PKCα and PKCδ Regulate ADAM17-Mediated Ectodomain Shedding of Heparin Binding-EGF through Separate Pathways

Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCα as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCδ and ERK activity. While PKCα specifically regulated PMA-induced shedding, PKCδ and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction

Key Legislative and Jurisprudential Developments of Polish Antitrust Law in 2012

This article has two objectives. First, it presents the most important developments of Polish antitrust legislation of 2012. These include recent amendments to legal provisions on judicial antitrust proceedings contained in the Code of Civil Procedure, and some novel issues in the area of non-binding guidelines of the Polish NCA, the UOKiK President. Second, the article introduces key developments in Polish competition law jurisprudence of 2012. It characterises selected rulings delivered by the Polish Supreme Court, the Court of Appeals in Warsaw and the Court of Competition and Consumer Protection. Judgments are divided according to their subject matter.Cet article a deux objectifs. Premièrement, il présente les développements les plus importants de la législation antitrust polonais de 2012. Il s'agit notamment de récentes modifications apportées à des dispositions juridiques en matière de procédure antitrust judiciaires qui se trouve dans le Code de procédure civile, et quelques nouvelles questions dans le domaine des lignes directrices non-contraignantes de l'Autorité natinale du contrôle polonaise, le président de l’Organe pour la protection de la concurrence et des consommateurs (UOKiK). Deuxièmement, l'article présente les développements principaux en matière de jurisprudence de 2012 relative à la loi polonaise de la concurrence. Il caractérise des jugements sélectionnés prononcés par la Cour suprême polonaise, la Cour d'appel de Varsovie et la Cour de la concurrence et de la protection des consommateurs. Les jugements sont présentés selon les sujects qu’ils concernent

Collecting Evidence Through Access to Competition Authoritiess Files Interplay or Potential Conflicts between Private and Public Enforcement Proceedings?

Information asymmetry between claimants seeking damages for competition law violations and the alleged infringing undertaking(s) is a key problem in the development of private antitrust enforcement because it often prevents successful actions for damages. The Damages Directive is a step forward in the facilitation of access to evidence relevant for private action claims. Its focus lies on, inter alia, 3rd party access to files in proceedings conducted by national competition authorities (NCAs). The harmonization was triggered by the inconsistencies in European case-law and yet the uniform rules on access to documents held in NCAs’ files proposed in the Damages Directive seem to follow a very stringent approach in order to protect public competition law enforcement. The article summarizes the most relevant case-law and new provisions of the Damages Directive and presents practical issues with respect to its implementation from the Polish perspective

Commitment Decisions Under the Polish Competition Act – Enforcement Practice and Future Perspectives

The aim of this paper is to provide an analysis of the commitments procedure under the Polish competition law, including both legal and economic perspective. The outcome of this research is supposed to help in estimation whether novel negotiated instruments may be successfully employed in the field of antitrust enforcement. Hence, the paper first introduces the legal background of the commitments decisions, with focus on the specific features of the procedure. Being a tool of antitrust enforcement, commitment decisions should contribute to its goals. Therefore, the paper identifies such objectives drawing on the economic literature. It is in the light of these criteria that the decision practice of the Polish competition authority, still in the stage of development, is subsequently evaluated. This assessment reveals circumstances, under which the competition authority is particularly apt to engage into commitments procedure. It allows also for a conclusion that the application of this negotiated instrument is in principle commensurate with the exigencies following from economic theory.Le but de cet article est de présenter une analyse de la procédure d’engagements en droit polonais de la concurrence, d’un point de vue juridique et économique. Le résultat de cette recherche permettra d’estimer l’efficacité de ces nouvelles procédures négociées dans le domaine du droit de la concurrence. Ainsi, l’article introduit le cadre juridique de la procédured’engagements en Pologne, en se focalisant sur les éléments spécifiques d’un tel mécanisme. Instrument de mise en œuvre du droit de la concurrence, la procédure d’engagements devrait contribuer à accomplir les buts de cette politique. Par conséquent, l’article essaie d’identifier de tels objectifs, en s’appuyant sur la littérature économique. La pratique décisionnelle de l’autorité de la concurrence polonaise est par la suite analysée à la lumière de ces critères, tout en gardant à l’esprit qu’elle n’en est qu’à ses prémisses. Cette analyse revèle les circonstances dans lesquelles l’autorité de la concurrence est particulièrement susceptible de mettre en œuvre une procédure d’engagements. Elle nous permet aussi de constater que l’application des procédures négociées en Pologne est, en principe, conforme aux exigences relevant de la théorie économique. Néanmoins, quelques suggestions visant à l’amélioration de la procédure d’engagements sont proposées, au cas où cela soit nécessaire

Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial.

PURPOSE: External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE). METHODS: In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS). RESULTS: A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm ( CONCLUSION: Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted