Doklady Biochemistry and Biophysics最新文献

The aim of this study was to assess the baseline rates and five-years outcomes of mild cognitive impairments (MCIs) in patients with rheumatoid arthritis (RA) and comorbid anxiety and depressive disorders (ADDs) receiving traditional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone or in combination with biologic DMARDs (bDMARDs) and/or adequate psychopharmacotherapy (PPT), as well as to assess the factors associated with MCI after five years.

A total of 128 RA patients were enrolled, ADDs were diagnosed in 123 (96.1%) patients by a licensed psychiatrist. Severity of depression and anxiety was evaluated with Montgomery–Asberg and Hamilton Anxiety scales. CIs were diagnosed during clinical and psychological examination using the battery of pathopsychological and projective techniques. CI outcomes were considered favourable in cases with no CI diagnosed throughout the study and in cases of CI reversal. PPT was offered, 52 (42.3%) patients agreed. Patients were  divided into the following treatment groups: сsDMARDs (n = 39), сsDMARDs + PPT (n = 43), сsDMARDs + bDMARDs (n = 32), and сsDMARDs + bDMARDs + PPT (n = 9). Multivariable logistic regression was performed to determine factors associated with CI after five years.

MCIs were diagnosed in the majority of RA patients (73.2%), including logical thinking impairments (51.2%) and memory deficit (67.5%). At a 5-year endpoint, 74 patients were included. Total CI rates in no-PPT groups increased from 69 to 85.7% (p = 0.024) and was higher compared to PPT groups (р = 0.021, 85.7% vs 62.5%, RR 1.37). Patients with favourable CI outcomes had lower major depression prevalence and baseline Montgomery–Asberg scores, major improvement in depression symptoms, and higher rates of ADD remission after five years. Baseline DAS28 (OR 1.29, p < 0.001) was positively associated and remission of ADD negatively associated with MCI after five years (OR 0.25, p = 0.03), R² = 0.48, p < 0.001.

ADDs and MCIs are highly prevalent in RA patients. While CIs tend to persist and worsen over time, PPT is associated with lower CI rates in long-term perspective. Personalized PPT with antidepressants and neuroleptics may show potential to lessen the rates of MCIs in RA patients with ADDs.

The study aims to evaluate the clinical efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of seniprutug (BCD-180) in patients with active radiographic axial spondyloarthritis (r-axSpA, or ankylosing spondylitis).

Two hundred sixty patients with active r-axSpA and inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) were randomized into three groups to receive either seniprutug (BCD-180) 5 or 7 mg/kg, or placebo. BCD-180 was administered in the respective group dose using a 0–12–36 week regimen. The placebo group patients were switched to BCD-180 5 mg/kg at Week 24, with therapy continued at Week 36. The primary endpoint was the proportion of patients achieving 40% improvement in the Assessment in Spondyloarthritis International Society (ASAS40) score at Week 24.

The secondary endpoints included the proportion of patients achieving an ASAS20/40 response, improvement in 5 of 6 ASAS criteria (ASAS5/6), partial remission according to ASAS, ASDAS-CRP clinically important improvement in (Ankylosing Spondylitis Disease Activity Score with C-reactive protein level, ASDAS-CII) and ASDAS-CRP major improvement (ASDAS-MI). An analysis of changes over time in the disease activity status according to ASDAS-CRP, BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) scores, as well as changes over time in laboratory markers (CRP and erythrocyte sedimentation rate (ESR)) was also conducted. Safety was assessed based on the frequency and profile of adverse events (AE) and adverse reactions (AR).

The proportion of patients who achieved an ASAS40 response at Week 24 on seniprutug (BCD-180) at doses of 7 and 5 mg/kg was 51.4 and 40.8%, respectively, compared with 24% in the Placebo group (p = 0.0012 and p = 0.0417, respectively). Analysis of secondary endpoints showed that the efficacy of BCD-180 at both study doses was statistically significantly superior to placebo in patients with r-axSpA at Week 24 in the following respects: reduction in the proportion of subjects with very high disease activity (ASDAS-CRP > 3.5), achieving ASDAS-CII, ASAS20, ASAS5/6 response. A statistically significant decrease in the ASDAS-CRP, BASDAI, BASFI score, as well as CRP and ESR levels was demonstrated. Tolerability of seniprutug therapy was assessed as acceptable. The most common AEs were infusion-related reactions, most of which were mild to moderate according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events) and developed mainly during the first administration. The proportion of patients with detected binding antibodies was 5.1%. No neutralizing antibodies were detected.

