Colorectal cancer (CRC) is a primary cause of cancer-related mortality in the United States. Asian Americans have the highest CRC mortality rates. CRC screening tests can reduce CRC incidence, yet Asian Americans, specifically the subgroup of Vietnamese Americans, underuse CRC screening. The purpose of this phenomenological study was to understand why Vietnamese Americans, ages 50 to 75, underuse CRC screening. The health belief model constructs of susceptibility, severity, benefits, barriers, and self-efficacy were the framework for understanding this population's health-related behaviors. Three research questions focused on how knowledge, language, and cultural beliefs and perceptions affect Vietnamese Americans' CRC screening decisions. Interviews were conducted with 11 participants, and transcribed interview responses were input into NVivo 11 software to maintain a reliable database and to identify emerging themes. Key study findings revealed knowledge and English language gaps as well as adverse cultural perceptions of fear and doubt that influenced CRC screening choices among these 11 Vietnamese Americans. Future researchers might focus on cultural-tailored strategies to minimize these barriers for Vietnamese Americans. An understanding of this study population's perspectives offers the promise of positive social change for health services and public health administrations to develop cultural-tailored interventions that promote healthy lifestyles, prevention, early CRC detection and, consequently, reduce mortality rates and associated health care costs.

African American (AA) men in the state of Alabama are affected by colorectal cancer (CRC) more than all other races. The purpose of this phenomenological study was to gain understanding of colorectal cancer screening health benefits in AA men in Mobile, Alabama. The health beliefs model (HBM) developed by Hochum, Rosemstock, and Kegels was used to to explore the barriers and facilitators to CRC screening in AA men with health insurance in Mobile, Alabama. The research questions explored knowledge, perceptions, and facilitators to CRC screening among AA men age 40 to 75. Participants were selected using purposive sampling and data were collected through face-to-face individual interviews with 13 participants living in Mobile, Al. Data were inductively coded and subjected to a thematic analysis procedure. The study findings revealed that participants had a general knowledge of cancer but a low awareness of CRC screening. Findings also revealed a perceived gap in CRC screening education from participants' doctors. Few reported understanding or remembering a conversation about the need for CRC screening during their last doctor's visit. There was no indication that age or level of education played a meaningful role in participants' knowledge or perception of CRC screening requirements. Positive social change implications stemming from this study include recommendations to Alabama public health officials and policy makers to invest in the development of intervention and education efforts to increase CRC screening among AA men, which in turn, may reduce CRC related morbidity and mortality.

