We describe the role of genomic and postgenomic technologies in the study of the preeclampsia genetic architecture in this review. Preeclampsia is a severe hypertensive disease of pregnancy that causes a significant level of maternal and perinatal morbidity and mortality. We emphasize the importance of integrative analysis of genomic, methylomic, transcriptomic, and proteomic data for characterizing the molecular mechanisms of preeclampsia, identifying new candidate genes and molecules for targeted therapy of this gestational complication.

В представленном обзоре рассмотрена роль геномных и постгеномных технологий в раскрытии генетической архитектуры преэклампсии (ПЭ) – тяжелого гипертензивного расстройства беременности, обусловливающего значительный уровень материнской и перинатальной заболеваемости и смертности. Отмечается особая актуальность интегративного анализа геномных, метиломных, транскриптомных и протеомных данных в характеристике молекулярных механизмов ПЭ и идентификации новых генов-кандидатов и мишеней для таргетной терапии этого гестационного осложнения.

The secretome of human mesenchymal stem cells (MSCs) after osteogenic differentiation of FetMSC cells in vitro was obtained to develop tissue engineering technologies for bone tissue. For standard secretome samples a large number of FetMSC cells (7 × 108 cells) were cultured in serum-free conditioned medium (SFCM). All steps of cell processing were performed in the CompacT SelecT automatic system (Sartorius, United Kingdom). The SFCM was concentrated by ultrafiltration, then subjected to dialysis and dried in a vacuum rotary evaporator. The osteoinductive properties of SFCM concentrate (SFCMC) were tested on FetMSC cells by means of adding it to the growth medium at different concentrations. There were no changes in cell morphology during cultivation in the presence of SFCMC. Analysis of the transcription factors Runx2 and YAP1 (markers of osteogenic differentiation) expression using immunofluorescence staining and real-time polymerase chain reaction (RT-PCR) showed an increase in their level of expression in the presence of SFCMC. These findings demonstrate that it is possible to use SFCMC obtained from osteogenic MSCs to induce differentiation of other (undifferentiated) MSCs. The results are useful for the development of cell therapy products for bone restoration based on MSCs secretome.

С целью разработки технологии восстановительной терапии костных тканей получен секретом мезенхимных стволовых клеток (МСК) человека после остеогенной дифференцировки МСК линии FetMSC in vitro. Для получения стандартного образца секретома использовали бессывороточную кондиционированную среду (БКС), в которой культивировали большое число клеток FetMSC (до 700 млн). Все этапы клеточного процессинга проводили в автоматизированной системе CompacT SelectT (Sartorius, Великобритания). БКС концентрировали путем ультрафильтрации, затем подвергали диализу, высушивали в вакуумном ротационном испарителе. Остеоиндуктивные свойства концентрата БКС (КБКС) тестировали на клетках линии FetMSC при его добавлении в ростовую среду в разных концентрациях. Не было выявлено изменений морфологии клеток в процессе культивирования в присутствии КБКС. Анализ экспрессии транскрипционных факторов Runx2 и YAP1 (маркеров остеогенной дифференцировки клеток), с помощью иммунофлуоресцентного окрашивания и полимеразной цепной реакции в реальном времени (RT-PCR), показал повышение уровня их экспрессии в клетках в присутствии КБКС. Результаты позволяют сделать заключение о возможности использования КБКС, полученного от остеогенных МСК, для индукции дифференцировки других МСК. Полученные результаты могут быть использованы при разработке биомедицинских клеточных продуктов для восстановления костной ткани на основе секретома МСК.

Идентификация хромосомных аномалий на субмикроскопическом уровне и установление их роли в этиологии интеллектуальных расстройств являются важной научной и практической задачей. Оценка патогенного значения менее изученного типа вариаций копийности ДНК - хромосомных микродупликаций представляет актуальный предмет для обсуждения. В исследовании предложен алгоритм интерпретации клинической значимости частичных трисомий, который является неотъемлемой составляющей в диагностике и профилактике хромосомных болезней.

The simultaneous development of several diseases (comorbidity, syntropy) in particular patients is a common phenomenon in modern clinical practice. However, the results of recent epidemiological studies have pointed to the new phenomenon of inverse comorbidity (or dystropy)—that means that some diseases can occur together in one person more rarely than in other people according to frequencies of these disorders in the population as a whole. Such dystropic (inversely comorbid) diseases are Huntington’s disease and oncological ones. In this paper, we perform a review of existing information supporting the hypothesis of the oncoprotection in carriers of HTT mutation, also including features of interactions of genes and proteins in such processes as autophagy and apoptosis.

