Preclinical modeling of multi-drug cancer therapies

Anticancer drugs typically are administered in the clinic in the form of mixtures, sometimes called combinations. Only in rare cases, however, are mixtures approved as drugs. Rather, research on mixtures tends to occur after single drugs have been approved. The goal of this research project was to develop modeling approaches that would encourage rational preclinical mixture design. To this end, a series of models were developed. First, several QSAR classification models were constructed to predict the cytotoxicity, oral clearance, and acute systemic toxicity of drugs. The QSAR models were applied to a set of over 115,000 natural compounds in order to identify promising ones for testing in mixtures. Second, an improved method was developed to assess synergistic, antagonistic, and additive effects between drugs in a mixture. This method, dubbed the MixLow method, is similar to the Median-Effect method, the de facto standard for assessing drug interactions. The primary difference between the two is that the MixLow method uses a nonlinear mixed-effects model to estimate parameters of concentration-effect curves, rather than an ordinary least squares procedure. Parameter estimators produced by the MixLow method were more precise than those produced by the Median-Effect Method, and coverage of Loewe index confidence intervals was superior. Third, a model was developed to predict drug interactions based on scores obtained from virtual docking experiments. This represents a novel approach for modeling drug mixtures and was more useful for the data modeled here than competing approaches. The model was applied to cytotoxicity data for 45 mixtures, each composed of up to 10 selected drugs. One drug, doxorubicin, was a standard chemotherapy agent and the others were well-known natural compounds including curcumin, EGCG, quercetin, and rhein. Predictions of synergism/antagonism were made for all possible fixed-ratio mixtures, cytotoxicities of the 10 best-scoring mixtures were tested, and drug interactions were assessed. Predicted and observed responses were highly correlated (r2 = 0.83). Results suggested that some mixtures allowed up to an 11-fold reduction of doxorubicin concentrations without sacrificing efficacy. Taken together, the models developed in this project present a general approach to rational design of mixtures during preclinical drug development. ^

Electron intensity modulation for mixed-beam radiation therapy with an x-ray multi-leaf collimator

The current standard treatment for head and neck cancer at our institution uses intensity-modulated x-ray therapy (IMRT), which improves target coverage and sparing of critical structures by delivering complex fluence patterns from a variety of beam directions to conform dose distributions to the shape of the target volume. The standard treatment for breast patients is field-in-field forward-planned IMRT, with initial tangential fields and additional reduced-weight tangents with blocking to minimize hot spots. For these treatment sites, the addition of electrons has the potential of improving target coverage and sparing of critical structures due to rapid dose falloff with depth and reduced exit dose. In this work, the use of mixed-beam therapy (MBT), i.e., combined intensity-modulated electron and x-ray beams using the x-ray multi-leaf collimator (MLC), was explored. The hypothesis of this study was that addition of intensity-modulated electron beams to existing clinical IMRT plans would produce MBT plans that were superior to the original IMRT plans for at least 50% of selected head and neck and 50% of breast cases. Dose calculations for electron beams collimated by the MLC were performed with Monte Carlo methods. An automation system was created to facilitate communication between the dose calculation engine and the treatment planning system. Energy and intensity modulation of the electron beams was accomplished by dividing the electron beams into 2x2-cm2 beamlets, which were then beam-weight optimized along with intensity-modulated x-ray beams. Treatment plans were optimized to obtain equivalent target dose coverage, and then compared with the original treatment plans. MBT treatment plans were evaluated by participating physicians with respect to target coverage, normal structure dose, and overall plan quality in comparison with original clinical plans. The physician evaluations did not support the hypothesis for either site, with MBT selected as superior in 1 out of the 15 head and neck cases (p=1) and 6 out of 18 breast cases (p=0.95). While MBT was not shown to be superior to IMRT, reductions were observed in doses to critical structures distal to the target along the electron beam direction and to non-target tissues, at the expense of target coverage and dose homogeneity. ^

