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Biomedical subjects

S G Andreev

Publications and source records attributed to S G Andreev.

13 recordsLinked to original sources
PubMed2006

Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis.

Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed.

Alpha Particles↗
PubMed2006

Prediction of dose response for radiation induced exchange aberrations taking cell cycle delays into account.

Chromosomal aberrations (CAs) are regarded as one of the most sensitive biological indicators of genetic alterations. The aberration frequency is routinely determined in the first metaphase. Yet, the data interpretation can be complicated due to radiation induced mitotic delays. To investigate the effect of delays on CA frequency in the first mitosis, human lymphocytes were irradiated with X rays and Giemsa detectable CAs were measured at different sampling times. Besides, a computer simulation was performed reproducing the main effects under investigation, that is, CA induction and cell progression through the mitotic cycle. The CA formation model takes into account the structural organisation of interphase chromosomes in a lymphocyte nucleus, DNA double-strand break (DSB) induction and their rejoining/misrejoining. Lymphocyte transition through the cell cycle was simulated by a Monte Carlo technique. The delay was proposed to result from DNA DSBs. The predicted ratios of first/second/third cycle metaphases agree with the experimental data for control and irradiated samples. Both experimental and calculated CA frequencies in the first mitosis were nearly time-independent. This was proposed to result from de-synchronisation of the lymphocyte population.

Cell Cycle↗
PubMed2002

Biophysical analysis of radiation induced initial DNA fragmentation.

Production of double strand breaks (DSBs) and double-stranded DNA fragments after irradiation with high energy nitrogen ions was simulated with stochastic track generation and a high-order chromatin structure (HOCS) model representing a segment of interphase chromosome. The non-random distribution of DNA fragments is predicted for irradiation of HOCS. Agreement with the experimental data is obtained. The influence of HOCS and the role of the background component in DNA fragment distributions are discussed.

Biophysics↗
PubMed2002

Intrachromosomal exchange aberrations predicted on the basis of the globular interphase chromosome model.

One of the key questions in understanding mechanisms of chromosome aberration production is how does interphase chromosome structure affect aberration formation. To explore this a modelling approach is presented which combines Monte Carlo simulation of both alpha particle track and interphase chromosome structure. The structural state of interphase chromosome influences a dose-effect relationship for intrachromosomal exchange aberrations (intrachanges). It is shown that intrachanges are induced frequently by both X rays and alpha particles if the chromosome is in the condensed globular but not in the decondensed coiled state. Truly simple intra-arm intrachanges induced by X rays are dose squared in coiled chromosomes, but exhibit linear dose dependence in globular chromosomes. Experimental data on interarm intrachanges obtained by dual arm chromosome painting are analysed by means of the technique presented. Results of analysis support the conclusion about the arms proximity of chromosome 1 in human lymphocytes.

Chromatids↗
PubMed2002

Biophysical study of the globular organisation of interphase chromosomes.

The globular model of interphase chromosomes is studied using methods involving the statistical physics of polymers. An interphase chromatid is represented as a flexible chain of structural sub-units, or superdomains (SDs). Each SD is simulated as a number of chromatin fibre loops fixed at a nuclear matrix core. A chain of SDs is further folded in the nucleus in a compact conformation owing to volumetric interactions between SDs. The algorithm used is extended to incorporate the chain anchorage at different points. Excluded volume effects are taken into account in Monte Carlo simulation at both the SD and whole chromosome level. A variety of structures is observed in computer experiments. The simulation results correlate with the available experimental data.

Biophysics↗
PubMed1998

Kinetics of T cell proliferation: a mathematical model and data analysis.

A mathematical model of in vitro T cell proliferation controlled by IL-2 internalization is presented. The model describes the T cell transition from G1 to S+G2+M stages of the cell cycle and introduces "molecular" equations for the G1-S phase control. These equations consider current knowledge of the biochemical mechanisms of receptor synthesis, ligand-receptor binding, and internalization of ligand-receptor complexes. The model describes the kinetic data for in vitro T cell proliferation at various IL-2 concentrations (50-500 pM) for various exposure time (6-26 h). The kinetic parameters were calculated based on the model. The results obtained suggest that increase in the IL-2 concentration and exposures decrease the critical ligand-receptor concentration in the cells which control proliferation. The time tau, which characterizes the delay in the G1-S transition, was constant at various IL-2 concentrations.

Animals↗
PubMed1990

Differentiation control in cell cycle and development based on the alterations of higher-order chromatin structure. Theory and applications to radiation and chemical action.

