Thesis--PlanB (M.S.)--University of Wisconsin--Stout, 2004. / Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 92-100).

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 86-101). Also available in print.

Thesis (M. Med. Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 71-78).

Thesis (M.S.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vi, 38 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 35-37).

Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vii, 124 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Mijo emerged as an alternate project to fulfill my MFA thesis requirement when Foreign Puzzle my initial thesis project faced serious setbacks. Foreign Puzzle is an hour-long documentary about love, life, breast cancer, dance and the transcending power of the human spirit. In an attempt to unravel an individual's struggle with mortality, to understand a child's adaptation to a mother's illness and to document the healing power of creativity, I began filming Sharon Marroquin's life from September 2010. Unfortunately, when filming real people undergoing life threatening medical illness it is impossible to stick to a timeline. Sharon Marroquin, the central character in the film developed serious medical complications that pushed the deadline for Foreign Puzzle significantly. While, I was committed to the completion of the film Foreign Puzzle, I did not want to delay my graduation from film school by almost two years and hence was forced to come up with an alternate thesis project. I had an animation script ready to go into production. But, I was so deeply involved with the production of Foreign Puzzle that it became impossible to work earnestly on a completely new film. The only viable alternative was to make a short film from the footage filmed for Foreign Puzzle. For the film to work and function independently, it had to have a strong and distinct thematic strand and not seem like a trailer or a scene from a longer film. This report is an elaboration of the process that went into the creation and exhibition of Mijo and its influence on Foreign Puzzle. / text

Breast cancer is the second leading cause of mortality among women in the US. A contributing factor to such dire statistics is that conventional therapies are all too often compromised due to tumor relapse. Clearly there is an urgent need for agents that can circumvent resistance when combined with conventional therapies. RRR-α-tocopherol ether-linked acetic acid analog (α-TEA), a small bioactive lipid, exhibits in vitro and in vivo anticancer actions in a variety of cancers, including breast, prostate, and ovarian with little or no effect on normal cells and tissues, which potentially makes it an ideal chemotherapeutic agent. My studies investigated the anticancer actions of α-TEA alone and in combination with therapeutic agents using human breast cancer cell lines. Data show that: (i) Endoplasmic reticulum (ER) stress plays an important role in α-TEA induced apoptosis by enhancing DR5/caspase-8 pro-apoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling, (ii) α-TEA plus tamoxifen act cooperatively to circumvent acquired and de novo tamoxifen resistance, resulting in cancer cell death by apoptosis. Mechanistically, the circumvention of tamoxifen resistance involved induction of DR5/caspase-8 pro-apoptotic mediators and suppression of anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling. (iii) α-TEA alone or with tamoxifen circumvents tamoxifen resistance via disruption of membrane cholesterol rich lipid raft microdomains. Cholesterol blocked the ability of α-TEA + tamoxifen to circumvent tamoxifen resistance. (iv) α-TEA in combination with PI3K, MEK or mTOR inhibitors acted cooperatively to induce apoptosis, by down-regulation of IRS-1/PI3K mediators via JNK. (v) α-TEA plus doxorubicin or cisplatin enhanced apoptosis in p53 mutant human breast cancer cells via targeting p53-inducible genes in a p73-dependent manner; namely, via up-regulation of death receptor-5 (DR5), CD95/APO-1 (Fas), Bax and Noxa, as well as down-regulation of anti-apoptotic mediator Bcl-2. Data showed that p73 responses were downstream of c-Abl, JNK and Yap. (vi) FASN inhibitor alone or with Tamoxifen or α-TEA circumvents tamoxifen resistance, thereby, providing novel strategies for restoring tamoxifen sensitivity to tamoxifen resistant cancers. In summary data show, α-TEA alone and in combination with multiple clinically-relevant anticancer agents is a promising anticancer agent. / text

Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ER alpha) positive, postmenopausal patients. It has also been correlated with elevated levels of inflammation, which can stimulate adipose tissue aromatase expression and subsequent estrogen production. Given that obese patients have a lower response rate to aromatase inhibitor treatment and greater mammary tissue aromatase levels, it was hypothesized that obesity promotes ER alpha positive postmenopausal breast cancer progression in part via an inflammation-induced increase in mammary tissue aromatase expression and ER alpha activity. These studies utilized an in vitro model of obesity in which cultured cells were exposed to postmenopausal breast cancer patients’ serum samples, pooled by body mass index category (Obese (OB): ≥30.0 kg/m2; Normal weight (N): 18.5-24.9 kg/m2). OB versus N patient sera induced greater breast cancer cell (BCC) aromatase expression, as well as higher ER alpha activity and cell viability in the presence of testosterone, the substrate for aromatase. Pre-adipocytes exposed to OB versus N patient sera also indirectly stimulated greater BCC aromatase expression, ER alpha activity, and viability. A retrospective review of breast cancer patient data demonstrated that daily use of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase-2 (COX-2) activity, is associated with reduced ER alpha positive breast cancer recurrence in obese and overweight women. The mechanisms mediating this effect were examined using the same in vitro model. Exposure to OB versus N patient sera stimulated greater macrophage and BCC COX-2 expression and prostaglandin E2 production, leading to enhanced pre-adipocyte aromatase expression. These OB patient sera-induced effects were further linked with greater BCC ER alpha activity, proliferation, and migration in the presence of testosterone, and these differences were eliminated or reduced with aromatase inhibition. Based on these findings, prospective studies designed to examine the clinical benefit of NSAID use in obese ER alpha positive postmenopausal breast cancer patients are warranted. Additional obesity-associated mechanisms that may also promote breast cancer progression were also explored, including enhanced cross-talk between non-genomic ER alpha and growth factor signaling pathways, reduced estrogen receptor beta expression, and resistance to chemotherapy. Finally, the impact of obesity on tumor incidence and characteristics in the MMTV-Wnt1 mouse model of mammary carcinogenesis was explored. / text

published_or_final_version / Pathology / Master / Master of Medical Sciences