New genetic models and mesenchymal cells as tools to ameliorate anti-tumor immunity

Résumé Le but final de ce projet est d'utiliser des cellules T ou des cellules souches mésenchymateuses modifiées génétiquement afin de surexprimer localement les deux chémokines CXCL13 et CCL2 ensemble ou chacune séparément à l'intérieur d'une tumeur solide. CXCL13 est supposé induire des structures lymphoïdes ectopiques. Un niveau élevé de CCL2 est présumé initier une inflammation aiguë. La combinaison des deux effets amène à un nouveau modèle d'étude des mécanismes régulateur de la tolérance périphérique et de l'immunité tumorale. Les connaissances acquises grâce à ce modèle pourraient permettre le développement ou l'amélioration des thérapies immunes du cancer. Le but premier de ce travail a été l'établissement d'un modèle génétique de la souris permettant d'exprimer spécifiquement dans la tumeur les deux chémokines d'intérêt à des niveaux élevés. Pour accomplir cette tâche, qui est en fait une thérapie génétique de tumeurs solides, deux types de cellules porteuses potentielles ont été évaluées. Des cellules CD8+ T et des cellules mésenchymateuses de la moelle osseuse transférées dans des receveurs portant une tumeur. Si on pouvait répondre aux besoins de la thérapie génétique, indépendamment de la thérapie immune envisagée, on posséderait là un outil précieux pour bien d'autres approches thérapeutiques. Plusieurs lignées de souris transgéniques ont été générées comme source de cellules CD8+ T modifiées afin d'exprimer les chémokines d'intérêt. Dans une approche doublement transgénique les propriétés de deux promoteurs spécifiques de cellules T ont été combinées en utilisant la technologie Cre-loxP. Le promoteur de granzyme B confère une dépendance d'activation et le promoteur distal de lck assure une forte expression constitutive dès que les cellules CD8+ T ont été activées. Les transgènes construits ont montré une bonne performance in vivo et des souris qui expriment CCL2 dans des cellules CD8+ T activées ont été obtenues. Ces cellules peuvent maintenant être utilisées avec différents protocoles pour transférer des cellules T cytotoxiques (CTL) dans des receveurs porteur d'une tumeur, permettant ainsi d'évaluer leur capacité en tant que porteuse de chémokine d'infiltrer la tumeur. L'établissement de souris transgéniques, qui expriment pareillement CXCL13 est prévu dans un avenir proche. L'évaluation de cellules mésenchymateuses de la moelle osseuse a démontré que ces cellules se greffent efficacement dans le stroma tumoral suite à la co-injection avec des cellules tumorales. Cela représente un outil précieux pour la recherche, vu qu'il permet d'introduire des cellules manipulées dans un modèle tumoral. Les résultats confirment partiellement d'autres résultats rapportés dans un modèle amélioré. Cependant, l'efficacité et la spécificité suggérées de la migration systémique de cellules mésenchymateuses de la moelle osseuse dans une tumeur n'ont pas été observées dans notre modèle, ce qui indique, que ces cellules ne se prêtent pas à une utilisation thérapeutique. Un autre résultat majeur de ce travail est l'établissement de cultures de cellules mésenchymateuses de la moelle osseuse in vitro conditionnées par des tumeurs, ce qui a permis à ces cellules de s'étendre plus rapidement en gardant leur capacité de migration et de greffe. Cela offre un autre outil précieux, vu que la culture in vitro est un pas nécessaire pour une manipulation thérapeutique. Abstract The ultimate aim of the presented project is to use genetically modified T cells or mesenchymal stem cells to locally overexpress the two chemokines CXCL13 and CCL2 together or each one alone inside a solid tumor. CXCL13 is supposed to induce ectopic lymphoid structures and a high level of CCL2 is intended to trigger acute inflamation. The combination of these two effects represents a new model for studying mechanisms that regulate peripheral tolerance and tumor immunity. Gained insights may help developing or improving immunotherapy of cancer. The primary goal of the executed work was the establishment of a genetic mouse model that allows tumor-specific expression of high levels of the two chemokines of interest. For accomplishing this task, which represents gene therapy of solid tumors, two types of potentially useful carrier cells were evaluated. CD8+ T cells and mesenchymal bone marrow cells to be used in adoptive cell transfers into tumor-bearing mice. Irrespectively of the envisaged immunotherapy, satisfaction of so far unmet needs of gene therapy would be a highly valuable tool that may be employed by many other therapeutic approaches, too. Several transgenic mouse lines were generated as a source of CD8+ T cells modified to express the chemokines of interest. In a double transgenic approach the properties of two T cell-specific promoters were combined using Cre-loxP technology. The granzyme B promoter confers activation-dependency and the lck distal promoter assures strong constitutive expression once the CD8+ T cell has been activated. The constructed transgenes showed a good performance in vivo and mice expressing CCL2 in activated CD8+ T cells were obtained. These cells can now be used with different protocols for adoptively transferring cytotoxic T cells (CTL) into tumor-bearing recipients, thus allowing to study their capacity as tumor-infiltrating chemokine carrier. The establishment of transgenic mice likewisely expressing CXCL13 is expected in the near future. In addition, T cells from generated single transgenic mice that have high expression of an EGFP reporter in both CD4+ and CD8+ cells can be easily traced in vivo when setting up adoptive transfer conditions. The evaluation of mesenchymal bone marrow cells demonstrated that these cells can efficiently engraft into tumor stroma upon local coinjection with tumor cells. This represents a valuable tool for research purposes as it allows to introduce manipulated stromal cells into a tumor model. Therefore, the established engraftment model is suited for studying the envisaged immunotherapy. These results confirm to some extend previously reported results in an improved model, however, the suggested systemic tumor homing efficiency and specificity of mesenchymal bone marrow cells was not observed in our model indicating that these cells may not be suited for therapeutic use. Another major result of the presented work is the establishment oftumor-conditioned in vitro culture of mesenchymal bone marrow cells, which allowed to more rapidly expand these cells while maintaining their tumor homing and engrafting capacities. This offers another valuable tool as in vitro culture is a necessary step for therapeutic manipulations.

Testing new identity models and processes in French-speaking adolescents and emerging adults students

Developing a sense of identity is a crucial psychosocial task for young people. The purpose of this study was to evaluate identity development in French-speaking adolescents and emerging adults (in France and Switzerland) using a process-oriented model of identity formation including five dimensions (i.e., exploration in breadth, commitment making, exploration in depth, identification with commitment, and ruminative exploration). The study included participants from three different samples (total N = 2239, 66.7% women): two samples of emerging adult student and one sample of adolescents. Results confirmed the hypothesized five-factor dimensional model of identity in our three samples and provided evidence for convergent validity of the model. The results also indicated that exploration in depth might be subdivided in two aspects: a first form of exploration in depth leading to a better understanding and to an increase of the strength of current commitments and a second form of exploration in depth leading to a re-evaluation and a reconsideration of current commitments. Further, the identity status cluster solution that emerged is globally in line with previous literature (i.e., achievement, foreclosure, moratorium, carefree diffusion, diffused diffusion, undifferentiated). However, despite a structural similarity, we found variations in identity profiles because identity development is shaped by cultural context. These specific variations are discussed in light of social, educational and economic differences between France and the French-speaking part of Switzerland. Implications and suggestions for future research are offered.

Real wage rigidities and the new Keynesian model

Most central banks perceive a trade-off between stabilizing inflation and stabilizing the gap between output and desired output. However, the standard new Keynesian framework implies no such trade-off. In that framework, stabilizing inflation is equivalent to stabilizing the welfare-relevant output gap. In this paper, we argue that this property of the new Keynesian framework, which we call the divine coincidence, is due to a special feature of the model: the absence of non trivial real imperfections.We focus on one such real imperfection, namely, real wage rigidities. When the baseline new Keynesian model is extended to allow for real wage rigidities, the divine coincidence disappears, and central banks indeed face a trade-off between stabilizing inflation and stabilizing the welfare-relevant output gap. We show that not only does the extended model have more realistic normative implications, but it also has appealing positive properties. In particular, it provides a natural interpretation for the dynamic inflation-unemployment relation found in the data.

Labor markets and monetary policy: A new-Keynesian model with unemployement

We construct a utility-based model of fluctuations, with nominal rigidities andunemployment, and draw its implications for the unemployment-inflation trade-off and for the conduct of monetary policy.We proceed in two steps. We first leave nominal rigidities aside. We show that,under a standard utility specification, productivity shocks have no effect onunemployment in the constrained efficient allocation. We then focus on theimplications of alternative real wage setting mechanisms for fluctuations in un-employment. We show the role of labor market frictions and real wage rigiditiesin determining the effects of productivity shocks on unemployment.We then introduce nominal rigidities in the form of staggered price setting byfirms. We derive the relation between inflation and unemployment and discusshow it is influenced by the presence of labor market frictions and real wagerigidities. We show the nature of the tradeoff between inflation and unemployment stabilization, and its dependence on labor market characteristics. We draw the implications for optimal monetary policy.

The new Keynesian approach to monetary policy analysis: Lessons and new directions

I discuss several lessons regarding the design and conduct of monetary policy that have emerged out of the New Keynesian research program. Those lessons include the bene.ts of price stability, the gains from commitment about future policies, the importance of nat-ural variables as benchmarks for policy, and the bene.ts of a credible anti-inflationary stance. I also point to one challenge facing NK modelling efforts: the need to come up with relevant sources of policy tradeoffs. A potentially useful approach to meeting that challenge, based on the introduction of real imperfections, is presented.

MANAGING STRATEGIC CHANGE:New Business Models Applying Wireless Technology as a Source of Competitive Edge

The diffusion of mobile telephony began in 1971 in Finland, when the first car phones, called ARP1 were taken to use. Technologies changed from ARP to NMT and later to GSM. The main application of the technology, however, was voice transfer. The birth of the Internet created an open public data network and easy access to other types of computer-based services over networks. Telephones had been used as modems, but the development of the cellular technologies enabled automatic access from mobile phones to Internet. Also other wireless technologies, for instance Wireless LANs, were also introduced. Telephony had developed from analog to digital in fixed networks and allowed easy integration of fixed and mobile networks. This development opened a completely new functionality to computers and mobile phones. It also initiated the merger of the information technology (IT) and telecommunication (TC) industries. Despite the arising opportunity for firms' new competition the applications based on the new functionality were rare. Furthermore, technology development combined with innovation can be disruptive to industries. This research focuses on the new technology's impact on competition in the ICT industry through understanding the strategic needs and alternative futures of the industry's customers. The change speed inthe ICT industry is high and therefore it was valuable to integrate the DynamicCapability view of the firm in this research. Dynamic capabilities are an application of the Resource-Based View (RBV) of the firm. As is stated in the literature, strategic positioning complements RBV. This theoretical framework leads theresearch to focus on three areas: customer strategic innovation and business model development, external future analysis, and process development combining these two. The theoretical contribution of the research is in the development of methodology integrating theories of the RBV, dynamic capabilities and strategic positioning. The research approach has been constructive due to the actual managerial problems initiating the study. The requirement for iterative and innovative progress in the research supported the chosen research approach. The study applies known methods in product development, for instance, innovation process in theGroup Decision Support Systems (GDSS) laboratory and Quality Function Deployment (QFD), and combines them with known strategy analysis tools like industry analysis and scenario method. As the main result, the thesis presents the strategic innovation process, where new business concepts are used to describe the alternative resource configurations and scenarios as alternative competitive environments, which can be a new way for firms to achieve competitive advantage in high-velocity markets. In addition to the strategic innovation process as a result, thestudy has also resulted in approximately 250 new innovations for the participating firms, reduced technology uncertainty and helped strategic infrastructural decisions in the firms, and produced a knowledge-bank including data from 43 ICT and 19 paper industry firms between the years 1999 - 2004. The methods presentedin this research are also applicable to other industries.

New business models for open research

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

NEW BUSINESS MODELS – Sustainability as a main focus

A business model is a structure frame of an organization that can bring significant benefits and competitive advantage when structured properly. The aim of this paper was to observe and describe development of business models’ and identify factors and elements of a business model that are in a key role from the perspective of an organizational sustainability. One is striving to bring out in this thesis how should truly sustainable business model look like and what are main characteristics of it. Additionally, some recommendations that could be helpful in order to build sustainable and balanced business model in a company are presented in this work. The meaning was to make theoretical and in some extent practical acquaintance with such new business models as open business model and sustainable business model. Long-term sustainability achievement in a company was in a centric role and used as a main criteria when constructing sustainable business model structure. The main research question in this study aims to answer: What a firm should consider in order to develop profitable and sustainable business model? This study is qualitative in nature and it was conducted using content analyze as a main method of this research. The perspective of the target data in this study is an outlook of its producers of how sustainability is reached in an organization throw business model and which practices are important and has to be taken into account. The material was gathered mainly from secondary sources and the theoretical framework was outright built based on secondary data. The secondary data that have been mostly dissertations, academic writings, cases, academic journals and academic books have been analyzed from the point of view of sustainability perspective. As a result it became evident that a structure of a business model and its implementation along with a strategy is often what leads companies to success. However, for the most part, overall business environment decides and delimits how the most optimal business model should be constructed in order to be effective and sustainable. The evaluation of key factors and elements in business model leading organization to sustainability should be examined throw triple bottom line perspective, where key dimensions are environmental, social and economic. It was concluded that dimensions should be evaluated as equal in order to attain total long lasting sustainability, contradicting traditional perspective in business where profit production is seen as only main goal of a business.

New Architectural Models for Visibly Controllable Computing: The Relevance of Dynamic Object Oriented Architectures and Plan Based Computing Models

Traditionally, we've focussed on the question of how to make a system easy to code the first time, or perhaps on how to ease the system's continued evolution. But if we look at life cycle costs, then we must conclude that the important question is how to make a system easy to operate. To do this we need to make it easy for the operators to see what's going on and to then manipulate the system so that it does what it is supposed to. This is a radically different criterion for success. What makes a computer system visible and controllable? This is a difficult question, but it's clear that today's modern operating systems with nearly 50 million source lines of code are neither. Strikingly, the MIT Lisp Machine and its commercial successors provided almost the same functionality as today's mainstream sytsems, but with only 1 Million lines of code. This paper is a retrospective examination of the features of the Lisp Machine hardware and software system. Our key claim is that by building the Object Abstraction into the lowest tiers of the system, great synergy and clarity were obtained. It is our hope that this is a lesson that can impact tomorrow's designs. We also speculate on how the spirit of the Lisp Machine could be extended to include a comprehensive access control model and how new layers of abstraction could further enrich this model.

The small open-economy New Keynesian Phillips Curve: empirical evidence and implied inflation dynamics

In this paper we apply GMM estimation to assess the relevance of domestic versus external determinants of CPI inflation dynamics in a sample of OECD countries typically classified as open economies. The analysis is based on a variant of the small open-economy New Keynesian Phillips Curve derived in Galí and Monacelli (Rev Econ Stud 72:707–734, 2005), where the novel feature is that expectations about fluctuations in the terms of trade enter explicitly. For most countries in our sample the expected relative change in the terms of trade emerges as the more relevant inflation driver than the contemporaneous domestic output gap.

New Business Models And Editorial Exemption: A Study On Service Journalism Based On Ecommerce Operations

The paper presents and discusses business strategies based on the association from journalistic content to new commercial practices in digital media. We describe selected examples from Folha de S. Paulo and El País involving service guides, links and ecommerce advertisements. The employed method provides content analysis to illustrate how the search for new business models in journalism may conduct its commercial activities beyond the conventional sale of advertising and subscriptions, including a discussion on the challenges and implications of this practice. The hypothesis is demonstrated by describing operations for the sale of tickets, books, music, and films related to news features and service journalism contents. The text finally wonders and discusses how such commercial actions may affect editorial autonomy and publishing exemption.