Johan Swinnen

A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance.

PURPOSE We identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib. MATERIALS AND METHODS We performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay. RESULTS Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions. CONCLUSIONS In our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment.

TRIIODOTHYRONINE MODULATES GROWTH, SECRETORY FUNCTION AND ANDROGEN RECEPTOR CONCENTRATION IN THE PROSTATIC CARCINOMA CELL LINE LNCAP

There is increasing evidence that the course of prostatic carcinoma is determined by a complex interplay between genetic events, paracrine interactions, and hormonal and dietary factors. These latter factors include several ligands of the nuclear receptor family such as androgens, vitamin D3 and retinoids. To test whether thyroid hormones also influence the growth and differentiated function of prostatic carcinoma cells, LNCaP cells were treated with or without triiodothyronine (T3) in the absence or in the presence of other regulatory factors. Exposure of LNCaP cells to T3 for 6 days in the absence of androgens caused a dose-dependent increase in [3H]-thymidine incorporation with a maximal stimulation of 2.5-fold at 10(-9) M T3. Secretion of prostate-specific antigen (PSA) was also stimulated 2-3-fold. The observed effects may well be mediated by a nuclear T3 receptor as evidenced by displaceable T3 binding studies. Combined treatment of LNCaP cells with androgens and T3 revealed intriguing interactions between these two pathways. Below and up to 10(-10) M of the synthetic androgen R1881, the concentration that evokes optimal proliferative responses, T3 stimulated [3H] thymidine incorporation. At higher concentrations of androgens, T3 displayed antiproliferative effects. No androgen-dependent effects on T3 receptor levels were observed. Conversely, T3 increased androgen receptor levels up to twofold. Androgen as well as T3 stimulation of proliferation was abolished by high concentrations of the retinoid 9-cis-retinoic acid. These data add T3 to the list of factors that influence growth and differentiation of prostatic tumor cells and contribute to our understanding of the intricate pathways that ultimately determine the course of prostatic carcinoma.

How Distorted Have Agricultural Incentives Become in Europe's Transition Economies?

Over the past two decades, earnings from farming in the former communist countries of Eastern Europe and Central Asia have been altered hugely by government sectoral and trade policy reforms. This paper summarizes evidence on the changing extent of distortions to markets for farm products since the transition away from planned prices began. In particular, it examines the extent to which, following initial shocks, there has been a gradual improvement in farmer incentives. This new evidence is not inconsistent with the past pattern of earlier-developing countries, but the speed of assistance increase is relatively rapid and is linked with actual or desired accession to the European Union. The final section focuses on future prospects, particularly what might be done to prevent agricultural protection levels from becoming excessive.

The development of agricultural policies in Central and Eastern Europe: An endogenous policy theory perspective

Abstract Agricultural and food subsidies and fixed prices, imposed by the old central command system, have been abolished recently throughout Central and Eastern Europe (CEE). However, protectionist government regulations have been reintroduced. This Viewpoint argues that these policy changes are consistent with the results from the literature on new political economy or endogenous policy theory. Moreover, as privatization of farms continues and the non-agricultural sectors of the economy start growing, this theory predicts that protectionist policies will increase in the agricultural sector in Central and Eastern Europe. In addition, agricultural protectionism in Western countries stimulates the increase in CEE agricultural protectionism.

Political Power and Economic Policy: Public Policy: The Lens of Political Economy

Introduction Conflicts between the public interest and special interests naturally emerge in the design and implementation of public policies. Some public policies pursue the public interest by attempting to correct for market imperfections, lower transaction costs, effectively regulate externalities, or enhance productivity. Still other public policies are the result of manipulation by powerful groups actively engaged in the pursuit of their own self-interest. Regardless, conceptual formulations that attempt to explain or prescribe public policy emphasizing only one type of interest are doomed to fail. Frameworks that neglect the role of special-interest groups have little explanatory power. Models that presume that government has neither autonomy nor any interest in the size of the economic pie will also face serious limitations as an explanatory, predictive, or prescriptive framework. In any public-policy-making process, political and economic forces are at play in resolving the strategic interactions among the various interests. A schematic representation of the policy-making process reflecting these forces is represented in Figure 1.1. Historically, the right-hand box has been the domain of political science and the left-hand box has been the domain of economics. At the top of the right-hand box, particular governance structures set the constitutional design establishing voting rules, the rule of law, property rights, laws governing exchange, and more generally the rules by which rules are made. Governance structures also determine the nature and scope of the political feedback mechanisms of groups affected by public policies.

S15-03 Activation of Wnt/β-catenin signalling in Xenopus embryos and cancer cells by de novo lipogenesis is associated with impaired formation of the primary cilium

The specification of cell types in the ventral half of the mouse neural tube depends on graded activity of the Sonic hedgehog (Shh) signaling pathway. Our genetic studies on neural patterning led to the surprising discovery that primary cilia are required for mammalian cells to transmit signals from the membrane protein Smoothened (Smo) to the Gli transcription factors. To understand why the primary cilium is an appropriate venue for Shh signal transduction, we are investigating the relationships among cilia genes and between cilia genes and the components of the Shh pathway that act between Smo and Gli proteins. Protein kinase A (PKA) is a conserved negative regulator that acts at that step of the pathway. We find that embryos that lack all PKA catalytic activity show a very strong activation of the pathway, and our data indicate that PKA activity depends on the presence of cilia. Costal2 is a negative regulator of the Shh pathway, and we find that the mouse homologue of Costal2, Kif7, has complex roles as both a negative and positive regulator of Shh signaling. Kif7 activity also depends on cilia, and the Kif7 protein appears to act as a motor within cilia. Finally, certain combinations of mutations in proteins that affect transport within the cilium partially restore normal Hedgehog signaling, suggesting that the balance of anterograde and retrograde trafficking within the cilium can control the level of signal output.