The activities of some polycyclic hydrocarbons and their "K region" epoxides in an in vitro-in vivo carcinogenicity test system.

Benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, dibenz(a)anthracene and benzo(a)pyrene and their related "K region" epoxides were tested for carcinogenic activities using a system in which mouse lung tissue was incubated in the presence of the test compound for 30 min and then implanted into isologous mice. Only 7,12-dimethylbenz(a)anthracene showed any marked carcinogenic activity under the conditions used, but all the compounds tested produced extensive proliferative outgrowths in the implanted tissues that may represent specific responses to the carcinogens

Beyond Rules

Our article, in contrast to the predominant scholarly view, contends that the influential Legal Realist Movement of the 1930s was actually two movements—radical legal realism and conservative legal realism (CLR). CLR is best understood through the works of Nathan Isaacs. This article will investigate the legitimacy and determinacy of the legal order through the lens of CLR as represented by Isaacs. Isaacs and CLR are especially worthy subjects for study given the current economic crisis. It is a crisis, much like the Great Depression, that has spurred many people to question core capitalistic premises, such as the superiority of minimal government regulation of business and the structuring of financial instruments through freedom of contract. CLR’s merger of anti-formalism and an idealism inspired by the Jewish legal tradition resulted in its rejection of Lochner-era judicial decision-making while supporting an attack on the constitutionality of New Deal interventionism. CLR asserts that although legal rules provide indeterminate answers in hard cases, principled-guided rules will lead to a correct answer. CLR calls on judges to continuously strive to uncover underlying objective principles and to understand their historical evolution. Isaacs sought to blend an evolving, but cyclical, organic theory of legal development with the pragmatism needed to make rules workable. To do this, the contingent nature of law must be contained within a framework of moral, political, and cultural values. This framework characterizes CLR as both a critical and positive theory of the legal order. This fusion of an organic natural law with the inherent indeterminacy of legal conceptualism moves beyond rules to a principle-based contextualism. We use previously neglected archival material, found in the Harvard Law and Harvard Business School’s “Special Collections,” as well as other archives, to connect Isaacs to major figures in the Legal Realist Movement. Isaacs’ broad contextual framework allowed him to play a pioneering role in the development of the social-scientific study of law and the critique of legal formalism that was the basis for the Legal Realist Movement. However, his belief in the integrity of the legal order moved him beyond rule skepticism. His understanding of the dynamic nature of law provided insights into constitutional interpretation, cycle theory of legal development, status-based regulation of standard form contracts, re-conceptualization of law, and the need for an interdisciplinary approach to law study and reform

Beyond Rules

Our article, in contrast to the predominant scholarly view, contends that the influential Legal Realist Movement of the 1930s was actually two movements—radical legal realism and conservative legal realism (CLR). CLR is best understood through the works of Nathan Isaacs. This article will investigate the legitimacy and determinacy of the legal order through the lens of CLR as represented by Isaacs. Isaacs and CLR are especially worthy subjects for study given the current economic crisis. It is a crisis, much like the Great Depression, that has spurred many people to question core capitalistic premises, such as the superiority of minimal government regulation of business and the structuring of financial instruments through freedom of contract. CLR’s merger of anti-formalism and an idealism inspired by the Jewish legal tradition resulted in its rejection of Lochner-era judicial decision-making while supporting an attack on the constitutionality of New Deal interventionism. CLR asserts that although legal rules provide indeterminate answers in hard cases, principled-guided rules will lead to a correct answer. CLR calls on judges to continuously strive to uncover underlying objective principles and to understand their historical evolution. Isaacs sought to blend an evolving, but cyclical, organic theory of legal development with the pragmatism needed to make rules workable. To do this, the contingent nature of law must be contained within a framework of moral, political, and cultural values. This framework characterizes CLR as both a critical and positive theory of the legal order. This fusion of an organic natural law with the inherent indeterminacy of legal conceptualism moves beyond rules to a principle-based contextualism. We use previously neglected archival material, found in the Harvard Law and Harvard Business School’s “Special Collections,” as well as other archives, to connect Isaacs to major figures in the Legal Realist Movement. Isaacs’ broad contextual framework allowed him to play a pioneering role in the development of the social-scientific study of law and the critique of legal formalism that was the basis for the Legal Realist Movement. However, his belief in the integrity of the legal order moved him beyond rule skepticism. His understanding of the dynamic nature of law provided insights into constitutional interpretation, cycle theory of legal development, status-based regulation of standard form contracts, re-conceptualization of law, and the need for an interdisciplinary approach to law study and reform

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data

<p>Abstract</p> <p>Background</p> <p><it>Saccharomyces cerevisiae </it>is the first eukaryotic organism for which a multi-compartment genome-scale metabolic model was constructed. Since then a sequence of improved metabolic reconstructions for yeast has been introduced. These metabolic models have been extensively used to elucidate the organizational principles of yeast metabolism and drive yeast strain engineering strategies for targeted overproductions. They have also served as a starting point and a benchmark for the reconstruction of genome-scale metabolic models for other eukaryotic organisms. In spite of the successive improvements in the details of the described metabolic processes, even the recent yeast model (i.e., <it>i</it>MM904) remains significantly less predictive than the latest <it>E. coli </it>model (i.e., <it>i</it>AF1260). This is manifested by its significantly lower specificity in predicting the outcome of grow/no grow experiments in comparison to the <it>E. coli </it>model.</p> <p>Results</p> <p>In this paper we make use of the automated GrowMatch procedure for restoring consistency with single gene deletion experiments in yeast and extend the procedure to make use of synthetic lethality data using the genome-scale model <it>i</it>MM904 as a basis. We identified and vetted using literature sources 120 distinct model modifications including various regulatory constraints for minimal and YP media. The incorporation of the suggested modifications led to a substantial increase in the fraction of correctly predicted lethal knockouts (i.e., specificity) from 38.84% (87 out of 224) to 53.57% (120 out of 224) for the minimal medium and from 24.73% (45 out of 182) to 40.11% (73 out of 182) for the YP medium. Synthetic lethality predictions improved from 12.03% (16 out of 133) to 23.31% (31 out of 133) for the minimal medium and from 6.96% (8 out of 115) to 13.04% (15 out of 115) for the YP medium.</p> <p>Conclusions</p> <p>Overall, this study provides a roadmap for the computationally driven correction of multi-compartment genome-scale metabolic models and demonstrates the value of synthetic lethals as curation agents.</p

Regular use of analgesics is a risk factor for renal cell carcinoma

Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case–control study involving 1204 non-Asian RCC patients aged 25–74 and an equal number of sex-, age- and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4–1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non- or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6–1.4). © 1999 Cancer Research Campaig