Molecular pathways: Sterols and receptor signaling in cancer

Accelerated cholesterol and lipid metabolism are the hallmarks of cancer and contribute to malignant transformation due to the obligatory requirement for cholesterol for the function of eukaryotic membranes. To build new membranes and maintain active signaling, cancer cells depend on high intensity of endogenous cholesterol biosynthesis and uptake of lipid particles. This metabolic dependency of cancer cells on cholesterol and other lipids is tightly regulated by the cholesterol homeostasis network, including (i) sterol response element-binding proteins (SREBP), master transcriptional regulators of cholesterol and fatty acid pathway genes; (ii) nuclear sterol receptors (liver X receptors, LXR), which coordinate growth with the availability of cholesterol; and (iii) lipid particle receptors, such as low-density lipid particle (LDL) receptor, providing exogenous sterol and lipids to cancer cells. In addition, activity of oncogenic receptors, such as MUC1 or EGFR, accelerates sterol uptake and biosynthesis. Therefore, a general strategy of reducing the cholesterol pool in cancer cells is challenged by the highly efficient feedback loops compensating for a blockade at a single point in the cholesterol homeostatic network. Besides the well-established structural role of cholesterol in membranes, recent studies have uncovered potent biologic activities of certain cholesterol metabolic precursors and its oxidized derivatives, oxysterols. The former, meiosis-activating sterols, exert effects on trafficking and signaling of oncogenic EGF receptor (EGFR). Cholesterol epoxides, the highly active products of cholesterol oxidation, are being neutralized by the distal sterol pathway enzymes, emopamyl-binding protein (EBP) and dehydrocholesterol-7 reductase (DHCR7). These recently discovered "moonlighting" activities of the cholesterol pathway genes and metabolites expand our understanding of the uniquely conserved roles these sterol molecules play in the regulation of cellular proliferation and in cancer. Clin Cancer Res; 20(1); 28-34. © 2013 AACR

An Analysis of the Vocational-Educational Problematics for Substantiating Production Specialist Competencies

Introduction. Today, the system of secondary vocational education (SVE) is faced by a multi-factorial problem: the training of qualified specialists, taking into account approved federal unified standards; the fulfillment of potential employers’ requirements, which often do not coincide with these standards; and the determination of rapid responses to continuous changes in labour market conditions, i. e. the requirement for a qualitative human resources upgrade in regional production clusters and holding companies, as well as numerous small enterprises. The aim of the research was to develop a methodology for analysing vocational-educational problematics. The methodology was designed for the differentiation, specification and justification of relevant specialised competencies, which complement universal and general professional competencies documented in educational standards.Methodology and research methods. As a research methodology, a causal approach was used, specifically implemented in the form of a multi-dimensional matrix informing a stage-by-stage analysis, which links the need for qualified personnel (experts, who have necessary competencies) with the pedagogical conditions for their preparation (formation of necessary competencies in students).Results and scientific novelty. We present a recommendation for the organisational and content-based improvement of specialist education in terms of key SVE tasks and factors. This education should be conducted by means of systematic identification and assessment of multi-dimensional regional and sectoral needs for trained personnel, projections of results of monitoring on educational programmes and development of means for the acquisition of the relevant skills. The structure and algorithm of multi-dimensional matrix analysis, providing a stageby-stage presentation of problems found in industrial enterprises concerning specified SVE graduate competencies, are described and visually presented. This also enables to effectively build and timely adjust the learning process of really demanded, competitive experts capable to realise innovative projects, to master and create new equipment, i. e. to keep the successful operation and development of production and economics of a region and a country in general. The logic-semantic model of formation of transprofessional competencies, which integrates technological, informational, legislative and communicative-interprofessional components, is designed. The model consists of eight coordinate axes (“Structure of package tasks”, “Significant factors”, “Components”, “Theoretical bases”, “Implementation”, “Criteria of formation of competencies”, “Result”, “Strategic partners”) and reflects internal interrelations between all the elements of process of vocational education.Practical significance. The materials of the research and its results complement the theory and practice of vocational education, on the one hand, by new tools for development of federal and other standards, on the other hand, by methodological means of rational choice and justification through the introduction of the specific profile of variable professional competencies into SVE programmes. The authors proposed the methodological and graphic solutions of the problems and the recommendations, which can be used in the organisations of vocational education.Введение. Сегодня системе среднего профессионального образования (СПО) приходится решать многофакторную задачу – готовить квалифицированных специалистов, ориентируясь на утвержденные федеральные унифицированные нормативы, учитывать часто несовпадающие с этими нормативами требования потенциальных работодателей выпускников и оперативно реагировать на непрерывные изменения конъюнктуры рынка труда – запросы на новое, повышенное качество кадрового состава региональных производственных кластеров и холдингов, а также многочисленных малых предприятий.Цель изложенного в публикации исследования состояла в разработке методики анализа профессионально-образовательной проблематики, предназначенной для дифференциации, детализации и обоснования актуальных специализированных компетенций, дополняющих зафиксированные в образовательных стандартах универсальные и общепрофессиональные компетенции. Методология и методики. Работа выполнялась с опорой на каузальный или причинно-следственный, подход, воплощенный в форме многомерно-матричного поэтапного анализа, связывающего производственные потребности в квалифицированных кадрах (специалистах, обладающих необходимыми компетенциями) с педагогическими условиями их подготовки (формирования у обучающихся этих необходимых компетенций). Результаты и научная новизна. Исходя из основных факторов ключевой для СПО задачи, предложена концепция совершенствования организации и содержания подготовки специалистов посредством планомерного выявления и оценки многоаспектных варьирующихся нужд регионального производственного сектора в обученных кадрах и проецирования результатов данного мониторинга на образовательные программы и способы их усвоения. Описаны и визуально представлены структура и алгоритм многомерно-матричного анализа, проведение которого предусматривает поэтапное наложение обнаруживаемых у отраслевых предприятий проблем на перманентно уточняющиеся компетенции выпускников СПО, что позволяет эффективно выстраивать и своевременно корректировать процесс подготовки действительно востребованных, конкурентоспособных специалистов, готовых претворять в жизнь инновационные проекты, осваивать и создавать новую технику, т. е. поддерживать успешное функционирование и развитие производства и экономики региона и страны в целом. Сконструирована логико-смысловая модель формирования транспрофессиональных компетенций, объединяющих технологические, информационные, нормативно-правовые и коммуникативно-межпрофессиональные компоненты. Модель, состоящая из восьми координатных осей («Структура пакетных задач», «Значимые факторы», «Компоненты», «Теоретические основы», «Практическая реализация», «Критерии сформированности компетенций», «Результат», «Стратегические партнеры»), отражает внутренние взаимосвязи между всеми элементами процесса профессиональной подготовки. Практическая значимость. Материалы исследования и его результаты дополняют теорию и практику профессионального образования, с одной стороны, новым инструментарием для разработки федеральных и иных стандартов, с другой – методическими средствами рационального выбора и обоснования введения в программы СПО конкретного профиля вариативных профессиональных компетенций. Предложенные авторами методические и графические решения обсуждаемых в статье проблем и подготовленные на их основе рекомендации могут быть массово использованы в организациях профессионального образования

