Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).

Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.

Design of new tools to improve the efficacy of DNA-damaging drugs used in cancer therapy

Résumé Les tumeurs sont diverses et hétérogènes, mais toutes partagent la capacité de proliférer sans contrôle. Une prolifération dérégulée de cellules couplée à une insensibilité à une réponse apoptotique constitue une condition minimale pour que l'évolution d'une tumeur se produise. Un des traitements les plus utilisés pour traité le cancer à l'heure actuelle sont les chimiothérapies, qui sont fréquemment des composés chimiques qui induisent des dommages dans l'ADN. Les agents anticancéreux sont efficaces seulement quand les cellules tumorales sont plus aisément tuées que le tissu normal environnant. L'efficacité de ces agents est en partie déterminée par leur capacité à induire l'apoptose. Nous avons récemment démontré que la protéine RasGAP est un substrat non conventionnel des caspases parce elle peut induire à la fois des signaux anti et pro-apoptotiques, selon l'ampleur de son clivage par les caspases. A un faible niveau d'activité des caspases, RasGAP est clivé, générant deux fragments (le fragment N et le fragment C). Le fragment N semble être un inhibiteur général de l'apoptose en aval de l'activation des caspases. À des niveaux plus élevés d'activité des caspases, la capacité du fragment N de contrecarrer l'apoptose est supprimée quand il est clivé à nouveau par les caspases. Ce dernier clivage produit deux nouveaux fragments, N 1 et N2, qui contrairement au fragment N sensibilisent efficacement des cellules cancéreuses envers des agents chimiothérapeutiques. Dans cette étude nous avons prouvé qu'un peptide, appelé par la suite TAT-RasGAP317-326, qui est dérivé du fragment N2 de RasGAP et est rendu perméable aux cellules, sensibilise spécifiquement des cellules cancéreuses à trois génotoxines différentes utilisées couramment dans des traitements anticancéreux, et cela dans des modèles in vitro et in vivo. Il est important de noté que ce peptide semble ne pas avoir d'effet sur des cellules non cancéreuses. Nous avons également commencé à caractériser les mécanismes moléculaires expliquant les fonctions de sensibilisation de TAT-RasGAP317-326. Nous avons démontré que le facteur de transcription p53 et une protéine sous son activité transcriptionelle, nommée Puma, sont indispensables pour l'activité de TAT-RasGAP317-326. Nous avons également prouvé que TAT-RasGAP317-326 exige la présence d'une protéine appelée G3BP1, une protéine se liant a RasGAP, pour potentialisé les effets d'agents anticancéreux. Les données obtenues dans cette étude montrent qu'il pourrait être possible d'augmenter l'efficacité des chimiothérapies à l'aide d'un composé capable d'augmenter la sensibilité des tumeurs aux génotoxines et ainsi pourrait permettre de traiter de manière plus efficace des patients sous traitement chimiothérapeutiques. Summary Tumors are diverse and heterogeneous, but all share the ability to proliferate without control. Deregulated cell proliferation coupled with suppressed apoptotic sensitivity constitutes a minimal requirement upon which tumor evolution occurs. One of the most commonly used treatments is chemotherapy, which frequently uses chemical compounds that induce DNA damages. Anticancer agents are effective only when tumors cells are more readily killed than the surrounding normal tissue. The efficacy of these agents is partly determined by their ability to induce apoptosis. We have recently demonstrated that the protein RasGAP is an unconventional caspase substrate because it can induce both anti- and pro-apoptotic signals, depending on the extent of its cleavage by caspases. At low levels of caspase activity, RasGAP is cleaved, generating an N-terminal fragment (fragment N) and a C-terminal fragment (fragment C). Fragment N appears to be a general Mocker of apoptosis downstream of caspase activation. At higher levels of caspase activity, the ability of fragment N to counteract apoptosis is suppressed when it is further cleaved. This latter cleavage event generates two fragments, N1 and N2, which in contrast to fragment N potently sensitizes cancer cells toward DNA-damaging agents induced apoptosis. In the present study we show that a cell permeable peptide derived from the N2 fragment of RasGAP, thereafter called TAT-RasGAP317-326, specifically sensitizes cancer cells to three different genotoxins commonly used in chemotherapy in vitro and in vivo models. Importantly this peptide seems not to have any effect on non cancer cells. We have also started to characterize the molecular mechanisms underlying the sensitizing functions of TAT-RasGAP317-326. We have demonstrated that the p53 transcription factor and a protein under its transcriptional activity, called Puma, are required for the activity of TATRasGAP317-326. We have also showed that TAT-RasGAP317-326 requires the presence of a protein called G3BP1, which have been shown to interact with RasGAP, to increase the effect of the DNA-damaging drug cisplatin. The data obtained in this study showed that it is possible to increase the efficacy of current used chemotherapies with a compound able to increase the efficacy of genotoxins which could be beneficial for patients subjected to chemotherapy.

Dissecting the compression of mortality in Switzerland, 1876-2005

This paper aims to examine changes in common longevity and variability of the adult life span, and attempts to answer whether or not the compression of mortality continues in Switzerland in the years 1876-2005. The results show that the negative relationships between the large increase in the adult modal age at death, observed at least from the 1920s, and the decrease in the standard deviation of the ages at deaths occurring above it, illustrate a significant compression of adult mortality. Typical adult longevity increased by about 10% during the last fifty years in Switzerland, and adult heterogeneity in the age at death decreased in the same proportion. This analysis has not found any evidence suggesting that we are approaching longevity limits in term of modal or even maximum life spans. It ascertains a slowdown in the reduction of adult heterogeneity in longevity, already observed in Japan and other low mortality countries.

Characterizing the impact of minor cannula design modification.

OBJECTIVE: Bench evaluation of the hydrodynamic behavior of venous cannulas is a valuable technique for the analysis of their performance during cardiopulmonary bypass (CPB). The aim of this study was to investigate the effect of the internal diameter of the extracorporeal connecting tube of venous cannulas on flow rate (Q), pressure drop (delta P), and cannula resistance (delta P/Q²) values, using a computer assisted test bench.¦METHODS: An in vitro circuit was set up with silicone tubing between the test cannula encased in a movable reservoir, and a static reservoir. The delta P, defined as the difference between the drainage pressure and the preload pressure, was measured using high-fidelity Millar pressure transducers. Q was measured using an ultrasonic flowmeter. Data display and data recording were controlled using virtual instruments in a stepwise fashion.¦RESULTS: The 27 F smartcanula® with a 9 mm connecting tube diameter showed 17% less resistance compared to that with an 8 mm connecting tube diameter. Q values were 7.22±0.1 and 7.81±0.04 L/min for cannulas with 8 mm and 9 mm connecting tube diameters, respectively. The delta P/Q² ratio values were 72% lower for the Medtronic cannula with a 9 mm connecting tube diameter compared to that with an 8 mm connecting tube diameter. Q values for the Medtronic cannula were 3.94±0.23 and 6.58±0.04 L/min with 8 mm and 9 mm connecting tube diameters, respectively. The 27 F smartcanula® showed 13% more flow rate compared to the 28 F Medtronic cannula using the unpaired Student t-test (p<0.0001).¦CONCLUSIONS: Our results demonstrated that Q was increased but delta P and delta P/Q² values were significantly decreased when the connecting tube diameter was increased for venous cannulas. The connecting tube diameter significantly affected the resistance to liquid flow through the cannula. Smartcanulas® outperform Medtronic cannulas.

Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Patterns of neurovascular compression in patients with classic trigeminal neuralgia: A high-resolution MRI-based study.