Als einer der ersten gegen HIV gerichteten Restriktionsfaktoren konnte die Cytidindeaminase APOBEC3G isoliert werden. Dieses zelluläre Enzym hemmt äußerst effizient die Replikation von HIV. Weiterführende Untersuchungen konnten demonstrieren, dass die Hemmung der Virusreplikation hauptsächlich auf einer Deaminase-katalysierten G zu A-Hypermutation des viralen Genoms während der Reversen Transkription beruht. Als Gegenstrategie zur antiretroviralen Wirkung von A3G kodiert HIV-1 das Protein Vif (virion infectivity factor), welches durch eine direkte Wechselwirkung den Ubiquitin-abhängigen proteasomalen Abbau von A3G bewirkt. Vor diesem Hintergrund wird der Inhibition des Vif induzierten A3G- Abbaus großes Potential als neuartiges Wirkstoffziel bei der Behandlung von HIV Infektionen vorhergesagt. Das Ziel der vorliegenden Arbeit bestand deshalb in der Etablierung von zellulären Screening-Assays für die Identifizierung von Inhibitoren des Vif induzierten A3G-Abbaus. Im Rahmen dieser Arbeit konnten insgesamt vier fluoreszenzbasierte zelluläre Assays erfolgreich entwickelt und als Screeningsysteme für die Wirkstoffsuche etabliert werden. Drei dieser Assays basieren auf stabilen Zelllinien, von denen eine Vif und ein mit EYFP markiertes A3G ko-exprimiert. Dieser sogenannte A3G-Abbauassay stellt den primären Assay für die Identifizierung von Inhibitoren des Vif induzierten A3G-Abbaus dar und wird durch zwei weitere Zelllinien-basierte Assays ergänzt. Diese sekundäre Assays erlauben die Detektion von Substanzen, die falsch-positive oder falsch-negative Signale im A3G-Abbauassays generieren. Zusammengenommen ermöglichen die drei Assays die präzise Identifizierung von Inhibitoren, die spezifisch auf den A3G-Abbau wirken und stellen damit eine wesentliche Verbesserung bereits existierender Screeningsysteme dar. Weiterhin wurde ein auf dem Prinzip der bimolekularen Fluoreszenzkomplementation (BiFC) basierendes Testsystem entwickelt. Besagtes System misst die direkte Interaktion zwischen Vif und ElonginC in lebenden Zellen und repräsentiert damit ein weiteres Testsystem für die Identifizierung von Inhibitoren der Vif induzierten A3G-Degradation. Den zweiten Teil dieser Arbeit umfasste die Analyse von Derivaten des Vif Antagonisten RN-18 und neu entwickelten niedermolekularen Inhibitoren der Vif-ElonginC- Interaktion. Als ein wichtiges Ergebnis der Derivat-Analyse ergab sich, dass RN-18 zytotoxisch wirkt und im hier etablierten A3G-Abbauassay ein falsch-positives Signal generiert. Unter den analysierten Vif-ElonginC-Interaktionsinhibitoren fand sich eine Verbindung, die in einem initialen Screening, unter Verwendung des A3G-Abbauassays, eine deutliche Inhibition der Vif induzierten A3G-Degradation bewirkte. Zusammenfassend konnten im Rahmen dieses Promotionsprojektes erfolgreich mehrere Screeningsysteme für die Identifizierung von spezifischen Inhibitoren des A3G-Abbaus etabliert werden. Diese Systeme werden zukünftig dazu beitragen, dass Auffinden von neuartigen Therapeutika für die Behandlung von HIV-Infektionen zu beschleunigen. / One of the first cellular HIV restriction factors isolated was the cytosine deaminase APOBEC3G. This cellular enzyme was shown to efficiently inhibit the replication of HIV and other viruses. Further research revealed that restriction of the viral replication is primarily based on a deaminase-catalyzed G to A hypermutation of the viral genome during reverse transcription. As a mode of counteraction, the HIV-1 encoded accessory protein Vif (virion infectivity factor) binds to A3G leading to its ubiquitin-dependent proteasomal degradation. It has been hypothesized that inhibition of the A3G degradation rescues the antiviral properties of the APOBEC3 protein and thus represents an attractive target for novel antiretroviral drugs. Therefore, the goal of this study was to establish cellular screening assays for the identification of inhibitors of the Vif mediated A3G degradation. Four fluorescent based cellular assays have been established for the screening of small organic compounds. Three of these assays are based on stable cell lines, one of which co-expresses Vif and an EYFP tagged A3G protein. This so-called A3G degradation assay represents the primary assay for identification of degradation inhibitors and is complemented by two additional cell line based assays. These secondary assays enable the detection of compounds generating false-positive or false-negative signals in the A3G degradation assay. These systems allow the precise identification of true-positive A3G degradation inhibitors and thus representing a significant improvement of existing screening platforms. Furthermore, a cellular assay based on the bimolecular fluorescence complementation (BiFC) was developed. The BiFC-assay measures the direct interaction between Vif and ElonginC in living cells and can be used as a new screening platform for identification of inhibitors targeting the Vif- ElonginC interaction, which is an essential step in the A3G degradation sequence. The aim of the second part of the project was the application of the established screening assays for testing of derivatives of the Vif antagonist RN-18 and rational designed inhibitors targeting the direct interaction between Vif and ElonginC. As a result of the compound testing it was shown, that RN-18 is cytotoxic and generates a false-positive signal in the A3G degradation assay. In case of the Vif-ElonginC interaction inhibitors one compound exhibited a strong inhibitory effect on A3G degradation in an initial screen. Taken together, screening assays for the precise identification of specific inhibitors of the A3G degradation were successfully established. These screening assays will accelerate the identification of novel anti-HIV agents.

Computational modeling approaches have lately been earning their place as viable tools in drug discovery. Research efforts more often include computational component and the usage of the scientific software is commonplace at more stages of the drug discovery pipeline. However, as software takes on more responsibility and the computational methods grow more involved, the gap grows between research entities that have the means to maintain the necessary computational infrastructure and those that lack the technical expertise or financial means to obtain and include computational component in their scientific efforts. To fill this gap and to meet the need of many, mainly academic, labs numerous community contributions collectively known as open source projects play an increasingly important role. This work describes design, implementation and application of a set of drug discovery workflows based on the CHARMMing (CHARMM interface and graphics) web-server. The protocols described herein include docking, virtual target screening, de novo drug design, SAR/QSAR modeling as well as chemical education. The performance of the newly developed workflows is evaluated by applying them to a number of scientific problems that include reproducibility of crystal poses of small molecules in protein-ligand systems, identification of potential targets of a library of natural compounds as well as elucidating molecular targets of a vitamin. The results of these inquiries show that protocols developed as part of this effort perform comparably to commercial products, are able to produce results consistent with the experimental data and can substantially enrich the research efforts of labs with otherwise little or no computational component.

acase@tulane.edu / 1 / Kathryn M. Jones

The malaria pre-erythrocytic stages have been identified as an ideal therapeutic target, but complex in vitro models for Plasmodium vivax and Plasmodium falciparum lack the efficiency needed for rapid screening and evaluation of new vaccines and drugs, especially targeting the P. vivax hypnozoite. To address this challenge, we employed a multi-parameter approach using “omics’” to identify pre-erythrocytic targets and biomarkers, guide phenotypic therapeutic screening, and study parasite functionality with innovative bioassays using highcontent screening. Herein, we discuss three novel bioassays formatted in 384-well plate systems with utilization of commercially-available materials and application of high-content imaging for rapid bio-image analysis. To refine functional assessment of pre-erythrocytic targets in early infection phases, we developed a real-time, ‘live’ sporozoite motility assay and a live sporozoite hepatocyte cell traversal assay to examine chemotherapeutic and immunoprophylactic interventions in biologically relevant environments. Furthermore, our 384-well primary hepatocyte culture system and methodology maintains stable hepatocyte physiology of cryopreserved primary human hepatocytes in addition to primary non-human primate hepatocytes for greater than 30 days, thus ideal for robust liver parasite development following infection with P. vivax, P. falciparum or P. cynomolgi sporozoites. We report antimalarial drug and vaccine studies performed in all bioassays with identification of novel anti-LS inhibition mechanisms. Additionally, this research discusses the discovery of potential sporozoite and liver stage targets identified through transcriptomic profiling of freshly isolated P. vivax and P. cynomolgi sporozoites using a candid approach of recapitulating the pivotal transition period from mosquito to human through microenvironment reconstruction and exposure to biological stimuli. We further characterize sporozoite invasive phenotypes through the application of the bioassays. Together, these novel functional assays enable us to rapidly evaluate potential preerythrocytic therapeutic candidates and analyze complex Plasmodium sporozoite phenotypes.

Human capital and screening theories of the role of education in the labour market have similar predictions about individual behaviour and labour market outcomes. This makes it difficult to test between the theories. Nevertheless, the task of doing so is important since the social return to education is likely to be small unless education adds to productivity as human capital theory, but not screening theory, assumes. Education may only convey information about likely individual productivity under screening. It serves this function because individual productivity is difficult for employers to observe. In fact, there is very little evidence from existing tests of the theories that education does not add to productivity. However, few of the tests that have been undertaken between the theories are convincing. The three empirical chapters of this thesis contain tests of some aspects of the theories.

