Browsing by Subject "Department of Surgery"
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Item The Biomechanical Puncture Study of the Fossa Ovalis in Human and Porcine Hearts(2011-04-13) Balto, DanielAbout 1 in every 4 adults here in the U.S. has some sort of congenital heart defect, the majority of these defects is caused by a Patent Fossa Ovalis (PFO). It occurs when the hole between the left and right atria (Foramen Ovale) does not close completely at the moment of birth. The study involved designing and then constructing an apparatus to hold an excised heart in proper anatomical position so that the Fossa Ovalis was accessible from both atria of the heart. Once that was accomplished, a catheter type device was designed and then used to measure the force required to puncture the fossa membrane and the data was recorded. Many different factors were analyzed with this data such as fossa morphology and anatomy. The reason for creating such a device for testing fossa strength was to observe if the fixation of the tissue with formalin would change the properties of the fossa in a variety of human and pig hearts that have been preserved in formalin and used as in vivo equivalents. The data gained will allow me to compare how current PFO’s (heart defects) are fixed and what new surgical procedures or biomedical devices can be created based on the strength of the average Fossa Ovalis of a human.Item The Effects of Hypoxia and Cytotoxic Stress on β-cells During Transplantation(2009-04-08) Mian, IstiaqType 1 diabetes is a devastating disorder resulting from the autoimmune destruction of insulin-producing β-cells within the islets of Langerhans. Complications from hyperglycemia lead to a lower quality of life characterized by seizures, heart attack, kidney failure or retinopathy. Recent advances in islet cell transplantation have presented a possible cure for Type 1 diabetes, however the viability of a graft is drastically lowered by hypoxia and cytotoxic stress during isolation and transplantation. In this study, we mimicked the process of islet transplantation by exposing rat INS-1 cells to hypoxia (1% oxygen) and three different concentrations of three cytokines (IL-1β, TNF-α and IFN-gamma) for 24 hours and analyzed their effects via oxygen consumption rate (OCR), ATP and caspase assay. Results from this study would be able to characterize the extent of the effects of hypoxia on graft viability and could implicate the most potent cytokine at a specific concentration. Results could also suggest a specific pathway that a certain cytokine uses. Implications from this study can lead to improved methods of transplanting islet cells, perhaps via additives such as tocopherols, antioxidants, or JNK inhibitors that may increase islet protection throughout the transplantation process. If graft viability can be increased, this can increase the availability of islet cells and quality of life for Type 1 diabetic patients.Item Evaluation of Mechanical Properties of Swine Tissue as it Relates to Atrial Fibrillation(2014-04-16) Gangeness, GrantItem IL-4 Induces Protection of Porcine Endothelial Cells from Anti-Endothelial Cell Antibody in Association with Upregulation of Claudin-5(2010-04-21) Goldish, DannyInterspecies organ transplantation offers a potential strategy to the global shortage in vital human organs for donation. Multiple obstacles remain before rejection of foreign organ grafts (xenotransplantation) can be avoided. In pig-to-primate combinations, the vascular endothelium of the transplant is the main target of injury by the host immune system. We are using an in vitro system in which pig endothelial cells (EC) are modified to make them resistant to injury by anti-EC antibodies (abs) in human blood. These abs damage the EC by causing cellular retraction and intercellular gap formation. My aim is to study methods and mechanisms that protect the EC from injury caused by the abs. The cytokine interleukin-4 (IL-4) induces protection of EC from apoptosis and from killing by human complement. My results demonstrated that pretreatment of the EC with pig IL-4 decreases the amount of abinduced cellular retraction and intercellular gap formation. This finding suggested that IL-4 might regulate the expression of proteins that maintain cell-to-cell junctions in the monolayer. Using immunofluoresce, we examined the expression of the junction proteins CD31, VEcadherin, and claudin-5, in IL-4-treated and untreated EC. We found that IL-4 strongly induces claudin-5 expression, but not expression of VE-cadherin or CD31. We now plan to use siRNA silencing of claudin-5 to investigate whether increases in claudin-5 protein are important for protection of EC from ab-induced damage. If this silencing abolishes EC protection, claudin-5 must play a pivotal role in IL-4-induced protection. Conversely, if protection still occurs, claudin-5 is an unnecessary side reaction of the protection. This information will help uncover mechanisms behind IL-4 induced protection, and contribute to new approaches for xenotransplantation.Item Improved Antitumor Effect of Adenovirus-Mediated Interferon Therapy in Combination with Chemoradiotherapy in a Syngeneic Immunocompetent Hamster Model(2012-04-18) Han, JooheePancreatic cancer is one of the deadliest diseases without a cure. Approximately 85-90% of newly diagnosed patients will present inoperable disease due to an advanced stage of the cancer or metastases. The median survival length of these patients is about 6 months. Even with well-established chemotherapy (5-FU), 95% of the patients will not be alive within five years. Although interferon- α (IFN) emerged as a promising treatment strategy in recent clinical studies, excess toxicity and insufficient level of IFN in tumor site remain as serious concerns. Hence, we designed a novel adenovirus as a vehicle system to deliver high dosage of IFN to only the pancreatic cancer cells, leaving the normal tissues unharmed. We hypothesize that our novel adenovirus expressing IFN (Ad-IFN) in combination with either 5-FU or