Dynamics of erythroid progenitors and erythroleukemia

International audienceThe paper is devoted to mathematical modelling of erythropoiesis, production of red blood cells in the bone marrow. We discuss intra-cellular regulatory networks which determine self-renewal and differentiation of erythroid progenitors. In the case of excessive self-renewal, immature cells can fill the bone marrow resulting in the development of leukemia. We introduce a parameter characterizing the strength of mutation. Depending on its value, leukemia will or will not develop. The simplest model of treatment of acute myeloid leukemia with chemotherapy allows us to determine the conditions of successful treatment or of its failure. We show that insufficient treatment can worsen the situation. In some cases curing may not be possible even without resistance to treatment. Modelling presented in this work is based on ordinary differential equations, reaction-diffusion systems and individual based approach

Multi-Agent Systems and Blood Cell Formation

International audienceThe objective of this chapter is to give an insight of the mathematical modellng of hematopoiesis using multi-agent systems. Several questions may arise then: what is hematopoiesis and why is it interesting to study this problem from a mathematical point of view? Has the multi-agent system approach been the only attempt done until now? What does it bring more than other techniques? What were the results obtained? What is there left to do

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747)

Entwicklung einer Plattform für Second Screen Experimente

Second Screen ist seit Jahren ein fester Bestandteil der Medienlandschaft. Diese Arbeit befasst sich mit der Entwicklung einer Untersuchungsplattform für Second Screen Experimente. Es präsentiert einen Weg, auf Basis von Feature Extraction aus Texten passende Informationsabfragen zu kuratierten Archiven zu generieren. Um den Benutzer nicht zu überfordern und ihm kompakte Informationsblöcke zu präsentieren, werden Texte anhand von Textzusammenfassungsalgorithmen komprimiert. Die Validierung der Untersuchungsplattform basiert auf der Frage, inwieweit Second Screen die Informationsaufnahme der Nutzer beein usst. Dazu wurde ein Experiment mit Probanden im Living Place Hamburg durchgeführt.Second Screen has been an integral part of the media landscape. This work is concerned with the development of an investigation platform for Second Screen experiments. It presents a way to generate pertinent information queries to curated archives based on feature extraction from texts. In order not to overwhelm the user and to present him compact blocks of information, texts are compressed using text summarization algorithms. The validation of the investigation platform is based on the question, in how far second screen a ects the information receiving of users. For this purpose, an experiment was conducted with volunteers at the Living Place Hamburg

