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.

Ongoing research in the fields of genetics and biotechnology hold the promise of improved diagnosis and treatment of genetic diseases, and potentially the development of individually tailored pharmaceuticals and gene therapies. Difficulty, however, arises in determining how these services are to be evaluated and integrated equitably into public health care systems such as Canada's. The current context is one of increasing fiscal restraint on the part of governments, limited financial resources being dedicated to health care, and rising costs for new health care services and technologies. This has led to increasing public debate in the last few years about how to reform public health care, and whether we should prohibit, permit or perhaps even encourage private purchase of health care services. In Canada, some of these concerns have crystallized around the issue of gene patents and commercial genetic testing, in particular as illustrated by the case of Myriad Genetics' patented BRACAnalysis test for hereditary breast and ovarian cancer. While most Canadians who currently access genetic services do so through the public health care system, for those with the means, private purchase is becoming an option. This situation raises serious concerns - about justice in access to health care; about continued access to safe and reliable genetic testing supported by unbiased patient information; and about the broader effects of commercialization for ongoing research and the Canadian public health care system. Commercial genetic testing presents a challenge to health care professionals, policy analysts, and academics concerned with the social, ethical and policy implications of new genetic technologies. Using the Myriad case as an exemplar, tools from moral philosophy, the social sciences, and health policy and law will be brought to bear on the larger issues of how as a society we should regulate commercial research and product development, and more coherently decide which services to cover under public health insurance and which to leave to private purchase. Generally, the thesis is concerned with the question of "how best to bring capital, morality, and knowledge into a productive and ethical relationship" (Rabinow 1999, 20).

Ongoing research in the fields of genetics and biotechnology hold the promise of improved diagnosis and treatment of genetic diseases, and potentially the development of individually tailored pharmaceuticals and gene therapies. Difficulty, however, arises in determining how these services are to be evaluated and integrated equitably into public health care systems such as Canada's. The current context is one of increasing fiscal restraint on the part of governments, limited financial resources being dedicated to health care, and rising costs for new health care services and technologies. This has led to increasing public debate in the last few years about how to reform public health care, and whether we should prohibit, permit or perhaps even encourage private purchase of health care services. In Canada, some of these concerns have crystallized around the issue of gene patents and commercial genetic testing, in particular as illustrated by the case of Myriad Genetics' patented BRACAnalysis test for hereditary breast and ovarian cancer. While most Canadians who currently access genetic services do so through the public health care system, for those with the means, private purchase is becoming an option. This situation raises serious concerns - about justice in access to health care; about continued access to safe and reliable genetic testing supported by unbiased patient information; and about the broader effects of commercialization for ongoing research and the Canadian public health care system. Commercial genetic testing presents a challenge to health care professionals, policy analysts, and academics concerned with the social, ethical and policy implications of new genetic technologies. Using the Myriad case as an exemplar, tools from moral philosophy, the social sciences, and health policy and law will be brought to bear on the larger issues of how as a society we should regulate commercial research and product development, and more coherently decide which services to cover under public health insurance and which to leave to private purchase. Generally, the thesis is concerned with the question of "how best to bring capital, morality, and knowledge into a productive and ethical relationship" (Rabinow 1999, 20). / Graduate and Postdoctoral Studies / Graduate

This study utilized a self-reported survey design to obtain information from 47 Latinas to determine their breast cancer knowledge levels and compliance with early detection methods.

Barriers to Colorectal Cancer Screening in People Obtaining Care From Community Mental Health Agencies by Kelly Gardiner MSN, Wayne State University, 1997 BSN, Wayne State University, 1988 Dissertation Submitted in Fulfillment of the Requirements for the Degree of Doctor of Philosophy Public Health Walden University August 2016 Despite being highly treatable with early intervention and preventative screenings, the overall mortality rate of colorectal cancer is substantially higher in participants with a preexisting mental disorder. Variables affecting the likelihood of completing screening for those with mental illnesses were unknown in people who obtain services from a Community Mental Health agency. Using the Health Belief Model, the proposed study investigated the effects of access to transportation, referral to screening, physical ability to complete the colonoscopy prep, type of procedure, awareness of the purpose of screening, anxiety, embarrassment, gender, race, and age to determine which affect completion of colorectal cancer screening. Significant relationships existed between embarrassment, fear of pain, fear of cancer, anxiety, physical ability to do testing, awareness of screening at age 50, FOBT vs Scope procedures, age of first screening, being told to get screening, knowing someone who had screening, and completion of colorectal cancer screening. In the binary logistic model Anxiety was negatively correlated and being told to get screening was positively correlated to completion of colorectal cancer screening and those choosing Scope were more likely to complete than those choosing FOBT. The results of this study may effect positive social change by providing healthcare providers with an increased understanding of variables that influence colorectal cancer screening completion among persons with a diagnosed mental illness, resulting in a changing agenda for effective mental and physical health care in this population.

Purpose Lower serum vitamin D levels have been associated with an increased risk of aggressive prostate cancer. Among men with localized prostate cancer, especially with low-or intermediate-risk disease, vitamin D may serve as an important biomarker of disease aggression. The aim of this study was to assess the relationship between adverse pathology at the time of radical prostatectomy and serum 25-hydroxyvitamin D (25-OH D) levels. Methods This cross-sectional study was carried out from 2009 to 2014, nested within a large epidemiologic study of 1,760 healthy controls and men undergoing prostate cancer screening. In total, 190 men underwent radical prostatectomy in the cohort. Adverse pathology was defined as the presence of primary Gleason 4 or any Gleason 5 disease, or extraprostatic extension. Descriptive and multivariate analyses were performed to assess the relationship between 25-OH D and adverse pathology at the time of prostatectomy. Results Eighty-seven men (45.8%) in this cohort demonstrated adverse pathology at radical prostatectomy. The median age in the cohort was 64.0 years (interquartile range, 59.0 to 67.0). On univariate analysis, men with adverse pathology at radical prostatectomy demonstrated lower median serum 25-OH D (22.7 v 27.0 ng/mL, P = .007) compared with their counterparts. On multivariate analysis, controlling for age, serum prostate specific antigen, and abnormal digital rectal examination, serum 25-OH D less than 30 ng/mL was associated with increased odds of adverse pathology (odds ratio, 2.64; 95% CI, 1.25 to 5.59; P = .01). Conclusion Insufficiency/deficiency of serum 25-OH D is associated with increased odds of adverse pathology in men with localized disease undergoing radical prostatectomy. Serum 25-OH D may serve as a useful biomarker in prostate cancer aggressiveness, which deserves continued study. (C) 2016 by American Society of Clinical Oncology

BACKGROUND: Colorectal cancer (CRC) is the fourth most common and second most deadly cancer in the United States. However, it is highly preventable and treatable if detected at the precancerous or local stage of development. There exists multiple screening methods each with varying sensitivity, required effort, and recommended frequency of use. Complete adherence to screening guidelines by the recommended, at-risk population would halve the current mortality rate. Unfortunately, screening adherence remains the lowest of all screened cancers with a median state screening adherence rate of about 65%. To understand what individual-level factors influence an individual’s decision to be screened, health behavior theory is used. However, few studies have evaluated the performance of entire behavioral theories in their ability to explain CRC screening intentions and behaviors. METHOD: Health Belief Model, Theory of Reasoned Action, Theory of Planned Behavior, and Attribution Theory were evaluated within the context of colorectal cancer screening using an online national sample (N=403) of at-risk individuals age 50 and older. Confirmatory factor analyses were performed for each evaluated construct of the theory. Structural equation models were created using the estimated constructs for each theory. Each theory was evaluated for the following screening use: colonoscopy, sigmoidoscopy, fecal occult blood test (FOBT), and general screening use. Fit statistics were estimated for each model. Models with acceptable fit were examined for significant pathways within the model as well as consistency of the model with the behavioral theory. RESULTS: All models displayed adequate fit statistics. While not all pathways were significant in each model, no estimate was the inverse in directionality to that hypothesized. This provides support that each theory lends some explanatory power and none of the theories evaluated detract from understanding CRC screening intentions and behaviors. Comparison of the models illustrates advantages to each theory and suggests potential integration of theories. CONCLUSION: The constructs of the Health Belief Model, Theory of Planned Behavior, and Attribution Theory all provide adequate explanations of individual-level CRC screening behavior influences. Although, further review and refinement of the theories is warranted and recommended.

