Role of Lipids in Spheroidal High Density Lipoproteins

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly

Eribulin-trastuzumab combination in HER2-positive metastatic breast cancer: updated results from a Russian observational study

Introduction. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.Aim. We sought to describe treatment patterns of  eribulin  and clinical outcomes of  metastatic HER2-positive breast cancer treated with eribulin  plus trastuzumab combination in  academic institutions and community oncology practices across the Russian Federation.Materials and methods. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.Results. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.Conclusions. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients

Dye-loaded porous nanocapsules immobilized in a permeable polyvinyl alcohol matrix: A versatile optical sensor platform

In this work we report on a versatile sensor platform based on encapsulated indicator dyes. Dyes are entrapped in hollow nanocapsules with nanometer-thin walls of controlled porosity. The porous nanocapsules retain molecules larger than the pore size but provide ultrafast access to their interior for molecules and ions smaller than the pore size. Dye-loaded nanocapsules are immobilized in a polyvinyl alcohol (PVA) matrix with high solvent permeability and rapid analyte diffusion. This approach provides robust sensing films with fast response and extended lifetime. To demonstrate the performance characteristics of such films, pH-sensitive indicator dyes were entrapped in vesicle-templated nanocapsules prepared by copolymerization of tert-butyl methacrylate, butyl methacrylate, and ethylene glycol dimethacrylate. As pH sensitive dyes, Nile blue A, bromophenol blue, and acid fuchsin were tested. Time-resolved absorbance measurements showed that the rate of the color change is controlled by the rate of diffusion of protons in the hydrogel. The pH-induced color change in a ∼400 μm thick film is complete within 40 and 60 s. The porous nanocapsule loaded films showed excellent stability and reproducibility in long-term monitoring experiments. Compartmentalization of the indicator dyes within the nanocapsules increased their stability. The matrix caused a shift in the position of the color change of the dye compared to that in an aqueous buffer solution. The encapsulation/immobilization protocol described in this account is expected to be broadly applicable to a variety of indicator dyes in optical sensor applications. © 2012 American Chemical Society

Directed Assembly of Vesicle-Templated Polymer Nanocapsules under Near-Physiological Conditions

This work addresses the challenge of creating hollow polymer capsules with wall thickness in the single-nanometer range under mild conditions. We present a simple and scalable method for the synthesis of hollow polymer nanocapsules in the bilayers of spontaneously assembled surfactant vesicles. Polymerization is initiated thermally with the help of a peroxide initiator and an amine activator codissolved with monomers and cross-linkers in the hydrophobic interior of the surfactant bilayer. To avoid premature polymerization, the initiator and the activator were added separately to the mixtures of cetyltrimethylammonium tosylate (CTAT) and sodium dodecylbenzenesulfonate (SDBS) containing monomers and cross-linkers. Upon hydration and mixing of the aqueous solutions, equilibrium monomer-loaded vesicles formed spontaneously after a brief incubation. The removal of oxygen and further incubation at slightly elevated temperatures (35–40 °C) for 1 to 2 h has led to the formation of hollow polymer nanocapsules. Structural and permeability characterization supported the high yield of nanocapsules with no pinhole defects

Ion-Selective Optodes in a Sampling Capillary for Tear Fluid Analysis

Plasticized PVC membrane-based potassium or sodium ion-selective optodes were incorporated into sampling capillaries in combination with sol-gel-based hydrogen ion-selective optodes for the sampling and analysis of minute tear fluid samples. The performance characteristic of the K +/pH and Na +/pH sensor arrays were optimized for an adequate dynamic response range, sensitivity, stability, and response time. The precision and accuracy of the combined sampling/measurement system was evaluated both in stopped flow and continuous flow modes using aqueous standard solutions. By using a two point calibration protocol, with pH standards bracketing the sample, the pH of 20μL pooled human tear samples could be determined with a precision less than ±0.03pH units. Errors in the pH measurements have a significant influence on the attainable precision and accuracy of the ion-exchange-based K + and Na + optodes. Nevertheless, the results of the quantitative assessment of the K + and Na + concentrations in check standards and pooled human tear fluid samples were within ±5% of the nominal values or of the results of the determinations with atomic absorption spectrophotometry. Cationic surfactants in artificial tear drops were found to interfere with the K + and Na + optode responses. No interference was detected in the presence of anionic and nonionic surfactants. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Small-Volume pH Sensing with a Capillary Optode Utilizing Dye-Loaded Porous Nanocapsules in a Hydrogel Matrix

To develop simple optical pH sensors with adequate sensitivity, short response time, and extended life time for the analysis of very small sample volumes, high concentrations of pH sensitive indicator dyes were encapsulated into ∼200nm diameter nanocapsules (NCs) with ∼1nm thick porous walls. The capsules were immobilized into high-porosity polyvinyl alcohol (PVA) gels for robust and versatile sensor platform design (double immobilization). The NCs-loaded gels were molded into sensing cylinders and secured in glass capillaries, which served as sampling devices and flow-through optical detector cells (capillary optodes). The color of the sensing cylinder was measured as a function of the sample pH using an optical fiber-based UV-VIS spectrophotometer. To optimize the optical properties of the sensing gel the influence of the size of the NCs, the dye concentration in the NCs and the NCs concentration within the PVA gel were studied. The NCs-based optodes allowed the measurement of the pH within 2minutes in as little as ∼30μL volume of sample, with ∼±0.03pH unit uncertainty and less than 0.001 pH/hour drift

Circular RNAs Variously Participate in Coronary Atherogenesis

Over the past decade, numerous studies have shown that circular RNAs (circRNAs) play a significant role in coronary artery atherogenesis and other cardiovascular diseases. They belong to the class of non-coding RNAs and arise as a result of non-canonical splicing of premature RNA, which results in the formation of closed single-stranded circRNA molecules that lack 5′-end caps and 3′-end poly(A) tails. circRNAs have broad post-transcriptional regulatory activity. Acting as a sponge for miRNAs, circRNAs compete with mRNAs for binding to miRNAs, acting as competing endogenous RNAs. Numerous circRNAs are involved in the circRNA–miRNA–mRNA regulatory axes associated with the pathogenesis of cardiomyopathy, chronic heart failure, hypertension, atherosclerosis, and coronary artery disease. Recent studies have shown that сirc_0001445, circ_0000345, circ_0093887, сircSmoc1-2, and circ_0003423 are involved in the pathogenesis of coronary artery disease (CAD) with an atheroprotective effect, while circ_0002984, circ_0029589, circ_0124644, circ_0091822, and circ_0050486 possess a proatherogenic effect. With their high resistance to endonucleases, circRNAs are promising diagnostic biomarkers and therapeutic targets. This review aims to provide updated information on the involvement of atherogenesis-related circRNAs in the pathogenesis of CAD. We also discuss the main modern approaches to detecting and studying circRNA–miRNA–mRNA interactions, as well as the prospects for using circRNAs as biomarkers and therapeutic targets for the treatment of cardiovascular diseases