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Рассмотрены понятие, сущность и классификация инвестиций, механизм инвестиционного планирования на предприятии и государственный инвестиции в федеральные округи России. Также были проанализированы существующие методики управления инвестиционными проектами и обоснована необходимость реализации проектов технического перевооружения на ФГУП УЭМЗ. Была разработана интегрированная методика подготовки инвестиционных проектов, которая включает в себя как этапы подготовки проекта в пределах ФГУП УЭМЗ, так и этапы рассмотрения документации по проекту на уровне ГК «Росатом», что повысит эффективность инвестиционной деятельности предприятия путем расширения инвестиционного портфеля за счет проектов, финансируемых из консолидированного ресурса ГК «Росатом»; был произведен расчет показателей инвестиционной привлекательности проекта технического перевооружения производственного подразделения ФГУП УЭМЗ. / Examines the concept, nature and classification of investments, the mechanism of investment planning at the enterprise and state investments in Federal districts of Russia. Also analysed the existing methods of management of investment projects and the necessity of implementation of projects of technical re-equipment of the FSUE UEMP. Developed the integrated methodology of investment projects preparation, which includes stages of preparation of the project within the FSUE UEMP, and the stages of processing of project documentation at the level of Rosatom, which will increase the effectiveness of the company's investment activities through expansion of the investment portfolio at the expense of projects financed from the consolidated resource of Rosatom state Corporation; has been made to the calculation of indicators of investment attractiveness of the project of technical re-equipment of the production unit of the FSUE UEMP.

The relevance of the work. Currently, there is an introduction of the modern methods and management tools. Program-target management is the one of such tools. The essence of the program-target approach is to offer a way to solve the most important economic and social problems, which involves the development of a system of policy measures to minimize or even eliminate the problem. The object of the research is the implementation of the program – target management in the educational organization development. The subject of the research is the program-target management of the educational organization as a tool of its development. The purpose of the study is to analyze the program – target management of the educational organization development on the basis of the state policy, and to develop a program of the educational organization development. Scientific and practical novelty of the results: We have clarified the basic concepts of the program-target management and identified its characteristics at the municipal level; The system of principles of the organization of program-target management of the educational organization development is proved; We have also identified the main defects of the organizational and productive solutions in the modern Russian practice; the program of the educational organization development is developed; We have justified the productive options of the basic tasks for improving the program-target management organization. The practical significance of the results is that the analysis of 10 programs of development of the educational institutions of Yekaterinburg is made, and the main indicators of development which include strict reporting and rating of the results are identified. / Объект исследования – реализация программно-целевого управления в развитии общеобразовательной организации. Предмет исследования – программно-целевое управление общеобразовательной организации как инструмент развития. Цель исследования – проанализировать программно-целевое управление развитием общеобразовательной организации на основе государственной политики и разработать программу развития общеобразовательной организации. Практическая значимость полученных результатов состоит в том, что осуществлен анализ 10 программ развития общеобразовательных организаций г. Екатеринбурга и определены основные индикаторы развития, которые включают в себя строгую отчетность и рейтингование полученных результатов. Однако, как показало исследование, в программах отсутствует такой показатель как «эффективность». Предложенная программа развития общеобразовательной организации представляет собой методическое руководство к ее разработке.

The author focuses on the fact that at the present stage the information support of the population is becoming one of the most important tasks of state authorities and social protection, in particular. The main priority of the social protection authorities in this area is that citizens receive the necessary information as quickly as possible, regardless of their location and reduction in the number of citizens who need social support, but do not receive it due to the lack of information about their rights. The paper reveals the theoretical, regulatory, and practical foundations for organizing public information on social support measures, and gives recommendations for its improvement. / Автор акцентирует внимание на том, что на современном этапе информационное обеспечение населения становится одной из важнейших задач органов государственной власти и социальной защиты, в частности. Основным приоритетом органов социальной защиты в данной области является как можно более быстрое получение гражданами необходимой информации, независимо от места их нахождения и снижение количества граждан, которые нуждаются в оказании социальной поддержки, но не получают ее из-за отсутствия информации о своих правах. В работе раскрываются теоретические, нормативно-правовые и практические основы деятельности по организации информирования населения о мерах социальной поддержки, даются рекомендации по ее совершенствованию.

