Metastasis is the spread of cancer cells from the primary tumor to distant sites. It is the most dangerous attribute of cancer, and also the principle cause of cancerrelated morbidity and mortality. Metastasis suppressor genes are a group of genes that suppress tumor metastasis without significant effect on tumorigenicity. NM23 was the first identified metastasis suppressor gene, and loss of its expression is a frequent hallmark of metastatic growth in multiple cancers (e.g. melanoma, carcinomas of breast, stomach and liver). NM23-H1 possesses at least three enzymatic activities, including nucleoside diphosphate kinase (NDPK), histidine kinase (hisK), and a more recently described 3f-5f exonuclease (EXO). While the hisK has been shown to be linked to the suppression of cell motility, the NDPK has been reported to be unrelated to the suppression of metastatic potential indirectly. Relevance of EXO has not been addressed. Other known 3f-5f exonuclease are closely associated with DNA repair functions, suggesting NM23-H1 may suppress mutations required for metastasis. As a transcription factor, NM23 has been shown to modestly downregulate the transcription on PDGF-A chain, a growth factor oncogene, either alone or in association with another transcriptional factor, Pur@. At the same time, identification of NM23-H1 as a 3f-5fexonuclease suggests the role of NM23-H1 in DNA repair. Etoposide and cisplatin elicited nuclear translocation of H1 within 4 h in HeLa and HepG2 cells, seen as accumulation of H1 in small intranuclear foci, strongly suggesting the DNA repair function of H1. To investigate the enzymatic function contributing to metastasis suppressor activity of H1, complementation system was used by transfecting NM23-H1 with individually disrupted enzymatic function into 2 melanoma cell lines, 1205LU and WM793. Overexpression of H1 in 1205LU suppressed lung metastasis in vivo without effect on indices of transformation (e.g. proliferation, soft agar colonization). EXO- deficient H1 and NDPK-deficient H1 lost suppression of lung metastasis, while hisK-deficient H1 maintained suppressor activity. Consistent with the results in 1205LU cells, EXO-deficient H1 and NDPKdeficient H1 lost suppression of the progression of WM793 cells in protein-free medium, while WT and hisK-deficient H1 prevented the progression. Taken together, these data suggest that the NDPK and/or 3f-5fEXO activity of H1 inhibits the progression of premetastatic cells to the metastatic phenotype, possibly via a DNA repair function or other structural transactions with DNA.

Tedlar™ bags are a promising medium for remote breath collection and later analysis using SIFT-MS for disease diagnosis. It is important to understand the changes in integrity of samples stored in Tedlar™ bags. However, there is little work into this problem completed to date, and thus little known about these issues. Therefore, a study into the integrity of samples stored in Tedlar™ bags and analysed using SIFT-MS was undertaken. The sample integrity of ammonia, acetone, ethanol, isoprene and pentane, all initially at 3ppm in breath and nitrogen substrates, and stored in Tedlar™ bags was investigated. Experiments tested the effect of storage size (0.5, 1, 3L), storage time (6-48 hours), storage temperature (23℃ - 25℃, 37℃), humidity (0.4 - 4.5% absolute) and inter-bag variation using triplicate bags. The SIFT-MS instrument used was LDI2 located at Christchurch Hospital. The repeatability and precision of LDI2 was established using prepared cylinder samples (0.05% absolute humidity) of acetone, pentane and ethanol tested at seven times over a 250 min time period. A generalised Cauchy distribution was used to give a combined distribution from multiple bags for the sample humidity and compound concentration. A combined measure of the repeatability and precision, T s , ranged between 217 - 349 ppb for ethanol, acetone and pentane. The factors affecting the repeatability and precision were both machine and compound dependant. The effect of the factors differed over time, with different precursors and compounds. No obvious effects of bag storage size on the sample integrity of pentane, isoprene, ethanol and acetone were observed. The absolute humidity change within bag samples was linked to the volume to surface area ratio because it was more affected by permeation and condensation. All compounds in the nitrogen substrate (except for 37℃ stored acetone (NO+)) displayed decreases in sample integrity with time. All compounds in the breath substrate displayed regular losses of sample integrity, except for the 37℃ and 23℃ - 25℃ stored ethanol (NO+) and 37℃ stored ethanol (H3O+), pentane (O2+) and ammonia (H3O+, O2+). The average change of sample integrity for pentane, isoprene, ethanol and acetone ranged from 0.2 to 3.6 times the maximum T s , while ammonia ranged from 0.9 - 10 times. All observed behaviour was reproducible. Absolute humidity and storage temperature affected the sample integrity of acetone, ethanol and ammonia. Generally, the intra-bag variance was comparable between all storage temperatures and substrates while the inter-bag variation was affected by the absolute humidity. Only the initial and final concentrations between precursors for the 23℃ - 25℃ stored breath and nitrogen substrates agreed. The breath substrate samples gave erroneous values for ammonia. Permeation of compounds into the bags from the atmosphere was not significant. The overall issues surrounding storing breath in Tedlar™ bags for analysis using SIFTMS is not the loss of sample integrity, but the kinetics, precision and repeatability of the SIFT-MS instrument. The current kinetics are not adequate to accurately monitor acetone, isoprene, pentane, ammonia and ethanol in breath and stored in Tedlar™ bags at breath absolute humidity levels greater than 3%. Generally, the loss of sample integrity was only marginally outside the repeatability and precision of the machine.

