Synthesis and biological evaluation of the first example of NO-donor histone deacetylase inhibitor

[Image: see text] The NO-donor histone deacetylase inhibitor 2, formally obtained by joining Entinostat 1, a moderately selective Class I histone deacetylases (HDACs) inhibitor, to a 4-(methylaminomethyl)furoxan-3-carbonitrile scaffold, is described and its preliminary biological profile discussed. This hybrid regulates Classes I and II HDACs. Nitric oxide (NO) released by the compound activates soluble guanylate cyclase (sGC), causing Class II nuclear shuttling and chromatin modifications, with consequences on gene expression. The hybrid affects a number of micro-RNAs not modulated by its individual components; it promotes myogenic differentiation, inducing the formation of larger myotubes with significantly more nuclei per fiber, in a more efficient manner than the 1:1 mixture of its two components. The hybrid is an example of a new class of NO-donor HDACs now being developed, which should be of interest for treating a number of diseases

Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells

Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib’s ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-induced apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients

Israel’s Associated Regime: Exceptionalism, Human Rights and Alternative Legality

In the context of Israel’s declared permanent state of exception, this article focuses on the legal protection awarded to the Palestinian populations under Israeli control. To broaden the discussion over Palestinian people’s rights, which generally focuses on the confiscation of land and the right to return, the author consciously focuses on anti-terrorism and security measures, which contribute to the creation of what the International Court of Justice has defined as an ‘associated regime’ of occupation. The article is divided into three parts. In the first part, the author discusses Israel’s domestic obligations towards Palestinians (arguing the case of both Palestinian citizens of Israel, and Palestinian residents) and their de jure and de facto discrimination. The second part discusses the applicability of humanitarian law, specifically the applicability of the Fourth Geneva Convention. This section discusses the applicability of the Convention to both territories and people under Israeli control. The third part discusses the applicability of international human rights law to all territories under Israeli control and delves into the issue of the mutual relationship between the two international legal regimes in the territories under occupation. The article posits that Israel’s rationale for the non-applicability of such legislation to the Palestinian territories and populations it controls constitutes a form of ‘alternative legality’. The article concludes that Israel’s disproportionate application of security practices and anti-terrorism measures to the Palestinian segment of its population violates Palestinian rights protected under Israel’s domestic and international legal obligations

The promise and challenges of new actors and new technologies in international justice

This article addresses the role of new technologies in the international justice and accountability landscape, drawing from research we conducted into new United Nations (UN) accountability mechanisms that have the explicit mandate to collect, collate, analyse and preserve evidence of international crimes according to criminal justice standards. The article is divided in four parts. First, we contextualize our research by discussing some of our findings and situating them against what we define as a ‘third wave’ of institutional developments in international justice, prompted by an ‘accountability-turn’ affecting civil society groups and UN mandates. Secondly, we discuss — using real-world examples — both the opportunities and challenges arising from the use of digital and new documentation technologies in the field. Thirdly, the article pays particular attention to the role of UN mandates affected by the ‘accountability-turn’; our research reveals such UN mandates now often sit at the heart of the ‘life cycle’ of information and evidence collected for justice and accountability purposes. In this section of the article, we also briefly discuss issues relating to third party control of information, in particular by social media companies. Finally, we discuss the need (and welcome initiative) to develop better international guidance and best practices for actors across the board in order to maximize the effective use of new technologies and digital evidence in international justice and accountability processes

Circulating 16S RNA in Biofluids: Extracellular Vesicles as Mirrors of Human Microbiome?

The human body is inhabited by around 1013 microbes composing a multicomplex system, termed microbiota, which is strongly involved in the regulation and maintenance of homeostasis. Perturbations in microbiota composition can lead to dysbiosis, which has been associated with several human pathologies. The gold-standard method to explore microbial composition is next-generation sequencing, which involves the analysis of 16S rRNA, an indicator of the presence of specific microorganisms and the principal tool used in bacterial taxonomic classification. Indeed, the development of 16S RNA sequencing allows us to explore microbial composition in several environments and human body districts and fluids, since it has been detected in “germ-free” environments such as blood, plasma, and urine of diseased and healthy subjects. Recently, prokaryotes showed to generate extracellular vesicles, which are known to be responsible for shuttling different intracellular components such as proteins and nucleic acids (including 16S molecules) by protecting their cargo from degradation. These vesicles can be found in several human biofluids and can be exploited as tools for bacterial detection and identification. In this review, we examine the complex link between circulating 16S RNA molecules and bacteria-derived vesicles