Pyrrolobenzodiazepine (PBD) derivatives interact with the minor-groove of DNA to form mono-adducts (monomers) or cross-links (dimers). They show remarkable activity in vitro and in vivo in a wide range of tumour types and one dimer, SJG-136 is currently in clinical development. Preclinical studies have shown that SJG-136 is a P-gp substrate limiting its anti-tumour activity. The work presented in this thesis identifies key physicochemical properties influencing both the interaction of PBDs with ABC transporters P-gp, MRP1 and BCRP and their growth inhibitory potency. A testable hypothesis for further optimisation of PBDs is proposed. The biological activity of 4 dimers and 12 monomers was assessed using several in vitro models presenting differential expression of ABC transporters. Biological endpoints were the growth inhibitory effect determined using a sulforhodamine B assay and γ-H2AX foci formation. In addition PBD transport was evaluated using a Caco-2 transwell assay. P-gp substrate specificity was restricted to dimers. The MW, the number of (N+O) atoms (>8), a polar surface area (>75 Ǻ2) and hydrogen bonding energy (>10) could discriminate substrates among the PBDs. P-gp polymorphism was also evaluated. The mutation in position 2677 (G/T) was associated with reduced sensitivity to the PBDs. When combined mutations in position 3435/2677 were linked, the transporter abrogated this apparent gain of function. The impact of MRP1 was identified for all dimers and 1/12 monomers. In addition, the cooperative role of glutathione in the resistance mediated by MRP1 to the PBDs was revealed. The presence of a carbonyl moiety at the extremity was shown to discriminate the 7 substrate for MRP1 among the monomers. A structure-activity-relationship study showed that negatively charged (N+O) atoms and a greater number of aromatic rings confer greater dependency to BCRP. BCRP polymorphism was also evaluated. The T482 mutant was associated with an increase in drug transport. The cytotoxicity of the PBDs correlated to the interaction of the DNA as measured by ΔTm. Compounds, being non surface active, with a greater polar surface area and number of aromatic rings and a lower solvent accessible surface area were associated with a greater cytotoxicity. Van-der-waals energy and the electrostatic forces were identified in silico as predictable features involved in the DNA binding. New PBDs were designed and were predicted to be associated with a greater affinity for DNA and with minimal interaction with ABC transporters.

Dissertação (mestrado)—Universidade de Brasília, Instituto de Artes, Programa de Pós-Graduação em Design, 2017. / Submitted by Raquel Almeida (raquel.df13@gmail.com) on 2017-07-10T20:58:23Z No. of bitstreams: 1 2017_MarcoAurélioLoboJunior.pdf: 2897522 bytes, checksum: a5317ddbbd7608a6c09f80a610a74df4 (MD5) / Approved for entry into archive by Raquel Viana (raquelviana@bce.unb.br) on 2017-07-31T21:42:52Z (GMT) No. of bitstreams: 1 2017_MarcoAurélioLoboJunior.pdf: 2897522 bytes, checksum: a5317ddbbd7608a6c09f80a610a74df4 (MD5) / Made available in DSpace on 2017-07-31T21:42:52Z (GMT). No. of bitstreams: 1 2017_MarcoAurélioLoboJunior.pdf: 2897522 bytes, checksum: a5317ddbbd7608a6c09f80a610a74df4 (MD5) Previous issue date: 2017-07-31 / O objetivo deste trabalho foi analisar o design para a competitividade internacional de produtos brasileiros, tendo como estudo de caso o Projeto Design Export, da Agência Brasileira de Promoção das Exportações e Investimentos (Apex-Brasil). Desde o início do século XXI percebe-se que o preço competitivo e a alta qualidade do produto não são mais as garantias para manter e conquistar mercados. Destaca-se as contribuições do design para enfrentar esses novos desafios no desenvolvimento de elementos e características que identificam e diferenciam os produtos e serviços das empresas em relação aos seus competidores, tanto no mercado nacional quanto no internacional. Para isso, foi necessário pesquisar: a história recente da competitividade internacional brasileira; o Programa Brasileiro do Design (PBD) e seus resultados e consequências no setor industrial; os principais programas de apoio ao design para o aumento da competitividade, em outros países; e o papel da Apex-Brasil, na inserção do design para o aumento das exportações brasileiras, por meio dos resultados do Projeto Design Export. O trabalho em parceria dos atores envolvidos – designers, empresários, associações setoriais e gestores – esteve diretamente relacionado ao sucesso do processo de gestão do projeto, que proporcionou melhores condições de competição para as empresas exportadoras, pois demonstrou e revelou a importância da utilização do design no processo de desenvolvimento de novos produtos, novas embalagens, novas marcas e novos serviços. Foram 610 empresas brasileiras sensibilizadas para o design, com 144 empresas visitadas e 114 empresas diagnosticadas quanto ao uso do design. Foram contratados 50 escritórios de design, que desenvolveram 108 projetos, em 60 cidades de 7 estados brasileiros. A experiência direta contribuiu para criar uma cultura de inovação entre as empresas brasileiras envolvidas, o que poderá resultar no aumento da excelência da produção industrial brasileira com vistas à exportação e no fomento ao mercado profissional de design e áreas afins. / The aim of the present study is to analyze the role of design in the international competitiveness of Brazilian products, through a case study from the Design Export Project from the Brazilian Trade and Investment Promotion Agency (Apex-Brasil). In the beginning of the 21st century, competitive prices and higher quality of a product were not guarantees of conquering and keeping international markets. Thus, the contributions of design in the development of elements and characteristics must be noted, as they serve to identify and distinguish the companies’ products and services from their competitors. In this context, the first step was the research of four mains issues: the recent story of the Brazilian international competitiveness; the Brazilian Design Program, its results and consequences in the industrial sector; the most important design support programs to improve competitiveness abroad; and the role of the Brazilian Trade and Investment Promotion Agency in the insertion of design in the development of Brazilian exports through the Design Export Project. The partnership between designers, entrepreneurs, trade associations and project managers was directly related with the success of the Project administration, which supplied better competitive conditions to the involved export companies. In such way, the project showed and revealed the importance of using design in the development process of new products, packages, brands and services. Out of 610 companies that were made aware of the importance of design, 144 companies were visited and 144 companies were alerted to the importance of the proper use of design. 50 design agencies were hired, developing 108 projects in 60 cities of 7 Brazilian states. Such direct experience contributed to the creation of a culture of innovation within the companies involved. This culture will possibly result in an increase of the excellence of Brazilian industrial export production, and in the stimulation of the market of design and its related areas.