Integrity tests are used as a pre-employment screening technique by companies and organizations, and the fakability of such tests remain a concern. The present study used two separate designs to analyze the fakability of the Personnel Reaction Blank (PRB), a covert integrity test, and the personality constructs predictive of honest and fake scores. This study shows that the PRB can be successfully faked. The personality constructs conscientiousness, agreeableness, and neuroticism are significantly correlated with honest integrity test scores while conscientiousness and neuroticism are predictors of faking behavior. Finally, the type of design used to examine the fakability of the PRB affects the magnitude of faking found. I conclude by discussing the theoretical and practical uses of the results and directions for future research. / Department of Psychological Science

In this paper, I defend Rawlsian Political Liberalism from the integrity objection. Integrity objectors claim that political liberals unjustifiably exclude certain religious citizens from making use of their religious values when voting upon basic principles of justice and constitutional essentials. I argue, first, that the integrity objection does not apply to political liberalism. Second, I claim that there is a place in the public, political culture for citizens to make use of their comprehensive values. Third, I argue that attempts to reformulate political liberalism to avoid the integrity objection are ultimately unsuccessful.

Bloom syndrome is a rare autosomal recessive disorder that is caused by mutations in the BLM gene. BLM associates with TopoIIIα and RMI1 to form a complex that is essential to maintain genome integrity. This complex catalyzes a dissolution reaction that resolves recombination intermediates containing two Holliday junctions without crossing over of genetic material. Dissolution activity is remarkable because it accounts for the in vivo role of BLM-TopoIIIα-RMI1 in suppressing sister chromatid exchanges. To further understand the biochemical roles that each member of the BLM complex plays in dissolution, I generated single-stranded catenanes that resemble the proposed intermediates at the latest steps of dissolution. Using this substrate, I demonstrated that TopoIIIα is a single-stranded DNA decatenase that is specifically stimulated by BLM and RMI1. Interaction between TopoIIIα and RMI1 is essential for the optimal decatenase activity. Furthermore, binding of RPA to single-stranded DNA substrate inhibits TopoIIIα decatenase activity. However, complex formation between BLM, TopoIIIα and RMI enables TopoIIIα to displace RPA and catalyze decatenation. Since the decatenase activity is presumed to be involved in many aspects of DNA metabolism, I investigated the roles of RMI1 and TopoIIIα in DNA replication in vivo. Using the molecular combing technique, I showed that RMI1 functions downstream of BLM to promote normal replication fork progression. In addition, BLM, TopoIIIα and RMI1 colocalize with one another in response to replication stress. Finally, interaction between TopoIIIα and RMI1 is essential for nuclear localization of the complex and for the complex to promote recovery from replication stress. This work defines molecular functions for RMI1 and TopoIIIα in DNA replication and repair, providing insight into their roles as suppressors of genome instability.

This thesis examines the determinants of ethical leadership and the manner in which they are associated with the directive, transactional, and transformational leadership styles, as well as their effects on organizational followers. A review is first conducted of the major theories of leadership and ethics, and current perspectives on ethical leadership are discussed. The determinants of ethical leadership are postulated to be altruism, manifested through some combination of teleological and deontological values, intellectual integrity, and moral integrity. A framework is then presented which integrates ethics and leadership by illustrating the proposed linkages among the ethics variables, leadership styles and effects on followers. This is followed by a series of hypotheses concerning the suggested relationships among the variables. The empirical investigation to test the hypotheses was conducted in a series of Canadian hospitals. Leaders were heads of various departments and services while followers were individuals who reported directly to the leader. Leader altruism was measured by a self-report questionnaire completed by the leaders themselves. Since leadership style and integrity are conceptualized as attributions by followers, all other variables were assessed via a self-report questionnaire having subordinates as respondents. The main findings of the thesis are the significant relationships between intellectual integrity and the three leadership styles compared with insignificant associations observed for moral integrity, as well as the stronger, although indirect, effects of leader intellectual integrity on subordinates compared with those for moral integrity. The thesis concludes with suggestions for future research and practical implications for management.

