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US–Renewable Energyis the last in a series of WTO disputes involving subsidies schemes with local content requirements. Local content requirements (LCRs) are highly discriminatory and trade distortive instruments and therefore all cases concerning green energy have been found to violate WTO law. However, recent jurisprudence has developed a different definition of prohibited LCRs under the GATT and the SCM agreement, the latter allowing for some leeway to define origin of products under a government subsidy scheme. Depending how the subsidy scheme is framed, it will be able to be excused from the GATT's more stringent prohibition of LCRs, this raises question of consistency in the application of the LCRs prohibition. Moreover, we review a simple and robust approach that modern welfare economics suggests for framing discussions of subsidy policy. We apply this approach to the case of renewable energy subsidies and discuss some complexities with respect to local content requirements. In conclusion, this allows us to critically assess and review proposals to increase coherence between WTO subsidy policy and green energy promotion policies and submit proposals to achieve better suited WTO subsidy rules.

Background Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal, and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, have failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials. Methods We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples. Results Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen-related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype. Conclusion This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.

The European Union (EU) can only act internationally on competences that have been transferred to it by its Member States. Trade agreements negotiated by the EU that include provisions outside its exclusive competences should be concluded as ‘mixed’. Mixed trade agreements must be ratified following not only the procedures set out in the EU treaties, but also the national ratification procedures of the Member States. As a result, national or even regional parliaments may block trade deals agreed between the EU and its trading partners after years of negotiations. Should the EU then avoid negotiating mixed trade agreements? We argue that the answer to this question depends crucially on the objectives of the EU when negotiating with its trading partners. If the EU is mostly driven by market-access motives, it should restrict the agreement to policy areas under its exclusive competence, thus insulating the trade deal from the legal and political risks of mixity. When instead its motives are mostly political, mixity is a ‘necessary evil’ to achieve non-trade objectives. Trade Agreements, European Unity, Competences, Ratification Procedures

US-Renewable Energy is the last in a series of WTO disputes involving subsidies schemes with local content requirements. Local content requirements (LCRs) are highly discriminatory and trade distortive instruments and therefore all cases concerning green energy have been found to violate WTO law. However, recent jurisprudence has developed a different definition of prohibited LCRs under the GATT and the SCM agreement, the latter allowing for some leeway to define origin of products under a government subsidy scheme. Depending how the subsidy scheme is framed, it will be able to be excused from the GATT’s more stringent prohibition of LCRs, this raises question of consistency in the application of the LCRs prohibition. Moreover, we review a simple and robust approach that modern welfare economics suggests for framing discussions of subsidy policy. We apply this approach to the case of renewable energy subsidies and discuss some complexities with respect to local content requirements. In conclusion, this allows us to critically assess and review proposals to increase coherence between WTO subsidy policy and green energy promotion policies and submit proposals to achieve better suited WTO subsidy rules.

Funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 770680 (RESPECT).

Published: 02 April 2020 We critically assess the Appellate Body (AB) report on the Brazil–Taxation dispute, taken to the World Trade Organisation by the European Union and Japan, and encompassing seven different Brazilian industrial programmes granting tax benefits to different firms and products. The trigger of the dispute was most likely the automotive sector programme, instituted under pressure from the local industry and without much attention to effects on consumers or imports. The resulting WTO case underscores some salient issues related to the WTO compatibility of subsidy programmes, in particular the application of the National Treatment rules to subsidies provided exclusively to domestic producers, and the identification of local content requirements, prohibited under the Agreement on Subsidies and Countervailing Measures (SCM). The AB diverged from the Panel report and its jurisprudence on those issues. The AB tried to reconcile the existence of legitimate eligibility criteria in subsidy programmes and their discriminatory features with WTO rules under the General Agreement on Tariffs and Trade and the SCM. However, the legal test, developed by the AB in this dispute to distinguish prohibited local content requirements from legitimate eligibility criteria, may facilitate circumvention of the SCM prohibition of local content requirements and have important impacts on trade flows. Puccio acknowledges the receipt of funding under the H2020 grant agreement project ‘Realizing Europe's Soft Power in External Cooperation and Trade (RESPECT),’ grant agreement no. 77068.

