ИНТЕРСТИЦИАЛЬНЫЕ ПЕЙСМЕЙКЕРНЫЕ КЛЕТКИ

This article is devoted to interstitial Cajal cells (syn. telocytes, interstitial pacemaker cells, IPC). First those cells were discovered by C.R Cajal in the muscle coat of the gut in 1893. Nowadays they have revealed in all parts of digestive systems (from esophagus to rectum), urinary and biliary tracts, prostate, liver, the walls of arteries and lymphatics, as well Fallopian tube, myometrium, mammary glands. Characteristic ultrastructural features are elongated spindle shape, length from 40 to 100 μm, the thickness of 0.2–0.5 μm, the presence of 2–5 processes. Length of them ranging from tens to hundreds of micrometers, some of them have secondary and tertiary branching, forming a three-dimensional network. IPC having spontaneous electrical (pacemaker) activity are cause to contraction of smooth muscle cells. Depending on the location of IPC have different morphological and ultrastructural characteristics. Characteristic immunohistochemical markers are CD117, CD34, S100, vimentin. IPC replay to acetylcholine, norepinephrine, estrogen, progesterone, and nitric oxide by influence of corresponding receptors. IPC have specific gap junctions with lymphocytes, basophiles, eosinophils, neutrophils, mast cells and dendritic cells. Grave pathology of those cells are forming gastrointestinal stromal tumors.Представлены данные литературы об интерстициальных клетках Кахаля (син. телоциты, интерстициальные пейсмейкерные клетки, ИПК). Впервые эти клетки были описаны C.Р. Кахалем в мышечном слое стенки кишки в 1893 г. В настоящее время они обнаружены во всех отделах желудочно-кишечного тракта от нижней трети пищевода до прямой кишки, а также в мочевых и желчных путях, предстательной железе, печени, стенках артерий и лимфатических сосудов, фаллопиевых трубах, миометрии, молочной железе. Их характерными ультраструктурными признаками являются вытянутая веретеновидная форма, длина от 40 до 100 μм, толщина 0,2–0,5 μм, наличие 2–5 отростков. Длина отростков колеблется от нескольких десятков до сотни μм, часть из них имеет вторичное и третичное ветвление, образуя трехмерную сеть. За счет спонтанной электрической (пейсмейкерной) активности ИПК обусловливают сокращение гладкомышечных клеток. В зависимости от локализации ИПК имеют различные морфологические и ультраструктурные характеристики. Характерными иммуногистохимическими маркерами являются CD117, CD34, S100, виментин. Посредством влияния на соответствующие рецепторы ИПК отвечают на воздействия ацетилхолина, норадреналина, эстрогена, прогестерона, оксида азота. ИПК также взаимодействуют с лимфоцитами, базофилами, эозинофилами, нейтрофилами, тучными и дендритными клетками. Грозной патологией этих клеток является развитие т.н. гастроинтестинальных стромальных опухолей

Blood plasma small non-coding RNAs as diagnostic molecules for the progesterone-receptor-negative phenotype of serous ovarian tumors

The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of MMP7 and MUC16, along with downregulation of PGR, in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target MUC16, MMP7, and MMP9, as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial–mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment’s effectiveness and the patient’s longevity.Proteomic

Инфекции, связанные с оказанием медицинской помощи (ИСМП), в родовспомогательных учреждениях Российской Федерации (состояние проблемы в начале XXI века)

Over the past decade, the healthcare system of the Russian Federation has undergone progressive changes in the system of maternity care, which relate to the development of infrastructure and the introduction of new organizational models. In particular, a three-level system of providing medical care to mothers and children has been created, including a network of perinatal centers for patients at high perinatal and obstetric risk. Field events of specialists of National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation to the medical organizations of maternity care in various regions of Russia revealed hot spots that require primary attention: acute shortage of staff for the implementation of diagnostic and therapeutic measures at the modern methodological level, as well as for ensuring epidemiological safety in the medical organizations (medical microbiologists (bacteriologists), clinical pharmacologists and epidemiologists); the lack of registration of healthcare-associated infections, which is associated with the prevailing in the country mainly punitive methods of combating hospital infections. In modern conditions of nursing preterm babies, newborns with various severe somatic and surgical pathologies, it is necessary to know the real indicators of morbidity in order to reasonably and promptly carry out therapeutic and preventive measures; the need to organize modern microbiological laboratories in the perinatal centers with the availability of fast methods (proteomic and molecular-genetic) diagnostics, allowing for microbiological monitoring in specialized departments of newborns and promptly respond to the changes in the epidemiological situation in the hospital, to prevent the development of clinically pronounced cases of healthcare-associated infections.За последнее десятилетие в здравоохранении Российской Федерации произошли прогрессивные изменения в системе родовспоможения, которые касаются развития инфраструктуры и внедрения новых организационных моделей. В частности, создана трехуровневая система оказания медицинской помощи матери и ребенку, включающая сеть перинатальных центров. Выездные мероприятия специалистов ФГБУ НМИЦ АГП им. В.И. Кулакова Минздрава России в медицинские организации родовспоможения различных регионов России выявили горячие точки, требующие первостепенного внимания, такие как: острая нехватка кадров для осуществления диагностических и лечебных мероприятий на современном методическом уровне, а также для обеспечения эпидемиологической безопасности в медицинских организациях (медицинские микробиологи (бактериологи), клинические фармакологи и эпидемиологи); недоучет регистрации инфекций, связанных с оказанием медицинской помощи, что обусловлено сложившимися в стране преимущественно карательными методами борьбы с госпитальными инфекциями. В современных условиях выхаживания недоношенных детей, новорожденных с различными тяжелыми соматическими и хирургическими патологиями необходимо знать реальные показатели заболеваемости, чтобы обоснованно и оперативно проводить лечебные и профилактические мероприятия; необходимость организации современных микробиологических лабораторий в перинатальных центрах с наличием быстрых методов диагностики (протеомных и молекулярно-генетических), позволяющих вести микробиологический мониторинг в специализированных отделениях новорожденных и оперативно реагировать на изменения эпидемиологической ситуации в стационаре, предотвращать развитие клинически выраженных случаев инфекций, связанных с оказанием медицинской помощи