Youth empowerment evaluation to improve afterschool programming

Community-based participatory research necessitates that community members act as partners in decision making and mutual learning and discovery. In the same light, for programs/issues involving youth, youth should be partners in knowledge sharing and evaluation (Checkoway & Richards-Schuster, 2004). This study is a youth-focused empowerment evaluation for the Successful Youth program. Successful Youth is a multi-component youth development after-school program for Latino middle school youth, created with the goal of reducing teen pregnancy. An empowerment evaluation is collaborative and participatory (Balcazar and Harper 2003). The three steps of an empowerment evaluation are: (1) defining mission, (2) taking stock, and (3) planning for the future (Fetterman 2001).^ In a program where youth are developing leadership skills, making choices, and learning how to self reflect and evaluate, the empowerment evaluation could not be more aligned with promoting and enhancing these skills. In addition, an empowerment evaluation is designed to "foster improvement and self-determination" and "build capacity" (Fetterman 2001). Four empowerment groups were conducted with approximately 6-9 Latino 7th grade students per group. All participants were enrolled in the Successful Youth program. Results indicate points where students' perceptions of the program were aligned with the program's mission and where gaps were identified. Students offered recommendations for program improvements. Additionally, students enjoyed expressing their feelings about the program and appreciated that their opinions were valued. Youth recommendations will be brought to program staff; and, where possible, gaps will be addressed. Empowerment evaluations with youth will continue during the duration of the program so that youth involvement and input remains integral in the evaluation and to ascertain whether the program's goals are being met. ^

A systematic review of community-based colorectal cancer screening randomized controlled trials with multi-ethnic groups

Background. The CDC estimates that 40% of adults 50 years of age or older do not receive time-appropriate colorectal cancer screening. Sixty percent of colorectal cancer deaths could be prevented by regular screening of adults 50 years of age and older. Yet, in 2000 only 42.5% of adults age 50 or older in the U.S. had received recommended screening. Disparities by health care, nativity status, socioeconomic status, and race/ethnicity are evident. Disparities in minority, underserved populations prevent us from attaining Goal 2 of Healthy People 2010 to “eliminate health disparities.” This review focuses on community-based screening research among underserved populations that includes multiple ethnic groups for appropriate disparities analysis. There is a gap in the colorectal cancer screening literature describing the effectiveness of community-based randomized controlled trials. ^ Objective. To critically review the literature describing community-based colorectal cancer screening strategies that are randomized controlled trials, and that include multiple racial/ethnic groups. ^ Methods. The review includes a preliminary disparities analysis to assess whether interventions were appropriately targeted in communities to those groups experiencing the greatest health disparities. Review articles are from an original search using Ovid Medline and a cross-matching search in Pubmed, both from January 2001 to June 2009. The Ovid Medline literature review is divided into eight exclusionary stages, seven electronic, and the last stage consisting of final manual review. ^ Results. The final studies (n=15) are categorized into four categories: Patient mailings (n=3), Telephone outreach (n=3), Electronic/multimedia (n=4), and Counseling/community education (n=5). Of 15 studies, 11 (73%) demonstrated that screening rates increased for the intervention group compared to controls, including all studies (100%) from the Patient mailings and Telephone outreach groups, 4 of 5 (80%) Counseling/community education studies, and 1 of 4 (25%) Electronic/multimedia interventions. ^ Conclusions. Patient choice and tailoring education and/or messages to individuals have proven to be two important factors in improving colorectal cancer screening adherence rates. Technological strategies have not been overly successful with underserved populations in community-based trials. Based on limited findings to date, future community-based colorectal cancer screening trials should include diverse populations who are experiencing incidence, survival, mortality and screening disparities. ^

A multi-site pilot test study to measure safety climate in the university work setting

Next to leisure, sport, and household activities, the most common activity resulting in medically consulted injuries and poisonings in the United States is work, with an estimated 4 million workplace related episodes reported in 2008 (U.S. Department of Health and Human Services, 2009). To address the risks inherent to various occupations, risk management programs are typically put in place that include worker training, engineering controls, and personal protective equipment. Recent studies have shown that such interventions alone are insufficient to adequately manage workplace risks, and that the climate in which the workers and safety program exist (known as the "safety climate") is an equally important consideration. The organizational safety climate is so important that many studies have focused on developing means of measuring it in various work settings. While safety climate studies have been reported for several industrial settings, published studies on assessing safety climate in the university work setting are largely absent. Universities are particularly unique workplaces because of the potential exposure to a diversity of agents representing both acute and chronic risks. Universities are also unique because readily detectable health and safety outcomes are relatively rare. The ability to measure safety climate in a work setting with rarely observed systemic outcome measures could serve as a powerful means of measure for the evaluation of safety risk management programs. ^ The goal of this research study was the development of a survey tool to measure safety climate specifically in the university work setting. The use of a standardized tool also allows for comparisons among universities throughout the United States. A specific study objective was accomplished to quantitatively assess safety climate at five universities across the United States. At five universities, 971 participants completed an online questionnaire to measure the safety climate. The average safety climate score across the five universities was 3.92 on a scale of 1 to 5, with 5 indicating very high perceptions of safety at these universities. The two lowest overall dimensions of university safety climate were "acknowledgement of safety performance" and "department and supervisor's safety commitment". The results underscore how the perception of safety climate is significantly influenced at the local level. A second study objective regarding evaluating the reliability and validity of the safety climate questionnaire was accomplished. A third objective fulfilled was to provide executive summaries resulting from the questionnaire to the participating universities' health & safety professionals and collect feedback on usefulness, relevance and perceived accuracy. Overall, the professionals found the survey and results to be very useful, relevant and accurate. Finally, the safety climate questionnaire will be offered to other universities for benchmarking purposes at the annual meeting of a nationally recognized university health and safety organization. The ultimate goal of the project was accomplished and was the creation of a standardized tool that can be used for measuring safety climate in the university work setting and can facilitate meaningful comparisons amongst institutions.^

Statistical issues on studies of mixed longitudinal design

Mixed longitudinal designs are important study designs for many areas of medical research. Mixed longitudinal studies have several advantages over cross-sectional or pure longitudinal studies, including shorter study completion time and ability to separate time and age effects, thus are an attractive choice. Statistical methodology used in general longitudinal studies has been rapidly developing within the last few decades. Common approaches for statistical modeling in studies with mixed longitudinal designs have been the linear mixed-effects model incorporating an age or time effect. The general linear mixed-effects model is considered an appropriate choice to analyze repeated measurements data in longitudinal studies. However, common use of linear mixed-effects model on mixed longitudinal studies often incorporates age as the only random-effect but fails to take into consideration the cohort effect in conducting statistical inferences on age-related trajectories of outcome measurements. We believe special attention should be paid to cohort effects when analyzing data in mixed longitudinal designs with multiple overlapping cohorts. Thus, this has become an important statistical issue to address. ^ This research aims to address statistical issues related to mixed longitudinal studies. The proposed study examined the existing statistical analysis methods for the mixed longitudinal designs and developed an alternative analytic method to incorporate effects from multiple overlapping cohorts as well as from different aged subjects. The proposed study used simulation to evaluate the performance of the proposed analytic method by comparing it with the commonly-used model. Finally, the study applied the proposed analytic method to the data collected by an existing study Project HeartBeat!, which had been evaluated using traditional analytic techniques. Project HeartBeat! is a longitudinal study of cardiovascular disease (CVD) risk factors in childhood and adolescence using a mixed longitudinal design. The proposed model was used to evaluate four blood lipids adjusting for age, gender, race/ethnicity, and endocrine hormones. The result of this dissertation suggest the proposed analytic model could be a more flexible and reliable choice than the traditional model in terms of fitting data to provide more accurate estimates in mixed longitudinal studies. Conceptually, the proposed model described in this study has useful features, including consideration of effects from multiple overlapping cohorts, and is an attractive approach for analyzing data in mixed longitudinal design studies.^

Engaging stakeholders in community-level obesity prevention programming: Evaluation of the Fit Family Challenge

Introduction: Both a systems approach to change and a focus on multi-sector interventions ensures obesity prevention programming within the community is equitable, sustainable, and cost-effective. An authentic community engagement approach is required to implement interventions guided by best-evidence research and practice. Although there are examples illustrating the benefits of community engagement, there is no standardized method to implement it. The San Antonio Sports Foundation (SA Sports), a non-profit community-based organization, implements a variety of free events and programs promoting active life styles. One such program is the Fit Family Challenge which is a summer-long program implemented at the school level targeted at families. ^ Aims: This thesis was a culmination of the experience from the student collaborating with SA Sports as part of a practicum opportunity. Using secondary data collected by the Fit Family Challenge during the 2011 year, the goals of this thesis were: to assess individual changes; evaluate short-term impact; and describe the community engagement process. ^ Methods: SA Sports collected quantitative and qualitative data during the implementation and evaluation of the FFC program. SA Sports allowed the used of de-identified data to be analyzed to study the aims of this thesis. ^ Results: The program was able to provide families with the knowledge, information, and opportunity to exercise as a family and cook healthier meals. School district coordinators were generally satisfied and illustrated the benefits of a community partnership. An authentic community engagement was present highlighting the importance of communication, collaboration and the sustainability of such partnerships in the community. ^ Conclusion: The success of an obesity program should focus on triggers that initiate behavioral change rather than physiological changes. The evaluation was guided by a community engagement approach, which illustrated the development of new partnerships and the strengthening of other collaborations. Ultimately, the engagement approach empowered the community to identify their own problems and build collaboration, rather than tackling obesity prevention alone. ^