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[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

Recently, there has been an increase in the prevalence of gastroesophageal reflux disease (GERD) in Northern Europe, North America and East Asia. However data on GERD prevalence in Russian population are very limited.To determine the prevalence of GERD among the population of Russia, the clinical spectrum of GERD symptoms, the main drugs used for GERD treatment, and the rate of their administration.The study was conducted from November 2015 to January 2017 in 8 cities of Russia. A survey of patients over the age of 18 years old visiting outpatient medical institutions for any reason, including patients without gastrointestinal complaints was carried out using a short version of the Mayo Clinic questionnaire.In total, 6132 questionnaires of patients aged 1890 years were analyzed [2456 men (40.1%) and 3676 women (59.9%), mean age 46.615.4 years]. The GERD prevalence among the interviewed patients was 34.2%. The incidence of GERD increased depending on body mass index and the age of the patients. Medications used by the patients for heartburn relief included proton pump inhibitors 59.96%, antacids 67.92%, H2-histamine receptor blockers 11.42%, alginates 18.41% of patients.The results of this study indicate a high prevalence of GERD among residents of Russian cities applying for primary health care (34.2%). In comparison with previous studies, an increase in the proportion of GERD patients taking proton pump inhibitors was noted; in most cases the regimen of their intake was in accordance with the recommendations.Обоснование. В последние годы отмечается увеличение распространенности гастроэзофагеальной рефлюксной болезни (ГЭРБ) в странах Северной Европы, Северной Америки и Восточной Азии. Данные о распространенности ГЭРБ в российской популяции весьма ограничены. Цель. Определить распространенность ГЭРБ среди населения России, клинический спектр симптомов ГЭРБ, основные лекарственные препараты, применяемые для лечения заболевания, и частоту их приема. Материалы и методы. Исследование было проведено в период с ноября 2015 по январь 2017 г. в 8 городах России. Проводилось анкетирование пациентов старше 18 лет по короткому варианту опросника клиники Мэйо, посещавших амбулаторные медицинские учреждения по любой причине, в том числе не имевших жалоб со стороны органов пищеварения. Результаты. Всего проанализировано 6132 анкеты пациентов в возрасте 1890 лет [2456 (40,1%) мужчин и 3676 (59,9%) женщин, средний возраст 46,615,4 года]. Распространенность ГЭРБ среди опрошенных пациентов составила 34,2%. Наблюдалось увеличение частоты ГЭРБ с повышением индекса массы тела и возраста пациентов. Наиболее часто для купирования изжоги и регургитации опрошенные пациенты принимали ингибиторы протонной помпы 59,96% и антациды 67,92%, реже блокаторы Н2-рецепторов гистамина 11,42%, альгинаты 18,41%. Заключение. Результаты настоящего исследования свидетельствуют о высокой распространенности ГЭРБ среди жителей городов России, обратившихся за первичной медицинской помощью (34,2%). В сравнении с ранее проведенными исследованиями отмечено увеличение доли больных ГЭРБ, получавших ингибиторы протонной помпы, при этом в большинстве случаев режим их приема соответствует рекомендациям.

International audience; AimsDilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe.Methods and resultsPatients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01).ConclusionsWe observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence.

Neurodegenerative diseases are currently incurable. Numerous experimental data accumulated over the past fifty years have brought us closer to understanding the molecular and cell mechanisms responsible for their development. However, these data are not enough for a complete understanding of the genesis of these diseases, nor to suggest treatment methods. It turns out that many cellular pathologies developing during neurodegeneration coincide from disease to disease. These observations give hope to finding a common intracellular target(s) and to offering a universal method of treatment. In this review, we attempt to analyze data on similar cellular disorders among neurodegenerative diseases in general, and polyglutamine neurodegenerative diseases in particular, focusing on the interaction of various proteins involved in the development of neurodegenerative diseases with various cellular organelles. The main purposes of this review are: (1) to outline the spectrum of common intracellular pathologies and to answer the question of whether it is possible to find potential universal target(s) for therapeutic intervention; (2) to identify specific intracellular pathologies and to speculate about a possible general approach for their treatment.

Corynebacterium spp. are part of the human microbiome, but can cause the development of inflammatory diseases of various localization. Purpose - to evaluate the relationship between pathogenic properties and resistance to antimicrobial drugs (AMD) of Corynebacterium spp. from patients with inflammatory diseases of the respiratory tract. Strains of Corynebacterium spp. isolated from patients with inflammatory diseases of the respiratory tract (99 pcs.) and practically healthy individuals (33 pcs.). Isolates were identified by mass spectrometric method (MALDI-ToFMS), their adhesive and invasive activity on Hep-2 cells, cytopathic effect (CPE) in CHO-K1 cell culture, and resistance to antimicrobial drugs (AMD) were determined. Indicators of adhesion (3.65±0.679(CFU±m)x102/ml), invasion (1.72±0.230 (CFU±m)x102/ml), cytotoxicity (69.1±3.8% of dead CHO-K1 cells ) Corynebasterium spp. strains isolated from patients are higher (p≤0.05) than similar indicators in practically healthy people. 90.9% of isolates from patients had resistance to AMD, in most cases (57.6±4.9%) resistance to only one AMP was noted, less often to two (25.2±4.3%), three or more (8.08±2.7%). According to the results of correlation-regression analysis, pathogenic properties (adhesiveness, invasiveness, cytotoxicity) of Corynebacterium spp. strains isolated from patients are in close direct relationship with resistance to AMD. This indicates the importance of identifying strains of non-diphtheria corynebacteria resistant to AMDs, which, under the influence of developing resistance to AMDs, can increase their pathogenic potential, moving from commensalism to parasitism.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited., Aims: The interaction between common cardiovascular risk factors (CVRF) and hypertrophic cardiomyopathy (HCM) is poorly studied. We sought to explore the relation between CVRF and the clinical characteristics of patients with HCM enrolled in the EURObservational Research Programme (EORP) Cardiomyopathy registry. Methods and results: 1739 patients with HCM were studied. The relation between hypertension (HT), diabetes (DM), body mass index (BMI) and clinical traits was analyzed. Analyses were stratified according to the presence or absence of a pathogenic variant in a sarcomere gene.The prevalence of HT, DM and obesity (Ob) was 37%, 10%, and 21%, respectively. HT, DM and Ob were associated with older age (p

Most qualitative research to date on HIV self-testing (HIVST) has been devoted to questions related to perceptions of HIVST among various groups of men who have sex with men (MSM) in different countries. However, little is known about HIV testing patterns of HIVST testers. Thrity-two Russian MSM, 10 with HIV and 22 without, from five cities were interviewed about their HIV testing and risk behaviors. Five types of testers "maintenance testers," "risk-based testers," "convenience testers," "test avoiders," and "HIVST-only testers" were identified in the study. Three dimensions of HIV testing patterns-testing motive, frequency, and mode-were proposed to improve existing typifications. Almost all informants practiced condomless sex with their primary partners; HIV testing or condom negotiation in primary partnerships before proceeding to condomless sex was rare. Increase in HIVST availability at no cost for MSM and targeted prevention efforts for MSM on both individual and dyadic level are urgently needed.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Glioblastoma is diagnosed by biopsy or, if clinically feasible, tumor resection. However, emerging evidence suggests that this surgical intervention may increase the risk of tumor cell spread. It has been hypothesized that the damage to the tumor leads to infiltration of immune cells that consequently form an environment that favors tumor cell motility. In mouse glioma models, it was previously found that biopsy induced migration of tumor cells in vivo and that recruitment of monocytes from the blood was involved in this effect. However, the role of neutrophils in this process is still unclear. Here, we study the contribution of neutrophils on the pro-migratory effect of surgical interventions in glioma. Using repetitive intravital microscopy, in vivo migration of glioma tumor cells before and after biopsy was compared in mice systemically depleted of neutrophils. Interestingly, macrophages/microglia were almost completely absent from neutrophil-depleted tumors, indicating that neutrophils may be indirectly involved in biopsy-induced migration of glioma tumor cells through the recruitment of macrophages to the tumor. To further investigate whether neutrophils have the potential to also directly promote glioblastoma tumor cell migration, we performed in vitro migration assays using human neutrophils. Indeed, wound-healing of human primary glioblastoma tumor cell lines was promoted by human neutrophils. The pro-migratory effects of human neutrophils on glioblastoma tumor cells could also be recapitulated in transwell migration assays, indicating that soluble factor(s) are involved. We therefore provide evidence for both an indirect and direct involvement of neutrophils in tumor spread following biopsy of glioblastoma tumors.

