ИСТИНА

Изучение механизмов тканевого взаимодействия, поиск новых диагностических маркеров ряда социально-значимых заболеваний, а также разработка инновационных методов их лечения на основе изучения физиологических, биохимических и молекулярных механизмов с учетом возможностей междисциплинарного взаимодействия

The aim of the research is to study the mechanisms of tissue interaction, to search for new diagnostic markers of a number of socially significant diseases, as well as to develop innovative methods of their treatment based on the study of physiological, biochemical and molecular mechanisms, taking into account the possibilities of interdisciplinary interaction. Cicatricial deformity of the bladder neck is characterized by the development of a connective tissue scarring process due to inflammation in the area of the bladder neck with partial involvement of the urethra and the bladder wall. Among complications after transurethral resection of the prostate (TURP), the incidence of cervical cancer ranges from 4.9% to 12.3%. The incidence of cervical cancer after adenomectomy, according to the European Association of Urologists, is 6%. Surgical endoscopic treatment has an efficiency of no more than 72%, and the disease itself is prone to frequent relapses. If a relapse occurs, patients are considered resistant to endoscopic treatment, then more radical treatment can be performed, including open or laparoscopic reconstructive surgery, in some cases up to prostatectomy. The study of the mechanisms of penetration and clinical efficacy of drugs into scar tissue with narrowing (strictures) of the urethra is an extremely relevant clinical and experimental task facing researchers studying the course of pronounced sclerosing processes and the effect of conservative treatment using a special catheter carrying a number of drugs on the membrane used for targeted delivery to the site of injury. In the previous stages (2019-2023), a drug-coated urethral catheter was developed during research to prevent recurrent cicatricial deformity of the bladder neck in patients after endoscopic removal of prostate hyperplasia, and a technique for balloon dilation of the bladder neck using a urethral catheter with an ultrasound-induced biopolymer drug coating was developed. With minimal complications, 75% effectiveness of the procedure was found in 12 people who completed the study. Another extremely important area of the project is to explore new possibilities in conducting litholytic therapy in patients with urolithiasis (urolithiasis), which is one of the most common diseases of the urinary system, which occurs in 12% of the world's population and is characterized by an extremely high recurrence rate, reaching 75-80%. Studies from various Western countries show that the incidence of urolithiasis has reached a plateau in recent decades. Thus, according to the results of a national study conducted in Germany, the annual incidence of urolithiasis is 120,000 cases per year with a ratio of men to women of 2:1. Nevertheless, the incidence in many countries of Eastern Europe, Central and Southeast Asia is steadily increasing. A similar growth is observed in our country. An analysis of the prevalence of ICD in the Russian Federation showed that from 2005 to 2019, the total number of detected cases of ICD increased by 35.4%, and the frequency of occurrence per 100,000 population increased by 16.2%. The modern development of endoscopic lithotripsy techniques makes it possible to almost completely remove any stone from the patient's urinary tract, however, this treatment is not only invasive, but also symptomatic, without affecting the pathogenetic links of the ICD. Urinary stones consist of various crystalline substances that are poorly soluble in water, including uric acid, oxalates and ammonium phosphates of calcium and magnesium. Today, in vivo, it is possible to dissolve stones consisting mainly of uric acid salts using citrate mixtures, while up to 90% of stones are inaccessible for chemical degradation. In this regard, the chemical dissolution of stones and the prevention of further relapses are of particular interest, and the search for conditions for the chemical destruction of kidney stones using solutions of special reagents may become a new treatment option, an alternative to mechanical destruction during lithotripsy. The study of the mechanisms of early manifestation of the disease during the diagnosis of bladder cancer is also extremely relevant, since bladder cancer is the most common cancer of the urinary tract, while it ranks 9th in morbidity and 13th in mortality among all types of cancer. This disease is characterized by a high frequency of relapses. It is known that after transurethral resection of a tumor, every third patient experiences a relapse. Thus, patients need regular monitoring during the