No description available.

Parmi les cibles architecturales susceptibles d'être utilisées pour réaliser un système de traitement sur puce (SoC), les architectures reconfigurables dynamiquement (ARD) offrent un potentiel de flexibilité et de dynamicité intéressant. Cependant ce potentiel est encore difficile à exploiter pour réaliser des applications massivement parallèles sur puce. Dans nos travaux nous avons recensé et analysé les solutions actuellement proposées pour utiliser les ARD et nous avons constaté leurs limites parmi lesquelles : l'utilisation d'une technologie particulière ou d'architecture propriétaire, l'absence de prise en compte des applications parallèles, le passage à l'échelle difficile, l'absence de langage adopté par la communauté pour l'utilisation de la flexibilité des ARD, ...Pour déployer une application sur une ARD il est nécessaire de considérer l'hétérogénéité et la dynamicité de l'architecture matérielle d'une part et la parallélisation des traitements d'autre part. L'hétérogénéité permet d'avoir une architecture de traitement adaptée aux besoins fonctionnels de l'application. La dynamicité permet de prendre en compte la dépendance des applications au contexte et de la nature des données. Finalement, une application est naturellement parallèle.Dans nos travaux nous proposons une solution pour le déploiement sur une ARD d'une application parallèle en utilisant les flots de conception standard des SoC. Cette solution est appelée MATIP (MPI Application Task Integreation Platform) et utilise des primitives du standard MPI version 2 pour effectuer les communications et reconfigurer l'architecture de traitement. MATIP est une solution de déploiement au niveau de la conception basée plate-forme (PBD).La plateforme MATIP est modélisée en trois couches : interconnexion, communication et application. Nous avons conçu chaque couche pour que l'ensemble satisfasse les besoins en hétérogénéité et dynamicité des applications parallèles . Pour cela MATIP utilise une architecture à mémoire distribuée et exploite le paradigme de programmation parallèle par passage de message qui favorise le passage à l'échelle de la plateforme.MATIP facilite le déploiement d'une application parallèle sur puce à travers un template en langage Vhdl d'intégration de tâches. L'utilisation des primitives de communication se fait en invoquant des procédures Vhdl.MATIP libère le concepteur de tous les détails liés à l'interconnexion, la communication entre les tâches et à la gestion de la reconfiguration dynamique de la cible matérielle. Un démonstrateur de MATIP a été réalisée sur des FPGA Xilinx à travers la mise en oe{}uvre d'une application constituée de deux tâches statiques et deux tâches dynamiques. MATIP offre une bande passante de 2,4 Gb/s et une la latence pour le transfert d'un octet de 3,43 µs ce qui comparée à d'autres plateformes MPI (TMD-MPI, SOC-MPI, MPI HAL) met MATIP à l'état de l'art. / Among the architectural targets that could be buid a system on chip (SoC), dynamically reconfigurable architectures (DRA) offer interesting potential for flexibility and dynamicity . However this potential is still difficult to use in massively parallel on chip applications. In our work we identified and analyzed the solutions currently proposed to use DRA and found their limitations including: the use of a particular technology or proprietary architecture, the lack of parallel applications consideration, the difficult scalability, the lack of a common language adopted by the community to use the flexibility of DRA ...In our work we propose a solution for deployment on an DRA of a parallel application using standard SoC design flows. This solution is called MATIP ( textit {MPI Application Platform Task Integreation}) and uses primitives of MPI standard Version 2 to make communications and to reconfigure the MP-RSoC architecture . MATIP is a Platform-Based Design (PBD) level solution.The MATIP platform is modeled in three layers: interconnection, communication and application. Each layer is designed to satisfies the requirements of heterogeneity and dynamicity of parallel applications. For this, MATIP uses a distributed memory architecture and utilizes the message passing parallel programming paradigm to enhance scalability of the platform.MATIP frees the designer of all the details related to interconnection, communication between tasks and management of dynamic reconfiguration of the hardware target. A demonstrator of MATIP was performed on Xilinx FPGA through the implementation of an application consisting of two static and two dynamic hardware tasks. MATIP offers a bandwidth of 2.4 Gb / s and latency of 3.43 microseconds for the transfer of a byte. Compared to other MPI platforms (TMD-MPI, SOC-MPI MPI HAL), MATIP is in the state of the art.

