The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.     

Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque

(1) Background: Cardiovascular diseases (CVDs) are the main cause of death in developed countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) modulate the expression of their targets and have emerged as key players in CVDs; (2) Methods: 18 miRNAs were selected (Pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from apolipoprotein E-deficient (ApoE^−/−) mice. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE^−/− mice were studied in human aortic and carotid samples; (3) Results: miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease in protein kinase B (AKT), target of miR-155-5p, and an increase in insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE^−/− mice and in carotid plaques from patients with advanced carotid atherosclerosis (ACA). Finally, the overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells, while miR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells; (4) Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of atherosclerosis.     

TFG-β Nuclear Staining as a Potential Relapse Risk Factor in Early-Stage Non-Small-Cell Lung Cancer

Nowadays, the impact of the tumor-immune microenvironment (TME) in non-small-cell lung cancer (NSCLC) prognosis and treatment response remains unclear. Thus, we evaluated the expression of PD-L1, tumor-infiltrating lymphocytes (TILs), and transforming growth factor beta (TGF-β) in NSCLC to identify differences in TME, detect possible new prognostic factors, and assess their relationship. We retrospectively analyzed 55 samples from patients who underwent NSCLC surgery and had over a 5-year follow-up. PD-L1 expression was determined by immunohistochemistry following standard techniques. The presence of TILs was evaluated at low magnification and classified into two categories, “intense” and “non-intense”. Cytoplasmic TGF-β staining visualization was divided into four categories, and unequivocal nuclear staining in >1% of viable tumor cells was defined as “present” or “absent”. Our aim was to identify differences in disease-free survival (DFS) and overall survival (OS). Tumor stage was the only objective prognostic factor for OS. PD-L1 expression and the presence of TILs had no prognostic impact, neither their combination. There seems to be a lower expression of PD-L1 and a higher expression of TILs in early stages of the disease. Our TGF-β nuclear staining analysis was promising, since it was associated with worse DFS, revealing this protein as a possible prognostic biomarker of recurrence for resectable NSCLC.     

CO₂ capture from cement plants using oxyfired precalcination and/or calcium looping

This paper compares two alternatives to capture CO(2) from cement plants: the first is designed to exploit the material and energy synergies with calcium looping technologies, CaL, and the second implements an oxyfired circulating fluidized bed precalcination step. The necessary mass and heat integration balances for these two options are solved and compared with a common reference cement plant and a cost analysis exercise is carried out. The CaL process applied to the flue gases of a clinker kiln oven is substantially identical to those proposed for similar applications to power plants flue gases. It translates into avoided cost of of 23 $/tCO(2) capturing up to 99% of the total CO(2) emitted in the plant. The avoided cost of an equivalent system with an oxyfired CFBC precalcination only, goes down to 16 $/tCO(2) but only captures 89% of the CO(2) emitted in the plant. Both cases reveal that the application of CaL or oxyfired CFBC for precalcination of CaCO(3) in a cement plant, at scales in the order of 50 MWth (referred to the oxyfired CFB calciner) is an important early opportunity for the development of CaL processes in large scale industrial applications as well as for the development of zero emissions cement plants.     

Oxygen Reduction Reaction Promotes Li+ Desorption from Cathode Surface in Li‐O2 Batteries

Li‐O₂ batteries are claimed to be one of the future energy storage technologies. Great number of scientific and technological challenges should be solved first to transform Li‐O₂ battery from a promise to real practical devices. Proposed mechanisms for oxygen reduction assume a reservoir of solved Li⁺ ions in the electrolyte. However, the role that adsorbed Li⁺ on the electrode surface might have on the overall oxygen reduction reaction (ORR) has not deserved much attention. Adsorbed Li⁺ consumption is monitored here using impedance measurements from extended electrochemical double layer capacitance, which depends on the carbon matrix surface area. The presence of O₂ drastically reduces the amount of adsorbed Li⁺, signaling the kinetic competition between Li⁺ surface adsorption and its consumption, only for potentials corresponding to the oxygen reduction reaction. Noticeably double layer capacitance remains unaltered after cycling. This fact suggests that the ORR products (Li₂O₂ and Li₂CO₃) are not covering the internal electrode surface, but deposited on the outer electrode‐contact interface, hindering thereby the subsequent reaction. Current results show new insights into the discharge mechanism of Li‐O₂ batteries and reveal the evidence of Li⁺ desorption from the C surface when the ORR starts.     

Enhanced Permeability and Binding Activity of Isobutylene‐Grafted Peptides

We present a new peptide‐macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both for linear and cyclic peptides. The resulting isobutylene‐grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR spectroscopy and molecular dynamics simulations. The isobutylene‐stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin. Importantly, we found that structural preorganization forced by the isobutylene graft leads to a significant improvement in binding. The combined advantages of directness, selectivity, and smallness could allow application to peptide macrocyclization based on this attachment of the isobutylene graft.