Möjligheten för aktiemarknadsbolag att kunna genomföra riktade nyemissioner av aktier är ett viktigt inslag på marknaden – inte minst för bolagens kapitalanskaffning. Men med möjligheter kommer också, ofta, risker. Så även här. När en riktad nyemission genomförs och huvudregeln om aktieägarnas företrädesrätt därmed frångås, uppkommer en risk för att befintliga aktieägare, åtminstone vissa av dem, missgynnas. Så sker vanligtvis genom att de aktieägare som står utanför nyemissionen upplever en ekonomisk eller inflytandemässig utspädning av sina innehav. I syfte att reglera dessa risker finns det – inom såväl aktiebolags- som aktiemarknadsrätten – vissa begränsningar som aktiemarknadsbolag behöver iaktta vid beslut om riktade nyemissioner av aktier. Syftet med denna uppsats är att utreda, formulera och diskutera dessa påstådda begränsningar. Den första begränsningen består av beslutsreglerna i ABL, det vill säga reglerna som föreskriver de åtgärder som behöver vidtas inför, vid och efter ett emissionsbeslut. Dessa regler återfinns främst i 13 kap. ABL och innefattar bland annat krav på att ett förslag till beslut ska upprättas och på att beslut fattas med kvalificerad majoritet. Likabehandlingsreglerna i ABL, främst generalklausulerna, utgör den andra begränsningen. En prövning mot generalklausulerna innebär att bolaget i fråga inte får genomföra en riktad nyemission som på ett otillbörligt sätt gynnar någon, en aktieägare eller utomstående, på annan aktieägares bekostnad. Otillbörlighetsrekvisitet inbegriper en helhetsbedömning med fokus på de affärsmässiga motiven, bolagets intresse och förekomsten av missbruk. Nyemissioner torde stå i strid med generalklausulerna i undantagsfall, mot bakgrund av att de är tänkta att tillämpas restriktivt. Den tredje begränsningen som – till skillnad från de två tidigare kategorierna – inte är aktiebolagsrättslig, omfattar de ytterligare krav som aktiemarknadsrättens självreglering, främst god sed på aktiemarknaden, ställer. Med ett fåtal undantag tycks dock några sådana ytterligare eller högre krav inte finnas, vilket ger vid handen att aktiebolags- och aktiemarknadsrätten i hög grad är överlappande på området. De rättsliga följderna av att begränsningarna inte iakttas är, beroende på den enskilda situationen, framför allt klander, skadestånd eller ”marknadens dom”. Slutsatsen är att de tre begränsningarna på ett rimligt sätt balanserar majoritetens och bolagets intresse av en effektiv kapitalanskaffning och minoritetens behov av skydd. Undantag gäller eventuellt för de två generalklausulerna, vilkas tillämpningsområden, främst på grund av otillbörlighetsrekvisitet, är förhållandevis otydliga. Det hade därför varit önskvärt att grunderna för den bedömningen konkretiserades i den vägledande rättstillämpningen framöver.

