Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs. Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated. The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.

The thesis explains the formation of the PPP project feasibility study as an essential document in the preparatory phase of the project lifecycle. Its closer focus is on the economic evaluation of the investment project implementation using the PPP compared to the implementation using public procurement. The practical part refers to a specific example of calculating of the public sector comparator that is compared with the referential project and a value of money is determined as an indicator of profitability of both forms of implementation.

O presente trabalho tem por objetivo apresentar ao leitor as diversas formas de garantia que poderão ser oferecidas ao particular, pelo Estado, como forma de atraí-lo à contratação de parcerias público-privadas, instituídas em âmbito federal pela lei nº. 11.079, de 30 de dezembro de 2004. A escassez de recursos públicos, culminando com a incapacidade estatal de investir em áreas de sua responsabilidade, fez com que se buscassem novas formas de interação entre os setores público e privado. Contudo, o histórico de mau pagador da Administração Pública brasileira implicou na necessidade de oferecimento de garantias àqueles que irão contratar com o poder público, sem as quais talvez poucos ousassem investir seu capital em atividades nem sempre certamente rentáveis. A proposta é analisar as diversas modalidades de garantias, apontando suas fragilidades e seus aspectos favoráveis, sempre no intuito de mostrá-las viáveis e eficientes. Por fim, algumas sugestões de novas espécies serão apresentadas, aumentando a gama de opções que o administrador terá ao seu alcance quando pretender levar a efeito uma contratação desta natureza. / The present work aims at presenting the reader a wide range of guarantees which can be offered to private companies by the State, so as to attract them to contracting public-private partnerships, instituted in federal extent under law number 11.079, dated December 30, 2004. The shortage in public resources, culminating with the incapacity of the State to invest in sectors of its own responsibility, has brought about the pursuit of new ways of interaction between the public and private sectors. Notwithstanding, the fact that Brazilian Public Administration has a history of being a bad payer has implied the need for guarantees to those who will hire the Public Power, taking into consideration that perhaps only a few people will be willing to invest their funds in doubtfully profitable activities. The purpose of this paper is to analyze the various forms of guarantees, pointing out weaknesses and favorable aspects, always targeting on turning them viable and efficient. At last, some other new suggestions will be introduced, enhancing the range of options the administrator may have at reach whenever one intends to put into practice such kind of hiring.

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2018-10-10T10:21:10Z No. of bitstreams: 1 Juliana Cristina Rodrigues Criscuolo Rebehy.pdf: 1402790 bytes, checksum: 7d8a0b0c29bfcac1f23fed9e5cf0adad (MD5) / Made available in DSpace on 2018-10-10T10:21:10Z (GMT). No. of bitstreams: 1 Juliana Cristina Rodrigues Criscuolo Rebehy.pdf: 1402790 bytes, checksum: 7d8a0b0c29bfcac1f23fed9e5cf0adad (MD5) Previous issue date: 2018-09-05 / This research discusses the legal basis of an Urban Mobility Inter-federative Public-Private Partnership (PPP), provided with a viability gap payment by the Public Administration. The aim of this work is to further the identification in the Brazilian legal system (i) of the rules that relate to an Inter-federative PPP, (ii) the specific characteristics of a PPP provided with a viability gap payment by the Public Administration, (iii) the competent authority to tender, regulate and inspect Inter-federative PPPs, (iv) the federative entities’ responsibility in Inter-federative PPP’ for the payment of the viability gap and provision of guarantees that may be presented to the Private Partner, and (v) the peculiar requirements for urban mobility projects. In order to achieve such goal, this work investigates (i) the contours of the constitutional competencies of the federation entities, especially with regard to the ownership of services of regional interest within a metropolitan region and urban agglomeration, (ii) the rules regulating inter-federative governance and the PPP, with a viability gap, (iii) the creation of an intergovernmental entity to enable the provision of public services of regional interest within a metropolitan region or urban agglomeration, (iv) the specific requirements of urban mobility projects and (v) identification of the Interfederative PPP’s peculiarities. In order to meet its goals, this study applied a methodology based on current legislation and cases that have been subject to Court evaluation / Esta pesquisa versa sobre o regime jurídico da Parceria Público-Privada (PPP) Interfederativa, na modalidade patrocinada, de Mobilidade Urbana. O objetivo desse trabalho é aprofundar a identificação no ordenamento jurídico brasileiro (i) das normas que regem a PPP Interfederativa, (ii) das características específicas da PPP, na modalidade patrocinada, (iii) da autoridade competente para licitar, regular e fiscalizar a PPP Interfederativa, (iv) da responsabilidade dos entes federativos na PPP Interfederativa pelo pagamento da contraprestação e aporte público e prestação de garantias a serem dadas ao Parceiro Privado, e (v) das exigências peculiares para os projetos de mobilidade urbana. Para essa finalidade, o estudo investiga (i) os contornos das competências constitucionais dos entes da federação, especialmente, no que tange à titularidade da prestação dos serviços de interesse regional no âmbito de uma região metropolitana e aglomeração urbana, (ii) as normas que disciplinam a governança interfederativa e a PPP, na modalidade patrocinada, (iii) , as formas de criação de entidade intergovernamental para viabilizar a prestação dos serviços públicos de interesse regional no âmbito de uma região metropolitana ou aglomeração urbana, (iv) as exigências específicas dos projetos de mobilidade urbana e (v) a identificação das peculiaridades da PPP Interfederativa. Para responder aos seus objetivos, traz uma metodologia pautada em legislação atual e casos concretos analisados pelo Poder Judiciário

