Advances in molecular oncology (E-Journal) / Успехи молекулярной онкологии
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Химиотерапия: возможные риски при обращении с противоопухолевыми препаратами
Get PDFThere is a large number of healthcare workers who may be exposed to anticancer drugs in different healthcare settings in Russia. Contamination of working environment, throughout the hospital medication system from hospital pharmacy to medical waste facilities, is found in a number of studies. Monitoring of the environmental contamination with these drugs was performed by different methods in various countries. Daily uptake of the anticancer drugs by the personnel exposed for many years may be realized in reproductive impairments and increased cancer risk. The female healthcare workers who handle antineoplastic drugs showed a greater risk of birth defects in offspring, spontaneous abortions, breast cancer and a number of other cancer site revealed by epidemiological methods. Data on the cancer incidence of pharmacists and laboratory workers potentially exposed to the cytostatic drugs are provided. In Russia, the monitoring of occupational cytostatic exposure is required as it would not be correct to apply data obtained in other countries to the Russian conditions. The data for biological and epidemiological monitoring are considered as the background for effective prevention of adverse health effects in healthcare personnel exposed to antineoplastic drugs
ЦИКЛОФИЛИН А: СТРОЕНИЕ И ФУНКЦИИ
Get PDFCyclophilins belong to a large family of ancient conservative proteins with peptidyl-prolyl-cis-trans isomerase activity. The main member of this family – cyclophilin A – was discovered as an intracellular ligand for cyclosporine A. Further investigations revealed a wide range of functions of cyclophilin A. Cyclophilin A is involved in T-cell signaling, it takes part in folding, assembly and intracellular transport of proteins, as well as acts as an antioxidant. Different cell types secrete cyclophilin A under infection or oxidative stress. Cyclophilin A is one of the main factors involved in inflammation and pathogenesis of autoimmune, cardiovascular and other diseases. This protein is thought to take part in tumor progression. In this review we describe the structure of cyclophilin A and its main known functions in health and disease
Влияние нарушенной экспрессии HNF4α на чувствительность клеток гепатоцеллюлярной карциномы к действию ингибиторов проопухолевых сигнальных каскадов
Get PDFIntroduction. Hepatocellular carcinoma (HCC) is characterized by aggressive course, high lethality rate and resistance to current systemic treatment. Analysis of molecular aberrations associated with HCC pathogenesis that control biological properties of HCC allows to evaluate potential efficacy of inhibiting certain oncogenic cascades. The present study is focused on investigation of the impact of reduced expression of the key hepatocyte differentiation regulator, HNF4α, often downregulated in HCC, that influences sensitivity of HCC cells to inhibitors of the major oncogenic pathways mTOR, CDK4/6-pRb and ROCK.Materials and methods. Changes in cells proliferation and migration caused by HNF4А gene stable knockdown were tested in human HCC cell cultures HepG2 and Huh7 followed by examination of these cellular properties under mTOR (rapamycin), CDK4/6 (PD0332991, palbociclib) and ROCK 1/2 (Y27632) inhibitors treatment. Gene expression levels were estimated by the real-time polymerase chain reaction method (Real-Time PCR).Results. HNF4А gene knockdown alters HepG2 and Huh7 cell migration associated with E-cadherin and N-cadherin expression changes. The HNF4α repression weakens Y27632-induced blockade of HCC cells migration potential. HNF4А gene knockdown causes resistance of Huh7 cells and increase of HepG2 cells sensitivity to rapamycin and PD0332991 that block cells migration ability.Conclusions. Expression level of HNF4α renders influence on migration of HCC cells and contributes to their sensitivity to mTOR, CDK4/6 and ROCK1/2 inhibitors’ impact on cell migration activity
Материалы III Всероссийской конференции по молекулярной онкологии 6–8 декабря 2017 г., Москва
Get PDFMaterials of the 3nd All-Russian Conference on Molecular Oncology Moscow, 6–8 December 2017.Материалы III Всероссийской конференции по молекулярной онкологии 6–8 декабря 2017 г., Москва
Экзосомы и развитие резистентности опухолевых клеток к метформину: пилотное исследование
Get PDFObjective: to study the role of the intercellular interactions in the progression of the cancer cells resistance to metformin, a biguanide antidiabetic drug exhibited the marked anti-tumor activity.Results. Earlier we have demonstrated the effect of horizontal transferring of hormonal resistance of breast cancer cells from cell to cell, and showed the key role of exosomes on the transferring of the resistance. Here we have shown the effect of the horizontal transferring of metformin resistance in breast cancer cells – similar to the progression of hormonal resistance. We found that horizontal transferring of the metformin resistance is mediated via exosomes secreted by the resistant cells. The proteome analysis of the exosomes revealed several proteins differentially expressed in the exosomes of metformin-resistant cells and associated with the regulation of cell response to apoptotic drugs.Conclusions. Totally, the data presented demonstrate the new mechanism of the development of the cancer cell resistance based on the intercellular interactions, opening the new insights in the target therapy of breast cancer
Рак как следствие генетического мозаицизма
Get PDFContrary to the generally accepted opinion about stable DNA as the carrier of hereditary information, in a normal (not just cancer) cell, this molecule is subject to the continuous changes as a result of copying errors (in the course of replication), defects of chromosome segregation (in mitosis) and direct chemical attacks (by reactive oxygen species). Genetic diversification of cells starts during embryonic development and lasts during whole life, generating a phenomenon of the somatic mosaicism. New data on genetic variety of somatic cells lead to a different, than earlier, perception of cancer etiology, pathogenesis and prevention.Вопреки устоявшемуся мнению о стабильной ДНК как носителе наследственной информации, в нормальной (а не только раковой) клетке геном подвержен непрерывным изменениям в результате различных воздействий: ошибок копирования (в процессе репликации), дефектов сегрегации хромосом (в митозе) и прямых химических атак (активными формами кислорода). Процесс генетической диверсификации клеток стартует в эмбриональном развитии и длится всю жизнь, порождая феномен соматического мозаицизма. Новые представления о генетическом разнообразии клеток организма заставляют в ином, чем ранее, ракурсе рассматривать проблемы этиологии, патогенеза и профилактики злокачественных новообразований
Эритроцитарный диагностикум для выявления опухолевого процесса
Get PDFA method is proposed for the development of an erythrocyte diagnosticum based on the evidence of patent № 2452501 (10.06.2012) via development of sensitine obtained from the serum of mares in foal, the above factor being used for diagnosis of malignant neoplasms. In order to reveal the practical significance of the diagnosticum proposed the findings of the testing of the blood serum of 215 patients with variously located tumors and from 67 individuals without malignant tumors are analyzed. Sensitivity of the method was 88 %, specificity – 89 %, accuracy – 89 %. The accessibility of the method proposed and simplicity of the reaction as well as the rapid response make it possible to use the method under discussion in any medical institution individually or in the course of screening to obtain primary diagnosis or to reveal risk groups.Предложен метод создания эритроцитарного диагностикума, в основе которого лежат данные патента № 2 452501 (от 10.06.2012) по способу получения сенситина из сыворотки жеребых кобыл, для использования этого фактора в качестве биомаркера для диагностики злокачественных новообразований. В целях выявления практической значимости предложенного диагностикума представлены результаты тестирования сыворотки крови 215 больных с опухолями различных локализаций и 67 лиц без злокачественных новообразований. Проведена оценка полученных результатов по общепринятым критериям для диагностических наборов. При этом чувствительность метода составила 88 %, специфичность – 89 %, точность – 89 %. Доступность и простота постановки реакции, а также быстрота получения ответа позволяют применять данный метод в условиях любого лечебного учреждения индивидуально или в процессе скрининга в целях определения предварительного диагноза, а также в мониторинге процесса лечения больного и раннем выявлении рецидива заболевания
Выявление мутаций в «горячих» участках генома: ампликоны-«шпильки» в методе плавления ДНК
Get PDFPolymerase chain reaction (PCR) followed by DNA melting analysis with TaqMan probes effectively reveals mutations in the human genome “hot” spots. The necessity to carry out PCR in the asymmetric variant causes, however, a number of restrictions of this method: 1) an inability of quantitative estimates of gene copy numbers; 2) the need for 2 independent PCR tests for detection of mutations in both complementary strands of an amplicon (this approach improves reliability and sensitivity of the analysis); 3) the complication of PCR design and decrease in efficiency of amplification. Overcoming these restrictions was possible by means of symmetric PCR with primers containing the specific and universal sequences: the single-stranded “hairpins” (sense and antisense) are not capable to anneal with each other, but they can hybridize independently with 2 TaqMan probes present in the reaction mixture. The proposed approach allows quantitative and qualitative characterization of a DNA sample (the copy number estimates as well as mutation scanning of both complementary amplicon strands).Амплификация с последующим плавлением ДНК с зондами TaqMan эффективно выявляет мутации в «горячих» участках генома. Однако необходимость проводить полимеразную цепную реакцию (ПЦР) в асимметричном варианте обусловливает ряд ограничений этого метода: 1) невозможность количественного анализа из‑за снижения эффективности амплификации; 2) необходимость выполнения 2 независимых ПЦР для выявления мутаций в комплементарных нитях ампликона; 3) усложнение дизайна ПЦР. Преодоление этих ограничений оказалось возможным при использовании в симметричной ПЦР комбинированных праймеров, состоящих из универсальной и специфической последовательностей: образующиеся в результате однонитевые «шпилечные» (hairpin) ампликоны (sense и antisense) не способны ренатурировать друг с другом, но независимо гибридизуются с присутствующими в среде зондами TaqMan (antisense и sense соответственно). Разработанный способ позволяет в одном тесте получить количественные (число копий) и качественные (наличие мутаций в обеих нитях ампликона) характеристики исследуемого участка ДНК
Мутации изоцитратдегидрогеназ 1 и 2 и ме тилирование гена MGMT в глиомах
Get PDFGliomas are the most common brain tumors. It is difficult to detect them at early stages of disease and there is a few available therapies providing significant improvement in survival. Mutations of isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) play significant role in gliomogenesis, diagnostics and selection of patient therapy. We tested the distribution of IDH1 and IDH2 mutations in gliomas of different histological types and grades of malignancy by DNA melting analysis using our protocol with a sensitivity of 5 %. The results of this assay were confirmed by conventional Sanger sequencing. IDH1/2 mutations were detected in 74 % of lower grade gliomas (II and III, World Health Organization) and in 14 % of glioblastomas (IV, World Health Organization). Mutation rate in gliomas with oligodendroglioma component were significantly higher then in other glioma types (р = 0.014). The IDH1 mutations was the most common (79 % of general mutation number). IDH1/2 mutations can induce aberrant gene methylation. Detection of methylation rate of the gene encoding for O6-methylguanine-DNA-methyltransferase (MGMT), predictive biomarker for treatment of gliomas with the alkylating agents, has demonstrated a partial association with IDH1/2 mutations. In 73 % of IDH1/2-mutant tumors MGMT promoter methylation were observed. At the same time IDH1/2 mutations were not revealed in 67 % tumors with MGMT promoter methylation. These results indicate existence of another mechanism of MGMT methylation in gliomas. Our data strong support for necessity of both markers testing when patient therapy is selected
