Differential Activity of the KRAS Oncogene by Method of Activation: Implications for Signaling and Therapeutic Intervention

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure shows that different amino acids substituted at the codon 12 position influences how KRas interacts with its effecters. In the absence of a direct inhibitor of mutant KRas several agents have recently entered clinical trials alone and in combination directly targeting two of the common downstream effecter pathways of KRas, namely the Mapk pathway and the Akt pathway. These inhibitors were evaluated for efficacy against different KRAS activating mutations. An isogenic panel of colorectal cells with wild type KRas replaced with KRas G12C, G12D, or G12V at the endogenous loci differed in sensitivity to Mek and Akt inhibition. In contrast, screening was performed in a broad panel of lung cell lines alone and no correlation was seen between types of activating KRAS mutation due to concurrent oncogenic lesions. To find a new method to inhibit KRAS driven tumors, siRNA screens were performed in isogenic lines with and without active KRas. The knockdown of CNKSR1 (CNK1) showed selective growth inhibition in cells with an oncogenic KRAS. The deletion of CNK1 reduces expression of mitotic cell cycle proteins and arrests cells with active KRas in the G1 phase of the cell cycle similar to the deletion of an activated KRas regardless of activating substitution. CNK1 has a PH domain responsible for localizing it to membrane lipids making KRas potentially amenable to inhibition with small molecules. The work has identified a series of small molecules capable of binding to this PH domain and inhibiting CNK1 facilitated KRas signaling.

Development and evaluation of a video-based modeling strategy for the dissemination phase of a school health tobacco -use prevention program

Even the best school health education programs will be unsuccessful if they are not disseminated effectively in a manner that encourages classroom adoption and implementation. This study involved two components: (1) the development of a videotape intervention to be used in the dissemination phase of a 4-year, NCI-funded diffusion study and (2) the evaluation of that videotape intervention strategy in comparison with a print (information transfer) strategy. Conceptualization has been guided by Social Learning Theory, Diffusion Theory, and communication theory. Additionally, the PRECEDE Framework has been used. Seventh and 8th grade classroom teachers from Spring Branch Independent School District in west Houston participated in the evaluation of the videotape and print interventions using a 57-item preadoption survey instrument developed by the UT Center for Health Promotion Research and Development. Two-way ANOVA was used to study individual score differences for five outcome variables: Total Scale Score (comprised of 57 predisposing, enabling, and reinforcing items), Adoption Characteristics Subscale, Attitude Toward Innovation Subscale, Receptivity Toward Innovation, and Reinforcement Subscale. The aim of the study is to compare the effect upon score differences of video and print interventions alone and in combination. Seventy-three 7th and 8th grade classroom teachers completed the study providing baseline and post-intervention measures on factors related to the adoption and implementation of tobacco-use prevention programs. Two-way ANOVA, in relation to the study questions, found significant scoring differences for those exposed to the videotape intervention alone for both the Attitude Toward Innovation Subscale and the Receptivity to Adopt Subscale. No significant results were found to suggest that print alone influences favorable scoring differences between baseline and post-intervention testing. One interaction effect was found suggesting video and print combined are more effective for influencing favorable scoring differences for the Reinforcement for the Adoption Subscale.^ This research is unique in that it represents a newly emerging field in health promotion communications research with implications for Social Learning Theory, Diffusion Theory, and communication science that are applicable to the development of improved school health interventions. ^

Knowledge representation tool for cognitiveprocesses modeling

In the last decades, neuropsychological theories tend to consider cognitive functions as a result of the whole brainwork and not as individual local areas of its cortex. Studies based on neuroimaging techniques have increased in the last years, promoting an exponential growth of the body of knowledge about relations between cognitive functions and brain structures [1]. However, so fast evolution make complicated to integrate them in verifiable theories and, even more, translated in to cognitive rehabilitation. The aim of this research work is to develop a cognitive process-modeling tool. The purpose of this system is, in the first term, to represent multidimensional data, from structural and functional connectivity, neuroimaging, data from lesion studies and derived data from clinical intervention [2][3]. This will allow to identify consolidated knowledge, hypothesis, experimental designs, new data from ongoing studies and emerging results from clinical interventions. In the second term, we pursuit to use Artificial Intelligence to assist in decision making allowing to advance towards evidence based and personalized treatments in cognitive rehabilitation. This work presents the knowledge base design of the knowledge representation tool. It is compound of two different taxonomies (structure and function) and a set of tags linking both taxonomies at different levels of structural and functional organization. The remainder of the abstract is organized as follows: Section 2 presents the web application used for gathering necessary information for generating the knowledge base, Section 3 describes knowledge base structure and finally Section 4 expounds reached conclusions.

