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INTRODUCTION. Urinary incontinence in children is an interdisciplinary problem. The prevalence of urinary incontinence ranges from3.1% to 8.6% and decreases with age. Urinary incontinence can be caused by both organic (diseases of the genitourinary system,neurological pathology) and functional causes. One of the methods of non-drug correction of urinary incontinence is extracorporealmagnetic stimulation, used in adult patients. At the same time, the effectiveness of the method among the pediatric population hasnot been sufficiently studied. AIM. To study the effectiveness and safety of extracorporeal magnetic stimulation in the comprehensive rehabilitation of children withneurogenic urinary incontinence. MATERIAL AND METHODS. A prospective open randomized controlled clinical study included 75 pediatric patients (from 5 years to 16years and 6 months) with a clinical form of day and night urinary incontinence, who were divided by simple randomization into a maingroup (n=39), who received a standard rehabilitation and extracorporeal magnetic stimulation program for 21 days, and a comparisongroup (n=36), in which the standard rehabilitation program did not include the use of extracorporeal magnetic stimulation. RESULTS AND DISCUSSION. A prospective open randomized comparative study revealed that the clinical effectiveness of theextracorporeal magnetic stimulation method in the comprehensive rehabilitation of children with neurogenic urinary incontinenceis 94.8%, which is 25.4% higher than in the comparison group. After treatment, patients in the main group had a noticeable decreasein urinary incontinence episodes, an increase in the micturition volume, and an improvement in the quality of life. Patients withvarious background neurological pathology responded to treatment, which indicates the common pathogenetic mechanisms of thedevelopment of lower urinary tract symptoms in these conditions and the independence of the final effect from the basic diagnosis. CONCLUSION. The use of the perineal extracorporeal magnetic stimulation method in children with neurogenic urinary incontinenceincreases the effectiveness of rehabilitation and is a promising and safe direction of rehabilitation treatment.

Modern sheep breeding should be based on the production of high quality sheep products. Knowing the limits of animal productivity potential allows to manage the breeding process in the most effective way. Applying PCR-RFLP method makes it possible to identify allelic variants of genes associated with quantitative and qualitative characteristics of animals. By identifying different polymorphic variations and their phenotypic manifestations, one can create and replenish a database for managing the genetic progression of breeding-significant traits. The paper determines the gene polymorphism of growth hormone (GH), calpastatin (CAST) and growth differentiation factor (GDF9) of experimental animals and reflects an associative connection between the dynamics of growth and that of development of crossbred one-shear sheep of different origin (Russian meat merino ewes and imported producers). The article concludes that in order to increase sheep meat productivity, farms should give preference to animals carrying genes with the identified desired genotype on the studied polymorphisms and take into account their presence in the breeding process.

BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions. AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions. METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold. RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways. CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.

Aim. To improve the long-term outcomes of patients with atrial fibrillation (AF) after cardioembolic stroke by creating and testing a comprehensive ambulatory monitoring system.Material and methods. The present study included 139 AF patients after cardioembolic stroke for the period 2016-2019, of which 80 (57,55%) were women and 59 (42,45%) were men. The mean age of the patients was 72,25±6,33years. Before the hospital discharge, all patients signed an informed consent and were randomized into two groups. Patients of the group I (n=72) were followed up during the year in accordance with a specially developed comprehensive ambulatory monitoring system. This system included a rehabilitation program created individually for each patient, monthly visits to a physician-researcher, during which a complex of diagnostic tests was carried out. Also, the changes of complaints, symptoms, and medical adherence were assessed. The latter was corrected. A physician talked with the patient's relatives about the need to comply with the recommended medication regimen, supporting the motivation for treatment. Patients of group II (n=67) were followed up at the primary care level in accordance with the current program, and a control visit to was performed for them once — after 12 months.Results. After one-year follow-up, a significant decrease in all-cause mortality was obtained in the first group in comparison with the second one: 3 (4,17%) and 18 (26,87%) deaths, respectively (p=0,021).In addition, in group II, a relationship was found between the death and absence of anticoagulant therapy (odds ratio, 7,68; 95% confidence interval, 1,59-37,03; p=0,01). The ROC analysis confirmed the relationship between the absence of anticoagulant therapy and death, while the regression quality was good (area under the curve, 0,77, sensitivity — 94,74%, specificity — 59,17%).Conclusion. Comprehensive ambulatory monitoring program for AF patients after cardioembolic stroke has proven high effectiveness, and its widespread practice is an urgent task of modern healthcare.

The advances of biomedicine include the new technologies, diagnosis and treatment techniques, as well as the practical use of new types of biological targets, in particular, nucleic acids. Genomic deoxyribonucleic acid (DNA), extracellular DNA (exDNA) and microbiome DNA obtained from different types of samples (tissues, blood and its derivatives, feces, etc.) are used as objects of genetic research. The use of new technologies for DNA analysis required the development of standardized methods for processing biological samples in order to obtain high-quality DNA samples. The research uses various methods for collecting, preparing samples and storing various DNA-containing biomaterials and isolated DNA, as well as methods for assessing the quality of samples and biobank standards. It is obvious that the use of uniform standards will allow large-scale genetic research on the basis of biobanks and research laboratories. Specialists from professional organizations such as International Society for Biological and Environmental Repositories (ISBER), Biobanking and BioMolecular Resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC), European, Middle Eastern & African Society for Biopreservationa and Biobanking (ESBB) and the Russian National Association of Biobanks and Biobanking Professionals.

This article aims at contributing to the current debate over the effects of illicit transnational activities on states. Recent avenues of conceptualizing transnational organized crime call for defining it as an economic activity with the scope of profit, rather than a criminal activity. Illicit transnational business activities largely follow the trends in development of legal business. The transnational criminal enterprises emerged in parallel to the growth of multinational corporations, making use of the same opportunities as legal business did. The article discusses violence by illicit enterprises and reviews current theoretical debate on the linkages between illicit enterprises and the state. The paper then proceeds with an empirical analysis of the effects of the presence of illicit enterprises on state weakness. We have hypothesized that weak states may have higher presence of criminal businesses. The findings generally confirm significant correlation between the two variables. State fragility is positively correlated with the presence of organized crime. Testing these results against empirical evidence partially confirms the findings. However, this correlation might be weakened by the observation that the presence of illicit enterprises alone does not determine state fragility or strength.

Aberrant methylation of gene promoter regions is the main epigenetic change characterizing colorectal cancer. Methylation levels of 42 CpG-sites of promoter regions of the MGMT, APC and CDH13 genes in colorectal cancer were studied in comparison with methylation levels of the adjacent normal tissue in 25 patients. Pyrosequencing showed an increase in methylation levels of promoter regions of the MGMT, APC and CDH13 genes in tumor samples by 3 to 5 times. These tumor samples were screened for activating SNP-mutations in the KRAS (40 %), NRAS (0 %) and BRAF (0 %) oncogenes. SNP-mutations in the KRAS gene were accompanied by hypermethylation of one or more promoters of the studied genes. Association of this epigenetic index with tumor metastasis was proved. The data on an increase in methylation of the promoter regions of oncosupressor genes can be used as sensitive prognostic markers of progression and metastasis of colorectal cancer.

In the article the calculation formulas for determination of unloadings (finishings loadings) of wheels and bendings of a spring suspension of 8-wheel electric locomotive DS 3 with the hauling transmission of the second kind at the transmission of tractive forces from the bogies to the body through sloping tractions are presented. Numerical calculations are executed on the example of mainline freight-and-passenger electric locomotive DS 3.

Транснациональная организованная преступность в XXI веке представляет глобальную проблему в связи с вызовами международной безопасности и развития. Эта проблема требует комплексного ответа со стороны международного сообщества. Мир без преступности является одним из ценностных ориентиров человеческого развития в условиях глобализации. Конвенция ООН против транснациональной организованной преступности (2000 г.) предложила механизмы по предупреждению и борьбе с транснациональными преступлениями, сформировала принципы универсального понимания криминальных угроз и императивов их преодоления на многосторонней основе. Summary: Transnational organized crime in the 21st century constitutes a global threat to international security and development, thus entailing a multifaceted respond from the international community. The world without crime has become a crucial value of the mankind development agenda within logic of globalization. The UN Convention against Transnational Organized Crime (2000) has provided a framework for international cooperation, formulated principles of universal understanding of criminal threats and importance of combatting them on a multilateral basis.

A series of natural and novel aspartyl derivatives of histamine were obtained by the classical peptide chemistry methods in a solution. During the synthesis of Nacetylaspartylhistamine easy and spontaneously cyclization of the protected Ac-AspOBzl into succinimide derivative was observed even after one day storage.

Introduction: Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD., Methods: In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients., Results: Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1., Conclusion: These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Naessens, Demuynck, Vershinina, Efimova, Saviuk, De Smet, Mishchenko, Vedunova, Krysko, Catanzaro and Krysko.)

Ferroptosis has gained interest due to it immunogenicity and the higher sensitivity of cancer cells to it. However, it was recently shown that ferroptosis in tumor-associated neutrophils leads to immunosuppression and negatively impacts therapy. Here, we discuss the potential implications of the two sides (friend versus foe) of ferroptosis in cancer immunotherapy., Competing Interests: Authors declare no conflict of interests., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Gliomas, the most frequent type of primary tumor of the central nervous system in adults, results in significant morbidity and mortality. Despite the development of novel, complex, multidisciplinary, and targeted therapies, glioma therapy has not progressed much over the last decades. Therefore, there is an urgent need to develop novel patient-adjusted immunotherapies that actively stimulate antitumor T cells, generate long-term memory, and result in significant clinical benefits. This work aimed to investigate the efficacy and molecular mechanism of dendritic cell (DC) vaccines loaded with glioma cells undergoing immunogenic cell death (ICD) induced by photosens-based photodynamic therapy (PS-PDT) and to identify reliable prognostic gene signatures for predicting the overall survival of patients. Analysis of the transcriptional program of the ICD-based DC vaccine led to the identification of robust induction of Th17 signature when used as a vaccine. These DCs demonstrate retinoic acid receptor-related orphan receptor-γt dependent efficacy in an orthotopic mouse model. Moreover, comparative analysis of the transcriptome program of the ICD-based DC vaccine with transcriptome data from the TCGA-LGG dataset identified a four-gene signature (CFH, GALNT3, SMC4, VAV3) associated with overall survival of glioma patients. This model was validated on overall survival of CGGA-LGG, TCGA-GBM, and CGGA-GBM datasets to determine whether it has a similar prognostic value. To that end, the sensitivity and specificity of the prognostic model for predicting overall survival were evaluated by calculating the area under the curve of the time-dependent receiver operating characteristic curve. The values of area under the curve for TCGA-LGG, CGGA-LGG, TCGA-GBM, and CGGA-GBM for predicting five-year survival rates were, respectively, 0.75, 0.73, 0.9, and 0.69. These data open attractive prospects for improving glioma therapy by employing ICD and PS-PDT-based DC vaccines to induce Th17 immunity and to use this prognostic model to predict the overall survival of glioma patients., (© 2022. The Author(s).)

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in vivo on mice, translation into the clinic remains challenging. A major hindrance in antitumor research is the poor predictive ability of classic 2D in vitro models, which do not consider tumor biological complexity, such as the contribution of the tumor microenvironment (TME), which plays a crucial role in immunosuppression and cancer evasion. In this review, we describe different tumor models, from 2D cultures to organ-on-a-chip technology, as well as spheroids and perfusion bioreactors, all of which mimic the different degrees of the TME complexity. Next, we discuss how 3D cell cultures can be applied to study ICD and how to increase the translational potential of the ICD inducers. Finally, novel research directions are provided regarding ICD in the 3D cellular context which may lead to novel immunotherapies for cancer.

Background: The authors describe the developmental process of intravenous anti-COVID-19 hyperimmune immunoglobulin from anti-SARS-CoV-2 neutralizing antibody-containing plasma. Furthermore, the authors investigated its safety and protective activity in animal models. Materials & methods: The manufacturing process included standard ethanol fractionation, chromatographic purification steps and virus removal or inactivation. Results: The authors produced pure and safe immunoglobulin for intravenous administration, with 98.1 ± 6.5 mg/ml protein content, of which 97.6 ± 0.7% was IgG. The concentration factor of SARS-CoV-2 neutralizing antibodies was 9.4 ± 1.4-times. Safety studies in animals showed no signs of acute/chronic toxicity or allergenic or thrombogenic properties. Intravenous anti-COVID-19 hyperimmune immunoglobulin protected immunosuppressed hamsters against SARS-Cov-2. Conclusion: The obtained results can allow the start of clinical trials to study the safety and efficacy in healthy adults.

Ferroptosis is a recently discovered form of regulated cell death that is morphologically, genetically, and biochemically distinct from apoptosis and necroptosis, and its potential use in anticancer therapy is emerging. The strong immunogenicity of (early) ferroptotic cancer cells broadens the current concept of immunogenic cell death and opens up new possibilities for cancer treatment. In particular, induction of immunogenic ferroptosis could be beneficial for patients with cancers resistant to apoptosis and necroptosis. However, ferroptotic cancer cells may be a rich source of oxidized lipids, which contribute to decreased phagocytosis and antigen cross-presentation by dendritic cells and thus may favor tumor evasion. This could explain the non-immunogenicity of late ferroptotic cells. Besides the presence of lactate in the tumor microenvironment, acidification and hypoxia are essential factors promoting ferroptosis resistance and affecting its immunogenicity. Here, we critically discuss the crucial mediators controlling the immunogenicity of ferroptosis that modulate the induction of antitumor immunity. We emphasize that it will be necessary to also identify the tolerogenic (ie, immunosuppressive) nature of ferroptosis, which can lead to tumor evasion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The immunogenicity of dying cancer cells determines the efficacy of anti-cancer therapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD), which is characterized by the emission of damage-associated molecular patterns (DAMPs) from dying cells. This emission can trigger effective anti-tumor immunity. Only a few photosensitizers are known to induce ICD and, therefore, there is a need for development of new photosensitizers that can induce ICD. The purpose of this work was to analyze whether photosensitizers developed in-house from porphyrazines (pz I and pz III) can induce ICD in vitro and in vivo when used in PDT. We indetified the optimal concentrations of the photosensitizers and found that, at a light dose of 20 J/cm 2 (λ ex 615-635 nm), both pz I and pz III efficiently induced cell death in cancer cells. We demonstrate that pz I localized predominantly in the Golgi apparatus and lysosomes while pz III in the endoplasmic reticulum and lysosomes. The cell death induced by pz I-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) but not by ferrostatin-1 and DFO (ferroptosis inhibitors) or by necrostatin-1 s (necroptosis inhibitor). By contrast, the cell death induced by pz III-PDT was inhibited by z-VAD-fmk and by the necroptosis inhibitor, necrostatin-1 s. Cancer cells induced by pz I-PDT or pz III-PDT released HMGB1 and ATP and were engulfed by bone marrow-derived dendritic cells, which then matured and became activated in vitro. We demonstrate that cancer cells, after induction of cell death by pz I-PDT or pz III-PDT, are protective when used in the mouse model of prophylactic tumor vaccination. By vaccinating immunodeficient mice, we prove the role of the adaptive immune system in protecting against tumours. All together, we have shown that two novel porphyrazines developed in-house are potent ICD inducers that could be effectively applied in PDT of cancer.

Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR ( Gipr -/- BM) and GIPR / S100A8/A9 (Gipr -/- / S100a9 -/- BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing Gipr fl/fl mice and Lyz2 cre/+ mice ( LysM ΔGipr ). Under both short and progressive HFD regimens, Gipr -/- BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3 + regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr -/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysM ΔGipr mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity., Competing Interests: DD has served as an advisor or consultant or speaker within the past 12 months to Boehringer Ingelheim Inc., Forkhead Biotherapeutics, Intarcia Therapeutics, Kallyope, Merck Research Laboratories, Eli Lilly Inc., Novo Nordisk Inc. Neither DD nor his family members hold stock directly or indirectly in any of these companies. GLP-2 is the subject of a patent license agreement between Shire Inc and the University of Toronto, Toronto General Hospital (UHN), and Daniel Drucker. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Efimova, Steinberg, Zvibel, Neumann, Mantelmacher, Drucker, Fishman and Varol.)

Purpose: Cystic fibrosis (CF) is one of the most common monogenic diseases with an autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with CF disease. The aim of this study was to develop the custom panel for the diagnosis of heterozygous carriage of polymorphic variants in the CFTR gene and to establish their allelic frequencies (AF) in one of the Russian regions where ethnic Russians predominate., Patients and Methods: The diagnostic panel was designed on the basis of data from the register of CF patients in Russia for 2017 and validated on 22 blood samples of patients with previously genetically established CF. The study participants (n=642) for CF variants estimation were randomly selected from the population-based cohort study ESSE-Vologda. Genotypes were determined by real-time PCR on the QuantStudio 12K Flex Real-Time PCR System. Data processing was performed using the TaqMan Genotyper Software., Results: The proposed diagnostic panel allowed simultaneous analysis of 60 variants of the CFTR gene. A total of 23 carriers of the following variants were identified among 642 participants: F508del (rs113993960) with a frequency of 2.02%, L138ins (rs397508686) and 394delTT (rs121908769) - 0.47%, CFTRdele2.3 (c.54-5940_273+10250del21080; p.S18Rfs*16) - 0.31%, R117H (rs78655421), and G542X (rs113993959) - 0.16%. The frequency of heterozygotes in the Russian population was 3.58% or 1:28 (CI95%: 2.28-5.33% by Clopper-Pearson exact method)., Conclusion: High frequency of heterozygous CFTR variants carriers and availability of highly productive diagnostic panel for detection of CFTR variants suggest the prospect of carrier screening for some common CF variants among Russian population., Competing Interests: The authors declare that they have no competing interests., (© 2020 Kiseleva et al.)