Macrophage Modification Strategies for Efficient Cell Therapy

Macrophages, important cells of innate immunity, are known for their phagocytic activity, capability for antigen presentation, and flexible phenotypes. Macrophages are found in all tissues and therefore represent an attractive therapeutic target for the treatment of diseases of various etiology. Genetic programming of macrophages is an important issue of modern molecular and cellular medicine. The controllable activation of macrophages towards desirable phenotypes in vivo and in vitro will provide effective treatments for a number of inflammatory and proliferative diseases. This review is focused on the methods for specific alteration of gene expression in macrophages, including the controllable promotion of the desired M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes in certain pathologies or model systems. Here we review the strategies of target selection, the methods of vector delivery, and the gene editing approaches used for modification of macrophages

Phenotypical and Functional Polymorphism of Liver Resident Macrophages

Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages

Regenerative medicine of pancreatic islets

The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration"strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement"strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally. ©The Author(s) 2020

Functional deficit of sperm and fertility impairment in men with antisperm antibodies

Autoimmune reactions against the sperm cells play an ambiguous role in fertility impairment. The objective of this study was to characterize functional deficit of sperm conditioned by antisperm immune response in normozoospermic men. This was a multi-centric, cross-sectional, case-control study. The study subjects were 1060 infertile normozoospermic men and 107 fertile men. The main outcome measures were clinical examination, semen analysis including MAR test for antisperm antibodies (ASA), computer-aided sperm analysis, acrosome reaction (AR) detected with flow cytometry, DNA fragmentation measured with sperm chromatin dispersion, reactive oxygen species (ROS) assessed using the luminol-dependent chemiluminescence method. 2% of the fertile men had MAR-IgG ≥ 50%, but all subjects with MAR-IgG ≤ 12% were outliers; 16% infertile men had MAR-IgG ≥ 50% (p< 0.0001). There was a direct correlation between the infertility duration and MAR-IgG (R= 0.3; p< 0.0001). The ASA-positive infertile men had AR disorders 2.1 times more frequently (p< 0.02), predominantly inductivity disorders. We found signs of hyperactivation proportionate to the ASA level (p< 0.001). DNA fragmentation was more highly expressed and was 1.6 and 1.3 times more frequent compared with the fertile and the ASA-negative patients, respectively (p< 0.001 and p< 0.05). We found signs of oxidative stress (OS): ROS generation by washed ASA-positive spermatozoa was 3.7 times higher than in the fertile men (p< 0.00001) and depended on the ASA levels (R = 0.5; p< 0.0001). The ASA correlation with ROS generation in native sperm was weak (R = 0.2; p< 0.001). We concluded that autoimmune reactions against spermatozoa are accompanied by a fertility decrease in normozoospermia. This results from AR and capacitation disorders and DNA fragmentation. The pathogenesis of sperm abnormalities in immune infertility is associated with the OS of spermatozoa. © 2015 Elsevier Ireland Ltd

Draft Genome Sequence of Lactobacillus gasseri Strain 2016

Different common factors contribute to the antagonistic properties of Lactobacillus gasseri toward various pathogens. However, there is strain-to-strain variation in the probiotic properties of this bacterium. The draft genome sequence of L. gasseri strain 2016 determined in this study will assist in understanding the genetic basis for such variation

Male fertility and varicocoele: Role of immune factors

The role of antisperm antibodies (ASA) in the aetiopathogenesis of varicocoele-related male infertility remains unclear. The objective of this study was to determine whether varicocoele is associated with antisperm immune response and whether this factor provides additional affect on male fertility. We performed a multicentral, prospective study that included the clinical examination of 1639 male subjects from infertile couples and 90 fertile men, the evaluation of the absolute and relative risks of immune infertility associated with varicocoele and the impact of the autoimmune response on the semen quality. The methods used were as follows: standard examination of seminal fluid according to WHO criteria; ASA detection in seminal fluid using mixed antiglobulin reaction (MAR) and direct flow cytometry; measurement of spontaneous and ionophore-induced acrosome reactions; oxidative stress evaluation with luminal-dependent chemiluminescence method and evaluation of DNA fragmentation by sperm chromatin dispersion. The prevalence of varicocoele-related immune infertility is about 15% and does not depend on the grade of vein dilatation both in primary and secondary fertility disorders. Varicocoele is not an immediate cause of autoimmune reactions against spermatozoa, but is a cofactor increasing ASA risk; the OR of immune infertility after a testicular trauma in varicocoele patients increases twofold. In varicocoele patients, the autoimmune antisperm reaction is accompanied by a more significant decrease in the semen quality (concentration and number of progressively motile and morphologically normal spermatozoa in the ejaculate), acrosome reaction disorders (presence of pre-term spontaneous and lack of induced reactions) and an increase in the proportion of spermatozoa with DNA fragmentation. These disorders correlate with the level of sperm oxidative stress; reactive oxygen species (ROS) production in ASA-positive varicocoele patients is 2.8 and 3.5 times higher than in ASA-negative varicocoele patients and fertile men respectively. We did not find correlation between the grade of spermatic cord vein dilatation and ROS production. © 2013 American Society of Andrology and European Academy of Andrology