Modeling the development of acquired clinical immunity to Plasmodium falciparum malaria

Individuals living in regions where malaria is endemic develop an acquired immunity to malaria which enables them to remain asymptomatic while still carrying parasites. Field studies indicate that cumulative exposure to a variety of diverse Plasmodium parasites is required for the transition from symptomatic to asymptomatic malaria. This study used a simulation model of the within-host dynamics of P. falciparum to investigate the development of acquired clinical immunity under different transmission conditions and levels of parasite diversity. Antibodies developed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), a clonally variant molecule, were assumed to be a key human immunological response to P. falciparum infection, along with responses to clonally conserved but polymorphic antigens. The time to the development of clinical immunity was found to be proportional to parasite diversity and inversely proportional to transmission intensity. The effect of early termination of symptomatic infections by chemotherapy was investigated and found not to inhibit the host's ability to develop acquired immunity. However, the time required to achieve this state was approximately double that compared to when no treatment was administered. This study demonstrates that an immune response primarily targeted against PfEMP1 has the ability to reduce clinical symptoms of infections irrespective of whether treatment is administered, supporting its role in the development of acquired clinical immunity. The results also illustrate a novel use for simulation models of P. falciparum infections, investigation of the influence of intervention strategies on the development of naturally acquired clinical immunity.

A Drug-Based Intervention Study on the Importance of Buffaloes for Human Schistosoma Japonicum Infection around Poyang Lake, People’s Republic of China

Schistosomiasis japonica is a zoonosis of major public health importance in southern China. We undertook a drug intervention to test the hypothesis that buffalo are major reservoirs for human infection in the marshlands/lake areas, where one million people are infected. We compared human and buffalo infection rates and intensity in an intervention village (Jishan), where humans and buffalo were treated with praziquantel, and a control village (Hexi), where only humans were treated, in the Poyang Lake region. Over the four-year study, human incidence in Jishan decreased but increased in Hexi. Adjustment of incidence by age, sex, water exposure, year, and village further confirmed the decreased human infection in Jishan. Chemotherapy for buffaloes resulted in a decrease in buffalo infection rates in Jishan, which coincided with the reduction in human infection rates there in the last two years of the study. Mathematical modeling predicted that buffalo are responsible for 75% of human transmission in Jishan. Copyright © 2006 by The American Society of Tropical Medicine and Hygiene.

Using Rasch modeling to re-evaluate three scales related to physical activity: Enjoyment, perceived benefits and perceived barriers

Studies suggest that enjoyment, perceived benefits and perceived barriers may be important mediators of physical activity. However, the psychometric properties of these scales have not been assessed using Rasch modeling. The purpose of this study was to use Rasch modeling to evaluate the properties of three scales commonly used in physical activity studies: the Physical Activity Enjoyment Scale, the Benefits of Physical Activity Scale and the Barriers to Physical Activity Scale. The scales were administered to 378 healthy adults, aged 25–75 years (50% women, 62% Whites), at the baseline assessment for a lifestyle physical activity intervention trial. The ConQuest software was used to assess model fit, item difficulty, item functioning and standard error of measurement. For all scales, the partial credit model fit the data. Item content of one scale did not adequately cover all respondents. Response options of each scale were not targeting respondents appropriately, and standard error of measurement varied across the total score continuum of each scale. These findings indicate that each scale's effectiveness at detecting differences among individuals may be limited unless changes in scale content and response format are made.

