Discovery and Development of Cyclic Peptide Inhibitors of CIB1

Calcium and integrin binding protein 1 (CIB1) is a small, intracellular protein recently implicated in survival and proliferation of triple-negative breast cancer (TNBC). Considering its interactions with PAK1 and downstream signaling, CIB1 has been suggested as a potential therapeutic target in TNBC. As such, CIB1 has been the focus of inhibitor discovery efforts. To overcome issues of potency and stability in previously reported CIB1 inhibitors, we deploy mRNA display to discover new cyclic peptide inhibitors with improved biophysical properties and cellular activity. We advance UNC10245131, a cyclic peptide with low nanomolar affinity and good selectivity for CIB1 over other EF-hand domain proteins and improved permeability and stability over previously identified linear peptide inhibitor UNC10245092. Unlike UNC10245092, UNC10245131 lacks cytotoxicity and does not affect downstream signaling. Despite this, UNC10245131 is a potent ligand that could aid in clarifying roles of CIB1 in TNBC survival and proliferation and other CIB1-associated biological phenotypes

Analysis of biomechanical parameters of the first metatarsal bone osteotomy

The main objective of the research was to study the stress-strain state in biotechnical systems formed in the performance of corrective osteotomies of the first metatarsal bone. The hallux valgus is a common pathology in humans. The incidence of this pathology in females is up to 64 and 25%-in males. Surgical reconstructive treatment remains an urgent problem in modern orthopedics. The situation is caused by unsatisfactory results of treatment. In addition, there is a question about the admissibility of the load in the early postoperative period in patients with quantitative individual assessment. This assessment can be performed using biomechanics. The paper presents methodology for assessing the bone-screw system when performing corrective osteotomies of the first metatarsal bone based on biomechanical methods. The technique allows us to perform a comparative analysis of various methods of osteotomy for a particular patient. In this study, Chevron and Scarf osteotomy with displacement of bone fragments by 1/3 and 2/3 with different variants of their fixation were examined. To solve this problem, personalized geometric models of the first metatarsal bone were built on the basis of computed tomography data using 3D Slicer and SolidWorks systems. Also models of implants were built. The finite element analysis was carried out in the Ansys Workbench software. The focus was on analyzing the stresses that occur on the plantar surface of the first metatarsal bone head during walking. An assessment of the maximum allowable shear of bone fragments for the normalization of deformities of the forefoot was carried out. The developed technique allows us the choice of an osteotomy variant with the justification of the possibility of simultaneous surgery on both feet for a particular patient. © Golyadkina A.A., Polienko A.V., Kireev S.I., Kurmanov A.G., Kireev V.S., 2019

Simulation of the insulating properties of two-layer material

Mathematical simulation of the process of diffusion of liquid vapors through a binary layer consisting of a light granular material and a layer of gel applied on its surface is shown. Using the proposed model the coefficient of octane evaporation rate reduction on the onset of the stationary mode was determined, and the time for reaching this mode was estimated. For a gel layer with thickness of 2 mm and a layer of foam glass with thickness of 5 cm, the evaporation rate of octane is reduced by more than 100 times compared with the evaporation rate from the free surface of the liquid. Two-layer insulating materials are proposed to use for elimination of emergencies associated with the spill of toxic and flammable liquids, as well as for extinguishing fires involving flammable liquids