This master thesis focuses on the Trans-European Transport Network and especially on the possibilities of financing the TEN-T with private-sector participation. The thesis is devided in three chapters. In the first part of the thesis, the author discusses the importance of transport in the economy of the European Union and summarises the development, principles and objectives of the Common Transport Policy. The concept of the Trans-European Network is also introduced in this chapter. The key documents related to the TEN-T are briefly summarized and the gains and lasting setbacks of the TEN-T are discussed in this part of the thesis. The second chapter provides an overview of the costs of the TEN-T and the existing possibilities of their financing. The last chapter introduces the Public Private Partnerhip as a possible efficient means of the TEN-T financing.

<p>The purpose of this Master's Thesis is to investigate the outlooks for a seed stage venture capital fund investing in biotechnology-related spinouts from public research to be established in Mecklenburg-Western Pomerania, Germany. Recommendations on how to improve any discovered deficits of the fund's prerequisites are also to be presented. </p><p>Analyses showed that the spinout potential of the research in the region is weak. The entrepreneurial prerequisites of the researchers, in terms of previous experience, business knowledge and a track record that would vouch for them being suitable entrepreneurs, are generally poor. Nor is there sufficient industry in the region to facilitate the establishment of and subsequent businesses for the spinouts. The seed fund must therefore provide any future portfolio ventures with a substantial amount of Hands-on Management. </p><p>To improve the prerequisites for the seed fund, PVA-MV must influence the researchers'attitude towards spinouts and make the monetary gains more visible. The researchers must be imbued with a business approach in their research and PVA-MV must market its services as being the intermediary of government, universities and industry and as being able to create opportunities for researchers as well as for industry. PVA-MV should also focus on the few institutes and individual researchers that do have some favourable entrepreneurial characteristics, in order to evoke professional entrepreneurs with a forming track record. To cope with the deficient prerequisites of the fund, PVA-MV must expand the competence of its own work force and focus on the rate of return rather than on building regional infrastructure pro bono as a governmental agency.</p>

The purpose of this Master's Thesis is to investigate the outlooks for a seed stage venture capital fund investing in biotechnology-related spinouts from public research to be established in Mecklenburg-Western Pomerania, Germany. Recommendations on how to improve any discovered deficits of the fund's prerequisites are also to be presented. Analyses showed that the spinout potential of the research in the region is weak. The entrepreneurial prerequisites of the researchers, in terms of previous experience, business knowledge and a track record that would vouch for them being suitable entrepreneurs, are generally poor. Nor is there sufficient industry in the region to facilitate the establishment of and subsequent businesses for the spinouts. The seed fund must therefore provide any future portfolio ventures with a substantial amount of Hands-on Management. To improve the prerequisites for the seed fund, PVA-MV must influence the researchers'attitude towards spinouts and make the monetary gains more visible. The researchers must be imbued with a business approach in their research and PVA-MV must market its services as being the intermediary of government, universities and industry and as being able to create opportunities for researchers as well as for industry. PVA-MV should also focus on the few institutes and individual researchers that do have some favourable entrepreneurial characteristics, in order to evoke professional entrepreneurs with a forming track record. To cope with the deficient prerequisites of the fund, PVA-MV must expand the competence of its own work force and focus on the rate of return rather than on building regional infrastructure pro bono as a governmental agency.

