This final report documents the theoretical development and preliminary empirical testing of a model that predicts the conditions under which Hispanics will seek preventive health care. Research shows that Hispanics delay preventive care, resulting in higher morbidity and mortality rates for serious diseases such as cancer. Since many serious diseases, such as heart disease, diabetes and cancer can be prevented or treated more effectively if detected early, it is crucial to understand the motivating forces behind Hispanics’ preventive health behavior. The Hispanic model, which is an extension of the Health Behavior in Cancer Prevention Model developed by Atwood, et al. (1986), includes as core variables environmental barriers to access and English-language proficiency, as well as social support, health beliefs, self-efficacy (or perceived skill), health locus of control, and health values. This correlational descriptive study employed snowballing sampling methods and consisted of 199 Hispanics between 49 and 94 years of age. Measures consist of multi-item scales whose content follows that of the Parent Project. The final instruments showed reliability (Alphas between .69 and .95), although the model testing was limited by the exclusion of some constructs that did not demonstrate reliability. The outcome of predisposition to self-care was predicted by utilization barriers to care, Chance Health Locus of Control, and General Health threat, resulting in an R-square of .07. The findings dealing with dietary preferences and preferred dietary modifications also have great implications for interventions aimed at preventing colon cancer among Hispanics. The practical health policy applications of the model are also discussed.

Liu Bonnie Pui-ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 134-163). / Abstracts in English and Chinese. / Acknowledgments --- p.i / Abbreviations --- p.ii / Abstract / English --- p.1 / Chinese --- p.3 / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- Colorectal Cancer Statistics --- p.5 / Chapter 1.2 --- Colon Cancer --- p.5 / Chapter 1.3 --- Treatment --- p.6 / Chapter 1.4 --- Effects of Cytotoxic Drug Treatment --- p.7 / Chapter 1.5 --- Cell Cycle --- p.8 / Chapter 1.6 --- Oxidases --- p.9 / Chapter 1.7 --- Chemistry of Novel β-carboline: Tangutorine --- p.11 / Chapter 1.8 --- Aim of Study --- p.14 / Chapter Chapter 2 --- Cytotoxicity / Chapter 2.1 --- Introduction --- p.15 / Chapter 2.2 --- Materials and Methods --- p.18 / Chapter 2.3 --- Results --- p.23 / Chapter 2.4 --- Discussion --- p.44 / Chapter Chapter 3 --- Oxidase Activity and Protein Oxidation / Chapter 3.1 --- Introduction --- p.48 / Chapter 3.2 --- Materials and Methods --- p.54 / Chapter 3.3 --- Results --- p.60 / Chapter 3.4 --- Discussion --- p.80 / Chapter Chapter 4 --- Cell Cycle / Chapter 4.1 --- Introduction --- p.89 / Chapter 4.2 --- Materials and Methods --- p.93 / Chapter 4.3 --- Results --- p.96 / Chapter 4.4 --- Discussion --- p.118 / Chapter Chapter 5 --- General Discussion --- p.126 / References --- p.134

The current study examined the impact of plant sterols, stanols, sterol esters, and stanol esters on (i) cholesterol-lowering efficiency, (ii) gene expression of ABCG5 and ABCG8 sterol transporters in the liver and small intestine, and (iii) colon mucosal cell proliferation in hamsters. After 5 weeks on experimental diets, plasma total cholesterol levels were reduced ( P<0.05) by stanols, sterol esters and stanol esters compared to cholesterol-control diet. Different PS analogs did not alter ABCG5 and ABCG8 mRNA levels in small intestine and liver as compared to cholesterol control. In addition, colon mucosal cell proliferation was 21.4% lower (P<0.01) in group fed 0.7% stanol esters relative to cholesterol control. Results suggest that hypocholesterolemic effects of PS analogs are not associated with changes of liver and small intestine ABCG5 and ABCG8 sterol transporters. Data also indicated that plant stanol ester may possess anticarcinogenic properties.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) prevention, screening, and treatment strategies. With CRC incidence on the rise in younger populations, there is an increased need to engineer technologies that enhance patient access to diagnostic exams and disease management. This dissertation presents the development of an orally-delivered probiotic to screen for and treat early CRC lesions with a particular emphasis on translatability factors including: safety of probiotic use, exploration of oral delivery, and testing in clinically relevant models. At the interface of immunology, synthetic biology, and the microbiome fields is the overarching concept that microbes play a critical role in the tumor microenvironment (TME). The innate ability of bacteria to seek out tumor-specific signatures and proliferate within their necrotic cores due to reduced immune surveillance enables the precise immunoengineering of the local TME. Here, we will design, characterize, and test a probiotic encoded with a lysis mechanism to aid in biocontainment and maximize the release of recombinantly-produced diagnostic and immunotherapeutic cargo. In this lysis circuit, bacteria grow to a critical density within tumors and synchronously lyse, locally releasing their payload. A small fraction of bacteria remains to reseed the population and the cycle continues, resulting in repeated and sustained drug delivery. Drawing from advancements in immunology, we engineered bacteria to produce immune checkpoint inhibitors. Monoclonal antibodies targeting immune checkpoints have revolutionized cancer therapy, but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Due to their preferential colonization of tumors, bacteria are a natural chassis for the localized delivery of such therapeutics. Therefore, we engineered a commercially available probiotic, E.coli Nissle 1917 (EcN), for the controlled production and intratumoral release of nanobodies targeting programmed cell death protein – ligand 1 (PD-L1) and cytotoxic T- lymphocyte-associated protein-4 (CTLA-4) using the described lysing release mechanism. We demonstrate that a single injection of this engineered probiotic enhanced therapeutic response compared to analogous clinically-relevant antibodies, resulting in tumor regression in syngeneic mouse models. In an effort to create a more effective therapeutic for poorly immunogenic cancers, we utilized the modularity of our platform to slow tumor growth in mouse models of established CRC by combining it with a probiotically-produced cytokine, granulocyte-macrophage colony stimulating factor (GM-CSF). We sought to expand upon the relevance of this approach for early-stage CRC screening and treatment, by characterizing the platform in CRC precancerous lesions, or adenomas. When orally-delivered, EcN robustly colonized adenomas in genetically-engineered and orthotopic murine models of CRC, and human CRC patients. Leveraging adenoma-specific colonization, we probed for EcN presence in fecal matter, demonstrating its utility as a non-invasive screen for adenomas. For more accessible testing, we engineered EcN to produce salicylate and showed that it could be detected in the urine of tumor-bearing mice for days after oral delivery of the probiotic. Moreover, we demonstrated that the therapeutic effectiveness of our previously engineered therapeutic strain, producing PD-L1, CTLA-4 and GM-CSF, was maintained when delivered orally, ultimately resulting in significant adenoma reduction. Altogether, this dissertation aims to highlight the potential for engineered EcN to be used as a safe, orally-deliverable screening and therapeutic platform for early-stage CRC disease. While we have chosen to focus on CRC here, we will conclude by discussing efforts to adapt this platform to work in combination with other cellular therapies and therapeutic indications, ultimately engineering a platform to impact a broader patient population.

No description available.

強心苷是一類多年普遍用於心力衰竭治療的化合物,包括蟾蜍靈和地高辛。鈉泵（也可稱為鈉鉀ATP酶）是強心苷的受體。最近流行病學研究，體外實驗，動物實驗和臨床試驗表明，強心苷具有癌症治療的強大潛力。 / 大腸癌是全球第三大殺手，約有一半的大腸癌患者需要手術切除後的輔助治療。因此，通過化療殺死腫瘤細胞，是一個可行的辦法來治療大腸癌患者。在本課題的研究中，強心苷抗人結腸癌的作用在HT-29和Caco-2細胞上進行了評價與闡釋。在結腸癌細胞研究模型中，蟾蜍靈誘導caspase非依賴性的細胞死亡，伴隨沒有早期凋亡，沒有聚（ADP-核糖）聚合酶(PARP)與caspase-3裂解，這些發現與強心苷誘發其它類腫瘤細胞凋亡的機製完全不同。相反，蟾蜍靈激活自噬途徑，促進LC3-II積累和自噬流動。此外，其它強心苷如地高辛與烏本苷也促使LC3-II在HT-29細胞內聚集。沉默ATG5和Beclin-1顯著降低蟾蜍靈誘導的LC3- II積累和細胞死亡。蟾蜍靈誘導的自噬與活性氧（ROS）產生和JNK活化相關。我們的研究結果揭示了蟾蜍靈藥物對抗結腸癌細胞的一種新的機制，開闢了強心苷通過自噬途徑來治療大腸癌的可能性。 / 最近的研究表明，強心苷誘導多種癌細胞系的細胞包括促使凋亡與自噬的細胞週期阻滯在G2／M期。然而，沒有詳細的信息闡述強心苷如何阻滯細胞週期進展。在本課題研究中，我們研究了強心苷介導的細胞週期阻滯的分子機制。蟾蜍靈處理的HeLa H2B-YFP細胞被阻滯在前中期，伴隨姐妹染色單體凝聚，染色體未排列在赤道板，未退出有絲分裂期。這一結果被蟾蜍靈誘導的四倍DNA含量細胞既不在四倍體G1期也不在胞質分裂期進一步證明。此後，我們檢測了紡錘體組裝和染色體分離所需的Aurora激酶和Polo-like kinase 1 (Plk1)。結果發現，在HT-29和HeLa細胞上，蟾蜍靈和其它強心苷能顯著降低總蛋白質和磷酸化的Aurora激酶與Plk1。此外，我們還發現，蟾蜍靈通過PI3K下調有絲分裂酶的活性。這些結果已經通過沉默鈉泵α做了驗證。總之，我們的結果表明, 蟾蜍靈和其它強心苷鈉鉀泵抑製劑強有力的抑制細胞在前中期是通過PI3K/HIF-1α/NF-κB途徑下調Aurora激酶的蛋白質和磷酸化水平和Plk1的蛋白質水平。我們的研究發現在了解如何利用強心苷的潛能治療癌症以及認知鈉泵在細胞週期中的功能方面提供了有用的信息。 / The sodium pump (also known as Na+/K+-ATPase) is the receptor for cardiac glycosides, a group of compounds including bufalin and digoxin which have been commonly used for heart failure treatment for many years. Recent epidemiological studies, in vitro studies, animal studies and clinical trials have shown that cardiac glycosides have potential applications for cancer treatment. / Colorectal cancer is the third leading cause of cancer death worldwide and about half of the patients with colorectal cancer require adjuvant therapy after surgical resection. Therefore, the eradication of cancer cells via chemotherapy constitutes a viable approach to treat patients with colorectal cancer. In this study, the effects of cardiac glycosides were evaluated and characterized in HT-29 and Caco-2 human colon cancer cells. Contrary to their well documented apoptosis-promoting activity in other cancer cells, bufalin did not cause caspase-dependent cell death in colon cancer cells, as indicated by the absence of significant early apoptosis, as well as poly(ADP-ribose) polymerase (PARP) and caspase-3 cleavage. Instead, bufalin activated an autophagy pathway, as characterized by the accumulation of LC3-II and the stimulation of autophagic flux. Moreover, other cardiac glycosides digoxin and ouabain could also induce the accumulation of LC3-II in HT-29 cells. The silencing of ATG5 and Beclin-1 significantly reduced bufalin-induced LC3-II accumulation and cell death. The induction of autophagy by bufalin was linked to the generation of reactive oxygen species (ROS) and JNK activation. My findings unveil a novel mechanism of drug action by bufalin in colon cancer cells and open up the possibility of treating colorectal cancer by cardiac glycosides through an autophagy pathway. / Recent studies have revealed that cardiac glycosides induce G2/M phase arrest in many cancer cells, which include apoptosis- and autophagy-promoting cells. However, no detailed information is available on how cardiac glycosides arrest cell cycle progression. In this study, I studied the molecular mechanisms of cell cycle arrest mediated by cardiac glycosides. Bufalin-treated HeLa H2B-YFP cells were arrested at prometaphase, as characterized by the presence of sister chromatid cohesion, absence of chromosomes alignment on the metaphase plate, and failure to exit mitosis. This result was further confirmed by bufalin-induced cells with 4N DNA content in neither tetraploid G1 phase nor cytokinesis. Thereafter, I detected the Aurora kinases and Polo-like kinase 1 (Plk1), which