Vol 54, No 3 (2026)

Background: Thiopurines, including azathioprine and 6-mercaptopurine, are widely used in the treatment of inflammatory and autoimmune diseases, as well as hematological malignancies; however, their use is limited by the risk of severe myelosuppression. Pharmacogenetic variants in the TPMT and NUDT15 genes significantly affect drug tolerability, and their frequencies vary markedly across ethnic groups, making population-based studies of these markers in different regions of Russia particularly important.

Aim: To assess interethnic variability in the frequencies of clinically relevant TPMT rs1142345 and NUDT15 rs116855232 polymorphisms in populations of the Volga-Ural region, North Caucasus, and the Lower Volga region.

Methods: Data from 1687 healthy males from 27 populations and 15 ethnogeographic groups (Bashkirs, Tatars, Mordvins, Chuvash, Mari, Udmurts, Komi, Besermyans, Kalmyks, Balkars, Karachays, Circassians, Ingush, Chechens, and Moldovans), collected during field expeditions in 2000–2025, were retrospectively analyzed. Information on date and place of birth, family history of disease, ethnicity of parents and grandparents (maternal and paternal lines), and causes of death of closed relatives was collected by questionnaire. Individuals with mixed ancestry were excluded. Genomic DNA was extracted from venous blood; genotyping of TPMT rs1142345 and NUDT15 rs116855232 was performed by real-time polymerase chain reaction with TaqMan probes.

Results: The minor allele rs1142345*C of TPMT (TPMT*3C) was rare or absent in most of the studied groups, with the highest frequencies observed in Chuvash (3.65%), Circassians (3.23%), and Mordvins (3.16%). The minor allele rs116855232*T of NUDT15 (NUDT15*3) was more frequent in Kalmyks (15.6%), Bashkirs from Perm Krai (14.77%), and Bashkirs of the Samara and Saratov Regions (14.63%), whereas it was absent in Moldovans and occurred at minimal frequencies in Mordvins (0.52%), Chechens (1.03%) and Ingush (1.61%). The most significant differences in NUDT15*3 allele frequency were observed between Kalmyks and Mordvins (15.60% vs 0.52%; p = 2.7 × 10^-9, p_FDR = 9.3 × 10^-7), Kalmyks and Chechens (15.60% vs 1.03%; p = 2.4 × 10^-8, p_FDR = 3.8 × 10^-6), and Kalmyks and Moldovans (15.60% vs 0.0%; p = 3.2 × 10^-8, p_FDR = 3.8 × 10^-6). Among the Bashkir subgroups, the greatest differences were found between Bashkirs from Perm Krai and Mordvins (14.77% vs 0.52%; p = 1.4 × 10^-6, p_FDR = 1.3 × 10^-4), between Bashkirs from Samara and Saratov Regions and Mordvins (14.63% vs 0.52%; p = 2.5 × 10^-6, p_FDR = 1.8 × 10^-4), and between Bashkirs from Perm Krai and Moldovans (14.77% vs 0.0%; p = 3.4 × 10^-6, p_FDR = 2.0 × 10^-4) and Chechens (14.77% vs 1.03%; p = 8.0 × 10^-6, p_FDR = 3.5 × 10^-4).

Conclusion: The results confirm substantial ethnic heterogeneity in the distribution of pharmacogenetic markers of thiopurine toxicity. The minor allele rs116855232*T of NUDT15 was significantly more prevalent in the studied populations than the minor allele rs1142345*C of TPMT, and its frequencies in several groups were comparable to those in East Asian populations. This supports the utility of genotyping for personalizing azathioprine therapy in Russian regions.

Background: Differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) in patients with chronic pancreatitis (CP) remains challenging because of overlapping morphological and imaging features. Transcripts of tumor-associated genes and microRNAs (miRNAs) are considered promising biomarkers of malignant transformation. Our group previously investigated the expression of 17 tumor-associated messenger RNAs (mRNAs) in pancreatic neoplasms; however, their expression in PDAC compared with CP and their regulatory interactions with tissue miRNAs have not been comprehensively evaluated.

Aim: To analyze the differential expression of 17 tumor-associated mRNAs genes and miRNA profiles in tissue samples of PDAC and CP, and to perform an integrative assessment of regulatory patterns to determine the potential diagnostic value of the identified markers.

Methods: A single-center, prospective, cross-sectional, exploratory diagnostic biomarker study was conducted. Pancreatic tissue samples obtained by ultrasound-guided fine-needle aspiration biopsy between October 2020 and July 2023 were examined. The relative expression of 17 target mRNAs (CCNB1, PYGL, KIF22, UBE2C, CDK1, PKM, ELOVL6, NAPEPLD, MYC, CLDN18, GPC1, MUC1, MUC5AC, MUC4, MUC16, PLAU, and ITGA2) was assessed by real-time polymerase chain reaction. Subsequently, small RNA next generation sequencing and bioinformatic analysis were performed to assess differential miRNA expression. Integrative in silico analysis included evaluation of miRNA-mRNA regulatory interactions and functional annotation of the identified molecules using miRNet 2.0, KEGG, and Gene Ontology databases.

