Browsing by Subject "Leukemia"

Now showing 1 - 4 of 4
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    Assessment on the Precision of Total Marrow Irradiation: From Clinical to Preclinical Implementation
    (2021-06) Zuro, Darren
    Total Body irradiation (TBI) has been used for many years as the preconditioning regime before bone marrow transplant. Dose escalation of TBI produced decreased relapse rates in patients with leukemia; however, treatment-related deaths increased because of organ toxicity from TBI negating any potential therapeutic gain. In 2005 a new technique called Total Marrow radiation (TMI) was founded as an alternative to TBI. TMI is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. However, there are several challenges to establish and advance TMI treatment; specifically, 1) the existence of differences in treatment setup between centers which may cause differences in dose delivery and treatment accuracy. 2) the lack of a preclinical model to better understand the biological differences between TMI and TBI. Lack of preclinical TMI model, limits us for in depth understanding of how TMI dose escalation and bone marrow microenvironment plays role in leukemia relapse and whether new therapeutics (e.g. TMI and immune modulation) could be developed to improve treatment outcomes. In this thesis, I assessed the state of current clinical TMI pre-treatment setup and its effect on dose delivery. Patient setup techniques differed between centers, creating variations in dose delivery. Image fusion accuracy varied by anatomical regions and by imaging technique. This effort allowed us to standardize treatment setup which can be used as reference for all centers. After creating a multi-center reference for TMI dose distribution, we developed and validated image guided preclinical TMI treatment technique in mice. Dose reduction in preclinical TMI mirrored that in clinical TMI.TMI treated mice showed full long-term donor engraftment after primary bone marrow transplant (BMT) and second serial BMT. Engraftment was similar to TBI. TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI. MVCT imaging and whole-body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs. The development of a new 3D targeted preclinical system paves the way for new exploratory studies in the field of bone marrow transplant and radiobiology.
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    Evaluation of the Role of Cytomegalovirus Infection in the Development of Acute Lymphoblastic Leukemia and Other Cancers
    (2022-05) Geris, Jennifer
    Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, and a leading cause of death in children. Understanding the risk factors of pediatric ALL is necessary to enable early detection and prevention. Congenital cytomegalovirus (cCMV) has recently been identified as a possible risk factor of ALL. In Manuscript 1, we compared the prevalence of cCMV infection in newborn dried blood spots of ALL cases and cancer-free controls. There was no difference in the odds of cCMV infection comparing ALL cases to controls in our primary analysis. However, cCMV was significantly more prevalent among hyperdiploid ALL cases compared to unmatched controls. These findings offer partial support for the association of cCMV with ALL.CMV is among the most common viral infections following solid organ transplantation (SOT). CMV disease post-SOT has been associated with an increased risk of subsequent non-Hodgkin lymphoma but has not been well-studied for other hematologic malignancies. In Manuscript 2, we aimed to describe CMV infection status pre-transplant as it relates to the incidence of leukemias, lymphomas, and myeloma. We identified that CMV recipient and donor sero-mismatch (R-/D+) was associated with significantly lower risk of diffuse large B-cell lymphoma compared to CMV seronegative R/D pairs, indicating CMV may have a protective role in carcinogenesis. Lastly, in Manuscript 3, we leveraged the same dataset as Manuscript 2 to examine associations of CMV with solid tumor cancer risk among SOT recipients. Using linked data from the United States SOT registry and 32 cancer registries, we report an inverse association between R-/D+ CMV serostatus and small intestine cancer, and a positive association between CMV R+ serostatus and lung cancer. CMV status was not associated with risk for other cancers. Findings from this dissertation may motivate and inform future work to further understand the relationship between this highly prevalent virus and cancer.
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    The functional role of the activating receptors Tim-3 and CD16 in human natural killer (NK) cell biology
    (2012-09) Gleason, Michelle Kathleen
    Human natural killer (NK) cells are lymphocytes that develop in the bone marrow from hematopoietic progenitor cells (HPCs) and are also found in the lymph nodes, spleen and peripheral blood (PB), where they comprise 10-15% of the mononuclear cell fraction. PB NK cells are phenotypically defined as expressing the surface receptor CD56 (NCAM, neural cell adhesion molecule) and lacking expression of CD3. They mediate their function through the exocytosis of granules that contain lytic enzymes such as perforin and granzymes, the expression of death receptor ligands, the expression of FcRgammaIIIA (CD16, a mediator of antibody-dependent cell-mediated cytotoxicity or ADCC), and the secretion of cytokines and chemokines. As a result, NK cells take part in both the innate and adaptive immune responses and have critical roles in the control of early viral infection, hematopoietic cell transplantation (HCT) and tumor immunosurveillance. The ability of NK cells to differentiate normal healthy cells (self) from infected or transformed (non-self) cells is regulated by a sophisticated repertoire of cell surface receptors that control their activation, proliferation and effector functions. The net balance of inhibitory and activating signals transmitted by these receptors determines whether an NK cell will eliminate its target. The work presented in this manuscript focuses on the modulation of NK cell effector function by two receptors found in their activating repertoire, namely Tim-3 and CD16, and their potential for enhancing the therapeutic effects of NK cells for the treatment of human hematopoietic malignancies.
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    Regulation of PHLPP2 Expression in AML
    (2012-12) Theede, Kelly Mary
    The phosphatase PHLPP2 functions as a tumor suppressor by activating the proapoptotic function of Bcl-2 protein Noxa in leukemia cells. PHLPP2 is downregulated or depleted in specific acute myeloid leukemia (AML) subtypes. We hypothesize that AML has evolved mechanisms to suppress PHLPP2 expression and/or phosphatase activity. We measured the expression of PHLPP2 in a small panel of leukemia cell lines. PHLPP2 transcript was found in the lines despite the lack of protein expression. To test the hypothesis that PHLPP2 translation is blocked in AML cell lines, we assayed levels of miR-17-92, a miRNA cluster which targets PHLPP2. Levels of miR-17-92 were increased in AML versus acute lymphoid leukemia (ALL) lines. Furthermore, PHLPP2 protein was less stable in an M5 AML line compared to ALL. These studies offer insights into novel protein suppression mechanisms and lay the foundation for further investigations into PHLPP2 as a biomarker and therapeutic target for AML.