Improving the use of G-CSF during chemotherapy using physiological mathematical modelling : a quantitative systems pharmacology approach

La diminution des doses administrées ou même la cessation complète d'un traitement chimiothérapeutique est souvent la conséquence de la réduction du nombre de neutrophiles, qui sont les globules blancs les plus fréquents dans le sang. Cette réduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de myélosuppression, est précipitée par les effets létaux non spécifiques des médicaments anti-cancéreux, qui, parallèlement à leur effet thérapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'atténuer cet impact myélosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogène du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libération dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothérapie soient bien établis, les protocoles d'administration demeurent mal définis et sont fréquemment déterminés ad libitum par les cliniciens. Avec l'optique d'améliorer le dosage thérapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothérapeutique, nous avons développé un modèle physiologique du processus de granulopoïèse, qui incorpore les connaissances actuelles de pointe relatives à la production des neutrophiles des cellules souches hématopoïétiques dans la moelle osseuse. À ce modèle physiologique, nous avons intégré des modèles pharmacocinétiques/pharmacodynamiques (PK/PD) de deux médicaments: le PM00104 (Zalypsis®), un médicament anti-cancéreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents à la physiologie, nous avons estimé les paramètres de manière exhaustive sans devoir recourir à l'ajustement des données, ce qui nous a permis de prédire des données cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothérapie avec une période de 14 jours où l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothérapie). En utilisant ce modèle physio-PK/PD, nous avons démontré que le nombre d'administrations du rhG-CSF pourrait être réduit de dix (pratique actuelle) à quatre ou même trois administrations, à condition de retarder le début du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilité clinique de notre approche de modélisation, nous avons investigué l'impact de la variabilité PK présente dans une population de patients, sur les prédictions du modèle, en intégrant des modèles PK de population (Pop-PK) des deux médicaments. En considérant des cohortes de 500 patients in silico pour chacun des cinq scénarios de variabilité plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons établi qu'il n'y avait aucune différence significative dans les prédictions du modèle entre le patient-type et la population. Ceci démontre la robustesse de l'approche que nous avons développée et qui s'apparente à une approche de pharmacologie quantitative des systèmes (QSP). Motivés par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies périodiques telles que la neutropénie cyclique, nous avons ensuite soumis l'étude du modèle au contexte des maladies dynamiques. En mettant en évidence la non validité du paradigme de la rétroaction des cytokines pour l'administration exogène des mimétiques du G-CSF, nous avons développé un modèle physiologique PK/PD novateur comprenant les concentrations libres et liées du G-CSF. Ce nouveau modèle PK a aussi nécessité des changements dans le modèle PD puisqu’il nous a permis de retracer les concentrations du G-CSF lié aux neutrophiles. Nous avons démontré que l'hypothèse sous-jacente de l'équilibre entre la concentration libre et liée, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endogènes et mènerait en fait à la surestimation de la clairance rénale du médicament. En procédant ainsi, nous avons réussi à reproduire des données cliniques obtenues dans diverses conditions (l'administration exogène du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mécanismes responsables de la réponse physiologique aux deux médicaments. Finalement, afin de mettre en exergue l’approche intégrative en pharmacologie adoptée dans cette thèse, nous avons démontré sa valeur inestimable pour la mise en lumière et la reconstruction des systèmes vivants complexes, en faisant le parallèle avec d’autres disciplines scientifiques telles que la paléontologie et la forensique, où une approche semblable a largement fait ses preuves. Nous avons aussi discuté du potentiel de la pharmacologie quantitative des systèmes appliquées au développement du médicament et à la médecine translationnelle, en se servant du modèle physio-PK/PD que nous avons mis au point.

La comunidad del filicidio : La vida de Dominguito de Domingo Sarmiento y su transposición fílmica

El artículo propone una lectura comparativa de La vida de Dominguito, de Domingo Sarmiento, y su transposición cinematográfica de 1944, titulada Su mejor alumno y escrita por Homero Manzi y Ulyses Petit de Murat. Para ello, se exploran las continuidades y desplazamientos en las imágenes de Sarmiento y Dominguito que ambas obras postulan. Primero, se aborda la película en tanto escenificación del pasaje de una imagen de Sarmiento que va del proyecto de la educación popular a la cultura pop. Luego, se introduce la idea de que en las dos obras la imagen del hijo funciona como el sustento de una comunidad política basada en el ideal ético de la philia. Sin embargo, el lugar fallado de ese modelo comunitario está determinado por el acto del filicidio, que a través de la metáfora del pueblo-niño que no puede superar su propia infancia, habilita una lectura de la película en relación con el contexto sociohistórico de emergencia de la imagen pop de Sarmiento en el momento de gestación del peronismo.

La comunidad del filicidio : La vida de Dominguito de Domingo Sarmiento y su transposición fílmica

El artículo propone una lectura comparativa de La vida de Dominguito, de Domingo Sarmiento, y su transposición cinematográfica de 1944, titulada Su mejor alumno y escrita por Homero Manzi y Ulyses Petit de Murat. Para ello, se exploran las continuidades y desplazamientos en las imágenes de Sarmiento y Dominguito que ambas obras postulan. Primero, se aborda la película en tanto escenificación del pasaje de una imagen de Sarmiento que va del proyecto de la educación popular a la cultura pop. Luego, se introduce la idea de que en las dos obras la imagen del hijo funciona como el sustento de una comunidad política basada en el ideal ético de la philia. Sin embargo, el lugar fallado de ese modelo comunitario está determinado por el acto del filicidio, que a través de la metáfora del pueblo-niño que no puede superar su propia infancia, habilita una lectura de la película en relación con el contexto sociohistórico de emergencia de la imagen pop de Sarmiento en el momento de gestación del peronismo.

Stable isotopes, PCBs and pesticide concentrations in zooplankton, seawater and POM from Kongsfjorden and Liefdefjorden, Svalbard

Differences in bioaccumulation of persistent organic pollutants (POPs) between fjords characterized by different water masses were investigated by comparing POP concentrations, patterns and bioaccumulation factors (BAFs) in seven species of zooplankton from Liefdefjorden (Arctic water mass) and Kongsfjorden (Atlantic water mass), Svalbard, Norway. No difference in concentrations and patterns of POPs was observed in seawater and POM; however higher concentrations and BAFs for certain POPs were found in species of zooplankton from Kongsfjorden. The same species were sampled in both fjords and the differences in concentrations of POPs and BAFs were most likely due to fjord specific characteristics, such as ice cover and timing of snow/glacier melt. These confounding factors make it difficult to conclude on water mass (Arctic vs. Atlantic) specific differences and further to extrapolate these results to possible climate change effects on accumulation of POPs in zooplankton. The present study suggests that zooplankton do biomagnify POPs, which is important for understanding contaminant uptake and flux in zooplankton, though consciousness regarding the method of evaluation is important.

(Table 1) Concentrations of polybrominated diphenyl ethers in liver and plasma samples of ringed seals (Phoca hispida)

The present study investigated the concentrations and patterns of PBDEs and hydroxylated (OH) PBDE analogues in two ringed seal populations: less contaminated Svalbard and more contaminated Baltic Sea. Mean concentration of hepatic sum-PBDE, which was dominated by BDE47, was six times higher in the ringed seals from the Baltic Sea compared to the seals from Svalbard. BDE47/sum-PBDE was higher in the seals from Svalbard compared to that for Baltic seals, while the trend was opposite for BDE153 and 154. The geographical difference in contaminant pattern of PBDEs in ringed seals could be explained by biotransformation via oxidative metabolism and/or by dietary differences. OH-PBDEs were detectable in the majority of plasma samples from both locations, and dominated by bioaccumulation of naturally occurring congeners. Low levels of 3-OH-BDE47 and 4'-OH-BDE49 in the Baltic ringed seals suggested minor oxidative biotransformation of BDE47. In the Baltic seals, BDE153/sum-PBDEs and BDE154/sum-PBDEs increased and BDE28/sum-PBDE decreased with increasing sum-POP concentration, which suggests BDE153 and 154 are more persistent than BDE28. Contrasting diets of the ringed seals in these two locations may influence the PBDE congener pattern due to selective long-range transport and direct effluent emissions to Svalbard and the Baltic, respectively.

