Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth.

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.

FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells.

We previously found that FoxM1B is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic glioblastoma in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, whereas blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1 siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human glioblastoma specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis.

Consumer satisfaction with primary care provider choice and associated trust

Trust is important in medical relationships and for the achievement of better health outcomes. Developments in managed care in the recent years are believed to affect the quality of healthcare services delivery and to undermine trust in the healthcare provider. Physician choice has been identified as a strong predictor of provider trust but has not been studied in detail. Consumer satisfaction with primary care provider (PCP) choice includes having or not having physician choice. This dissertation developed a conceptual framework that guided the study of consumer satisfaction with PCP choice as a predictor of provider trust, and conducted secondary data analyses examining the association between PCP choice and trust, by identifying factors related to PCP choice satisfaction, and their relative importance in predicting provider trust. The study specific aims were: (1) to determine variables related to the factors: consumer characteristics and health status, information and consumer decision-making, consumer trust in providers in general and trust in the insurer, health plan financing and plan characteristics, and provider characteristics that may relate to PCP choice satisfaction; (2) to determine if the factors in aim one are related to PCP choice satisfaction; and (3) to analyze the association between PCP choice satisfaction and provider trust, controlling for potential confounders. Analyses were based on secondary data from a random national telephone survey in 1999, of residential households in the United States which included respondents aged over 20 and who had at least two visits with a health professional in the past two years. Among 1,117 eligible households interviewed (response rate 51.4%), 564 randomly selected to respond to insurer related questions made up the study sample. Analyses using descriptive statistics, and linear and logistic regressions found continual effective care and interaction with the PCP beyond the medical setting most predictive of PCP choice satisfaction. Four PCP choice satisfaction factors were also predictive of provider trust. Findings highlighted the importance of the PCP's professional and interpersonal competencies for the development of sustainable provider trust. Future research on the access, utilization, cognition, and helpfulness of provider specific information will further our understanding of consumer choice and trust. ^

THE BACON CHOW STUDY: THE RELATIONSHIP BETWEEN INFECTIOUS ILLNESS AND GROWTH OF INFANTS

Multiple dietary deficiencies and high rates of infectious illness are major health problems leading to malnutrition and limitation of growth of children in developing countries. Longitudinal studies which provide information on illness incidence and growth velocity are needed in order to untangle the complex interrelationship between nutrition, illness and growth. From 1967 to 1973, researchers led by Dr. Bacon Chow of the Johns Hopkins University School of Hygiene undertook a quasi-experimental prospective study in Suilin Township, Taiwan to determine the effects of a nutritional supplement to the diets of pregnant and lactating women on the growth, development and resistance to disease of their offspring. This dissertation presents results from the analysis of infant morbidity and postnatal growth.^ Maternal nutritional supplementation has no apparent effect on the postnatal growth or morbidity of infants. Significant sex differences exist in growth response to illness and in illness susceptibility. Male infants have more diarrhea and upper respiratory illness. Respiratory illness is positively associated with growth rate in weight in the first semester of life. Diarrhea is significantly negatively associated with growth in length in the second semester. Small-for-date infants are more susceptible to illness in general and have a different pattern of growth response than large-for-date infants.^ Principal components analysis of illness data is shown to be an effective technique for making more precise use of ambiguous morbidity data. Multiple regression with component scores is an accurate method for estimating variance in growth rate predicted by indepenent illness variables. A model is advanced in which initial postnatal growth rate determines subsequent susceptibility to nutritional stress and infection. Initial growth rate is a function of prenatal nutrition, but is not significantly affected by maternal supplementation during gestation or lactation. Critical evaluation is made of nutritional supplementation programs which do not afford disease control.^

Analysis of pp60$\sp{{\rm c}{-}src}$ and pp62$\sp{{\rm c}{-}yes}$ intracellular protein tyrosine kinase function in colon tumor cell growth regulation using herbimycin A, a tyrosine kinase specific inhibitor

Two approaches were utilized to investigate the role of pp60c-src activation in growth control of model colon tumor cell lines. The first approach involved analysis of pp60c-src activity in response to growth factor treatment to determine if transient activation of the protein was associated with ligand induced mitogenic signal transduction as occurs in non-colonic cell types. Activation of pp60c-src was detected using colon tumor cell lysates after treatment with platelet derived growth factor (PDGF). Activation of pp60c-src was also detected in response to epidermal growth factor (EGF) treatment using cellular lysates and intact cells. In contrast, down-regulation of purified pp60c-src occurred after incubation with EGF-treated EGFr immune complexes in vitro suggesting additional cellular events were potentially required for the stimulatory response observed in intact cells. The results demonstrated activation of pp60c-src in colon tumor cells in response to PDGF and EGF which is consistent with the role of the protein in mitogenic signal transduction in non-colonic cell types.^ The second approach used to study the role of pp60c-src activation in colonic cell growth control focused on analysis of the role of constitutive activation of the protein, which occurs in approximately 80% of colon tumors and cell lines, in growth control. These studies involved analysis of the effects of the tyrosine kinase specific inhibitor Herbimycin A (HA) on monolayer growth and pp60c-src enzymatic activity using model colon tumor cell lines. HA induced dose-dependent growth inhibition of all colon tumor cell lines examined possessing elevated pp60c-src activity. In HT29 cells the dose-dependent growth inhibition induced by HA correlated with dose-dependent pp60c-src inactivation. Inactivation of pp60c-src was shown to be an early event in response to treatment with HA which preceded induction of HT29 colon tumor cell growth inhibition. The growth effects of HA towards the colon tumor cells examined did not appear to be associated with induction of differentiation or a cytotoxic mechanism of action as changes in morphology were not detected in treated cells and growth inhibition (and pp60c-src inactivation) were reversible upon release from treatment with the compound. The results suggested the constitutive activation of pp60c-src functioned as a proliferative signal in colon tumor cells. Correlation between pp60c-src inactivation and growth inhibition was also observed using HA chemical derivatives confirming the role of tyrosine kinase inactivation by these compounds in inhibition of mitogenic signalling. In contrast, in AS15 cells possessing specific antisense mRNA mediated inactivation of pp60c-src, HA-induced inactivation of the related pp62c-yes tyrosine kinase, which is also activated during colon tumor progression, was not associated with induction of monolayer growth inhibition. These results suggested a function for the constitutively activated pp62c-yes protein in colon tumor cell proliferation which was different from that of activated pp60c-src. (Abstract shortened by UMI.) ^