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

© 2015 The Authors. Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRASG12D. Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling

Experience the group correction of problems of socialization in adolescents with mental retardation in a hospital

The purpose of the study is the development and approbation of group classes purposeed at the adaptation of adolescents with mental retardation in a hospital setting.Цель исследования – разработка и апробация групповых занятий, направленных на адаптацию подростков с умственной отсталостью к нормам социальных отношений, в условиях стационара

Об одном опыте музыкального коллекционирования: проект «Жизнь замечательных мелодий»

The article presents the experience of musical collectibles using the method of comparative music and technical means. In the formation of audio content, cultural and educational tasks were solved; thanks to the use of information technology tools, the Life of Remarkable Melodies training program has been created, protected (as RIA).В статье представлен опыт музыкального коллекционирования с использованием метода сравнительного музыкослушания и технических средств. При формировании аудиоконтента решались культурологические и образовательные задачи; благодаря использованию информационно-технологических средств создан Обучающий программный комплекс «Жизнь замечательных мелодий», защищенный (как РИД)

Thirteen-Year Follow-Up of a Patient with Liver Cirrhosis Resulting from the Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cholangitis: Severe COVID-19 and Liver Transplantation

Aim: to present the difficulties of long-term management of a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) who suffered from severe COVID-19 infection.Key points. The diagnosis of liver cirrhosis as an outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) was established at the patient’s age of 33 years. At the age of 40, the patient became pregnant for the first time, the pregnancy proceeded well, and a cesarean section was performed at 36 weeks. At the age of 45, the patient suffered a severe new coronavirus infection, followed by decompensation of liver cirrhosis, which required liver transplantation 4 months after COVID-19, followed by a favorable postoperative course.Conclusion. This clinical case demonstrates the successful onset and outcome of pregnancy in a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis). The pronounced activity of the disease after severe new coronavirus infection required liver transplantation with successful outcome

Реализация стандартов четвертого поколения: обоснование специализированных и дополнительных компетенций

The article considers a testing approach to explanation of special and university competencies of prospective specialists through detailed analysis of professional and educational issues of the regional production cluster.В статье рассматривается апробируемый подход к обоснованию специализированных и дополнительных компетенций будущих специалистов путем поэтапного анализа профессионально-образовательной проблематики регионального производственного кластера международных связей

Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target in pancreatic cancer

©2016 AACR.Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. Experimental Design: We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically. Results: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro. Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors. Conclusions: This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers

Molecular pathways: Sterols and receptor signaling in cancer

Accelerated cholesterol and lipid metabolism are the hallmarks of cancer and contribute to malignant transformation due to the obligatory requirement for cholesterol for the function of eukaryotic membranes. To build new membranes and maintain active signaling, cancer cells depend on high intensity of endogenous cholesterol biosynthesis and uptake of lipid particles. This metabolic dependency of cancer cells on cholesterol and other lipids is tightly regulated by the cholesterol homeostasis network, including (i) sterol response element-binding proteins (SREBP), master transcriptional regulators of cholesterol and fatty acid pathway genes; (ii) nuclear sterol receptors (liver X receptors, LXR), which coordinate growth with the availability of cholesterol; and (iii) lipid particle receptors, such as low-density lipid particle (LDL) receptor, providing exogenous sterol and lipids to cancer cells. In addition, activity of oncogenic receptors, such as MUC1 or EGFR, accelerates sterol uptake and biosynthesis. Therefore, a general strategy of reducing the cholesterol pool in cancer cells is challenged by the highly efficient feedback loops compensating for a blockade at a single point in the cholesterol homeostatic network. Besides the well-established structural role of cholesterol in membranes, recent studies have uncovered potent biologic activities of certain cholesterol metabolic precursors and its oxidized derivatives, oxysterols. The former, meiosis-activating sterols, exert effects on trafficking and signaling of oncogenic EGF receptor (EGFR). Cholesterol epoxides, the highly active products of cholesterol oxidation, are being neutralized by the distal sterol pathway enzymes, emopamyl-binding protein (EBP) and dehydrocholesterol-7 reductase (DHCR7). These recently discovered "moonlighting" activities of the cholesterol pathway genes and metabolites expand our understanding of the uniquely conserved roles these sterol molecules play in the regulation of cellular proliferation and in cancer. Clin Cancer Res; 20(1); 28-34. © 2013 AACR