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Introduction: Despite the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), most patients with non-small-cell lung cancer (NSCLC) eventually develop resistance to these agents. Notably, EGFR _C797S mutations confer resistance to the third-generation EGFR-TKI osimertinib and no approved post-osimertinib targeted pharmacology options are currently available. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI that selectively targets EGFR-activating ( EGFR m) and resistance mutations (including EGFR_C797S) with nanomolar potency while sparing wild-type EGFR in vitro. Methods: In vitro activity of BLU-945 as a single agent and in combination with osimertinib was tested in engineered EGFR -mutant cell lines as well as patient-derived cells and patient-derived organoids. In vivo activity was evaluated in osimertinib-resistant patient-derived xenograft mouse models. Three patient cases from the global, first-in-human, phase I/II SYMPHONY trial (NCT04862780) demonstrating the clinical efficacy of BLU-945 were reported. Results: In vitro BLU-945 demonstrated inhibited cell viability and growth of EGFR -mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR _L858R/C797S and third line: EGFR _ex19del/T790M/C797S and L858R/T790M/C797S) both as monotherapy and in combination with osimertinib. BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial. Conclusion: Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFR m NSCLC progressing on previous EGFR-TKIs.

Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80-100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.

In order to study the point of view of doctors supervising patients with dementia regarding the methods and tactics of treating diseases that occur with severe cognitive impairment, their experience in the use of drugs and criteria for choosing a drug for long-term treatment of dementia, an online survey of 197 specialists was conducted.The majority of Russian physicians surveyed prefer basic therapy for dementia, while the main criteria for choosing a drug for long-term therapy are effectiveness and safety of the drug. Despite the absence of drugs capable of complete curing of dementia, Russian doctors have certain expectations and goals when prescribing therapy, in particular, the hope for the longest possible preservation of the quality of life and capacity of patients, as well as slowing down the progression of the disease. 90% of respondents consider it necessary to continue (and even start) therapy even at a severe stage, despite the depletion of the effect. Memantine has become the main drug of choice in different regions of Russia as a drug with a wide range of registered indications, the fewest side effects and a low percentage of patient refusals.

Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ pathogenesis was found. Clinical features of schizophrenia (SCZ) have been demonstrated in patients with several lysosomal storage disorders (LSDs). Taking into account the critical role of lysosomal function for neuronal cells’ lysosomal dysfunction could be proposed in SCZ pathogenesis. The current study analyzed lysosomal enzyme activities and the alpha-synuclein level in the blood of patients with late-onset SCZ. In total, 52 SCZ patients with late-onset SCZ, 180 sporadic Parkinson’s disease (sPD) patients, and 176 controls were recruited. The enzymatic activity of enzymes associated with mucopolysaccharidosis (alpha-L-Iduronidase (IDUA)), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (GALC), glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase)) and concentration of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), and lysosphingomyelin (LysoSM)) were measured using LC-MS/MS. The alpha-synuclein level was estimated in magnetically separated CD45+ blood cells using the enzyme-linked immunosorbent assay (ELISA). Additionally, NGS analysis of 11 LSDs genes was conducted in 21 early-onset SCZ patients and 23 controls using the gene panel PGRNseq-NDD. Decreased ASMase, increased GLA activities, and increased HexSpn, LysoGb3, and LysoSM concentrations along with an accumulation of the alpha-synuclein level were observed in late-onset SCZ patients in comparison to the controls (p < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I (IDUA (rs532731688, rs74385837) and type III (HGSNAT (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy (ARSA (rs201251634)) were identified in five patients from the group of early-onset SCZ patients but not in the controls. Our findings supported the role of sphingolipid metabolism in SCZ pathogenesis. Aberrant enzyme activities and compounds of sphingolipids associated with ceramide metabolism may lead to accumulation of alpha-synuclein and may be critical in SCZ pathogenesis.

Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause different pathologies as single protein can adopt various amyloidogenic, disease-specific conformations. The conformation governs the interaction of amyloid aggregates with other proteins that are prone to misfolding and, thus, determines disease-specific spectrum of concomitant pathologies. In this regard, a detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins become a key point for drafting of precise description of the disease. The majority of clinical cases of neuronal proteinopathies is caused by the aggregation of rather limited range of amyloidogenic proteins. Here, we provided the characterization of pathologies, related to the aggregation of amyloid β peptide, tau protein, α-synuclein, TDP-43, and amylin, giving a short description of pathologies themselves, recent advances in elucidation of misfolded protein conformation, with emphasis on those protein aggregates extracted from biological samples, what is known about the interaction of this proteins, and the influence of this interaction on the progression of underlying disease and comorbidities.

Summary. The aim of the study was to identify nosologically nonspecific signs of hospitalism in patients of a gerontopsychiatric hospital and to develop, on their basis, a method for screening diagnostics of hospitalism.Materials and methods. We examined 194 inpatients aged 55 to 91 years, hospitalism was detected in 102 people, 92 people made up the comparison group. The survey was carried out at the stage of preparation for discharge in the form of a semi-structured interview, supplemented by the collection of anamnestic and follow-up data.Results. The most common signs of hospitalism in this sample were the deterioration of the mental and somatic state before discharge (78% of the examined patients of the main group, a confidence interval (CI) of 68–85%), a long duration of the current hospitalization (73%, CI 64–82%), violations of compliance (73%, CI 63-81%), long duration of inpatient treatment in anamnesis (71%, CI 61-80%), deterioration soon after discharge (67%, CI 52-80%), a large number of hospitalizations during the entire period of illness (67%, CI 57-76%), lack of discharge intention (62%, CI 51-72%), tendency to increase the duration of hospitalizations (54%, CI 43-64%), high level of anxiety before discharge (50% , CI 34-66%), reduction in the intervals between hospitalizations (49%, CI 38-59%), p

Introduction: Despite the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), most patients with non-small-cell lung cancer (NSCLC) eventually develop resistance to these agents. Notably, EGFR _C797S mutations confer resistance to the third-generation EGFR-TKI osimertinib and no approved post-osimertinib targeted pharmacology options are currently available. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI that selectively targets EGFR-activating (EGFR m) and resistance mutations (including EGFR_C797S) with nanomolar potency while sparing wild-type EGFR in vitro. Methods: In vitro activity of BLU-945 as a single agent and in combination with osimertinib was tested in engineered EGFR -mutant cell lines as well as patient-derived cells and patient-derived organoids. In vivo activity was evaluated in osimertinib-resistant patient-derived xenograft mouse models. Three patient cases from the global, first-in-human, phase I/II SYMPHONY trial (NCT04862780) demonstrating the clinical efficacy of BLU-945 were reported. Results: In vitro BLU-945 demonstrated inhibited cell viability and growth of EGFR -mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR _L858R/C797S and third line: EGFR _ex19del/T790M/C797S and L858R/T790M/C797S) both as monotherapy and in combination with osimertinib. BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial. Conclusion: Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFR m NSCLC progressing on previous EGFR-TKIs. [ABSTRACT FROM AUTHOR]

Introduction There is no consensus about whether late-onset schizophrenia(LOS) is a type of schizophrenia or a secondary psychotic disorder. One of the theories of the occurrence of late-onset psychoses is neurodegeneration caused by the imbalance of proteostasis. Objectives To study the concentration and expression of alpha-synuclein in patients with LOS compared with controls. Methods The study involved 42 patients with the ICD-10 criteria of schizophrenia with the onset of the disease after 45 years and 104 controls with no dementia and severe somatic pathology, comparable in age and gender. The alpha-synuclein level was estimated in a lymphocytic cell fraction from patients with LOS N=42 and controls N=104 using the Human alpha-synuclein ELISA kit. The expression of the SNCA gene was studied in 22 LOS patients and 22 controls and determined by PCR using the SYBR Green Supermix kit and the CFX96 instrument in comparison with the referent genes using previously developed primers. LOS group underwent psychopathological examination including scales. Statistics: SPSS 12.0; the Mann–Whitney test; exponential regression analysis; data is given as median (min–max). The level of significance was set at p

The amount of publications devoted to the endothelial cells, on the one hand, and neurological diseases, on the other hand, has been growing rapidly in recent years. Nevertheless, the relationship between the endothelial monolayer and the cells of the nervous system remains poorly studied. This review presents the available information about endothelial markers, molecular and cellular mechanisms for maintaining the integrity of the endothelial monolayer and the violations in some acute and chronic neuropsychiatric diseases. At the molecular level, the most important pathogenetic link in endothelial dysfunction is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species. Genetic and epigenetic factors that cause these disorders and their cause-and-effect relationships are considered. Of the genetic diseases, the most studied are monogenic diseases associated with impaired blood-brain barrier integrity: this is a deficiency of protein molecules that ensure glucose transport, structural and functional integrity of tight junctions and the basement membrane of endothelial cells themselves, as well as mutations in pericytes and smooth muscle cells. Mutations that increase the risk of developing known neurodegenerative diseases, but are also the cause of cerebrovascular pathology, are less studied. The small vessel diseases constitute a whole group of primarily epigenetically caused diseases, the clinical consequence of which is often vascular dementia. Special attention is paid to one of the least studied problems—the pathogenesis of toxicological diseases that occur at different times after acute and chronic organophosphate poisoning. Microangiopathies caused by damage to the endothelium in the central and peripheral nervous systems can be the main cause for the development of delayed effects in organophosphate poisoning. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of the nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

Nitric oxide plays an important role in regulating adaption of the model alga Chlamydomonas reinhardtii to various environmental stresses. One response to abiotic stresses is the accumulation of protective molecules such as proline and putrescine. The NO treatment led to a significant accumulation of proline in cells. Quantitative real-time expression analysis of proline metabolic genes in NO-treated cells showed a prolonged upregulation of the gene encoding γ-glutamyl kinase 1 (GGK1) in the glutamate biosynthetic pathway. Furthermore, truncated hemoglobin 2 (THB2)-underexpressing strains with an enhanced endogenous NO demonstrated a higher proline content and GGK1 mRNA abundances than the wild type. In contrast, transcription of the gene encoding ornithine δ-aminotransferase in the ornithine pathway of proline biosynthesis decreased after treatment with NO. This suggests the predominance of the glutamate pathway over the ornithine pathway. We also found that the expression of the proline dehydrogenase gene encoding a key enzyme in proline catabolism was downregulated in NO-treated cells. Chlamydomonas reinhardtii exposed to exogenous NO also showed an increased ornithine decarboxylase 2 mRNA and putrescine content. Our findings indicate a clear link between changes in NO application and proline and putrescine content via transcriptional regulation of respective enzymes.

Authors describe a new software and computer complex designed and developed for the processing of the data of the whole genomes of mycobacterium tuberculosis with the purpose of obtaining information about the profile of tuberculosis resistance and virulence.

The work annotates the goals and objectives of the planned joint Russian-Israeli research project aimed at a comprehensive assessment of the data obtained during the examination of patients with mild cognitive decline and autism spectrum disorders. The process of their analysis will be based on complex methods, the effective use of which requires readily available means of operating with clinical and biological data, which, in turn, can be implemented through modern cloud and high-performance computing technologies. It is planned to use the new approach associated with the use of newSQL database as an API, and then use the distributed computing tools for working with heterogeneous data, which will lead to features in the analysis of correlations in multidimensional data arrays. For this purpose it is planned to use the methods of multidimensional statistical analysis and modern methods of machine learning.

Introduction Anti-NMDA-receptor encephalitis is a severe rare acute form of encephalitis caused by an autoimmune process with the synthesis of autoantibodies to the glutamate receptors. The average age of onser is estimated to be 23-25 years. A typical clinical picture consist of prodromal, psychotic, areactive, hyperkinetic phases, and a phase of gradual regression of symptoms. The disease usually lasts for a several weeks with spontaneous recovery or fatal outcome and caused by neoplastic process. Our case demonstrates that the course of anti-NMDAR encephalitis is possible at more mature age in the form of a long process with cultural features, without significant catadrome, inflammation and associated neoplastic process. Objectives 50-year-old Buddhist Buryat woman with complaints about hypomnesia, anosmia and dissomnia. The disease began with impaired consciousness, disorientation, seizures and memory loss 4 years ago. Then after a visit of Lama, the symtoms described above spontaneously reduced and schizophrenia-like psychosis developed (voice of Lama in the head, a belief in the existence of super-powers, disorganized behavior), mild neurological and severe neurocognitive symptoms, weight loss, intolerance to antipsychotics in minimal daily doses. Methods Examination included: CBC, metabolic panel, coagulogram, tumor markers, CSF, MRI, PET, specialists. Results CBC, metabolic blood analysis, tumor markers - within the reference values. CSF: cytosis 9/3, glucose 5.5 mmol/l, Pandi++, Nonnet-Apeltau+, antibodies to the NMDA receptor - 8. MRI: signs of the consequences of encephalitis. PET: no signs of metabolic activity of the malignant process. Conclusions The diagnosis of anti-NMDA-receptor-encephalitis was confirmed by the laboratory and clinical criteria despite unususal course and age. The trigger role of herpes is possible, but not verified. Disclosure No significant relationships.

Introduction Anti-NMDA-receptor encephalitis is a severe rare acute form of encephalitis caused by an autoimmune process with the synthesis of autoantibodies to the glutamate receptors. The average age of onser is estimated to be 23-25 years. A typical clinical picture consist of prodromal, psychotic, areactive, hyperkinetic phases, and a phase of gradual regression of symptoms. The disease usually lasts for a several weeks with spontaneous recovery or fatal outcome and caused by neoplastic process. Our case demonstrates that the course of anti-NMDAR encephalitis is possible at more mature age in the form of a long process with cultural features, without significant catadrome, inflammation and associated neoplastic process. Objectives 50-year-old woman complained about hypomnesia, anosmia and dissomnia. The disease began with impaired consciousness, disorientation, seizures and memory loss 4 years ago. After 3 weeks IgG to the herpes simplex and cytomegalovirus were detected. Then after a discharge with no improvement and visit of Lama, the symtoms described above spontaneously reduced and schizophrenia-like psychosis developed, accompanied by mild neurological and severe neurocognitive symptoms, weight loss, intolerance to antipsychotics in minimal daily doses. This state was mantained till 2020. Methods Examination included: CBC, metabolic panel, coagulogram, tumor markers, CSF, MRI, PET, specialists. Results CBC, metabolic blood analysis, tumor markers - within the reference values. CSF: cytosis 9/3, glucose 5.5 mmol/l, Pandi++, Nonnet-Apeltau+, antibodies to the NMDA receptor - 8. MRI: signs of the consequences of encephalitis. PET: no signs of metabolic activity of the malignant process. Conclusions This case brings additional data about a couse, age of onset, duration and trigger factors for anti-NMDAR encephalitis.

In our study we have analyzed MRI of mediobasal parts of temporal lobes in healthy volunteers and patients with Alzheimer disease in early stage based on medical literature and our experience. We have determined method of defnition and volume evaluation of different hippocampal subfelds.

Abstract Background The PII proteins constitute a large superfamily, present in all domains of life. Until now, PII proteins research in Chloroplastida (green algae and land plants) has mainly focused on post-translation regulation of these signal transductors. Emerging evidence suggests that PII level is tightly controlled with regard to the nitrogen source and the physiological state of cells. Result Here we identify that a balance of positive (nitrate and nitrite) and negative (nitric oxide) signals regulates Chlamydomonas GLB1. We found that PII expression is downregulated by ammonium through a nitric oxide (NO)-dependent mechanism. We show that nitrate reductase (NR) and its partner, truncated hemoglobin 1 (THB1), participate in a signaling pathway for dual control of GLB1 expression. Moreover, NO dependent guanilate cyclase appeared to be involved in the negative control of GLB1 transcription. Conclusion This study has revealed the existence of the complex GLB1 control at transcription level, which is dependent on nitrogen source. Importantly, we found that GLB1 gene expression pattern is very similar to that observed for nitrate assimilation genes, suggesting interconnecting/coordinating PII-dependent and nitrate assimilation pathways.

Tere are 44 patients (5 males and 39 females), aged 56 to 90 years were included in the study. To assess the tolerability and safety of the drug, undesirable events were recorded, associated and not associated with taking the drugwith taking the drug, a physical examination of patients was performed, an ECG was recorded and a biochemical blood test was performed at each visit of the patient to the center. During the observation period, two undesirable events chronologically associated with taking the drug were recorded During the study, none of the patients was excluded from the program due to the development of side effects and none of the patients refused to take the drug. We did not fnd any statistically signifcant increase in the incidence of cardiac pathology in patients taking the study drug, nor worsening of the already existing symptoms on the background of taking the drug for six months. Te observed growth trends in the level of blood creatinine a give grounds to recommend monitoring of kidney function in the patients taking the drug. In general, noogerone showed good tolerability, despite the elderly age of its patients and the high prevalence of concomitant somatic diseases in the sample.

One of the most important parts in biomarkers research is finding of atrophic changes in strategic for cognition brain structures. In the study one of the structural neurovisual bi-omarkers of neuronal damage were analised - MRI visual scale of atrophy. 94 patients with early signs of Alzheimer disease were examined. Using of visual scales show atrophy slight and mild of mediobasal temporal lobe in 64 patients (68%), interuncal distance was Increased in 27 patients (28%). Atrophic changes of the cortex of parietal lobe were not found in most of patients.

The article discusses the problem of long-term therapy of dementia, provides information on factors playing a role in the formation of commitment to therapy in patients with Alzheimer’s disease, discusses factors that influence the organization of care to patients with dementia. The article presents data on the clinical and economical effectiveness of akatinol memantine and opportunities to improve adherence to treatment at application of a once-daily memantine

In recent years, new data in neuroanatomy of patients with various neurodegenerative diseases, including Alzheimer’s disease, were obtained usingmagnetic resonance morphometry. Morphometry of the brain structures using MRI became widespread because of the introduction into clinical practice of a high-resolution mode and the emergence of the voxel transformations of three-dimensional data. The analysis of the brain structures is made more precise with the help of such programs. They help to avoid the «subjectivity» of the operator when the so-called «manual» method of the separation of brain structures. In the current study voxel-based morphometry method revealed a number of morphological characteristicsin the group of patients with dementia of Alzheimer’s type, namely, the gray matter atrophy of the cerebral cortex, subcortical gray matter structures, structures of the white matter of the brain, and the increase in the volume of the ventricular system of the brain. These results are connected with the functional features in this disease.

The objective of this study was to evaluate the efficacy of the noojerone in patients with moderate Alzheimer disease and to compare obtained data with results of clinical trials of memantine. This was a 24-week open - label post-marketing clinical trial conducted in Department of Geriatric Psychiatry St. Petersburg V.M. Bekhterev Psychoneurological Research Institute. Participants were 44 outpatients with moderate AD and Mini-Mental State Examination scores of 10-19 at start - point. This study have demonstrated efficacy in modifying course of AD and no significant deterioration activities of daily living and frequency and severity of behavioral symptoms, comparable with the results of memantine clinical trials.

There are researched psychosocial components of hospitalism in elderly patients with affective disorders. We were using clinical and psychological semi-structured interview as a method focused on the investigation of relations in the parent and the relevant families of patients. In addition there were being used personality and family relationships questionnaires, locus of control personality research. According to the survey, there have been found out signs indicating de-emphasis of family, reducing of emotional involvement in family relationships and distancing from relatives in patients with hospitalism compared with the control group.

Free radical processes, the degree of their intensification are one of the main pathogenetic factors in the development of many diseases in old age. The purpose of this study was to identify the severity of OS in patients with mild cognitive decline (presumably Alzheimer’s disease), with mild cognitive decline in vascular etiology, in persons suffering from a depressive disorder compared to a control group of the same age. A special vulnerability of the glutathione system was found in patients of all the examined groups, in particular, in people with depression, in comparison with healthy elderly people. A decrease in the activity of glutathione peroxidase, significantly more pronounced in the examined patients with late depression, was revealed. The data obtained agree with the IDEA existing in modern science on the role of OS as a key element in the pathogenesis of depressive states.

This paper is devoted to some of the infrastructural problems of neuroinformatics in the context of existing analog-to-digital systems and high-performance solutions. We surveyed results and analyzed some of the existing methods required in various experiments. Special attention was devoted to the problem of the human brain simulation, based on a combination of digital and analog subsystems. Paper shows various approaches to modeling of interactions between brain neurons and explores different algorithms. We consider different applications of cloud solutions to neuroinformatics problems. Paper highlights areas of particular interest such as working with external storage, distributed data processing and visualization of acquired results. For each of them we survey existing options for creating cloud-based distributed computing solutions that can solve important challenges faced by researchers in their work.

The traditional approach to human brain modeling suggests modification of modern systems and microcircuits as long as their performance reaches a permissible limit. A different hybrid approach is based on neuromorphic computing. The idea we utilize is combination of artificial neural networks with specialized microcircuits. The architecture of the microchip needs to reproduce the mechanisms of the human brain and to be a kind of hardware support for neural networks. Existing models of the brain even on powerful supercomputers require significant computation time and are not yet able to solve problems in real time. Since the human brain consists of two parts with different functions and different data processing principles, there is a very promising approach which suggests combining digital and analog systems into single one. In current collaboration we incorporate some results of study of activity of human brain as a base of building of hybrid computational system and foundation to the approach of running it.