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14 - Integration of Cancer Omics Data into a Whole-Cell Pathway Model for Patient-Specific Interpretation
- from Part C - Vertical Integrative Analysis (Methods Specialized to Particular Data Types)
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- By Charles Vaske, NantOmics, Culver City, CA, Sam Ng, University of California at Santa Cruz, Santa Cruz, CA, Evan Paull, Joshua Stuart, University of California at Santa Cruz, Santa Cruz, CA
- George Tseng, University of Pittsburgh, Debashis Ghosh, Pennsylvania State University, Xianghong Jasmine Zhou, University of Southern California
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- Book:
- Integrating Omics Data
- Published online:
- 05 September 2015
- Print publication:
- 23 September 2015, pp 310-336
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- Chapter
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Summary
Abstract
Recent surveys of multiple types of cancer reveal that most tumors are composed of populations of different cells with distinct sets of mutations. The variety of such subclones are thought to fuel drug resistance – targeting any single gene or pathway nearly always selects for those sub-clones lucky enough to have evolved backup mechanisms. The picture for treating cancer is thus becoming more clear: treating one cancer means keeping an entire population of cells in check. One angle, based on the principles of combinatorics that has worked in treating HIV for example, is to target multiple pathways simultaneously to better the chances of eliminating every malignant cell in the population. However, this approach requires gene regulatory network models that accurately describe the causes underlying tumor cell fitness.
This chapter overviews computational representations of genetic pathways for capturing salient aspects of tumor biology such as the activation of key genes and processes, how mutations confer gain- or loss-of-function in their cognate genes, and whether explanatory subnetworks can be identified for specific subtypes of disease. Pathway modeling provides a much-needed theoretical foundation to postulate tumor vulnerabilities that can scale to the consideration of multiple targets. Advances in the development of such mathematical frameworks should aid the clinical application of patient-specific treatments that minimize or eliminate malignant cell populations.
Introduction
Cancer genomics utilizes a wide variety of data types on individual tumors. Microarrays have been used to profile genome copy number, gene expression, DNA methylation, and more. Profiling of DNA mutations, DNA breakpoints, gene fusions, RNA expression, and RNA editing are now becoming routine. These techniques have established that even though cancer is a genomically driven disease, any one type of genomic alteration is not enough to explain the altered be haviors and transcriptional states of various tumors. Drivers genes cluster into groups of biochemically interacting genes, and individual tumors often have a mutation in just one of the genes in the cluster. For example, PIK3CA or its suppressor PTEN is mutated in tumor samples far more frequently than expected, but samples with both mutations are far less frequent than expected. A full understanding of the diversity and pattern of mutations and abnormal regulation in cancer therefore requires integration of data types and the cellular network.
COMMENTARY: Overcoming Impediments to Public Agency Acquisition of Brownfield Sites
- Evans Paull
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- Journal:
- Environmental Practice / Volume 11 / Issue 4 / December 2009
- Published online by Cambridge University Press:
- 16 December 2009, pp. 311-319
- Print publication:
- December 2009
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- Article
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As Congress begins to entertain proposals to reauthorize the Environmental Protection Agency Brownfields Program, local governments will be paying particular attention to one issue: a proposed amendment to grant public agencies greater liability protection when they acquire contaminated property. Supporters contend that cities play a unique role in brownfield redevelopment—acquiring, cleaning up, and repositioning properties that are unlikely to attract private investment either because of depressed neighborhood conditions or because the properties are being held off the market by corporate mothballing practices. Current federal law offers minimal and confusing liability protection for these activities, and the result is that many cities pass over brownfield acquisitions for fear of engendering environmental liability. Those cities that proceed with brownfield acquisitions are rolling the dice in favor of community revitalization but also argue that federal law should be more protective. To rectify these issues, several states have adopted liability reforms that establish a more “causation based” liability scheme for local government acquisitions. A number of groups are advocating for similar reforms at the federal level. Acquisition of contaminated land by public entities is also often complicated by the complexities involved in eminent domain. First, if the acquiring agency lacks the authority to gain access to the site and cannot perform a site assessment prior to taking possession, fiscal concerns are heightened because cleanup costs will not be taken into account in determining fair market value. Secondly, the acquiring agency may not be allowed to deduct cleanup costs from fair market value, so the locality will, in effect, pay twice for cleanup costs. This article explores the statutory issues related to public agency acquisitions, focusing particularly on state reforms and exploring whether particular state liability reforms might serve as a model for a federal liability reform.
Environmental Practice 11:311–319 (2009)