PKR-like kinase (PERK) plays a significant role in inducing angiogenesis in various cancer types including glioblastoma. By proteomics analysis of the conditioned medium from a glioblastoma cell line treated with a PERK inhibitor, we showed that peptidylglycine α-amidating monooxygenase (PAM) expression is regulated by PERK under hypoxic conditions. Moreover, PERK activation via CCT020312 (a PERK selective activator) increased the cleavage and thus the generation of PAM cleaved cytosolic domain (PAM sfCD) that acts as a signaling molecule from the cytoplasm to the nuclei. PERK was also found to interact with PAM, suggesting a possible involvement in the generation of PAM sfCD. Knockdown of PERK or PAM reduced the formation of tubes by HUVECs in vitro. Furthermore, in vivo data highlighted the importance of PAM in the growth of glioblastoma with reduction of PAM expression in engrafted tumor significantly increasing the survival in mice. In summary, our data revealed PAM as a potential target for antiangiogenic therapy in glioblastoma.

BACKGROUND Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis, even with surgical and chemoradiotherapy. Expression profiling studies classify IDH-wildtype Glioblastoma into three subtypes: Proneural (PN), mesenchymal (MES) and classical (CL). A promising target to inhibit in Glioblastoma is the non-receptor tyrosine kinase and proto-oncogene SRC. After robust pre-clinical results, SRC inhibitors like dasatinib did not improve survival of Glioblastoma patients after recurrence in clinical trials. MATERIAL AND METHODS Consolidating efforts to personalize cancer therapy, we use in silico analyses backed by in vitro and in vivo experiments on Glioblastoma stem-like cells (GSCs) derived from primary patient tumors to present a novel stratification strategy for dasatinib therapy in glioblastoma. To further tackle dasatinib resistance in GSCs, a pooled shRNA library against 5000 genes was combined with dasatinib to identify genes whose knockdown sensitizes GSCs to dasatinib. This was integrated with proteomics and phosphoproteomics data of dasatinib inhibited GSCs. RESULTS We found MES tumors with high expression of SERPINH1 to be sensitive to dasatinib inhibition, compared to the CL and PN subtypes. Interestingly, SRC phosphorylation status did not predict the efficacy of dasatinib inhibition. Computational analyses integrating data from the loss-of-function dropout viability screen and proteomics/phosphoproteomics using a novel modification of the SamNet algorithm identified Wee1, a tyrosine kinase involved in cell-cycle signaling, as a potential combination inhibition target with dasatinib. Further validation experiments showed a robust synergistic effect through combination of dasatinib and the wee1 inhibitor, MK-1775 in PN GSCs. CONCLUSION This study highlights strategies to optimize dasatinib treatment in different glioblastoma subtypes. While the stratification of patients harboring mesenchymal glioblastoma with SERPINH1 overexpression could provide an option in this particular subtype, combining dasatinib or other SRC inhibitors with Wee1 inhibitors could present an additional possibility for treating resistant proneural tumors

The Brazil-Taxation dispute concerns the complaints taken to the World Trade Organisation by the European Union and Japan against seven different Brazilian industrial subsidy programmes. One concerned the automotive sector and represents a clear case of policies dictated by strong domestic political-economy forces, with little attention to impacts on consumers or imports. The ensuing WTO dispute raises important issues concerning the WTO-compatibility of subsidy measures. In particular, the Appellate Body (AB) reversed the panel findings with respect to two issues: the extent to which subsidy measures can be exempted from complying with National Treatment rules under the General Agreement on Tariffs and Trade, and the identification of local content requirements (LCRs), which are prohibited under the Agreement on Subsidies and Countervailing Measures (SCM). In particular, the AB considered that subsidies, if not based on discriminatory taxation, could be justified under the GATT and could have some discriminatory elements without violating the National Treatment disciplines. Furthermore, it concluded that legitimate eligibility criteria under a subsidy programme should not be construed as prohibited LCRs under the SCM. However, the test devised by the AB to distinguish legitimate eligibility criteria from prohibited LCRs could facilitate circumvention of the LCRs prohibition under the SCM.

Most of the recent literature on the European Parliament’s (EP) role in trade policy focuses on the new, post-Lisbon, legislative and ratification powers. This contribution instead analyses the monitoring role and argues that the EP’s incentive to monitor the implementation of EU trade policy has increased significantly after the Lisbon Treaty. Adopting an interdisciplinary approach, the chapter examines the rationale for the EP’s monitoring of EU trade policy implementation and links this to the different monitoring instruments at the institution’s disposal. It concludes with some of the key findings from a survey conducted on the EP’s monitoring of three areas of trade policy, namely free trade agreements, trade defence instruments and the Generalized Scheme of Preferences.