No description available.

No / SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selectivity and interstrand DNA cross-linking activity, SJG-136 has been selected for clinical trials. This study examines the pharmacological characteristics of SJG-136 and provides the first report of pharmacokinetic properties for this agent. A sensitive, selective and reproducible reversed-phase gradient LC/MS assay has been developed for detection and analysis, where a molecular ion ( m / z 557.2) is detectable for the SJG-136 parent imine. Fluorescence detection (260 nm excitation, 420 nm emission) gives a limit of sensitivity of 5 nM (2.5 ng ml(-1)) for analysis of SJG-136 in mouse plasma. Extraction efficiencies from plasma were >65% across a range of concentrations (5-1000 nM). Following administration to mice at the MTD (i.p., 0.2 mg kg(-1)), high peak plasma concentrations of SJG-136 were seen ( C (max) = 336 nM) at 30 min after dosing. A calculated terminal t (1/2) of 0.98 h and AUC of 0.34 microM.h resulted in a clearance rate of 17.7 ml min(-1) kg(-1). The PBD dimer binds only moderately to proteins (65-75%), and in vitro cytotoxicity studies confirmed IC(50) values of 4-30 nM with a panel of human cell lines. This finding demonstrates that plasma concentrations achieved in the mouse are substantially higher than those required to elicit an anti tumour response in vitro. This report forms an important phase in the pre-clinical characterization of the compound.

The EU General Data Protection Regulation (GDPR) replaces the Data Protection Directive 95/46/EC in May 25, 2018. This will generate major changes for organizations that process personal data. Privacy by Design is a requirement in GDPR and a concept that implies that IT systems are designed in such way that personal privacy is protected. By taking early consideration of Privacy by Design in procurement of IT, public organizations can ensure that integrity requirements are met and that privacy is protected. This study aims at studying differences between clients from public sector and IT providers in their knowledge and attitude to the concept Privacy by Design in relation to GDPR. The study is a qualitative study that includes four interviews, two interviews with respondents from public organizations, and two with respondents from IT provider organizations. The interviews were based on an interview guide with a summary of Datainspektionens (2012) checklist for built-in data protection and data protection by default. The result shows that neither the clients nor IT providers in general know much about the concept of Privacy by Design, but they are aware of its principles. All respondents have a positive attitude to the principles of Privacy by Design and believe that the knowledge in their respective operation is generally low and must be raised. Some interesting differences have been shown in this study. One of them is that the IT providers lean towards the client regarding issues in data minimization because the client wear the responsibility, and public organizations tend to collect more personal data than necessary. This contradicts data minimization, which is a core principle of Privacy by Design.