PURPOSE: To describe the anatomical characteristics and patterns of neurovascular compression in patients suffering classic trigeminal neuralgia (CTN), using high-resolution magnetic resonance imaging (MRI). MATERIALS AND METHODS: The analysis of the anatomy of the trigeminal nerve, brain stem and the vascular structures related to this nerve was made in 100 consecutive patients treated with a Gamma Knife radiosurgery for CTN between December 1999 and September 2004. MRI studies (T1, T1 enhanced and T2-SPIR) with axial, coronal and sagital simultaneous visualization were dynamically assessed using the software GammaPlan?. Three-dimensional reconstructions were also developed in some representative cases. RESULTS: In 93 patients (93%), there were one or several vascular structures in contact, either, with the trigeminal nerve, or close to its origin in the pons. The superior cerebellar artery was involved in 71 cases (76%). Other vessels identified were the antero-inferior cerebellar artery, the basilar artery, the vertebral artery, and some venous structures. Vascular compression was found anywhere along the trigeminal nerve. The mean distance between the nerve compression and the origin of the nerve in the brainstem was 3.76±2.9mm (range 0-9.8mm). In 39 patients (42%), the vascular compression was located proximally and in 42 (45%) the compression was located distally. Nerve dislocation or distortion by the vessel was observed in 30 cases (32%). CONCLUSIONS: The findings of this study are similar to those reported in surgical and autopsy series. This non-invasive MRI-based approach could be useful for diagnostic and therapeutic decisions in CTN, and it could help to understand its pathogenesis.

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort.

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10 % of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicine.

Should biomarkers be used to design personalized medicine for the treatment of glioblastoma?

Significant progress has been made in understanding the molecular pathogenesis of gliomas and in predicting general outcome depending on a limited set of clinical parameters and molecular markers. However, methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter is the only molecular marker linked to sensitivity of a specific treatment, that is, alkylating agent chemotherapy, and this predictive value may be limited to glioblastoma. Moreover, in the absence of potent alternative drugs, temozolomide chemotherapy should not be withheld from patients with newly diagnosed glioblastoma without MGMT promoter methylation in general practice. In the context of clinical trials, however, irrespective of whether classical cytotoxic drugs, tyrosine kinase inhibitors or antiangiogenic agents are used, tissue should be centrally collected. Appropriate research programs should seek to define enriched patient populations for future trials and ultimately facilitate individualized cancer treatments.

The business model ontology a proposition in a design science approach

The goal of this dissertation is to find and provide the basis for a managerial tool that allows a firm to easily express its business logic. The methodological basis for this work is design science, where the researcher builds an artifact to solve a specific problem. In this case the aim is to provide an ontology that makes it possible to explicit a firm's business model. In other words, the proposed artifact helps a firm to formally describe its value proposition, its customers, the relationship with them, the necessary intra- and inter-firm infrastructure and its profit model. Such an ontology is relevant because until now there is no model that expresses a company's global business logic from a pure business point of view. Previous models essentially take an organizational or process perspective or cover only parts of a firm's business logic. The four main pillars of the ontology, which are inspired by management science and enterprise- and processmodeling, are product, customer interface, infrastructure and finance. The ontology is validated by case studies, a panel of experts and managers. The dissertation also provides a software prototype to capture a company's business model in an information system. The last part of the thesis consists of a demonstration of the value of the ontology in business strategy and Information Systems (IS) alignment. Structure of this thesis: The dissertation is structured in nine parts: Chapter 1 presents the motivations of this research, the research methodology with which the goals shall be achieved and why this dissertation present a contribution to research. Chapter 2 investigates the origins, the term and the concept of business models. It defines what is meant by business models in this dissertation and how they are situated in the context of the firm. In addition this chapter outlines the possible uses of the business model concept. Chapter 3 gives an overview of the research done in the field of business models and enterprise ontologies. Chapter 4 introduces the major contribution of this dissertation: the business model ontology. In this part of the thesis the elements, attributes and relationships of the ontology are explained and described in detail. Chapter 5 presents a case study of the Montreux Jazz Festival which's business model was captured by applying the structure and concepts of the ontology. In fact, it gives an impression of how a business model description based on the ontology looks like. Chapter 6 shows an instantiation of the ontology into a prototype tool: the Business Model Modelling Language BM2L. This is an XML-based description language that allows to capture and describe the business model of a firm and has a large potential for further applications. Chapter 7 is about the evaluation of the business model ontology. The evaluation builds on literature review, a set of interviews with practitioners and case studies. Chapter 8 gives an outlook on possible future research and applications of the business model ontology. The main areas of interest are alignment of business and information technology IT/information systems IS and business model comparison. Finally, chapter 9 presents some conclusions.