Seniprutug (BCD-180) as a therapy for r-axSpA has demonstrated superiority over placebo in the clinical efficacy, a good safety profile and low immunogenicity.

Objective: to evaluate subpopulations of B lymphocytes and features of interferon (IFN) status in patients with systemic lupus erythematosus (SLE), to clarify the relationship of immunological parameters with clinical manifestations of the disease.

A total of 139 patients (123 women (88%) and 16 men (12%)) with a definite diagnosis of SLE were included in the analysis. The disease duration was 3.0 [0.3; 12.0] years, SLEDAI-2K 7 [4; 11] points, SDI 0 [0; 1] points. Immunophenotyping of peripheral blood lymphocytes, including determination of B cells, the general population of memory B cells, non-switched and switched memory B cells, naive, transient B cells, and plasmablasts was carried out using multicolor flow cytometry. IFN status was assessed by the expression of IFN-stimulated genes (MX1, RSAD2, and EPSTI1) using real-time polymerase chain reaction.

. Two immunological “patterns” were identified—the prevailing immunological mechanism of the pathogenesis of the disease (SLE) with predominant activation of type I IFN and with predominant activation of the B-cell component of the immune system. The immunological phenotype with activation of type I IFN was associated with high immunological activity, predominant skin damage, and leukopenia, whereas the phenotype with predominant activation of the B-cell component was associated with damage to the kidneys and nervous system.

. The results of the work suggest a wide variety of immune mechanisms underlying the pathogenesis of SLE. It is possible to identify a number of leading molecular “patterns” of the pathogenesis of the disease, which must be taken into account to select an effective “targeted” drug.

Heterodimeric phospholipase A2 HDP-1 from the venom of Nikolsky viper consists of two noncovalently bound subunits—HDP-1P and HDP-1In, the first of which exhibits lipolytic activity, while the second does not. The subunits have similar molecular masses and amino acid sequences. Administration of HDP-1 and HDP-1P to anesthetized rats is accompanied by prolonged hypotensive effects, the intensity of which depends on the dose. After the administration of HDP-1P, the effect develops more slowly than in the case of HDP-1, containing both subunits, while individual HDP-1In does not affect hemodynamic parameters. It was found using electrocardiography that HDP-1 and HDP-1P affect the functioning of the rat heart, causing arrhythmia, which may indicate their ability to affect the innervation of the heart. The administration of HDP-1 and its subunits also leads to changes in blood biochemical parameters, indicating their damaging effect on cells and internal organs.

The aim of the study was to compare clinical characteristics of patients with axial spondyloarthritis (axSpA)/ankylosing spondylitis (AS) and with axial psoriatic arthritis (axPsA).

. A total of 100 patients were examined: 45 with axSpA/AS (group 1) and 55 with axPsA (group 2). Patients of group 1 were included according to axSpA/AS criteria; patients of group 2, according to CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria, and having axial involvement (axPsA). Axial involvement was detected in case of radiologically significant sacroiliitis (SI, bilateral grade ≥2 or unilateral grade ≥3), or active MRI significant sacroiliitis, or ≥1 syndesmophyte(s) of the cervical and/or lumbar spine. Patients were evaluated for the presence of inflammatory back pain (IBP) by ASAS (Assessment of Spondyloarthritis International Society) criteria.

Patients of group 1 were younger (p < 0.001), more often were HLA-B27 positive (p < 0.001), and more often had IBP (p = 0.001). Patients of group 2 had older age (> 40 years) at back pain onset (p < 0.001) and more often had peripheral arthritis (p < 0.001), dactylitis (p = 0.004), and skin psoriasis (p < 0.001). Nail psoriasis was found only in group 2 patients (p < 0.001). Group 1 patients more often had heel enthesitis (p = 0.005). Group 2 patients had worse axial disease activity scores: BASDAI (Bath Ankylosing Spondylitis Disease Activity Index; p = 0.006) and ASDAS-СRP (Ankylosing Spondylitis Disease Activity Score with C-reactive protein level determination; р < 0.001); and worse patient-reported outcomes: BASFI (Bath Ankylosing Spondylitis Functional Index; p = 0.004), patients’ pain (p = 0.005) and patients’ global assessments (p = 0.036). Patients of group 2 had more syndesmophytes of the lumbar (р = 0.009) and cervical (р = 0.007) spine. Only in group 2 patients, chunky “non-marginal” syndesmophytes (in 32.1%), as well as spinal lesions without sacroiliitis (in 20.0%) were found. Patients of group 2 had more joint erosions (р = 0.001), osteolysis (р = 0.015), juxta-articular bone formation (р < 0.001) and joint ankyloses (р = 0.02). All patients of group 1 and only 80% of group 2 (р = 0.003) met ASAS criteria for axSpA. AxSpA/AS and axPsA seem to be two different diseases. In our cohort of patients, axPsA patients had worse disease status compared to axSp and AS.

