Humanized Mouse Model of HIV Infection Leontyev, D. S.; Glazkova, D. V.; Bezborodova, O. A. ...
Bulletin of experimental biology and medicine,
05/2023, Letnik:
175, Številka:
1
Journal Article
Recenzirano
The development of new drugs for the treatment of HIV infection requires testing of their efficacy in a relevant animal model, such as humanized mice, which, unfortunately, are not yet available in ...Russia. In the present study, we have developed conditions for the humanization of immunodeficient NSG mice with human hematopoietic stem cells. Humanized animals generated during the study showed a high degree of chimerism and harbored repopulation of the entire range of human lymphocytes required for HIV replication in the blood and organs. Inoculation of these mice with HIV-1 virus led to stable viremia, which was confirmed by the presence of viral RNA in blood plasma throughout the entire period of observation and proviral DNA in the organs of animals 4 weeks after HIV infection.
Preclinical study of therapeutic properties of an innovative drug Doxorubicin-NPh (doxorubicin in the form of ultrafine suspension of phospholipid liposomes) in comparison with free doxorubicin ...(Doxorubicin-Teva) and protected doxorubicin (Caelyx) was performed on transplanted murine tumor models. All these drugs were efficient in Ca755 breast carcinoma model (tumor growth inhibition ≈100%, increase in lifespan 90.6-114.3%). In P388 lymphocytic leukemia and LLC lung carcinoma, advantages of the protected doxorubicin by the benefit/risk ratio (width of therapeutic interval) were demonstrated: Caelyx>Doxorubicin-NPh>Doxorubicin-Teva. Doxorubicin-NPh and Caelyx exhibited similar therapeutic activity in the LLC model, especially when administered 3 times with 3-day intervals; for Doxorubicin-Teva, the optimal interval between the injections was 7 days.
This article presents the results of the work on the creation of an experimental plant, its testing, as well as the development of a computational model of a rotor magnetic suspension with the use of ...axial electromagnets. The main purpose of producing the plant was to test the results of the developed numerical finite element model. An automatic control system was developed for the experimental installation. The electrical circuit was assembled on the basis of a ESP32 microcontroller with a clock frequency of 240 MHz and a PWM with a capacity of 10 bits. A PID-regulator program was developed. The coefficients kP, kD, kI used in the code of the electronic control system program (PID-controller) were selected. An experimental study of the bearing capacity of the axial active magnetic bearing under the influence of an external axial force was conducted. The required power of the axial active magnetic bearing was determined. The maximum load-bearing capacity of the installation for the selected coefficients of the PID-controller was determined. An axisymmetric finite-element model of the axial active magnetic bearing was created in the open-source program FEMM 4.2. The load-bearing capacity of the installation for a given current intensity value was calculated. The results of the numerical modelling were compared with the experimental data obtained. The basic principles of creation and operation of the experimental plant and its numerical model are outlined.
One of the most important steps in the development of drugs and vaccines against a new coronavirus infection is their testing on a relevant animal model. The laboratory mouse, with well-studied ...immunology, is the preferred mammalian model in experimental medicine. However, mice are not susceptible to infection with SARS-CoV-2 due to the lack of human angiotensin-converting enzyme (hACE2), which is the cell receptor of SARS-CoV-2 and necessary for the entry of the virus into the cell. In present work, it was shown that intranasal administration of the adeno-associated vectors AAV9 and AAV-DJ encoding the hACE2 provided a high level of expression of
ACE2
gene in the lungs of mice. In contrast, the introduction of the AAV6 vector led to a low level
ACE2
expression. Infection with SARS-CoV-2 of mice expressing hACE2 in the lungs led to virus replication and development of bronchopneumonia on the 7th day after infection. Thus, a simple method for delivering the human
ACE2
gene to mouse lungs by intranasal administration of the AAV vector has been proposed. This approach enabled rapid generation of mouse model for studying coronavirus infection.
To ensure the safe operation of a local technosphere, a concept of comprehensive monitoring aimed at predicting, identification, analysis, and assessment of anthropogenic threats to society is ...needed. This paper puts forth a concept of comprehensive monitoring of a local technosphere based on a quantitative assessment of a multivariate object, including the problem, tasks, methods, and algorithms that ensure its implementation. The author substantiates the necessity to develop this concept given the importance of anthropogenic threats to society. An algorithm for comprehensive monitoring of a local technosphere has been developed. Within the framework of this concept, a method of compression of information linked to the state of a multivariate object was justified and proposed. Introduction of an overall index of multivariate information compression was justified, and method of its assessment was proposed. An approach to assessing the state of objects of a local technosphere using a combination of parameters, taking into account the weighting factors, has been proposed.
The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become ...the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.
In this study, we evaluated the antitumor activity of a gene therapy complex in which the tumor-specific control of the expression of the effector suicide gene
FCU1
was performed using a two-vector ...system based on the site-specific Cre–LoxP recombinase system. The complex of interest showed a high therapeutic potential in a mouse colon adenocarcinoma model.
The deformation behavior of {111}Al Ω plates has been analyzed in an Al-Cu-Mg-Ag alloy after creep tests to fracture by atomic-resolution scanning transmission electron microscopy (STEM). A ...transition from particle shearing to Orowan dislocation loop formation was found to occur at critical plate thicknesses of 3 and 3.5 cθ-o (i.e., 2.54-2.97 nm) at elevated temperature if the Ω phase is considered to compose of the orthorhombic θ lattice (θ-o). For the plates thinner than the critical value, a full dislocation provides the particle segments to shift relative to each other in the planes orthogonal to the particle habit plane. These discrete particle shifts/shears are proportional to ¼ cθ-o(1 d111Al) normal to the broad plate surfaces or the plate habit plane. A full dislocation with Burgers vector b→ = 001θ-o can dissociate to a few partials inside the θ-o lattice. For the thick plates, a dislocation loop was found to consist of the two most extent segments with jogs making its line somewhat parallel to the broad plate surfaces. Interposition of these two segments belonging to the same dislocation loop along the broad interfaces, depends on elastic strain fields, e.g., originating from the ledges formed after particle shearing, broad coherent interface structures and the precipitate/matrix volumetric incompatibility in Al// θ-o. The dislocation loops cause particle segmentation and deviation by lattice rotation around Al axes from the well-known Al/Ω orientation relationship.
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The coarsening behavior of strengthening particles has been studied in a peak-aged Al–Cu–Mg–Ag alloy during creep at 150 °C and 165 °C. The average {111}Al Ω plate thickness and diameter were ...observed to strongly depend on creep time and less on the applied stress levels and total plastic strain accommodated during creep. The volume fraction (FV) of Ω particles increased during long-term creep up to values exceeding that after peak-aging. The S-phase (Al2CuMg, Cmcm) fragments independently nucleate along dislocations and then intergrowth each other to form precipitate complexes together with the θ′-phase (Al2Cu, I4‾m2). The complex particle size including the θ′ plate thickness and the S rod diameter are sensitive to the total plastic strain level achieved at different applied stresses during creep.
Antitumor efficacy of the combined suicide gene therapy and radiotherapy was studied on the model of CT26 murine colon adenocarcinoma. CMV-FCU1-IRES-mGM-CSF-pGL3 construct with PEG-PEI-TAT ...(FCU1–mGM/5-FC) block copolymer as a vector was used for intratumoral administration. Tumors were irradiated with a single 5 Gy dose. The efficacy was evaluated according to the grade of tumor growth inhibition (T/C) and lifespan of the animals. Pronounced antitumor activity of the combined use of FCU1–mGM/5-FC system with radiotherapy on the background of prolonged lifespan and the synergism of the applied methods was revealed.
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