Application of mathematical modelling methods for acoustic images reconstruction

The article considers the reconstruction of images by Synthetic Aperture Focusing Technique (SAFT). The work compares additive and multiplicative methods for processing signals received from antenna array. We have proven that the multiplicative method gives a better resolution. The study includes the estimation of beam trajectories for antenna arrays using analytical and numerical methods. We have shown that the analytical estimation method allows decreasing the image reconstruction time in case of linear antenna array implementation

Experience with olaparib in a patient with luminal HER2-positive metastatic breast cancer

Hereditary breast cancer (BC) accounts for about 5-10% of cases. BRCA-associated tumors have been identified as a separate group of malignant neoplasms with distinctive clinical manifestations and specific treatment features. Understanding of biological mechanisms leading to cancer in BRCA1/2 mutation carriers and discovery of potential molecular targets, such as poly (ADP-ribose) polymerase (PARP), involved in base excision repair mechanisms, led to the development of a new class of targeted drugs belonging to the PARP inhibitors group. PARP inhibition leads to the preservation of single-stranded DNA breaks, the arrest of the replication fork, and the realization of the “synthetic lethality” phenomenon due to the inability to repair double-stranded DNA breaks by homologous recombination in cells with mutations in the BRCA1/2 genes. Two randomized trials OlympiAD and EMBRACA evaluated and proved the effectiveness of PARP inhibitors in patients with metastatic BRCA-mutated HER2-negative breast cancer in comparison with standard chemotherapy. At the same time, data on the potential use of PARP inhibitors for the treatment of BRCA-mutated HER2-positive breast cancer patients are extremely limited. This article presents a clinical example of the use of olaparib in a patient with BRCA-mutated HER2-positive metastatic breast cancer

Enantioselective Protein-Sterol Interactions Mediate Regulation of Both Prokaryotic and Eukaryotic Inward Rectifier K+ Channels by Cholesterol

Cholesterol is the major sterol component of all mammalian cell plasma membranes and plays a critical role in cell function and growth. Previous studies have shown that cholesterol inhibits inward rectifier K+ (Kir) channels, but have not distinguished whether this is due directly to protein-sterol interactions or indirectly to changes in the physical properties of the lipid bilayer. Using purified bacterial and eukaryotic Kir channels reconstituted into liposomes of controlled lipid composition, we demonstrate by 86Rb+ influx assays that bacterial Kir channels (KirBac1.1 and KirBac3.1) and human Kir2.1 are all inhibited by cholesterol, most likely by locking the channels into prolonged closed states, whereas the enantiomer, ent-cholesterol, does not inhibit these channels. These data indicate that cholesterol regulates Kir channels through direct protein-sterol interactions likely taking advantage of an evolutionarily conserved binding pocket

High-sensitivity troponin I as a predictor of left ventricular dysfunction in the use of cardiotoxic anticancer agents for breast cancer in patients with predominantly low and moderate risk of cardiotoxicity

Aim. To study the significance of monitoring high-sensitivity troponin I (hs-cTnI) for predicting anthracycline-induced left ventricular (LV) dysfunction in the treatment of breast cancer in patients with moderate and low risk of cardiotoxicity (CT).Material and methods. The study involved 49 patients with breast cancer aged 50±10 years who underwent neoadjuvant or adjuvant chemotherapy, which included doxorubicin at a course dose of 60 mg/m2 and an average cumulative dose of 251±60 mg/m2. The level of hs-cTnI was determined by an ultrasensitive method before the start of chemotherapy, after each course of anthracyclines and in 18 patients before the administration of anthracyclines. The level of hscTnI >0,017 ng/ml was considered elevated. Echocardiography was performed before the start of chemotherapy, after the end of anthracycline therapy, and every 3 months for 12 months thereafter. CT was defined as a decrease in LV ejection fraction (EF) by ≥10% to <53%.Results. CT risk before chemotherapy was considered low and moderate in 96% of patients. An increase in hs-сTnI was detected ≥1 times in 56,8% of patients: before chemotherapy — in 13,5%, after 1 and 2 courses of anthracycline therapy — in 13,9%, after 3, 4, 5 and 6 courses — in 44%, 62%, 71% and 66% of patients, respectively. The levels of hs-cTnI before and after administration of anthracyclines did not differ significantly. The development of LV dysfunction was observed in 16,3% of patients. There were following prognostic significance of an increase in hs-cTnI at any time of chemotherapy for a decrease in LV EF: sensitivity — 87,5%, specificity — 50%, the positive predictive value — 28%, the negative predictive value — 94,7%. The closest relationship was noted between CT and hs-cTnI value before the start of chemotherapy (β=0,45, p=0,005) and after the 3rd course of anthracycline therapy (β=0,56, p=0,002).Conclusion. An increase in hs-cTnI level before and during anthracycline thera py in patients with a low risk of cardiotoxicity has a prognostic value in relation to the development of left ventricular dysfunction. Hs-cTnI assessment should be performed before the start of therapy, and then starting from the 3rd course of anthracycline therapy in all patients, regardless of the risk of cardiotoxicity

Specificity of cholesterol and analogs to modulate BK channels points to direct sterol–channel protein interactions

The activity (Po) of large-conductance voltage/Ca2+-gated K+ (BK) channels is blunted by cholesterol levels within the range found in natural membranes. We probed BK channel–forming α (cbv1) subunits in phospholipid bilayers with cholesterol and related monohydroxysterols and performed computational dynamics to pinpoint the structural requirements for monohydroxysterols to reduce BK Po and obtain insights into cholesterol’s mechanism of action. Cholesterol, cholestanol, and coprostanol reduced Po by shortening mean open and lengthening mean closed times, whereas epicholesterol, epicholestanol, epicoprostanol, and cholesterol trisnorcholenic acid were ineffective. Thus, channel inhibition by monohydroxysterols requires the β configuration of the C3 hydroxyl and is favored by the hydrophobic nature of the side chain, while having lax requirements on the sterol A/B ring fusion. Destabilization of BK channel open state(s) has been previously interpreted as reflecting increased bilayer lateral stress by cholesterol. Lateral stress is controlled by the sterol molecular area and lipid monolayer lateral tension, the latter being related to the sterol ability to adopt a planar conformation in lipid media. However, we found that the differential efficacies of monohydroxysterols to reduce Po (cholesterol≥coprostanol≥cholestanol>>>epicholesterol) did not follow molecular area rank (coprostanol>>epicholesterol>cholesterol>cholestanol). In addition, computationally predicted energies for cholesterol (effective BK inhibitor) and epicholesterol (ineffective) to adopt a planar conformation were similar. Finally, cholesterol and coprostanol reduced Po, yet these sterols have opposite effects on tight lipid packing and, likely, on lateral stress. Collectively, these findings suggest that an increase in bilayer lateral stress is unlikely to underlie the differential ability of cholesterol and related steroids to inhibit BK channels. Remarkably, ent-cholesterol (cholesterol mirror image) failed to reduce Po, indicating that cholesterol efficacy requires sterol stereospecific recognition by a protein surface. The BK channel phenotype resembled that of α homotetramers. Thus, we hypothesize that a cholesterol-recognizing protein surface resides at the BK α subunit itself