Live trapping design for the harvest mouse (Micromys minutus) in its summer habitat

documented accurately since 1960. Most records are based on nest findings and there have been few direct observations or captures, mainly because live trapping of this species is not simple. Therefore, an efficient trapping technique is needed for population studies and to facilitate the management of its habitat. By combining the methods used to capture very small (Suncus etruscus) and climbing (Muscardinus avellanarius) mammals, we developed a design using Longworth traps with mouse excluders set on suspended platforms. This allowed us to trap more harvest mice in four field sessions of 60 trap-nights than have ever been caught previously since its discovery in Switzerland.

Le renforcement de la loi fédérale sur la protection des données : le cas de la protection de la vie privée dès la conception (privacy by design)

La protection des données est un élément essentiel d'un Etat de droit et une société démocratique, car elle accorde à chaque individu le droit de disposer de ce qui fait partie de sa sphère privée. Actuellement en Suisse, la loi fédérale sur la protection des données (LPD) est en vigueur depuis 1993. En 2010, l'Office fédéral de la justice a supervisé une évaluation de son efficacité : il en résulte que cette dernière a été prouvée, mais tendra à diminuer fortement dans les années à suivre. Pour causes principales : l'évolution des technologies, caractérisée notamment par le développement des moyens de traitement de données toujours plus variés et conséquents, et un manque d'informations des individus par rapport à la protection des données en générale et à leurs droits. Suite à l'évaluation, cinq objectifs de révision ont été formulés par le Conseil fédéral, dont celui d'intégrer la privacy by design ou « protection de la vie privée dès la conception » dans la loi. Ce concept, qui est également repris dans les travaux européens en cours, est développé à l'origine par l'Information and Privacy Commissionner de l'Ontario (Canada), Ann Cavoukian. Le principe général de la privacy by design est que la protection de la vie privée doit être incluse dans les systèmes traitant les données lors de leur conception. Souvent évoquée comme une solution idéale, répondant au problème de l'inadéquation de la loi par la logique de prévention qu'elle promeut, la privacy by design demeure toutefois un souhait dont l'application n'est que peu analysée. Ce travail cherche justement à répondre à la question de la manière de la mettre en oeuvre dans la législation suisse. Se basant sur les textes et la doctrine juridiques et une littérature dans les domaines de l'économie, l'informatique, la politique et la sociologie des données personnelles, il propose tout d'abord une revue générale des principes et définitions des concepts-clés de la protection des données en Suisse et dans le cadre international. Puis, il propose deux possibilités d'intégration de la privacy by design : la première est une solution privée non contraignante qui consiste à promouvoir le concept et faire en sorte que les responsables de traitement décident par eux-mêmes d'intégrer la privacy by design dans leurs projets ; ce procédé est possible grâce au renforcement du processus de certification déjà en cours. La deuxième option est une solution contraignante visant à intégrer le principe directement dans la loi et de prendre les mesures pour le rendre effectif ; ce travail montre que le développement de la figure du conseiller à la protection des données permet d'atteindre cet objectif. Enfin, des considérations générales sur l'application du principe sont abordées, telles que l'influence des développements en cours dans l'Union européenne sur la Suisse par rapport à la protection des données et la limite posée par le principe de territorialité.