Homeostasis limits the development of mature CD8+ but not CD4+ thymocytes.

The involvement of a variety of clonal selection processes during the development of T lymphocytes in the thymus has been well established. Less information, however, is available on how homeostatic mechanisms may regulate the generation and maturation of thymocytes. To investigate this question, mixed radiation bone marrow chimeras were established in which wild-type T cell precursors capable of full maturation were diluted with precursors deficient in maturation potential because of targeted mutations of the RAG1 or TCR-alpha genes. In chimeras in which the majority of thymocytes are blocked at the CD4- CD8- CD25+ stage (RAG1 deficient), and only a small proportion of T cell precursors are of wild-type origin, we observed no difference in the maturation of wild-type CD4- CD8- CD25+ cells to the CD4+ CD8+ stage as compared with control chimeras. Therefore, the number of cell divisions occurring during this transition is fixed and not subject to homeostatic regulation. In contrast, in mixed chimeras in which the majority of thymocytes are blocked at the CD4+ CD8+ stage (TCR-alpha deficient), an increased efficiency of development of wild-type mature CD8+ cells was observed. Surprisingly, the rate of generation of mature CD4+ thymocytes was not affected in these chimeras. Thus, the number of selectable CD8 lineage thymocytes apparently saturates the selection mechanism in normal mice while the development of CD4 lineage cells seems to be limited only by the expression of a suitable TCR. These data may open the way to the identification of homeostatic mechanisms regulating thymic output and CD4/CD8 lineage commitment, and the development of means to modulate it.

Controlled dynamic generation of standard 1,6-hexamethylene diisocyanate aerosols

A procedure for the dynamic generation of 1,6-hexamethylene diisocyanate (HDI) aerosol atmospheres of 70 micrograms m-3 (0.01 ppm) to 1.75 mg m-3 (0.25 ppm), based on the precise control of the evaporation of pure liquid HDI and subsequent dilution with air, was developed. The apparatus consisted of a home-made glass nebulizer coupled with a separation stage to exclude non-respirable droplets (greater than 10 microns). The aerosol concentrations were achieved by passing air through the nebulizer at 1.5-4.5 l. min-1 to generate dynamically 0.01-0.25 ppm of diisocyanate in an experimental chamber of 8.55 m3. The distribution of the liquid aerosol was established with an optical counter and the diisocyanate concentration was determined from samples collected in impingers by a high-pressure liquid chromatographic method. The atmospheres generated were suitable for the evaluation both of sampling procedures full scale, and of analytical methods: at 140 micrograms m-3 (0.02 ppm) they remained stable for 15-min provocation tests in clinical asthma, as verified by breath-zone sampling of exposed patients.

Analysis of susceptibility to human immunodeficiency virus 1 (HIV-1) by comparative genetics

Summary [résumé français voir ci-dessous] From the beginning of the 20th century the world population has been confronted with the human immune deficiency virus 1 (HIV-1). This virus has the particularity to mutate fast, and could thus evade and adapt to the human host. Our closest evolutionary related organisms, the non-human primates, are less susceptible to HIV-1. In a broader sense, primates are differentially susceptible to various retrovirus. Species specificity may be due to genetic differences among primates. In the present study we applied evolutionary and comparative genetic techniques to characterize the evolutionary pattern of host cellular determinants of HIV-1 pathogenesis. The study of the evolution of genes coding for proteins participating to the restriction or pathogenesis of HIV-1 may help understanding the genetic basis of modern human susceptibility to infection. To perform comparative genetics analysis, we constituted a collection of primate DNA and RNA to allow generation of de novo sequence of gene orthologs. More recently, release to the public domain of two new primate complete genomes (bornean orang-utan and common marmoset) in addition of the three previously available genomes (human, chimpanzee and Rhesus monkey) help scaling up the evolutionary and comparative genome analysis. Sequence analysis used phylogenetic and statistical methods for detecting molecular adaptation. We identified different selective pressures acting on host proteins involved in HIV-1 pathogenesis. Proteins with HIV-1 restriction properties in non-human primates were under strong positive selection, in particular in regions of interaction with viral proteins. These regions carried key residues for the antiviral activity. Proteins of the innate immunity presented an evolutionary pattern of conservation (purifying selection) but with signals of relaxed constrain if we compared them to the average profile of purifying selection of the primate genomes. Large scale analysis resulted in patterns of evolutionary pressures according to molecular function, biological process and cellular distribution. The data generated by various analyses served to guide the ancestral reconstruction of TRIM5a a potent antiviral host factor. The resurrected TRIM5a from the common ancestor of Old world monkeys was effective against HIV-1 and the recent resurrected hominoid variants were more effective against other retrovirus. Thus, as the result of trade-offs in the ability to restrict different retrovirus, human might have been exposed to HIV-1 at a time when TRIM5a lacked the appropriate specific restriction activity. The application of evolutionary and comparative genetic tools should be considered for the systematical assessment of host proteins relevant in viral pathogenesis, and to guide biological and functional studies. Résumé La population mondiale est confrontée depuis le début du vingtième siècle au virus de l'immunodéficience humaine 1 (VIH-1). Ce virus a un taux de mutation particulièrement élevé, il peut donc s'évader et s'adapter très efficacement à son hôte. Les organismes évolutivement le plus proches de l'homme les primates nonhumains sont moins susceptibles au VIH-1. De façon générale, les primates répondent différemment aux rétrovirus. Cette spécificité entre espèces doit résider dans les différences génétiques entre primates. Dans cette étude nous avons appliqué des techniques d'évolution et de génétique comparative pour caractériser le modèle évolutif des déterminants cellulaires impliqués dans la pathogenèse du VIH- 1. L'étude de l'évolution des gènes, codant pour des protéines impliquées dans la restriction ou la pathogenèse du VIH-1, aidera à la compréhension des bases génétiques ayant récemment rendu l'homme susceptible. Pour les analyses de génétique comparative, nous avons constitué une collection d'ADN et d'ARN de primates dans le but d'obtenir des nouvelles séquences de gènes orthologues. Récemment deux nouveaux génomes complets ont été publiés (l'orang-outan du Bornéo et Marmoset commun) en plus des trois génomes déjà disponibles (humain, chimpanzé, macaque rhésus). Ceci a permis d'améliorer considérablement l'étendue de l'analyse. Pour détecter l'adaptation moléculaire nous avons analysé les séquences à l'aide de méthodes phylogénétiques et statistiques. Nous avons identifié différentes pressions de sélection agissant sur les protéines impliquées dans la pathogenèse du VIH-1. Des protéines avec des propriétés de restriction du VIH-1 dans les primates non-humains présentent un taux particulièrement haut de remplacement d'acides aminés (sélection positive). En particulier dans les régions d'interaction avec les protéines virales. Ces régions incluent des acides aminés clé pour l'activité de restriction. Les protéines appartenant à l'immunité inné présentent un modèle d'évolution de conservation (sélection purifiante) mais avec des traces de "relaxation" comparé au profil général de sélection purifiante du génome des primates. Une analyse à grande échelle a permis de classifier les modèles de pression évolutive selon leur fonction moléculaire, processus biologique et distribution cellulaire. Les données générées par les différentes analyses ont permis la reconstruction ancestrale de TRIM5a, un puissant facteur antiretroviral. Le TRIM5a ressuscité, correspondant à l'ancêtre commun entre les grands singes et les groupe des catarrhiniens, est efficace contre le VIH-1 moderne. Les TRIM5a ressuscités plus récents, correspondant aux ancêtres des grands singes, sont plus efficaces contre d'autres rétrovirus. Ainsi, trouver un compromis dans la capacité de restreindre différents rétrovirus, l'homme aurait été exposé au VIH-1 à une période où TRIM5a manquait d'activité de restriction spécifique contre celui-ci. L'application de techniques d'évolution et de génétique comparative devraient être considérées pour l'évaluation systématique de protéines impliquées dans la pathogenèse virale, ainsi que pour guider des études biologiques et fonctionnelles