The purpose of our thesis is to investigate the incentive mechanisms that may be used for a timely and successful implementation of Public-Private Partnership (PPP) projects. This purpose is achieved by investigating challenges and success factors within one of the largest Public-Private Partnership projects in Europe, the SESAR programme which stands for Single European Sky ATM Research and that aims at modernising the European air traffic management (ATM) system. The categories of SESAR actors that we investigated include: stakeholders (airspace users such as Air France, KLM, SAS; ANSPs from Sweden,Finland, Netherlands and the CANSO organisation; airport representatives including Swedavia, Zürich Airport and Guernsey Airport); as well as manufacturers (e.g. Airbus, Frequentis, Thales); international organisations as principals (e.g. European Commission – SESAR Joint Undertaking-, EUROCONTROL) and advisers (e.g. Helios UK). Referring to our contribution to the theory, we identify four categories of incentive mechanisms for timely implementation of large PPP projects: i. Financial incentives such as loans, proportionate with the level of risks the implementer bears; the deduction of loan fees or reduction of service charges can motivate stakeholders to implement earlier, once they identify a positive business case. ii. Operational incentives can refer to certain preferential treatment to those who comply and detrimental treatment to those who do not comply. iii. Legal incentives such as mandates can force commitment and have an impact on the timely implementation of PPP projects within a certain time-frame. iv. Intangible incentives, such as transparent communication, collaboration and less political behaviour, are seen as major factors contributing to the commitment and trust level among the actors involved, thus, enabling the success of the PPP project implementation.

Most dynamic program analysis techniques such as profile-driven compiler optimizations, software testing and runtime property checking infer program properties by profiling one or more executions of a program. Unfortunately, program profiling does not come for free. For example, even the most efficient techniques for profiling acyclic, intra-procedural paths can slow down program execution by a factor of 2. In this thesis, we propose techniques that significantly lower the overheads of profiling paths, enabling the use of path-based dynamic analyzes in cost-sensitive environments. Preferential path profiling (PPP) is a novel software-only path profiling scheme that efficiently profiles given subsets of paths, which we refer to as interesting paths. The algorithm is based on the observation that most consumers of path profiles are only interested in profiling a small set of paths known a priori. Our algorithm can be viewed as a generalization of the Ball-Larus path profiling algorithm. Whereas the Ball-Larus algorithm assigns weights to the edges of a given CFG such that the sum of the weights of the edges along each path through the CFG is unique, our algorithm assigns weights to the edges such that the sum of the weights along the edges of interesting paths is unique. Furthermore, our algorithm attempts to achieve a minimal and compact encoding of the interesting paths; such an encoding significantly reduces the overheads of path profiling by eliminating expensive hash operations during profiling. Interestingly, we find that both the Ball-Larus algorithm and PPP are essentially a form of arithmetic coding. We use this connection to prove that the numbering produced by PPP is optimal. We also propose a programmable, non-intrusive hardware path profiler (HPP). The hardware profiler consists of a path detector that detects paths by monitoring the stream of retiring branch instructions emanating from the processor pipeline. The path detector can be programmed to detect various types of paths and track architectural events that occur along paths. The second component of the hardware profiling infrastructure is a Hot Path Table (HPT), that collects accurate hot path profiles. Our experimental evaluation shows that PPP reduces the overheads of profiling paths to 15% on average (with a maximum of 26%). The algorithm can be easily extended to profile inter-procedural paths at minimal additional overheads (average of 26%). We modeled HPP using a cycle-accurate superscalar processor simulator and find that HPP generates accurate path profiles at extremely low overheads (0.6% on average) with a moderate hardware budget. We also evaluated the use of PPP and HPP in a realistic profiling scenarios. We find that the profiles generated by HPP can effectively replace expensive profiles used in profile-driven optimizations. We also find that even well-tested programs tend to exercise a large number of untested paths in the field, emphasizing the need for efficient profiling schemes that can be deployed in production environments.

L'objet de cette thèse est de comprendre la gouvernabilité de divers modes d'organisation (en particulier le réseau comme un idéal type), dans des institutions organisationnelles par un modèle hypothétique de gouvernance. Par celui-ci, nous avons essayé de comprendre le sens de l'action organisée dans le cadre de la circularité herméneutique et de la critique de l'idéologie et de l'utopie. Ce cadre d'analyse est nécessaire à la mise en scène de la potentialité des acteurs stratégiques (des organisations/des individus) dans l'espace de jeu de l'action organisée. Il permet sous couvert de l'option pragmatique de donner du sens au modèle élaboré qu'à mi-chemin des concepts de souveraineté et de gouvernementalité. Ce sont ces derniers qui participent à le délimiter et en même temps de lui offrir le caractère dynamique et producteur de nouvelles hypothèses. Ainsi mobilisées comme hypothèses, le capital social, la codification, l'abstraction, le consensus et le consentement rendent possible les différentes facettes de potentialités des acteurs stratégiques dans leur échange politique et économique. Elles conduisent alors à la transformation du modèle hypothétique en un système dynamique d'action organisée efficace et efficient. Plus particulièrement, cette recherche trouve un terrain de prédilection dans la gouvernance du mode d'organisation dit partenariat public-privé (PPP), dans la perspective de remplissage de l'abîme des considérations linguistiques et extralinguistiques en convoquant l'opérateur de cohérence du sens théorique et du sens empirique de la gouvernance des organisations (en réseau).