In a previous study, Protein Kinase C iota (PRKCI) emerged as an important candidate gene for glioblastoma (GBM) stem-like cell (GSC) survival. Here, we show that PKCι is overexpressed and activated in patient derived GSCs compared with normal neural stem cells and normal brain lysate, and that silencing of PRKCI in GSCs causes apoptosis, along with loss of clonogenicity and reduced proliferation. Notably, PRKCI silencing reduces tumor growth in vivo in a xenograft mouse model. PKCι has been intensively studied as a therapeutic target in non-small cell lung cancer, resulting in the identification of an inhibitor, aurothiomalate (ATM), which disrupts the PKCι/ERK signaling axis. However, we show that, although sensitive to pharmacological inhibition via a pseudosubstrate peptide inhibitor, GSCs are much less sensitive to ATM, suggesting that PKCι acts along a different signaling axis in GSCs. Gene expression profiling of PRKCI-silenced GSCs revealed a novel role of the Notch signaling pathway in PKCι mediated GSC survival. A proximity ligation assay showed that Notch1 and PKCι are in close proximity in GSCs. Targeting PKCι in the context of Notch signaling could be an effective way of attacking the GSC population in GBM.

Recent decades have witnessed a surge of trade in intermediate goods and a proliferation of free trade agreements (FTAs). FTAs use rules of origin (RoO) to distinguish goods originating from member countries from those originating from third countries. In this paper, we show that the sourcing restrictions embedded in RoO greatly distort trade in intermediaries. We focus on the North American Free Trade Agreement (NAFTA), the world's largest FTA, and construct a unique dataset that allows us to map the input‐output linkages in its RoO. Using a difference‐in‐differences approach, we find that RoO on final goods reduced imports of intermediate goods from third countries by around 30 percentage points. Even if external tariffs are unchanged, FTAs may thus violate multilateral trade rules, by substantially increasing the level of protection faced by non‐members.

Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside–nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state.

In a previous study, Protein Kinase C iota (PRKCI) emerged as an important candidate gene for glioblastoma (GBM) stem-like cell (GSC) survival. Here, we show that PKCι is overexpressed and activated in patient derived GSCs compared with normal neural stem cells and normal brain lysate, and that silencing of PRKCI in GSCs causes apoptosis, along with loss of clonogenicity and reduced proliferation. Notably, PRKCI silencing reduces tumor growth in vivo in a xenograft mouse model. PKCι has been intensively studied as a therapeutic target in non-small cell lung cancer, resulting in the identification of an inhibitor, aurothiomalate (ATM), which disrupts the PKCι/ERK signaling axis. However, we show that, although sensitive to pharmacological inhibition via a pseudosubstrate peptide inhibitor, GSCs are much less sensitive to ATM, suggesting that PKCι acts along a different signaling axis in GSCs. Gene expression profiling of PRKCI-silenced GSCs revealed a novel role of the Notch signaling pathway in PKCι mediated GSC survival. A proximity ligation assay showed that Notch1 and PKCι are in close proximity in GSCs. Targeting PKCι in the context of Notch signaling could be an effective way of attacking the GSC population in GBM.

The concept of cancer stem-like cells (CSCs) has gained considerable attention in various solid tumors including glioblastoma, the most common primary brain tumor. This sub-population of tumor cells has been intensively investigated and their role in therapy resistance as well as tumor recurrence has been demonstrated. In that respect, development of therapeutic strategies that target CSCs (and possibly also the tumor bulk) appears a promising approach in patients suffering from primary brain tumors. In the present study, we utilized RNA interference (RNAi) to screen the complete human kinome and phosphatome (682 and 180 targets, respectively) in order to identify genes and pathways relevant for the survival of brain CSCs and thereby potential therapeutical targets for glioblastoma. We report of 46 putative candidates including known survival-related kinases and phosphatases. Interestingly, a number of genes identified are involved in metabolism, especially glycolysis, such as PDK1 and PKM2 and, most prominently PFKFB4. In vitro studies confirmed an essential role of PFKFB4 in the maintenance of brain CSCs. Furthermore, high PFKFB4 expression was associated with shorter survival of primary glioblastoma patients. Our findings support the importance of the glycolytic pathway in the maintenance of malignant glioma cells and brain CSCs and imply tumor metabolism as a promising therapeutic target in glioblastoma.

