Browsing by Subject "bone marrow transplantation"
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Item Individualized Drug Use in Hematopoietic Cell Transplantation: Application of Pharmacometric and Pharmacogenomic Study(2022-08) Takahashi, TakutoHematopoietic cell transplantation (HCT) is a high-risk therapeutic procedure that is reserved for patients, whose disease is either refractory or incurable by other measures. Conditioning therapy is an important first step in HCT with multiple purposes (i.e., treat refractory malignancy, ablate bone marrow to make physical space, and suppress host immune rejection). Conditioning therapy often entails high-dose cytotoxic chemotherapy, and the resultant high toxicity allows only a narrow therapeutic window, and either under- or over-exposure to these agents can result in detrimental consequences. When the cost of therapeutic failure is very high, as in HCT patients, a minor adjustment in dosing can have a clinically significant impact on patient outcomes. Population pharmacokinetic modeling approach enables delineation of dose-exposure relationship by identification of covariate effects within a patient population. One potentially critical covariate is germline genetic variation that may influence the pharmacokinetic-pharmacodynamic genes of drugs. In this thesis, I studied the individualization of dosing in commonly used drugs in HCT including busulfan, voriconazole, and cyclophosphamide. The studies presented in this thesis attempted to generate new knowledge that would improve drug utilization through dosing individualization. Although proper validation is needed, each of the studies has the potential to directly improve patient outcomes. An important knowledge, gained through the literature, is that conventional dose identification studies utilized in the field tend to test oversimplified dosing regimens (i.e., one-size-fits-all approach), which likely insufficiently accommodate the complexity in the pharmacokinetic-pharmacodynamic variabilities in HCT setting.Item The role of bone marrow-derived progenitor cells in pancreatic cancer(2021-12) Edwards, RachelPancreatic ductal adenocarcinoma (PDA) is the most common type of pancreatic cancer, and it has an extremely poor prognosis for patients. PDA is distinct from many other cancer types in that it has a robust desmoplastic reaction deposited by the large number of pancreatic stellate cells (PSC) present within the tumor microenvironment (TME). In the human disease, the number of PSC can be so high that the number of quiescent, resident PSC present in the normal pancreas could not undergo enough rounds of proliferation without becoming a transformed cell type to result in the number of activated PSC observed in the tumor. Review articles have posited that mesenchymal stem cells (MSC) are one source of these cells for nearly a decade even though, to our knowledge, no one has conclusively shown this to be true. In this work, we set out to show this to be true, but our findings largely contradicted this hypothesis. We attempted to show that MSC home to PDA through multiple different methods, which are described in the following chapters. A bone marrow transplantation (BMT) method was employed to transplant two distinctly labelled stem cell populations in our GEMM of pancreatic cancer with Kras, p53, and Cre mutations (KPC). The results were inconclusive for our hypothesis because we found that MSC could not be transplanted into and reconstitute the mesenchymal niche in the bone marrow in the same manner as hematopoietic stem cells (HSC). A parabiosis surgical model was used to connect the circulation between a genetically engineered mouse model (GEMM) with fluorescently labelled MSC in the bone marrow and our KPC model. This was done to observe homing from resident, labelled MSC to overcome the limitations of transplanting MSC. We were unable to observe any signs of fluorescent MSC in the pancreas of diseased mice. Other subcutaneous (SQ) and injection models were used to compare our models and results with previous literature to gain a better understanding of the limitations of each system. We found that artifacts of less physiologically relevant models of disease may have contributed to the misunderstanding of pancreas cancer biology for over a decade.