Veganism (or following a PBD) is scientifically proven to be one of the possible answers to the environmental, ethical and health issues our society is currently facing. The documentary film What the Health advocates this claim and presents the tremendous impacts, meat and dairy production and consumption, have on our environment, our personal health and for the people living on our planet. The documentary’s attempt of persuading people to adopt a PBD remained unanswered and was the chosen case-study for this research on audience reception and media effects. The purpose of this research is to provide new empirical data on how the documentary film What the Health changes females’ and males’ perception of a PBD. Using a qualitative method of in-depth interviews, this study aimed to understand how the documentary film What the Health changes females’ and males’ perception of a PBD in times of the 21st century Vegan social movement. Using theoretical insights from the following theories: Framing theory, schema theory, social representation theory, social cognition theory and the concept of hegemonic masculinity, this study aimed to assess whether the documentary film What the Health contributed to perception changes among its audience. And whether gender differences were prominent.The findings of this study indicated perception changes of a PBD among its audience. Preconceptions of Veganism as a social trend or for ethical justifications were changed to understanding people’s individual motivations for attaining such a diet. Overall, no significant gender differences were detected. The social determinant of perceived restrictions within a social context were the most dominant factors of not transitioning to a PBD. Meat is undoubtedly an inherent and substantial part of people’s lives and restricting oneself from it is not perceived to be the answer to environmental, personal health and ethical issues. However, the audience was observed to admire Vegans for their discipline and strength.This study indicated that the documentary film What the Health might have an effect on its audience in the long term, which is proposed as future research respectively.

Accelerating physics-based simulations has been an evergreen topic across different scientific communities. This dissertation is devoted to this subject addressing bottlenecks in state-of-the-art approaches to the simulation of fluids of large-scale scenes, viscous threads, magnetic fluids, and the simulation of fibers and thin structures. The contributions within the thesis are rooted in mathematical modeling and numerical simulation as well as in machine learning. The first part deals with the simulation of incompressible flow in a multigrid fashion. For the variational viscous equation, geometric multigrid is inefficient. An Unsmoothed Aggregation Algebraic Multigrid method is devised with a multi-color Gauss-Seidel smoother, which consistently solves this equation in a few iterations for various material parameters. This framework is 2.0 to 14.6 times faster compared to the state-of-the-art adaptive octree solver in commercial software for the large-scale simulation of both non-viscous and viscous flow. In the second part, a new physical model is devised to accelerate the macroscopic simulation of magnetic fluids. Previous work is based on the classical Smoothed-Particle Hydrodynamics (SPH) method and a Kelvin force model. Unfortunately, this model results in a force pointing outwards causing significant levitation problems limiting the application of more advanced SPH frameworks such as Divergence-Free SPH (DFSPH) or Implicit Incompressible SPH (IISPH). This shortcoming has been addressed with this new current loop magnetic force model resulting in more stable and fast simulations of magnetic fluids using DFSPH and IISPH. Following a different trajectory, the third part of this thesis aims for the acceleration of iterative solvers widely used to accurately simulate physical systems. We speedup the simulation for rod dynamics with Graph Networks by predicting the initial guesses to reduce the number of iterations for the constraint projection part of a Position-based Dynamics solver. Compared to existing methods, this approach guarantees long-term stability and therefore leads to more accurate solutions.

no / The pyrrolobenzodiazepine monomer DRH-417 is a member of the anthramycin group of anti-tumor antibiotics that bind covalently to the N2 of guanine within the minor groove of DNA. DRH-417 emerged from the EORTC-Drug Discovery Committee and NCI 60 cell line in vitro screening programs as a potent antiproliferative agent with differential sensitivity towards certain cancer types such as melanoma, breast and renal cell carcinoma (mean IC(50) = 3 nM). DRH-417 was therefore tested for in vivo activity. The maximum tolerated dose (MTD) was established as 0.5 mg/kg given i.p. Marked anti-tumor activity was seen in two human renal cell cancers, one breast cancer and a murine colon tumor model (p<0.01). A selective HPLC (LC/MS) analytical method was developed and plasma pharmacokinetics determined. At a dose of 0.5 mg kg(-1), the plasma AUC was 540 nM h (197.1 ng h ml(-1)) and the peak plasma concentration (171 nM [62.4 ng ml(-1)]) occurred at 30 min., reaching doses levels well above those needed for in vitro antiproliferative activity. Genomic profiling of in vivo sensitive tumors revealed that the latter have an activated insulin-like growth factor signaling pathway.