The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell-Based Cancer Immunotherapy with Genetically Modified T Cells.

This review focuses on the structure and molecular action mechanisms of chimeric antigen receptors (CARs) and major aspects of the manufacturing and clinical application of products for the CAR-T (CAR-modified T lymphocyte) therapy of hematological and solid tumors with special emphasis on the strategies for combined use of CAR-T therapy with immuno-oncological monoclonal antibodies (checkpoint inhibitors) and cytokines to boost survival, persistence, and antitumor efficacy of CAR-T therapy. The review also summarizes preclinical and clinical data on the additive effects of the combined use of CAR-T therapy with interleukins and monoclonal antibodies targeting immune checkpoints.

Hamiltonian models for the propagation of irrotational surface gravity waves over a variable bottom.

A single incompressible, inviscid, irrotational fluid medium bounded by a free surface and varying bottom is considered. The Hamiltonian of the system is expressed in terms of the so-called Dirichlet-Neumann operators. The equations for the surface waves are presented in Hamiltonian form. Specific scaling of the variables is selected which leads to approximations of Boussinesq and Korteweg-de Vries (KdV) types, taking into account the effect of the slowly varying bottom. The arising KdV equation with variable coefficients is studied numerically when the initial condition is in the form of the one-soliton solution for the initial depth.This article is part of the theme issue 'Nonlinear water waves'.

[New aspects of non-waste use of secondary raw materials of horse breeding in Yakutia].

In the diet of the population of Yakutia, the meat of 6-month-old and local herd horses is especially valued for its high nutritive value, excellent taste and dietary properties. In addition to meat, a number of other slaughter products, such as by-products, intestinal raw materials, internal fat, blood, etc., can be received during primary processing. Many of them are not fully used. The relevance of this work is to study the possibilities of waste-free use of the Yakut horse products. Biochemical investigation of the composition of the secondary products of slaughter (fat, blood, by-products, intestinal raw materials) was carried out, a concentrate from the internal fat of foals and dry blood were obtained. The inner fat of the Yakut horse in terms of the content of polyunsaturated fatty acids (PUFA) exceeded the PUFA level in subcutaneous fat. The content of linoleic acid was 10.91-12.25%. A low-temperature method for recovering fat has been tested, a fat-containing feed with a PUFA content of about 23% has been obtained. Slaughter blood is a high-value raw material for the production of functional food products as a source of iron, amino acids and other components. The iron content in the blood dried in the infrared dryer fluctuated in insignificant limits from 216.8 to 242.0 mg/kg that indicated a stable level of provision of horses with this trace element. The protein level in the dry blood of mature mares (8-19 years) was 87%. The results of the study of young offspring of the Yakut horse showed that such offal of the first category as liver, heart, kidneys were rich in protein (from 19.1±0.1 to 22.0±0.1%). The esophagus was high in fat (22.3±0.1%). The stomach and intestines were characterized by high ash content (from 3.2±0.2 to 8.0±0.7%).

[Comparative Analysis of the Effectiveness of STR and SNP Markers for Intraspecific and Interspecific Differentiation of the Genus Ovis].

A comparative study of the informativeness of SNP and STR markers for interspecific and intraspecific differentiation of the two species of the genus Ovis, snow sheep (O. nivicola) and domestic sheep (O. aries), was conducted. Eleven STR loci combined into two multiplex panels were examined. SNP analysis was performed with the DNA microarray OvineSNP50K BeadChip featuring 54241 SNPs. The possibility of clear differentiation of the studied Ovis species with both types of genetic markers was demonstrated. The advantages of SNP markers for intraspecific differentiation of the O. aries breeds and O. nivicola geographical groups were revealed. The areas of application of the studied types of DNA markers are discussed.

[Influence of Different Type of Surfactant on Bacteriolytic Activity of Lysozyme].

The influence ofvarious surfactants (anionic sodium dodecyl sulfate, SDS, cationic dodecyltrimethylarnmonium bromide, DTAB, and zwitterionic cocoamidopropylbetaine, CAPB) on the activity of the chicken egg lysozyme is investigated. Lysis of Gram-positive bacteria by the enzyme was carried out at pH 7.2 and ionic strength of 0.15 M. It was found that at low SDS and DTAB concentrations (less than 1 x 10(-5) M) the bacteriolytic activity increases by 30-140%. At higher concentrations (1 x 10(-5) - 1 x 10(4) M) the activity returns to the level observed in the absence of the surfactants. The elevated activity correlated with the formation of hydrophobic lysozyme-surfactant complexes. Introduction of CAPB at concentrations above 1 x 10(-5) M sig, nificantly diminished the bacteriolytic activity due to CAPB induced aggregation of lysozyme.