Summary Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers., Highlights • shRNA screen identified kinases that alter GSC viability in a subtype-dependent manner • AXL is highly expressed in mesenchymal GSCs • Targeting AXL decreases mesenchymal GSC self-renewal, viability, and tumorigenicity • AXL expression predicts poor prognosis in several tumor types, To identify mechanistic differences between the mesenchymal and proneural glioblastoma subtypes, Goidts, Nakano, and colleagues performed a phenotypic screen, silencing the whole kinome in patient-derived mesenchymal and proneural glioblastoma stem-like cells (GSCs). AXL was identified as an important regulator of mesenchymal GSC viability and tumorigenicity, making it an attractive therapeutic target.

In a world of increasing globalisation and liberalisation, production and value chains become global with inputs sourced from all over the world and production processes being scattered across countries. This tendency renders more difficult the definition of origin of a good. However, being trade liberalisation still far from non-discriminatory, the concept of origin becomes cardinal for the granting of benefits, as well as for sanctioning unfair trade practices. Globalisation has therefore brought forward a multiplication of varieties of domestic contents regulations imposed by States or groups of States (in bilateral or regional regimes) in order to discriminate between the goods receiving benefits and those whose exports are subject to trade remedies. We are going to consider here two regimes that involve, inter alia, the use of domestic content rules, preferential trade regimes and their preferential rules of origin regimes, and anti-dumping circumvention rules. Very few authors (if none) have treated jointly the question of WTO regulation of preferential rules of origin and anti-circumvention rules. However, both regulations, albeit being different and occurring in different contexts, have similarities in their objectives and in the challenges they create to the WTO legal system. Through the analysis of preferential rules of origin and anti-dumping circumvention measures, the article’s main objective is also to have a broader reflection on the concept of circumvention at large and its discipline within the WTO system.

The International Monetary Fund (IMF) was created at Bretton Woods, with the aim of promoting monetary cooperation, facilitate growth and trade, and maintain exchange rate stability. Such exchange rate stability was considered fundamental for the smooth development of trade relations. The Union's representation at the IMF is an example of the complexities involved in the delimitation of European Union(EU) external relations competences. The Economic and Monetary Union is characteristic of a double-speed and asymmetric policy. Indeed, while some Member States have united in a currency union, others have chosen to preserve their own currency. While economic policy is only subject to coordination, for members of the Euro zone, monetary policy is an exclusive competence. In the future though, it is more likely that the greater political opposition of Member States towards rationalizing their IMF chairs will be countered by sustained pressure from developing countries. Keywords:Economic union; European Union(EU); International Monetary Fund (IMF); Member States; Monetary Union

This Working Paper is a collection of contributions presented during the Workshop Framework for Economic Development in EU External Relations on 22nd and 23rd January 2010. The contributions explore various facets of what is known as economic development and what with time has incorporated many new aspects and developed links with other policy fields. Starting off with the traditional realm of the development policies – trade – the paper shifts to explore how the solely economic notion of development has been enhanced through the introduction of the concept of sustainable development, and how this concept was integrated into two policy areas – that of migration and human rights. Each of the contributors provides an in-depth analysis of a respective facet which build up a very complex picture of what economic development in EU external relations has become.

Chromosomal band 11q13 is frequently amplified in oral squamous cell carcinoma (OSCC) and assumed to be critically involved in tumor initiation and progression by proto-oncogene activation. Though cyclin D1 (CCND1) is supposed to be the most relevant oncogene, several additional putative candidate genes are inside this chromosomal region, for which their actual role in tumorigenesis still needs to be elucidated. To characterize the 11q13 amplicon in detail, 40 OSCCs were analyzed by comparative genomic hybridization to DNA microarrays (matrix-CGH) containing BAC clones derived from chromosomal band 11q13. This high-resolution approach revealed a consistent amplicon about 1.7 Mb in size including the CCND1 oncogene. Seven BAC clones covering FGF3, EMS1, and SHANK2 were shown to be frequently coamplified inside the CCND1 amplicon. Subsequent analysis of tissue microarrays by FISH revealed amplification frequencies of 36.8% (88/239) for CCND1, 34.3% (60/175) for FGF3, 37.4% (68/182) for EMS1, and 36.3% (61/168) for SHANK2. Finally, quantitative mRNA expression analysis demonstrated consistent overexpression of CCND1 in all tumors and of EMS1 and SHANK2 in a subset of specimens with 11q13 amplification, but no expression of FGF3 in any of the cases. Our study underlines the critical role of CCND1 in OSCC development and additionally points to the functionally related genes EMS1 and SHANK2, both encoding for cytoskeleton-associated proteins, which are frequently coamplified with CCND1 and therefore could cooperatively contribute to OSCC pathogenesis.