Although there has been an increasing incidence of breast cancer among Non-English speaking background (NESB) women in many developed countries, existing screening services are being underused by these women. Studies show that the barriers to the accessibility of breast cancer screening by NESB women include their lack of awareness, low level of education, low self-efficacy and lack of social interaction with other women. This study aimed to investigate the knowledge relating to breast cancer and mammography, self-efficacy and barriers to mammography use among NESB women in an Australian regional city before and after their attendance at a health education session. This health education session aimed to increase the awareness and use of mammography among these NESB women. Two widely used behaviour theories, ‘Health belief model’ and ‘Social Cognitive Theory,’ were applied as the theoretical framework for this study. A quasi-experimental study was conducted in which the health education session was used as an intervention. Pre-test and post-test questionnaires were completed by study participants before and after the health education session. Their knowledge of breast cancer and mammography was assessed. In addition, their self-efficacy and barriers to the use of mammography were also analysed. Results indicated that informal recruitment strategies were more effective with these NESB women. Initially 49 women were recruited. Of these, 23 women (47%) attended the health education session. As data showed tertiary educated and employed women who already had mammogram/s were more likely to attend the session. After attending the health education session, the women’s knowledge relating to breast cancer and mammography was improved and the perceived barriers to the use of mammography were reduced. During a three month follow-up period, there was no change of mammogram use by the women. However, the results showed a trend of increased intention to use the mammogram over a period of two years (41.7%) compared to six months (25.0%). Based on these results, further studies are recommended to explore the beneficial outcomes of health promotion programs targeting NESB women who are not in the workforce or have a low level of education.

Human capital and screening theories of the role of education in the labour market have similar predictions about individual behaviour and labour market outcomes. This makes it difficult to test between the theories. Nevertheless, the task of doing so is important since the social return to education is likely to be small unless education adds to productivity as human capital theory, but not screening theory, assumes. Education may only convey information about likely individual productivity under screening. It serves this function because individual productivity is difficult for employers to observe. In fact, there is very little evidence from existing tests of the theories that education does not add to productivity. However, few of the tests that have been undertaken between the theories are convincing. The three empirical chapters of this thesis contain tests of some aspects of the theories.

Degree awarded (2003): EdDHRD, Counseling, Human and Organizational Studies, George Washington University / ABSTRACT OF DISSERTATION<p>The Effect of Patient Race upon Physicians Colorectal Cancer Screening: A Retrospective Medical Record Review and Physician Pattern Variable Analysis<p>There is a significant disparity in the health status of African-Americans and whites in the United States. Studies have revealed that African-Americans have higher mortality rates from colorectal cancer than whites. Differences in colorectal cancer screening of African-Americans compared to whites may account for a proportion of the excess mortality. This study evaluated internal medicine resident physicians colorectal cancer screening practices in African-American and white patients. Additionally, an analysis of physicians pattern variable orientation was performed to determine if there was a relationship between physicians orientation and adherence to colorectal cancer screening guidelines.<p>A retrospective review of medical records from January 2002 through March 2002 was conducted to assess internal medicine resident physicians performance of colorectal cancer screening. Univariate analysis revealed that there were statistically significant differences in the rate at which physicians performed rectal examinations (p=0.0039), fecal occult blood testing (p=0.0006) and colonic examinations (p<0.0001) in African-American compared to white patients. Multivariate analysis, evaluating patient race, patient gender, patient age and physician gender, demonstrated that patient race was the only factor significant for not performing colorectal cancer screening tests.<p>Physicians perspectives about the medical profession and the delivery of medical services were assessed by evaluating pattern variable orientations. Integrative, value and motivational orientations of the physicians were determined by using semi-structured interviews. All of the physicians had a self-orientation (integrative pattern variable), a universalistic-achievement orientation (value pattern variables) and a specificity orientation (motivational pattern variable). However, the physicians differed in their affectivity-affective neutrality orientation (motivational pattern variable). All of the physicians who had an affective orientation toward their patients adhered to colorectal cancer screening recommendations. The physicians who expressed affective neutrality toward their patients did not adhere to colorectal cancer screening recommendations.<p>This study revealed significant differences in the performance of colorectal cancer screening in African-American compared to white patients. Additionally, physicians pattern variable orientations correlated with adherence to practice guidelines. This study is important because it provides information about physician practice patterns. The results of this study can serve as the basis for the development of educational interventions for physicians that can improve health care delivery. / Advisory Committee: Dr. John Williams, Dr. David Schwandt (Chair), Dr. Andrea Casey, Dr. Jeffrey Lenn, Dr. Victor Scott