Development of personalized osteotomy technique for the first metatarsal bone

Surgical methods form the basis of modern approach to forefoot deformities correction. Scientific and practical interest in this topic is based on the patients' growing need for specialized care, which is required by 64% of women and 25% of men. In most cases, there is bilateral deformation of both feet. Some scientists are strongly against simultaneous surgery on both feet. It is obvious that the solution regarding acceptability of the load in the early postoperative period requires quantitative individual assessment. This assessment can be performed using biomechanics. This paper presents the technique for assessing the bone-screw system when performing corrective osteotomies of the first metatarsal bone based on biomechanical methods. This technique allows to perform comparative analysis of various osteotomy methods for a particular patient. In this study we examined Chevron and Scarf osteotomy with displacement of bone fragments by 1/3 and 2/3 with different fixation variants. To solve this problem, personalized geometric models of the first metatarsal bone were built on the basis of computed tomography data using 3D Slicer and SolidWorks systems. The implant models were built as well. Finite element analysis was carried out using Ansys Workbench software. The focus of the study was to analyse stresses that occur on the plantar surface of the first metatarsal bone head during walking. Assessment of the maximum allowable shift of bone fragments for normalization of the forefoot deformities was carried out. The developed technique allows to choose osteotomy variant and justify the possibility of simultaneous surgery on both feet for a particular patient. © 2019 SPIE

Evaluation of the HIV-1 drug resistance to elsulfavirine and the effectiveness of it among Russian treatment-naïve patients [ОцЕНКА ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТИ ВИЧ-1 К ЭЛСУЛЬФАВИРИНУ И ЭФФЕКТИВНОСТЬ ЕГО ПРИМЕНЕНИя СРЕДИ РОССИЙСКИХ ПАцИЕНТОВ, РАНЕЕ НЕ ПОЛУЧАВШИХ АНТИРЕТРОВИРУСНЫЕ ПРЕПАРАТЫ]

The aim of the study: to analyze the prevalence of resistance mutations to elsulfavirine and to evaluate the effectiveness of it among HIV-infected treatment-na ve patients in real clinical practice. Materials and methods. The study included 578 patients with HIV infection, which divided into 3 groups. The first group is 354 HIV-infected treatment-na ve patients for whom HIV-1 nucleotide sequences were obtained as part of routine drug resistance testing. The second study group included 111 HIV-infected treatment-na ve patients, tested for drug resistance before the antiretroviral therapy containing elsulfavirine. The third study group included 113 HIV-infected treatment-na ve patients, each of whom was assigned a treatment regimen containing elsulfavirine without prior drug resistance testing. The observation period for patients of the second and third groups who received treatment was 24 weeks. To assess the effectiveness of antiretroviral therapy in patients, viral load, CD4+ T-cell counts, and adherence to therapy were assessed. HIV-1 subtypes and drug resistance mutations were determined using the Stanford HIV Resistance Database (v. 8.9-1). To clarify the results of subtyping, phylogenetic analysis of nucleotide sequences was carried out using the MEGA program (v. 6.0). Results. The prevalence of mutations associated with decreased susceptibility to elsulfavirine among HIV-infected treatment-na ve patients was 1.7% and 4.5% for the first and second groups of patients, respectively. All of the patients have only single resistance mutations which, according to the results of preclinical studies, cannot cause drug resistance. The use of elsulfavirine in real clinical practice among treatment-na ve patients has demonstrated good virological and immunological efficacy of the drug. As a result of 24 weeks of therapy in patients of the second group, no treatment ineffectiveness, and the development of drug resistance were observed. Among the patients of the third group, 6 patients (5.3%) have the virological failure of therapy associated with the resistance to the used drugs. All patients with virological failure had a resistance mutation profile associated with a high level of drug resistance to one of the drugs in the treatment regimen, lamivudine. Additionally, 1 patient had a combination of mutations that reduce susceptibility to elsulfavirine, and 4 patients had mutations that can reduce susceptibility to elsulfavirine in combination with other mutations. Conclusion. The low prevalence of mutations associated with a decrease in susceptibility to elsulfavirine and the absence of combinations of mutations make it possible to predict the successful use of this drug for Russian treatment-na ve patients. Reported cases of virological failure of antiretroviral therapy are difficult to interpret in the context of elsulfavirine due to the lack of an exact list of mutations and their combinations, and associations with the degree of resistance to it. This study describes for the first time the mutation profiles in patients with virological failure of therapy containing elsulfavirine and demonstrates the necessity of the further study of drug resistance profile to drug in vitro and in vivo. © 2021 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved