubal, Chandrashekhar A.; Pennington, Catherine; Fridell, Jonathan; Ekser, Burcin; Muhaylov, Plamen; Mangus, Richard; Surgery, School of MedicineBACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re-transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm³. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re-transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re-transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used.Item Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy(Taylor & Francis, 2021) Baiocchi, Leonardo; Sato, Keisaku; Ekser, Burcin; Kennedy, Lindsey; Francis, Heather; Ceci, Ludovica; Lenci, Ilaria; Alvaro, Domenico; Franchitto, Antonio; Onori, Paolo; Gaudio, Eugenio; Wu, Chaodong; Chakraborty, Sanjukta; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of MedicineIntroduction: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA. Areas covered: In this review, we discuss CCA-related: i) experimental systems used in preclinical studies; ii) pharmacological targets identified by genetic analysis; iii) results obtained in preliminary trials in human with their pros and cons; and iv) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term “cholangiocarcinoma” with “experimental model”, “preclinical model”, “genetic target”, “targeted therapy”, “clinical trial” or “translational research” was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing. Expert opinion: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.Item Clinical Islet Xenotransplantation: A Step Forward(Elsevier, 2016-10) Ekser, Burcin; Bottino, Rita; Cooper, David K. C.; Department of Surgery, IU School of MedicineItem Clinical lung xenotransplantation – what donor genetic modifications may be necessary?(Wiley, 2012) Cooper, David K. C.; Ekser, Burcin; Burlak, Christopher; Ezzelarab, Mohamed; Hara, Hidetaka; Paris, Leela; Tector, A. Joseph; Phelps, Carol; Azimzadeh, Agnes M.; Ayares, David; Robson, Simon C.; Pierson, Richard N., III; Surgery, School of MedicineBarriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible.