Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles ...to improve current treatments is represented by the impermeability of the blood vessels residing within nervous tissue as well as of the new vascular net generating from the tumor, commonly referred to as blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively. In this review, we focused on established and emerging strategies to overcome the blood-brain barrier to increase drug delivery for brain cancer. To date, there are three broad strategies being investigated to cross the brain vascular wall and they are conceived to breach, bypass, and negotiate the access to the nervous tissue. In this paper, we summarized these approaches highlighting their working mechanism and their potential impact on the quality of life of the patients as well as their current status of development.
Dendritic cells (DCs) have shown great potential as a component or target in the landscape of cancer immunotherapy. Different in vivo and ex vivo strategies of DC vaccine generation with different ...outcomes have been proposed. Numerous clinical trials have demonstrated their efficacy and safety in cancer patients. However, there is no consensus regarding which DC-based vaccine generation method is preferable. A problem of result comparison between trials in which different DC-loading or -targeting approaches have been applied remains. The employment of different DC generation and maturation methods, antigens and administration routes from trial to trial also limits the objective comparison of DC vaccines. In the present review, we discuss different methods of DC vaccine generation. We conclude that standardized trial designs, treatment settings and outcome assessment criteria will help to determine which DC vaccine generation approach should be applied in certain cancer cases. This will result in a reduction in alternatives in the selection of preferable DC-based vaccine tactics in patient. Moreover, it has become clear that the application of a DC vaccine alone is not sufficient and combination immunotherapy with recent advances, such as immune checkpoint inhibitors, should be employed to achieve a better clinical response and outcome.
Nickel-based superalloys are known for their high-temperature performance regarding oxidation, creep and fatigue resistance. For this reason, they are widely used as structural components in the ...aerospace industry. However, because of these properties, they are difficult to machine, and normally a rigorous control of the surface integrity and residual stresses are required to avoid structural premature failures. Residual stresses are present in all mechanical components regardless of the manufacturing process applied, and they are either of thermal or mechanical origins. In machining several variables affect the residual stresses, but the tool quality is one that is most influential. The present work studies the influence of the wear of coated cemented carbide tools on the surface integrity of Inconel 718 alloy in the face milling process. Tools with different stages of wear were tested under finishing, roughing, and moderate machining conditions. During milling tests, the machining forces and cutting temperatures were monitored, the latter by two different techniques, using a thermal camera and with J-type thermocouples welded on the workpiece surface close to the cutting region. The surface roughness, microhardness, and residual stresses were measured after each machining test. The results showed that there is a close relationship between the tool wear and the residual stresses that varied from compressive to tensile stresses – the latter being of thermal origin. A direct relationship between tool wear and machining forces and cutting temperature were also observed.
•The artificially produced tool wear types had a significant influence on the machinability.•The cutting temperatures were correlated with the residual stresses in the workpiece.•The cutting conditions significantly influenced the hardness of the machined surface.
Malignant melanoma is one of the most aggressive forms of cancer and the leading cause of death from skin tumors. Given the increased incidence of melanoma diagnoses in recent years, it is essential ...to develop effective treatments to control this disease. In this regard, the use of cancer vaccines to enhance cell-mediated immunity is considered to be one of the most modern immunotherapy options for cancer treatment. The most recent cancer vaccine options are mRNA vaccines, with a focus on their usage as modern treatments. Advantages of mRNA cancer vaccines include their rapid production and low manufacturing costs. mRNA-based vaccines are also able to induce both humoral and cellular immune responses. In addition to the many advantages of mRNA vaccines for the treatment of cancer, their use is associated with a number of challenges. For this reason, before mRNA vaccines can be used for the treatment of cancer, comprehensive information about them is required and a large number of trials need to be conducted. Here, we reviewed the general features of mRNA vaccines, including their basis, stabilization, and delivery methods. We also covered clinical trials involving the use of mRNA vaccines in melanoma cancer and the challenges involved with this type of treatment. This review also emphasized the combination of treatment with mRNA vaccines with the use of immune-checkpoint blockers to enhance cell-mediated immunity.
Unlike traditional cancer therapies, cancer vaccines (CVs) harness a high specificity of the host's immunity to kill tumor cells. CVs can train and bolster the patient's immune system to recognize ...and eliminate malignant cells by enhancing immune cells' identification of antigens expressed on cancer cells. Various features of antigens like immunogenicity and avidity influence the efficacy of CVs. Therefore, the choice and application of antigens play a critical role in establishing and developing CVs. Tumor-associated antigens (TAAs), a group of proteins expressed at elevated levels in tumor cells but lower levels in healthy normal cells, have been well-studied and developed in CVs. However, immunological tolerance, HLA restriction, and adverse events are major obstacles that threaten TAA-based CVs' efficacy due to the "self-protein" characteristic of TAAs. As "abnormal proteins" that are completely absent from normal cells, tumor-specific antigens (TSAs) can trigger a robust immune response against tumor cells with high specificity and without going through central tolerance, contributing to cancer vaccine development feasibility. In this review, we focus on the unique features of TAAs and TSAs and their application in vaccines, summarizing their performance in preclinical and clinical trials.
