A consensus of experimental and clinical data suggests that carcinogenesis is a multistep process. Several theories of carcinogenesis propose that one necessary step in the development of cancer is the inactivation of cellular anticancer mechanisms. The term anticancer activity includes any process that prevents or reverses the transformed phenotype, including activities previously designated anti-oncogenesis, tumor/cancer suppression, recessive oncogenesis, and other similar terms. Suppression of the transformed phenotype by fusing nontumorigenic cells with tumorigenic cells has been reported by numerous investigators and this topic has been covered extensively in the last few years. A great deal of evidence suggests that the hereditary predisposition to cancer is due to the inactivation, via mutations, and deletions of anticancer mechanisms. This evidence comes from the study of inherited cancers in many species including Drosophila and man. The classical experiments demonstrating the induction of anticancer activity by extracellular factors involve the placement of teratocarcinoma or embryonal carcinoma cells into the blastocyst of mice.

The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint is associated with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats, and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes, and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co‐vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose, and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty‐three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with P = e−13 to e−36. Cell cycle expression networks show species, sex and tissue variability, and they are enriched in mRNA transcripts associated with mitosis, many of which are associated with chromosomal instability. J. Cell. Physiol. 230: 2533–2542, 2015. © 2015 Wiley Periodicals, Inc.

A significant amount of nuclear p53 is found associated with the nuclear matrix in cells that were exposed to genotoxic stress. In this study we identified Scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein that binds the scaffold or matrix attachment regions (S/MARs) of genomic DNA, as a novel p53-interacting protein. SAFB1 was able to associate with p53 through its C-terminal domain, while significant co-localization of the two proteins was observed in cells treated with 5-fluorouracil or mithramycin. Binding of p53 to SAFB1 had a significant functional outcome, since SAFB1 was shown to suppress p53-mediated reporter gene expression. These data suggest that nuclear matrix-associated proteins may play a critical role in regulating p53 localization and activity.

Background The 250 kDa P2P-R protein (also known as PACT and Rbbp6) was cloned over a decade ago and was found to bind both the p53 and Rb1 tumor suppressor proteins. In addition, P2P-R has been associated with multiple biological functions, such as mitosis, mRNA processing, translation and ubiquitination. In the current studies, the online GeneNetwork system was employed to further probe P2P-R biological functions. Molecular studies were then performed to confirm the GeneNetwork evaluations. Results GeneNetwork and associated gene ontology links were used to investigate the coexpression of P2P-R with distinct functional sets of genes in an adipocyte genetic reference panel of HXB/BXH recombinant strains of rats and an eye genetic reference panel of BXD recombinant inbred strains of mice. The results establish that biological networks of 75 and 135 transcription-associated gene products that include P2P-R are co-expressed in a genetically-defined manner in rat adipocytes and in the mouse eye, respectively. Of this large set of transcription-associated genes, >10% are associated with hormone-mediated transcription. Since it has been previously reported that P2P-R can bind the SRC-1 transcription co-regulatory factor (steroid receptor co-activator 1, [Ncoa1]), the possible effects of P2P-R on estrogen-induced transcription were evaluated. Estrogen-induced transcription was repressed 50-70% by the transient transfection of P2P-R plasmid constructs into four different cell types. In addition, knockdown of P2P-R expression using an antisense oligonucleotide increased estrogen-mediated transcription. Co-immunoprecipitation assays confirmed that P2P-R interacts with SRC-1 and also demonstrated that P2P-R interacts with estrogen receptor α. Conclusions The findings presented in this study provide strong support for the value of systems genetics, especially GeneNetwork, in discovering new functions of genes that can be confirmed by molecular analysis. More specifically, these data provide evidence that the expression of P2P-R co-varies in a genetically-defined manner with large transcription networks and that P2P-R can function as a co-repressor of estrogen-dependent transcription.

The conventional wisdom among contemporary scholars is that courts will impose promissory estoppel liability for reliance invest- ments undertaken prior to any agreement between commercial par- ties. 1 Evidence of promises made and relied upon during the negotia- tion process together with a "general obligation arising out of the nego- tiations themselves" are the supposed grounds for imposing liability even for preliminary negotiations that ultimately break down. 2 But even a casual survey of contemporary case law casts significant doubt on the accuracy of the conventional view. Courts actually make some form of agreement a necessary pre-condition to a promisee's recovery. The real issues are: When will a preliminary agreement be found? And how does the nature of such agreement determine when and how a promisee can recover?