are required for both spindle assembly and chromosome segregation. It was found that bufalin and other cardiac glycosides could significantly reduce the total protein and phosphorylation of Aurora kinases and Plk1 in HT-29 and HeLa cells. In addition, I found that PI3K was responsible for the bufalin-induced downregulation of the activities of mitotic kinases. This result was validated by silencing of sodium pump alpha. Taken together, my results demonstrate that bufalin and other cardiac glycoside inhibitors of the sodium pump potently arrest cancer cells at prometaphase by downregulating the total protein and phosphorylation of Aurora kinases and the total protein of Plk1 through the PI3K/HIF-1α/NF-κB pathway. My findings provide useful information in understanding how cardiac glycosides could be exploited for their potentials in treating cancer and in identifying the function of sodium pump in cell cycle progression. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xie, Chuanming. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 133-152). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Declaration of Originality --- p.i / Acknowledgements --- p.iii / Abstract --- p.vi / Abstract (in Chinese) --- p.viii / List of Abbreviations --- p.xiv / List of Figures --- p.xvi / List of Tables --- p.xix / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Cancer --- p.1 / Chapter 1.2 --- The chemical structure of cardiac glycosides --- p.2 / Chapter 1.3 --- The traditional use of cardiac glycosides in cardiology --- p.4 / Chapter 1.4 --- The role of cardiac glycosides in cancer treatment --- p.4 / Chapter 1.5 --- The mechanisms of action by cardiac glycosides in cancer --- p.5 / Chapter 1.5.1 --- The structure and functions of cardiac glycosides receptor sodium pump --- p.5 / Chapter 1.5.2 --- Sodium pump as anticancer target --- p.6 / Chapter 1.5.3 --- The signal pathways involved in anticancer effect of cardiac glycosides --- p.7 / Chapter 1.6 --- The role of cardiac glycosides in apoptosis and autophagy --- p.8 / Chapter 1.7 --- Objectives of this project --- p.12 / Chapter Chapter 2 --- Bufalin induces autophagy but not apoptosis in human colon cancer cells --- p.17 / Chapter 2.1 --- Introduction --- p.17 / Chapter 2.2 --- Materials and Methods --- p.19 / Chapter 2.2.1 --- Reagents and antibodies --- p.19 / Chapter 2.2.2 --- Cell culture --- p.19 / Chapter 2.2.3 --- Cell viability and cell death assay --- p.20 / Chapter 2.2.4 --- Annexin V and PI staining --- p.20 / Chapter 2.2.5 --- Cell cycle analysis --- p.21 / Chapter 2.2.6 --- Analysis of cleaved caspase-3-positive cells by flow cytometry --- p.21 / Chapter 2.2.7 --- Western blot analysis --- p.21 / Chapter 2.2.8 --- Immunofluorescence analysis of LC3 distribution --- p.22 / Chapter 2.2.9 --- RNA isolation and RT-PCR --- p.22 / Chapter 2.2.10 --- siRNAs transfection and treatments --- p.23 / Chapter 2.2.11 --- Transmission electron microscopy --- p.23 / Chapter 2.2.12 --- Statistical analysis --- p.24 / Chapter 2.3 --- Results --- p.24 / Chapter 2.3.1 --- Bufalin induces cell death and cell cycle arrest at G2/M phase in colon cancer cells --- p.24 / Chapter 2.3.2 --- Bufalin induces caspase-independent cell death in colon cancer cells --- p.28 / Chapter 2.3.3 --- Bufalin induces autophagy in colon cancer cells --- p.30 / Chapter 2.3.4 --- Bufalin-induced autophagy is dependent on ATG5 and Beclin-1 --- p.37 / Chapter 2.3.5 --- Increased autophagy is responsible for bufalin-induced cell death --- p.40 / Chapter 2.4 --- Discussion --- p.42 / Chapter