Lead optimization of tubulin inhibitor for cancer treatment

Tubulin-containing structures are important for many important cellular functions, including chromosome segregation during cell division, development and maintenance of cell shape, cell motility, and distribution of molecules on cell membranes. The rapid growth of cancer cells makes them very sensitive to the disruption of tubulin polymerization/depolymerization. Taxol (paclitaxel), a tubulin inhibitor approved by the FDA in 1992 for cancer treatment, is one of the most powerful chemotherapeutic agents. However, the low water solubility and drug resistance limits its clinical application. Various effort in drug discovery field focuses on more water soluble smaller molecular tubulin inhibitors. Our previous study led to the discovery of tubulin inhibitors with IC50s below 1nM to inhibit cancer cell proliferation, and these compounds have much small molecular weight than Taxol. In addition, our compounds showed promising in vivo anti-cancer activity as well. To further improve the druggable characteristics of our drug candidates, we focus on the ligand efficiency of these compounds in the current proposed study. A series of new analogs were designed and synthesized, and their structures were elucidated with NMR spectrum. Their anti-cancer activity was determined with breast cancer cell lines. Several new compounds exhibited promising anti-cancer activity.https://engagedscholarship.csuohio.edu/u_poster_2015/1017/thumbnail.jp

RNase L contributes to lipid metabolism

Macrophage-derived foam cell formation is a milestone of the atherosclerotic lesion initiation and progression, leading to cardiovascular diseases and stroke. Foam cells are formed from the disruption of a homeostatic mechanism that manipulates the uptake, intracellular metabolism and efflux of cholesterol within macrophages. Although studies have yielded much information about the homeostatic mechanism, the molecular basis of foam cell formation remains to be fully understood. We recently found that deficiency of RNase L attenuated macrophage functions including macrophage migration and its endocytic activity. Furthermore, RNase L markedly impacted the expression of certain pro- and anti-foam cell genes in macrophages. Most interestingly we have revealed that lack of RNase L significantly increased the formation of foam cells from bone marrow derived macrophages (BMMs). The increase of foam cell formation was associated with up-regulation of the expression of scavenger receptors such as CD36, SR-A, and PPAR-g. These studies provide new insights into foam cell formation and novel therapeutic strategies for atherosclerosis may be designed through activation/up-regulation of RNase L.https://engagedscholarship.csuohio.edu/u_poster_2014/1001/thumbnail.jp

Copalic Acid Analogs Down-regulate Androgen Receptor and Inhibit Small Chaperone Protein

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well

Copalic Acid Analogs Down-regulate Androgen Receptor and Inhibit Small Chaperone Protein

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well

Hedge Funds, Financial Intermediation, and Systemic Risk

Hedge funds are significant players in the U.S. capital markets, but differ from other market participants in important ways such as their use of a wide range of complex trading strategies and instruments, leverage, opacity to outsiders, and their compensation structure. The traditional bulwark against financial market disruptions with potential systemic consequences has been the set of counterparty credit risk management (CCRM) practices by the core of regulated institutions. The characteristics of hedge funds make CCRM more difficult as they exacerbate market failures linked to agency problems, externalities, and moral hazard. While various market failures may make CCRM imperfect, it remains the best line of defense against systemic risk

Inhibition of StearoylCoA Desaturase-1 Inactivates Acetyl-CoA Carboxylase and Impairs Proliferation in Cancer Cells: Role of AMPK

Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Δ9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetylCoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation

Understanding the Securitization of Subprime Mortgage Credit

In this paper, we provide an overview of the subprime mortgage securitization process and the seven key informational frictions that arise. We discuss the ways that market participants work to minimize these frictions and speculate on how this process broke down. We continue with a complete picture of the subprime borrower and the subprime loan, discussing both predatory borrowing and predatory lending. We present the key structural features of a typical subprime securitization, document how rating agencies assign credit ratings to mortgage-backed securities, and outline how these agencies monitor the performance of mortgage pools over time. Throughout the paper, we draw upon the example of a mortgage pool securitized by New Century Financial during 2006

Organizational Discourse: Domains, Debates, and Directions

Interest in the analysis of organizational discourse has expanded rapidly over the last two decades. In this article, we reflect critically on organizational discourse analysis as an approach to the study of organizations and management, highlighting both its strengths and areas of challenge. We begin with an explanation of the nature of organizational discourse analysis and outline some of the more significant contributions made to date. We then discuss existing classifications of approaches to the study of organizational discourse and suggest that they fall into two main categories: classifications by level of analysis and classifications by type of method. We argue that both of these approaches are inherently problematic and present an alternative way to understand the varieties of approaches to the analysis of organizational discourse based on within domain and across domain characterizations. We conclude with a discussion of the challenges that remain in the development of organizational discourse as an area of study and point to some of the opportunities for important and unique contributions to our understanding of organizations and management that this family of methods brings. © 2012 Copyright Academy of Management

The Bankruptcy Abuse Prevention and Consumer Protection Act: Means-Testing or Mean Spirited?

Thousands of U.S. households filed for bankruptcy just before the bankruptcy law changed in 2005. That rush-to-file was more pronounced, we find, in states with more generous bankruptcy exemptions and lower credit scores. We take that finding as evidence that the new law effectively reduces exemptions, which in turn should reduce the “demand” for bankruptcy and the resulting losses to suppliers of consumer credit. We expect the savings to suppliers will be shared with borrowers by way of lower credit card rates, although credit card spreads have not yet fallen. If cheaper credit is the upside of the new law, the downside is reduced bankruptcy “insurance” against bad luck. The overall impact of the new law on the average household depends on how one weighs those two sides