An investigation of multiple pathways of developmental intervention change

Convergence among treatment, prevention, and developmental intervention approaches has led to the recognition of the need for evaluation models and research designs that employ a full range of evaluation information to provide an empirical basis for enhancing the efficiency, efficacy, and effectiveness of prevention and positive development interventions. This study reports an investigation of a positive youth development program using an Outcome Mediation Cascade (OMC) evaluation model, an integrated model for evaluating the empirical intersection between intervention and developmental processes. The Changing Lives Program (CLP) is a community supported positive youth development intervention implemented in a practice setting as a selective/indicated program for multi-ethnic, multi-problem at risk youth in urban alternative high schools. This study used a Relational Data Analysis integration of quantitative and qualitative data analysis strategies, including the use of both fixed and free response measures and a structural equation modeling approach, to construct and evaluate the hypothesized OMC model. Findings indicated that the hypothesized model fit the data (χ2 (7) = 6.991, p = .43; RMSEA = .00; CFI = 1.00; WRMR = .459). Findings also provided preliminary evidence consistent with the hypothesis that in addition to having effects on targeted positive outcomes, PYD interventions are likely to have progressive cascading effects on untargeted problem outcomes that operate through effects on positive outcomes. Furthermore, the general pattern of findings suggested the need to use methods capable of capturing both quantitative and qualitative change in order to increase the likelihood of identifying more complete theory informed empirically supported models of developmental intervention change processes.

Use of structural equation modeling to examine the association between breast cancer risk perception and repeat screening mammography among United States women

Breast cancer is the second leading cause of cancer death in United States women, estimated to be diagnosed in 1 out of 8 women in their lifetime. Screening mammography detects breast cancer in its pre-clinical stages when treatment strategies have the greatest chance of success, and is currently the only population-wide prevention method proven to reduce the morbidity and mortality associated with breast cancer. Research has shown that the majority of women are not screened annually, with estimates ranging front 6% - 30% of eligible women receiving all available annual mammograms over a 5-year or greater time frame. Health behavior theorists believe that perception of risk/susceptibility to a disease influences preventive health behavior, in this case, screening mammography The purpose of this dissertation is to examine the association between breast cancer risk perception and repeat screening mammography using a structural equation modeling (SEM) framework. A series of SEM multivariate regressions were conducted using self-reported, nationally representative data from the 2005 National Health Interview Survey. Interaction contrasts were tested to measure the potential moderating effects of variables which have been shown to be predictive of mammography use (physician recommendation, economic barriers, structural barriers, race/ethnicity) on the association between breast cancer risk perception and repeat mammography, while controlling for the covariates of age, income, region, nativity, and educational level. Of the variables tested for moderation, results of the SEM analyses identify physician recommendation as the only moderator of the relationship between risk perception and repeat mammography, thus the potentially most effective point of intervention to increase mammography screening, and decrease the morbidity and mortality associated with breast cancer. These findings expand the role of the physician from recommendation to one of attenuating the effect of risk perception and increasing repeat screening. The long range application of the research is the use of the SEM methodology to identify specific points of intervention most likely to increase preventive behavior in population-wide research, allowing for the most effective use of intervention funds.^

A developmental intervention science outreach research approach to promoting positive youth development

Recent intervention efforts in promoting positive identity in troubled adolescents have begun to draw on the potential for an integration of the self-construction and self-discovery perspectives in conceptualizing identity processes, as well as the integration of quantitative and qualitative data analytic strategies. This study reports an investigation of the Changing Lives Program (CLP), using an Outcome Mediation (OM) evaluation model, an integrated model for evaluating targets of intervention, while theoretically including a Self-Transformative Model of Identity Development (STM), a proposed integration of self-discovery and self-construction identity processes. This study also used a Relational Data Analysis (RDA) integration of quantitative and qualitative analysis strategies and a structural equation modeling approach (SEM), to construct and evaluate the hypothesized OM/STM model. The CLP is a community supported positive youth development intervention, targeting multi-problem youth in alternative high schools in the Miami Dade County Public Schools (M-DCPS). The 259 participants for this study were drawn from the CLP’s archival data file. The model evaluated in this study utilized three indices of core identity processes (1) personal expressiveness, (2) identity conflict resolution, and (3) informational identity style that were conceptualized as mediators of the effects of participation in the CLP on change in two qualitative outcome indices of participants’ sense of self and identity. Findings indicated the model fit the data (χ2 (10) = 3.638, p = .96; RMSEA = .00; CFI = 1.00; WRMR = .299). The pattern of findings supported the utilization of the STM in conceptualizing identity processes and provided support for the OM design. The findings also suggested the need for methods capable of detecting and rendering unique sample specific free response data to increase the likelihood of identifying emergent core developmental research concepts and constructs in studies of intervention/developmental change over time in ways not possible using fixed response methods alone.

