Distinct roles of BMP and LKB1/AMPK signalling impacting ovarian cancer spheroid biology

High-grade serous (HGS) carcinoma, the most prevalent and most deadly subtype of epithelial ovarian cancer (EOC), presents unique therapeutic challenges since the majority of cases are diagnosed at advanced, metastatic stage. At this point widespread intraperitoneal metastatic lesions are numerous, which is why models that recapitulate disease dissemination are critical to uncover novel therapeutic targets. One of the initiating events in ovarian cancer metastasis is shedding from the primary tumour into the peritoneal cavity where cells must survive in suspension in order to seed secondary tumours. This non-adherent population of cells exists as multicellular aggregates, or spheroids; data from our lab has demonstrated that cells within spheroids are dormant, yet are readily alter their phenotype upon reattachment to an adherent substratum. To further explore the pathobiology of ovarian cancer spheroids, my thesis work describes the functional characterization of two different signalling pathways— bone morphogenetic protein (BMP), and the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)—which mediate distinct and important aspects of spheroid formation and reattachment. Activated BMP signalling resulted in smaller, loosely-aggregated spheroids, which were more readily able to reattach and disperse. These phenotypic alterations observed as a result of active BMP signalling were mediated, at least in part, by cooperation with the AKT signalling pathway. These studies implicate inhibition of BMP and AKT signalling as potential strategies for therapeutic targeting of reattaching spheroids, which is critical for the formation of secondary metastatic lesions. Other work in our lab implicated the downregulation of AKT signalling in spheroid formation-induced dormancy. In an attempt to uncover additional pathways promoting the dormant phenotype of ovarian cancer spheroids, I investigated the LKB1/AMPK signalling cascade given its ability to alter cellular metabolism in response to nutrient and energy availability. Despite a dramatic enhancement in AMPK activity observed in ovarian cancer spheroids, targeted knockdown had no effect on viability of cells in this context. However, knockdown of its upstream kinase, LKB1, revealed a dramatic decrease in ovarian cancer spheroid viability, suggesting a role for this kinase in mediating anoikis-resistance in an AMPK-independent manner. Taken together, my results have uncovered two distinct and important signalling pathways that regulate unique aspects of spheroid formation, cell survival, and reattachment. By understanding the molecular mechanisms used by ovarian cancer spheroids to survive during dissemination and promote secondary metastasis, my work has uncovered additional therapeutic targets for the potential treatment of advanced-stage ovarian cancer

Requirements of a global information system for corn production and distribution

There are no author-identified significant results in this report

Adam Smith, Collusion and “Right” at the Supreme Court

Adam Smith’s views on collusion were injected into the Supreme Court’s ruling in Bell Atlantic v. Twombly as Justice Stevens puzzled over why a collusive action might be viewed as “right.” Motivation by a desire for approbation provides Smith’s explanation for the existence of well- functioning groups. “Right” action is approved by the group. The question is what happens when the groups are in conflict. For Smith, collusion is one instance of the larger problem of faction in which a small group organizes to exploit the larger society

Not an Average Human Being : How Economics Succumbed to Racial Accounts of Economic Man

In this chapter, we shall show how the attacks on the doctrine of human homogeneity succeeded—how, late in the century, economists came to embrace accounts of racial heterogeneity entailing different capacities of optimization.1 We attribute the demise of the classical tradition largely to the ill-understood influence of anthropologists and eugenicists2 and to a popular culture that served to disseminate racial theories visually and in print. Specifically, W. R. Greg, James Hunt, and Francis Galton all attacked the analytical postulate of homogeneity that characterized classical economics from Adam Smith3 through John Stuart Mill. Greg cofounded the eugenics movement with Galton, and he persistently attacked classical political economy for its assumption that the Irishman is an “average human being,” rather than an “idiomatic” and an “idiosyncratic” man, prone to “idleness,” “ignorance,” “jollity,” and “drink” (quoted in full later in this chapter)

Numerical simulation of streamflow process in a small headwater catchment in Hong Kong

postprintThe PRAGMA 20th Workshop cum HKU Centennial IT Conference on Grid Applications and Research collaboration (PRAGMA20), Computer Centre, The University of Hong Kong, Hong Kong, China, 2-4 March 2011

Sympathy and Approbation in Hume and Smith: A Solution to the Other Rational Species Problem

This paper examines a key implication of the different conceptions of sympathy and the approbation associated with sympathy in the writings of David Hume and Adam Smith. For Hume, sympathy is an empathy we feel for those like us and hence we are motivated to obtain the praise or approbation of those with whom we sympathize. In Hume’s construction there is a direct link from sympathy to motivation because sympathy is reflected self-love. By contrast, in Smith’s construction sympathy is an act of imagination which only habit makes motivational. The abstraction by our imagination means we earn the approbation (or disapprobation) from those unlike as well as those like us. In Smith’s account we can obtain approbation as we step outside ourselves and regard our own actions dispassionately

Escape from Democracy: the Role of Experts and the Public in Economic Policy

The orthodox view of economic policy holds that public deliberation sets the goals or ends, and then experts select the means to implement these goals. This assumes that experts are no more than trustworthy servants of the public interest. David M. Levy and Sandra J. Peart examine the historical record to consider cases in which experts were trusted with disastrous results, such as eugenics, the regulatory use of security ratings, and central economic planning. This history suggests that experts have not only the public interest but also their own interests to consider. The authors then recover and extend an alternative view of economic policy that subjects experts\u27 proposals to further discussion, resulting in transparency and ensuring that the public obtains the best insights of experts in economics while avoiding pitfalls such as expert bias.https://scholarship.richmond.edu/bookshelf/1244/thumbnail.jp

Adam Smith and the Place of Faction

Our approach to faction focuses on Smith’s account of the interrelation between social distance and small group cohesion. We make the case that social distance is not necessarily constant in Smith’s system. As social distance shrinks, sympathy becomes more habitual and the affection we have for others increases (Peart and Levy, 2005b). Factions reduce social distance, and this gives them power and makes them dangerous. By modifying social distance, they created a disconnect between behavior of which we approve (cooperation) and consequences of which we disapprove. It is in this context that we find virtuous behavior with deleterious consequences. The identification of ‘corruption’ with faction is emphasized in Young (1997, pp.157-158). We take the additional step of connecting the identification to the conclusion that the institution that allows corrupt actions to flourish is in need of reform

Learning from Failure: A Review of Peter Schuck’s Why Government Fails So Often: And How It Can Do Better (Book Review)

Peter Schuck catalogs an overwhelming list of US government failures. He points to both structural problems (culture and institutions) and incentives. Despairing of cultural change, Schuck focuses on incentives. He relies on Charles Wolf ’s theory of nonmarket failures in which “internalities” replace the heavily-studied market failure from externalities (Wolf 1979). Internalities are evidence of a discord between the public goals by which a program is defended and the private goals of its administrators. What might economists contribute? We suggest that economists have neglected internalities because they take group goals as exogenously determined and we defend an alternative tradition in which group goals are endogenously determined. ( JEL A11, D72, D82

The Ethics Problem: Toward a Second-Best Solution to the Problem of Economic Expertise

The collective action problem of economic experts was diagnosed acutely by Knight and Pigou in the 1930s. The interest of economists as a group is in pursuing the public good of truth; the interest of an individual economist is in pursuing the private good of happiness. Pigou’s example is the pursuit of political influence. Deviation from truth-seeking devastates the theory of governance as objective inquiry laid out by Knight and John Rawls, as we saw in the eugenic era. We reformulate the Knight–Rawls position as truth-seeking contingent on a presupposed system. The best case for the Knight–Rawls position is transparency, where presuppositions are common knowledge. If transparency is infeasible making the nontransparency of inquiry itself transparent will serve as a second-best solution to warn third parties to make adjustments. A code of ethics can itself serve as a warning about the temptation. Pigou’s concern about nonpecuniary temptation should be added to the American Economic Association code of ethics