radiotherapy would significantly enhance anticancer effect of existing IFN-based treatments while reducing toxicity. In vitro assays in human and hamster pancreatic cancer cells revealed that combination of Ad-IFN with either 5-FU or radiation killed cancer cells better than either of the single treatments. Successfully establishing a fully syngeneic pancreatic cancer model in immunocompetent hamsters, we treated them with a single dose of Ad-IFN followed by radiation. Ad-IFN combined with radiotherapy showed remarkable decrease in tumor volume and was significantly superior to single treatments. At day 42, the tumors in the combination group nearly disappeared. Thus, we have the first report of the improved combination effect of Ad-IFN with radiotherapy and 5-FU. Such a strategy may change the paradigm of pancreatic cancer treatment.Item Injury by human complement causes large membrane lesions that reseal in IL-4-treated porcine endothelial cells(2011-04-13) Yeh, AlexCurrently, successful xenotransplantation is restricted to theoretical conception due to the fact that an organism’s innate immune response rejects any tissue or organs transplanted from a different species. The complement system is a key component of this response in rejecting foreign substances, and mitigating the effects of this system could potentially revolutionize medical transplants. Complement system activation in an organism creates lesions in the membranes of foreign cells, leading to lysis and cell death. IL-4 is a cytokine, or a cell-signaling molecule, that seems to have a protective property against complement. Porcine endothelial cells first incubated in IL-4 exhibit decreased cell death after treatment with human complement, but the exact mechanism of protection is still unknown. A combination of the Neutral Red assay and the LDH assay were used to study cell recovery after complement treatment. Fluorescent microscopy was also used, in which labeled dextrans of different sizes were incubated with the cells along with complement. Should the mechanism of IL-4 protection be correctly identified, it may have potential uses in mitigating the innate immune response and the rejection of organs in xenotransplantation.Item A Novel Gene Therapy in Combination with Chemotherapeutic to Treat Pancreatic Cancer(2011-04-13) Han, Joohee; Armstrong, Leonard; Brown, Eric; Vickers, Selwyn; Yamamoto, Masato; Davydova, JuliaA cure for pancreatic cancer is not possible, yet. For more than 80% of U.S. patients diagnosed with unresectable pancreatic cancer, the average length of survival is less than one year. Even with well-established chemotherapeutic agent 5-Fluorouracil (5-FU) treatment, 95% of the patients will not be alive within five years. In recent clinical studies, interferon-α (IFN) therapy in conjunction with 5-FU has emerged as a promising treatment strategy, but systemic toxicity and an unsustainable level of IFN in tumor sites remain serious challenges. Hence, we designed and cloned a novel adenovirus with replication restricted to Cox2-overexpressing pancreatic cancer cells as a vehicle system to deliver high dosage of IFN to only the pancreatic cancer cells, leaving the normal cells intact. We hypothesize that adenovirus expressing IFN in combination with 5-FU would significantly enhance selectivity and anti-cancer effect of existing IFN-based regimens while reducing toxicity to healthy tissues. The cytocidal effect of the combination therapy on pancreatic cancer cells were analyzed in vitro by MTS assay. Eight days post-infection, the lone treatment of adenovirus expressing IFN, the lone treatment of 5uM of 5-FU, and the combination therapy killed 21%, 10%, and 59% of pancreatic cancer cells, respectively. Remarkably, the adenovirus expressing IFN combined with 5-FU exhibited greater oncolysis than either of the treatments alone. Additional experimentation and assessment of the combination therapy may provide new insights into its efficacy. The combination therapy possesses great potential in improving the long term survival of pancreatic cancer patients.Item A Tribute to the Incomparable John S. Najarian, MD (1927-2020)(Journal of Opinions, Ideas & Essays (JOIE), 2021-05-08) Knatterud, Mary EIn this article, author Mary E. Knatterud, PhD, pays tribute to her incomparable longtime boss, transplant surgeon-scientist John S. Najarian, MD, who died at the age of 92 on August 31, 2020. The two worked together for several decades in the University of Minnesota Department of Surgery, which he chaired from July 1967 until February 1993. With deep affection and abiding respect, Knatterud describes his stellar academic background, internationally renowned career, and high-achieving yet genial style. She also showcases a cross-section of heartfelt comments (gathered by her, via email and/or phone, the sad week of his death) from colleagues in the workplace he built: Mary Jane Towle; Mary Dodds; Rainer W.G. Gruessner, MD; Barbara Elick, RN, BSN, MA; Henry Buchwald, MD, PhD; Catherine Statz, RN, MPH; and David A. Rothenberger, MD.Item Using δ-Opioid Receptor Agonists to Protect Skeletal Muscle against Low pH Hypoxic Damage(2010-03-31) Tetzner, Melissa A.During many surgical procedures, tissue experiences a period of ischemia which can cause stunning, apoptosis, and necrosis of the tissue. By minimizing this damage, procedural outcomes and patient recovery could be improved. It is unclear as to whether opioid receptor agonists demonstrate protective properties against ischemic injury or not. It is thought that δ-agonists could be beneficial while κ-agonists could be detrimental. Even less is known about μ-agonists. Previous in vitro models that have addressed ischemia/reperfusion injury utilize buffering systems which maintain a constant pH of 7.4. This is not the most accurate representation of ischemia as it does not account for the drop in tissue pH caused by the buildup of metabolic wastes. By creating a high CO2 hypoxic event, thus lowering the pH to 6.5, our model was better able to mimic real-life ischemic conditions.