Differences in expression profiles in malingant melanoma patients according to immunotherapy response

One of the most important branch of modern molecular genetics and biomedicine is the search for predictive markers that help choose the most effective way of treatment, drug and also determine its individual dosage. Among the markers, those that can provide the possibility of using a non­invasive, so­called “liquid biopsy” are considered particularly promising. This method allows the condition of the tumor to be assessed by analyzing the body’s natural fluids, such as blood, urine or saliva. Such studies are most convenient in those cases when it is necessary to monitor the effectiveness of therapy in order to record the time of the onset of resistance of tumor cells, the onset of relapse and to move on to the next line of therapy. In the treatment of aggressive and rapidly became metastatic malignant tumors, such as melanoma, the presence of reliable markers that allow quick and accurate determination of treatment tactics is especially important. Nowadays, there is an increasing number of studies devoted to the search for predictive markers of the effectiveness of immunotherapy. Melanoma is one of the most immunogenic tumors and, as a result, has become a model object for research into and introduction of new approaches to immunotherapy. In this study, we compared two groups of patients with metastatic skin melanoma, with different responses to immunotherapy with blockers of immune control points, to identify new predictive expression biomarkers among microRNAs and mRNAs, and to identify the genes responsible for the occurrence of an objective response to therapy. As a result, the study detected several microRNAs with a significant change in expression level within the tumor tissue of patients responding differently to immunotherapy. Differences in the level of expression of their target genes have also been found, that will allow a more detailed analysis of the molecular mechanisms that determine the sensitivity or resistance of malignant melanoma cells to the immunotherapy. Based on the obtained data, we have proposed expression markers (mRNAs and microRNAs) that can be used as predictors of malignant melanoma tumors to immunotherapy

Опыт использования системы вакуумной терапии ран при лечении высокого наружного тонкокишечного свища

The article presents the experience of successful patient treatment with a high external small bowel fistula using a combined approach: surgery and vacuum therapy.В статье приведен опыт успешного лечения пациента с высоким наружным тонкокишечным свищом с помощью комбинированного подхода, сочетающего хирургическое вмешательство и вакуумную терапию

НАСЛЕДСТВЕННЫЙ РАК МОЛОЧНОЙ ЖЕЛЕЗЫ И ЯИЧНИКОВ

The annual incidence of breast cancer (BC) in the world is 1,383,000 cases. Genetic predisposition is one of the major risk factors for breast cancer and ovarian cancer (OC). The proportion of hereditary breast cancer ranges from 5 to 10%, which amounts 69 150-138 000 cases. Family history of accumulation of breast cancer and tumors of the female reproductive system have 25% of patients. Thus, patients with hereditary forms and family breast cancer account 345,700 of all diagnosed cases of breast cancer. Hereditary ovarian cancer occurs in 10-17% cases. Hereditary breast and ovarian cancer are characterized by autosomal dominant inheritance with high (incomplete) penetrance, incidence in early age and pronounced phenotypic and genotypic heterogeneity. According to numerous studies, 20-50% of hereditary breast cancer cases and 90-95% of hereditary ovarian cancer cases in women, and from 4 to 40% of breast cancer cases in men are caused by germinal mutations in the BRCA1 and BRCA2 genes. Considering the syndromic pathology of hereditary BC and OC and can also be associated with mutations in genes TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2, and others.Ежегодная заболеваемость раком молочной железы (РМЖ) в мире составляет 1 383 000 случаев. Генетическая предрасположенность является одним из основных факторов риска развития РМЖ и рака яичников (РЯ). Доля наследственно-обусловленного РМЖ колеблется от 5 до 10 %, что составляет 69 150-138 000 случаев. Семейную историю накопления РМЖ и опухолей женской репродуктивной системы отмечают 25 % заболевших женщин. Таким образом, пациенты с наследственными и семейными формами РМЖ в целом составляют 345 700 от всех диагностированных случаев РМЖ [1]. Наследственный рак яичников встречается с частотой 10-17 % [2,3]. Наследственные РМЖ и РЯ характеризуются аутосомно-доминантным типом наследования с высокой (неполной) пенетрантностью, ранним возрастом возникновения и выраженной генотипической и фенотипической гетерогенностью [3-6]. По данным многочисленных исследований, 20-50 % наследственного рака молочной железы (НРМЖ) и 90-95 % — наследственного рака яичников (НРЯ) у женщин, а также от 4 до 40 % РМЖ у мужчин обусловлены герминальными мутациями в генах BRCA1 и BRCA2 [2,3,7,8]. С учетом синдромальной патологии НРМЖ и НРЯ могут быть ассоциированы также с мутациями в генах TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2 и др. (таблица 1)

ГЕРМИНАЛЬНЫЕ МУТАЦИИ В ГЕНАХ ГОМОЛОГИЧНОЙ РЕКОМБИНАЦИИ В ПОПУЛЯЦИИ ПАЦИЕНТОВ РАКОМ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ: ОПЫТ ОДНОГО ЦЕНТРА

Objective. To estimate the frequency of germline mutations in homologous recombination genes in a population of patients with pancreatic cancer and to assess the possibility to predict the risk of mutation carriage based on the clinical and anamnestic data.Materials and methods. The study included patients diagnosed with pancreatic cancer, blood samples of which were taken to detect clinically significant germline mutations in the BRCA1, BRCA2, CHEK2, BLM, NBS1, and PALB2 genes. Clinical data and family history data were collected for each patient.Results. The study included 99 patients. Mutations in BRCA1 gene were detected in 4 % of cases, in CHEK2 gene – in 2 %. No mutations were detected in the BRCA2, as in BLM, NBS1, and PALB2 genes. Localization of primary tumor, presence of distant metastases, stage of disease, family history of malignant neoplasms did not correlate with the risk of BRCA1 mutation (p>0.05). The patient’s eligibility for NCCN criteria for BRCA1 gene mutation diagnosis proved to be a significant marker of germline mutation presence (p=0.043).Conclusions. NCCN criteria for genetic testing are the best predictor of BRCA1 germline mutation in patients with pancreatic cancer.Цель исследования. Изучить частоту герминальных мутаций в генах гомологичной рекомбинации в популяции пациентов раком поджелудочной железы и оценить возможность предсказания риска носительства мутации в этих генах на основе сбора клинических и анамнестических данных.Материалы и методы. В исследование включались пациенты с диагнозом рака поджелудочной железы, у которых осуществлялся забор крови для выявления клинически значимых герминальных мутаций генов BRCA1, BRCA2, CHEK2, BLM, NBS1 и PALB2. У каждого пациента проводился сбор клинических данных и данных семейного анамнеза.Результаты исследования. В исследование включено 99 пациентов. Мутации в гене BRCA1 выявлены в 4 % случаев, в CHEK2 – в 2 %. В гене BRCA2 не выявлено ни одной мутации, как и в генах BLM, NBS1, PALB2. Локализация первичного очага, наличие отдаленных метастазов, стадия опухолевого процесса, отягощенный семейный анамнез по любому из злокачественных новообразований не коррелировали с риском носительства мутации BRCA1 (p>0,05). Соответствие пациента критериям отбора NCCN для диагностики мутаций в гене BRCA1 оказалось значимым маркером наличия герминальной мутации (р=0,043).Выводы. Критерии отбора NCCN для генетического тестирования являются наилучшим предиктором наличия герминальной мутации BRCA1 у пациентов раком поджелудочной железы.риска носительства мутации в этих генах на основе сбора клинических и анамнестических данных.Материалы и методы. В исследование включались пациенты с диагнозом рака поджелудочной железы, у которых осуществлялся забор крови для выявления клинически значимых герминальных мутаций генов BRCA1, BRCA2, CHEK2, BLM, NBS1 и PALB2. У каждого пациента проводился сбор клинических данных и данных семейного анамнеза.Результаты исследования. В исследование включено 99 пациентов. Мутации в гене BRCA1 выявлены в 4 % случаев, в CHEK2 – в 2 %. В гене BRCA2 не выявлено ни одной мутации, как и в генах BLM, NBS1, PALB2. Локализация первичного очага, наличие отдаленных метастазов, стадия опухолевого процесса, отягощенный семейный анамнез по любому из злокачественных новообразований не коррелировали с риском носительства мутации BRCA1 (p>0,05). Соответствие пациента критериям отбора NCCN для диагностики мутаций в гене BRCA1 оказалось значимым маркером наличия герминальной мутации (р=0,043).Выводы. Критерии отбора NCCN для генетического тестирования являются наилучшим предиктором наличия герминальной мутации BRCA1 у пациентов раком поджелудочной железы

Adaptive Learning Systems: Theory and Practice

Adaptive systems allow to take into account the individual features of operators, the level of development and the features of training throughout the entire learning process. These training systems assume the possibility of managing the assimilation not only of the final results achieved, but also of the pre-determined parameters of the process that determine its conditions. To implement the adaptive learning process, two factors are necessary. First, a method of measuring the rate of adaptation of the operator is necessary in order to regulate the diversity of the stimulus sequence, and, secondly, a method of organizing this diversity is necessary. For purposeful adaptation, we first used the rate of change of the correct answer criterion as an index of the rate of adaptation and, secondly, the variation in the degree of simplification with variation in the diversity of the stimulus sequence was identified. On the path of introducing adaptive learning systems, a number of difficulties and limitations arise that are analyzed in the report. The exposition of the theory of adaptive learning is made in close connection with practical implementation by the example of the adaptive system developed by us for studying the individual features of the sensory-perceptual characteristics of a person and forming at him the skill of perceptive identification of a useful signal under interference conditions. There is no doubt that this model can be used to form the entire range of structured skills. In support of this, the report examines the adaptive intelligent simulator that we created to train the traffic control staff, including the study of technology, the possibilities of the road development scheme and options for implementing control solutions. Full skill includes these components of the skill: the reception of trains, departure, disbanding, formation, freight work. In conclusion, we note the advantages that the use of adaptive training systems in simulators gives, and which have been confirmed in our experimental work with the adaptive intelligent simulator. The experiments were carried out according to the standard scheme: the experimental group worked with an adaptive intellectual simulator, and the control group worked in a traditional way on conventional simulators. Groups were formed from management students of 12 people each. 1 A significant (twofold) reduction in the time of formation of the skill (3 sessions of 45 minutes in the experimental group versus 6 sessions in the control group). 2 The strength of the skill of operators trained with the use of an adaptive learning system is significantly higher than with traditional training. 3 Adaptive self-organizing system allows to provide equally strong formation of all the sub-skills included in the structured skill. The strength of the skill and the components of the skill included in it was defined as the permissible duration of the break between training, which was 15 days in the experimental group versus 7 days in the control group). The time of formation, the strength of the skill and the sub-skills included in it were then used to compile a mathematical model that will allow us to analyze the processes of acquiring, losing and restoring the skills of error-free work when using adaptive learning systems

The susceptibility of human melanoma cells to infection with the Leningrad-16 vaccine strain of measles virus

Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)