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Targeting the tumor microenvironment

Description: Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.
Date: November 7, 2006
Creator: Kenny, P.A.; Lee, G.Y. & Bissell, M.J.
Partner: UNT Libraries Government Documents Department

TRWG developmental pathway for biospecimen-based assessment modalities

Description: The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of NCI's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of biospecimen-based assays that utilize biomarkers for the detection, diagnosis, prognosis, and assessment of response to cancer treatment. The biospecimen-based assessment modality (BM) pathway was conceived not as comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper introduces the pathway in the context of prior work and discusses key challenges associated with the biomarker development process in light of the pathway.
Date: September 3, 2008
Creator: Group, Translational Research Working; Srivastava, Sudhir; Gray, Joe W.; Reid, Brian J.; Grad, Oren; Greenwood, Addison et al.
Partner: UNT Libraries Government Documents Department

Predicting cancer outcome

Description: We read with interest the paper by Michiels et al on the prediction of cancer with microarrays and the commentary by Ioannidis listing the potential as well as the limitations of this approach (February 5, p 488 and 454). Cancer is a disease characterized by complex, heterogeneous mechanisms and studies to define factors that can direct new drug discovery and use should be encouraged. However, this is easier said than done. Casti teaches that a better understanding does not necessarily extrapolate to better prediction, and that useful prediction is possible without complete understanding (1). To attempt both, explanation and prediction, in a single nonmathematical construct, is a tall order (Figure 1).
Date: March 24, 2005
Creator: Gardner, S N & Fernandes, M
Partner: UNT Libraries Government Documents Department

Lattice Boltzmann Simulation of Particle Laden Flows in Microfluidic Systems

Description: The goal of this effort was to develop dynamic simulation tools to study and characterize particulate transport in Microfluidic devices. This includes the effects of external fields and near-field particle-particle, particle-surface interactions. The unique aspect of this effort is that we focused on the particles in suspension and rigorously accounted for all of the interactions that they experienced in solution. In contrast, other numerical methods within the program, finite element and finite volume approaches, typically treat the suspended species as non-interacting point particles. Later in the program, some of these approaches incorporated approximations to begin to account for particle-particle interactions. Through the programs (BioFlips and SIMBIOSYS), we developed collaborative relationships with device-oriented efforts. More specifically and at the request of the SIMBIOSYS program manager, we allowed our efforts/milestones to be more guided by the needs of our BioFlips colleagues; therefore, our efforts were focused on the needs of the MD Anderson Cancer Center (Peter Gascoyne), UCDavis (Rosemary Smith), and UC Berkeley (Dorian Liepmann). The first two collaborations involved the development of Dielectrophoresis analysis tools and the later involved the development of suspension and fluid modeling tools for microneedles.
Date: July 22, 2003
Creator: Clague, D S; Weisgraber, T; Wheeler, E; Hon, G; Radford, J; Gascoyne, P et al.
Partner: UNT Libraries Government Documents Department

Aging Impacts Transcriptome but not Genome of Hormone-dependentBreast Cancers

Description: Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age-at-diagnosis has been shown to be an independent indicator of breast cancer prognosis. However, except for inherited forms of breast cancer, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.
Date: October 9, 2007
Creator: Yau, Christina; Fedele, Vita; Roydasgupta, Ritu; Fridlyand, Jane; Hubbard, Alan; Gray, Joe W. et al.
Partner: UNT Libraries Government Documents Department

Translating the cancer genome: Going beyond p values

Description: Cancer cells are endowed with diverse biological capabilities driven by myriad inherited and somatic genetic and epigenetic aberrations that commandeer key cancer-relevant pathways. Efforts to elucidate these aberrations began with Boveri's hypothesis of aberrant mitoses causing cancer and continue today with a suite of powerful high-resolution technologies that enable detailed catalogues of genomic aberrations and epigenomic modifications. Tomorrow will likely bring the complete atlas of reversible and irreversible alteration in individual cancers. The challenge now is to discern causal molecular abnormalities from genomic and epigenomic 'noise', to understand how the ensemble of these aberrations collaborate to drive cancer pathophysiology. Here, we highlight lessons learned from now classical examples of successful translation of genomic discoveries into clinical practice, lessons that may be used to guide and accelerate translation of emerging genomic insights into practical clinical endpoints that can impact on practice of cancer medicine.
Date: April 3, 2008
Creator: Chin, Lynda; Chin, Lynda & Gray, Joe W.
Partner: UNT Libraries Government Documents Department

Evaluation of normalization methods for cDNA microarray data by k-NN classification

