Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

It has now been demonstrated that the μ, δ(1), δ(2), and κ(1) opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias

The origin and composition of carbonatite-derived carbonate-bearing fluorapatite deposits

Carbonate-bearing fluorapatite rocks occur at over 30 globally distributed carbonatite complexes and represent a substantial potential supply of phosphorus for the fertiliser industry. However, the process(es) involved in forming carbonate-bearing fluorapatite at some carbonatites remain equivocal, with both hydrothermal and weathering mechanisms inferred. In this contribution, we compare the paragenesis and trace element contents of carbonate-bearing fluorapatite rocks from the Kovdor, Sokli, Bukusu, Catalão I and Glenover carbonatites in order to further understand their origin, as well as to comment upon the concentration of elements that may be deleterious to fertiliser production. The paragenesis of apatite from each deposit is broadly equivalent, comprising residual magmatic grains overgrown by several different stages of carbonate-bearing fluorapatite. The first forms epitactic overgrowths on residual magmatic grains, followed by the formation of massive apatite which, in turn, is cross-cut by late euhedral and colloform apatite generations. Compositionally, the paragenetic sequence corresponds to a substantial decrease in the concentration of rare earth elements (REE), Sr, Na and Th, with an increase in U and Cd. The carbonate-bearing fluorapatite exhibits a negative Ce anomaly, attributed to oxic conditions in a surficial environment and, in combination with the textural and compositional commonality, supports a weathering origin for these rocks. Carbonate-bearing fluorapatite has Th contents which are several orders of magnitude lower than magmatic apatite grains, potentially making such apatite a more environmentally attractive feedstock for the fertiliser industry. Uranium and cadmium contents are higher in carbonate-bearing fluorapatite than magmatic carbonatite apatite, but are much lower than most marine phosphorites

A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease

Background Bulk cancer and minimal residual disease (MRD) are characterised by different molecular drivers and therefore necessitate different therapeutic strategies. However, there are currently no 3D models that can faithfully recapitulate MRD ex vivo for therapy development. Methods A microfluidic technique was implemented to construct 3D microtumours, in which tumour cells, either by themselves or with fibroblasts, were encapsulated in viscous hydrogels. The 3D microtumours were analysed for their response to first-line chemotherapeutics and characterised through RNA-Seq, by comparing them to both 2D cultures and clinical samples. Results Our microfluidic platform guarantees the fabrication of 3D microtumours of tailorable size and cell content, which recreate key features of tumours such as hypoxia, characteristic organization of the cytoskeleton and a dose-response to chemotherapeutics close to the physiological range. The 3D microtumours were also used to examine non-genetic heterogeneity in ovarian cancer and could fully reflect the recently described “Oxford Classic” five molecular signatures. The gene expression profile of 3D microtumours following chemotherapy treatment closely resembled that of MRD in ovarian cancer patients, showing the upregulation of genes involved in fatty acid metabolism. We demonstrate that these 3D microtumours are ideal for drug development by showing how they support the identification of a promising inhibitor of fatty acid oxidation, perhexiline, which specifically targets chemotherapy-resistant MRD ovarian cancer cells and not bulk cancer cells. Conclusion We have obtained the first 3D model of ovarian cancer MRD by using microtumours generated through microfluidics. This system is ideal for high-throughput drug screening and, given its versatility, it can be readily extended to additional types of cancer, as well as accommodate multiple cell types to generate complex tumour microenvironments