A theoretical model of genes switching during development and cell cycle is proposed. The model is based on the assumption concerning the connection between differentiation state and distribution of chromatin domains in the nucleus. Radiation and chemicals action as supposed in the model is realized not at the DNA secondary structure level, but by the damage of chromatin supramolecular states spectrum and transition probabilities between states.

Animals↗
PubMedDate not supplied

[Globular model of interphase chromosome and intrachromosomal exchange aberrations].

A globular folding model formerly proposed for large-scale interphase chromatin/chromosome organization is investigated here by computer simulation. Large-scale structure of interphase chromosome is suggested to be determined by volumetric interactions between chromosome subunits resulting in folding of subunit chain in a globular state. Structure unit of interphase chromosome is considered as a spherical structure consisting of a cluster of compact chromatin domains. These structure units/domain clusters were termed as a superdomains to emphasize their supradomain organization. Globular state of superdomain chain with excluded volume as well as phase transitions between condensed (globular) and decondensed (coiled) states are studied by dynamic Monte-Carlo approach. Globular model is supported by confocal microscopy data. It extends current view on interphase chromosome as a random Gauss polymer chain. Radiation-induced intrachromosome exchange aberrations (intrachanges) are modeled on the basis of the contact hypothesis. It implies that intrachanges result from radiation damage of chromatin mainly in contacted subunits. Computer modeling of chromosome structure provides a wealth of information about proximity effects and results in prediction of pattern of intrachromosome contacts. Calculated intrachange frequencies agree well with experimental data. Globular model suggests a physical mechanism for conformational changes of large-scale chromosome structure similar to phase transitions in polymer systems. These rearrangements of structure organization of chromosomes in the nuclei following irradiation could be mechanistically linked to the complex chromosome aberrations formation as well as to alteration of gene expression due to position variegation effect.

Chromatin↗
PubMedDate not supplied

[Rejoining pathways underlying intrachange formation depend on interphase chromosome structure].

Fluorescence in situ hybridization technique with dual-arm painting of the same chromosome allows to study radiation induced intrachromosomal exchange aberrations (intrachanges). The formal method for analysis of FISH data developed by Savage and Simpson includes an arrangement of chromosomal reactive breaks on chromosomes and chromosome arms (CAB system). That method predicts types and frequencies of aberrations assuming random restitution/rejoining of breaks free ends. However experimental data suggest that many aberrations are formed non-uniformly along the chromosomes and chromosome arms. In the present paper the system for classifying rejoining pathways underlying intrachange formation is proposed which does not require random restitution/rejoining suggestion. It takes into account the parameters of interphase chromosome structure. Types and frequencies of intrachanges are considered by exploring different hypotheses about exchange initiating chromosomal lesions.

Chromosome Aberrations↗
PubMedDate not supplied

[Biophysical modeling of radiation induced genetic damage to cells].

The paper deals with the new approach for high accurate prediction of ionising radiation induced lesions of the cellular genetic structures. The previous techniques mainly were based on the assumption of the random radiation-induced breakage of the cellular DNA. They did not consider higher-order DNA organisation in the chromatin and in the interphase chromosomes. The paper discusses the new methods of the biophysical modelling of DNA breakage following high LET irradiation which takes into account the information on 3-dimensional structural organisation of DNA in interphase chromosomes. On this basis the influence of DNA organisation in the chromosomes on both dsb clusters induction and on repair were quantitatively studied, that was impossible by the means of previous computational techniques.

Biophysical Phenomena↗
PubMedDate not supplied

[Structural chromosome organisation and radiation-induced interchromosomal aberrations].

The quantitative prediction of the biological effects of radiation is one of the actual tasks of radiobiology. The experimental study may be impossible under certain conditions (low doses, complex radiation fields, etc). The development of theoretical tools is required to predict biological and medical consequence of the irradiation of cell and organism. The effect under the consideration in the present paper is chromosome aberrations (CA) induced by low and high LET radiation. One of the most uncertain factors in CA prediction is the impact of chromosomal and nuclear architecture. In the present study the quantitative evaluation of the mechanisms of CA induction are discussed in the framework of the biophysical modelling technique taking into account interphase chromosomes structure in the nucleus of living (human) cell. We show that the surface contacts mechanism of interchromosomal aberrations (interchange) formation does not explain the observed ratio of simple/complex interchanges induced by both low and high LET radiation. The chromatin structure repositioning following irradiation is proposed as a possible mechanism involved in the formation of the complex aberrations.

Cell Nucleus↗