Description: Non-biological factors give rise to unwanted variations in cDNA microarray data. There are many normalization methods designed to remove such variations. However, to date there have been few published systematic evaluations of these techniques for removing variations arising from dye biases in the context of downstream, higher-order analytical tasks such as classification. Ten location normalization methods that adjust spatial- and/or intensity-dependent dye biases, and three scale methods that adjust scale differences were applied, individually and in combination, to five distinct, published, cancer biology-related cDNA microarray data sets. Leave-one-out cross-validation (LOOCV) classification error was employed as the quantitative end-point for assessing the effectiveness of a normalization method. In particular, a known classifier, k-nearest neighbor (k-NN), was estimated from data normalized using a given technique, and the LOOCV error rate of the ensuing model was computed. We found that k-NN classifiers are sensitive to dye biases in the data. Using NONRM and GMEDIAN as baseline methods, our results show that single-bias-removal techniques which remove either spatial-dependent dye bias (referred later as spatial effect) or intensity-dependent dye bias (referred later as intensity effect) moderately reduce LOOCV classification errors; whereas double-bias-removal techniques which remove both spatial- and intensity effect reduce LOOCV classification errors even further. Of the 41 different strategies examined, three two-step processes, IGLOESS-SLFILTERW7, ISTSPLINE-SLLOESS and IGLOESS-SLLOESS, all of which removed intensity effect globally and spatial effect locally, appear to reduce LOOCV classification errors most consistently and effectively across all data sets. We also found that the investigated scale normalization methods do not reduce LOOCV classification error. Using LOOCV error of k-NNs as the evaluation criterion, three double-bias-removal normalization strategies, IGLOESS-SLFILTERW7, ISTSPLINE-SLLOESS and IGLOESS-SLLOESS, outperform other strategies for removing spatial effect, intensity effect and scale differences from cDNA microarray data. The apparent sensitivity of k-NN LOOCV classification error to dye biases suggests that ...
Date: December 17, 2004
Creator: Wu, Wei; Xing, Eric P; Myers, Connie; Mian, Saira & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

Comparative Deposition of Zr95 in a Reticulo Endothelial Tumor to Normal Tissue in a Human Patient

Description: A test dose of Zr{sup 95} was given to a female patient which had a metastatic reticula endothelial tumor at the distal portion of the left femur. A comparison of the deposition of Zr{sup 95} showed greater uptake 24 hours after administration than any of the normal tissues investigated.
Date: March 1, 1948
Creator: Low-Beer, B.V.; Scott, K.G.; Hamilton, J.G. & Stone, R.S.
Partner: UNT Libraries Government Documents Department

Apical polarity in three-dimensional culture systems: where to now?

Description: Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide a useful platform for dissecting these processes but, as discussed in a recent study in BMC Biology on the culture of mammary gland epithelial cells, multiple parameters that influence the model must be taken into account.
Date: January 21, 2010
Creator: Inman, J. L. & Bissell, Mina
Partner: UNT Libraries Government Documents Department

Prospects for the Precision Measurement of {alpha}{sub s}

Description: The prospects for the measurement of the strong coupling constant {alpha}{sub MS}(M{sub Z}) to a relative uncertainty of 1 % are discussed. Particular emphasis is placed on the implications relating to future High Energy Physics facilities.
Date: December 1996
Creator: Burrows, P. N.; Dixon, L. & El-Khadra, A. X.
Partner: UNT Libraries Government Documents Department

QUANTIFICATION OF TISSUE PROPERTIES IN SMALL VOLUMES

Description: The quantification of tissue properties by optical measurements will facilitate the development of noninvasive methods of cancer diagnosis and detection. Optical measurements are sensitive to tissue structure which is known to change during tumorigenesis. The goals of the work presented in this paper were to verify that the primary scatterers of light in cells are structures much smaller than the nucleus and then to develop an optical technique that can quantify parameters of structures the same size as the scattering features in cells. Polarized, elastic back-scattering was found to be able to quantify changes in scattering properties for turbid media consisting of scatterers of the size found in tissue.
Date: December 1, 2000
Creator: MOURANT, J. & AL, ET
Partner: UNT Libraries Government Documents Department

The Evolutionary Dynamics of Cancer

Description: We hypothesized that a subset of the mutations observed in the progression to cancer confer beneficial selective effects on the cell. Our aim was to identify these selective mutations and to infer the interactions between the mutant clones in Barrett's esophagus (BE) that eventually lead to the development of esophageal adenocarcinoma. The results were to be a set of predictions about the roles of specific mutations in the progression to cancer.
Date: August 29, 2000
Creator: Maley, Carlo C.
Partner: UNT Libraries Government Documents Department

Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk From Trichloroethylene-Contaminated Ground Water Beale Air Force Base in California: Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response

Description: Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability after applying a unified probabilistic approach to the distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such an approach was applied to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA{sub g}) vs. a cytotoxic/nonlinear (MA{sub c}) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA{sub G} based on seven rodent-bioassay data sets, and under MA, based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were <10{sup -6} and <10{sup -4}, respectively, while corresponding estimates based on traditional deterministic methods were >10{sup -5} and >10{sup -4}, respectively. It was estimated that no TCE-related harm is likely occur due any plausible residential exposure scenario involving the site. The unified approach illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action.
Date: September 29, 1999
Creator: Bogen, K.T.
Partner: UNT Libraries Government Documents Department

Procedures for addressing uncertainty and variability in exposure to characterize potential health risk from trichloroethylene contaminated ground water at Beale Air Force Base in California

Description: Conservative deterministic, screening-level calculations of exposure and risk commonly are used in quantitative assessments of potential human-health consequences from contaminants in environmental media. However, these calculations generally are based on multiple upper-bound point estimates of input parameters, particularly for exposure attributes, and can therefore produce results for decision makers that actually overstate the need for costly remediation. Alternatively, a more informative and quantitative characterization of health risk can be obtained by quantifying uncertainty and variability in exposure. This process is illustrated in this report for a hypothetical population at a specific site at Beale Air Force Base in California, where there is trichloroethylene (TCE) contaminated ground water and a potential for future residential use. When uncertainty and variability in exposure were addressed jointly for this case, the 95th-percentile upper-bound value of individual excess lifetime cancer risk was a factor approaching 10 lower than the most conservative deterministic estimate. Additionally, the probability of more than zero additional cases of cancer can be estimated, and in this case it is less than 0.5 for a hypothetical future residential population of up to 26,900 individuals present for any 7.6-y interval of a 70-y time period. Clearly, the results from application of this probabilistic approach can provide reasonable and equitable risk-acceptability criteria for a contaminated site.
Date: October 5, 1999
Creator: Daniels, J I; Bogen, K T & Hall, L C
Partner: UNT Libraries Government Documents Department

CANCELLED EMT and back again: does cellular plasticity fuel neoplastic progression?

Description: Epithelial-mesenchymal transition (EMT) is a cellular transdifferentiation program that facilitates organ morphogenesis and tissue remodeling in physiological processes such as embryonic development and wound healing. However, a similar phenotypic conversion is also detected in fibrotic diseases and neoplasia, in which it is associated with disease progression. EMT in cancer epithelial cells often appears to be an incomplete and bi-directional process. Here we discuss the phenomenon of EMT as it pertains to tumor development, focusing on exceptions to the commonly held rule that EMT promotes invasion and metastasis. We also highlight the role of the Ras-controlled signaling mediators, ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT.
Date: February 24, 2007
Creator: Turley, Eva A.; Veiseh, Mandana; Radisky, Derek C. & Bissell, MinaJ.
Partner: UNT Libraries Government Documents Department

Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

Description: The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, we demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.
Date: June 15, 2005
Creator: Kenny, Paraic A. & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Of extracellular matrix, scaffolds, and signaling: Tissuearchitectureregulates development, homeostasis, and cancer

Description: The microenvironment surrounding cells influences gene expression, such that a cell's behavior is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble cues released locally or by distant tissues. We describe the essential role of context and organ structure in directing mammary gland development and differentiated function, and in determining response to oncogenic insults including mutations. We expand on the concept of 'dynamic reciprocity' to present an integrated view of development, cancer, and aging, and posit that genes are like piano keys: while essential, it is the context that makes the music.
Date: March 9, 2006
Creator: Nelson, Celeste M. & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Extracellular Matrix, Nuclear and Chromatin Structure and Gene Expression in Normal Tissues and Malignant Tumors: A Work in Progress

Description: Almost three decades ago, we presented a model where theextracellular matrix (ECM) was postulated to influence gene expressionand tissue-specificity through the action of ECM receptors and thecytoskeleton. This hypothesis implied that ECM molecules could signal tothe nucleus and that the unit of function in higher organisms was not thecell alone, but the cell plus its microenvironment. We now know that ECMinvokes changes in tissue and organ architecture and that tissue, cell,nuclear, and chromatin structure are changed profoundly as a result ofand during malignant progression. Whereas some evidence has beengenerated for a link between ECM-induced alterations in tissuearchitecture and changes in both nuclear and chromatin organization, themanner by which these changes actively induce or repress gene expressionin normal and malignant cells is a topic in need of further attention.Here, we will discuss some key findings that may provide insights intomechanisms through which ECM could influence gene transcription and howtumor cells acquire the ability to overcome these levels ofcontrol.
Date: August 1, 2006
Creator: Spencer, Virginia A.; Xu, Ren & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department