Using modeling as a co-design approach in the planning process of new care environments

Current research shows a relationship between healthcare architecture and patient-related Outcomes. The planning and designing of new healthcare environments is a complex process; the needs of the various end-users of the environment must be considered, including the patients, the patients’ significant others, and the staff. The aim of this study was to explore the experiences of healthcare professionals participating in group modelling utilizing system dynamics in the pre-design phase of new healthcare environments. We engaged healthcare professionals in a series of workshops using system dynamics to discuss the planning of healthcare environments in the beginning of a construction, and then interviewed them about their experience. An explorative and qualitative design was used to describe participants’ experiences of participating in the group modelling projects. Participants (n=20) were recruited from a larger intervention study using group modeling and system dynamics in planning and designing projects. The interviews were analysed by qualitative content analysis. Two themes were formed, representing the experiences in the group modeling process: ‘Partaking in the G-M created knowledge and empowerment’and ‘Partaking in the G-M was different from what was expected and required time and skills’. The method can support participants in design teams to focus more on their healthcare organization, their care activities and their aims rather than focusing on detailed layout solutions. This clarification is important when decisions about the design are discussed and prepared and will most likely lead to greater readiness for future building process.

Evaluation of a Quality Improvement (QI) Intervention for Maternal, Newborn, and Child Health (MNCH) in Colombia: The Mil Días Intervention of SINERGIAS in the Department of Bolívar

Thesis (Master's)--University of Washington, 2016-06

THE EFFECTIVENESS OF POINT-OF-VIEW VIDEO MODELING IN TEACHING SOCIAL INITIATION SKILLS TO CHILDREN WITH AUTISM SPECTRUM DISORDERS

Deficits in social communication and interaction have been identified as distinguishing impairments for individuals with an autism spectrum disorder (ASD). As a pivotal skill, the successful development of social communication and interaction in individuals with ASD is a lifelong objective. Point-of-view video modeling has the potential to address these deficits. This type of video involves filming the completion of a targeted skill or behavior from a first-person perspective. By presenting only what a person might see from his or her viewpoint, it has been identified to be more effective in limiting irrelevant stimuli by providing a clear frame of reference to facilitate imitation. The current study investigated the use of point-of-view video modeling in teaching social initiations (e.g., greetings). Using a multiple baseline across participants design, five kindergarten participants were taught social initiations using point-of-view video modeling and video priming. Immediately before and after viewing the entire point-of-view video model, the participants were evaluated on their social initiations with a trained, typically developing peer serving as a communication partner. Specifically, the social initiations involved participants’ abilities to shift their attention toward the peer who entered the classroom, maintain attention toward the peer, and engage in an appropriate social initiation (e.g., hi, hello). Both generalization and maintenance were tested. Overall, the data suggest point-of-view video modeling is an effective intervention for increasing social initiations in young students with ASD. However, retraining was necessary for acquisition of skills in the classroom environment. Generalization in novel environments and with a novel communication partner, and generalization to other social initiation skills was limited. Additionally, maintenance of gained social initiation skills only occurred in the intervention room. Despite the limitations of the study and variable results, there are a number of implications moving forward for both practitioners and future researchers examining point-of-view modeling and its potential impact on the social initiation skills of individuals with ASD.

Transfer function-noise modeling and spatial interpolation to evaluate the risk of extreme (shallow) water-table levels in the Brazilian Cerrados

Water regimes in the Brazilian Cerrados are sensitive to climatological disturbances and human intervention. The risk that critical water-table levels are exceeded over long periods of time can be estimated by applying stochastic methods in modeling the dynamic relationship between water levels and driving forces such as precipitation and evapotranspiration. In this study, a transfer function-noise model, the so called PIRFICT-model, is applied to estimate the dynamic relationship between water-table depth and precipitation surplus/deficit in a watershed with a groundwater monitoring scheme in the Brazilian Cerrados. Critical limits were defined for a period in the Cerrados agricultural calendar, the end of the rainy season, when extremely shallow levels (< 0.5-m depth) can pose a risk to plant health and machinery before harvesting. By simulating time-series models, the risk of exceeding critical thresholds during a continuous period of time (e.g. 10 days) is described by probability levels. These simulated probabilities were interpolated spatially using universal kriging, incorporating information related to the drainage basin from a digital elevation model. The resulting map reduced model uncertainty. Three areas were defined as presenting potential risk at the end of the rainy season. These areas deserve attention with respect to water-management and land-use planning.