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The aim of our trial was to evaluate the prognostic significance of qualitative ctDNA analysis on different stages of EGFR mutated non-small cell lung cancer (NSCLC) treatment. We included 99 patients amendable for the first line treatment with either gefitinib/erlotinib (n = 87), afatinib (n = 10) or osimertinib (n = 2). Sequential qualitative analysis of ctDNA with cobas® EGFR Mutation Test v2 were performed before first dose, after 2 and 4 months of treatment, and on progression. Our analysis showed clinically significant heterogeneity of EGFR-mutated NSCLC treated with 1st line tyrosine kinase inhibitors (TKIs) in terms of progression-free and overall survival. When treated with conventional approach, i.e. monotherapy with TKIs, the patients falls into three subgroups based on ctDNA analysis before and after 2 months of treatment. Patients without detectable ctDNA at baseline (N = 32) possess the best prognosis on duration of treatment (PFS: 24.07 [16.8-31.3] and OS: 56.2 [21.8-90.7] months). Those who achieve clearance after two months of TKI (N = 42) have indistinguishably good PFS (19.0 [13.7 - 24.2]). Individuals who retain ctDNA after 2 months (N = 25) have the worst prognosis (PFS: 10.3 [7.0 - 13.5], p = 0.000). 9/25 patients did not develop ctDNA clearance at 4 months with no statistical difference in PFS from those without clearance at 2 months. Prognostic heterogeneity of EGFR-mutated NSCLC should be taken into consideration in planning further clinical trials and optimizing the outcome of patients., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Therapeutic effects of PDT depend on many factors, including the amount of singlet oxygen, localization of photosensitizer and irradiation protocol. The present study was aimed to compare the cytotoxic mechanisms of PDT under continuous-wave (CW) and pulsed irradiation using a tumor spheroid model and a genetically encoded photosensitizer miniSOG., Methods: 1 O 2 detection in miniSOG and flavin mononucleotide (FMN) solutions was performed. Photobleaching of miniSOG in solution and in HeLa tumor spheroids was analyzed. Tumor spheroid morphology and growth and the cell death mechanisms after PDT in CW and pulsed modes were assessed., Results: We found a more rapid 1 O 2 generation and a higher photobleaching rate in miniSOG solution upon irradiation in pulsed mode compared to CW mode. Photobleaching of miniSOG in tumor spheroids was also higher after irradiation in the pulsed mode. PDT of spheroids in CW mode resulted in a moderate expansion of the necrotic core of tumor spheroids and a slight inhibition of spheroid growth. The pulsed mode was more effective in induction of cell death, including apoptosis, and suppression of spheroid growth., Conclusions: Comparison of CW and pulsed irradiation modes in PDT with miniSOG showed more pronounced cytotoxic effects of the pulsed mode. Our results suggest that the pulsed irradiation regimen enables enhanced 1 O 2 production by photosensitizer and stimulates apoptosis., General Significance: Our results provide more insights into the cellular mechanisms of anti-cancer PDT and open the way to improvement of light irradiation protocols., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Metronomic chemotherapy (MC) is a promising approach where, in contrast to the conventional maximal tolerated dose (MTD) strategy, regular fractionated doses of the drug are used. This approach has proven its efficacy, although drug dosing and scheduling are often chosen empirically. Pharmacokinetic/pharmacodynamic (PK/PD) models provide a way to choose optimal protocols with computational methods. Existing models are usually too complicated and are valid for only a subset of drug schedules. To address this issue, we propose herein a simple model that can describe MC and MTD regimens simultaneously., Methods: The minimal model comprises tumor suppression due to antiangiogenic drug effect together with a cell-kill term, responsible for its cytotoxicity. The model was tested on data obtained on tumor-bearing mice treated with gemcitabine in ether MTD, MC, or combined (MTD + MC) regimens., Results: We conducted a number of tests in which data were divided in various ways into training and validation sets. The model successfully described different trends in the MTD and MC regimens. With parameters obtained by fitting the model to MTD data, the simulations correctly predicted trends in both the MC and combined therapy groups., Conclusion: Our results demonstrate that the proposed model presents a minimal yet efficient tool for modeling outcomes in different treatment regimens in mice. We hope that this model has the potential for use in clinical practice in the development of patient-specific chemotherapy scheduling protocols based on observed treatment response., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We studied the effects of apoptotic bodies of cardiomyocytes (ApBc) and fibroblasts (ApBf) on myocardial regeneration and contractility in rats and the dynamics of RNA concentrations in cardiomyocytes and fibroblasts at different stages of apoptosis. ApBc increase the contractility of rat myocardium, while ApBf reduce it. ApBc stimulate the development of clones of cardiomyocyte precursors in the myocardium, while ApBf stimulate the formation of endothelial precursor clones. In doxorubicin cardiomyopathy, ApBc, similar to the reference drug (ACE inhibitor) improve animal survival, while ApBf produce no such effect. RNA concentrations in cardiomyocytes and fibroblasts before apoptosis and at the beginning of cell death significantly differed, while in apoptotic bodies of these cells, it was practically the same. It has been hypothesized that RNA complex present in ApBc and ApBf represents an "epigenetic code" of directed differentiation of cardiac stem cells.

One of the factors limiting photodynamic therapy (PDT) is hypoxia in tumor cells during photodynamic action. PDT with pulse mode irradiation and appropriate irradiation parameters could be more effective in the singlet oxygen generation and tissue re-oxygenation than continuous wave (CW) mode. We theoretically demonstrate differences between the cumulative singlet oxygen concentration in PDT using pulse mode and CW mode of laser irradiation. In vitro experimental results show that photodynamic treatment with pulse mode irradiation has similar cytotoxicity to CW mode and induces mainly cell apoptosis, whereas CW mode induces necrotic cell death. We assume that the cumulative singlet oxygen concentration and the temporal distribution of singlet oxygen are important in photodynamic cytotoxicity and apoptosis initiation. We expect our research may improve irradiation protocols and photodynamic therapy efficiency., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The purpose of this study was to establish the role of scintimammography with 99mTs-technetril for predicting pathological status of regional lymph nodes after neoadjuvant chemotherapy. In 123 primary patients with locally advanced breast cancer stage cT1-4N0-3M0 there was performed scintimammography: before treatment and after 2-3 cycles of neoadjuvant chemotherapy 63 patients; after 2-3 cycles of neoadjuvant chemotherapy and before surgery--in 5 patients; after 4-6 cycles of neoadjuvant chemotherapy--55 women. All patients were divided into 2 groups: the first included 68 patients whom scintimammography was performed before and after 2-3 cycles of neoadjuvant chemotherapy; the second--60 women whom scintimammography was performed before treatment and before surgery. In patients of the first group positive results were obtained in 16 (23.5%), negative--26 (38.3%), false positive--16 (23.5%) and false negative--10 (14.7%) cases. Sensitivity, specificity, overall accuracy, positive predictive value and negative results were 61.5%, 61.9%, 61.7%, 50% and 72.2%, respectively. During the scintimammography after 4-6 cycles of neoadjuvant chemotherapy positive results were observed in 17 (28.3%) negative--18 (30%), false positive--19 (31.7%) and false negative--6 (10%) of patients. Thus, the sensitivity, specificity, overall accuracy, positive predictive value and negative results amounted to 73.9%, 48.6%, 58.3%, 47.2%, 75% respectively.

Analysis of mammoscintigraphy is presented to assess the effectiveness of neoadjuvant polychemotherapy for locally advanced breast cancer. In 90% of patients there is defined conformity of scintigraphy data on the effectiveness of performed polychemotherapy to the results of histologic examination of the postoperative material. The sensitivity of scintigraphy in assessing the effectiveness of neoadjuvant polychemoterapy was 83.3%, specificity--87.9%, accuracy--86.3%, predictive value of positive and negative results-78.9% and 90.1%, respectively. Mammoscintigraphy is an effective method to control the response of locally advanced breast cancer to neoadjuvant polychemotherapy.

The absolute sensitivity signs of breast cancer to the drug have not yet been developed. Data from clinical trials on the study of experimental laboratory predictive markers of chemosensitivity: TOP2alpha (topoisomerase 2-alpha), beta-tubulin (subunit of dimeric protein tubulin), and BRCA1 (breast cancer 1) are contradictory and not numerous. Analysis of the results by the end of the clinical trial will allow examining the correlation between the effectiveness of preoperative taxane-chemotherapy and the level of experimental and standard molecular markets that is important for development of algorithm of treatment tactics for patients with locally advanced breast cancer.

Having used hematoxylin as a stain, some features of silkworm embryo chromatin in diapause have been studied in normal and parthenogenetic development. With found direct correlation between the number of interphase chromatin grains and the number of chromosomes in the nucleus, we examined cell polyploidization in the embryo at diapause stage. Polyploidization by parthenogenesis is not reducible to endomitotic doubling of the chromosome set because it comprises 6n-nuclei. Explanation of more diverse range of polyploid cells in parthenogenesis needs to consider the fusion of cleavage nuclei that is carried out by the cytoplasmic karyogamic mechanism in the absence of fertilization. For the first time on squash preparations, in diapausing embryo, we have identified primary germ cells (PGC) that are characterized by less compact chromatin, especially in the zygotic form of development, a larger size of the nucleus and cytoplasm, and irregular number and size of nucleoli. Evaluation of PGC ploidy in parthenogenesis by calculation of "loose" chromatin grains in diapause is possible and testifies polyploidization in embryo germ-line. This explains the inevitable admixture of tetraploid eggs in diploid parthenoclone grain and its absence in normal development. Cytological method used has revealed a spiral arrangement of chromatin grains on the inner surface of the nucleus at different levels of ploidy.

The efficiencies of modern intravenous anesthetics, analgesics, and hypnotics (dormicum, diprivan, ketamine, and fentanyl) in various combinations for artificial abortions was evaluated. Hemodynamic parameters, autonomic status, and clinical signs of awakening were evaluated. The most effective protection was attained with a combination of diprivan, dormicum, and fentanyl.

At anaphase-telophase I of meiosis in mouse, porcine and bovine oocytes matured in vitro, "eliminatory chromatin" stained by acetohaematoxylin was found. The transformation of this structure was observed to early metaphase II stage by microscopic analysis. The origin and the nature of the "eliminatory chromatin" are discussed.

Instrumental methods of investigation were used for the demonstration of changes in the fatty acid composition of F. tularensis, strain 15 Gaĭskiĭ, during cultivation in solid culture medium, storage after lyophilization, as well as changes in the functioning of the system of membrane-dependent enzymes of the respiratory chain and in the permeability of cell wall membranes by water molecules and NADH after lyophilization. A relationship between the survival rate of F. tularensis cells after lyophilization and stimulation of their endogenic respiration with NADH and succinate was revealed. An increase in residual moisture from 6 to 10-12% was found to intensify the process of lipid peroxidation during the storage of lyophilized F. tularensis cells of strain 15 Gaĭskiĭ.

Effect of temperature shock treatments (0 and 37 degrees C) in early ontogenesis on recombination frequency was studied in two strains of Drosophila X1 and X2. Recombination frequency under treatment with temperature of 0 degrees C and 37 degrees C (shock treatment), as well as at 14 degrees C and 29 degrees C nonshock treatment was found to be dependent on strain genotype, the chromosomal segments under consideration, developmental stage and the age of individuals analysed. Shock treatments usually increase recombination frequency, whereas nonshock treatments lead to unstable and variable recombination frequencies. A concept of ontogenic homeostasis of recombination has been introduced. It is assumed that the effect of temperature treatments on recombination frequency is indirect--i.e. physiologically mediated.

The proliferative activity of gastric mucous cells (GMC) was studied in white mice following the administration of acetylsalicylic acid (200 mg/kg). One hour before sacrifice all the animals received intraperitoneal injection of 3H-thymidine. The mitotic index and index of labeling nuclei were calculated by means of radioautographers 3, 10 and 20 days after administering the drug. Following 3-day exposure to acetylsalicylic acid the proliferative activity of GMC remained unchanged as compared to controls. Long-term administration (10 and 20 days) of the drug produced no increase in the number of erosions, but there was a statistically significant rise in the proliferative activity of GMC. This rise was accounted for by increased number of proliferating cells in the foveated and cervical divisions of the glands as well as due to the extension of the zone of distribution of precursor cells in the gastric glands as far as the basal divisions. These changes may be considered as manifestation of the protective-adaptive reaction of the gastric mucosa in response to the damaging effect of acetylsalicylic acid.

The number of cells in diapausing silkworm embryos of different ploidies was determined. Thermal activation was shown to lead to a decrease in the number of cells in parthenogenetic embryos in comparison with normal, zygotic development. The number of cells in the embryo is a direct function of egg volume and a reciprocal function of embryo ploidy and is affected by the maternal genotype.

Photometric measurements showed that DNA content of the cells in the posterior portion of the silk gland to be higher in triploid caterpillars than in diploids. The somatic polyploidy level of posterior silk gland cells therefore increases as the number of cells in the organ decreases with rising overall organism ploidy.

As a result of investigations of the functional acitivty of eukaryote cells damaged by ionizing radiation and alkylating mutagens under conditions of extreme loading, the authors have suggested that natural aging and aging accelerated by mutagens are based on a process of accumulation of functional genetic damages. The molecular nature of these damages differs from the mutational changes and repairable damages of DNA.

A spreading technique was used to prepare synaptonemal complexes from animals (Bombyx mori and Mus musculus spermatocytes) and plants (Zea mays microsporocytes). Suspension of hypotonically treated cells was spread over plastic-coated slides and air-dried. Fixed and phosphotungsten acid-stained spread preparations were studied by phase-contrast and electron microscopes. The spreading-through-drying method is more efficient and thereby more preferable as compared to the classical hypophase spreading technique.

In experiments on mongrel rats it was found that heparin in doses of 2, 5, and 10 mg/kg had an inducing effect on the oxidative systems of hepatic microsomes: hexenal test period was shortened, cytochrome P450 content increased, relative liver weight rose; the activity of histochemically-detectable NAD-enzymes of hepatocytes became greater. Heparin was capable of considerable (2-3-fold) stimulation of antitoxic activity of the liver reduced in experimental glomerulonephritis. The effect of heparin on the antitoxic function of the liver did not correlate with its effect, on the blood coagulation system.

The antigen activity of bile of rabbits, sheep and cattle infected with F. hepatica was investigated by the immunodiffusion methods. The sera obtained from animals with experimental fasciolosis and other infections were used. At the experimental fasciolosis and intensive natural infection antigens were found in bile, one of which was present in all the animals and turned to be identical immunologically to the specific protein antigene (molecular weight is 27 500) isolated from the extract of F. hepatica. Titres of this antigene in bile depended usually on the infection intensity and were, as a rule, higher than titres of corresponding antibodies in the blood serum. The presence of this antigen in bile can serve as a diagnostic indication of fasciolosis especially when ovoscope or immunological methods based on the finding of antibodies are inefficient.