Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4months (95% confidence interval [CI], 4.6-8.0months) and median overall survival (OS) 13.5months (95% CI, 10.0-21.0months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.

Are niche-based species distribution models transferable in space?

Aim To assess the geographical transferability of niche-based species distribution models fitted with two modelling techniques. Location Two distinct geographical study areas in Switzerland and Austria, in the subalpine and alpine belts. Methods Generalized linear and generalized additive models (GLM and GAM) with a binomial probability distribution and a logit link were fitted for 54 plant species, based on topoclimatic predictor variables. These models were then evaluated quantitatively and used for spatially explicit predictions within (internal evaluation and prediction) and between (external evaluation and prediction) the two regions. Comparisons of evaluations and spatial predictions between regions and models were conducted in order to test if species and methods meet the criteria of full transferability. By full transferability, we mean that: (1) the internal evaluation of models fitted in region A and B must be similar; (2) a model fitted in region A must at least retain a comparable external evaluation when projected into region B, and vice-versa; and (3) internal and external spatial predictions have to match within both regions. Results The measures of model fit are, on average, 24% higher for GAMs than for GLMs in both regions. However, the differences between internal and external evaluations (AUC coefficient) are also higher for GAMs than for GLMs (a difference of 30% for models fitted in Switzerland and 54% for models fitted in Austria). Transferability, as measured with the AUC evaluation, fails for 68% of the species in Switzerland and 55% in Austria for GLMs (respectively for 67% and 53% of the species for GAMs). For both GAMs and GLMs, the agreement between internal and external predictions is rather weak on average (Kulczynski's coefficient in the range 0.3-0.4), but varies widely among individual species. The dominant pattern is an asymmetrical transferability between the two study regions (a mean decrease of 20% for the AUC coefficient when the models are transferred from Switzerland and 13% when they are transferred from Austria). Main conclusions The large inter-specific variability observed among the 54 study species underlines the need to consider more than a few species to test properly the transferability of species distribution models. The pronounced asymmetry in transferability between the two study regions may be due to peculiarities of these regions, such as differences in the ranges of environmental predictors or the varied impact of land-use history, or to species-specific reasons like differential phenotypic plasticity, existence of ecotypes or varied dependence on biotic interactions that are not properly incorporated into niche-based models. The lower variation between internal and external evaluation of GLMs compared to GAMs further suggests that overfitting may reduce transferability. Overall, a limited geographical transferability calls for caution when projecting niche-based models for assessing the fate of species in future environments.

Holism and structural realism

We first introduce structural realism as a position in the metaphysics of science, pointing out the way in which this position replaces intrinsic properties with relations so that it amounts to a holistic in contrast to an atomistic metaphysics. We argue in favour of a moderate version of structural realism that puts objects and relations on the same ontological footing and assess the general philosophical arguments for this position. The second section shows how structural realism gains support from quantum physics. The third section explains how structural realism can be applied to the metaphysics of space-time.

Holism and structural realism

We first introduce structural realism as a position in the metaphysics of science, pointing out the way in which this position replaces intrinsic properties with relations so that it amounts to a holistic in contrast to an atomistic metaphysics. We argue in favour of a moderate version of structural realism that puts objects and relations on the same ontological footing and assess the general philosophical arguments for this position. The second section shows how structural realism gains support from quantum physics. The third section explains how structural realism can be applied to the metaphysics of space-time.

Organization and plasticity of auditory spatial representations

Spatial hearing refers to a set of abilities enabling us to determine the location of sound sources, redirect our attention toward relevant acoustic events, and recognize separate sound sources in noisy environments. Determining the location of sound sources plays a key role in the way in which humans perceive and interact with their environment. Deficits in sound localization abilities are observed after lesions to the neural tissues supporting these functions and can result in serious handicaps in everyday life. These deficits can, however, be remediated (at least to a certain degree) by the surprising capacity of reorganization that the human brain possesses following damage and/or learning, namely, the brain plasticity. In this thesis, our aim was to investigate the functional organization of auditory spatial functions and the learning-induced plasticity of these functions. Overall, we describe the results of three studies. The first study entitled "The role of the right parietal cortex in sound localization: A chronometric single pulse transcranial magnetic stimulation study" (At et al., 2011), study A, investigated the role of the right parietal cortex in spatial functions and its chronometry (i.e. the critical time window of its contribution to sound localizations). We concentrated on the behavioral changes produced by the temporarily inactivation of the parietal cortex with transcranial magnetic stimulation (TMS). We found that the integrity of the right parietal cortex is crucial for localizing sounds in the space and determined a critical time window of its involvement, suggesting a right parietal dominance for auditory spatial discrimination in both hemispaces. In "Distributed coding of the auditory space in man: evidence from training-induced plasticity" (At et al., 2013a), study B, we investigated the neurophysiological correlates and changes of the different sub-parties of the right auditory hemispace induced by a multi-day auditory spatial training in healthy subjects with electroencephalography (EEG). We report a distributed coding for sound locations over numerous auditory regions, particular auditory areas code specifically for precise parts of the auditory space, and this specificity for a distinct region is enhanced with training. In the third study "Training-induced changes in auditory spatial mismatch negativity" (At et al., 2013b), study C, we investigated the pre-attentive neurophysiological changes induced with a training over 4 days in healthy subjects with a passive mismatch negativity (MMN) paradigm. We showed that training changed the mechanisms for the relative representation of sound positions and not the specific lateralization themselves and that it changed the coding in right parahippocampal regions. - L'audition spatiale désigne notre capacité à localiser des sources sonores dans l'espace, de diriger notre attention vers les événements acoustiques pertinents et de reconnaître des sources sonores appartenant à des objets distincts dans un environnement bruyant. La localisation des sources sonores joue un rôle important dans la façon dont les humains perçoivent et interagissent avec leur environnement. Des déficits dans la localisation de sons sont souvent observés quand les réseaux neuronaux impliqués dans cette fonction sont endommagés. Ces déficits peuvent handicaper sévèrement les patients dans leur vie de tous les jours. Cependant, ces déficits peuvent (au moins à un certain degré) être réhabilités grâce à la plasticité cérébrale, la capacité du cerveau humain à se réorganiser après des lésions ou un apprentissage. L'objectif de cette thèse était d'étudier l'organisation fonctionnelle de l'audition spatiale et la plasticité induite par l'apprentissage de ces fonctions. Dans la première étude intitulé « The role of the right parietal cortex in sound localization : A chronometric single pulse study » (At et al., 2011), étude A, nous avons examiné le rôle du cortex pariétal droit dans l'audition spatiale et sa chronométrie, c'est-à- dire le moment critique de son intervention dans la localisation de sons. Nous nous sommes concentrés sur les changements comportementaux induits par l'inactivation temporaire du cortex pariétal droit par le biais de la Stimulation Transcrânienne Magnétique (TMS). Nous avons démontré que l'intégrité du cortex pariétal droit est cruciale pour localiser des sons dans l'espace. Nous avons aussi défini le moment critique de l'intervention de cette structure. Dans « Distributed coding of the auditory space : evidence from training-induced plasticity » (At et al., 2013a), étude B, nous avons examiné la plasticité cérébrale induite par un entraînement des capacités de discrimination auditive spatiale de plusieurs jours. Nous avons montré que le codage des positions spatiales est distribué dans de nombreuses régions auditives, que des aires auditives spécifiques codent pour des parties données de l'espace et que cette spécificité pour des régions distinctes est augmentée par l'entraînement. Dans « Training-induced changes in auditory spatial mismatch negativity » (At et al., 2013b), étude C, nous avons examiné les changements neurophysiologiques pré- attentionnels induits par un entraînement de quatre jours. Nous avons montré que l'entraînement modifie la représentation des positions spatiales entraînées et non-entrainées, et que le codage de ces positions est modifié dans des régions parahippocampales.

Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis.

OBJECTIVES: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. METHODS: A series of 20 dipeptides of general structure NH(2) -L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1) , pK(2) and pK(3) ) and lipophilicity parameters (log P(N) and log D(7.4) ) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP) , meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). RESULTS: Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. CONCLUSION: This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression. Chirality 24:566-576, 2012. © 2012 Wiley Periodicals, Inc.

Efficient transduction of dendritic cells and induction of a T-cell response by third-generation lentivectors.

In order to induce a therapeutic T lymphocyte response, recombinant viral vaccines are designed to target professional antigen-presenting cells (APC) such as dendritic cells (DC). A key requirement for their use in humans is safe and efficient gene delivery. The present study assesses third-generation lentivectors with respect to their ability to transduce human and mouse DC and to induce antigen-specific CD8+ T-cell responses. We demonstrate that third-generation lentivectors transduce DC with a superior efficiency compared to adenovectors. The transfer of DC transduced with a recombinant lentivector encoding an antigenic epitope resulted in a strong specific CD8+ T-cell response in mice. The occurrence of lower proportions of nonspecifically activated CD8+ cells suggests a lower antivector immunity of lentivector compared to adenovector. Thus, lentivectors, in addition to their promise for gene therapy of brain disorders might also be suitable for immunotherapy.

Providing more informative projections of climate change impact on plant distribution in a mountain environment

Summary Due to their conic shape and the reduction of area with increasing elevation, mountain ecosystems were early identified as potentially very sensitive to global warming. Moreover, mountain systems may experience unprecedented rates of warming during the next century, two or three times higher than that records of the 20th century. In this context, species distribution models (SDM) have become important tools for rapid assessment of the impact of accelerated land use and climate change on the distribution plant species. In my study, I developed and tested new predictor variables for species distribution models (SDM), specific to current and future geographic projections of plant species in a mountain system, using the Western Swiss Alps as model region. Since meso- and micro-topography are relevant to explain geographic patterns of plant species in mountain environments, I assessed the effect of scale on predictor variables and geographic projections of SDM. I also developed a methodological framework of space-for-time evaluation to test the robustness of SDM when projected in a future changing climate. Finally, I used a cellular automaton to run dynamic simulations of plant migration under climate change in a mountain landscape, including realistic distance of seed dispersal. Results of future projections for the 21st century were also discussed in perspective of vegetation changes monitored during the 20th century. Overall, I showed in this study that, based on the most severe A1 climate change scenario and realistic dispersal simulations of plant dispersal, species extinctions in the Western Swiss Alps could affect nearly one third (28.5%) of the 284 species modeled by 2100. With the less severe 61 scenario, only 4.6% of species are predicted to become extinct. However, even with B1, 54% (153 species) may still loose more than 80% of their initial surface. Results of monitoring of past vegetation changes suggested that plant species can react quickly to the warmer conditions as far as competition is low However, in subalpine grasslands, competition of already present species is probably important and limit establishment of newly arrived species. Results from future simulations also showed that heavy extinctions of alpine plants may start already in 2040, but the latest in 2080. My study also highlighted the importance of fine scale and regional. assessments of climate change impact on mountain vegetation, using more direct predictor variables. Indeed, predictions at the continental scale may fail to predict local refugees or local extinctions, as well as loss of connectivity between local populations. On the other hand, migrations of low-elevation species to higher altitude may be difficult to predict at the local scale. Résumé La forme conique des montagnes ainsi que la diminution de surface dans les hautes altitudes sont reconnues pour exposer plus sensiblement les écosystèmes de montagne au réchauffement global. En outre, les systèmes de montagne seront sans doute soumis durant le 21ème siècle à un réchauffement deux à trois fois plus rapide que celui mesuré durant le 20ème siècle. Dans ce contexte, les modèles prédictifs de distribution géographique de la végétation se sont imposés comme des outils puissants pour de rapides évaluations de l'impact des changements climatiques et de la transformation du paysage par l'homme sur la végétation. Dans mon étude, j'ai développé de nouvelles variables prédictives pour les modèles de distribution, spécifiques à la projection géographique présente et future des plantes dans un système de montagne, en utilisant les Préalpes vaudoises comme zone d'échantillonnage. La méso- et la microtopographie étant particulièrement adaptées pour expliquer les patrons de distribution géographique des plantes dans un environnement montagneux, j'ai testé les effets d'échelle sur les variables prédictives et sur les projections des modèles de distribution. J'ai aussi développé un cadre méthodologique pour tester la robustesse potentielle des modèles lors de projections pour le futur. Finalement, j'ai utilisé un automate cellulaire pour simuler de manière dynamique la migration future des plantes dans le paysage et dans quatre scénarios de changement climatique pour le 21ème siècle. J'ai intégré dans ces simulations des mécanismes et des distances plus réalistes de dispersion de graines. J'ai pu montrer, avec les simulations les plus réalistes, que près du tiers des 284 espèces considérées (28.5%) pourraient être menacées d'extinction en 2100 dans le cas du plus sévère scénario de changement climatique A1. Pour le moins sévère des scénarios B1, seulement 4.6% des espèces sont menacées d'extinctions, mais 54% (153 espèces) risquent de perdre plus 80% de leur habitat initial. Les résultats de monitoring des changements de végétation dans le passé montrent que les plantes peuvent réagir rapidement au réchauffement climatique si la compétition est faible. Dans les prairies subalpines, les espèces déjà présentes limitent certainement l'arrivée de nouvelles espèces par effet de compétition. Les résultats de simulation pour le futur prédisent le début d'extinctions massives dans les Préalpes à partir de 2040, au plus tard en 2080. Mon travail démontre aussi l'importance d'études régionales à échelle fine pour évaluer l'impact des changements climatiques sur la végétation, en intégrant des variables plus directes. En effet, les études à échelle continentale ne tiennent pas compte des micro-refuges, des extinctions locales ni des pertes de connectivité entre populations locales. Malgré cela, la migration des plantes de basses altitudes reste difficile à prédire à l'échelle locale sans modélisation plus globale.