Penetration into the female genital tract of infectious agents is associated with the cause of the onset of cervicitis. In most cases, these are sexually transmitted diseases (STDs). A high level of viral and bacterial load in the study of clinical material from women with infectious and inflammatory pathology (IVP) of the cervix affects the activity of innate immunity reactions. The total number of examined patients was 76 patients of reproductive age, of which 36 women with cervical IVP and 40 women made up the comparison group. The imbalance of microbiocenosis can be accompanied by immune and microbiological disorders. The aim of the study was to study immune and microbiological disorders in women with infectious and inflammatory pathology of the cervix. To achieve the goal, the following tasks were set: to identify the relationship between the expression level of TLR2 and TLR4 genes in the epithelial cells of the cervical canal of women in which UPM is determined. To determine the species spectrum and etiological significance of the microbiota of bacterial biofilm of the cervical mucosa in the pathogenesis of cervicitis in women of reproductive age. It has been established that the determination of indicators of innate immunity, such as interferons, in blood serum and the expression of TLR2 and TLR4 receptors, with the study of their balance, taking into account the pro-inflammatory and anti-inflammatory properties in IVP of the cervix, has an important prognostic value. An increase in the level of the immune response in the form of hyperstimulation of antigens of IVP pathogens leads to the chronization of the inflammatory process in the urogenital tract, to scarring of tissues, which can play an important role in the development of infertility and termination of pregnancy in women of reproductive age.

The aim of the work is to investigate the clinical symptoms of thrombotic complications (TC) and the tendency of patients to increased thromb-formation in patients with beta-thalassemia (β-T). Female patients with β-T aged 18-40 years were studied: 130 beta-thalassemia major (β-TM), 95 patients beta-thalassemia intermediate (β-TI), 60 patients with beta-thalassemia minor (β-Tm). In patients with βT, the frequency of occurrence of TC was studied. In patients with βT who do not have TC and splenectomy, hemostasis parameters were studied; and also the risk factors were analyzed for the development of latent hypercoagulation. Conducted questionnaire included questions about the tendency to increased thrombosis (TIT), about various clinical signs, symptoms, extended medical history data. Clinical manifestations of TC (arterial and venous thrombosis, chronic venous insufficiency) were detected in 10.0±2.6% of patients with β-TM and 14.7±3.6% of patients with βTI; TC occurred more frequently in splenectomy patients compared to non-splenectomized patients, respectively, with β-TM 15.0±4.6% and 5.7±2.8% (p≥0.05); with β-TI 22.5±6.6% and 9.1±3.9% (p≥0.05). The level of D-dimer characterizes the activity of fibrinolysis and the intensity of intravascular hemocoagulation; an increase in this marker of thrombinemia500 ng/ml was regarded as a predisposition to LH. It was found that 37.9% of patients with β-TM and 30,4±6,8% of patients with β-TI had pre-thrombotic readiness for hemostasis ̶ latent hypercoagulability. Questionnaire indicted that in βT patients with latent hypercoagulability, D-dimer and fibrinogen levels were increased, fibrinolytic activity, activated partial thromboplastin time were reduced, and antithrombin III activity was slightly reduced. Also, questionnaire indicated the validity, significant reliability and internal consistency of the developed propensity to increased thrombosis. The results of the TIT questionnaire indicate an increased propensity for hypercoagulability in a significant proportion of non-splenectomized β-T patients.

Our understanding of the cellular composition and architecture of cancer has primarily advanced using 2D models and thin slice samples. This has granted spatial information on fundamental cancer biology and treatment response. However, tissues contain a variety of interconnected cells with different functional states and shapes, and this complex organization is impossible to capture in a single plane. Furthermore, tumours have been shown to be highly heterogenous, requiring large‐scale spatial analysis to reliably profile their cellular and structural composition. Volumetric imaging permits the visualization of intact biological samples, thereby revealing the spatio‐phenotypic and dynamic traits of cancer. This review focuses on new insights into cancer biology uniquely brought to light by 3D imaging and concomitant progress in cancer modelling and quantitative analysis. 3D imaging has the potential to generate broad knowledge advance from major mechanisms of tumour progression to new strategies for cancer treatment and patient diagnosis. We discuss the expected future contributions of the newest imaging trends towards these goals and the challenges faced for reaching their full application in cancer research.

The paper presents the results of a study of the prevalence of Ixodid ticks - potential carriers of tick-borne rickettsiosis pathogens. Ectoparasites were collected in various natural and climatic zones of the Crimean Peninsula within the year 2016-2018. As a result of screening with the help of real-time PCR analysis (PCR-RT), a genetic marker (a section of the gltA gene) of the rickettsia group of tick-borne spotted fever was detected in ticks. The most common DNA marker of rickettsia was found in ticks in the eastern regions of the steppe zone - 50,6 %, in the north-western part of the steppe zone this value was 12,0 %. The least amount of rickettsia target DNA was detected in ticks collected in the mountain forest and south bank zones - 4,5 %. As a result of sequencing of positive DNA samples from fragments of the gltA, ompA, ompB, and sca4 genes, the species composition of rickettsias was established. The DNA of 8 species of rickettsia was identified: Circulation of three R. conorii, R. massiliae, R. sibirica subsp. mongolotimonae, R. slovaca, R. aeschlimannii, R. monacensis, R. helvetica, R. raoultii. R. massiliae, R. slovaca, and R. helvetica were established in the Crimean Peninsula for the first time. The peculiarities of the geographical distribution of the identified rickettsia species were determined, which was due to the spread of mites-carriers of pathogens. The revealed diversity of rickettsia species and their vectors, due to the isolation of the areas of the main feeding animals and the established routes of migratory birds, suggests the circulation of other rickettsia species on the territory of the Crimean Peninsula. The obtained results suggest that the diseases of tick-borne rickettsiosis in the Crimean Peninsula can be caused not only by R. conorii, as previously thought, but also by other types of rickettsii.

We investigated distribution and functions of beta- and gamma-cytoplasmic actins (CYAs) at different stages of non-neoplastic epithelial cell division using laser scanning microscopy (LSM). Here, we demonstrated that beta- and gamma-CYAs are spatially segregated in the early prophase, anaphase, telophase, and cytokinesis. Small interfering RNA (siRNA) experiments revealed that in both beta-CYA- and gamma-CYA-depleted cells, the number of cells was significantly reduced compared with the siRNA controls. Beta-CYA depletion resulted in an enlargement of the cell area in metaphase and high percentage of polynuclear cells compared with the siRNA control, indicating a potential failure of cytokinesis. Gamma-CYA depletion resulted in a reduced percentage of mitotic cells. We also observed the interdependence between the actin isoforms and the microtubule system in mitosis: (i) a decrease in the gamma-CYA led to impaired mitotic spindle organization; (ii) suppression of tubulin polymerization caused impaired beta-CYA reorganization, as incubation with colcemid blocked the transfer of short beta-actin polymers from the basal to the cortical compartment. We conclude that both actin isoforms are essential for proper cell division, but each isoform has its own specific functional role in this process.

Transfection with a fluorescently labeled marker protein of interest in combination with time-lapse video microscopy is a classic method of studying the dynamic properties of the cytoskeleton. This protocol offers a technique for human primary fibroblast transfection, which can be difficult because of the specifics of primary cell cultivation conditions. Additionally, cytoskeleton dynamic property maintenance requires a low level of transfection to obtain a good signal-to-noise ratio without causing microtubule stabilization. It is important to take measures to protect the cells from light-induced stress and fluorescent dye fading. In the course of our work, we tested different transfection methods and protocols as well as different vectors to select the best combination of conditions suitable for human primary fibroblast studies. We analyzed the resulting time-lapse videos and calculated microtubule dynamics using ImageJ. The dynamics of microtubules' plus-ends in the different cell parts are not similar, so we divided the analysis into subgroups - the centrosome region, the lamella, and the tail of fibroblasts. Notably, this protocol can be used for in vitro analysis of cytoskeleton dynamics in patient samples, enabling the next step towards understanding the dynamics of the various disease development.

Insects vastly outnumber us in terms of species and total biomass, and are among the most efficient and voracious consumers of plants on the planet. As a result, to preserve crops, one of the primary tasks in agriculture has always been the need to control and reduce the number of insect pests. The current use of chemical insecticides leads to the accumulation of xenobiotics in ecosystems and a decreased number of species in those ecosystems, including insects. Sustainable development of human society is impossible without useful insects, so the control of insect pests must be effective and selective at the same time. In this article, we show for the first time a natural way to regulate the number of insect pests based on the use of extracellular double-stranded DNA secreted by the plant Pittosporum tobira. Using a principle similar to one found in nature, we show that the topical application of artificially synthesized short antisense oligonucleotide insecticides (olinscides, DNA insecticides) is an effective and selective way to control the insect Coccus hesperidum. Using contact oligonucleotide insecticide Coccus-11 at a concentration of 100 ng/μL on C. hesperidum larvae resulted in a mortality of 95.59 ± 1.63% within 12 days. Green oligonucleotide insecticides, created by nature and later discovered by humans, demonstrate a new method to control insect pests that is beneficial and safe for macromolecular insect pest management.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. In most cases, the development of the disease is sporadic and is not associated with any currently known mutations associated with PD. It is believed that changes associated with the epigenetic regulation of gene expression may play an important role in the pathogenesis of this disease. The study of individuals with an almost identical genetic background, such as monozygotic twins, is one of the best approaches to the analysis of such changes. A whole-transcriptome analysis of dermal fibroblasts obtained from three pairs of monozygotic twins discordant for PD was carried out in this work. Twenty-nine differentially expressed genes were identified in the three pairs of twins. These genes were included in seven processes within two clusters, according to the results of an enrichment analysis. The cluster with the greatest statistical significance included processes associated with the regulation of the differentiation of fat cells, the action potential, and the regulation of glutamatergic synaptic transmission. The most significant genes, which occupied a central position in this cluster, were PTGS2, SCN9A, and GRIK2. These genes can be considered as potential candidate genes for PD. Electronic supplementary material The online version of this article (10.1007/s12031-019-01452-3) contains supplementary material, which is available to authorized users.

Parkinson’s Disease (PD) is a widespread severe neurodegenerative disease that is characterized by pronounced deficiency of the dopaminergic system and disruption of the function of other neuromodulator systems. Although heritable genetic factors contribute significantly to PD pathogenesis, only a small percentage of sporadic cases of PD can be explained using known genetic risk factors. Due to that, it could be inferred that changes in gene expression could be important for explaining a significant percentage of PD cases. One of the ways to investigate such changes, while minimizing the effect of genetic factors on experiment, are the study of PD discordant monozygotic twins. In the course of the analysis of transcriptome data obtained from IPSC and NPCs, 20 and 1906 differentially expressed genes were identified respectively. We have observed an overexpression of TNF in NPC cultures, derived from twin with PD. Through investigation of gene interactions and gene involvement in biological processes, we have arrived to a hypothesis that TNF could play a crucial role in PD-related changes occurring in NPC derived from twins with PD, and identified INHBA, WNT7A and DKK1 as possible downstream effectors of TNF.

The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.

A critical aspect of real-time PCR is the presence of housekeeping genes (HKGs) as an internal control for the normalization of expression data for genes of interest. It is necessary to select correct HKGs in the investigation of various pathologies. Thereby, we analyzed the stability of expression of the HKGs in Parkinson’s disease (PD). The work was carried out in the peripheral blood of patients with PD and in the brain tissues and peripheral blood of mice with MPTP-induced PD. As a result, Aars was the most stably expressed HKG in the mouse brain as a whole. However, different genes were more stably expressed in different parts of the brain. Polr2f was the most stably expressed in the cortex, Psmd6 was the most stably expressed in the cerebellum, and Psmd7 was the most stably expressed in the striatum and substantia nigra. HKGs were different in similar tissues of the studied organisms. Polr2f was the most stably expressed HKG in the peripheral blood of mice, whereas PSMD6 was the most stably expressed gene in humans. Thus, there is no universal HKG both for different brain tissues of one organism and for similar tissues of different organisms. Furthermore, the identified most stably expressed HKGs can be considered as such only under conditions in PD.

The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in maintaining endothelial barrier function. Actin cytoskeleton reorganization result in EC contraction and provides a structural basis for the increase in vascular permeability, which is typical for many diseases. Actin cytoskeleton in non-muscle cells presented two actin isoforms: non-muscle β-cytoplasmic and γ-cytoplasmic actins (β-actins and γ-actins), which are encoded by ACTB and ACTG1 genes, respectively. They are ubiquitously expressed in the different cells in vivo and in vitro and the β/γ-actin ratio depends on the cell type. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division and play different roles in neoplastic transformation. In this review, we briefly summarize the research results of recent years and consider the features of the cytoplasmic actins: The spatial organization in close connection with their functional activity in different cell types by focusing on endothelial cells.

Study the impact of various combinations of comorbid original diseases in patients infected with COVID-19 later on the disease progression and outcomes of the new coronavirus infection.The ACTIV registry was created on the Eurasian Association of Therapists initiative. 5,808 patients have been included in the registry: men and women with COVID-19 treated at hospital or at home.gov ID NCT04492384.Most patients with COVID-19 have original comorbid diseases (oCDs). Polymorbidity assessed by way of simple counting of oCDs is an independent factor in negative outcomes of COVID-19. Search for most frequent combinations of 2, 3 and 4 oCDs has revealed absolute domination of cardiovascular diseases (all possible variants). The most unfavorable combination of 2 oCDs includes atrial hypertension (AH) and chronic heart failure (CHF). The most unfavorable combination of 3 oCDs includes AH, coronary heart disease (CHD) and CHF; the worst combination of 4 oCDs includes AH, CHD, CHF and diabetes mellitus. Such combinations increased the risk of lethal outcomes 3.963, 4.082 and 4.215 times respectively.Polymorbidity determined by way of simple counting of diseases may be estimated as a factor in the lethal outcome risk in the acute phase of COVID-19 in real practice. Most frequent combinations of 2, 3 and 4 diseases in patients with COVID-19 primarily include cardiovascular diseases (AH, CHD and CHF), diabetes mellitus and obesity. Combinations of such diseases increase the COVID-19 lethal outcome risk.Цель. Изучить влияние различных комбинаций сопутствующих заболеваний, существовавших у пациентов исходно, до инфицирования вирусом SARS-CoV-2, на тяжесть течения и исходы новой коронавирусной инфекции. Материалы и методы. Регистр АКТИВ создан по инициативе Евразийской ассоциации терапевтов. В регистр включены 5808 пациентов: мужчины и женщины с диагнозом COVID-19, находящиеся на лечении в стационаре или получающие лечение на дому. Регистрация регистра: идентификатор ClinicalTrials.gov: NCT04492384. Результаты. Подавляющее большинство пациентов с COVID-19 имеют исходные сопутствующие заболевания (иСЗ). Полиморбидность, оцененная методом простого подсчета иСЗ, является самостоятельным фактором негативного прогноза больных COVID-19. Поиск наиболее часто встречающихся комбинаций из 2, 3, 4 и более СЗ выявил абсолютное доминирование сердечно-сосудистых заболеваний во всех возможных вариантах. Наиболее неблагоприятной при сочетании 2 иСЗ была комбинация, включающая артериальную гипертензию (АГ) и хроническую сердечную недостаточность (ХСН), при сочетании 3 иСЗ комбинация, включающая АГ, ишемическую болезнь сердца (ИБС), ХСН, и при сочетании 4 иСЗ комбинация, включающая АГ, ИБС, ХСН и сахарный диабет. Наличие таких комбинаций приводило к росту риска летального исхода в 3,963, 4,082, 4,215 раза соответственно. Заключение. Полиморбидность, определенная методом простого подсчета заболеваний, может использоваться в реальной практике как фактор риска летальности в остром периоде COVID-19. В состав наиболее часто встречающихся комбинаций из 2, 3, 4 заболеваний у пациентов с COVID-19 входят преимущественно сердечно-сосудистые заболевания (АГ, ИБС, ХСН), сахарный диабет и ожирение. Комбинации этих заболеваний повышают риск летального исхода при COVID-19.

When the nasopharynx is colonized with toxigenic strains of the diphtheria pathogen, toxin is released, which contributes to the death of epithelial cells. But in bacterial carriers, the development of the clinical picture of the disease does not occur. This is due to the peculiarities of the state of their immune system, as well as the peculiarities of the production of diphtheria exotoxin by corynebacteria in the biofilm. Goal. Determining the nature of the cytopathic effect of C. diphtheriae as part of a biofilm in CHO-K1 cell culture. The planktonic and biofilm (120- and 720-hour) cultures of the strains were studied: C. diphtheriae gravis tox+ № 665, C. diphtheriae gravis tox+ № 6765, C. diphtheriae mitis tox+ № 269, C. diphtheriae gravis tox+ isolated from a patient with a diagnosis Localized oropharyngeal diphtheria C. diphtheriae gravis with a silent tox-gene. Biofilm (120- and 720-hour) cultures of diphtheria pathogen strains were obtained according to the Watnik method. The cytopathic effect of corynebacterial strains was studied on a CHO-K1 cell culture, taking into account in an inverted microscope. When studying the cytopathic effect of planktonic cultures of toxigenic strains of corynebacteria, it was found that the number of living CHO-K1 cells after 24 hours was insignificant (25.3±1.2%) and sharply decreased (2.5±0.5%) after 72 hours of cultivation. Under the influence of biofilm and, especially, 720-hour cultures, a different cytopathic effect dynamics was found: the number of living cells after 24 hours remained significant (82.5±2.2%), while at 72-hour it decreased to 25.0±3.0%. In the study of filtrates of planktonic and biofilm cultures of C. diphtheriae strain with a «silent» tox-gene, similar patterns were revealed. However, the number of live CHO-K1 cells when exposed to the filtrate of a 720-hour biofilm culture was significantly higher (p≤0.05) than when studying toxigenic strains of corynebacteria. Considering the nature of the cytopathic action, it was found that planktonic cultures of toxigenic strains of corynebacteria are characterized by a change in the cell monolayer, manifested by their thinning and elongation. The study of 720-hour biofilm cultures at 72-hour exposure revealed the appearance of a large number of rounded cells (63-69%). The cytopathic effect, formed under the influence of filtrates of planktonic and biofilm cultures of C. diphtheriae with a «silent» tox-gene, as well as strains of non-diphtheria corynebacteria, is characterized by rounding of cells and the formation of symplasts. In the biofilm, the intensity of the cytopathic effect of toxigenic C. diphtheriae strains and C. diphtheriae strain with a silent tox-gene decreased. CPD, manifested by thinning and lengthening of CHO-K1 cells, is associated with the action of diphtheria exotoxin, and rounding is associated with corynebacterial enzymes and, apparently, fragments of surface structures - adhesins. Decreased release of toxin and enzymes beyond the C. bihfilm matrix is a significant cause of the «asymptomatic» carriage of diphtheria.

Despite the progress of modern medicine, oncological diseases are still among the most common causes of death of adult populations in developed countries. The current therapeutic approaches are imperfect, and the high mortality of oncological patients under treatment, the lack of personalized strategies, and severe side effects arising as a result of treatment force seeking new approaches to therapy of malignant tumors. During the last decade, cancer immunotherapy, an approach that relies on activation of the host antitumor immune response, has been actively developing. Cancer immunotherapy is the most promising trend in contemporary fundamental and practical oncology, and restoration of the pathologically altered tumor microenvironment is one of its key tasks, in particular, the reprogramming of tumor macrophages from the immunosuppressive M2-phenotype into the proinflammatory M1-phenotype is pivotal for eliciting antitumor response. This review describes the current knowledge about macrophage classification, mechanisms of their polarization, their role in formation of the tumor microenvironment, and strategies for changing the functional activity of M2-macrophages, as well as problems of targeted delivery of immunostimulatory signals to tumor macrophages using nanoparticles.

In vitro 3D organoid systems have revolutionized the modeling of organ development and diseases in a dish. Fluorescence microscopy has contributed to the characterization of the cellular composition of organoids and demonstrated organoids' phenotypic resemblance to their original tissues. Here, we provide a detailed protocol for performing high-resolution 3D imaging of entire organoids harboring fluorescence reporters and upon immunolabeling. This method is applicable to a wide range of organoids of differing origins and of various sizes and shapes. We have successfully used it on human airway, colon, kidney, liver and breast tumor organoids, as well as on mouse mammary gland organoids. It includes a simple clearing method utilizing a homemade fructose-glycerol clearing agent that captures 3D organoids in full and enables marker quantification on a cell-by-cell basis. Sample preparation has been optimized for 3D imaging by confocal, super-resolution confocal, multiphoton and light-sheet microscopy. From organoid harvest to image analysis, the protocol takes 3 d.

Russia has a widespread injection drug use epidemic with high prevalence of HIV and HCV among people who inject drugs (PWID). We conducted a mixed methods study of young (age 18-26) hard drug users in St. Petersburg. Thirty-nine structured and 10 semi-structured interviews were conducted. No HIV cases and two HCV cases were detected among the PWID subsample (n = 29). Amphetamine and other stimulants were common (70%), opioid use was rare and episodic. Consistent condom use was 10%. No PWID reported syringe-sharing, 51% reported other drug paraphernalia sharing. Most (89%) never or rarely communicated with older (30 +) opiate users. A new cohort of drug users in St. Petersburg may have emerged, which is much safer in its injection practices compared to previous cohorts. However, risky sexual practices among this new cohort may expose them to the possibility of sexual transmission of HIV and widespread drug paraphernalia sharing to the HCV epidemic.

Background Theranostics application of superparamagnetic nanoparticles based on magnetite and maghemite is impeded by their toxicity. The use of additional protective shells significantly reduced the magnetic properties of the nanoparticles. Therefore, iron carbides and pure iron nanoparticles coated with multiple layers of onion-like carbon sheath seem to be optimal for biomedicine. Fluorescent markers associated with magnetic nanoparticles provide reliable means for their multimodal visualization. Here, biocompatibility of iron nanoparticles coated with graphite-like shell and labeled with Alexa 647 fluorescent marker has been investigated. Methods Iron core nanoparticles with intact carbon shells were purified by magnetoseparation after hydrochloric acid treatment. The structure of the NPs (nanoparticles) was examined with a high resolution electron microscopy. The surface of the NPs was alkylcarboxylated and further aminated for covalent linking with Alexa Fluor 647 fluorochrome to produce modified fluorescent magnetic nanoparticles (MFMNPs). Live fluorescent imaging and correlative light-electron microscopy were used to study the NPs intracellular distribution and the effects of constant magnetic field on internalized NPs in the cell culture were analyzed. Cell viability was assayed by measuring a proliferative pool with Click-IT labeling. Results The microstructure and magnetic properties of superparamagnetic Fe@C core–shell NPs as well as their endocytosis by living tumor cells, and behavior inside the cells in constant magnetic field (150 mT) were studied. Correlative light-electron microscopy demonstrated that NPs retained their microstructure after internalization by the living cells. Application of constant magnetic field caused orientation of internalized NPs along power lines thus demonstrating their magnetocontrollability. Carbon onion-like shells make these NPs biocompatible and enable long-term observation with confocal microscope. It was found that iron core of NPs shows no toxic effect on the cell physiology, does not inhibit the cell proliferation and also does not induce apoptosis. Conclusions Non-toxic, biologically compatible superparamagnetic fluorescent MFMNPs can be further used for biological application such as delivery of biologically active compounds both inside the cell and inside the whole organism, magnetic separation, and magnetic resonance imaging (MRI) diagnostics.

Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data regarding the genotype–phenotype correlation can help in the diagnosis and proper management of these patients. The aim of this study was to survey the clinical and genetic characteristics of 55 patients with MED type 4 caused by variants in the SLC26A2 gene. Diagnosis confirmation was carried out by radiography and custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. This was followed by the validation of the identified variants using automated Sanger sequencing (for six patients) and the direct automatic Sanger sequencing of the coding sequence and the adjacent intron regions of the SLC26A2 gene for 49 patients. Based on the clinical and genetic analysis of our sample of patients, two main MED type 4 phenotypes with early and late clinical manifestations were identified. An early and more severe form of the disease was observed in patients with the c.835C > T variant (p.Arg279Trp), and the late and milder form of the disease was observed in patients with the c.1957T > A variant (p.Cys653Ser) in the homozygous or compound heterozygous state with c.26 + 2T > C. It was also shown that only three pathogenic variants were found in 95.3% of the alleles of Russian patients with MED type 4: c.1957T > A (p.Cys653Ser), c.835C > T (p.Arg279Trp), and c.26 + 2T > C; thus, it can be assumed that the primary analysis of these variants will contribute to the optimal molecular genetic diagnostics of MED type 4.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Investigating individuals with the most identical genetic background is optimal for minimizing the genetic contribution to gene expression. These individuals include monozygotic twins discordant for PD. Monozygotic twins have the same genetic background, age, sex, and often similar environmental conditions. The aim of this study was to carry out a transcriptome analysis of the peripheral blood of three pairs of monozygotic twins discordant for PD. We identified the metabolic process “circadian behavior” as a priority process for further study. Different expression of genes included in the term “circadian behavior” confirms that this process is involved in PD pathogenesis. We found increased expression of three genes associated with circadian behavior, i.e., PTGDS, ADORA2A, and MTA1, in twins with PD. These genes can be considered as potential candidate genes for this disease.

