Functional Activity of Circulating Phagocytes as Potential Pretreatment Marker of Tumor Drug Resistance

The aim of this work was a study of the functional activity of neutrophils and peripheral blood monocytes in rats with the transplanted Walker carcinosarcoma as potential predictors of the sensitivity of this tumor to doxorubicin treatment. This study provides an evidence that such indices of the functional activity of circulating phagocytes of the tumor-bearing rats as the quantity and the phagocytosis intensity of monocytes, as well as the intensity of ROS production by monocytes and neutrophils, may reflect the degree of sensitivity of the tumor to doxorubicin. So it was shown that the growth of the resistant tumor caused a significant increase of the number of circulating phagocytic cells and the intensity of phagocytosis by more than 100% (p < 0.001) compared with the corresponding indices of intact rats and rats with the parental variant of the tumor. The ability of blood mono-cytes and neutrophils of rats with a resistant tumor to produce ROS was also significantly different from that in intact rats and animals with the parental carcinosarcoma variant. The predictive value of these indices is especially important in the dynamic monitoring of the development of tumor drug resistance during long-term cancer chemotherapy. Considering the standard 2 - 3 week interval between the courses of cancer therapy and the short lifetime of circulating phagocytes, an assessment of the indices of their functional activity before each subsequent course can be considered as a pretreatment assessment. Meanwhile, further studies are needed to determine the spectrum of malignant neoplasms for which the degree of tumor drug resistance correlates with the functional activity of circulating phagocytes.

Combined action of low temperature and magnetic field of different intensities on growth of some bacterial species <i>in vitro</i>

Growth dynamic of bacterial population after influence of magnetic field and cryoaction has been studied. In vitro experiments were performed on Bacillus cereus, Staphylococcus aureus, and Lactobacillus delbrueckii cultures. The most significant result was obtained in experiments with Bacillus cereus. When applied separately, cryoaction and alternating magnetic field were not able to kill this microorganism, whereas combined action of these factors led to the complete devitalization of bacterial culture.

A Comparative Study on Pharmacokinetics of Tricin, a Flavone from Gramineous Plants with Antiviral Activity

Tricin (and tricin containing plant extracts) has been shown to exert a pronounced antiviral activity, high radical scavenging activity and is favored for its safety profile. In the present study we have analyzed the pharmacokinetics of tricin after a single intravenous and oral administration to Wistar rats of an ethanol extract of Calamagrostis Adans and Deschampsia Beauv plants (test agent) at different doses. Tricin concentrations in blood plasma and blood cells were measured at different time points. Two-compartment (for intravenous injection) and one compartment (for oral administration) models were used for the analysis of tricin pharmacokinetics. The results showed that the pharmacokinetics of tricin after intravenous injection of test agent has a pronounced biphasic character, is well described by a two-compartment pharmacokinetic model, and is characterized by non-linear dose-dependence. The pharmacokinetics of tricin administered orally is characterized by a high rate of absorption from the gastrointestinal tract into the blood and rather slow elimination, which leads to a large volume of distribution in the body and a fairly high bioavailability. The obtained results indicate the advantages of the oral route of administration over the intravenous route.

Introduction of antineoplastic drug NSC631570 in an inpatient and outpatient setting:Comparative evaluation of biological effects

The aim of this study is to evaluate the effect of moderate physical exercise and treatment time on the organism’s response to NSC631570. The sensitivity of circulating phagocytes to the drug at different times of day was estimated in in vitro experiments. NSC631570 was administered intravenously to healthy volunteers (eleven men, 23 ± 2 years) in a single therapeutic dose in an inpatient and an outpatient setting. Blood samples were obtained before the drug administration, 30 min after the drug injection and every fourth hour throughout the 24 hour period. Biochemical parameters were determined using the hematological analyzer. Flow cytometry was used to evaluate phagocyte metabolism. Treatment of circulating phagocytes with NSC631570 in vitro resulted in an increase in ROS production along with a decrease in their phagocytic activity, most expressed in the morning time. Drug injection to sedentary persons resulted in pro-inflammatory metabolic polarization of circulating phagocytes. Introduction of NSC631570 to active persons was accompanied by a significant increase in phagocyte endocytosis along with a decrease in the daily mean of ROS generation. Significant oscillation (but in the normal ranges) of urea, creatinine, alanine aminotransferase and aspartate aminotransferase after NSC631570 introduction in the outpatient setting was shown during the day. Physical activity interferes with immunomodulatory action of NSC631570 and abrogates pro-inflammatory shift of circulating phagocytes. Biochemical parameters of blood from patients treated with NSC631570 in the outpatient setting must be interpreted cautiously considering the effect of physical activity on some metabolic biomarkers.

Evaluation of Biological Effects of Nanosystems of Directed Transport in Experiments <i>in Vivo</i>and Their Application Possibilities in Anti-Tumor Therapy

The aim of the investigations was to evaluate benefits of the directed transport system - a nanocomposite, based on cisplatin and magnetite combined with local action of constant magnetic field on the tumor, in experiments in vivo in animals with transplantable Guerin carcinoma. Animals were divided into 5 groups according to the type of agent. We showed that nanocomposite in combination with static magnetic field exercises more prominent anti-tumor activity than cisplatin alone. It should be noted that regardless of the therapeutic agent, in Guerin carcinoma we observed </

Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells

Effects of the nanocomposite and its components (magnetic fluid, cisplatin) on the level of endogenous iron exchange and the key links of genetic and epigenetic regulation of apoptotic program of sensitive and resistant MCF-7 cells were examined. We showed genetic and epigenetic mechanisms of action of nanocomposite of magnetic fluid and cisplatin. Nanocomposite caused elevation of number of cells in apoptosis in sensitive and especially resistant MCF-7 cells compared to cisplatin alone. It was proved that impact of nanocomposite on MCF-7/S and MCF-7/DDP cells caused more significant changes in expression of apoptosis regulators p53, Bcl-2 and Bax. We also suggested that changes in endogenous iron homeostasis and activation of free radical processes caused significant impact on apoptosis. Those changes included changes in methylation and expression of transferrin, its receptors, ferritin heavy and light chains (predominantly in resistant cell line), which caused activation of free radical synthesis and development of oxidative stress. We also showed that nanocomposite impact resulted into significant changes in expression of miRNA-34a and miRNA-200b, which regulated apoptosis, cell adhesion, invasion and activity of ferritin heavy chains gene. Thus, use of nanocomposite containing cisplatin and ferromagnetic as exogenous source of Fe ions caused changes of endogenous iron levels in sensitive and resistant cells allowing to increase specific activity of cytostatics and overcome factors, which promoted MDR development. Pharmacocorrection of endogenous iron metabolism allowed increasing antitumor activity of cisplatin and overcoming drug resistance.

Prognostic Significance of Hormonal Receptor Status of Malignant Ovarian Tumors

The objective of this study is to investigate hormonal receptor status of MOT （malignant ovarian tumor） and to evaluate its clinical and prognostic significance. Retrospective analysis of the case reports of 284 patients with MOT of different histogenesis, stages I-IV, and immunohistochemical study of paraffin-embedded tissues were performed. Hormonal receptor status of tumors with different morphology genesis was studied and hormonal receptor phenotype of serous OC （ovarian cancer） was determined. The analysis of correlation between the expression of steroid hormone receptors （receptors to estrogens （ER）, progesterone （PR） and testosterone （TR）） in ovarian tumors, histological type of tumors and clinical morphological parameters were performed. Overall and relapse-free survival rates of the patients with serous OC depending on the hormonal receptor phenotype of the tumor were assessed. Presence of positive expression of steroid hormone receptors in serous OC （ER-66.4%, PR^53.4%, TR-53.0%）, mucinous OC （ER-88.0%, PR-84.0%, TR-60.0%） and in sex cord stromal tumors （ER-74.1%, PR and TR-77.8%） is proved by correlation of all steroid receptors expression with morphology type of ovarian tumors （ER - r = 0.4; PR - r = 0.4; TR - r = 0.3; p 〈 0.05）. Direct correlation between hormonal receptor phenotype of serous OC and the age period of the patients was established （r = 0.5; p = 0.002）： postmenopausal women patients reported the most increased frequency of serous OC with positive hormonal receptor tumor phenotypes （52.4%）, in particular during their late post-menopausal period （39.0%）. Significantly low overall survival among the patients with positive hormonal receptor phenotype of serous OC was recorded （29.5±3.4%） in comparison with the same score in the patients with negative phenotype of tumors （44.5±3.7%） （p 〈 0.05）. Multifactor analysis of Cox-regression model has defined that positive hormonal receptor phenotype of serous OC increases the risk of disease relapse （HR 1.4; 95.0% CI 1.1-1.7）, significantly decreases overall survival rates in the patients （HR 1.4; 95.0% CI 1.1-1.8）. Positive hormonal receptor status of MOT is an independent factor of unfavorable clinical progress of tumor process which can be regarded as the criterion for development of the methods of hormonal therapy application in complex treatment of the patients, and demands further large-scale multi-center studies in that direction.

Protective Effect of Ubiquinone and Precursors of ItsSynthesis on Mitochondrial Respiratory Chain andActivity of Matrix Metalloproteinases in Animal Tissuesunder Effect of Doxorubicin

Mitochondrial dysfunction, oxidative stress, and their regulation are important fields of study in modem clinical research.Exogenous CoQ is an efficient therapeutic agent, yet its application has leads to continued suppression of endogenous CoQ synthesis,which limits CoQ applicability. Our aim was to study the state of mitochondrial electron transport chain components, CoQ contentand redox state, superoxide anion radicals and NO production rates, and active MMP-2 and MMP-9 content in rat liver and heartunder treatment with Doxorubicin, CoQ10, and complex preparation of modulators and precursors of CoQ biosynthesis （EPMcomplex）. The results demonstrate that treatment with EPM complex and CoQ10 in addition to Doxorubicin administration exertsprotective effect on liver and heart mitochondria, evidenced by restoration of electron transport in respiratory chain, which isexpressed as decreased nitrile complexes formation with Fe-S-proteins and increased ubisemiquinone content. The protective effectsof EPM complex on mitochondrial electron transport chain under Doxorubicin administration is on par with those of CoQ10, anddecreased MMP2 and MMP9 activities signify lessened extracellular matrix destruction. These results demonstrate the viability ofapproaches to correct adverse effects of Doxorubicin by treatment with CoQ10 and e complex of precursors and modulators of itsbiosynthesis.

地鼠和人胚肺上皮细胞对致癌剂毒性和染色体损伤反应

为了检查人染色体比啮齿类动物染色体更为稳定的假设,我们比较了人和叙利亚地鼠胚胎肺上皮细胞对诱导性细胞毒性,染色体畸变和姐妹染色体交换(SCE)的敏感性。接种细胞一天后,用不同剂量乙基亚硝基脲(ENU)处理2小时,然后用标准法检查其染色体畸变和SCE率,用细胞计数法测定细胞毒性。染色体畸变和SCE率均表明清楚的剂量依赖关系,而且在地鼠细胞的发生率明显高于人细胞,但两种细胞表明相同的细胞毒性反应。这些结果提示人细胞染色体比地鼠细胞染色体更为稳定和细胞毒性反应不一定总是与染色体损伤有关。

Empty nose syndrome pathogenesis and cell-based biotechnology products as a new option for treatment

Empty nose syndrome (ENS) is a rare complication that develops after partial orcomplete turbinectomy. The main feature of ENS is paradoxical nasal obstructionfeeling despite objectively wide nasal airway. ENS pathogenesis is multifactorialand includes changes in laminar physiological airflow, disruption of mucosafunctions and deficient neural sensation. This leads to the development of ENSsymptomatology such as dyspnea, nasal dryness, nasal burning, nasalobstruction, feeling of suffocation and even comorbid psychiatric disorders thatsignificantly impairs life quality. Specific effective treatment of ENS does not existup to date. In this review we outline existing biomaterial for surgical reconstitutionof nasal anatomy and discuss the perspective of stem cell-based technologiesin ENS management. The main focus is directed to justification ofrationality application of adult mesenchymal stem cells (MSCs) from differenttissues origin and neural crest-derived stem cells (NCSCs) based on their intrinsicbiological properties. MSCs transplantation may stimulate mucosa tissueregeneration via trophic factors secretion, direct transdifferentiation into epithelialcells and pronounced immunosuppressive effect. From the other hand, NCSCsbased on their high neuroprotective properties may reconstitute nerve structureand functioning leading to normal sensation in ENS patients. We postulate thatapplication of cell-based and tissue-engineered products can help to significantlyimprove ENS symptomatology only as complex approach aimed at reconstitutionof nasal anatomy, recovery the nasal mucosa functionality and neural tissuesensation.

Tumor-Infiltrating Lymphocytes in Primary Tumor and Bone Marrow in Patients with Gastric Cancer and Overweight

Immune infiltration in human tumors is a key prognostic factor.In this aspect it has to be noted that the publications concerning the tumor-infiltrating lymphocytes(TILs)under overweight and obesity are limited,especially in the clinical setting in particular concerning gastric cancer.This study has shown that density of TILs consistently associated with body mass index(BMI)and density of cancer-associated adipocytes(CAA)in tumors,decreased significantly in patients with BMI>30 having high density of CAA.Hypoxia in tumor does not affect this process.Patients with BMI>30 having high density of CAA with slight infiltrating of TILs in tumors demonstrated better overall survival than the same patients with BMI<25 whereas the same patients with BMI<25 but with low density of CAA have shown much longer overall survival.Presence of TILs in BM was not affected by both the high density of CAA and level of hypoxia in primary tumor;moreover it has not been associated with BMI as well as patients survival time.Understanding the metabolic changes that occur in obese individuals may help to pave the way for more effective treatments for patients with gastric cancer having overweight.

Neutrophils are shaped by the tumor microenvironment:novel possibilities for targeting neutrophils in cancer

In a recent paper published in Science,Ng et al.provide seminal insights into the process through which neutrophils are reprogrammed by the tumor environment,leading to a convergent transition from different neutrophil states towards a unique end-stage differentiated pro-tumor phenotype.1 These findings have major translational implications as they provide potential neutrophil-related targets for tumor immunotherapy.

Trilateral interaction between innervation,leukocyte,and adventitia:a new driver of atherosclerotic plaque formation

A recent study by Mohanta et al.describes a new understanding of neuroimmune interactions in atherosclerosis.While atherosclerotic plaques are not innervated,ablating the sympathetic innervation to these regions attenuated atherosclerosis,suggesting a potential novel therapeutic strategy.Atherosclerosis continues to be the leading cause of death in industrialized countries due to its complications such as acute myocardial infarction or stroke.The disease is the result of a complex process,consisting of sub-endothelial lipid retention,immune cell migration,proteolytic injury,altogether leading to a chronic inflammatory responses in the wall of large arteries and ultimately plaque development.2 The inner layer of the blood vessels is not innervated and hence the nervous system connects with the vessel through its most outer layer,the lamina adventitia,hereby controlling important functions including arterial blood pressure.Beyond such homeostatic control of vessel function,increasing evidence demonstrates that activation of the sympathetic nervous system can modulate the degree of arterial inflammation.

Exaptation at the molecular genetic level

The realization that body parts of animals and plants can be recruited or coopted for novel functions dates back to, or even predates the observations of Darwin. S.J. Gould and E.S. Vrba recognized a mode of evolution of characters that differs from adaptation. The umbrella term aptation was supplemented with the concept of exaptation. Unlike adaptations, which are restricted to features built by selection for their current role, exaptations are features that currently enhance fitness, even though their present role was not a result of natural selection. Exaptations can also arise from nonaptations; these are characters which had previously been evolving neutrally. All nonaptations are potential exaptations. The concept of exaptation was expanded to the molecular genetic level which aided greatly in understanding the enormous potential of neutrally evolving repetitive DNA—including transposed elements, formerly considered junk DNA—for the evolution of genes and genomes. The distinction between adaptations and exaptations is outlined in this review and examples are given. Also elaborated on is the fact that such distinctions are sometimes more difficult to determine; this is a widespread phenomenon in biology, where continua abound and clear borders between states and definitions are rare.

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

Measles virus （MV） is highly contagious pathogen, which causes a profound immunosuppression, resulting in high infant mortality. This virus infects dendritic cells （DCs） following the binding of MV hemagglutinin （MV-H） to CD150 receptor and alters DC functions by a mechanism that is not completely understood. We have analyzed the effect of MV-H interaction with CD150-expressing DCs on the DC signaling pathways and consequent phenotypic and functional changes in the absence of infectious context. We demonstrated that contact between CD150 on human DCs and MV-H expressed on membrane of transfected CHO cells was sufficient to modulate the activity of two major regulatory pathways of DC differentiation and function： to stimulate Akt and inhibit p38 MAPK phosphorylation, without concomitant ERK1/2 activation. Furthermore, interaction with MV-H decreased the expression level of DC activation markers CD80, CD83, CD86, and HLA-DR and strongly downregulated IL-12 production but did not modulate IL-IO secretion. Moreover, contact with MV-H suppressed DC-mediated T-cell alloproliferation, demonstrating profound alteration of DC maturation and functions. Finally, engagement of CD150 by MV-H in mice transgenic for human CD150 decreased inflammatory responses, showing the immunosuppressive effect of CD150-MV-H interaction in vivo. Altogether, these results uncover novel mechanism of MV-induced immunosuppression, implicating modulation of cell signaling pathways following MV-H interaction with CD150-expressing DCs and reveal anti-inflammatory effects of CD150 stimulation.

CREMa overexpression decreases IL-2 production,induces a TH17 phenotype and accelerates autoimmunity

Dear Editor,External cytokines produced by cells of the innate immune system induce the dif-ferentiation of CD4+T cells into helper T cell subsets with distinct functions and cytokine profiles.Apart from TH1 and TH2 cells a third subset of helper T cells has been described,which is characterized by increased expression of IL-17A,IL-17F,IL-21 and IL-22(TH17 cells).

Correction to: Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

In this article,published online on 15 June 2015,there was an unintended error during the image processing of Figs.2 and 4.In Fig.2c,the time point 12 h was omitted and is included in the corrected Fig.2c.Figure 4a and b contain blots not intended for that experiment,which now have been replaced with the blots generated for that experiment.The conclusions drawn from the presented experiments remain unaltered,and this correction has no bearing on the final outcome of the study.The inconvenience caused by this error is deeply regretted.