The expression of defects in the control of cellular differentiation is thought to be of etiological significance in the early stages of carcinogenesis. This possibility is supported by a variety of experimental studies including those that have established that metaplastic changes in cells can represent preneoplastic lesions in vivo. To evaluate this question in greater detail, we have used 3T3 T mesenchymal stem cells as a model system. These cells express certain characteristics of preneoplastic cells even though they can regulate their proliferation and even though they can undergononterminaland terminal differentiation into adipocytes. For example, they are immortal and aneuploid, and they show a proclivity to undergo spontaneous or induced neoplastic transformation compared to normal human cells. The question we sought to answer in the current experiments concerns whether predifferentiation growth arrest and/or nonterminal differentiation in such preneoplastic cells is completely reversible or whether these processes induce the expression of the new stable program that limits the cells' proliferativi' potential and reduces the cells' subsequent differentiation potential in a manner comparable to that which is thought to occur in normal stem cells. The results show that arrest at both the predifferentiation state and at the nonterminal differentiation state is a completely reversible phenomenon that does not limit the cells1 subsequent growth or differentiation potential. In fact, the results show that, when nonterminally differentiated 3T3 T adipocytes are induced to dedifferentiate, they can subsequently redifferentiate into macrophages. We therefore suggest that preneoplasia as expressed in 3T3 T mesenchymal stem cells is associated with the expression of defects in the ability to integrally control cellular differentiation and proliferation. As a result, the data suggest that such cells express an increased proclivity to undergo metaplastic change and complete neo plastic transformation.

The rise in the U.S. trade deficit with Canada and Mexico through 2004 has caused the displacement of production that supported 1,015,291 U.S. jobs since the North American Free Trade Agreement (NAFTA) was signed in 1993. Jobs were displaced in every state and major industry in the United States. Two thirds of those lost jobs were in manufacturing industries. The proposed Dominican Republic-Central American Free Trade Agreement (DR- CAFTA) duplicates the most important elements of NAFTA, and it will only worsen conditions for workers in the United States and throughout the hemisphere (Faux, Campbell, Salas, and Scott 2001). Since NAFTA took effect, the growth of exports supported approximately 1 million U.S. jobs, but the growth of imports displaced domestic production that would have supported 2 million jobs. Consequently, the growth of the U.S. trade deficit with Mexico and Canada caused a net decline in U.S. production that would have supported about 1 million U.S. jobs. Before adopting an agreement such as DR-CAFTA, it is important to understand the following about NAFTA's effect on U.S. jobs:  The 1 million job opportunities lost nationwide are distributed among all 50 states and the District of Columbia. Those affected most in terms of total jobs displaced include: California (-123,995), Texas (-72,257), Michigan (-63,148), New York (-51,582), Ohio (-49,886), Illinois ( -47,701), Pennsylvania ( -44,173), Florida (-39,987), Indiana (-35,157), North Carolina ( -34,150), and Georgia (-30,464) (see Appendix Table A-1).  The 10 hardest-hit states, as a share of total state employment, are: Michigan (-63,148, -1.44%), Indiana (-35,157, -1.19%), Mississippi (-11,630, -1.03%), Tennessee (-25,588, -0.94%), Ohio (-49,886, -0.92%), Rhode Island (-4,482, -0.91%), Wisconsin (-25,403, -0.90%), Arkansas (-10,321, -0.89%), North Carolina (-34,150, -0.89%), and New Hampshire (-5,502, -0.87%) (see Appendix Table A-2).

Cellular de-differentiation can induce anticancer activity that makes cells resistant to carcinogenesis, but the molecular mechanism of this phenomenon has not been defined. To determine whether stable molecular changes develop in association with the process of de-differentiation, DNA microarray analyses were performed. These analyses compared control undifferentiated cells with three carcinogenesis-resistant clones of de-differentiated cells that were derived from mature adipocytes. The results of analysis of 6,000 genes and 6,000 ESTs establish that relative to control cells, all three de-differentiation-derived cell clones demonstrate that only one gene shows a consistent difference in expression. The expression of the H19 bioregulatory RNA is repressed an average of > fourfold in all de-differentiated cell clones. Real-time PCR analyses confirm these findings. This suggests that decreased H19 expression may account, at least in part, for the anticancer activity observed in de-differentiated cell clones.

