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Colorectal cancer (CRC) is the third most common and third deadliest cancer worldwide with rising incidence rates attributed to environmental risk factors like diet. Investigating how these factors impact carcinogenesis requires an understanding of how transcriptional events evolve with respect to neoplastic progression. We employed meta-transcriptomics and latent trajectory modeling to establish a compendium of profiled healthy, adenoma, and CRC samples scored by their position along a pseudotemporal axis. By interpolating a continuous scale from cross-sectional data, dynamic processes occurring throughout disease progression can be analyzed more accurately. For example, smaller pseudotimes represented pre-malignant dysplasia and was characterized by cellular hyperproliferation downstream of genomic stress. Larger pseudotimes represented post-malignant progression and was characterized by a prominent stromal and inflammatory response. As dysregulated bile acid (BA) metabolism is intrinsically linked with diet and CRC development, we next assessed how neoplastic progression modulated colonic BA-related pathways. Pseudotemporal analysis delineated a role and clinical utility of the FGFR4-KLB-FGF19 pathway in disease progression. FGFR4 was an early CRC oncogene and the only FGFR that could be directly associated with tumorigenesis, suggesting that targeted inhibition may be a novel therapeutic modality. KLB's expression and prognostic profile was inverse to FGFR4, indicating a tumor suppressor role in early CRC. In particular, predictive informatics ascribed a functional role for KLB in opposing FGFR4-mediated dysplastic processes, which was validated using cellular models of differentiation as well as transgenic and morphological studies. FGF19 was also identified as an oncogene and putative blood-based CRC biomarker due to its endocrine properties. Immunodeficient mice transplanted with FGF19-expressing cells demonstrated supraphysiologic levels of circulating FGF19 that exerted potent endocrine effects targeting hepatic metabolism and enterohepatic recirculation of BAs. Collectively, the data provide clear evidence for the importance of the FGFR4-KLB-FGF19 complex in modulating CRC oncogenesis as well as its potential translational applicability for screening/diagnostic purposes.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

No description available.

No description available.

Class of 2009 Abstract / OBJECTIVES: Skin cancer is particularly prevalent in Arizona, with incidence rates ranking number two worldwide. Pharmacists are useful advocates for educating patients about the risks of skin cancer and methods of prevention. This study was conducted to assess pharmacists’ knowledge of skin cancer and their demographics and to evaluate how these factors impact skin cancer prevention patient counseling. METHODS: Participants were recruited using a listserv from pharmacists that were members of the Arizona Pharmacy Alliance or preceptors of the University of Arizona College of Pharmacy. Subjects completed an online questionnaire consisting of knowledge- based questions, questions about patient counseling preferences and subject demographics. RESULTS: The average score by pharmacists on the Skin Cancer and Sun Exposure Knowledge Indicator was 5.8 + 1.9. Pharmacists living in Arizona for longer times were more likely to know the minimum recommended SPF of sunscreen for adults to use when outdoors (p=0.003) and the factors associated with malignant melanoma prognosis/survival (p=0.004), but were less likely to know the definition of ABCD acronym (p=0.027). Having a family or friend diagnosed with any form of skin cancer or precancerous skin condition led to more pharmacists knowing the risk factors for developing melanoma (p=0.046) and knowing how often to apply water resistant sunscreen (p=0.035). CONCLUSIONS: The length of pharmacy practice in Arizona and having a family member or close friend affected by skin cancer significantly impacted a pharmacists’ knowledge of skin cancer.

The world of cancer care is a strange land to a person newly diagnosed with cancer. Like someone who leaves the familiarity of home and arrives in a foreign place, the person with cancer loses equilibrium and feels lost, experiences an assault on self-identity, and encounters an alien language and culture. It is this person who knocks as a stranger on the door of cancerland. Many philosophic and religious traditions obligate those receiving the stranger to provide a deep hospitality. One model of the practice of deep hospitality is summarized as door, table, space. When applied to the relationship between the cancer care provider and the patient/stranger, this hospitality can humanize the experience for both parties and is education in its elemental sense of drawing out and leading forth—into healing and wisdom.

The purpose of the present thesis was to better understand the effect of targeting key biological mechanisms in order to improve radiotherapy response. Two important and distinct pathways were targeted using novel agents: (1) the phosphoinoside-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway; (2) the ataxia telangiectasia-mutated-Rad3-related (ATR)/Chkl pathway. The role of the PI3K1mTOR signalling pathway in tumour radiosensitivity and tumour microerivlronment (TME) was examined using three, recently-developed signalling inhibitors obtained from Novartis Pharma: NVP-BEZ235 (dual PI3K1mTOR inhibitor), NVP-BGT226 (dual PI3K1mTOR inhibitor) and NVP-BKM120 (single PI3K inhibitor). The radiosensitising potential of NVP-BEZ235 and NVP-BGT226 was demonstrated in tumour and endothelial cells. Additionally, a thorough research into the effects ofNVP-BKM120 and NVP-BEZ235 on TME showed that oncogenic signalling inhibitors can improve vascular morphology and increase tumour oxygenation and perfusion in tumour xenograft models, resulting in improved radiation response. Furthermore, a highly potent and selective A TR inhibitor, VE-822, that was obtained from Vertex Pharmaceuticals (Europe) Ltd, was tested in pancreatic ductal adenocarcinoma (PDAC) cells and tumour xenograft models. A TR inhibition by VE-822 resulted in sensitisation of tumour cells but not normal cells to radiation and gemcitabine. Similarly, VE-822 strongly enhanced radiation- and chemoradiation-induced tumour growth delay in tumour xenograft models. Importantly, VE-822 did not potentiate radiation-induced gastrointestinal tract epithelial damage. To summarize, the impact of targeting two distinct pathways in combination with radiation and chemoradiation was explored. Inhibition of the PI3K1mTOR and ATRlChkl signalling pathways increases response of tumours to radiotherapy they and might be promising targeting strategies for cancer treatment. Our findings have considerable translational implications and future clinical trials should aim to validate these observations.

University of Macau / Faculty of Health Sciences

Pancreatic cancer is often referred to as the “silent killer“ due to the asymptomatic nature of the disease in the early stages and the extremely poor prognosis overall. The average one-year survival rate for PDAC patients is 24% (American Cancer Society, facts and figures, 2010), decreasing to 5%-6% over 5 years (WHO report, Pancreatic cancer, 2010). Only 20% of patients are suitable for surgical resection at the time of diagnosis and treatment options available to PDAC patients have not improved significantly over the past few decades. Thus novel therapeutic approaches are essential to treat this disease. Our experimental, clinical and pre-clinical data suggest integrin αvβ6 may be a suitable target. Bioinformatics studies using the Pancreatic Expression Database revealed that the β6 gene (ITGB6) was highly up regulated in pancreatic ductal carcinoma (PDAC) compared with normal pancreas. Further analysis carried out showed that there was a significant correlation between ITGB6 expression at the mRNA level and survival in a cohort of 292 PDAC patients. Immunohistochemistry analysis on two separate patient cohorts (n=118 and n=147) showed that normal pancreas lacked αvβ6 expression whereas 91% of PDAC tissues expressed αvβ6 at the protein level. There was no significant correlation between αvβ6 expression and survival at the protein level in both cohorts of patients tested. Flow cytometry and Western blotting analyses on a panel of PDAC cell lines confirmed expression of αvβ6 in PDAC cell lines. This study investigated the functional role of αvβ6 in PDAC cell lines. Antibody mediated function blockade of αvβ6 significantly inhibited proliferation in a dose dependent manner, specifically in αvβ6 positive PDAC cell lines. A significant reduction in migration and invasion was also observed in a panel of αvβ6 positive PDAC cell lines when treated with an αvβ6 function-blocking antibody. αvβ6 targeted antibody mediated therapy in combination with gemcitabine significantly inhibited tumour growth in a physiologically relevant pre-clinical subcutaneous xenograft model of PDAC. These data reaffirms that αvβ6 is a potential novel therapeutic target and an αvβ6 specific function-blocking antibody can be used as a novel agent to treat pancreatic adenocarcinoma patients.