Background: A global cervical cancer health disparity persists despite the demonstrated success of primary and secondary preventive strategies, such as cervical visual inspection (VI). Cervical cancer is the leading cause of cancer incidence and death for women in many low resource areas. The greatest risk is for those who are unable or unwilling to access screening. Barriers include healthcare personnel shortages, cost, transportation, and mistrust of healthcare providers and systems. Using community health workers (CHWs) may overcome these barriers, increase facilitators, and improve participation in screening for women in remote areas with limited access to clinical resources. Aim: To determine whether the accuracy of VI performed by CHWs was comparable to VI by physicians or nurses and to consider the affect components of provider training had on VI accuracy. Methods: A systematic review and quantitative meta-analysis of published literature reporting on VI accuracy, provider type, and training was conducted. Strict inclusion/exclusion criteria, study quality, and publication bias assessments improved rigor and bivariate linear mixed modeling (BLMM) was used to determine the affect of predictors on accuracy. Unconditional and conditional BLMMs, controlling for VI technique, provider type, community, clinical setting, HIV status, and gynecological symptoms were considered. Results: Provider type was a significant predictor of sensitivity (p=.048) in the unconditional VI model. VI performed by CHWs was 15% more sensitive than physicians (p=.014). Provider type was not a significant predictor of accuracy in any other models. Didactic and mentored hours predicted sensitivity in both BLMMs. Quality assurance and use of a training manual predicted specificity in unconditional BLMMs, but was not significant in conditional models. Number of training days, with ≤5 being optimal, predicted sensitivity in both BLMMs and specificity in the unconditional model. Conclusion: Study results suggest that community based cervical cancer screening with VI conducted by CHWs can be as, if not more, accurate than VI performed by licensed providers. Locally based screening programs could increase access to screening for women in remote areas. Collaborative partnerships in “pragmatic solidarity” between healthcare systems, CHWs, and the community could promote participation in screening resulting in decreased cervical cancer incidence and mortality. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

There is a need to increase awareness among African American men regarding their potential risk of prostate cancer and inform them of screening and treatment options, given the health disparities that affect their group. To do so, an innovative e health video was developed, using an animated avatar video to educate African American males about prostate cancer and potential screening methods in a way that is culturally appropriate. Effectiveness of this e-health intervention was tested on a sample of 41 African American males. Efficacy was measured using a repeated measures design that used pre- and post-measures of four target behaviors regarding prostate cancer screening. These four target behaviors include: (1) getting an annual physical exam, (2) discussing the possibility of getting a digital rectal exam to screen for prostate cancer with a doctor, (3) discussing the possibility of getting a PSA exam to screen for prostate cancer with a doctor, and (4) spreading awareness about prostate cancer among other African American men. The stage of change, which is a theoretical framework adapted from Prochaska and DiClemente (1983), measures changes in human behavior from precontemplation and contemplation on the low end to action and maintenance on the high end. Self-efficacy was also measured before and after the intervention for each of the four target behaviors. Paired t-tests show that the stage of change for the third and fourth target behaviors and self-efficacy for the second, third, and fourth target behaviors were significantly increased by the e-health intervention, indicating that the intervention was successful. Additionally, participant ratings about the intervention were largely positive. In effect, this study finds that the e-health intervention developed in this study not only works, but is an affordable, scalable, and practical tool that can educate African American males about prostate cancer screening practices.

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