The efficiency of DNA integrity repair processes after radiation exposure may depend on hereditary variations of repair genes caused by single nucleotide polymorphisms. Disturbances or even failure of repair processes trigger a chain of reactions leading to genome instability and oncogenic transformation of the cell.

To investigate the association of single nucleotide polymorphism in genes of nucleotide excision repair (ERCC2 rs13 181, XPC rs2 228 001), AP site repair (APEX rs1 130 409), homologous recombination (XRCC3 rs861 539), single-strand DNA break repair (XRCC1 rs25 487), and double-strand DNA break repair (PARP rs1 136 410, XRCC4 rs2 075 685) with the risk of malignant neoplasm development of various localisations in chronically exposed persons.

. The study was conducted in 861 persons who were exposed to chronic low dose rate radiation, 274 of which had malignant neoplasms (MN) of various localisations and 587 made up the comparison group (exposed persons without MN). The mean accumulated dose to red bone marrow (RBM) in the group of persons with MN was 561.65 ± 25.31 mGy, while in the comparison group it was 543.14 ± 36.06 mGy. Genotyping of polymorphic loci rs13181, rs2 228 001, rs1130409, rs861 539, rs25 487, rs1136410, and rs2075685 was performed by real-time PCR. The association of polymorphic loci with the risk of MN development was determined by the odds ratio (OR) and 95% confidence interval (95% CI). A multifactor dimensionality reduction method was used to assess intergenic interactions.

Single-stranded DNA break repair gene (XRCC1) rs25 487 polymorphism in accordance with the dominant model is associated with an increased risk of MN development in the combined group of the examined persons (OR = 1.79 (1.12–2.87), p = 0.01). The polymorphism of the gene involved in homologous recombination rs861539 (XRCC3) in accordance with the recessive model is associated with a reduced risk of MN development both in the combined group of exposed persons (OR = 0.25 (0.15–0.41; p < 0.00001), and separately in the group of the Slavs (OR = 0.28 (0.13–0.60); p < 0.0001) and in the group of the Turkic people (OR = 0.22 (0.11–0.44); p < 0.0001). The model of interfactorial interactions allowed us to establish a protective effect with respect to the risk of MN development in carriers of polymorphic loci rs861539 of the XRCC3 gene and rs1130409 of the APEX1 gene (p < 0.001).

Intravital bioimaging based on luminescence is an important method for the development and testing of antitumor drugs on model animals and is an essential part of preclinical studies. Bioimaging based on luminescent systems, compared with fluorescent bioimaging, provides a high signal-to-noise ratio, which justifies the development of cell lines that stably express luciferase genes for their subsequent use in model animals. In this work, we describe the creation of a stable cell line SKOV3.ip1-NanoLuc constitutively expressing the NanoLuc luciferase gene. The developed cell line was shown to be effective for intravital luminescence bioimaging of immunodeficient animals with deep-seated intraperitoneal tumors, which can be considered as a model of late-stage ovarian cancer.

Cellular proteins, partners of viral enzymes, are involved in the replication of human immunodeficiency virus type I (HIV-1) at various stages. Thus, the viral enzyme integrase, participating in several stages of the viral cycle, interacts with various cellular proteins. A number of them are already known, and for some the mechanism of action has been established, but the search for cellular partners of integrase continues. In this work, the identification of cellular partners of HIV-1 integrase has been carried out by the method of cross-linking followed by mass spectrometry (XL-MS). Twelve new potential integrase partners have been identified, and some of them have been examined for their effect on the early stages of HIV-1 replication.