Перспективы таргетной терапии глиом низкой степени злокачественности у детей

Low grade gliomas are the most common brain tumors in children. Total resection for operable lesion helps to achieve local and system control. Nevertheless, for inaccessible tumors are required more effective treatment both to overcome the refractory course of the disease, and to mi nimize toxicity with conventional adjuvant chemotherapy and various types of radiation therapy. In recent years, there has been an accelerated understanding of the molecular pathogenesis of some tumors in children, including low grade gliomas. Given the fact that the basis of the molecular pathogenesis of the low grade gliomas is the activation of signaling pathways MARK (mitogen activated protein kinase) and mTOR (mammalian target of rapamycin), the most promising targeted agents are BRAF, MEK and mTOR inhibitors. Nevertheless, a number of other agents have been studied to find promising targeted therapy for this tumors type. This article summarizes the latest literature evaluating new drugs in low grade glioma.Глиомы низкой степени злокачественности являются преобладающим большинством в структуре опухолей головного мозга у детей. Достичь локального и системного контроля над опухолью возможно при полном удалении образования. Сложная локализация глубоко расположенных и диффузно растущих опухолей ограничивает объем оперативного вмешательства и требует поиска, а также совершенствования методов консервативного лечения данной нозологической группы. Необходимы более эффективные виды лечения как для преодоления рефрактерного течения заболевания, так и для минимизации токсичности, связанной с обычной адъювантной химиотерапией и различными видами лучевой терапии. С учетом того, что в основе молекулярного патогенеза большинства глиом низкой степени злокачественности лежит активация сигнальных путей МАРК (mitogen activated protein kinase) и mTOR (мишени рапамицина млекопитающих), наиболее перспективными агентами – таргетными препаратами являются BRAF, MEK и mTOR-ингибиторы. Тем не менее целый ряд других соединений был исследован в целях поиска перспективных агентов для таргетной терапии при опухолях указанного типа. Обзор суммирует новейшие данные литературы, посвященной новым препаратам при глиоме низкой степени злокачественности

Анализ генетических аберраций в глиомах высокой степени злокачественности у детей

Background. High-grade gliomas are characterized by a wide range of genetic abnormalities. The heterogeneous genomic landscape of pediatric high-grade gliomas allows identifying distinct subgroups of the disease in children and young adults. Most importantly, these subgroups differ by clinical course and prognosis, as well as treatment response to standard therapy.Objective: to assess the profile of molecular genetic markers of high-grade gliomas in children.Materials and methods. In the current study, we examine the frequency of H3F3A, Hist1H3B, BRAF, IDH1 / 2 mutations, the copy number alterations of CDKN2A / 2B genes and the expression of ETV6‑NTRK3 fusion gene in a cohort of 53 pediatric high-grade gliomas.Results. Driver mutations and CDKN2A / 2B deletions were observed in 24 (45 %) and 15 (28 %) of 53 tumors, respectively. Overall, the studied high-grade gliomas harbored 41 genetic aberrations including 24 (58.5 %) somatic missense mutations, 1 (2.4 %) genetic variant of unknown clinical significance, 1 (2.4 %) oncogenic fusion gene and 15 (36.6 %) deletions of the tumor suppressor genes.Conclusion. These findings point to the importance of molecular profiling of tumors for the optimal clinical care and development of new approaches to treatment aimed at molecular targets for personalized anticancer therapies.Введение. Высокозлокачественные глиомы характеризуются широким спектром генетических аномалий. Различия в молекулярно-генетическом профиле позволяют выделить несколько основных подгрупп глиом высокой степени злокачественности у детей и подростков, которые различаются как по клиническому течению заболевания, его прогнозу, так и по ответу на стандартные схемы терапии.Цель исследования – оценить профиль молекулярно-генетических маркеров глиом высокой степени злокачественности у детей.Материалы и методы. В исследование были включены 53 образца глиом высокой степени злокачественности у детей. Были проанализированы мутации в генах H3F3A, Hist1H3B, BRAF, IDH1/2, а также аномалии числа копий генов CDKN2A/2B и экспрессия химерного гена ETV6‑NTRK3.Результаты. В 24 (45 %) из 53 проанализированных случаев выявлена драйверная мутация в ткани опухоли, в 15 (28 %) – потеря копии CDKN2A / 2B, которая может выступать как второе мутационное событие. В общей сложности обнаружена 41 генетическая аберрация, из них 24 (58,5 %) составляют соматические миссенс-мутации, 1 (2,4 %) – вариант с неясным клиническим значением, 1 (2,4 %) – химерный онкоген и 15 (36,6 %) – делеции генов-онкосупрессоров.Заключение. Полученные данные свидетельствуют о важности углубленного изучения генетического профиля опухоли для определения тактики ведения пациентов, а также подбора персонализированной терапии для больных злокачественными глиомами

Promises of targeted therapy for low grade gliomas in children

Low grade gliomas are the most common brain tumors in children. Total resection for operable lesion helps to achieve local and system control. Nevertheless, for inaccessible tumors are required more effective treatment both to overcome the refractory course of the disease, and to mi nimize toxicity with conventional adjuvant chemotherapy and various types of radiation therapy. In recent years, there has been an accelerated understanding of the molecular pathogenesis of some tumors in children, including low grade gliomas. Given the fact that the basis of the molecular pathogenesis of the low grade gliomas is the activation of signaling pathways MARK (mitogen activated protein kinase) and mTOR (mammalian target of rapamycin), the most promising targeted agents are BRAF, MEK and mTOR inhibitors. Nevertheless, a number of other agents have been studied to find promising targeted therapy for this tumors type. This article summarizes the latest literature evaluating new drugs in low grade glioma

Analysis of genetic aberrations in pediatric high-grade gliomas

Background. High-grade gliomas are characterized by a wide range of genetic abnormalities. The heterogeneous genomic landscape of pediatric high-grade gliomas allows identifying distinct subgroups of the disease in children and young adults. Most importantly, these subgroups differ by clinical course and prognosis, as well as treatment response to standard therapy.Objective: to assess the profile of molecular genetic markers of high-grade gliomas in children.Materials and methods. In the current study, we examine the frequency of H3F3A, Hist1H3B, BRAF, IDH1 / 2 mutations, the copy number alterations of CDKN2A / 2B genes and the expression of ETV6‑NTRK3 fusion gene in a cohort of 53 pediatric high-grade gliomas.Results. Driver mutations and CDKN2A / 2B deletions were observed in 24 (45 %) and 15 (28 %) of 53 tumors, respectively. Overall, the studied high-grade gliomas harbored 41 genetic aberrations including 24 (58.5 %) somatic missense mutations, 1 (2.4 %) genetic variant of unknown clinical significance, 1 (2.4 %) oncogenic fusion gene and 15 (36.6 %) deletions of the tumor suppressor genes.Conclusion. These findings point to the importance of molecular profiling of tumors for the optimal clinical care and development of new approaches to treatment aimed at molecular targets for personalized anticancer therapies

BIOESOnet: A Tool for the Generation of Personalized Human Metabolic Pathways from 23andMe Exome Data

The lowering of costs of whole exome sequencing (WES) services registered in the last two years has greatly increased the demand for managing different metabolic diseases, including autism spectrum disorders (ASD). WES allows the detection of a large part of exome single nucleotide polymorphisms (SNPs), whose expression can be in some cases modulated by epigenetics, life style and microbioma changes. However, such raw data usually needs to be manipulated in order to allow useful interpretation and analysis. We present BIOESOnet, a tool for the filtering and visualization of exome 23andMe raw data into a customized methylation pathway. The tool, available at: http://www.bionumeri.org/joomla/restricted-area/onecarbon-tool, enables a fast and extensive overview of possible mutations inside an extended metabolic pathway

Development of a Technology of Vitaminized Blended Vegetable Oils and Their Identification by the Fatty Acid and Vitamin Contents

Due to the comparative analyses of physicochemical properties and fatty acid composition of vegetable oils, a reasonable choice has been made. Namely, sunflower, pumpkin, flaxseed, and camelina oils have been found optimal for the preparation of blends with a rational ratio of ω-6:ω-3 fatty acids in two-component (10:1, 5:1) and three-component (5:1) mixtures.A reasonable combination of vegetable oil blends with a rational ratio of ω-6:ω-3 fatty acids has been substantiated. Since oils belong to polyfunctional physiologically active products with a wide range of technological properties, they can be used with fat soluble vitamins (tocopherol and β-carotene). This reduces the oxidation processes in the vitaminized blended vegetable oils (VBVOs).A blended vegetable oil is a system in which PUFAs of the ω-6 and ω-3 groups are present in certain ratios and are subject to oxidative damage, to a greater extent due to the increased content of PUFAs. In accordance with the specifics of the blended oils as enriching ingredients, fat-soluble vitamins E (tocopherol) and β-carotene were used, which are not only physiologically important components for the human body but also active natural antioxidants. It has been found that adding a 0.2 % solution of β-carotene in the amount of 3.75 g and 1 % of tocopherol solution in the amount of 2.5 g provides 30 % of the daily requirement of these vitamins for the human body.The appropriateness of the joint use of tocopherol and β-carotene is based on the finding that it stabilizes oxidation and increases the induction period 1.5–2 times.The fatty acid composition of the created recipes of the blended systems with the ratio of PUFAs of the ω-6 and ω-3 families, in particular for healthy people's nutrition with a ratio of ω-6:ω-3 being equal to 10:1; for adequate nutrition the ω-6:ω-3 ratio should be 5:1, which indicates the expediency of the selected vegetable oils for the creation of blended systems, balanced on the fatty acid composition exactly in the proposed ratios.The technologies of blending and vitaminizing vegetable oils have been developed and introduced at the Odesa Stone Fruit and Vegetable Oils Plant, AVA Ltd. (Ukraine).When solving the problems of substantiating the blending and vitaminization technologies, it has been proven that these operations can be performed with equipment that is present in almost all oil and fat processing factories. The proposed blending technology involves only two stages: stage 1 is the dosage of the prescription amount of oil 1 in a temperature-maintaining container; stage 2 is the dosage of the prescription amount of oil 2 in the container with oil 1 and mixing for 5.0...10 min at t=28…30 °С. It does not require much time and allows the preparation of oil and mixing within 10–15 minutes