Results: The study included 18 patients, of whom 13 were diagnosed with PDAC and 5 with CP by histological examination. Comparative analysis of mRNA expression profiles revealed significantly elevated levels of ITGA2 (p = 0.028), MUC1 (p = 0.019), and PKM (p = 0.0007) in PDAC samples compared with CP. The highest AUC value was obtained for PKM (AUC = 1.00; 95% confidence interval 1.000–1.000; p = 0.0007). Small RNA sequencing identified 1319 miRNAs, of which 21 showed differential expression between PDAC and CP according to the criterion |log₂FC| ≥ 1.0 at p < 0.05; however, none reached the threshold for statistical significance after multiple testing (p_adj < 0.05) between the PDAC and CP groups. The most pronounced downregulation was observed for hsa-miR-205-5p (log₂FC = -11.885; p = 0.003), while hsa-miR-146a-5p showed the greatest upregulation (log₂FC = 2.993; p = 0.0001). Integrative analysis identified eight miRNAs (hsa-miR-335-5p, hsa-miR-155-5p, hsa-miR-335-3p, hsa-miR-342-3p, hsa-miR-31-5p, hsa-miR-205-5p, hsa-miR-22-3p, and hsa-miR-28-3p), that functionally connected to PKM, MUC1, and ITGA2. Hsa-miR-335-5p showed the highest network connectivity (degree of connectivity was 9,809,622).

Conclusion: The elevated expression of PKM, MUC1, and ITGA2, together with altered expression of hsa-miR-205-5p and hsa-miR-335-5p, suggests that these molecules may serve as potential components of a diagnostic panel for differentiating PDAC from CP. These findings require further validation in independent cohorts. Integrative analysis of mRNA and miRNA profiles may represent a promising approach for selecting combinations of molecular markers for subsequent development and validation of comprehensive diagnostic models for pancreatic neoplasms.

The effectiveness of new diagnostic and treatment methods, including artificial intelligence-based technologies, largely depends on how quickly and effectively they are implemented in clinical practice and on their accessibility to a wide range of patients. This article highlights the role of organizational technologies in implementing innovations in clinical practice. The success of such efforts is largely determined by the choice of an innovation implementation model: centralized (top-down), decentralized (bottom-up), hybrid (distributed responsibility), or academic-practice-community partnership. A step-by-step algorithm for innovation implementation is proposed, comprising 11 key stages – ranging from problem identification and bottleneck analysis to roadmap development, staff training, and regular monitoring of implementation progress.

The application of the hybrid organizational model is illustrated through the implementation of Nd:YAG laser ablation for the treatment of non-muscle-invasive bladder cancer (NMIBC) in urology clinics. Effective tools for overcoming typical barriers to innovation implementation (insufficient material and technical support, staff conservatism, and emotional resistance among staff) include matrix planning, early procurement of consumables, use of checklists and expert questionnaires, the development of standard operating procedures, staff training, key opinion leader engagement, and fostering a culture of innovation through targeted communication and consideration of team members' personal values. The clinical implementation stage was evaluated based on data from a comparative observational study of treatment outcomes in patients with primary NMIBC (TNM stages Ta–T1; tumor location on the anterior wall or bladder dome, tumor size ≤ 3 cm), conducted between 2023 and 2025. The 6-month recurrence rate was 9.2% (9/98) in the Nd:YAG laser ablation group compared to 33.3% (18/54) in the standard transurethral resection group (p < 0.001); at 12 months, it was 15.3% (15/98) vs 38.9% (21/54), respectively (p = 0.001). The relative risk reduction for recurrence was 72.4% and 60.6%, respectively. In the laser ablation group, no cases of intraoperative perforation or clinically significant bleeding were observed (0/98), whereas in the comparison group, such complications occurred in 3 patients (5.6%, p = 0.043). The use of laser ablation with organizational support reduced the average hospital stay by 3.3 bed-days per patient. A patient questionnaire administered at discharge showed an increase in overall satisfaction with the quality of care: 9.12 ± 1.52 points in the Nd:YAG laser ablation group vs 8.15 ± 1.10 points in the transurethral resection group (p < 0.001). This improvement was a direct consequence of both clinical success and improved management, as shorter hospital stays and a more comfortable postoperative course enhanced patient trust in the clinic.

Consequently, an approach based on systematic organizational support ensures a balance of clinical efficacy, safety, cost-effectiveness, and quality of healthcare delivery. The proposed innovation integration model, taking into account the multifactorial nature of organizational processes, is reproducible and can be adapted for the implementation of other medical technologies.