Neuronal calcium sensor-1 (NCS-1) is a four-EF-hand ubiquitous signaling protein modulating neuronal function and survival, which participates in neurodegeneration and carcinogenesis. NCS-1 ...recognizes specific sites on cellular membranes and regulates numerous targets, including G-protein coupled receptors and their kinases (GRKs). Here, with the use of cellular models and various biophysical and computational techniques, we demonstrate that NCS-1 is a redox-sensitive protein, which responds to oxidizing conditions by the formation of disulfide dimer (dNCS-1), involving its single, highly conservative cysteine C38. The dimer content is unaffected by the elevation of intracellular calcium levels but increases to 10-30% at high free zinc concentrations (characteristic of oxidative stress), which is accompanied by accumulation of the protein in punctual clusters in the perinuclear area. The formation of dNCS-1 represents a specific Zn
-promoted process, requiring proper folding of the protein and occurring at redox potential values approaching apoptotic levels. The dimer binds Ca
only in one EF-hand per monomer, thereby representing a unique state, with decreased α-helicity and thermal stability, increased surface hydrophobicity, and markedly improved inhibitory activity against GRK1 due to 20-fold higher affinity towards the enzyme. Furthermore, dNCS-1 can coordinate zinc and, according to molecular modeling, has an asymmetrical structure and increased conformational flexibility of the subunits, which may underlie their enhanced target-binding properties. In HEK293 cells, dNCS-1 can be reduced by the thioredoxin system, otherwise accumulating as protein aggregates, which are degraded by the proteasome. Interestingly, NCS-1 silencing diminishes the susceptibility of Y79 cancer cells to oxidative stress-induced apoptosis, suggesting that NCS-1 may mediate redox-regulated pathways governing cell death/survival in response to oxidative conditions.
The article discusses methods of processing and storing data archive used in the digital university. Disadvantages of these methods are found. As a result, a fundamentally new method of processing ...and storing information archive in a constantly changing scheme database is proposed. This method uses mivar technologies. The multidimensional space structure has been developed to store the data archive. This multidimensional space describes the temporal relational model. For processing data, archive is proposed scheme for selecting the subspace and converting it into relations. A method of transformation of relational databases into multidimensional mivar space for efficient execution of operations on temporal data with changing structure is proposed. The transition to a multidimensional space allows us to describe the process of changing temporal data and their structure in a unified way. As a result, the time required to adapt the database schema and the redundancy of information storage are reduced. The results of this work are used in the human resource management database of BMSTU.
The article deals with the creation of training courses scenarios. The main objective of the development of software components of the training system is the ability to create an algorithmic ...structure of training fragments representing test tasks, workshops and just information support. On the basis of this instrumental environment a practical work on the topic of statistical analysis, modeling and forecasting of passenger flows in the urban route network has been developed. The study of passenger flows is considered as one of the important stages of designing and organizing the route network of the urban passenger transport. The purpose of this article is to develop a training scenario aimed at identifying hidden patterns of passenger flows at stopping points of bus routes with the subsequent development stage of associated models of random flows with specified autocorrelation properties .In addition to the auto-correlation estimation and spectral analysis, the main components analysis which allows to reduce significantly the dimensionability of the multidimensional time series of passenger flows at the stopping points of the route is carried out.
Caveolin-1 is a cholesterol-binding scaffold protein, which is localized in detergent-resistant membrane (DRM) rafts and interacts with components of signal transduction systems, including visual ...cascade. Among these components are neuronal calcium sensors (NCSs), some of which are redox-sensitive proteins that respond to calcium signals by modulating the activity of multiple intracellular targets. Here, we report that the formation of the caveolin-1 complex with recoverin, a photoreceptor NCS serving as the membrane-binding regulator of rhodopsin kinase (GRK1), is a redox-dependent process. Biochemical and biophysical in vitro experiments revealed a two-fold decreased affinity of recoverin to caveolin-1 mutant Y14E mimicking its oxidative stress-induced phosphorylation of the scaffold protein. At the same time, wild-type caveolin-1 demonstrated a 5–10-fold increased affinity to disulfide dimer of recoverin (dRec) or its thiol oxidation mimicking the C39D mutant. The formation of dRec in vitro was not affected by caveolin-1 but was significantly potentiated by zinc, the well-known mediator of redox homeostasis. In the MDCK cell model, oxidative stress indeed triggered Y14 phosphorylation of caveolin-1 and disulfide dimerization of recoverin. Notably, oxidative conditions promoted the accumulation of phosphorylated caveolin-1 in the plasma membrane and the recruitment of recoverin to the same sites. Co-localization of these proteins was preserved upon depletion of intracellular calcium, i.e., under conditions reducing membrane affinity of recoverin but favoring its interaction with caveolin-1. Taken together, these data suggest redox regulation of the signaling complex between recoverin and caveolin-1. During oxidative stress, the high-affinity interaction of thiol-oxidized recoverin with caveolin-1/DRMs may disturb the light-induced translocation of the former within photoreceptors and affect rhodopsin desensitization.
Power units with an RBMK reactor have reached the stage of termination of operation and preparation for decommissioning. Having exceeded the assigned life of 30 years, as a result of aging of the ...graphite stack some state parameters are close to their maximum permissible value. Further operation required restoration work, which was made possible by the creation and implementation of special robotics. The evolution of the tasks in the management of the resource of RBMK reactors and their relationship with the development and implementation of robotics are described. It is noted that as RBMK power units are decommissioned the relevance of robotics will increase as the radioactive waste management activities expand.
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