The growing participation of international organizations and non-state actors in international litigation:: An empirical map of the International Court of Justice

Over the last decades, Intergovernmental organizations have increased their involvement in the process of international law-making. Recent changes also include the participation of new actors and a more influential role of the judicial bodies attached to Intergovernmental organizations (IGOs). Having the International Court of Justice (ICJ) as a focus, this analysis will address the potential and limits of the participation of IGOs and Non-State Actors (NSAs) in contentious and advisory proceedings. Amici curiae ‘are those actors who do not themselves have a legally protected interest in the particular case and yet want to intervene’, thereby opening bilateral litigation to issues of public or general interest. The ICJ Statute and Rules of Court contain no provision providing for amicus curiae participation in contentious cases. A similar situation occurs as far as advisory proceedings are concerned: there is no express provision for amicus curiae participation. There is no doubt that ICJ procedural law remains outdated and disconnected from the contemporary developments characterizing the international community nowadays. The participation of members of the international society in law-making has become one of the basic features of international law. By applying empirical research methodology for mapping the ICJ practice concerning the submission of relevant information to the Court, this research aims to discuss the limits and the potentials of the available mechanisms for ensuring the participation of IGOs and NSAs in contentious cases and advisory proceedingsNas últimas décadas, as organizações intergovernamentais aumentaram seu envolvimento no processo de elaboração do direito internacional. Mudanças recentes incluem a participação de novos atores e um papel mais influente dos órgãos judiciais ligados às organizações internacionais. Tendo como foco a Corte Internacional de Justiça (CIJ), esta análise abordará o potencial e os limites da participação de organizações intergovernamentais (OI) e atores não estatais em processos contenciosos e consultivos. Amici curiae “são aqueles atores que não têm um interesse legalmente protegido no caso particular e intencionam intervir”, abrindo assim o litígio bilateral para questões de interesse público ou geral. O Estatuto da CIJ e o seu Regulamento não contêm nenhuma disposição que preveja a participação como amicus curiae em casos contenciosos. Situação semelhante ocorre no que se refere aos procedimentos consultivos: não há previsão expressa de participação. Não há dúvida de que os procedimentos da CIJ permanecem desatualizados e desconectados dos desenvolvimentos contemporâneos que caracterizam a comunidade internacional atualmente. A participação dos membros da sociedade internacional no processo legislativo tornou-se uma das características básicas do direito internacional. Ao aplicar metodologia de pesquisa empírica para mapear a prática da CIJ no que diz respeito ao envio de informações relevantes ao Tribunal, esta pesquisa visa discutir os limites e as potencialidades dos mecanismos disponíveis para garantir a participação de OIs e atores não estatais em casos contenciosos e procedimentos consultivos

Cutaneous Angiomyolipoma—A Distinct Entity That Should Be Separated From Classic Angiomyolipoma: Complete Review of Existing Cases and Defining Fundamental Features

Cutaneous angiomyolipoma is a rare mesenchymal tumor that is demographically, clinically, and immunohistochemically distinct from its renal and extrarenal counterparts. We present a case of cutaneous angiomyolipoma in the right retroauricular area of a 35-year-old male patient and provide a broad systematic review of the literature and the largest compilation of cutaneous angiomyolipomas reported to date. According to the findings presented in this review, we conclude that cutaneous angiomyolipoma should be completely separated from renal and extrarenal angiomyolipomas and therefore be considered a distinct entity in the classification of skin tumors

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

The epithelial–mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer

Regulation of Epithelial-Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

The epithelial-mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90

Role of the E3 Ubiquitin-Ligase Hakai in Intestinal Inflammation and Cancer Bowel Disease

[Abstract] The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.This work was supported by Plan Estatal I + D + I 2013−2016, co-funded by the Instituto de Salud Carlos III (ISCIII, Spain) under grant agreements PI18/00121 and PI21/00238 and by Fondo Europeo de Desarrollo Regional (FEDER) “A way of Making Europe”. The project that gave rise to these results has received funding from ”la Caixa” Foundation and the European Institute of Innovation and Technology, EIT (body of the European Union that receives support from the European Union’s Horizon 2020 research and innovation program), un-der the grant agreements LCF/TR/CI19/52460016 and LCF/TR/CC21/52490003. Also supported by Consolidation of Competitive Research (IN607B2020/14) from GAIN from Xunta de Galicia. DRL was supported by a post-specialization fellowship from Fundación Profesor Novoa Santos and a public grant from Deputación de A Coruña (Spain), ADD by FPU contract (FPU014/02837) from Ministerio de Educación Cultura y Deporte (Spain), MQ was supported by supported by Consolidation of Competitive Research (IN607B2020/14) from GAIN from Xunta de Galicia and AR was supported by a predoctoral contract (PRDLC21591RODR) from Fundación Científica AECC/AECC.Fundación La Caixa; LCF/TR/CI19/52460016Fundación La Caixa; LCF/TR/CC21/52490003Xunta de Galicia; IN607B2020/14Asociación Española Contra el Cáncer; PRDLC21591ROD