Analysis of CD4+ and CD8+ T cells by defined MHC-peptide complexes

MHC class II-peptide multimers are important tools for the detection, enumeration and isolation of antigen-specific CD4+ Τ cells. However, their erratic and often poor performance impeded their broad application and thus in-depth analysis of key aspects of antigen-specific CD4+ Τ cell responses. In the first part of this thesis we demonstrate that a major cause for poor MHC class II tetramer staining performance is incomplete peptide loading on MHC molecules. We observed that peptide binding affinity for "empty" MHC class II molecules poorly correlates with peptide loading efficacy. Addition of a His-tag or desthiobiotin (DTB) at the peptide N-terminus allowed us to isolate "immunopure" MHC class II-peptide monomers by affinity chromatography; this significantly, often dramatically, improved tetramer staining of antigen-specific CD4+ Τ cells. Insertion of a photosensitive amino acid between the tag and the peptide, permitted removal of the tag from "immunopure" MHC class II-peptide complex by UV irradiation, and hence elimination of its potential interference with TCR and/or MHC binding. Moreover, to improve loading of self and tumor antigen- derived peptides onto "empty" MHC II molecules, we first loaded these with a photocleavable variant of the influenza A hemagglutinin peptide HA306-318 and subsequently exchanged it with a poorly loading peptide (e.g. NY-ESO-1119-143) upon photolysis of the conditional ligand. Finally, we established a novel type of MHC class II multimers built on reversible chelate formation between 2xHis-tagged MHC molecules and a fluorescent nitrilotriacetic acid (NTA)-containing scaffold. Staining of antigen-specific CD4+ Τ cells with "NTAmers" is fully reversible and allows gentle cell sorting. In the second part of the thesis we investigated the role of the CD8α transmembrane domain (TMD) for CD8 coreceptor function. The sequence of the CD8α TMD, but not the CD8β TMD, is highly conserved and homodimerizes efficiently. We replaced the CD8α TMD with the one of the interleukin-2 receptor a chain (CD8αTac) and thus ablated CD8α TMD interactions. We observed that ΤΙ Τ cell hybridomas expressing CD8αTacβ exhibited severely impaired intracellular calcium flux, IL-2 responses and Kd/PbCS(ABA) P255A tetramer binding. By means of fluorescence resonance energy transfer experiments (FRET) we established that CD8αTacβ associated with TCR:CD3 considerably less efficiently than CD8αβ, both in the presence and the absence of Kd/PbCS(ABA) complexes. Moreover, we observed that CD8αTacβ partitioned substantially less in lipid rafts, and related to this, associated less efficiently with p56Lck (Lck), a Src kinase that plays key roles in TCR proximal signaling. Our results support the view that the CD8α TMD promotes the formation of CD8αβP-CD8αβ dimers on cell surfaces. Because these contain two CD8β chains and that CD8β, unlike CD8α, mediates association of CD8 with TCR:CD3 as well as with lipid rafts and hence with Lck, we propose that the CD8αTMD plays an important and hitherto unrecognized role for CD8 coreceptor function, namely by promoting CD8αβ dimer formation. We discuss what implications this might have on TCR oligomerization and TCR signaling. - Les multimères de complexes MHC classe II-peptide sont des outils importants pour la détection, le dénombrement et l'isolation des cellules Τ CD4+ spécifiques pour un antigène d'intérêt. Cependant, leur performance erratique et souvent inadéquate a empêché leur utilisation généralisée, limitant ainsi l'analyse des aspects clés des réponses des lymphocytes Τ CD4+. Dans la première partie de cette thèse, nous montrons que la cause principale de la faible efficacité des multimères de complexes MHC classe II-peptide est le chargement incomplet des molécules MHC par des peptides. Nous montrons également que l'affinité du peptide pour la molécule MHC classe II "vide" n'est pas nécessairement liée au degré du chargement. Grâce à l'introduction d'une étiquette d'histidines (His-tag) ou d'une molécule de desthiobiotine à l'extrémité N-terminale du peptide, des monomères MHC classe II- peptide dits "immunopures" ont pu être isolés par chromatographic d'affinité. Ceci a permis d'améliorer significativement et souvent de façon spectaculaire, le marquage des cellules Τ CD4+ spécifiques pour un antigène d'intérêt. L'insertion d'un acide aminé photosensible entre l'étiquette et le peptide a permis la suppression de l'étiquette du complexe MHC classe- Il peptide "immunopure" par irradiation aux UV, éliminant ainsi de potentielles interférences de liaison au TCR et/ou au MHC. De plus, afin d'améliorer le chargement des molécules MHC classe II "vides" avec des peptides dérivés d'auto-antigènes ou d'antigènes tumoraux, nous avons tout d'abord chargé les molécules MHC "vides" avec un analogue peptidique photoclivable issu du peptide HA306-318 de l'hémagglutinine de la grippe de type A, puis, sous condition de photolyse, nous l'avons échangé avec de peptides à chargement faible (p.ex. NY-ESO-1119-143). Finalement, nous avons construit un nouveau type de multimère réversible, appelé "NTAmère", basé sur la formation chélatante reversible entre les molécules MHC-peptide étiquettés par 2xHis et un support fluorescent contenant des acides nitrilotriacetiques (NTA). Le marquage des cellules Τ CD4+ spécifiques pour un antigène d'intérêt avec les "NTAmères" est pleinement réversible et permet également un tri cellulaire plus doux. Dans la deuxième partie de cette thèse nous avons étudié le rôle du domaine transmembranaire (TMD) du CD8α pour la fonction coréceptrice du CD8. La séquence du TMD du CD8α, mais pas celle du TMD du CD8β, est hautement conservée et permet une homodimérisation efficace. Nous avons remplacé le TMD du CD8α avec celui de la chaîne α du récepteur à l'IL-2 (CD8αTac), éliminant ainsi les interactions du TMD du CD8α. Nous avons montré que les cellules des hybridomes Τ T1 exprimant le CD8αTacβ présentaient une atteinte sévère du flux du calcium intracellulaire, des réponses d'IL-2 et de la liaison des tétramères Kd/PbCS(ABA) P255A. Grâce aux expériences de transfert d'énergie entre molécules fluorescentes (FRET), nous avons montré que l'association du CD8αTacβ avec le TCR:CD3 est considérablement moins efficace qu'avec le CD8αβ, et ceci aussi bien en présence qu'en absence de complexes Kd/PbCS(ABA). De plus, nous avons observé que le CD8αTacβ se distribuait beaucoup moins bien dans les radeaux lipidiques, engendrant ainsi, une association moins efficace avec p56Lck (Lck), une kinase de la famille Src qui joue un rôle clé dans la signalisation proximale du TCR. Nos résultats soutiennent l'hypothèse que le TMD du CD8αβ favorise la formation des dimères de CD8αβ à la surface des cellules. Parce que ces derniers contiennent deux chaînes CD8β et que CD8β, contrairement à CD8α, favorise l'association du CD8 au TCR:CD3 aussi bien qu'aux radeaux lipidiques et par conséquent à Lck, nous proposons que le TMD du CD8α joue un rôle important, jusqu'alors inconnu, pour la fonction coreceptrice du CD8, en encourageant la formation des dimères CD8αβ. Nous discutons des implications possibles sur l'oligomerisation du TCR et la signalisation du TCR.