Dynamic Modelling of Material Flows and Sustainable Resource Use: Case Studies in Regional Metabolism and Space Life Support Systems

Sustainable resource use is one of the most important environmental issues of our times. It is closely related to discussions on the 'peaking' of various natural resources serving as energy sources, agricultural nutrients, or metals indispensable in high-technology applications. Although the peaking theory remains controversial, it is commonly recognized that a more sustainable use of resources would alleviate negative environmental impacts related to resource use. In this thesis, sustainable resource use is analysed from a practical standpoint, through several different case studies. Four of these case studies relate to resource metabolism in the Canton of Geneva in Switzerland: the aim was to model the evolution of chosen resource stocks and flows in the coming decades. The studied resources were copper (a bulk metal), phosphorus (a vital agricultural nutrient), and wood (a renewable resource). In addition, the case of lithium (a critical metal) was analysed briefly in a qualitative manner and in an electric mobility perspective. In addition to the Geneva case studies, this thesis includes a case study on the sustainability of space life support systems. Space life support systems are systems whose aim is to provide the crew of a spacecraft with the necessary metabolic consumables over the course of a mission. Sustainability was again analysed from a resource use perspective. In this case study, the functioning of two different types of life support systems, ARES and BIORAT, were evaluated and compared; these systems represent, respectively, physico-chemical and biological life support systems. Space life support systems could in fact be used as a kind of 'laboratory of sustainability' given that they represent closed and relatively simple systems compared to complex and open terrestrial systems such as the Canton of Geneva. The chosen analysis method used in the Geneva case studies was dynamic material flow analysis: dynamic material flow models were constructed for the resources copper, phosphorus, and wood. Besides a baseline scenario, various alternative scenarios (notably involving increased recycling) were also examined. In the case of space life support systems, the methodology of material flow analysis was also employed, but as the data available on the dynamic behaviour of the systems was insufficient, only static simulations could be performed. The results of the case studies in the Canton of Geneva show the following: were resource use to follow population growth, resource consumption would be multiplied by nearly 1.2 by 2030 and by 1.5 by 2080. A complete transition to electric mobility would be expected to only slightly (+5%) increase the copper consumption per capita while the lithium demand in cars would increase 350 fold. For example, phosphorus imports could be decreased by recycling sewage sludge or human urine; however, the health and environmental impacts of these options have yet to be studied. Increasing the wood production in the Canton would not significantly decrease the dependence on wood imports as the Canton's production represents only 5% of total consumption. In the comparison of space life support systems ARES and BIORAT, BIORAT outperforms ARES in resource use but not in energy use. However, as the systems are dimensioned very differently, it remains questionable whether they can be compared outright. In conclusion, the use of dynamic material flow analysis can provide useful information for policy makers and strategic decision-making; however, uncertainty in reference data greatly influences the precision of the results. Space life support systems constitute an extreme case of resource-using systems; nevertheless, it is not clear how their example could be of immediate use to terrestrial systems.

Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins.