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Abstract Background Awareness of age‐related features of carcinogenesis and the importance of cellular immunity is crucial for developing effective antitumor therapies for specific patient groups. Methods In this study, we examined different populations of cancer stem cells (CSCs) and circulating tumor cells (CTCs) in "young" (8‐10 weeks) and "aged" (80‐82 weeks) C57BL/6 male mice. We used an orthotopic model of Lewis lung carcinoma (LLC) to evaluate the effectiveness of cell therapy targeting lung cancer through reprogrammed CD8‐positive T cells (rCD8+ T cells) in mice from two different ages. Results The findings revealed that tumor progression with age is primarily caused by impaired recruitment of T cells to the lungs. Additionally, a lower number of CTCs and CSCs were observed in younger mice compared to the older mice. The antitumor effect of rCD8+ T cells in aged mice was found to be inferior to that in young mice, which can be attributed to the reduced impact of therapy on specific CSCs populations. Conclusions These results offer new insights into the treatment of lung cancer using rCD8+ T cells. Considering the age‐related characteristics influencing disease progression, this therapy has the potential to significantly enhance the effectiveness of treatment methods.

We studied the effect of reprogrammed CD8+ T cells (rT cells) from the bone marrow of intact mice on tumor cells and neovasculogenesis in mice with orthotopic Lewis lung carcinoma (LLC). Reprogramming of T cells was carried out using a MEK inhibitor and a PD-1 blocker; the targeting of rT cells to tumor cells was achieved by preincubation with LLC cell lysate. It was shown that the antitumor effect of rT cells was based on apoptosis of tumor cells. In addition, cell therapy reduced the number of endothelial cells (CD45—CD309+) and angiogenic cell precursors (CD45—CD117+CD309+), mesenchymal stem cells (CD45—CD31—CD34—CD44+), myeloid (CD45+CD34+CD31—) and non-myeloid (CD45+CD34—CD31—) fibrocytes, and leukocytes (CD45+) in the lungs and increased their number in the blood. Thus, rT cells impaired the recruitment of neovasculogenic cells to the lung. The antitumor effects of rT cells are superior to those of naive CD8+ T cells. The proposed reprogramming method can be useful in developing effective approaches to the therapy of lung cancer, as it allows obtaining cytotoxic rT cells capable of reducing the activity of neovasculogenesis. [ABSTRACT FROM AUTHOR]

Evgenii Skurikhin,1 Olga Pershina,1 Mariia Zhukova,1 Darius Widera,2 Edgar Pan,1 Angelina Pakhomova,1 Vyacheslav Krupin,1 Natalia Ermakova,1 Victoria Skurikhina,3 Lubov Sandrikina,1 Sergey Morozov,4 Aslan Kubatiev,4 Alexander Dygai1,4 1Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia; 2Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Whiteknights Campus, Reading, RG6 6AP, UK; 3Siberian State Medical University, Tomsk, Russia; 4Institute of General Pathology and Pathophysiology, Moscow, RussiaCorrespondence: Evgenii SkurikhinLaboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, 634028, 3, Lenin Street, Tomsk, RussiaTel/Fax +7-3822-418-375Email eskurihin@inbox.ruBackground: Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future.Methods: In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice.Results: Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45−CD34+CD31+), CD309+-endothelial cells, and angiogenesis precursors (CD45−CD117+CD309+) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309+-endothelial cells and Notch1+ EPCs.Conclusion: Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.Keywords: pulmonary emphysema, endothelial progenitor cells, VEGF2 (CD309), spiperone, Notch1, endothelial regeneration

The effect of dark deprivation on the morphofunctional state and rhythmostasis of the liver under CCl4 toxic exposure has been studied. The relevance of this study is due to the fact that the hepatotoxic effect of carbon tetrachloride on the liver is well studied, but there are very few data on the relationship between CCl4 intoxication and circadian biorhythms, and most of the studies consider the susceptibility of the organism in general and of the liver in particular to the influence of CCl4 in some separate periods of the rhythm, but not the influence of this chemical agent on the structure of the whole rhythm. In addition, earlier studies indicate that light disturbance causes certain changes in the morphofunctional state of the liver and the structure of the circadian rhythm of a number of parameters. As a result of this study, we found that the effect of CCl4 in conditions of prolonged dark deprivation causes more significant structural and functional changes in hepatocytes, as well as leading to significant changes in the circadian rhythms of a number of parameters, which was not observed in the action of CCl4 as a monofactor. We assume that the severity of structural and functional changes is due to the light-induced deficiency of melatonin, which has hepatoprotective properties. Thus, the mechanisms of CCl4 action on CRs under conditions of light regime violations leave a large number of questions requiring further study, including the role of melatonin in these processes. [ABSTRACT FROM AUTHOR]

Background: Awareness of age‐related features of carcinogenesis and the importance of cellular immunity is crucial for developing effective antitumor therapies for specific patient groups. Methods: In this study, we examined different populations of cancer stem cells (CSCs) and circulating tumor cells (CTCs) in "young" (8‐10 weeks) and "aged" (80‐82 weeks) C57BL/6 male mice. We used an orthotopic model of Lewis lung carcinoma (LLC) to evaluate the effectiveness of cell therapy targeting lung cancer through reprogrammed CD8‐positive T cells (rCD8+ T cells) in mice from two different ages. Results: The findings revealed that tumor progression with age is primarily caused by impaired recruitment of T cells to the lungs. Additionally, a lower number of CTCs and CSCs were observed in younger mice compared to the older mice. The antitumor effect of rCD8+ T cells in aged mice was found to be inferior to that in young mice, which can be attributed to the reduced impact of therapy on specific CSCs populations. Conclusions: These results offer new insights into the treatment of lung cancer using rCD8+ T cells. Considering the age‐related characteristics influencing disease progression, this therapy has the potential to significantly enhance the effectiveness of treatment methods. [ABSTRACT FROM AUTHOR]

Abstract Introduction The aim of this study was to evaluate the impact of the contouring methods on dose metrics and their predictive value on tumor control and survival, in both situations of pre-treatment and post-treatment dosimetry, for patients with advanced HCC treated with SIRT. Methods Forty-eight patients who underwent SIRT between 2012 and 2020 were retrospectively included in this study. Target volumes were delineated using two methods: MRI-based contours manually drawn by a radiologist and then registered on SPECT/CT and PET/CT via deformable registration (Pre-CMRI and Post-CMRI), 99mTc-MAA-SPECT and 90Y-microspheres-PET 10% threshold contouring (Pre-CSPECT and Post-CPET). The mean absorbed dose (Dm) and the minimal absorbed dose delivered to 70% of the tumor volume (D70) were evaluated with both contouring methods; the tumor-to-normal liver uptake ratio (TNR) was evaluated with MRI-based contours only. Tumor response was assessed using the mRECIST criteria on the follow-up MRIs. Results No significant differences were found for Dm and TNR between pre- and post-treatment. TNR evaluated with radiologic contours (Pre-CMRI and Post-CMRI) were predictive of tumor control at 6 months on pre- and post-treatment dosimetry (OR 5.9 and 7.1, respectively; p = 0.02 and 0.01). All dose metrics determined with both methods were predictive of overall survival (OS) on pre-treatment dosimetry, but only Dm with MRI-based contours was predictive of OS on post-treatment images with a median of 23 months for patients with a supramedian Dm versus 14 months for the others (p = 0.04). Conclusion In advanced HCC treated with SIRT, Dm and TNR determined with radiologic contours were predictive of tumor control and OS. This study shows that a rigorous clinical workflow (radiologic contours + registration on scintigraphic images) is feasible and should be prospectively considered for improving therapeutic strategy.

The survival and cytotoxicity of reprogrammed human CD8+ T-cells (hrT-cells) were evaluated in a culture of cancer stem cells (CSCs) isolated from a patient with small-cell lung cancer (SCLC). T-cells were isolated from the blood of healthy volunteers and patients with lung diseases. Reprogramming with MEK and PD-1 inhibitors increased the survival and cytotoxicity of allogeneic T-cells in vitro. The positive effect of reprogramming is more pronounced in patients with lung diseases than in healthy donors. Autologous hrT-cells showed high effectiveness in eliminating CSCs. Thus, in vitro studies are significant in the selection of potential cell donors and evaluating the effectiveness of their reprogramming.

We have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). In the orthotopic LLC model, cell therapy with rsCD8+T-cells increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung tissue from mice. The amount of cancer stem cells (CSC) decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

Despite the increasing urgency of the problem of treating small cell lung cancer (SCLC), information on the causes of its development is fragmentary. There is no complete understanding of the features of antitumor immunity and the role of the microenvironment in the development of SCLC resistance. This impedes the development of new methods for the diagnosis and treatment of SCLC. Lung cancer and chronic obstructive pulmonary disease (COPD) have common pathogenetic factors. COPD is a risk factor for lung cancer including SCLC. Therefore, the search for effective approaches to prevention, diagnosis, and treatment of SCLC in patients with COPD is an urgent task. This review provides information on the etiology and pathogenesis of SCLC, analyses the effectiveness of current treatment options, and critically evaluates the potential of chimeric antigen receptor T cells therapy (CART therapy) in SCLC. Moreover, we discuss potential links between lung cancer and COPD and the role of endothelium in the development of COPD. Finally, we propose a new approach for increasing the efficacy of CART therapy in SCLC.

Objective: to develop a new antigenic relevance influenza B virus suitable for modeling influenza infection in mice to assess of in vivo and in vitro therapeutic and preventive efficacy of antiviral drugs.Materials and methods: was carried out an adaptation of influenza B virus in BALB/c mice. Was performed, comparative assessment of in vivo and in vitro pathogenicity of the parenta! virus and. adapted, influenza B virus. Was assessed, inhibition of neuraminidase with antiviral drugs (oseltamivir ethoxyacrylate and. Tamiflu) in relation to the adapted, influenza B virus.Results: adapted influenza B virus (B/Novosibirsk/40/2017-MA strain) models non-lethal influenza infection with pronounced, clinical signs of the disease in experimental animals. Were described the destructive changes in lungs and. brain that increases during infection. Analysis of internal organs (lungs, brain, liver, heart, kidneys, spleen) were revealed viral load only in the lungs. Were evaluated, in vivo and in vitro efficacy of antiviral drugs (oseltamivir ethoxysuccinate and Tamiflu®) on the model of influenza infection. Were proved, the high, efficiency of the innovative drug — oseltamivir ethoxysuccinate.Conclusion: the antigen-relevant adapted, influenza B virus (B/Novosibirsk/40/2017-MA strain) can be used, to assess the drug effectiveness against influenza, as well as an additional tool for predicting the effectiveness of the vaccine against drifting strains.

The purpose of this work was to study the associations of RS3846663 variants in the HMG-CoA reductase gene with effectiveness of statin therapy. For the coronary heart disease patients group, 127 subjects (59 females and 68 males) were selected. In order to identify single nucleotide polymorphism, minisequencing was applied with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-ToF/MS) for subsequent detection of the reaction products. In this study, the statin significantly reduced total cholesterol, low density lipoprotein and triglyceride levels, both after one month and two months of treatment. It was established that carrying CC and TT genotypes of RS3846663 in HMG-CoA reductase gene had no impact on the change in total cholesterol and almost all values in the spectrum of lipoproteins during statin therapy, regardless of its duration. A weak tendency to an increase in high-density lipoproteins was observed in heterozygous CT carriers after one month of statin treatment. In addition, no significant association was found between carrying heterozygous CT genotype and TT homozygote and achievement of target levels of lipoproteins and total cholesterol during simvastatin treatment, regardless of its duration.

The purpose of this study was to establish an association between polymorphism rs3846663 in the HMG-CoA reductase gene and total cholesterol in relatively healthy individuals, without gender specification, as well as in men and in women separately. The study was conducted in a group of 173 relatively healthy individuals (105 women, 68 men). In order to identify single nucleotide polymorphism, minisequencing was applied with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-ToF/MS) for subsequent detection of the reaction products. In this study, total cholesterol levels in carriers of pathological genotypes (CT and TT) of rs3846663 in the HMG-CoA reductase gene were significantly higher than in individuals with a normal CC genotype. It was also found that carrying CT and TT genotypes increases the risk of elevated total cholesterol as compared to the target levels. Total cholesterol in women carrying CT and TT genotypes of rs3846663 in the HMG-CoA reductase gene was statistically significantly higher. Moreover, the risk of elevated total cholesterol was also high. In healthy men, the presence of a pathological T allele did not affect the total cholesterol levels.

CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors and PD-1 blockers to increase their antitumor activity. Antitumor effects of reprogrammed T-lymphocytes were shown in vitro and in vivo in the Lewis lung carcinoma model. The population of T- lymphocytes with persistent expression of CCR7 was formed as a result of reprogramming. Reprogrammed T-lymphocytes were resistant to apoptosis and characterized by high cytotoxicity against Lewis lung carcinoma (LLC) cells in vitro. Administration of reprogrammed T-lymphocytes to C57BL/6 mice with LLC reduced the number of lung metastases. The antitumor effect resulted from the elimination of tumor cells and cancer stem cells, and the effect of therapy on cytotoxic T-lymphocyte counts. Thus, reprogramming of T-lymphocytes using MEK inhibitors is a promising approach for targeted therapy of lung cancer.

Metabolic syndrome can lead to several challenging complications including degeneration of the pancreas and hypogonadism. Recently, we have shown that Bisamide Derivative of Dicarboxylic Acid (BDDA) can contribute to pancreatic restoration in mice with metabolic disorders via its positive effects on lipid and glucose metabolism, and by increasing the numbers of pancreatic stem cells. In the present study, we hypothesized that BDDA might also be effective in restoring hypogonadism caused by metabolic syndrome. Experiments were performed on male C57BL/6 mice with hypogonadism, where metabolic disorders have been introduced by a combination of streptozotocin treatment and high fat diet. Using a combination of histological and biochemical methods along with a flow cytometric analysis of stem and progenitor cell markers, we evaluated the biological effects of BDDA on testicular tissue, germ cells, spermatogonial stem cells in vitro and in vivo, as well as on fertility. We demonstrate that in mice with metabolic disorders, BDDA has positive effects on spermatogenesis and restores fertility. We also show that BDDA exerts its therapeutic effects by reducing inflammation and by modulating spermatogonial stem cells. Thus, our results suggest that BDDA could represent a promising lead compound for the development of novel therapeutics able to stimulate regeneration of the testicular tissue and to restore fertility in hypogonadism resulting from complications of metabolic syndrome.

Objective. To study the dose-dependent effect of simvastatin on the change of content of individual fatty acids (FA) profile of blood serum and their complexes with secondary prevention of chronic coronary heart disease (CHD) in groups of men and women.Materials and methods. Gas-liquid chromatography-mass spectrometry was used to establish the absolute and relative levels of FA in serum of 155 CHD patients before and after treatment by simvastatin in doses of 40 mg (89 people) and 80 mg (36 people).Results. The statin lowered the content of the FA proportionally by reducing the unsaturated (UFA), mainly polyunsaturated (PUFA) FA, and saturated (SFA) FA. The level of monounsaturated fatty acids (MUFA) decreased in women at a dose of 40 mg. The statin increased endogenous formation of ω6 PUFA, ω9 MUFA, and SFA even (except 80 mg), in group of women (40 mg) – ω3 PUFA, and in men (80 mg) – ω7 MUFA. In women after receiving simvastatin 80 mg, the ratio ω3/ω6 PUFA has been shifted to ω6 PUFA, but in men after receiving simvastatin 40 mg in the direction of ω3 PUFA. Only the dose of 80 mg shifted the ratio of C20:5/C20:4 in the direction of ω3 PUFA. In group of women after receiving simvastatin 40 mg was observed a shift to β-oxidation of C18:1(9), and in men at the dose of 80 mg in the direction of its synthesis. In all cases, increased antioxidant protection of PUFA, but less strong it was at the dose of 40 mg. At the same time the formation of MUFA prevailed over the synthesis of SFA. Absolute content of FA - substrates of energy decreased. In all cases, was noticed the decrease of content of FA this very long chain (C22-26), stronger in women.Conclusion. Simvastatin controlling the quantitative composition of the pool of circulating lipoproteins, FA and cholesterol, is ambiguous, depending on dose, affect the metabolism of fatty acids, changing their quantitative and qualitative composition and performing biological functions.

Background Metastatic disease is a major and difficult-to-treat complication of lung cancer. Considering insufficient effectiveness of existing therapies and taking into account the current problem of lung cancer chemoresistance, it is necessary to continue the development of new treatments. Methods Previously, we have demonstrated the antitumor effects of reprogrammed CD8+ T-cells (rCD8+ T-cells) from the spleen in mice with orthotopic lung carcinoma. Reprogramming was conducted by inhibiting the MAPK/ERK signalling pathway through MEKi and the immune checkpoint PD-1/PD-L1. Concurrently, CD8+ T-cells were trained in Lewis lung carcinoma (LLC) cells. We suggested that rCD8+ T-cells isolated from the spleen might impede the development of metastatic disease. Results The present study has indicated that the reprogramming procedure enhances the survival and cytotoxicity of splenic CD8+ T-cells in LLC culture. In an LLC model of spontaneous metastasis, splenic rCD8+T-cell therapy augmented the numbers of CD8+ T-cells and CD4+ T-cells in the lungs of mice. These changes can account for the partial reduction of tumors in the lungs and the mitigation of metastatic activity. Conclusions Our proposed reprogramming method enhances the antitumor activity of CD8+ T-cells isolated from the spleen and could be valuable in formulating an approach to treating metastatic disease in patients with lung cancer. [ABSTRACT FROM AUTHOR]