Doctor of Philosophy (PhD) / Allegations of market manipulation abound in the popular press, particularly during the recent financial turmoil. However, many aspects of manipulation are poorly understood. The purpose of this thesis is to enhance our understanding of market manipulation by providing empirical evidence on the prevalence, effects and determinants of closing price manipulation. The first issue examined in this thesis is the prevalence of closing price manipulation. This thesis uses a hand collected sample of prosecuted closing price manipulation cases from US and Canadian stock exchanges, and methods that explicitly model the incomplete and non-random detection of manipulation. The results suggest that approximately 1.1% of closing prices are manipulated. For every prosecuted closing price manipulation there are approximately 300 instances of manipulation that remain undetected or not prosecuted. Closing price manipulation is more prevalent on larger exchanges than smaller ones, but is detected at a higher rate on small exchanges. Second, this thesis examines the effects of closing price manipulation. Using a sample of prosecution cases, this thesis finds that closing price manipulation is associated with large day-end returns, subsequent return reversals, increases in day-end spreads and increases in day-end trading activity. At the broader level of market quality, this thesis provides evidence from a laboratory experiment that closing price manipulation decreases both price accuracy and liquidity. Even the mere possibility of manipulation decreases liquidity and increases trading costs. The third issue analysed in this thesis is the determinants of closing price manipulation and its detection. Estimating an empirical model of manipulation and detection, this thesis finds that the likelihood of closing price manipulation is increased by smaller regulatory budgets, greater information asymmetry, mid to low levels of liquidity, month-end days and lower volatility. Manipulation is more likely to be detected when regulatory budgets are larger and when the manipulation causes abnormal trading characteristics. Further evidence from laboratory experiments suggests that regulation helps restore price accuracy by deterring some manipulation and making remaining manipulation less aggressive. These experiments also show that regulation has an insignificant effect on liquidity because participants in regulated markets still face relatively high uncertainty about the presence of manipulators. This thesis also examines how closing price manipulation is conducted and how other market participants respond. It develops an index of closing price manipulation that can be used to study manipulation in markets or time periods in which prosecution data are not available. It also provides a tool for the detection of manipulation, which can be used by regulators in automated surveillance systems. Finally, this thesis has implications for economic efficiency and policy. Closing price manipulation is significantly more prevalent than the number of prosecution cases suggests. Further, it harms both pricing accuracy and liquidity and therefore undermines economic efficiency. The prevalence of closing price manipulation can be reduced by increasing regulatory budgets, improving the accuracy of market surveillance systems by using the detection tools developed in this thesis, structuring markets such that participants are better able to identify manipulation, and implementing closing mechanisms that are difficult to manipulate. These actions would enhance market integrity and economic efficiency.

This dissertation is motivated by two major factors. First, there have been no direct studies conducted for the relationship between market integrity and market efficiency and the driving forces behind the cross-sectional variations in market quality. Second, a better understanding the relationships among market integrity, market efficiency and other mechanism design factors for securities exchanges will facilitate securities exchanges achieve a satisfactory level of market quality. This dissertation consists of three chapters. In Chapter 1, a review of literature on market manipulation will be given. A series of common securities market manipulation strategies and corresponding market surveillance alerts will be explained and defined. In Chapter 2, we develop a testable hypothesis that market manipulation as proxied by the incidence of ramping alerts would raise transaction cost for completing larger trades. We find ramping alert incidence positively related to effective spreads in 8 of 10 turnover deciles from most liquid to thinnest-trading securities. The magnitude of the increase in effective spreads when ramping manipulation incidence doubles is economically significant, 30 to 40 basis points in many moderate liquidity deciles. This compares with an average effective spread of 72 basis points for index-listed securities in the most efficient electronic markets worldwide. In Chapter 3, In Chapter 3 of this thesis, we test the correlation between the levels of market integrity as proxied by the incidence of ramping alerts and a combination of proxies for factors from the following four potential drivers deciding the market quality across securities exchanges: ??? Securities Markets Trading Regulations ??? Securities Markets Technologies ??? Securities Market Infrastructure ??? Securities Market Participants The model we developed to test the correlation between the proxies for level of market integrity and seven proxies for the four potential drivers were estimated with Ordinary Least Square (OLS) and Two-stage Least Square (2SLS) error structures assumed, respectively to learn the most about the possible endogeneity of spreads and volatility. By performing Hausman-Wu specification tests, we concluded that simultaneity bias in the thickly-traded deciles is not material for the AI-Volatility and AI-Spread equation pairs. Subsequently, we used the PROBIT model to analyse the probability of adopting RTS across the 240 securities exchange deciles and the likelihood proves to be systematically related to four determinants in our sample. Finally we estimate the structural equations to investigate possible cross-equation correlation of the disturbances with either seemingly unrelated regression (SURL) estimation. Our findings are three-fold. Firstly, in the moderately-traded deciles, we find that the presence of a closing auction (CloseAucDum) reduces the incidence of ramping alerts. Trade-based manipulation proves more difficult when a manipulator???s counterparties can use closing auctions to unwind their intraday exposures. The RTS dummy variable is significantly positively related to alert incidence. In the absence of any panel data on the dynamic effects of adopting RTS, what we are observing in cross section is the perceived vulnerability of certain exchanges to manipulation and their consequent adoption of RTS plus the regulatory regimes required to have a salutary effect on market integrity. Second, in the moderately-traded deciles, we find that the closing auctions and more regulations in pursuit of market integrity lower quoted spreads. RTS and a regulation specifically prohibiting ramping indicate in cross-section the perceived likelihood of more ramping. Thirdly, in terms of the probability of the deployment of a real-time surveillance system, the estimations again differ by liquidity decile grouping. In the moderately-traded deciles, higher alert incidence, the presence of DMA, and higher FDI again increase the likelihood of adopting a real-time surveillance system. Our findings have a couple of policy implications for many securities exchanges in terms of market design and market surveillance. First, the exhibited relationship between alert incidence and effective spreads indicates trade-based manipulation has a significant impact on execution costs. Therefore, the prevention of securities market manipulation not only serves the indirect purpose of improving an exchange???s reputation for market integrity but also contributes directly to achieving a more efficient marketplace. Second, our results indicate that some market design changes can enhance the regulatory efforts to prevent securities market manipulations. For example, to prevent manipulators from marking the closing price, some exchanges could choose to adopt a closing auction or a random closing time, which would make manipulation more costly. Nevertheless, no securities exchange can be designed perfectly. Consequently, exchange and broker-level surveillance backed by effective regulatory enforcement is a necessary and pivotal complement to good design choices.