first 5 years after tumor removal (with a frequency of 3-6 months), as a result of which bladder cancer is one of the most expensive oncological diseases in terms of patient management. The gold standard for the diagnosis of bladder cancer is cystoscopy followed by biopsy and histological confirmation. Despite the fact that cystoscopy is an effective diagnostic tool, its accuracy is not absolute, which is compounded by the high cost of the procedure and the need for highly qualified personnel performing it. Thus, the sensitivity and specificity of this instrumental method vary in the ranges of 62-84% and 43-98%, respectively, depending on the stage and type of tumor, which is largely due to the high intra- and interoperative variability associated with its use. Moreover, due to the high invasiveness of this approach, patients often experience side effects such as pain when urinating (50%), frequent urination (37%), hematuria (17%) and urinary tract infections (3%). Cytological examination of urine is a non-invasive alternative, but it has extremely low sensitivity in “low-grade" tumors. Due to advances in the molecular characterization of tumor cells and the development of sensitive analytical methods, liquid biopsy has been considered as a promising replacement for traditional invasive methods of cancer diagnosis and monitoring. In bladder cancer, urine is the most suitable liquid substrate for analysis, as it is in constant contact with the surface of the tumor. This biomaterial contains not only cancer cells that have separated from the bladder wall, but also extracellular tumor DNA, which is secreted by the tumor either actively or as a result of cell death. Thus, it is relevant to develop approaches to liquid biopsy based on the detection of tumor DNA in urine for the diagnosis of bladder cancer, as well as for monitoring recurrence. One of the most serious problems facing modern clinical medicine is the course and treatment of diseases in conditions of increased antibiotic resistance. In medical science and the healthcare system, special attention is paid to the issues of resistance of pathogens of nosocomial infections, such as Klebsiella Pneumoniae, E. Coli, Pseudomonas aeruginosa, Acinetobacter spp., Staphylococcus aureus. The highest clinical significance is the high prevalence of resistance of nosocomial strains of enterobacteria to cephalosporins and carbapenems. This trend is typical for all countries of the world. According to expert estimates, the number of nosocomial infections in the Russian Federation is about 2.3 million cases per year for the total number of hospitalized patients (according to the ERGINI multicenter study), it is also noted that resistance to cephalosporins among state enterobacteria strains in Russia has reached a level of >80%, mainly due to the epidemic spread of strains producing extended-spectrum beta-lactamases (BLRS). An increase in the resistance of strains causing community-acquired infections is also being determined. There are natural difficulties in implementing nosocomial infection prevention programs at the level of medical organizations, primarily due to the lack of screening for patients carrying resistant (polyresistant) pathogens, adequate microbiological diagnostics, insufficient training of doctors in the field of antimicrobial therapy, and others. In turn, in recent years there has been a steady downward trend in the number of new antimicrobial drugs effective against resistant strains. Prospects for the development of fundamentally new antibiotics for treatment. Research objectives: 1) To study the mechanisms of interaction of drugs and scar-altered tissues of the urethra. 2) To study the possibilities of modern litholytic therapy for concretions of various origins ex vivo. To develop the most suitable litholysis schemes, determine the conditions and select reagents for the chemical destruction of kidney stones in vitro, taking into account the structural and chemical analysis. 3) To develop a technique for noninvasive molecular genetic analysis of extracellular DNA and evaluate its capabilities in the diagnosis of bladder cancer. To develop technologies for detecting tumor DNA in urine by analyzing a panel of mutations characteristic of urothelial carcinomas. To determine the diagnostic potential of the technology for detecting tumor DNA in urine in relation to the primary detection of bladder cancer, as well as post-resection relapses. To determine the prognostic potential of the technology for detecting tumor DNA in urine in patients with bladder cancer. Expected results: The data obtained on the interaction of drugs with scar-altered urethral tissues, conducted with an assessment of their clinical and morphological results, will form the basis for the development of a method for their personalized delivery to the site of injury.

