Oncogenes of the RAS family regulate many of the cell’s activities, including proliferation, survival and differentiation. Activating mutations in these genes are common events for many types of cancer. One of the contradictory points concerning the biological significance of Ras activation is its dual effect (pro- or anti-proliferative) on cell reproduction. One of mechanisms by which Ras proteins influence cell growth is a regulation of intracellular level of reactive oxygen species (ROS), second messengers affecting variety of cellular processes including cell proliferation. Recently it was shown that repression of SESN1 and SESN3 genes, whose protein products control regeneration of peroxiredoxins, can play a critical role in Ras-induced ROS upregulation. In the present study we have found that Ras-induced repression of SESN3 expression and ROS upregulation is mediated via the modifications of transcriptional activity of HSF1. Interestingly, mutant Ras overexpression altered the activity of HSF1 in opposite directions in different cell contexts, in particular in human normal fibroblasts and HaCaT immortalized keratinocytes, but these opposite changes caused similar repression of SESN3 expression followed by elevation of ROS content and inhibition of cell proliferation in corresponding cell types. The inhibitory effect on cell proliferation was mediated by upregulation of p21Cip1/WAF1. Thus, HSF1/SESN3/ROS/p21Cip1/WAF1-mediated deceleration of cell growth may contribute to cell defense systems protecting the organism from excessive proliferation of cells that overexpress activated Ras oncoproteins.

A number of novel di- and triorganotin(IV) complexes 1–5 (Ph₂SnL¹, Ph₂SnL², Et₂SnL², Ph₃SnL³, Ph₃SnL⁴) with mono- or dianionic forms of thio-Schiff bases containing antioxidant sterically hindered phenol or catechol fragments were synthesized. Compounds 1–5 were characterized by ¹H, ¹³C NMR, IR spectroscopy, and elemental analysis. The molecular structures of complexes 1 and 2 in the crystal state were established by single-crystal X-ray analysis. The antioxidant activity of new complexes as radical scavengers was estimated in DPPH and ABTS assays. It was found that compounds 4 and 5 with free phenol or catechol fragments are more active in these tests than complexes 1–3 with tridentate O,N,S-coordinated ligands. The effect of compounds 1–5 on the promoted oxidative damage of the DNA by 2,2’-azobis(2-amidinopropane) dihydrochloride and in the process of rat liver (Wistar) homogenate lipid peroxidation in vitro was determined. Complexes 4 and 5 were characterized by more pronounced antioxidant activity in the reaction of lipid peroxidation in vitro than compounds 1–3. The antiproliferative activity of compounds 1–5 was investigated against MCF-7, HTC-116, and A-549 cell lines by an MTT test. The values of IC₅₀ are significantly affected by the presence of free antioxidant fragments and the coordination site for binding.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte “on-target off-tumor” reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.

Plasticity of tumor cells (multitude of molecular regulation pathways) allows them to evade cytocidal effects of chemo- and/or radiation therapy. Metabolic adaptation of the surviving cells is based on transcriptional reprogramming. Similarly to the process of natural cell aging, specific features of the survived tumor cells comprise the therapy-induced senescence phenotype. Tumor cells with this phenotype differ from the parental cells since they become less responsive to drugs and form aggressive progeny. Importance of the problem is explained by the general biological significance of transcriptional reprogramming as a mechanism of adaptation to stress, and by the emerging potential of its pharmacological targeting. In this review we analyze the mechanisms of regulation of the therapy-induced tumor cell senescence, as well as new drug combinations aimed to prevent this clinically unfavorable phenomenon.

A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole‐exome sequencing. A heterozygous amino‐acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G‐actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G‐actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient.

A T cell receptor (TCR) consists of α- and β-chains. Accumulating evidence suggests that some TCRs possess chain centricity, i.e., either of the hemi-chains can dominate in antigen recognition and dictate the TCR’s specificity. The introduction of TCRα/β into naive lymphocytes generates antigen-specific T cells that are ready to perform their functions. Transgenesis of the dominant active TCRα creates transgenic animals with improved anti-tumor immune control, and adoptive immunotherapy with TCRα-transduced T cells provides resistance to infections. However, the potential detrimental effects of the dominant hemi-chain TCR’s expression in transgenic animals have not been well investigated. Here, we analyzed, in detail, the functional status of the immune system of recently generated 1D1a transgenic mice expressing the dominant active TCRα specific to the H2-K^b molecule. In their age dynamics, neither autoimmunity due to the random pairing of transgenic TCRα with endogenous TCRβ variants nor significant disturbances in systemic homeostasis were detected in these mice. Although the specific immune response was considerably enhanced in 1D1a mice, responses to third-party alloantigens were not compromised, indicating that the expression of dominant active TCRα did not limit immune reactivity in transgenic mice. Our data suggest that TCRα transgene expression could delay thymic involution and maintain TCRβ repertoire diversity in old transgenic mice. The detected changes in the systemic homeostasis in 1D1a transgenic mice, which are minor and primarily transient, may indicate variations in the ontogeny of wild-type and transgenic mouse lines.