Doctor of Philosophy (PhD) / Allegations of market manipulation abound in the popular press, particularly during the recent financial turmoil. However, many aspects of manipulation are poorly understood. The purpose of this thesis is to enhance our understanding of market manipulation by providing empirical evidence on the prevalence, effects and determinants of closing price manipulation. The first issue examined in this thesis is the prevalence of closing price manipulation. This thesis uses a hand collected sample of prosecuted closing price manipulation cases from US and Canadian stock exchanges, and methods that explicitly model the incomplete and non-random detection of manipulation. The results suggest that approximately 1.1% of closing prices are manipulated. For every prosecuted closing price manipulation there are approximately 300 instances of manipulation that remain undetected or not prosecuted. Closing price manipulation is more prevalent on larger exchanges than smaller ones, but is detected at a higher rate on small exchanges. Second, this thesis examines the effects of closing price manipulation. Using a sample of prosecution cases, this thesis finds that closing price manipulation is associated with large day-end returns, subsequent return reversals, increases in day-end spreads and increases in day-end trading activity. At the broader level of market quality, this thesis provides evidence from a laboratory experiment that closing price manipulation decreases both price accuracy and liquidity. Even the mere possibility of manipulation decreases liquidity and increases trading costs. The third issue analysed in this thesis is the determinants of closing price manipulation and its detection. Estimating an empirical model of manipulation and detection, this thesis finds that the likelihood of closing price manipulation is increased by smaller regulatory budgets, greater information asymmetry, mid to low levels of liquidity, month-end days and lower volatility. Manipulation is more likely to be detected when regulatory budgets are larger and when the manipulation causes abnormal trading characteristics. Further evidence from laboratory experiments suggests that regulation helps restore price accuracy by deterring some manipulation and making remaining manipulation less aggressive. These experiments also show that regulation has an insignificant effect on liquidity because participants in regulated markets still face relatively high uncertainty about the presence of manipulators. This thesis also examines how closing price manipulation is conducted and how other market participants respond. It develops an index of closing price manipulation that can be used to study manipulation in markets or time periods in which prosecution data are not available. It also provides a tool for the detection of manipulation, which can be used by regulators in automated surveillance systems. Finally, this thesis has implications for economic efficiency and policy. Closing price manipulation is significantly more prevalent than the number of prosecution cases suggests. Further, it harms both pricing accuracy and liquidity and therefore undermines economic efficiency. The prevalence of closing price manipulation can be reduced by increasing regulatory budgets, improving the accuracy of market surveillance systems by using the detection tools developed in this thesis, structuring markets such that participants are better able to identify manipulation, and implementing closing mechanisms that are difficult to manipulate. These actions would enhance market integrity and economic efficiency.

Thesis (D. Min.)--Westminster Theological Seminary, Philadelphia, 1989. / Includes indexes. Includes bibliographical references (leaves 242-249).