Полученные данные о взаимодействии лекарственных препаратов c рубцово-измененными тканями уретры, проводимые с оценкой их клинических и морфологических результатов лягут в основу разработки метода их персонифицированной доставки в место повреждения. Данные о возможности проведения ex vivo литолитической терапии камней не только уратного состава позволят подобрать эффективные схемы литолизиса, отработать режимы использования и наметить пути консервативного введения полученных комбинаций лекарственных средств к месту использования. При выполнении исследования планируется подобрать безопасные и эффективные реагенты для химической деструкции почечных камней любого химического состава. В 2025 году предполагается определить состав мочевых камней не только с учётом кристаллической, но и с учетом аморфной фазы, а также подобрать наиболее оптимальные условия для химической деструкции с учётом состава in vitro. Данные полученные при проведении молекулярно-генетического анализа внеклеточной ДНК позволят оценить ее возможности в диагностике мышечно-неинвазивного всех форм рака мочевого пузыря. При этом, будет разработана технология выявления опухолевой ДНК в моче, основанная на анализе панели кодирующих и некодирующих мутаций, характерных для карцином уротелия. Будет определен диагностический потенциал разработанной технологии выявления опухолевой ДНК в моче у пациентов с раком мочевого пузыря и будет оценен прогностический потенциал разработанной технологии выявления опухолевой ДНК в моче у пациентов с раком мочевого пузыря. В ходе клинического исследования будет определена чувствительность и специфичность технологии выявления опухолевой ДНК в моче с использованием расширенной панели с кодирующими и некодирующими мутациями. Будут сопоставлены фракции опухолевой ДНК, определенные по разным мутациям, входящим в расширенную панель, с учетом стадии заболевания, размера новообразования, а также с установлением вклада каждого генетического изменения во временную мутационную гетерогенность опухоли (для связанных данных). В пилотной выборке пациентов, проходящих пострезекционный мониторинг рецидивов будет оценен потенциал технологии выявления опухолевой ДНК в моче к раннему выявлению таковых при сравнении с данными цистоскопии.

Проводится первое в России научное исследование, посвященное определению определение чувствительности и специфичности мутаций к обратной транскриптазе теломеразы TERT 228T и TERT 250T при раке мочевого пузыря. Результатом пилотного исследования стал набор значительной базы данных и биоматериала пациентов, пригодной для дополнительного исследования. При этом, проанализировав данные 71 пациента с верифицированным раком мочевого пузыря, а также анализом 48 участников контрольной группы получены следующие данные: чувствительность составила 56%, специфичность 100%. Рубцово-склеротические изменения шейки мочевого пузыря, возникающие после траснуретральной резекции гиперплазии простаты и лазерной энуклеации гиперплазии простаты, обусловливают необходимость повторных оперативных вмешательств, что существенно снижает качество жизни пациентов и негативно влияет на состояние всей мочеполовой системы мужчины. С 2019 года в нашей клинике используется метод баллонной дилатации шейки мочевого пузыря с использованием специального катетера (патент № 2725549) от 2020г). Метод показал высокую эффективность и безопасность для пациента, однако полностью не решил проблему. Нанесение лекарственного вещества на баллон и дистанционное его высвобождение сможет улучшить результаты лечения за счет не только механического воздействия, но и таргетного действия лекарственного средства. Тулиевый волоконный лазер вошел в клиническую практику всего 6 лет назад, однако, уже сейчас множество его достоинств отмечены ведущими специалистами из этой области. В настоящее время имеются данные об эффективности и безопасности, функциональных результатах эндоскопической энуклеации с использованием тулиевого волоконного лазера и биполярной энергии. Однако сравнительные исследования ранее не проводились. В 2024 году получен патент "Биологический агент для проведения анализа внеклеточной опухолевой ДНК и способ его применения" №2816878 от 08.04.2024 г.