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Low Intensity Vibrations Mitigate Cancer-Induced Bone Loss with Indications of Reduced Tumor Progression

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dc.contributor.advisor Clark, Richard H en_US
dc.contributor.author Pagnotti, Gabriel M. en_US
dc.contributor.other Department of Biomedical Engineering en_US
dc.date.accessioned 2017-09-20T16:51:37Z
dc.date.available 2017-09-20T16:51:37Z
dc.date.issued 2014-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76995 en_US
dc.description 108 pgs en_US
dc.description.abstract Osteopenia is a comorbidity frequently observed in patients being treated for and recovering from cancer treatment, elevating their risk of fracture. These skeletal losses are compounded by chemotherapy and irradiation, damaging both bone and contents of the marrow, thereby undermining recovery efforts. Exercise is commonly prescribed as a non-pharmacological means of maintaining bone mass. However, in those with compromised bone strength, the loads imposed by rigorous exercises may facilitate a fracture it was intended to prevent. Low intensity vibrations (LIV), a mechanical signal demonstrated as anabolic to bone by biasing mesenchymal stem cells (MSCs) towards an osteogenic endpoint, may represent a novel strategy to circumvent the bone losses induced by cancer if it is able to do so without negatively affecting survivability. Two murine models of cancer were employed to assess the effects of LIV in mitigating cancer-induced bone loss. Following 1y of LIV administration, a murine model of spontaneous granulosa cell ovarian cancer demonstrated significant preservation of bone quantity and quality as evidenced by micro-CT analysis of tibial and vertebral trabecular bone without negatively influencing animal survivability. In quantifying tumor burden, fewer tumor foci pervaded the system in LIV mice. MSC populations were significantly lower in the marrow of LIV as compared to controls, indicating a modulation of stem cell progenitor differentiation towards skeletal endpoints while reducing their capacity to contribute towards neoplastic tissue expansion. Additionally, an immunocompromised mouse strain was xenografted with human multiple iv myeloma cells, inducing diffuse infiltration of aberrant plasma cells in the host bone marrow. Significant cortical osteolysis and trabecular destruction was observed after 8w. However, micro-CT analysis of the injected mice exposed to 8w of LIV revealed retention of trabecular bone in the distal femur and reduced instance of cortical perforations, all without influencing the survivability of the mice. Histological assessment of the femoral marrow cavity further demonstrated the infiltration of myeloma cells throughout the length of the medullary cavity, both across the diaphysis and extending past the epiphyseal growth plate resulting in anemic and neutropenic outcomes in both groups. Osteolysis was clearly evident in the diseased groups, particularly at the distal femur, as woven bone and cortical resorption pits were a consequence of disease progression. The bone marrow phenotype, as assessed by FACS analysis and histological evaluation, was also highly disrupted, reflected by the elevated hematopoietic stem cell and lineage-specific populations. A trend towards reduced pathology, including necrotic tumor and fewer tumor cells, were quantified in diseased animals exposed to LIV. These skeletal and marrow outcomes, however, were mildly reduced in those mice initially treated with LIV. Together, the data taken from these studies reinforce the known destructive capacity of cancer on the skeletal system and the constituents of bone marrow but in two different murine models of the disease. In addition, the two cancer models studied which demonstrate different mechanisms of cancer-induced bone loss, also reveal the positive effects low intensity vibrations impart on the skeletal system during tumorigenesis without negatively affecting survival outcome. Further, the outcomes of administering low intensity vibrations to ameliorate consequences of disease support its potential clinical use in mitigating cancer-induced bone losses and, perhaps, in slowing progression of the disease itself. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biomedical engineering en_US
dc.subject.other Granulosa Cell Tumor, Low Intensity Vibrations, Mechanical Signaling, Multiple Myeloma, Osteoporosis, Stem Cell en_US
dc.title Low Intensity Vibrations Mitigate Cancer-Induced Bone Loss with Indications of Reduced Tumor Progression en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Rubin, Clinton en_US
dc.contributor.committeemember Shroyer, Kenneth en_US
dc.contributor.committeemember Simon, Sanford en_US

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