[Binocularly co-activation modulate development of functional modular systems in cats visual cortex].

Using optical imaging technique and method for histochemical cytochrome oxidase revealing we investigated in three kitten's groups (two experimental and one control) a rhythmically light stimulation on ontogenetic development of orientation columns and cytochrome oxidase blobs in visual area 18. Experimental animals were stimulated by rhythmical light for 3 hrs or 12 hrs per day respectively. It was first obtained that binocular co-activation per se, not accompanied by strabismus, indeed influences cortical columns formation during critical period. We show an opposite effect of stimulation on two different types of cortical columns, and also revealed that these affects are have retained for at least 2 weeks after stimulation was terminated. It was obtained that duration of rhythmically light stimulation determines a volume of functional and anatomic alterations: alterations revealed were more pronounced in animals stimulated for12 hrs per day.

High-precision x-ray FEL pulse arrival time measurements at SACLA by a THz streak camera with Xe clusters.

The accurate measurement of the arrival time of a hard X-ray free electron laser (FEL) pulse with respect to a laser is of utmost importance for pump-probe experiments proposed or carried out at FEL facilities around the world. This manuscript presents the latest device to meet this challenge, a THz streak camera using Xe gas clusters, capable of pulse arrival time measurements with an estimated accuracy of several femtoseconds. An experiment performed at SACLA demonstrates the performance of the device at photon energies between 5 and 10 keV with variable photon beam parameters.

Magnetization and microstructure dynamics in Fe/MnAs/GaAs(001): Fe magnetization reversal by a femtosecond laser pulse.

Thin film magnetization reversal without applying external fields is an attractive perspective for applications in sensors and devices. One way to accomplish it is by fine-tuning the microstructure of a magnetic substrate via temperature control, as in the case of a thin Fe layer deposited on a MnAs/GaAs(001) template. This work reports a time-resolved resonant scattering study exploring the magnetic and structural properties of the Fe/MnAs system, using a 100 fs optical laser pulse to trigger local temperature variations and a 100 fs x-ray free-electron laser pulse to probe the induced magnetic and structural dynamics. The experiment provides direct evidence that a single optical laser pulse can reverse the Fe magnetization locally. It reveals that the time scale of the magnetization reversal is slower than that of the MnAs structural transformations triggered by the optical pulse, which take place after a few picoseconds already.

Double-configuration grating monochromator for extreme-ultraviolet ultrafast pulses.

We present the design and characterization of a double-configuration grating monochromator for the spectral selection of extreme-ultraviolet ultrafast pulses. Two grating geometries are joined in an instrument with two interchangeable diffracting stages, both used at grazing incidence: one with the gratings in the off-plane mount (OPM), the other in the classical diffraction mount (CDM). The use of two stages gives great flexibility: the OPM stage is used for sub-50 fs time response and low spectral resolution, while the CDM stage is for 100-200 fs time response and high spectral resolution. The monochromator spectral and temporal performances have been experimentally demonstrated on a high-order laser-harmonics beam line.

A Method for the Production of Recombinant VSVs with Confirmation of Biological Activity.

The design of new effective cancer treatment methods is a promising and important research field in translational medicine. Oncolytic viruses can induce immunogenic cell death by activating the body's immune system to recognize tumor cells. This work presents the results for optimizing the production of recombinant vesicular stomatitis viruses (rVSVs). To ensure the assembly of viral particles, we developed the HEK293TN-T7 cell line, which stably expresses DNA-dependent RNA polymerase 7 for viral genome transcription, and obtained helper plasmids encoding viral genes under the control of the CAG promoter. The oncolytic activity of the purified virus preparation was assessed in a murine model of B16F10Red melanoma cells expressing a red fluorescent protein. The presented method makes it possible to obtain purified viral preparations with a high titer and oncolytic activity. The amplification of viral particles in a HEK293 suspension culture allows for rapid scalability. Therefore, the developed approach can be used to obtain other recombinant VSV-based oncolytic viruses for tumor immunotherapy.

