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This study discusses the European Union’s proposal for a Regulation on Markets in Crypto-Assets, now subject to formal approval by the European Parliament. The objective is to explore whether it will positively impact the adoption of crypto-assets in the financial sector. The use of crypto-assets is growing. However, some stakeholders in the financial service sector remain skeptical and hesitant to adopt assets that are yet to be defined and have an unclear legal status. This regulatory uncertainty has been identified as the primary reason for the reluctant adoption. The proposed regulation (part of the EU’s Digital Finance Strategy) aims to provide this legal certainty for currently unregulated crypto-assets. This study investigates whether or not the proposed regulation can be expected to have the intended effect by reviewing the proposed regulation itself, the opinions and reactions of the various stakeholders, and secondary literature. Findings reveal that such regulation will most likely not accelerate the adoption of crypto-assets in the EU financial services sector, at least not sufficiently or as intended. Some suggestions are made to improve the proposal.

Despite the fact that cryptocurrency trading has been taking place in Poland for a dozen or so years, the issue of the existence and nature of the right to cryptocurrency units has not been resolved in civil law doctrine and case law. The legislature has also not taken any action in this regard, including in the draft act on the cryptoasset market currently in process. Meanwhile, this issue is of significant theoretical and practical importance. This article therefore examines the currently presented views together with their indicated consequences, and then supplements the ongoing discussion with comparative legal remarks usually omitted in Polish literature. In this respect, solutions proposed or in force in European Union, German, British and Chinese law are taken into account. This provides an opportunity to comment on existing concepts, in particular the rejection of the proposal to adopt in Polish law the right to a unit of cryptocurrency, effective (although with the submission of a application), and the view that there is no substantive right in this respect. In conclusion, it is considered that currently in Poland, the right to a unit of cryptocurrency is of a relative nature.

In a thriving crypto-assets market, crypto exchange platforms play a pivotal role. Indeed, such trading systems are instrumental to the matching of demand and supply (trading) as well as the transfer of tokens (settlement and post-trading). Yet, there is currently no bespoke regulatory framework applicable to crypto exchange, raising pressing questions on whether and how those platforms are regulated. This article examines the Italian regulatory framework applicable to crypto-exchange platforms. It shows that the present regulatory engagement with crypto exchanges relates to the qualification of the crypto assets traded. Depending on such qualification, different financial regimes could be triggered.

SummaryThe COVID-19 pandemic experience has driven us to rely on technology so much on the development and expansion of technology, including cashless transactions. Criminal groups may become more interested in electronic payments and virtual currencies because of increased traffic in these areas. When comparing the second half of the 2019 to the first half of the 2020, the number of fraudulent card transactions increased by 11.4%. New developments in virtual currency trading regulations, including the digital finance package, which includes, among other things, a draught regulation from the European Parliament and an amended act to combat money laundering and terrorist financing, among others. For the reasons stated above, these regulations may lead to a virtual currency market collapse and the withdrawal of investors and the siphoning of money into Asian markets as a result. The current regulations are a manifestation of total regulation and do not encourage technological advancement.

Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment.

(Series Information) European Papers - A Journal on Law and Integration, 2023 8(2), 665-687 | Article | (Table of Contents) I. Introduction. – II. Regulating innovation in the digitalised age. – II.1. Impact of regulation on innovation. – II.2. Crypto-assets as innovation: a moving target. – III. The regulation of crypto-assets in the EU. – III.1. The MiCA framework, its objectives and challenges. – III.2. Activity-and risk-based approach to regulating crypto-assets. – IV. Future-proofing the EU regulation of crypto-assets. – IV.1. The challenge of future-proofing a regulatory intervention in innovative markets. – IV.2. Activity-based regulation of crypto-assets: future-proofing the regulatory perimeter. – IV.3. Risk-based approach to regulating markets in crypto-assets. - V. Conclusion. | (Abstract) The 2023 EU regulation of markets in crypto-assets (MiCA) is a timely and ambitious response to the regulatory challenges of a fast-developing and technology-intensive field. The new regulation expands the regulatory perimeter, thus enabling EU-wide supervision of crypto-asset service providers and issuers of the so-called “stablecoins”. As such, the MiCA is in line with the key objectives of the 2020 EU Digital Finance Strategy: it updates the existing EU regulatory framework to facilitate digital innovation while protecting European consumers. “Same activity, same risk, same rule” approach is at the core of the MiCA regime. The new regulatory intervention, however, is to be put to test by the incessant technological and business model innovation within the crypto industry. Is this new regulation future-proof? This paper identifies and explores the two main points of vulnerability that often undermine the future-proof nature and, ultimately, the effectiveness of regulatory interventions in innovative sectors. First, it analyses the structures that define the scope of the new framework, and their capacity to adjust to and incorporate innovation falling outside of the regulatory perimeter. Second, the paper explores the mechanisms that ensure the regulatory and supervisory framework under the MiCA remains relevant and able to address the changes in the amplitude and sources of risks. Against this background, the paper discusses two features indispensable for a future-proof regulation: the openness of the regulatory perimeter, and the regulatory capacity for risk anticipation.

The Escherichia coli σE envelope stress response monitors and repairs the outer membrane, a function central to the life of Gram-negative bacteria. The σE stress response was characterized as a single-tier activation network comprised of

MicroRNAs （miRNAs） are a class of small non-coding regulatory RNAs, and changes in miRNAs are involved in tumor origin and progression. Studies have shown that miR-20a is overexpressed in human ovarian cancer tissues and that this miRNA enhances long-term cellular proliferation and invasion capabilities. In this study, a positive correlation between serum miR-20a expression and ovarian cancer stage was observed. We found that miR-20a binds directly to the 3＇-untranslated region of MICA/B mRNA, resulting in its degradation and reducing its protein levels on the plasma membrane. Reduction of membrane-bound MICA/B proteins, which are ligands of the natural killer group 2 member D （NKG2D） receptor found on natural killer （NK） cells, y＋ T cells and CD8＋ T cells, allows tumor cells to evade immune-mediated killing. Notably, antagonizing miR-20a action enhanced the NKG2D-mediated killing of tumor cells in both in vitro and in vivo models of tumors. Taken together, our data indicate that increased levels of miR-20a in tumor cells may indirectly suppress NK cell cytotoxicity by downregulating MICA/B expression. These data provide a potential link between metastasis capability and immune escape of tumor cells from NK cells.

Background: Epigenetic therapy using histone deacetylase inhibitors (HDACi) has shown promise in clinical trials for the treatment of human malignancies. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis. The molecular mechanism underlying is still unclear. Methods: The transcriptional regulation mechanism underlying suberoylanilide hydroxamic acid (SAHA)-mediated regulation of MICA and related miRNA expression was investigated using promoter acetylation assays, bioinformatics analysis and chromatin immunoprecipitation assay. Results: SAHA upregulates the transcription of MICA/B by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. The mechanism by which SAHA repressed miRNAs transcription involved repression of their host genes ( miR-17-92 cluster and MCM7 ). SAHA downregulated the miR-17-92 cluster by abolishing tyrosine phosphorylation of STAT3 and decreased MCM7 transcription through localised histone deacetylation. Conclusions: The HDACi SAHA epigenetically upregulates MICA expression through regulating the expression of miR-17-92 cluster and MCM7 in hepatoma, thus enhancing the sensitivity of HCC to natural killer cell-mediated lysis. This novel mechanism of action provides promise for HDACi in therapy of HCC.