Aim To study the effect of regular drug therapy for cardiovascular and other diseases preceding the COVID-19 infection on severity and outcome of COVID-19 based on data of the ACTIVE (Analysis of dynamics of Comorbidities in paTIents who surVived SARS-CoV-2 infEction) registry.Material and methods The ACTIVE registry was created at the initiative of the Eurasian Association of Therapists. The registry includes 5 808 male and female patients diagnosed with COVID-19 treated in a hospital or at home with a due protection of patients’ privacy (data of nasal and throat smears; antibody titer; typical CT imaging features). The register territory included 7 countries: the Russian Federation, the Republic of Armenia, the Republic of Belarus, the Republic of Kazakhstan, the Kyrgyz Republic, the Republic of Moldova, and the Republic of Uzbekistan. The registry design: a closed, multicenter registry with two nonoverlapping arms (outpatient arm and in-patient arm). The registry scheduled 6 visits, 3 in-person visits during the acute period and 3 virtual visits (telephone calls) at 3, 6, and 12 mos. Patient enrollment started on June 29, 2020 and was completed on October 29, 2020. The registry completion is scheduled for October 29, 2022. The registry ID: ClinicalTrials.gov: NCT04492384. In this fragment of the study of registry data, the work group analyzed the effect of therapy for comorbidities at baseline on severity and outcomes of the novel coronavirus infection. The study population included only the patients who took their medicines on a regular basis while the comparison population consisted of noncompliant patients (irregular drug intake or not taking drugs at all despite indications for the treatment).ResultsThe analysis of the ACTIVE registry database included 5808 patients. The vast majority of patients with COVID-19 had comorbidities with prevalence of cardiovascular diseases. Medicines used for the treatment of COVID-19 comorbidities influenced the course of the infectious disease in different ways. A lower risk of fatal outcome was associated with the statin treatment in patients with ischemic heart disease (IHD); with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists and with beta-blockers in patients with IHD, arterial hypertension, chronic heart failure (CHF), and atrial fibrillation; with oral anticoagulants (OAC), primarily direct OAC, clopidogrel/prasugrel/ticagrelor in patients with IHD; with oral antihyperglycemic therapy in patients with type 2 diabetes mellitus (DM); and with long-acting insulins in patients with type 1 DM. A higher risk of fatal outcome was associated with the spironolactone treatment in patients with CHF and with inhaled corticosteroids (iCS) in patients with chronic obstructive pulmonary disease (COPD).Conclusion In the epoch of COVID-19 pandemic, a lower risk of severe course of the coronavirus infection was observed for patients with chronic noninfectious comorbidities highly compliant with the base treatment of the comorbidity.

The evidence of the causal role of low-density lipoprotein cholesterol in the development of atherosclerotic cardiovascular disease is well-established. The clearly identified common position of the European guidelines proclaims necessity to decrease LDL-C concentrations based on a proper risk stratification. However, current worldwide situation with the lipid management still demonstrates inadequate dyslipidemia control, that is probably related to a healthcare system issues. As the need to standardize and implement approaches following the guidelines into clinical practice remains a challenge, the EAS initiates the Lipid Clinics Network project, aiming to provide a structure to establish uniform EU-wide standards of diagnosis, management and treatment of patients with lipid disorders, based on the ESC/EAS Guidelines on management of dyslipidaemias.

Acromegaly patients were reported to have an increased arterial stiffness that could contribute to the frequent cardiovascular complications in this population. The chronic excess of GH and IGF-1 may lead to arterial stiffening via different mechanisms, including hypertension, impaired glucose tolerance and dyslipidemia, however, it is not known whether the activation of GH/IGF-1 axis might influence arterial stiffening independently of cardiovascular risk factors. The objective of this prospective case-control study was to compare arterial stiffness assessed with pulse-wave velocity (PWV) in acromegaly versus non-acromegaly group with similar cardiovascular risk profile.This prospective case-control study included 27 patients with active acromegaly, who underwent the assessment of clinical, physiological, biochemical parameters and the evaluation of PWV with applanation tonometry. We used "The epidemiology of cardiovascular disease in different regions of the Russian Federation" study database (n = 522) to establish a non-acromegaly control group with similar cardiovascular risk profile (n = 54). Non-acromegaly control participants underwent the same assessment as acromegaly patients except for the measurement of serum GH and IGF-1 levels. We compared PWV in acromegaly patients to the general non-acromegaly cohort and its subset, matched with acromegaly patients for cardiovascular risk factors. We also investigated the associations of PWV with clinical, physiological and biochemical parameters in acromegaly and non-acromegaly group using correlation and regression analysis with adjustment for age and sex.Acromegaly patients had lower PWV (6.70 (5.75-7.65) m/s) compared to unmatched non-acromegaly control cohort (7.50 (6.70-8.57) m/s, p = 0.01) and to the non-acromegaly control group matched for cardiovascular risk factors (7.45 (6.73-8.60), p 0.01). In non-acromegaly control group PWV was associated with BMI (ρ = 0.40, p 0.01; β = 0.09, p 0.01), obesity (r = 0.46, p 0.01; β = 1.36, p 0.01), systolic blood pressure (ρ = 0.60, p 0.01; β = 0.05, p 0.01), diastolic blood pressure (ρ = 0.62, p 0.01; β = 0.07, p 0.01), triglycerides (ρ = 0.55, p 0.01; β = 0.58, p = 0.04), glucose (ρ = 0.54, p 0.01; β = 0.70, p 0.01) and diabetes (r = 0.40, p 0.01; β = 1.10, p = 0.03), while in acromegaly group PWV was associated with IGF-1 expressed in mcg/ml (ρ = -0.49, p ≤0.01; β = -0.002, p ≤0.01) and in percentage of the upper limit of the normal (ρ = -0.47, p = 0.01; β = -0.005, p ≤0.01) as well as with diuretics treatment (β = -1.17, p = 0.03).PWV is decreased in acromegaly patients compared to non-acromegaly control participants with similar cardiovascular risk profile. Future studies need to explore the role of GH/IGF-1 axis in the regulation of arterial wall properties and the reliability of PWV as a prognostic marker of cardiovascular complications in acromegaly.

Despite advances in three-dimensional (3D) imaging, it remains challenging to profile all the cells within a large 3D tissue, including the morphology and organization of the many cell types present. Here, we introduce eight-color, multispectral, large-scale single-cell resolution 3D (mLSR-3D) imaging and image analysis software for the parallelized, deep learning-based segmentation of large numbers of single cells in tissues, called segmentation analysis by parallelization of 3D datasets (STAPL-3D). Applying the method to pediatric Wilms tumor, we extract molecular, spatial and morphological features of millions of cells and reconstruct the tumor's spatio-phenotypic patterning. In situ population profiling and pseudotime ordering reveals a highly disorganized spatial pattern in Wilms tumor compared to healthy fetal kidney, yet cellular profiles closely resembling human fetal kidney cells could be observed. In addition, we identify previously unreported tumor-specific populations, uniquely characterized by their spatial embedding or morphological attributes. Our results demonstrate the use of combining mLSR-3D and STAPL-3D to generate a comprehensive cellular map of human tumors.

Lipoprotein (a) (Lp(a)) is considered a genetic factor for cardiovascular disease playing an important role in atherogenesis and thrombosis, but the evidence about its association with sleep duration is controversial. We evaluated the relation between self-reported sleep duration and Lp(a). Among 1600 participants of the population-based sample, we selected 1427 subjects without previously known cardiovascular events, who answered the questions about their sleep duration, had valid lipid profile results (total cholesterol, low- and high-density lipoproteins, Lp(a), apolipoprotein AI (ApoAI), ApoB, and ApoB/ApoAI), and did not take lipid-lowering drugs (mean age 46 &plusmn, 12 years). We performed a structured interview, which included questions about lifestyle, medical history, complaints, and sleep duration (How long have you been sleeping per night during the last month?). Sleep duration was classified as follows: &lt, 6 h/night&mdash, short, 6&ndash, 9 h/night&mdash, normal, and &ge, 10 h/night&mdash, long. Overall, 73 respondents (5.2%) were short-sleepers and 69 (4.8%) long-sleepers. Males were slightly more prevalent among short-sleepers. The groups matched by age, body mass index, blood pressure, diabetes mellitus, and hypertension rate. Short-sleepers had lower rates of high total cholesterol (&ge, 5.0 mmol/L), lower Lp(a) levels and lower rates of increased Lp(a) &ge, 0.5 g/L, and higher insulin and insulin resistance (assessed by the homeostatic model assessment for insulin resistance (HOMA-IR)). ApoAI, ApoB, their ratio, and other lab tests were similar in the groups. The multinomial logistic regression demonstrated that only the short sleep duration was independently (odds ratio (OR) 0.29, 95% confidence interval (CI) (0.09&ndash, 0.91), p = 0.033) associated with Lp(a) (&chi, 2 = 41.58, p = 0.003). Other influencing factors were smoking and HOMA-IR. Such an association was not found for long-sleepers. In conclusion, a short-sleep duration is associated with Lp(a). The latter might mediate the higher insulin resistance and higher cardiometabolic risks in short-sleepers.

Huntington’s disease is a severe and currently incurable neurodegenerative disease. An autosomal dominant mutation in the Huntingtin gene (HTT) causes an increase in the polyglutamine fragment length at the protein N-terminus. The consequence of the mutation is the death of neurons, mostly striatal neurons, leading to the occurrence of a complex of motor, cognitive and emotional-volitional personality sphere disorders in carriers. Despite intensive studies, the functions of both mutant and wild-type huntingtin remain poorly understood. Surprisingly, there is the selective effect of the mutant form of HTT even on nervous tissue, whereas the protein is expressed ubiquitously. Huntingtin plays a role in cell physiology and affects cell transport, endocytosis, protein degradation and other cellular and molecular processes. Our experimental data mining let us conclude that a significant part of the Huntingtin-involved cellular processes is mediated by microtubules and other cytoskeletal cell structures. The review attempts to look at unresolved issues in the study of the huntingtin and its mutant form, including their functions affecting microtubules and other components of the cell cytoskeleton.

Valosin-containing human protein (VCP) or p97 performs enzyme functions associated with the maintenance of protein homeostasis and control of protein quality. Disruption of its normal functioning might be associated with the development of Parkinson’s disease (PD). Tissues of mice with toxin-induced presymptomatic and early symptomatic stages of PD, as well as 52 treated and untreated patients with newly diagnosed PD and nine patients with a “predicted” form of PD, were investigated. Significant changes in Vcp gene expression were observed in almost all studied mouse tissues. A significant decrease in VCP expression specific for PD was also detected at both the late preclinical and the early clinical stages of PD in untreated patients. Thus, a decrease in VCP expression is important for changes in the function of the nervous system at early stages of PD. Analysis of changes in VCP expression in all patients with PD and in Vcp in the peripheral blood of mice used as models of PD revealed significant decreases in expression specific for PD. These data suggest that a decrease in the relative levels of VCP mRNA might serve as a biomarker for the development of pathology at the early clinical and preclinical stages of human PD.

To analyze the results of diagnosis and treatment of true splenic artery aneurysms.We analyzed the results of diagnosis and treatment of 27 patients with true splenic artery aneurysm. All ones underwent surgical treatment at the Botkin Municipal Clinical Hospital between 2017 and 2021. Splenic artery aneurysm1 cm was an indication for surgical treatment. Surgical option depended on aneurysm location. Laparoscopic splenectomy and aneurysmectomy were performed in 4 cases (14.8%), 5 (18.5%) patients underwent endovascular intervention, laparoscopic clipping was performed in 18 (66.7%) cases. Methods of surgical treatment, general and specific postoperative complications according to the Clavien-Dindo and ISGPS classifications were analyzed.Laparoscopic clipping was accompanied by fewer general and specific postoperative complications. Specific complications after laparoscopic splenectomy occurred in 2 patients (BL according to the ISGPS 2016 classification). There was one case of acute pancreatitis after endovascular interventions. In long-term postoperative period, aneurysm recanalization after endovascular intervention was observed in 1 case.Surgical treatment of splenic artery aneurysms requires a differentiated approach based on topographic and anatomical assessment of aneurysm relative to the arterial vessel.Аневризмы селезеночной артерии — редкое, но потенциально летальное заболевание. Истинная аневризма селезеночной артерии — третья по частоте встречаемости после аневризм инфраренального отдела аорты и подвздошных артерий. Наиболее грозным осложнением этого заболевания является спонтанный разрыв.Проанализированы результаты диагностики и лечения 27 больных с диагнозом «аневризма селезеночной артерии», которым произведено оперативное вмешательство в хирургической клинике Боткинской больницы в период с 2017 по 2021 г. Показанием к оперативному лечению служило наличие аневризмы селезеночной артерии диаметром более 1 см. Выбор способа оперативного вмешательства зависел от расположения аневризмы. Лапароскопическая спленэктомия с удалением аневризмы выполнена у 4 (14,8%) пациентов, эндоваскулярное вмешательство — у 5 (18,5%) пациентов, лапароскопическое клипирование — у 18 (66,7%) пациентов. В исследовании проанализированы непосредственные результаты хирургических вмешательств, общие и специфические послеоперационные осложнения по классификации Clavien—Dindo и ISGPS 2016.При сравнении непосредственных результатов хирургического лечения лапароскопическое клипирование ветвей аневризмы селезеночной артерии сопровождалось меньшим количеством общих и специфических послеоперационных осложнений. При лапароскопической спленэктомии специфические осложнения наблюдали у 2 больных (BL по классификации ISGPS 2016), при эндоваскулярном вмешательстве зафиксирован 1 случай острого панкреатита легкой степени тяжести. При анализе отдаленных результатов в подгруппе пациентов после эндоваскулярного вмешательства зафиксирован случай частичной реканализации аневризмы.Хирургическое лечение аневризм селезеночной артерии требует дифференцированного подхода, который основывается на топографо-анатомической оценке расположения аневризмы относительно артериального сосуда.

To explore the relationship between pharmacokinetic variables and enterococcal resistance to linezolid, a vancomycin-resistant strain whose mutant prevention concentration (MPC) exceeded the MIC by two fold was selected among six clinical isolates of Enterococcus faecium. The selected strain was exposed to simulated pharmacokinetics of twice-daily linezolid for five days. Mutants resistant to 2 × MIC of the antibiotic were enriched at ratios of the 24-h area under the concentration-time curve (AUC24) to the MIC of 15 and 30 h but not at 60 and 120 h. These observations could be explained by the different times when antibiotic concentrations exceed the MPC (T>MPC): 0 to 14, 63 and 100% of the dosing interval. Using the area under the bacterial mutant concentration-time curve (AUBCM) determined in this study and in previous work with other E. faecium strains (MPC/MIC 4), a strain-independent T>MPC relationship with mutant enrichment was established.

The aim of the present study was to assess the prevalence of increased arterial stiffness by different diagnostic methods and its association with cardiovascular risk in Russian population-based cohort.In terms of Russian epidemiological study ESSE-RF a random selection of 452 apparently healthy Saint-Petersburg inhabitants aged 25-65 years was performed. Fasting lipids, glucose and blood pressure measurements were performed. We used 3 diagnostic methods of arterial stiffness assessment: pulse wave velocity by applanation tonometry (SphygmoCor - PWV-S) and pulse wave velocity by volumetric sphygmography (VaSera - PWV-V), and cardio-ankle vascular index (CAVI) by VaSera.341 (75,4%) had normal parameters of arterial stiffness assessed by all methods. Spearmen's coefficient of correlation and "kappa" coefficient for PWV-S and CAVI were 0,74 and 0,04, for PWV-S and PWV-V - 0,10 and 0,06, for CAVI and PWV-V - 0,28 and 0,03, respectively. There was a significant correlation between cardiovascular risk (defined by SCORE) and PWV-S (r = 0,38, p 0,001) and a non-significant trend of increasing CAVI along with cardiovascular risk (r = 0,35, p = 0,14).Different methods of arterial stiffness assessment showed a weak correlation with each other. Carotid-femoral pulse wave velocity detected by applanation tonometry is associated with high cardiovascular risk score and might be considered as better additional risk marker for cardiovascular risk stratification.

Surgical procedures such as tumor resection and biopsy are still the gold standard for diagnosis and (determination of) treatment of solid tumors, and are prognostically beneficial for patients. However, growing evidence suggests that even a minor surgical trauma can influence several (patho) physiological processes that might promote postoperative metastatic spread and tumor recurrence. Local effects include tumor seeding and a wound healing response that can promote tumor cell migration, proliferation, differentiation, extracellular matrix remodeling, angiogenesis and extravasation. In addition, local and systemic immunosuppression impairs antitumor immunity and contributes to tumor cell survival. Surgical manipulation of the tumor can result in cancer cell release into the circulation, thus increasing the chance of tumor cell dissemination. To prevent these undesired effects of surgical interventions, therapeutic strategies targeting immune response exacerbation or alteration have been proposed. This review summarizes the current literature regarding these local, systemic and secondary site effects of surgical interventions on tumor progression and dissemination, and discusses studies that aimed to identify potential therapeutic approaches to prevent these effects in order to further increase the clinical benefit from surgical procedures.

To investigate whether intravenous contrast-enhanced multislice spiral computed tomography (computed tomography) (MSCT) versus myocardial morphological examination can diagnose myocarditis and the non-inflammatory causes of dilated cardiomyopathy (DCM) and evaluate prognosis in patients with the latter.A study group consisted of 130 patients, including 95 men (46.8±11.9 years), with DCM (mean left ventricular (LV) end-diastolic dimension (EDD), 6.6±0.8 cm; mean LV ejection fraction (EF), 29.8±9.3%; NYHA functional class (FC) III (II; III)). All the patients underwent intravenous contrast-enhanced 320-slice CT of the heart; myocardial morphological examination was made in 48 patients (endomyocardial biopsy in 29 patients, intraoperative biopsy in 7, and autopsy in 9, and study of the explanted heart in 3). In addition, cardiotropic viral DNA in the blood and myocardium and the level of anticardiolipin antibodies were determined; echocardiography (in all the patients), scintigraphy (n = 45), magnetic resonance imaging (MRI) (n = 21), and coronary angiography (CG) (n = 46), and a genetic consultation were performed. A comparison group comprised 20 patients, including 14 men (69.3±9.2 years), with coronary atherosclerosis (40% or more stenoses) according to MSCT findings in the absence of criteria for DCM (mean LV EDD, 4.8±0.5 cm; mean LV EF, 59.4±4.6%).Morphological/comprehensive examination showed that myocarditis as a cause of DCM was diagnosed in 76 (65%) patients; its concurrence with genetic cardiomyopathies was in 17 more patients (17%). MSCT of the heart revealed lower accumulation areas in 2 (1.5%) patients (type 1 based on the proposed rating scale), delayed myocardial contrast agent accumulation (DMCAA) in 81 (62.3%): subendocardial accumulation (type 2) in 8, intramyocardial accumulation in 4 (type 3), subepicardial accumulation in 52 (type 4), and transmural accumulation in 15 (type 5); DMCAA was not noted in 49 patients. DMCAA was not found in the comparison group. As compared with biopsy, the sensitivity, specificity, predictive value of positive and negative results of the tests in detecting active myocarditis for all the types of DMCAA were 77.4, 47.1, 72.7, and 53.3%, respectively; those for types 3-5 of DMCAA were 77.4, 52.9, 75.0, and 56.3%; those in detecting all the morphological types of myocarditis were 68.3, 28.6, 84.8, and 13.3%, and those for types 3-5 were 65.9, 28.6, 84.4, and 12.5%, respectively. Comparison of the data of MSCT and those of comprehensive examination in all the patients with DCM, the diagnostic significance in detecting myocarditis for all the types of DMCAA was 70.6, 67.9, 88.9 and 38.8%, respectively; that for DMCAA types 3-5 was 60.8, 67.9, 87.3, and 32.3%. In the study group, MSCT also identified the non-compacted myocardium (n = 31 (23.8%)), coronary atherosclerosis (n = 31 (23%)), which is confirmed by CG findings in 15 patients. The patients with DMCAA significantly more frequently showed a relationship with previous infection, acute onset, significantly higher NYHA FCs, end-diastolic and end-systolic LV volumes, and insignificantly lower LV EF. During a mean follow-up periods of 12 (6; 37.25) months, the overall mortality rate was 17.7% (23 deaths); the death + transplantation index was 20% (n = 26). All the types of DMCAA were found to be significantly related to prognosis: in the DMCAA group, the mortality rate was 21.5% versus 7.8% in the non-DMCAA group (odds ratio 3.22; 95% confidence interval, 1.02 to 10.21; p0.05).MSCT with the assessment of delayed contrast enhancement (and simultaneous CT coronary angiography) can be used for the non-invasive diagnosis of myocarditis in patients with DCM, including that in the presence of contraindications to MRI. DMCAA correlates with the presence of myocarditis, its activity, the degree of functional disorders, and prognosis.Цель исследования. Изучение возможности мультиспиральной компьютерной томографии (МСКТ) сердца с внутривенным контрастированием у больных с синдромом дилатационной кардиомиопатии (ДКМП) в диагностике миокардита (в сопоставлении с морфологическим исследованием миокарда), невоспалительных причин ДКМП и оценке прогноза. Материалы и методы. В основную группу вошли 130 пациентов (95 мужчин, средний возраст 46,8±11,9 года) с синдромом ДКМП: средний конечный диастолический размер (КДР) левого желудочка (ЛЖ) 6,6±0,8 см, средняя фракция выброса (ФВ) 29,8±9,3%; III (II; III) функциональный класс (ФК) по классификации NYHA. Всем проведена 320-срезовая МСКТ сердца с внутривенным контрастированием; 48 пациентам выполнено морфологическое исследование миокарда (эндомиокардиальная биопсия у 29, интраоперационная у 7, аутопсия у 9, исследование эксплантированного сердца у 3). Кроме того, определяли ДНК кардиотропных вирусов в крови и миокарде, уровень антикардиальных антител, проводили эхокардиографию (всем пациентам), сцинтиграфию (у 45), магнитно-резонансную томографию - МРТ (у 21), коронарографию - КГ (у 46), консультацию генетика. Группу сравнения составили 20 пациентов (14 мужчин, средний возраст 69,3±9,2 года) с коронарным атеросклерозом (стенозы 40% и более) по данным МСКТ в отсутствие критериев ДКМП (средний КДР ЛЖ 4,8±0,5 см, средняя ФВ 59,4±4,6%). Результаты. По данным морфологического комплексного обследования, миокардит как причина синдрома ДКМП диагностирован у 76 (65%) пациентов, его сочетание с генетическими кардиомиопатиями - у 17 (17%). При МСКТ сердца участки пониженного накопления выявлены у 2 (1,5%) больных (1-й тип по предложенной шкале оценки), отсроченное накопление контрастного препарата (ОНКП) в миокарде - у 81 (62,3%): у 8 субэндокардиальное (2-й тип), у 4 интрамиокардиальное (3-й тип), у 52 субэпикардиальное (4-й тип), у 15 трансмуральное (5-й тип); у 49 больных ОНКП не отмечено. В группе сравнения ОНКП не выявлено. В сопоставлении с биопсией чувствительность, специфичность, прогностическая ценность положительного и отрицательного результатов тестов всех типов ОНКП в выявлении активного миокардита составили 77,4, 47,1, 72,7 и 53,3%, 3-5-го типа ОНКП - 77,4, 52,9, 75 и 56,3%, в выявлении всех морфологических типов миокардита - 68,3, 28,6, 84,8 и 13,3%, 3-5-го типов 65,9, 28,6, 84,4 и 12,5% соответственно. При сопоставлении данных МСКТ и комплексного обследования у всех больных с ДКМП диагностическая значимость всех типов ОНКП в выявлении миокардита составила 70,6, 67,9, 88,9 и 38,8%, 3-5-го типа ОНКП - 60,8, 67,9, 87,3 и 32,3%. При МСКТ в основной группе выявлены также некомпактный миокард (n=31, или 23,8%), коронарный атеросклероз (n=31, или 23%), который подтвержден данными КГ у 15 пациентов. У больных с ОНКП достоверно чаще определялись связь дебюта с перенесенной инфекцией, острое начало, достоверно более высокие ФК по классификации NYHA, конечный диастолический и конечный систолический объемы ЛЖ, недостоверно более низкая ФВ ЛЖ. Общая летальность при среднем сроке наблюдения 12 (6; 37,25) мес составила 17,7% (умерли 23 больных), показатель смерть + трансплантация - 20% (26 больных). Выявлена достоверная связь всех типов ОНКП с прогнозом: в группе ОНКП летальность составила 21,5% по сравнению с 7,8% в группе без ОНКП (отношение шансов 3,22 при 95% доверительном интервале от 1,02 до 10,21; p0,05). Заключение. МСКТ с оценкой отсроченного контрастирования (и одновременной КТ-ангиографией коронарных артерий) может использоваться для неинвазивной диагностики миокардита у пациентов с синдромом ДКМП, в том числе при наличии противопоказаний к проведению МРТ. ОНКП в миокарде коррелирует с наличием миокардита, его активностью, степенью функциональных нарушений и прогнозом.

Background and aim The metabolic syndrome (MetS) has become one of the most important clinical issues in the cardiovascular field for this decade because of the marked increase in cardiovascular (CV) risk associated with a clustering of risk factors. The aim of the current study was to evaluate the relationship between MetS and its components and cardiovascular disease (CVD). Methods This population-based cross-sectional study was based on data from two studies carried out in Russia (ESSE-RF) and Italy (PLIC). One sample from each cohort was selected, matching individuals by sex and age. A comparison between samples of MetS components distribution and CV risk, according to SCORE chart, has been conducted. Results A total of 609 individuals (mean [SD] age 55 [8] years, about 39% males) for each cohort were selected. Almost half of PLIC cohort participants belonged to the moderate CV risk group (47% vs 27%), while in ESSE-RF cohort a relatively higher prevalence of individuals classified in the high and very high risk group was observed (19% vs 11%, 21% vs 6%, respectively). Overall, 43% of ESSE-RF participants were diagnosed with MetS, compared with the 27% of PLIC members (the difference in prevalence becomes 37% vs 21%, considering a more conservative cut-off for waist circumference). Both cohorts showed a trend towards the increase of MetS components moving from the lowest to the highest CV risk class, with a high prevalence of patients with four or five MetS determinants allocated in the high/very high CV risk group. Conclusions Developing effective public health strategies for the prevention, detection and treatment of MetS should be an urgent priority to reduce the burden of CVD, not only in subjects at high/very high CV risk, but also in those characterized by a lower risk, as even rare CV events that come from low risk group bring a tangible burden to healthcare systems.

Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are well-established, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G2–M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study. Mol Cancer Ther; 16(8); 1555–65. ©2017 AACR.

Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy.Российский консенсус по диагностике и лечению хронического панкреатита подготовлен по инициативе Российского 'Панкреатологического клуба' с целью выяснения и консолидации мнений отечественных специалистов (гастроэнтерологов, хирургов и педиатров) по наиболее важным проблемам диагностики и лечения хронического панкреатита. Настоящая статья продолжает серию публикаций, разъясняющих наиболее важные положения междисциплинарного консенсуса и посвящена вопросам заместительной ферментной терапии.

The centrosome is an intracellular structure of the animal cell responsible for organization of cytoplasmic microtubules. According to modern concepts, the centrosome is a very important integral element of the living cell whose functions are not limited to its ability to polymerize microtubules. The centrosome localization in the geometric center of the interphase cell, the high concentration of various regulatory proteins in this area, the centrosome-organized radial system of microtubules for intracellular transport by motor proteins, the centrosome involvement in the perception of external signals and their transmission - all these features make this cellular structure a unique regulation and distribution center managing dynamic morphology of the animal cell. In conjunction with the tissue-specific features of the centrosome structure, this suggests the direct involvement of the centrosome in execution of cell functions. This review discusses the involvement of the centrosome in the vital activity of endothelial cells, as well as its possible participation in the implementation of barrier function, the major function of endothelium.

One of the most important pathological consequences of renal ischemia/reperfusion (I/R) is kidney malfunctioning. I/R leads to oxidative stress, which affects not only nephron cells but also cells of the vascular wall, especially endothelium, resulting in its damage. Assessment of endothelial damage, its role in pathological changes in organ functioning, and approaches to normalization of endothelial and renal functions are vital problems that need to be resolved. The goal of this study was to examine functional and morphological impairments occurring in the endothelium of renal vessels after I/R and to explore the possibility of alleviation of the severity of these changes using mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decylrhodamine 19 (SkQR1). Here we demonstrate that 40-min ischemia with 10-min reperfusion results in a profound change in the structure of endothelial cells mitochondria, accompanied by vasoconstriction of renal blood vessels, reduced renal blood flow, and increased number of endothelial cells circulating in the blood. Permeability of the kidney vascular wall increased 48 h after I/R. Injection of SkQR1 improves recovery of renal blood flow and reduces vascular resistance of the kidney in the first minutes of reperfusion; it also reduces the severity of renal insufficiency and normalizes permeability of renal endothelium 48 h after I/R. In in vitro experiments, SkQR1 provided protection of endothelial cells from death provoked by oxygen-glucose deprivation. On the other hand, an inhibitor of NO-synthases, L-nitroarginine, abolished the positive effects of SkQR1 on hemodynamics and protection from renal failure. Thus, dysfunction and death of endothelial cells play an important role in the development of reperfusion injury of renal tissues. Our results indicate that the major pathogenic factors in the endothelial damage are oxidative stress and mitochondrial damage within endothelial cells, while mitochondria-targeted antioxidants could be an effective tool for the protection of tissue from negative effects of ischemia.

Antimicrotubule vinca alkaloids are widely used in the clinic but their toxicity is often dose limiting. Strategies that enhance their effectiveness at lower doses are needed. We show that combining vinca alkaloids with compounds that target a specific population of actin filaments containing the cancer-associated tropomyosin Tpm3.1 result in synergy against a broad range of tumor cell types. We discovered that low concentrations of vincristine alone induce supernumerary microtubule asters that form transient multi-polar spindles in early mitosis. Over time these asters can be reconstructed into functional bipolar spindles resulting in cell division and survival. These microtubule asters are organized by the nuclear mitotic apparatus protein (NuMA)–dynein–dynactin complex without involvement of centrosomes. However, anti-Tpm3.1 compounds at nontoxic concentrations inhibit this rescue mechanism resulting in delayed onset of anaphase, formation of multi-polar spindles, and apoptosis during mitosis. These findings indicate that drug targeting actin filaments containing Tpm3.1 potentiates the anticancer activity of low-dose vincristine treatment. Implications: Simultaneously inhibiting Tpm3.1-containing actin filaments and microtubules is a promising strategy to potentiate the anticancer activity of low-dose vincristine.

Biopsies are standard of care for cancer treatment and are clinically beneficial as they allow solid tumor diagnosis, prognosis, and personalized treatment determination. However, perturbation of the tumor architecture by biopsy and other invasive procedures has been associated with undesired effects on tumor progression, which need to be studied in depth to further improve the clinical benefit of these procedures. Conventional static approaches, which only provide a snapshot of the tumor, are limited in their ability to reveal the impact of biopsy on tumor cell behavior such as migration, a process closely related to tumor malignancy. In particular, tumor cell migration is the key in highly aggressive brain tumors, where local tumor dissemination makes total tumor resection virtually impossible. The development of multiphoton imaging and chronic imaging windows allows scientists to study this dynamic process in living animals over time. Here, we describe a method for the high-resolution longitudinal imaging of brain tumor cells before and after a biopsy in the same living animal. This approach makes it possible to study the impact of this procedure on tumor cell behavior (migration, invasion, and proliferation). Furthermore, we discuss the advantages and limitations of this technique, as well as the ability of this methodology to study changes in the cancer cell behavior for other surgical interventions, including tumor resection or the implantation of chemotherapy wafers.

Developing nanocarriers that accumulate in targeted organs and are harmlessly eliminated still remains a big challenge. Nanoparticles (NP) biodistribution is governed by their size, composition, surface charge and coverage. The current thinking in bionanotechnology is that renal clearance is limited by glomerular basement membrane pore size (≈6 nm), although there is a growing evidence that NP exceeding the threshold can also be excreted with urine. Here we compare biodistribution of PEGylated 140 nm iron oxide cubes and clusters with a special focus on renal accumulation and excretion. Atomic emission spectroscopy, fluorescent microscopy and magnetic resonance imaging revealed rapid and transient accumulation of magnetic NP in kidney. Using intravital microscopy we tracked in real time NP translocation from peritubular capillaries to basal compartment of tubular cells and subsequent excretion to the lumen within 60 min after systemic administration. Transmission electron microscopy revealed persistence of intact full-sized NP in urine 2 h post injection. The results suggest that translocation through peritubular endothelium to tubular epithelial cells is an alternative mechanism of renal clearance enabling excretion of NP above glomerular cut-off size.