[Comparison of its and orientation tuning dynamics in neurons located in different functional domains of cat's primary visual cortex].

Orientation tuning and its dynamics of cat's primary visual cortex neurons located in pinwheel centers and orientation columns were studied during development of response in time. Functional domains in the Cortex were revealed by intrinsic signal optical imaging on functional and vascular maps of cortex. Both maps were used for precise placement of electrodes during recordings. Orientation tuning dynamic of each neuron was analyzed by temporary slices technique. Several types of neurons were observed in different functional domains: neurons with stable preferred orientation (14.5%); cells with preferred orientation dynamically shifted by 102 +/- 5 degrees (40.8%) and neurons with mixed dynamics type (44.7%). In pinwheel centers neurons with stable preferred orientation are differed from neurons with unstable preferred orientation in their features. In particular, they are showing greater response strength for preferred orientation. In orientation columns neurons with stable tuning are demonstrating larger latent periods for all orientations including preferred and non-preferred in comparison to cells with unstable response dynamics. We observed better detection quality of stable orientation neurons than in unstable preferred orientation neurons. Further coding features of neurons belonging to one functional type but located in different domains were compared. In general, located in pinwheel centers stable neurons have shorter latencies and stronger responses than for the stable cells located in orientation columns. Detection features were similar for this functional type of neurons. Unstable neurons located in different functional domains don't differ from each other in orientation tuning characteristics. Functional significance of neurons with stable and unstable preferred orientation located in pinwheel center and orientation columns in visual information processing are discussed.

Intratumor heterogeneity: models of malignancy emergence and evolution.

Cancer is a complex and heterogeneous disease characterized by the accumulation of genetic alterations that drive uncontrolled cell growth and proliferation. Evolutionary dynamics plays a crucial role in the emergence and development of tumors, shaping the heterogeneity and adaptability of cancer cells. From the perspective of evolutionary theory, tumors are complex ecosystems that evolve through a process of microevolution influenced by genetic mutations, epigenetic changes, tumor microenvironment factors, and therapy-induced changes. This dynamic nature of tumors poses significant challenges for effective cancer treatment, and understanding it is essential for developing effective and personalized therapies. By uncovering the mechanisms that determine tumor heterogeneity, researchers can identify key genetic and epigenetic changes that contribute to tumor progression and resistance to treatment. This knowledge enables the development of innovative strategies for targeting specific tumor clones, minimizing the risk of recurrence and improving patient outcomes. To investigate the evolutionary dynamics of cancer, researchers employ a wide range of experimental and computational approaches. Traditional experimental methods involve genomic profiling techniques such as next-generation sequencing and fluorescence in situ hybridization. These techniques enable the identification of somatic mutations, copy number alterations, and structural rearrangements within cancer genomes. Furthermore, single-cell sequencing methods have emerged as powerful tools for dissecting intratumoral heterogeneity and tracing clonal evolution. In parallel, computational models and algorithms have been developed to simulate and analyze cancer evolution. These models integrate data from multiple sources to predict tumor growth patterns, identify driver mutations, and infer evolutionary trajectories. In this paper, we set out to describe the current approaches to address this evolutionary complexity and theories of its occurrence.

An alternative differential method of femtosecond pump-probe examination of materials.

We describe an alternative method for femtosecond pump-probe beam examination of energy transport properties of materials. All already reported techniques have several drawbacks which limit precise measurements of reflection coefficient as function of time. A typical problem is present when rough samples are being studied. In this case the pump-beam polarization changes randomly which may produce a spurious signal, drastically reducing the signal to noise ratio. Some proposals to alleviate such problem have been reported, however, they have not been totally satisfactory. The method presented here consists on measuring the difference between the two delays' signals of the probe-beam. As will be explained, our proposal is free of typical drawbacks. We also propose a numerical method to recover the ΔR(t)/R curve from the measured data. Numerical simulations show that our proposal is a viable alternative.

Coupling of gelatin to inner surfaces of pore walls in spongy alginate-based scaffolds facilitates the adhesion, growth and differentiation of human bone marrow mesenchymal stromal cells.

We have developed a novel wide-pore scaffold for cell 3D culturing, based on the technology of freeze-drying of Ca-alginate and gelatin. Two different preparation methodologies were compared: (i) freeze-drying of Na-alginate + gelatin mixed solution followed by the incubation of dried polymer in saturated ethanolic solution of CaCl2; (ii) freeze-drying of the Na-alginate solution followed by the chemical "activation" of polysaccharide core with divinylsulfone with subsequent gelatin covalent attachment to the inner surfaces of pore walls. The scaffolds produced using the first approach did not provide adhesion and proliferation of human bone marrow mesenchymal stromal cells (MSCs). Conversely, the second approach allowed to obtain scaffolds with a high adherence ability for the cells. When cultured within the latter type of scaffold, MSCs proliferated and were able to differentiate into adipogenic, osteogenic and chondrogenic cell lineages, in response to specific induction stimuli. The results indicate that Ca-alginate wide-pore scaffolds with covalently attached gelatin could be useful for stem cell-based bone, cartilage and adipose tissue engineering.

Comparison of the methods for seeding human bone marrow mesenchymal stem cells to macroporous alginate cryogel carriers.

We performed a comparative study of the localization, distribution, metabolic activity, and surface properties of human bone marrow mesenchymal stromal cells after static and perfusion seeding to macroporous alginate cryogels. A simple perfusion system for mesenchymal stromal cell seeding to macroporous alginate cryogel sponges proposed in this study resulted in rapid and uniform distribution of cells within the whole volume of the scaffold preserving functional and morphological properties of the cells.

[Adsorptive immobilization of rhodococcal cells in hydrophobized derivatives of wide-pore polyacrylamide cryogel].

Adsorption of Rhodococcus ruber cells on columns with polyacrylamide cryogel (CryoPAAG) partially hydrophobized by different quantities (0.2, 1, and 5 mol %) of chemically grafted n-dodecane residues has been studied. The adsorption capacity (1.1 x 10(9) cells/g) of gel carrier for rhodococcal cells and the optimal content (1 mol %) of hydrophobizing groups were determined. The respirometric method showed the high catalytic activity and functional stability of immobilized bacterial cells. Respiratory activity of immobilized rhodococci in the presence of a model mixture of oil hydrocarbons exceeded the respective parameter for free cells by 12-17%. Viability of rhodococcal cells adsorptionally fixed in hydrophobized cryoPAAG was maintained at a level of 93-95% after a half-year period of storage. The results may be used for development of immobilized biocatalyst for directed transformation of hydrocarbon compounds and biological purification of oil-polluted water.

[Overlapping of optical answers for cross-like figures and oriented bars in the cats primary visual cortex].

For the first time by the optical method the population activity of neurons in cat primary visual cortex was observed simultaneously for detectors participating in analysis of first-order (orientation) and second-order (line intersection) features. The maps for cross-like figures and oriented single bars were compared. The comparative analysis allowed us to estimate the degree of overlapping of the activated regions and parts of cortex that were free from overlap. Overlapping zones provided the evidence for the fact that neuronal detectors for line intersections are located in the same neuronal columns as neurons detecting orientations. Differences were observed between maps for vertically oriented and oblique crosses. Those differences were pronounced not only in topography but also in degree of overlapping of activity zones. This may evidence on different contribution of neurons detecting basic and intermediate orientations.

[Results of a phase 1 clinical study of anti-CD20 monoclonal antibody (BCD-132): pharmacokinetics, pharmacodynamics and safety]. / Rezul'taty I fazy klinicheskogo issledovaniia monoklonal'nogo antitela protiv CD20 (BCD-132): farmakokinetika, farmakodinamika i bezopasnost'.

AIM: To study the pharmacokinetics, pharmacodynamics, and immunogenicity of two intravenous dosing regimens of the new anti-B-cells drug BCD-132 (JSC BIOCAD, Russia) at ascending doses in patients with remitting multiple sclerosis. MATERIAL AND METHODS: Twenty-four patients with multiple sclerosis were sequentially randomized in the multicenter open-label uncontrolled multicohort phase I study (3+3 design) and assigned to 4 cohorts (8 groups). Patients in each cohort received an intravenous infusion of BCD-132 at a predefined dose ranging from 100 to 1000 mg based on the planned algorithm of dose escalation if no dose-limiting toxicities occurred. RESULTS: The assessment of the number of cells positive for the main B-cell antigens over time demonstrated a direct effect of BCD-132 on B lymphocytes when used at a wide range of doses (100 to 1000 mg) in patients with remitting multiple sclerosis. No significant variation of the number of T-cells was observed, which clearly proves strict specificity of BCD-132 exclusively to B lymphocytes. CONCLUSION: BCD-132 has an expected pharmacodynamic effect of long-term depletion of CD19+ and CD20+ B lymphocytes and an acceptable safety profile when used to treat patients with remitting multiple sclerosis at all tested doses.

[The new pegylated interferon beta-1a (sampeginterferon beta-1a, BCD-054) in the treatment of remitting multiple sclerosis]. / Novyi pegilirovannyi interferon beta-1a (sampéginterferon beta-1a, BCD-054) v terapii remittiruiushchego rasseiannogo skleroza.

AIM: To evaluate the efficacy and safety of BCD 054 180 µg and 240 µg administered once every 2 weeks for the treatment of remitting multiple sclerosis compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. Results of a 20 week blinded interim analysis from a double blind, comparative, randomised, placebo-controlled clinical study are included. MATERIAL AND METHODS: This multinational, multicentre, double blind, comparative, placebo-controlled study enrolled 399 patients with the diagnosis of remitting multiple sclerosis: 114 patients in the sampeginterferon beta 1a and LIB groups each and 57 patients in the placebo group. To ensure the objectivity of data, the study protocol includes a blinded interim analysis to demonstrate the superiority of BCD 054 over placebo based on the number of combined unique active lesions (CUA) on MRI scans after 20 weeks of treatment. RESULTS AND CONCLUSION: An integrated analysis of the efficacy, safety, pharmacokinetics, and pharmacodynamics was performed after 20 weeks of study. Mean CUA per scan was lower in the active treatment groups compared to placebo: 0,986±2,046, 0,619±1,055, 0,665±1,165, 1,673±2,376 (groups 1, 2, 3 and placebo group, respectively). The data for CUA per scan demonstrated the superiority of both BCD 054 180 µg and 240 µg over placebo. Patients receiving active treatment had fewer new and/or enlarging lesions after 20 weeks of treatment. The proportion of patients without new T2-weighted lesions was 74,3%, 86,7%, and 78,1% in groups 1, 2, and 3 compared to 64,9% in the placebo group. Manifestations of flu-like syndrome that is expected for interferon treatment were observed with the same incidence in all the active treatment groups. Its severity, duration or the need for symptomatic treatment did not appear to depend on the type of interferon used.

[Efficacy, tolerability and safety of the treatment with teberif: the results of a 2-year randomized clinical trial of treatment naïve patients with remitting multiple sclerosis, who have not received DMT, after switching from other interferon ß-1a]. / Éffektivnost', perenosimost' i bezopasnost' terapii preparatom teberif: rezul'taty dvukhletnego klinicheskogo issledovaniia u patsientov s remittiruiushchim rasseiannym sklerozom, ranee ne poluchavshikh PITRS, i pri perekliuchenii s drugogo interferona ß-1a.

OBJECTIVES: To evaluate efficacy, safety, and tolerability of the treatment with teberif/interferon ß-1a, to analyze safety, tolerability and dynamics of key efficacy variables after switching from referent drug rebif to biosimilar teberif in patients with remitting multiple sclerosis (RMS). MATERIAL AND METHODS: During the main period of the international multicenter randomized study patients were randomized to receive treatment with teberif for 52 weeks, or rebif for 52 weeks, or placebo for 16 weeks to evaluate efficacy and safety of treatment. After the main study period, patients were group-independently switched to take open-label teberif treatment during the next 48 weeks. RESULTS AND CONCLUSION: The analysis of multiple evaluation parameters of the efficiency during the 1st study period (blinded) and the 2nd study period (open-label) has shown that teberif and rebif demonstrate equivalent efficacy and stable 2-year efficacy of teberif was proven. There were no significant differences between teberif and rebif for all safety, and tolerability parameters. Switching from rebif to teberif didn't influence treatment efficacy. The 2-year study results confirmed a biosimilar teberif's benign tolerability and expected safety profile to other interferons ß-1a in patients with RMS.