Одновременное развитие нескольких заболеваний (коморбидность, синтропия) у отдельных пациентов распространено в современной клинике. Однако результаты недавних генетико-эпидемиологических исследований указывают на новое явление – заболевания могут быть обратно коморбидными (дистропия), т.е. могут наблюдаться вместе у отдельных индивидов реже, чем ожидается на основе их популяционных частот. К таким болезням относятся, в частности, болезнь Гентингтона и опухолевые заболевания. Приводится анализ имеющихся данных по обоснованию гипотезы онкопротекции у носителей мутации в гене гентингтина, включая особенности взаимодействия генов и белков, задействованных в процессах аутофагии и апоптоза.

Obesity is one of the major challenges in modern society. More than a third of the world's population suffers froms overweight. This phenotype affects the quality of life and is associated with cardiovascular diseases, diabetes, cancer and reproductive disorders. The population variability of allele frequencies of 26 single nucleotide polymorphisms, in association with obesity and body mass index, according to data from genome-wide association studies (GWASs) is discussed in this study. Genetic variability was analyzed in populations of Northern Eurasia and populations from the human genome diversity project (HGDP). The population samples are characterized by high genetic diversity that correlates with climatic and geographical parameters. The results of the test for searching for natural selection signals revealed a selection effect for rs1167827 of the HIP1 gene, rs7138803 and rs7164727 located in the intergenic region, rs7141420 of the NRXN3 gene, rs7498665 of the SH2B1 gene, and rs7903146 of the TCF7L2 gene.

Ожирение становится одной из глобальных проблем – более трети мирового населения имеют избыточный вес. Эта патология существенно влияет на качество жизни и является фактором риска сердечно-сосудистых заболеваний, сахарного диабета, рака и нарушений репродуктивной функции. Нами изучена популяционная вариабельность частот аллелей 26 однонуклеотидных полиморфных маркеров, ассоциированных с ожирением и индексом массы тела по данным полногеномных ассоциативных исследований (GWAS). Генетическая изменчивость проанализирована в популяциях Северной Евразии и популяциях из проекта по изучению разнообразия генома человека (HGDP). Исследованные этнические группы характеризуются высоким уровнем генетического разнообразия, которое коррелирует с климато-географическими параметрами. Результаты тестов на поиск сигналов естественного отбора свидетельствуют о действии отбора на маркеры rs1167827 гена HIP1, rs7138803 и rs7164727, расположенные в межгенной области, rs7141420 гена NRXN3, rs7498665 гена SH2B1, rs7903146 гена TCF7L2.

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age (“early MI” denoting individuals who had the first MI before the age of 60 years, and “late MI” the group of patients with the first “MI after 60 years”). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 (“StatSoft Inc.”, USA), as well as the “stats” and “genetics” packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23‒3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23‒4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11‒2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

Цель исследования заключалась в выявлении особенностей генетической структуры подверженности инфаркту миокарда (ИМ) в зависимости от возраста пациентов. Всего обследовано 355 пациентов (n = 121, ранний ИМ ‒ индивиды, у которых первый ИМ зарегистрирован в возрасте до 60 лет; и n = 234 c первым ИМ в возрасте старше 60 лет) и 285 жителей Сибирского региона (контрольная группа). Генотипирование 58 однонуклеотидных вариантов (SNP) выполнено с помощью MALDITOF масс-спектрометрии. Регуляторный потенциал SNP оценивали с помощью онлайн сервисов (http://rsnp.psych.ac.cn/; http://www.gtexportal.org/; https://genenetwork.nl/bloodeqtlbrowser/). Генотипы GG rs1143674 гена ITGA4, СС rs1333049 гена CDKN2B-AS1 и СС rs3739998 гена KIAA1462 ассоциированы с ИМ в общей группе больных. Генотипы АА гена ADAMDEC1 (OR = 2.03; 95% CI 1.23‒3.33; p = 0.004) и GG rs2878771 гена AQP2 (OR = 2.24; 95% CI 1.23‒4.09; p = 0.006) связаны с развитием ИМ в раннем возрасте, а генотип ТТ гена TAS2R38 (OR = 1.82; 95% CI 1.11‒2.89; p = 0.009) был фактором риска первого ИМ, произошедшего после 60 лет. Генетические варианты, ассоциированные с ИМ, относятся к регуляторным (rSNP): влияют на аффинность связывания ДНК с транскрипционными факторами, вовлечены в посттранскрипционный контроль генной активности и модулируют уровень экспрессии генов в различных тканях. Ранний и поздний ИМ имеют в своей основе как общие генетические варианты генов ITGA4, CDKN2B-AS1, KIAA1462, так и специфичные: ADAMDEC1 и AQP2 для раннего ИМ и TAS2R38 для ИМ, произошедшего после 60 лет.

Our previous studies have shown that BRCA1 gene deficiency caused by changes in the tumor such as low expression, deletion, loss of heterozygosity, etc., can be associated with the effectiveness of chemotherapy and the disease prognosis. However, even in the absence of these factors, the effectiveness of taxotere therapy was variable. This may be due to the availability of another BRCA1 gene somatic changes in the tumor tissue and their determination will help to define the personalize treatment strategy for each breast cancer patient. Here we investigated the entire spectrum germline and somatic mutation of coding region of the BRCA1 gene in tumor tissue. We obtained that absence of BRCA1 somatic mutation was associated with objective response on taxotere in the preoperative period. Germline mutations BRCA1: c.4837A>G (p.Ser1613Gly), c.999T>C (p.Ser333=), c.3548A>G (p.Lys1183Arg), c.3113A>G (p.Glu1038Gly), c.2612C>T (p.Pro871Leu), c.2311T>C (p.Leu771=), c.2082C>T (p.Ser694=) were associated with non-objective response on neoadjuvant chemotherapy (NAC), furthermore effect of chemotherapy was more than 80% without of these mutations. During chemotherapy, 13% of patients showed the appearance of 5 new BRCA1 mutations in the tumor and this is associated with a non-objective response to NAC by taxotere. Overall, our results suggest that it makes sense to take into account not only identified germline mutations, but also somatic changes in the BRCA1 gene when appointment taxotere

Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland.

The premalignant process preceding squamous cell lung cancer is not inevitable; it can stop at any of the bronchial lesions: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia and then progress or regress. At present, the mechanisms underlying the progression of the bronchial lesions remain undefined. Previously, we hypothesized that bronchial lesions that presented individually or combined with each other in the bronchi of lung cancer patients mirror the different ""scenarios"" of the premalignant process: individual BCH-the stoppage at the stage of hyperplasia, BCH plus SM-the progression of hyperplasia to metaplasia, and SM plus dysplasia-the progression of metaplasia to dysplasia. In this study, we analyzed gene expression profiles of BCH, SM, and dysplasia depending on their cooccurrence in the bronchi of lung cancer patients. The immune response gene expression was found to be a key difference between the individual BCH and BCH combined with SM lesions and a potential mechanism that determines the progression of hyperplasia to metaplasia. Upregulation of the cell cycle and downregulation of the cilium assembly genes mainly distinguished SM that copresented with dysplasia from SM that copresented with BCH and is a probable mechanism of the progression of metaplasia to dysplasia. Dysplasia showed mainly overexpression of the cell division genes and underexpression of the inflammation genes. Thus, this study demonstrates the significant gene expression differences between the premalignant lesions depending on their cooccurrence in the bronchi and sheds light on the mechanisms of the precancerous process preceding squamous cell lung cancer.

Current definitions of metabolic syndrome give no idea of the origin and metabolic essence of this medical condition. We have provided arguments that from the point of view of the human post-embryonic ontogenesis, MetS may represent metabolic features of the post-reproductive stage of ontogenesis. At this stage, sexual hormones diminish their influence and energy metabolism in men and women becomes based on predominant utilization of fats and proteins. This proposition is confirmed by the facts that the menopause increases incidence of MetS in aging women. Moreover, in younger women, surgical menopause is strongly linked with a higher incidence of MetS [50]. Because the pressure of natural selection on the post-reproductive stage of ontogenesis was weak, the metabolic features at the post-reproductive stage resemble those of our distant ancestors. We suggest that major symptoms of MetS may originate from the mismatch between the genetically predetermined ancient metabolic pattern and the contemporary lifestyle with excessive consumption carbohydrates and insufficient physical activity of elderly people. Inclusion of ontogenesis into the mechanisms of aging and development of MetS might be helpful in finding pharmacological and non-pharmacological methods to slowdown development of these medical conditions.