Pollen and macrofossil profiles from six cores in Illinois, U.S.A

Pollen analysis of Wisconsinan sediments from eleven localities in northern and central Illinois, combined with the results of older studies, allows a first general survey of the vegetational changes in Illinois during the last glaciation. In the late Altonian (after 40,000 B.P.), pine was already the most prevalent tree type in northern Illinois. Probably because of the influence of the last Altonian ice advance to northern Illinois, pine migrated to the south and reached south-central Illinois, which was at that time a region of prairie, with oak and hickory trees in favorable sites. Likewise in the late Altonian, spruce appeared in northern Illinois. Spruce also expanded its area to the south during the Wisconsinan, reaching south-central Illinois only after 21,000 B.P., in the early Woodfordian. Deciduous trees (predominantly oak) were present in south-central Illinois throughout the Wisconsinan. Their prevalence decreased to the north. The vegetation during the different subdivisions of the last glacial period in Illinois was approximately as follows: Late Altonian: Pine/spruce forest with some deciduous trees in northern and central Illinois; prairie and oak/hickory stands in south-central Illinois; immigration of pine. Farmdalian: Pine/spruce forest in central Illinois; deciduous trees and pine in south-central Illinois, with areas of open vegetation, perhaps similar to the present-day transition of prairie to forest in the northern Great Plains. Woodfordian: Northern and central Illinois ice covered; in south central Illinois, spruce and oak as dominant tree types, but also pine and grassland. During the Woodfordian, pine and spruce disappeared again from south-central Illinois, and oak/hickory forest and prairie again prevailed. The ice-free areas of northern Illinois become populated temporarily with spruce, but later there is proof of deciduous forest in this region. Pollen investigations in south-central Illinois have shown convincingly that deciduous trees could survive relatively close (less than 60 km) to the ice margin. Therefore the frequently presented view that arctic climatic conditions prevailed in North America during the last glaciation far south of the ice margin can be refuted for the Illinois area, confirming the opinion of other authors resulting from investigations of fossil mollusks and frost-soil features. The small number of localities investigated still permits no complete reconstruction of the vegetation zones and their possible movements in Illinois. During the Altonian and Farmdalian in Illinois, a vegetational zonation probably existed similar to that of today in North America. As the ice pushed southward as far as 39° 20' N. lat in the early Woodfordian, this zonation was apparently broken up under the influence of a relatively moderate climate. In any case, the Vandalia area, which was only about 60 km south of the ice, was at that time neither in a tundra zone nor in a zone of boreal coniferous forest.

Geochemistry of the water column of southern lake Baikal during 1967-2005

At present, when the influence of human economic activity is progressively increasing, significant attention is devoted to the state of water ecosystems. All researchers engaged in these problems agree that the state of the water system (pollution and eutrophication) can only be estimated on the basis of long-term researches. Systemic monitoring (at least once per month) of ionic components (Ca2+, Mg2+, Na+, K+, bicarbonates, sulfates, and chlorides) in unfiltered water of Lake Baikal and its tributaries had been carried out under the supervision of Votintsev since 1947. Based on the analysis of systematic data on trophic components obtained during 1965-2005, we tried to estimate the present-day trophic status of the pelagic zone in the lake, define the trend of long-term changes of trophic components and understand the reasons of the distortion of cyclicity in the development of spring diatom algae, which create a favorable environment in any water basin. It should be noted that the station near Cape Polovinnyi is located 20 km away from the town of Baikal'sk. Wastewaters of the Baikal'sk pulp and paper mill is the main source of dioxins and furans in Baikal. Based on the significant difference between sulfate contents in wastewaters of the plant (>300 mg/l), tributaries of Baikal (7.5 mg/l), and waters in the southern part of the lake (3.9 mg/l), we defined the following periods: (i) period of natural seasonal patterns until 1967-1968 (prior to putting the Baikal'sk Mill into operation; (ii) period of weak anthropogenic pollution (1969-1985); and (iii) period of strong anthropogenic pollution since 1986.

Seawater carbonate chemistry, nutrients, and Calcidiscus leptoporus (strain RCC1135) growth rate and calcification rate during experiments, 2012

The coccolithophore Calcidiscus leptoporus was grown in batch culture under nitrogen (N) as well as phosphorus (P) limitation. Growth rate, particulate inorganic carbon (PIC), particulate organic carbon (POC), particulate organic nitrogen (PON), and particulate organic phosphorus (POP) production were determined and coccolith morphology was analysed. While PON production decreased by 70% under N-limitation and POP production decreased by 65% under P-limitation, growth rate decreased by 33% under N- as well as P-limitation. POC as well as PIC production (calcification rate) increased by 27% relative to the control under P-limitation, and did not change under N-limitation. Coccolith morphology did not change in response to either P or N limitation. While these findings, supported by a literature survey, suggest that coccolith morphogenesis is not hampered by either P or N limitation, calcification rate might be. The latter conclusion is in apparent contradiction to our data. We discuss the reasons for this inference.

Pollen record from Eifel maar

A new interglacial pollen sequence from the Döttinger dry maar in the Eifel region of the Rheinish Schield is presented. Palynology is used to correlated to several classical north German Holsteinian sites. The lake sediments reveal the complete interglacial and also 60 m of laminated sediments from the glacial preceding the Holsteinian. The interglacial section indicates limnic conditions in its lower part and telmatic conditions in its upper part with an intermediate episode of peat formation. Ash layers document internsive volcansim during the interglacial in the Eifel region. Some of the north German Holsteinian sites reval spikes of high abundance of Pinus, Beutal and Poaceae and/or setbacks of more demanding taxa during the interglacial, often interpreted as cold events. The Döttingen profile shows similar pattern, but with little response from the thermophilous pollen taxa. In the Döttingen sequence these vegetation 'anomalies' are preceded, or accompanied by phases of active volcanism. The role/interaction of climate and/or volcanism as a likely cause for these vegetation 'anomalies' ist still to be quantified.