AREG und EREG sind Liganden des EGFR, deren Expression mit einem positiven EGFR-zielgerichtetem Therapieansprechen in Darmkrebs korreliert. Ziel dieser Arbeit war es, einen epigenetischen Einfluss auf die AREG und EREG Expression zu klären. Es wurde gezeigt, dass AREG und EREG in verschiedenen kolorektalen Krebszelllinien differenziell exprimiert sind, und dass die Expression beider Gene durch epigenetische Inhibitoren erhöht werden kann. Eine Analyse in fünf Zelllinien zeigte jedoch, dass die Promotoren beider Gene hauptsächlich unmethyliert vorlagen. Hingegen wurden kurze Regionen im Gen als differentiell methyliert identifiziert. Im AREG Gen liegt diese Region im Exon 2, was auf einen ungewöhnlichen Regulationsmechanismus hindeutet. Promotorfunktionsanalysen zeigten dann, dass diese Region eine methylierungs- und orientierungsabhängige Promotorfunktion hat, in die das MDB-Protein CTCF involviert sein könnte. Expressionsanalysen wiesen darauf hin, dass auch ZBTB33, ein anderes MDB-Protein, in die AREG Regulation involviert sein könnte. Die ZBTB33 Expression korrelierte negativ mit der AREG Expression in den Zelllinien. Eine ZBTB33-Bindungsstelle konnte ausserdem bioinformatorisch im AREG Exon 2 identifiziert werden. Des weiteren wurde gezeigt, dass die Behandlung der Zelllinie LIM1215 mit HDAC Inhibitoren in vitro zu einer Erhöhung der Sensitivität gegenüber EGFR-zielgerichteten Medikamenten führt, begleitet von einer Erhöhung der AREG und EREG Expression. Im in vivo Versuch konnte die Sensitivität von LIM1215 Zellen durch die Behandlung mit DNMT Inhibitoren erhöht werden. Begleitet wurde dies hier mit einer Verringerung der Methylierung der AREG und EREG intragenischen CpGs. Diese Ergebnisse zeigen auf, dass Patienten, die resistent gegenüber EGFR-zielgerichteten Therapien sind, möglicherweise sensitiv gemacht werden können. In dem Fall könnten AREG und EREG als prädiktive Marker eingesetzt werden, um den Effekt der epigenetischen Inhibitoren zu evaluieren. / AREG and EREG are ligands of the EGFR whose expression correlates with a positive EGFR-targeted therapy response in colorectal cancer. Aim of this work was to define the influence of epigenetic mechanisms on AREG and EREG gene expression. It could be shown that AREG and EREG are differentially expressed in a set of colorectal cancer cell lines and that the expression of both genes increases after treatment with epigenetically interfering compounds such as DNMT inhibitors and HDAC inhibitors. Methylation analysis showed that the promoters of both genes were mainly unmethylated. Nevertheless, short intragenic regions were identified to be differentially methylated. For AREG, this region is located within exon 2, indicating an uncommon epigenetic regulatory mechanism. Promoter function analyses showed that the AREG exon 2 region harbor methylation- and orientation dependent promoter function and they suggested CTCF, an MDB-protein, to be involved in this mechanism. Expression analysis experiments suggested also ZBTB33, another MDB-protein, to be involved in AREG regulation. ZBTB33 was differentially expressed in the cells and it correlated inversely with the AREG expression. Additionally, bioinformatic analyses identified a ZBTB33 binding site within AREG exon 2. It was also shown in this work that LIM1215 cells treated with HDACis were more sensitive towards EGFR inhibitors in vitro. This effect was accompanied by an increased AREG and EREG expression. In vivo, an increased sensitivity towards EGFR inhibitors was achieved in LIM1215 cells by treatment with a DNMT inhibitor. Here the effect was accompanied by a reduced methylation within the AREG and EREG intragenic CpGs. Together, the results suggested a new possibility to potentially make EGFR-targeted therapy resistant patients suitable for this therapy by epigenetic compound treatment. In that case AREG as well as EREG might be predictive markers to evaluate the effect of the epigenetic compounds during therapy.

Delivery of siRNAs for the treatment of tumors critically depends on the development of efficient nucleic acid carrier systems. The complexation of dendritic polymers (dendrimers) results in nanoparticles, called dendriplexes, that protect siRNA from degradation and mediate non-specific cellular uptake of siRNA. However, large siRNA doses are required for in vivo use due to accumulation of the nanoparticles in sinks such as the lung, liver, and spleen. This suggests the exploration of targeted nanoparticles for enhancing tumor cell specificity and achieving higher siRNA levels in tumors. In this work, we report on the targeted delivery of a therapeutic siRNA specific for BIRC5/Survivin in vitro and in vivo to tumor cells expressing the surface marker prostate stem cell antigen (PSCA). For this, polyplexes consisting of single-chain antibody fragments specific for PSCA conjugated to siRNA/maltose-modified poly(propylene imine) dendriplexes were used. These polyplexes were endocytosed by PSCA-positive 293TPSCA/ffLuc and PC3PSCA cells and caused knockdown of reporter gene firefly luciferase and Survivin expression, respectively. In a therapeutic study in PC3PSCA xenograft-bearing mice, significant anti-tumor effects were observed upon systemic administration of the targeted polyplexes. This indicates superior anti-tumor efficacy when employing targeted delivery of Survivin-specific siRNA, based on the additive effects of siRNA-mediated Survivin knockdown in combination with scFv-mediated PSCA inhibition. Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play also a prominent role in plasmid DNA delivery. However, limitations of polycationic polymer-based DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression, and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies (scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise β cyclodextrin-modified PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted transposition of a codon-optimized p53 into p53 deficient HCT116p53-/-/PSCA cells demonstrated decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping Beauty gene transposition, which, due to the modular design, can be extended to other target genes and tumor entities.

Le présent mémoire traite de la publicité comportementale en ligne (ci-après « PCL ») suite à la récente et importante vague de resserrements législatifs, des décisions judiciaires et enquêtes du CPVP, ainsi qu’aux récentes modifications technologiques impactant les pratiques de PCL. À la manière d’un guide, il y est recensé, décrit et analysées les obligations des entreprises participants à la PCL sous l’angle du droit à la vie privée et à la protection des renseignements personnels. Les enjeux et les principales zones d’ombre problématiques y sont identifiés et analysés, tel le critère de nécessité, l’exigence d’anonymisation et l’obligation de consentement, en incluant les enseignements des récentes décisions et enquêtes du CPVP. Une comparaison avec le cadre règlementaire de l’Union européenne est proposée sur certains points jugés plus pertinents. Le présent mémoire inclut une réflexion non seulement sur les obligations clés et leur évolution récente et rapide au Québec et au Canada dans un contexte de resserrement à l’international, mais également sur la PCL en soi en émettant des questionnements et des pistes de réflexion pour l’amélioration des pratiques. Ainsi, ce mémoire contient un volet pratique prononcé et un volet théorique qui se nourrissent l’un de l’autre. La partie I est un état des lieux où sont mises en lumière la complexité factuelle et juridique entourant la PCL, incluant une observation et une réflexion sur les interactions entre les différents acteurs (organisations, organismes d’autoréglementation, autorités de contrôle) et leur rôle dans la création et l’évolution des normes formelles et informelles. La partie II est consacrée à l’analyse des principales obligations incombant aux entreprises du secteur privé participant à la PCL en vertu de la LPRPDE et du Projet de loi C-27 au fédéral ainsi que des récentes modifications apportées par la Loi 25 au Québec en matière de protection des renseignements personnels. Finalement, la partie III propose une analyse de l’exercice de contrôle de l’utilisateur et des limites du consentement. / This master’s thesis is about online behavioral advertising (hereafter “OBA”). Like a guide, it lists, describes and analyzes the obligations of companies participating in the OBA from the perspective of the right to privacy and the protection of personal information. The issues and the main problematic gray areas are identified and analyzed, such as the criterion of necessity, the requirement of anonymization and the obligation of consent, including the lessons of recent decisions and investigations by the OPC. A comparison with the regulatory framework of the European Union is proposed on certain points deemed more relevant. This thesis includes a reflection not only on the key obligations and their recent and rapid evolution in Quebec and Canada in a context of international tightening, but also on the OBA itself by raising questions and lines of thought for improving practices. Thus, this dissertation contains a pronounced practical component and a theoretical component which feed off each other. Part I is an inventory highlighting the factual and legal complexity surrounding the OBA, including an observation and reflection on the interactions between the different actors (organizations, self-regulatory bodies, supervisory authorities) and their role in the creation and evolution of formal and informal norms. Part II is devoted to the analysis of the main obligations incumbent on private sector companies participating in the OBA under PIPEDA and draft law C-27 at the federal level and Bill 25 in Quebec with regards to the protection of personal information. Finally, Part III analyzes the exercise of user control and the limits of consent.

Background: Humanmilk oligosaccharides (HMOs) support and concurrently shape the neonatal immune system through various mechanisms. Thereby, they may contribute to lower incidence of infections in infants. However, there is limited evidence on the role of individual HMOs in the risk of otitis media (OM), as well as lower and upper respiratory tract infections (LRTI and URTI, respectively) in children up to 2 years. Objective: To investigate whether individual HMO concentrations measured at 6 weeks of lactation were associated with risk of OM, LRTI or URTI up to 2 years in breastfed infants. Associations with OM, LRTI and URTI were determined for the most prominent human milk oligosaccharides including 13 neutral, partly isomeric structures (trioses up to hexaoses), two acidic trioses, and lactose. Design: HMO measurements and physician reported data on infections were available from human milk samples collected at 6 weeks postpartum (n = 667). Associations of HMOs with infections were assessed in crude and adjusted models using modified Poisson regression. Results: Absolute concentrations (median [min, max], in g/L) of 2′-fucosyllactose (2′-FL) tended (p = 0.04) to be lower, while lacto-N-tetraose (LNT) was higher in the milk for infants with OM in the 1st year of life (p = 0.0046). In the milk of secretor mothers, LNT was significantly higher in the milk for infants with OM (RR [95% CI]: 0.98 [0.15, 2.60]) compared to infants without OM (RR [95% CI]: 0.76 [0.14, 2.90]) at 1 year (p = 0.0019). No statistically significant milk group differences and associations were observed for OM, LRTI, and URTI (p > 0.0031). Conclusion: Our findings suggest that neither prominent neutral individual HMOs (ranging from 2′-FL to LNDFHs) nor acidic human milk sialyllactoses or lactose are significantly associated with a reduced or increased risk of infections in infants up to 2 years of age. Further research is needed to determine whether specific HMOs could potentially reduce the incidence or alleviate the course of distinct infections in early life.

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