Promoters of the proposed Dominican Republic/Central American Free Trade Agreement (CAFTA) have asserted that it will provide significant benefits to the U.S. economy, especially to the agricultural sector. Similar promises were made in the debate on the North American Free Trade Agreement in 1992 and 1993. However, since that time NAFTA has failed to live up to these promises, and similar promises made for CAFTA are even less likely to be fulfilled. Some of the key promises made during the NAFTA debate in Congress that have since been broken are summarized in Table 1. It is clear from the table that NAFTA has failed to provide overall trade benefits or to fulfill many of the individual promises made to commodity producers. The exaggerated claims of expected benefits that are now being made for CAFTA are equally as likely to go unmet. NAFTA and CAFTA proponents have made broad promises about the potential for export growth and about the numbers of jobs that will be generated as a result. They imply that exports will grow faster than imports and that there will be trade surpluses for generations to come. While it is true that growing exports are good for the economy, growing imports actually displace domestic production that would support employment in the United States. When agricultural imports rise faster than exports, as was often the case under NAFTA, the result is a net drain on farm output and employment. Given that the United States had already made a free trade agreement with Canada in 1989, NAFTA was really about expanding trade with Mexico. But there has been absolutely no change in the U.S. agricultural or food products trade balances with Mexico since NAFTA took effect. This is remarkable since, as the Office of the United States Trade Representative (USTR) noted: “Mexican tariffs are 2.5 times as high as U.S. tariffs,

I Introduction Thirty years ago, Grant Gilmore predicted the death of contract.1 He saw the expansion of legal liability for relied-upon promises as evidence that contract was being swallowed up by tort and would soon disappear as an independent, coherent body of law. Gilmore interpreted this trend as the repudiation of the classical bargain theory of contract, a theory that emphasized the central role of the law in enforcing and interpreting bargained-for promises. In Gilmore's view, the bargain theory owed more to the imagination of Oliver Wendell Holmes than to the case law, but in any event, by 1972 the boundaries of the classical, consideration-based model had clearly been breached, a new expansive version of contract law was emerging, and, for Gilmore, the triumph of reliance over bargain was an entirely salutary development. If anything, the trend that Gilmore identified has accelerated. After the adoption of the Uniform Commercial Code ( UCC), the last half of the twentieth century witnessed a dramatic expansion in the domain of contract law. Courts deployed creative and expansive strategies to find promissory liability that would not have been recognized under the classical model. But despite the accuracy of Gilmore's empirical observations, his prediction that the bargain theory of contract was dying could not have been more inaccurate. Indeed, almost from the moment his book was published, contract theorists of various persuasions set out to demonstrate the vitality and coherence of the bargain paradigm. Legal philosophers argued that the state's role in enforcing bargains is both explained and justified by moral theories grounded in notions of autonomy.2 Law and economics scholars proposed the efficiency criterion (in [End Page 369] one form or another) as the basis for the bargain theory.3 Equally important is the fact that contract theory became one of the most significant fields in modern economics. Three Nobel prizes have been awarded largely for work in contract theory, even though the field is less than thirty years old.4 While Gilmore was wrong in predicting that the bargain theory was dying, his instinct that something was amiss was quite prescient. But it is contract law rather than contract itself that is in severe peril. My project is to trace the causes of the decline in contract law and suggest some possible cures for what may otherwise prove to be a fatal disease. My claim, in brief, is that contract law is dying from hubris, from the belief that more contract law is always better than less. A significant effect of this expansion of liability has been a measurable increase in the costs of enforcing contracts. Ignored in this development is the fact that contract law regulates a consensual activity. This means that the parties to contractual agreements have a choice between legally enforceable contracts regulated by the state and other alternatives. The peril that public contract law faces is that many contracting parties have chosen to exit the public system of legal enforcement in favour of less costly alternatives over which they have more control. The result is that the law of contract is suffering from stagnation and, even more embarrassingly, from irrelevance. I conclude that contract law can be revived, but only if courts and legislators come to see that, in fact, less contract law is better than more. My argument has three parts. I begin by tracing the expansion of the new contract law and the resulting move from bright line rules to vague standards and contextual interpretation. Second, I describe the exodus [End Page 370] of contracting parties in response to these developments. Third, and finally, I justify returning to a parsimonious contract law by proposing self-enforcement as the preferable alternative to legal enforcement for many of those promises that fall outside the boundaries of the classical model. II The imperialism of contract law A Classical Contract Law and the Problem of Fit Contrary to Gilmore's contention, the bargain theory of contract did...

