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Item Diagnostic Utility of IDH1/2 Mutations to Distinguish Dedifferentiated Chondrosarcoma from Undifferentiated Pleomorphic Sarcoma of Bone(Elsevier, 2017) Chen, Shaoxiong; Fritchie, Karen; Wei, Shi; Ali, Naser; Curless, Kendra; Shen, Tiansheng; Brini, Anna T.; Latif, Farida; Sumathi, Vaiyapuri; Siegal, Gene P.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of MedicineHistologically it is nearly impossible to distinguish the dedifferentiated component of dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone when the low-grade cartilaginous component is absent. Previous studies have revealed that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are present in a significant number of cartilaginous tumors including the majority of conventional chondrosarcoma and dedifferentiated chondrosarcomas. These mutations have not been studied in undifferentiated pleomorphic sarcomas of bone. We sought to investigate whether an IDH1 or IDH2 mutation signature could be used as a clinically diagnostic marker for the distinction of dedifferentiated component of chondrosarcoma from undifferentiated pleomorphic sarcoma of bone. Sixty-eight bone tumor cases, including 31 conventional chondrosarcomas, 23 dedifferentiated chondrosarcomas, and 14 undifferentiated pleomorphic sarcomas of bone, were collected for IDH1/2 mutation analysis either using the Qiagen IDH1/2 RGQ PCR Kit or using whole exome sequencing. IDH1/2 mutations were detected in 87% (20/23) of dedifferentiated chondrosarcomas and 30% (6/20) of conventional chondrosarcomas. No mutations were detected in the IDH1/2 codon 132 or codon 172 among 14 UPS of bone. Identification of IDH1 or IDH2 mutations supports the diagnosis of dedifferentiated chondrosarcoma rather than undifferentiated pleomorphic sarcoma of bone while also providing some insight into the pathogenesis of these two lesions.Item Studies on hydrodynamic delivery as a treatment for acute kidney injury(2017) Kolb, Alexander; Atkinson, Simon; Bacallao, Robert; Basile, David; Dai, Guoli; Szymanski, DanielHydrodynamic delivery is a powerful tool that allows delivery of macromolecules to the kidney culminating in gene expression. This finding is important in the fight against kidney disease. Current therapy for kidney injury, specifically acute kidney injury, is lacking. Supportive care in the form of IV fluids and medications aimed at restoring Glomerular Filtration Rate (GFR) and urine output are currently used. However, even with these treatments, prognoses of patients diagnosed with this disease remains poor. We believe that hydrodynamic delivery provides a mechanism that can be used to reverse and prevent AKI. Hydrodynamic delivery following ischemic injuries leads to reductions in serum creatinine and infiltrating mononuclear cells, as well as increased renal blood flow and survival. These changes are due to reductions in vascular congestion and inflammation typically seen following injury. To determine the underlying mechanisms of gene delivery preventing AKI, we used candidate genes identified in a proteomic screen on kidneys that recovered from AKI. We selected Isocitrate Dehydrogenase II (IDH2) and Sulfotransferase 1C2 (SULT1C2) for study and found that delivery prior to injury prevents serum creatinine increase and reduces cell death. We found that gene delivery of IDH2 prevents a glycolytic shift typically seen following ischemic injuries. The mechanism underlying the prevention of this shift are seen in increased ATP stores and spare respiratory capacity allowing the cell to remain in an oxidative state. Additionally, we show that SULT1C2 post-translationally modifies the mitochondria membrane, increasing oxidative phosphorylation providing the cell with additional energy needed in times of oxidative stress. These candidate genes allow cells to remain in an oxidative state preventing the activation of cell death pathways typically activated following injury, thereby preserving normal kidney function.