Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents.

Combining chemotherapy and hormone therapy is a prevalent approach in breast cancer treatment. While the cytotoxic impact of numerous chemotherapy drugs stems from DNA damage, the exact role of these DNA alterations in modulating estrogen receptor α (ERα) machinery remains elusive. The present study aimed to analyze the impact of DNA damage agents on ERα signaling in breast cancer cells and assess the signaling pathways mediating the influence of DNA damage drugs on the ERα machinery.

Exosomes are involved in the intercellular transfer of rapamycin resistance in the breast cancer cells.

Introduction: Resistance to chemotherapy and/or irradiation remains one of the key features of malignant tumors, which largely limits the efficiency of antitumor therapy. In this work, we studied the progression mechanism of breast cancer cell resistance to target drugs, including mTOR blockers, and in particular, we studied the exosome function in intercellular resistance transfer.

Methods: The cell viability was assessed by the MTT assay, exosomes were purified by successive centrifugations, immunoblotting was used to evaluate protein expression, AP-1 activity was analyzed using reporter assay.

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance.

Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of the activity or synthesis of hormone receptors), or by activation of oestrogen-independent signalling pathways. Recently the effect of exosome-mediated intercellular transfer of hormonal resistance was revealed, however, the molecular mechanism of this effect is still unknown.

Secretion of Mutant DNA and mRNA by the Exosomes of Breast Cancer Cells.

Exosomes are the small vesicles that are secreted by different types of normal and tumour cells and can incorporate and transfer their cargo to the recipient cells. The main goal of the present work was to study the tumour exosomes' ability to accumulate the parent mutant DNA or RNA transcripts with their following transfer to the surrounding cells. The experiments were performed on the MCF7 breast cancer cells that are characterized by the unique coding mutation in the gene.

Upregulation of Akt/Raptor signaling is associated with rapamycin resistance of breast cancer cells.

mTOR inhibitors are considered today to be one of the most promising anticancer drugs. Here to study the mechanism of the acquired resistance of MCF-7 breast cancer cells to mTOR inhibitors two different models of the cell resistance were used: rapamycin-resistant MCF-7/Rap subline developed under long-term rapamycin treatment, and metformin-resistant MCF-7/M subline obtained by long-term metformin treatment. We have found that both resistant sublines were characterized by common features: increased expression of mTOR-interacting Raptor protein, increased phosphorylation of Akt, and activation of growth-related transcriptional factor AP-1.

Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways.

The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the loss or mutation of estrogen receptor, alterations of antiapoptotic pathways, overexpression of growth-related signaling proteins, etc. The perspective approaches for overcoming the resistance may be based on the usage of compounds such as inhibitors of the cell energetic metabolism.

Peculiarities of Molecular Mechanisms Involved in Modification of the Structural and Molecular Organization of the Cell Genome.

Within the framework of the previously proposed model of structural organization of DNA that supplements the Watson-Crick model and is based on a mathematical regulation - Fibonacci sequence, we suppose the existence of nucleotides without nitrogenous base and acting as linkers connecting DNA subunits.

Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs.

Exosomes are small vesicles which are produced by the cells and released into the surrounding space. They can transfer biomolecules into recipient cells. The main goal of the work was to study the exosome involvement in the cell transfer of hormonal resistance.

Changes in the Quantitative Composition of the Population in Delayed Periods After γ-Radiation Exposure of the Cells in Various Phases of S Period of the First Mitotic Cycle.

Using the autoradiographic method, we studied the kinetics of DNA synthesis over the mitotic cycle in mouse corneal epithelium cells in delayed periods after γ-irradiation in different points of the S phase of the first mitotic cycle. The index labeled cells during 1-3 periods of DNA synthesis most adequately reflects quantitative changes in the cell population composition after cell exposure during the first S period. The relative number of labeled S phase cells in the second mitotic cycle in experiments where the cells were irradiated in the S phase of the first S period was 4-fold lower than in experiments where the cells were exposed during S phase.

Fibonacci Sequence and Supramolecular Structure of DNA.

We proposed a new model of supramolecular DNA structure. Similar to the previously developed by us model of primary DNA structure [11-15], 3D structure of DNA molecule is assembled in accordance to a mathematic rule known as Fibonacci sequence. Unlike primary DNA structure, supramolecular 3D structure is assembled from complex moieties including a regular tetrahedron and a regular octahedron consisting of monomers, elements of the primary DNA structure.

The Mechanism of Adaptation of Breast Cancer Cells to Hypoxia: Role of AMPK/mTOR Signaling Pathway.

We studied the mechanisms of adaptation of human breast cancer cells MCF-7 to hypoxia and analyzed the role of AMPK/mTOR signaling pathway in the maintenance of cell proliferation under hypoxic conditions. It was found that long-term culturing (30 days or more) of MCF-7 cells under hypoxic conditions induced their partial adaptation to hypoxia. Cell adaptation to hypoxia was associated with attenuation of hypoxia-dependent AMPK induction with simultaneous constitutive activation of mTOR and Akt.

Delayed Consequences of Changes in DNA Synthesis in Cells Exposed to Single Irradiation at the End of S Phase of the Mitotic Cycle.

Kinetics of DNA synthesis throughout the mitotic cycle in mouse corneal epithelial cells after single γ-irradiation of cells (4 Gy) at the end of S phase was studied by the method of radioautography. It was found that single irradiation increased the duration of S phase due to reparation of damage in the cell at the expense of time that normally falls on g1 phase. During reparation, two parallel DNA synthesis processes occur in the damaged cells: de novo synthesis at the site of injury after excision of the damaged fragments (reparative synthesis) and supplementary synthesis during the repair period in the remaining undamaged genome competent for replication.

[Investigations into the relationship between respiratory disorders and excessive body weight in the adolescents presenting with bronchial asthma treated based at a specialized health resort facility].

A total of 71 patients with bronchial asthma (BA) were examined and treated based at a specialized health facility of whom 43 ones presented with mild asthma and 26 patients with moderately severe asthma in remission. The median age of the patients was 12,04 ± 2,08 years. Spirometry parameters: MOS50, MOS75, and PSV, proved to be of high informative value combined with high enough sensitivity and specificity.

Reparation as a factor contributing to genetic variability of the biological system.

Kinetics of DNA synthesis in mitotic cycle of in mouse corneal epithelial cells after γ-irradiation in different S phase points was studied by the method of autoradiography. Normally, S phase of corneal epithelial cells consists of two phases (S1 and S2) separated by an interval without DNA synthesis. Each phase, in turn, includes two subphases with a pause in DNA synthesis.

Dynamics of DNA synthesis disturbance and recovery after fractionated irradiation of S phase cells.

Using the autoradiographic method we studied the kinetics of DNA synthesis during themitotic cycle of mouse corneal epithelial cells after γ-irradiation in a dose of 2 Gy at different S-phase points. Normally, S phase in corneal epitheliocytes includes S1 and S2 phases separated by an interval during which DNA is not synthesized. Double exposure modifies the pattern of DNA synthesis in the cell due to reparation of injuries.

Comparative analysis of the kinetics of DNA synthesis after exposure during different phases of the cell cycle S period.

The kinetics of DNA synthesis in the mitotic cycle of mouse corneal epithelial cells was studied after a single γ-irradiation of cells in a dose of 4 Gy at different S-phase points. Normally, corneal epitheliocyte S phase consists of S1 and S2 phases separated by an interval during which no DNA is synthesized. The duration of each phase was lengthened after single irradiation due to reparation of injuries in the cells at the expense of the time normally occupied by g1 period of the mitotic cycle.

Effect of irradiation on DNA synthetic period of the mitotic cycle in cells.

Kinetics of DNA synthesis in mitotic cycle of mouse corneal epithelial cells after single γ-irradiation (4 Gy) at the end of S period was studied by the method of radioautography. Normally, S period of corneal epithelial cells consists of several stages separated by intervals without DNA synthesis. The estimated mean duration of the first (S(1)) and second (S(2)) phases of S period was 16 and 10 h, respectively, and the interval between them was 7 h.

[To the history of organisation and development of cardiac anesthesiology in the A. N. Bakulev Research Center of Cardiovascular Surgery of the Russian Academy of Medical Sciences: the start of activities (1956-1965)].

The authors present data on the development and introduction of anesthetic techniques during cardiac surgery at the Institute of Thoracic Surgery, USSR Academy of Medical Sciences, in 1956-1960 and after its reorganization to the Institute of Cardiovascular Surgery, USSR Academy of Medical Sciences, in 1961-1965. It is shown that in the years of introduction of closed operations on the heart, the methods of one- and many component inhalational anesthesia were mastered, its techniques were developed, anesthesia apparatuses and an anesthesia schedule were designed, cardiac anesthesiological studies were conducted, training of physicians from the country's regions was initiated, and the first guidelines for general anesthesia were published. In these years, the firm foundation was laid for the development of cardiac anesthesia.

Lipoxygenase pathway of arachidonic acid metabolism in growth control of tumor cells of different type.

The influence of inhibitors of different lipoxygenases (LOX) on the growth of human tumor cells with different profiles of synthesized eicosanoids was studied. The studied LOX inhibitors had virtually no influence on the growth of A549 cells actively synthesizing cyclooxygenase and lipoxygenase metabolites of arachidonic acid (AA). The inhibitor of 12-LOX, baicalein, significantly inhibited proliferation in cultures of A431 epidermoid carcinoma cells with a characteristic domination of the major lipoxygenase metabolite of AA, 12-hydroxyeicosatetraenoic acid (12-HETE), in the profile of synthesized eicosanoids and reduced to 70% the incorporation of [3H]thymidine into DNA.

Arachidonic acid metabolism in growth control of A549 human lung adenocarcinoma cells.

The role of individual eicosanoids of the arachidonic acid (AA) cascade in the growth control of A549 human lung adenocarcinoma cells has been studied. Cyclooxygenase and lipoxygenase metabolites of [14C]AA incorporated were actively synthesized in the cultures of tumor cells with full confluence unaccomplished. In such cultures inhibitors of AA metabolism (indomethacin and esculetin) and also a lipoxygenase metabolite of AA, 15-hydroxyeicosatetraenoic acid (15-HETE), significantly suppressed the incorporation of [3H]thymidine and biosynthesis of prostaglandin E2 (PGE2).

[The pharmacotherapy of psychoautonomic disorders in patients with the surgical menopause syndrome].

Psychotropic drug lerivon (mianserin hydrochloride) was tested in patients with psychovegetative disorders as a result of surgical menopause (postovariectomy syndrome). The drug relieved emotional and vegetative symptoms and, therefore, can be used in affective disorders in surgical menopause.

[Transcobalamin II levels in blood plasma of children with acute leukemia].

Transcobalamin II (TcII) level was studied in plasma of 40 children with acute leukemia. TcII is a cobalamin-binding protein which mediated the cellular uptake of Cbl and interacted with surface membrane receptor of hemopoietic cells. Plasma TcII and cobalofilins were analysed by PAGE using 57Co-cyanocobalamin.

[Clinical-physiological characteristics and hormone therapy of patients with typical form of climacteric syndrome].

Clinical and physiological examinations of 76 women in the postmenopause revealed in 64 of them the typical form of the climacteric syndrome, characterized by not only typical symptoms ("flushes", increased exudation, headaches, etc.), but also by various emotional vegetative disturbances detected at profound clinical neurological examination of the autonomic nervous system and the emotional sphere. Individual hormone therapy was associated with an appreciable alleviation of all psychovegetative disorders: "flushes", exudation, irritability, arterial hypertension, severity of vegetative dystonia, hysterical stigmata.