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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

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

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

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

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

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

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

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

Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

Description: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Date: July 23, 2007
Creator: Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda et al.
Partner: UNT Libraries Government Documents Department

Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Description: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Date: May 2, 2008
Creator: Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle et al.
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

Involvement of extracellular matrix constituents in breast cancer

Description: It has recently been established that the extracellular matrix is required for normal functional differentiation of mammary epithelia not only in culture, but also in vivo. The mechanisms by which extracellular matrix affects differentiation, as well as the nature of extracellular matrix constituents which have major impacts on mammary gland function, have only now begun to be dissected. The intricate variety of extracellular matrix-mediated events and the remarkable degree of plasticity of extracellular matrix structure and composition at virtually all times during ontogeny, make such studies difficult. Similarly, during carcinogenesis, the extracellular matrix undergoes gross alterations, the consequences of which are not yet precisely understood. Nevertheless, an increasing amount of data suggests that the extracellular matrix and extracellular matrix-receptors might participate in the control of most, if not all, of the successive stages of breast tumors, from appearance to progression and metastasis.
Date: June 1, 1995
Creator: Lochter, Andre & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

MCF-10A-NeoST: A New Cell System for Studying Cell-ECM and Cell-Cell Interactions in Breast Cancer

Description: There is a continuing need for genetically matched cell systems to model cellular behaviors that are frequently observed in aggressive breast cancers. We report here the isolation and initial characterization of a spontaneously arising variant of MCF-10A cells, NeoST, which provides a new model to study cell adhesion and signal transduction in breast cancer. NeoST cells recapitulate important biological and biochemical features of metastatic breast cancer, including anchorage-independent growth, invasiveness in threedimensional reconstituted membranes, loss of E-cadherin expression, and increased tyrosine kinase activity. A comprehensive analysis of tyrosine kinase expression revealed overexpression or functional activation of the Axl, FAK, and EphA2 tyrosine kinases in transformed MCF-10A cells. MCF-10A and these new derivatives provide a genetically matched model to study defects in cell adhesion and signaling that are relevant to cellular behaviors that often typify aggressive breast cancer cells.
Date: August 22, 2001
Creator: Zantek, Nicole Dodge; Walker-Daniels, Jennifer; Stewart, Jane; Hansen, Rhonda K.; Robinson, Daniel; Miao, Hui et al.
Partner: UNT Libraries Government Documents Department

The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion

Description: The human breast comprises three lineages: the luminal epithelial lineage, the myoepithelial lineage, and the mesenchymal lineage. It has been widely accepted that human breast neoplasia pertains only to the luminal epithelial lineage. In recent years, however, evidence has accumulated that neoplastic breast epithelial cells may be substantially more plastic in their differentiation repertoire than previously anticipated. Thus, along with an increasing availability of markers for the myoepithelial lineage, at least a partial differentiation towards this lineage is being revealed frequently. It has also become clear that conversions towards the mesenchymal lineage actually occur, referred to as epithelial to mesenchymal transitions. Indeed, some of the so-called myofibroblasts surrounding the tumor may indeed have an epithelial origin rather than a mesenchymal origin. Because myoepithelial cells, epithelial to mesenchymal transition-derived cells, genuine stromal cells and myofibroblasts share common markers, we now need to define a more ambitious set of markers to distinguish these cell types in the microenvironment of the tumors. This is necessary because the different microenvironments may confer different clinical outcomes. The aim of this commentary is to describe some of the inherent complexities in defining cellular phenotypes in the microenvironment of breast cancer and to expand wherever possible on the implications for tumor suppression and progression.
Date: May 12, 2001
Creator: Petersen, Ole William; Nielsen, Helga Lind; Gudjonsson, Thorarinn; Villadsen, René Ronnov-Jessen, Lone & Bissell, Mina J.
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

Physicochemical properties and toxicities of hydrophobicpiperidinium and pyrrolidinium ionic liquids

Description: Some properties are reported for hydrophobic ionic liquids (IL) containing 1-methyl-1-propyl pyrrolidinium [MPPyrro]{sup +}, 1-methyl-1-butyl pyrrolidinium [MBPyrro]{sup +}, 1-methyl-1-propyl piperidinium [MPPip]{sup +}, 1-methyl-1-butyl piperidinium [MBPip]{sup +}, 1-methyl-1-octylpyrrolidinium [MOPyrro]{sup +} and 1-methyl-1-octylpiperidinium [MOPip]{sup +} cations. These liquids provide new alternatives to pyridinium and imidazolium ILs. High thermal stability of an ionic liquid increases safety in applications like rechargeable lithium-ion batteries and other electrochemical devices. Thermal properties, ionic conductivities, viscosities, and mutual solubilities with water are reported. In addition, toxicities of selected ionic liquids have been measured using a human cancer cell-line. The ILs studied here are sparingly soluble in water but hygroscopic. We show some structure-property relationships that may help to design green solvents for specific applications. While ionic liquids are claimed to be environmentally-benign solvents, as yet few data have been published to support these claims.
Date: June 25, 2007
Creator: Salminen, Justin; Papaiconomou, Nicolas; Kumar, R. Anand; Lee,Jong-Min; Kerr, John; Newman, John et al.
Partner: UNT Libraries Government Documents Department