JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs

Responding to Incorrect ISDS Decision-Making: Policy Options

Criticism of the quality of investor-State dispute settlement (ISDS) decision-making often focuses on inconsistency (comparing ISDS decisions), and less frequently, incorrectness (evaluating individual ISDS decisions on a standalone basis). This article situates incorrect ISDS decision-making within the broader context of public international law and develops potential policy responses, guided by three considerations. First, criticism of ISDS decision-making has been significant. Second, criticism of particular ISDS decisions, even when widespread and intense, does not necessarily establish their incorrectness. Finally, development of policy options should be informed by a broad understanding of ‘incorrectness’, to include instances of questionable legal analysis that cast doubt on the reliability of ISDS legal conclusions and outcomes; that approach can support not only the avoidance of incorrect ISDS decision-making in a strict sense, but also, more expansively, the achievement of correct ISDS decision-making, consisting of two core elements: correct identification and precise application of applicable law

reconciling party autonomy and the international rule of law

This paper focuses on one particular issue which has arisen in the course of the ongoing debate on the reform of investor-State dispute settlement (ISDS), namely that of the appointment of arbitrators. Taking as its starting point that there now exists tentative consensus that the present system for the appointment of arbitrators either causes or exacerbates certain problematic aspects of the current ISDS system, the paper explores one option for reform, namely the introduction of an independent panel for the selection of investment arbitrators. In doing so, it is argued that a shift in the normative basis of the rules governing appointments is required in order to accommodate the principles of party autonomy and the international rule of law. Such reform, while not completely removing the initiative that parties presently enjoy, is the most efficient way to introduce rule of law considerations such as a measure of judicial independence into the current appointments system. This, it is argued, would in turn help to address some of the problematic features of the appointment of arbitrators in ISDS

Capture numbers and islands size distributions in models of submonolayer surface growth

The capture numbers entering the rate equations (RE) for submonolayer film growth are determined from extensive kinetic Monte Carlo (KMC) simulations for simple representative growth models yielding point, compact, and fractal island morphologies. The full dependence of the capture numbers on island size, and on both the coverage and the D/F ratio between the adatom diffusion coefficient D and deposition rate F is determined. Based on this information, the RE are solved to give the RE island size distribution (RE-ISD). The RE-ISDs are shown to agree well with the corresponding KMC-ISDs for all island morphologies. For compact morphologies, however, this agreement is only present for coverages smaller than about 5% due to a significantly increased coalescence rate compared to fractal morphologies. As found earlier, the scaled KMC-ISDs as a function of scaled island size approach, for fixed coverage, a limiting curve for D/F going to infinity. Our findings provide evidence that the limiting curve is independent of the coverage for point islands, while the results for compact and fractal island morphologies indicate a dependence on the coverage.Comment: 13 pages, 12 figure

The Right to Regulate in Investor- State Arbitration: Slicing and Dicing Regulatory Carve-Outs

This Article examines the “right to regulate” as the power of a sovereign state to adopt and maintain government measures for public welfare objectives. It explores how claims by foreign investors in investor–state dispute settlement (ISDS) may interfere with the state’s ability to regulate, and how the state can protect its right in international investment agreements. The Article first explains the structure of modern international investment law and dispute resolution. It next turns to the right to regulate and explores why regulatory disputes represent a major challenge for ISDS. It continues by analyzing how exceptions, exclusions, and other safeguard provisions can be used in investment treaties to protect the right to regulate. It then critically examines the tobacco carve-out and other safeguard provisions of the Trans-Pacific Partnership (TPP) Agreement as to their ability to protect the right to regulate. Finally, the Article explores alternative solutions to the challenges of ISDS. It concludes by arguing that regulatory disputes are best resolved through a hybrid system of dispute resolution that is amenable to both private interests and public policy considerations

Evaluating the Legitimacy of the Investor-State Dispute Settlement Mechanism for the AfCFTA

Phase two of the negotiations on the African Continental Free Trade Area (AfCFTA) has begun. This phase includes negotiating the protocol on investment. The International Investment Regime (IIR) allows foreign investors to institute proceedings against states through Investor State Dispute Settlement (ISDS), which is criticised as undergoing a ‘legitimacy crisis’. This paper assesses the legitimacy of ISDS to evaluate whether it is a suitable mode of adjudicating international investment disputes in the AfCFTA. Accordingly, it sets out the criteria to be used in assessing legitimacy and further uses these criteria to appraise the legitimacy of ISDS, ultimately demonstrating that the present ISDS framework lacks sufficient legitimacy to be adopted as the mode of adjudicating international investment disputes in the AfCFTA. This is because of the perception that ISDS is unfair and biased due to its imperial and neo-colonial background and the excessive corporate power it grants to foreign investors. ISDS is also lacking in transparency and democratic values and conflicts with the AfCFTA’s objective of sustainable and inclusive socio-economic development. The paper advocates against the inclusion of ISDS in the AfCFTA protocol on investment and asserts that the challenge is in finding a mode of adjudication that is more equitable and inclusive than ISDS

Investment provisions in trade and investment treaties: the need for reform

This repository item contains a policy brief from the Boston University Global Economic Governance Initiative. The Global Economic Governance Initiative (GEGI) is a research program of the Center for Finance, Law & Policy, the Frederick S. Pardee Center for the Study of the Longer-Range Future, and the Frederick S. Pardee School of Global Studies. It was founded in 2008 to advance policy-relevant knowledge about governance for financial stability, human development, and the environment.Nations of the world are currently negotiating a variety of significant trade and investment treaties that cover upwards of eighty percent of the world economy. The Trans-Pacific Partnership (TPP) would further integrate a number of Pacific-Rim nations; the Trans-Atlantic Trade and Investment Partnership (TTIP) would be a treaty between the United States and European countries. The United States and others are also negotiating major bilateral investment treaties (BITs) with China and India