Multi-sample analysis of moment-structures: Asymptotic validity of inferences based on second-order moments

In moment structure analysis with nonnormal data, asymptotic valid inferences require the computation of a consistent (under general distributional assumptions) estimate of the matrix $\Gamma$ of asymptotic variances of sample second--order moments. Such a consistent estimate involves the fourth--order sample moments of the data. In practice, the use of fourth--order moments leads to computational burden and lack of robustness against small samples. In this paper we show that, under certain assumptions, correct asymptotic inferences can be attained when $\Gamma$ is replaced by a matrix $\Omega$ that involves only the second--order moments of the data. The present paper extends to the context of multi--sample analysis of second--order moment structures, results derived in the context of (simple--sample) covariance structure analysis (Satorra and Bentler, 1990). The results apply to a variety of estimation methods and general type of statistics. An example involving a test of equality of means under covariance restrictions illustrates theoretical aspects of the paper.

Analysis of the genetic diversity in Metopolophium dirhodum (Walker) (Hemiptera, Aphididae) by RAPD markers

The emergence of host-races within aphids may constitute an obstacle to pest management by means of plant resistance. There are examples of host-races within cereals aphids, but their occurrence in Rose Grain Aphid, Metopolophium dirhodum (Walker, 1849), has not been reported yet. In this work, RAPD markers were used to assess effects of the hosts and geographic distance on the genetic diversity of M. dirhodum lineages. Twenty-three clones were collected on oats and wheat in twelve localitites of southern Brazil. From twenty-seven primers tested, only four primers showed polymorphisms. Fourteen different genotypes were revealed by cluster analysis. Five genotypes were collected only on wheat; seven only on oats and two were collected in both hosts. Genetic and geographical distances among all clonal lineages were not correlated. Analysis of molecular variance showed that some molecular markers are not randomly distributed among clonal lineages collected on oats and on wheat. These results suggest the existence of host-races within M. dirhodum, which should be further investigated using a combination of ecological and genetic data.

Generalized canonical correlation analysis of matrices with different row and column orders

A Method is offered that makes it possible to apply generalized canonicalcorrelations analysis (CANCOR) to two or more matrices of different row and column order. The new method optimizes the generalized canonical correlationanalysis objective by considering only the observed values. This is achieved byemploying selection matrices. We present and discuss fit measures to assessthe quality of the solutions. In a simulation study we assess the performance of our new method and compare it to an existing procedure called GENCOM,proposed by Green and Carroll. We find that our new method outperforms the GENCOM algorithm both with respect to model fit and recovery of the truestructure. Moreover, as our new method does not require any type of iteration itis easier to implement and requires less computation. We illustrate the methodby means of an example concerning the relative positions of the political parties inthe Netherlands based on provincial data.

Analysis of the enantiomers of citalopram and its demethylated metabolites using chiral liquid chromatography.

A procedure using a chirobiotic V column is presented which allows separation of the enantiomers of citalopram and its two N-demethylated metabolites, and of the internal standard, alprenolol, in human plasma. Citalopram, demethylcitalopram and didemethylcitalopram, as well as the internal standard, were recovered from plasma by liquid-liquid extraction. The limits of quantification were found to be 5 ng/ml for each enantiomer of citalopram and demethylcitalopram, and 7.5 ng/ml for each enantiomer of didemethylcitalopram. Inter- and intra-day coefficients of variation varied from 2.4% to 8.6% for S- and R-citalopram, from 2.9% to 7.4% for S- and R-demethylcitalopram, and from 5.6% to 12.4% for S- and R- didemethylcitalopram. No interference was observed from endogenous compounds following the extraction of plasma samples from 10 different patients treated with citalopram. This method allows accurate quantification for each enantiomer and is, therefore, well suited for pharmacokinetic and drug interaction investigations. The presented method replaces a previously described highly sensitive and selective high-performance liquid chromatography procedure using an acetylated 3-cyclobond column which, because of manufactural problems, is no longer usable for the separation of the enantiomers of citalopram and its demethylated metabolites.

Cannabis use as a means of socialization?: new consumption patterns among heavy users

Purpose: After tobacco and alcohol, cannabis is the most used substance among adolescents in Switzerland. Our aim is to assess whether cannabis use has become an ordinary means of socialization. We hypothesize that cannabis consumption has become a normative, although still illegal, behavior. Methods: As part of a larger qualitative study aimed at assessing new ways [patterns] of cannabis consumption, 16 daily cannabis consumers (11 males) and 2 former heavy consumers (both females), aged 15 to 20 years, participated in interviews and focus groups. Data were transcribed verbatim and analyzed using Atlas.ti qualitative analysis software. Results: Most consumers define the beginning of their consumption as a moment when they made new friends. They commonly use cannabis in group settings, which encourages the belief that all adolescents use cannabis. Thus, cannabis is mainly identified as an everyday social act. Joints are smoked like cigarettes: at all times of the day, during or after school or work with peers, often starting at lunch break, and mostly in public places. Friends offer a joint in a group setting, much like beer in a bar, as a means of making contact. Consumption invariably increases while socializing on vacation: "During vacation, we smoke up to 10-15 joints a day; at the end we're just dead." Additionally, in order to obtain cannabis, consumers have to be part of the right networks; they generally have several dealers to assure their supply, buy and sell themselves, or practice group-buying. As a result, all friends or acquaintances of consumers are themselves cannabis users. For instance, 4 boys, who say they are best friends, always smoke together and that, in order to quit, "All four of us should say to ourselves, 'Okay, now, let's all stop smoking'. That would be the only solution. . .but it would be impossible!" The 2 former consumers state that when they started using cannabis, "I found myself little by little in a vicious circle where I saw only people who also smoked". When they quit, they separated from their group of friends: "Either you make new friends who don't smoke or you smoke." Conclusions: Discussions with consumers demonstrate a normative facet of cannabis consumption as part of teenage socialization. Consequently, cannabis consumers develop a significant dependency since a majority of their friends use cannabis and their consumption involves most of their daily social life. Our study highlights the need for clear messages about the harmful aspects of using this substance while also suggesting that cessation efforts should include helping users separate from their consumption milieu. Sources of Support: Dept. of Public Health of the canton of Vaud.

A note on the dual scaling of dominance data and its relationship to correspondence analysis

Dual scaling of a subjects-by-objects table of dominance data (preferences,paired comparisons and successive categories data) has been contrasted with correspondence analysis, as if the two techniques were somehow different. In this note we show that dual scaling of dominance data is equivalent to the correspondence analysis of a table which is doubled with respect to subjects. We also show that the results of both methods can be recovered from a principal components analysis of the undoubled dominance table which is centred with respect to subject means.

A glutathione precursor, N-acetyl-cysteine, modulates mismatch negativity generation in schizophrenia patients

Schizophrenia patients exhibit deficits in low-level processing, including pitch discrimination. This deficiency manifests in auditory evoked potentials (AEPs) as an impaired mismatch negativity (MMN), an electrophysiological response to infrequent target stimuli interspersed among frequent standard stimuli that typically peaks ~100ms post-stimulus onset. NMDA receptor antagonists have been shown to block MMN generation in both animals and humans, and NMDA dysfunction has been linked to the underlying pathophysiology of schizophrenia. A parallel line of evidence indicates that glutathione (GSH) regulation is perturbed in schizophrenia patients at the gene, protein and functional levels (Tosic et al., 2006). This GSH dysregulation leads to NMDA receptors' hypofunction through interaction with their redox site (Steullet et al., 2006). The present study aimed to modulate GSH levels in schizophrenia patients and assessed the effects of such a modulation on MMN generation mechanisms. N-acetyl-cysteine (NAC), a GSH precursor, was administered to schizophrenia patients, using a double-blind cross-over protocol. One group received NAC (2g/day) for 60 days and then placebo for another 60 days, and vice-versa for the second group. AEPs from patients were recorded at the onset of the protocol, at the point of cross-over, and at the end of the study. Participants were instructed to manually respond to target stimuli (2kHz pure tones occurring 20% of the time among 1kHz pure tones). Analyses of AEPs recorded at protocol onset indicated that patients (n=11) were significantly impaired in generating the MMN relative to age-matched controls (n=11). Specifically, the global field power (GFP), an index of AEP magnitude, was measured over the 70- 155ms post-stimulus interval and submitted to an analysis of variance (ANOVA). There was a significant interaction between population and stimulus frequency, indicating impaired MMN generation in patients at protocol onset. Analyses of AEPs recorded during administration of NAC (n=7) versus placebo (n=7) revealed the efficacy of this GSH precursor in modulating MMN generation mechanisms. ANOVA of GFP over the 70- 155ms post-stimulus interval, using stimulus frequency and treatment as within-participants variables, revealed a significant interaction and indicated that NAC can ameliorate MMN generation. We discuss these results in terms of potential therapeutic strategies for schizophrenia.