Chapter 3 --- Bufalin mediates autophagic cell death through ROS generation and JNK activation --- p.44 / Chapter 3.1 --- Introduction --- p.44 / Chapter 3.2 --- Materials and Methods --- p.46 / Chapter 3.2.1 --- Reagents and antibodies --- p.46 / Chapter 3.2.2 --- Cell culture --- p.47 / Chapter 3.2.3 --- Cell viability and cell death assay --- p.47 / Chapter 3.2.4 --- Western blot analysis --- p.47 / Chapter 3.2.5 --- Quantification of cells with > 5 LC3 punctate staining --- p.47 / Chapter 3.2.6 --- siRNAs transfection and treatments --- p.48 / Chapter 3.2.7 --- RNA isolation and RT-PCR --- p.48 / Chapter 3.2.8 --- ROS analysis --- p.48 / Chapter 3.2.9 --- JC-1 staining --- p.49 / Chapter 3.2.10 --- Statistical analysis --- p.49 / Chapter 3.3 --- Results --- p.50 / Chapter 3.3.1 --- Bufalin induces autophagy-mediated cell death via ROS generation --- p.50 / Chapter 3.3.2 --- Activation of JNK is required for the upregulation of ATG5 and Beclin-1, and subsequent autophagy-mediated cell death in response to bufalin --- p.54 / Chapter 3.3.3 --- ROS generation is upstream of JNK activation in bufalin-induced cell death --- p.59 / Chapter 3.3.4 --- Bufalin-induced ROS generation is derived from mitochondria --- p.62 / Chapter 3.4 --- Discussion --- p.66 / Chapter Chapter 4 --- Bufalin arrests cells at prometaphase --- p.69 / Chapter 4.1 --- Introduction --- p.69 / Chapter 4.2 --- Materials and Methods --- p.70 / Chapter 4.2.1 --- Reagents and antibodies --- p.70 / Chapter 4.2.2 --- Cell synchronization --- p.70 / Chapter 4.2.3 --- Mitotic index analysis of phosphorylation of MPM2 --- p.71 / Chapter 4.2.4 --- Cell cycle analysis --- p.71 / Chapter 4.2.5 --- Time-lapse experiments --- p.71 / Chapter 4.2.6 --- Immunofluorescence analysis of phospho-histone H3 (Ser10) --- p.72 / Chapter 4.2.7 --- Western blot analysis --- p.73 / Chapter 4.3 --- Results --- p.73 / Chapter 4.3.1 --- Bufalin reduces mitotic marker phosphorylation of histone H3 and MPM2 and increases cells with 4N DNA content --- p.73 / Chapter 4.3.2 --- Increased cells with 4N DNA content after bufalin treatment are in neither a tetraploid G1 phase nor a cytokinesis arrest --- p.77 / Chapter 4.3.3 --- Bufalin-treated cells can enter prophase, but fail to pass through metaphase --- p.80 / Chapter 4.4 --- Discussion --- p.83 / Chapter Chapter 5 --- Bufalin induces prometaphase arrest through downregulating mitotic kinases --- p.87 / Chapter 5.1 --- Introduction --- p.87 / Chapter 5.2 --- Materials and Methods --- p.89 / Chapter 5.2.1 --- Reagents and antibodies --- p.89 / Chapter 5.2.2 --- Cell synchronization --- p.90 / Chapter 5.2.3 --- Immunofluorescence staining --- p.90 / Chapter 5.2.4 --- siRNAs transfection and treatments --- p.91 / Chapter 5.2.5 --- Western blot analysis --- p.91 / Chapter 5.2.6 --- Statistic analysis --- p.91 / Chapter 5.3 --- Results --- p.92 / Chapter 5.3.1 --- Bufalin downregulates Aurora A and B in protein and phosphorylation levels --- p.92 / Chapter 5.3.2 --- Bufalin prevents Aurora A recruitment to mitotic centrosomes and Aurora B recruitment to unattached kinetochores --- p.97 / Chapter 5.3.3 --- Bufalin prevents Plk1 recruitment to mitotic centrosomes and unattached kinetochores through downregulation of protein levels of Plk1 --- p.101 / Chapter 5.3.4 --- Bufalin decreases the activities of Aurora A, Aurora B and Plk1 through PI3K pathway --- p.105 / Chapter 5.3.5 --- HIF-1α and NF-κB pathways are involved in sodium pump-mediated the regulation of mitotic kinases --- p.109 / Chapter 5.4 --- Discussion --- p.112 / Chapter Chapter 6 --- General discussion --- p.115 / Chapter 6.1 --- Potential toxicity of bufalin --- p.115 / Chapter 6.2 --- Cardiac glycosides induced programmed cell death --- p.115 / Chapter 6.3 --- Signal pathways involved in cardiac glycosides-mediated autophagy --- p.117 / Chapter 6.4 --- The relationship between ROS and JNK in cardiac glycosides-induced autophagy --- p.120 / Chapter 6.5 --- The role of ROS in apoptosis and autophagy --- p.121 / Chapter 6.6 --- The role of cardiac glycosides in cell cycle arrest --- p.122 / Chapter 6.7 --- Application of cardiac glycosides in combination with chemotherapy and radiotherapy --- p.125 / Chapter Chapter 7 --- Conclusions and future perspectives --- p.127 / References --- p.133 / Appendices --- p.153 / Publication --- p.153

Findings from this pioneer study demonstrate that CF, which is unique to rice bran oil, is capable of triggering apoptosis in CRC cells at early stages of carcinogenesis. Furthermore, CF enhances TRAIL-induced apoptosis in metastatic CRC cells. This study provides clear evidence that the health-beneficial properties of whole grain consumption are not only limited by the presence of dietary fiber but also other molecules that can either act as a chemopreventive agent to directly induce tumor regression or a sensitizer to enhance TRAIL-induced apoptosis in metastatic cancer cells. / High intake of whole grain food has been suggested as an important factor for reducing the risk of colon cancer, owing to the abundance of indigestible fiber. Rice bran, which is a component of raw rice after removal of starchy endosperm in milling process, has been shown to be a rich source of some health-beneficial compounds for preventing cancer, hyperlipidaemia, fatty liver, hypercalciuria, kidney stones, and heart disease (Jariwalla, 2001). In the present study, proliferation-inhibitory effects of some rice bran polyphenolic compounds were investigated on a panel of human colorectal cancer (CRC) cell lines, including SW480 (stage B), SW620 (stage C) and Colo-201 (stage D) with increasing metastatic potential according to the Dukes' classification system. / Results from the MTT study revealed that, among the polyphenolic compounds tested, cycloartenyl ferulate (CF) showed the most prominent proliferation inhibition on the CRC cells. CF is one of the typical ferulic acid esters of triterpene alcohols present in rice bran oil. The cancer cell proliferation was reduced by 62, 31 and 21% of their control levels after 72 h of 200 muM CF treatment, respectively. CF seemed to possess higher ability to control proliferation of tumor cells at early stages of cancer development. In meanwhile, results from Toxilight study showed that CF had low toxicity on normal colon CCD-18-Co cells. The anticancer activity of CF was further illustrated by its ability to induce significant regression of SW480 xenograft in nude mice. CF was found to induce apoptosis in SW480 cells in vitro. DNA flow cytometric studies demonstrated that CF elevated dose- and time-dependently the sub G1 or apoptotic cells with fragmented DNA. The pro-apoptotic effect of CF was further confirmed using immunoblotting study showing cleavage of poly(ADP-ribose) polymerase (PARP), which is a hallmark feature of apoptosis. Besides, the executioner procaspase-3, -6 and -7 were found to be processed and activated. On the other hand, administration of pan-caspase inhibitor Z-VAD-FMK completely rescued the cells from PARP cleavage, indicating that CF elicited solely caspase-dependent apoptosis. Elevation of death receptors