P2P‐R is the alternately spliced product of the P2P‐R/PACT gene in that P2P‐R lacks one exon encoding 34 amino acids. The 250 kDa P2P‐R protein is the predominate product expressed in multiple murine cell lines. It is a highly basic protein that contains multiple domains including an N‐terminal RING type zinc finger, a proline rich domain, an RS region, and a C‐terminal lysine‐rich domain. P2P‐R binds the p53 and the Rb1 tumor suppressors and is phosphorylated by the cdc2 and SRPK1a protein kinases. P2P‐R also interacts with scaffold attachment factor‐B (SAF‐B), a well characterized MARs (for matrix attachment regions) binding factor, and may interact with nucleolin, another MARs binding factor. In addition, P2P‐R binds single strand DNA (ssDNA). The expression of P2P‐R is regulated by differentiation and cell cycle events. P2P‐R mRNA is markedly repressed during differentiation, whereas immunoreactive P2P‐R protein levels are >10‐fold higher in mitotic than in G 0 cells. The localization of P2P‐R also is modulated during the cell cycle. During interphase, P2P‐R is present primarily in nucleoli and nuclear speckles whereas during mitosis, P2P‐R associates with the periphery of chromosomes. Overexpression of near full length P2P‐R induces mitotic arrest in prometaphase and mitotic apoptosis, and overexpression of selected P2P‐R segments also can promote apoptosis. This compendium of data supports the possibility that P2P‐R may form complexes with the Rb1 and/or p53 tumor suppressors and MARs‐related factors, in a cell cycle and cell differentiation‐dependent manner, to influence gene transcription/expression and nuclear organization. J. Cell. Biochem. 90: 6–12, 2003. © 2003 Wiley‐Liss, Inc.

Since the North American Free Trade Agreement (NAFTA) was signed in 1993, the rise in the U.S. trade deficit with Canada and Mexico through 2002 has caused the displacement of production that supported 879,280 U.S. jobs. Most of those lost jobs were high-wage positions in manufacturing industries. The loss of these jobs is just the most visible tip of NAFTA's impact on the U.S. economy. In fact, NAFTA has also contributed to rising income inequality, suppressed real wages for production workers, weakened workers' collective bargaining powers and ability to organize unions, and reduced fringe benefits. NAFTA is a free trade and investment agreement that provided investors with a unique set of guarantees designed to stimulate foreign direct investment and the movement of factories within the hemisphere, especially from the United States to Canada and Mexico. Furthermore, no protec-tions were contained in the core of the agreement to maintain labor or environmental standards. As a result, NAFTA tilted the economic playing field in favor of investors, and against workers and the environment, resulting in a hemispheric " race to the bottom " in wages and environmental quality. Proponents of new trade agreements that build on NAFTA, such as the proposed Free Trade Agreement of the Americas (FTAA), have frequently claimed that such deals create jobs and raise incomes in the United States. When the Senate recently approved President Bush's request for fast-track trade

On August 13, 2001 the National Conference of Commissioners on Uniform State Laws voted 89 to 53 to reject the 2001 Amendments to Article 2 of the Uniform Commercial Code that had just been approved in May by the American Law Institute. While negotiations continue, this public split between the two bodies that have together shepherded the UCC project for over fifty years represents the likely end of the fourteen year effort to revise the law of sales as embodied in Article 2. In this Essay, I examine the political economy of the Article 2 project from its origins to the present. I begin by analyzing the drafting and enactment process of the original Article 2 and evaluate the success of the new sales law it introduced, a success attributable in no small measure to the replacement of archaic vestiges of property law with efficient contract default rules. I then I consider the effects of the compromises Karl Llewellyn made to secure the enactment of the Code. Of particular significance is how the vague terms that invoke the commercial context (originally intended by Llewellyn as a means of incorporating ex ante default rules) have been used to challenge the objective meaning of disputed contracts. For many commercial contractors, exit may have been a cheaper option than lobbying for clearer and more predictable default rules. But the parties to mass-market sales transactions remain subject to Article 2, and their representatives have sought to influence the revision process. Thus, the focus has shifted from Llewellyn's original goal of prescribing optimal default rules for commercial contracts to the current debate over proscribing freedom of contract in mass-market transactions. The resulting divergence between the interests of producers and those of consumer buyers, computer information licensees and their representatives has produced deadlock. I conclude that the flaws in the Article 2 project were present from its inception. Given the limits of legal regulation, it is unlikely that any set of "uniform" rules that are promulgated for adoption in every state can both efficiently complete the gaps in commercial contracts as well as optimally police consumer transactions. In sum, the uniform laws process works when there is distributional symmetry (when today's buyer might be tomorrow's seller). On the other hand, the process deadlocks when it seeks to produce uniform rules for transaction-types in which the distributional effects are asymmetric and prices do not adjust efficiently to compensate for the victory of one group in the legislative process.

Mitotic cells show a tenfold increase in immunoreactive P2P-R protein. During mitosis, the distribution of P2P-R protein also changes from a primary nucleolar localization in interphase cells to the periphery of chromosome in mitotic cells. These findings suggest that P2P-R might serve a functional role in mitosis. To test this possibility, human Saos2 cells were stably transfected with P2P-R DNA constructs and the biological effects of P2P-R overexpression were evaluated. Overexpression of near full-length P2P-R was found to have paradoxical effects on the relationship between proliferation and mitosis in the nine Saos2 cell clones that were studied. A significant repression in the population doubling rates was observed in all nine clones even though a significant increase in the frequency of easily detached cells with a mitotic morphology was apparent. Flow cytometric analysis confirmed that greater than two thirds of the cells with a mitotic morphology had a 4n DNA content. Confocal microscopy further established that 85% of the mitotic cell population had prometaphase characteristics suggesting that P2P-R overexpression restricts mitotic progression at prometaphase. Many cells with a mitotic morphology also showed signs of apoptosis with prominent cell surface blebs. Confocal microscopy confirmed that 25-40% of such mitotic cells were apoptotic with chromosomal abnormalities and cell surface blebbing. In association with mitotic apoptosis, P2P-R protein appears to dissociate from the periphery of chromosomes and localize in the cytoplasm and in cell surface blebs. The presence of P2P-R in cell surface blebs was confirmed by analysis of highly enriched populations of apoptotic cell surface blebs wherein Western blotting documented the presence of 250 kDa P2P-R. These results therefore suggest that P2P-R overexpression promotes both prometaphase arrest in mitosis and mitotic apoptosis.

P2P-R is a nuclear protein that can bind both p53 and Rb1. Its functions include roles in the control of RNA metabolism, apoptosis, and p53-dependent transcription. The expression of P2P-R also is repressed in G1 arrested terminally differentiated cells. The current studies therefore evaluated if P2P-R undergoes cell cycle-associated changes in its abundance and/or localization. Western blots show that relative to G0 quiescent cells, P2P-R protein levels are higher in populations of G2/M cells prepared by the physiological parasynchronization technique of serum deprivation followed by serum stimulation. More striking is the > 10-fold enrichment of P2P-R protein in specimens of highly purified mitotic cells prepared by the mitotic shake-select technique, or by synchrony with the mitotic spindle disruption agents nocodazole or vinblastine. These changes in P2P-R protein occur without a concomitant change in P2P-R mRNA expression suggesting that P2P-R immunoreactivity increases during mitosis. Confocal microscopy next established the localization of P2P-R to nucleoli in interphase cells and at the periphery of chromosomes in mitotic cells that lack nucleoli. The high levels of P2P-R localized to the periphery of chromosomes in mitotic cells suggest that P2P-R shares characteristics with other nucleolar proteins that associate with the periphery of chromosomes during mitosis. These include: nucleolin, B23, Ki67, and fibrillarin.