Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability.

The trends in the spread of simple sequence repeats in the genomes of .

Due to their high number and variety, simple sequence repeats in DNA are a valuable source of genetic markers widely used in population genetics, genetic diversity, and fingerprinting. is a cosmopolitan basidiomycete and a valuable object for biotechnology and mycology. It is often used as a model organism in genetic and population studies.

Identification of novel SSR markers for predicting the geographic origin of fungus Schizophyllum commune Fr.

The fungus Schizophyllum commune is a cosmopolitan basidiomycete, which is popular as an edible, medical mushroom. It causes wood rot and often used as a model object in research. In this study, we analyzed thirty-two genomes of S.

DYNAMICS OF FIBROTIC CHANGES IN THE LIVER AFTER THE SUCCESSFUL ERADICATION OF HEPATITIS C VIRUS IN PATIENTS WITH NAFLD.

Objective: The aim: To assess the dynamics of serum levels of angiopoietin-2 and transforming growth factor-β1 in patients with chronic hepatitis C (CHC) with concomitant nonalcoholic fatty liver disease (NAFLD) after successful DAAs.

Patients And Methods: Materials and methods: 82 patients with CHC were examined, of which 56 were diagnosed with NAFLD and increased body weight. Ang-2, TGF-β1, leptin, adiponectin, and the degree of liver fibrosis were determined for all participants.

EFFICACY OF THE ALGORITHMIC STEP-UP APPROACH OF INTERVENTIONAL TREATMENT OF PATIENTS WITH ACUTE NECROTIZING PANCREATITIS.

Aim - to estimate the efficacy of the algorithmic step-up approach of interventional treatment of acute necrotizing pancreatitis (ANP).; We performed a prospective observational cohort study of the efficacy of the developed approach of surgical treatment of 317 patients with different morphological forms of ANP. The following parameters were collected for each episode: length of hospital stay, mortality rate, occurrence of organ failure and local complications.

SURGICAL TECHNIQUE IN LEIOMYOSARCOMA OF THE INFERIOR VENA CAVA DEPENDING ON ITS LOCATION.

Objective: The aim: To improve the outcomes of inferior vena cava (IVC) leiomyosarcoma, propose own classification of IVC segments, which correlates with surgical access, methodology, sequence and amount of surgery.

Patients And Methods: Materials and methods: In the period from 1991 to 2021 in the Transcarpathian Regional Clinical Hospital named after A. Novak and in the Transcarpathian Antitumor Center 8 patients with IVC leiomyosarcoma were operated.

Pan-segmental intraprostatic lesions involving mid-gland and apex of prostate (mid-apical lesions): assessing the true value of extreme apical biopsy cores.

Objective: When considering increased morbidity of apical biopsies, the added diagnostic value of separate targeting of mid-gland and apical segment of the pan-segmental mid-apical mpMRI prostate cancer (PCa) suspicious lesions was assessed.

Materials And Methods: A total of 420 patients with a single mpMRI PCa-suspicious PI-RADS ≥ 3 intraprostatic lesion extending from the mid-gland to the apical segment of the gland underwent transrectal MRI-targeted (TBx) and systematic prostate biopsy. Clinically significant PCa (CsPCa) was defined as Gleason Score (GS) ≥ 3 + 4.

Tape stripping: investigational, diagnostic, and therapeutic uses in dermatology.

Adhesive tape has been used in the scientific study of human skin for more than 90 years. Use of the tape stripping method in dermatology has aided the research and diagnosing of different skin diseases. Basic science, identification, and therapeutic interventions in skin diseases, such as psoriasis, atopic dermatitis, nonmelanoma skin cancer, and melanoma, have been studied using this technique.

Creating patient-directed education in pediatric dermatology: A guide for creators.

Current medical literature and practice utilize limited resources to enhance pediatric patients' coping with and understanding of disease. Here, we provide a template for accessing current resources and developing practice-specific written materials focused on the child's experience.

Optimizing Combined Magnetic Resonance Imaging (MRI)-Targeted and Systematic Biopsy Strategies: Sparing the Multiparametric MRI-Negative Transitional Zone in Presence of Exclusively Peripheral Multiparametric MRI-Suspect Lesions.

Purpose: We assessed whether sampling of the transitional zone can be spared in patients with exclusively peripheral prostate cancer (PCa)-suspicious multiparametric magnetic resonance imaging (mpMRI) lesions who undergo combined mpMRI targeted (TBx) and systematic prostate biopsies (SBx).

Materials And Methods: Of 1,685 patients who underwent extended SBx including transitional zone sampling and had TBx of ≥1 lesion in the peripheral and/or transitional zone, we selected 863 patients with exclusively peripheral PCa-suspicious lesions and negative transitional zone mpMRI. Clinically significant PCa (csPCa) was defined as Gleason score (GS) ≥3+4.

Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas.

BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context.

Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors.

Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.

Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase.

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits.

Optimization of a series of potent, selective and orally bioavailable SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition.

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells.

Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573.

AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode.

Potent and selective bivalent inhibitors of BET bromodomains.

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode.

Fabrication of carbohydrate microarrays on a poly(2-hydroxyethyl methacrylate)-based photoactive substrate.

We report the fabrication of carbohydrate microarrays on a photoactive polymer, poly(HEMA-co-HEMA-PFPA), synthesized by RAFT copolymerization of 2-hydroxyethyl methacrylate (HEMA) and perfluorophenyl azide (PFPA)-derivatized HEMA (HEMA-PFPA). PFPA allows the covalent immobilization of carbohydrates whereas the HEMA polymer provides an antifouling surface, thus the microarrays can be used directly without pretreating the array with a blocking agent. The microarrays were prepared by spin-coating the polymer followed by printing the carbohydrates.

[EXPERIMENTAL PHARMACOKINETICS AND PHARMACODYNAMICS OF GB-115 DIPEPTIDE ANXIOLYTIC SUBSTANCES].

Pharmacokinetics and pharmacological activity of GB-115 dipeptide anxiolytic after oral administration in the form of crystalline and micronized substances was studied in albino male rats. In contrast to crystalline, the micronized substance exhibited better pharmacokinetic parameters and higher bioavailability. In the "elevated plus maze" test, GB-115 in micronized form at a dose 0.

[Surgical treatment and prophylaxis of pulmonary thromboembolism for renal cancer with presence of the implantation clots of the inferior vena cava].

Surgical treatment of 91 patients, suffering the renal cell cancer (RCC), complicated by tumoral thrombosis of inferior vena cava, was analyzed. In accordance to the Mayo clinic classification, there in the patients the tumoral thrombus spreading was revealed, depending on tumoral affection of a kidney (right-sided/left-sided): level 0--in 39 (31/8); level I--in 20 (6/14); level II--in 17(12/5); level III--in 11 (11/0); level IV--in 4 (3/1). Incomplete apparatus cavaplication was performed in 32 patients.

[Pharmacokinetics of three peroral dosage forms of new dipeptide anxiolytic drug GB-115].

Comparative analysis of the pharmacokinetics and bioequivalence of a new dipeptide anxiolytic compound GB-115 in three drug forms for peroral administration, developed in the experimental technology department of the Institute of pharmacology RAMS, was carried out. Three drug forms of GB-115 and a micronized substance of this compound were different in composition and technology of production. As a result of the investigations of GB-115 pharmacokinetics, drug form No.

[Specific features in pharmacokinetics of the original neuroleptic dilept in animals and humans].

Interspecies differences in pharmacokinetics of the original neuroleptic drug dilept have been studied in experimental animals (rabbits and rats) and volunteers after single oral administration of tablets and tablet mass of the drug. Parent drug in the rabbit blood plasma was detected for 4 h, in the rat plasma for about 2 h, and in the human blood plasma for about 1 h after drug administration. The degrees of dilept biotransformation into metabolites (defined as metabolism intensity, AUCM/AUCP) in rats were 21.

[Clinic pharmacokinetics of a new original antipsychotic drug Dilept].

The pharmacokinetic study of a new original antipsychotic drug Dilept in healthy volunteers was performed. Volunteers received Dilept as single 20, 40 or 60 mg tablets. The parent drug in the human blood plasma was detected in low concentrations and short-term time due to intensive biotransformation with formation of two metabolites N-caproyl-L-prolyl-tyrosin (M-1) and N-caproyl-L-prolin (M-2).