Nilotinib compassionate use in advanced GIST : a retrospective analysis

Introduction: Tyrosine kinase inhibitors (TKI) have considerably improved outcome of patients with advanced GIST and extended overall survival to more than 5 years. Yet, the median progression-free survival is approximately 2 years with first-line imatinib and 24 weeks with second-line sunitinib, which calls for treatment alternatives. Nilotinib is a second-generation TKI with at least similar inhibitory activity as imatinib. A Phase I study has shown that nilotinib monotherapy has clinical activity in GIST. Methods: After failure of all available therapeutic options patients had access to nilotinib on a compassionate use (CU) programm. Nilotinib was started at a dose of 400 mg bid, with dose reduction to 400mg qd allowed in the case of toxicity. 94 pts were approved for nilotinib CU in 10 European countries. We herein present retrospective data of 42 pts from 5 European countries treated in 11 centers. Results: Median age at nilotinib treatment start was 59 years (median; range 24-79 y). 30 of 42 patients were male. Most pts had metastatic disease of gastric origin at initial diagnosis. KIT exon 11 mutations were most frequent. The median number of surgical resections was 1 (range 0-8). All pts had failed both imatinib and sunitinib before nilotinib, and few had also received additional investigational treatments. Nilotinib was well tolerated, and discontinued due to toxicity in 15% only. Median follow-up is 176 days (range 15-876 d). Nilotinib treatment duration is 75 days (median; range 3-727 d). Partial remission with nilotinib treatment was seen in 11% of pts. Median OS was 263 days (Kaplan-Meier). Conclusion: This is the largest series reported assessing efficacy of nilotinib for imatinib- and sunitinib-refractory GIST reported yet. Nilotinib displays significant clinical activity in this heavily pretreated group of pts. These results warrant further investigation of nilotinib in GIST, including its use in first or second-line treatment. Patient and data collection is ongoing, updated results will be presented.

Amyloïdose cardiaque: une urgence diagnostique [Echocardiographic analysis in cardiac amyloidosis]

Systemic amyloidosis with cardiac involvement may clinically be suspected in the presence of heart failure or arrhythmia of unknown origin. Herein two cases of cardiac amyloidosis are described with a clinical presentation of heart failure refractory to usual treatment. The key role of echocardiography in the diagnosis and prognosis evaluation of cardiac amyloidosis is discussed. A treatment targeted against the generation of amyloid fibril should ideally be initiated before apparition of heart failure.

A dynamic analysis of human welfare in a warming planet

Climate science indicates that climate stabilization requires low GHG emissions. Is thisconsistent with nondecreasing human welfare?Our welfare or utility index emphasizes education, knowledge, and the environment. Weconstruct and calibrate a multigenerational model with intertemporal links provided by education,physical capital, knowledge and the environment.We reject discounted utilitarianism and adopt, first, the Pure Sustainability Optimization (orIntergenerational Maximin) criterion, and, second, the Sustainable Growth Optimization criterion,that maximizes the utility of the first generation subject to a given future rate of growth. We applythese criteria to our calibrated model via a novel algorithm inspired by the turnpike property.The computed paths yield levels of utility higher than the level at reference year 2000 for allgenerations. They require the doubling of the fraction of labor resources devoted to the creation ofknowledge relative to the reference level, whereas the fractions of labor allocated to consumptionand leisure are similar to the reference ones. On the other hand, higher growth rates requiresubstantial increases in the fraction of labor devoted to education, together with moderate increasesin the fractions of labor devoted to knowledge and the investment in physical capital.

Improving electricity market price scenarios by means of forecasting factor models

In liberalized electricity markets, generation Companies must build an hourly bidthat is sent to the market operator. The price at which the energy will be paid is unknown during the bidding process and has to be forecast. In this work we apply forecasting factor models to this framework and study its suitability.