DR4 and DR5 with the CF treatment seems to originate the upstream activation of the initiator procaspase-8 and -10 of the extrinsic apoptosis pathway. Flow cytometric JC-1 studies further demonstrated that CF significantly altered the mitochondrial membrane potential in a dose-dependent manner together with cytochrome c and smac/DIABLO but not AIF release from mitochondria into the cytosol, as well as the activation of procaspase-9 of the intrinsic apoptosis pathway. Depletion of anti-apoptotic Bcl-2 and elevation of pro-apoptotic Bak were observed; meanwhile, Bid was found to be cleaved by caspase-8, so that the death receptor pathway might be exaggerated by the mitochondrial apoptosis pathway. / Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells (Gura, 1997). Result from MTT study illustrated that SW620 was more resistant than SW480 to TRAIL treatment. It is recognized that SW620 is the metastatic form of SW480 derived from the same patient at a later time, so it is important to develop agents that are able to sensitize the cancer cells to TRAIL, or to recover TRAIL sensitivity. We show for the first time that CF sensitizes SW620 cells to TRAIL-induced apoptosis and the mechanisms involved at least elevation of DR4, enhanced activation of caspase-8 and -3, as well as increase in DNA fragmentation. / Kong, Ka Lai. / Adviser: Wong Yum Shing. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 119-136). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Indiana University-Purdue University Indianapolis (IUPUI) / A study design has been developed that employs a dual modeling approach to identify factors associated with facility-level cancer screening improvement and how this is mediated by the use of clinical decision support. This dual modeling approach combines principles of (1) Health Informatics, (2) Cancer Prevention and Control, (3) Health Services Research, and (4) Organizational Change/Theory. The study design builds upon the constructs of a conceptual framework developed by Jane Zapka, namely, (1) organizational and/or practice settings, (2) provider characteristics, and (3) patient population characteristics. These constructs have been operationalized as measures in a 2005 HRSA/NCI Health Disparities Cancer Collaborative inventory of 44 community health centers. The first, statistical models will use: sequential, multivariable regression models to test for the organizational determinants that may account for the presence and intensity-of-use of clinical decision support (CDS) and information systems (IS) within community health centers for use in colorectal, breast, and cervical cancer screening. A subsequent test will assess the impact of CDS/IS on provider reported cancer screening improvement rates. The second, computational models will use a multi-agent model of network evolution called CONSTRUCT® to identify the agents, tasks, knowledge, groups, and beliefs associated with cancer screening practices and CDS/IS use to inform both CDS/IS implementation and cancer screening intervention strategies. This virtual experiment will facilitate hypothesis-generation through computer simulation exercises. The outcome of this research will be to identify barriers and facilitators to improving community health center facility-level cancer screening performance using CDS/IS as an agent of change. Stakeholders for this work include both national and local community health center IT leadership, as well as clinical managers deploying IT strategies to improve cancer screening among vulnerable patient populations.