Modélisations mathématiques de l’hématopoïèse et des maladies sanguines

This PhD thesis is devoted to mathematical modelling of haematopoiesis and blood diseases. We investigate several models, which deal with different and complementary aspects of haematopoiesis.The first part of the thesis concerns a multi-scale model of erythropoiesis where intracellular regulatory networks, which determine cell choice between self-renewal, differentiation and apoptosis, are coupled with dynamics of cell populations. Using experimental data on anemia in mice, we evaluate the roles of different feedback mechanisms in response to stress situations. At the next stage of modelling, spatial cell distribution in the bone marrow is taken into account, the question which has not been studied before. We describe normal haematopoiesis with a system of reaction-diffusion-convection equations and prove existence of a stationary cell distribution. We then introduce malignant cells into the model. For some parameter values the disease free solution becomes unstable and another one, which corresponds to leukaemia, appears. This leads to the formation of tumour which spreads in the bone marrow as a travelling wave. The speed of its propagation is studied analytically and numerically. Bone marrow cells exchange different signals that regulate cell behaviour. We study, next, an integro-differential equation which describes cell communication and prove the existence of travelling wave solutions using topological degree and the Leray-Schauder method. Individual based approach is used to study distribution of different cell types in the bone marrow. Finally, we investigate a Physiologically Based Pharmacokinetics-Pharmacodynamics model of leukaemia treatment with AraC drug. AraC acts as chemotherapy, inducing apoptosis of all proliferating cells, normal and malignant. Pharmacokinetics provides the evolution of intracellular AraC. This, in turn, determines cell population dynamics and, consequently, efficacy of treatment with different protocols.Cette thèse est consacrée à la modélisation mathématique de l'hématopoïèse et des maladies sanguines. Plusieurs modèles traitant d'aspects différents et complémentaires de l'hématopoïèse y sont étudiés.Tout d'abord, un modèle multi-échelle de l'érythropoïèse est analysé, dans lequel sont décrits à la fois le réseau intracellulaire, qui détermine le comportement individuel des cellules, et la dynamique des populations de cellules. En utilisant des données expérimentales sur les souris, nous évaluons les rôles des divers mécanismes de retro-contrôle en réponse aux situations de stress.Ensuite, nous tenons compte de la distribution spatiale des cellules dans la moelle osseuse, question qui n'avait pas été étudiée auparavant. Nous décrivons l'hématopoïèse normale à l'aide d'un système d'équations de réaction-diffusion-convection et nous démontrons l'existence d'une distribution stationnaire des cellules. Puis, nous introduisons dans le modèle les cellules malignes. Pour certaines valeurs des paramètres, la solution "disease-free" devient instable et une autre solution, qui correspond à la leucémie, apparaît. Cela mène à la formation d'une tumeur qui se propage dans la moelle osseuse comme une onde progressive. La vitesse de cette propagation est étudiée analytiquement et numériquement. Les cellules de la moelle osseuse échangent des signaux qui régulent le comportement cellulaire. Nous étudions ensuite une équation integro-différentielle qui décrit la communication cellulaire et nous prouvons l'existence d'une solution du type onde progressive en utilisant la théorie du degré topologique et la méthode de Leray et Schauder. L'approche multi-agent est utilisée afin d'étudier la distribution des différents types de cellules dans la moelle osseuse.Finalement, nous étudions un modèle de type "Physiologically Based Pharmacokinetics-Pharmacodynamics" du traitement de la leucémie par l'AraC. L'AraC agit comme chimiothérapie et induit l'apoptose de toutes les cellules proliférantes, saines et malignes. La pharmacocinétique donne accès à la concentration intracellulaire d'AraC. Cette dernière, à son tour, détermine la dynamique des populations cellulaires et, par conséquent, l'efficacité de différents protocoles de traitement

Mathematical modelling of haematopoiesis and blood diseases

Cette thèse est consacrée à la modélisation mathématique de l'hématopoïèse et des maladies sanguines. Plusieurs modèles traitant d'aspects différents et complémentaires de l'hématopoïèse y sont étudiés.Tout d'abord, un modèle multi-échelle de l'érythropoïèse est analysé, dans lequel sont décrits à la fois le réseau intracellulaire, qui détermine le comportement individuel des cellules, et la dynamique des populations de cellules. En utilisant des données expérimentales sur les souris, nous évaluons les rôles des divers mécanismes de retro-contrôle en réponse aux situations de stress.Ensuite, nous tenons compte de la distribution spatiale des cellules dans la moelle osseuse, question qui n'avait pas été étudiée auparavant. Nous décrivons l'hématopoïèse normale à l'aide d'un système d'équations de réaction-diffusion-convection et nous démontrons l'existence d'une distribution stationnaire des cellules. Puis, nous introduisons dans le modèle les cellules malignes. Pour certaines valeurs des paramètres, la solution "disease-free" devient instable et une autre solution, qui correspond à la leucémie, apparaît. Cela mène à la formation d'une tumeur qui se propage dans la moelle osseuse comme une onde progressive. La vitesse de cette propagation est étudiée analytiquement et numériquement. Les cellules de la moelle osseuse échangent des signaux qui régulent le comportement cellulaire. Nous étudions ensuite une équation integro-différentielle qui décrit la communication cellulaire et nous prouvons l'existence d'une solution du type onde progressive en utilisant la théorie du degré topologique et la méthode de Leray et Schauder. L'approche multi-agent est utilisée afin d'étudier la distribution des différents types de cellules dans la moelle osseuse.Finalement, nous étudions un modèle de type "Physiologically Based Pharmacokinetics-Pharmacodynamics" du traitement de la leucémie par l'AraC. L'AraC agit comme chimiothérapie et induit l'apoptose de toutes les cellules proliférantes, saines et malignes. La pharmacocinétique donne accès à la concentration intracellulaire d'AraC. Cette dernière, à son tour, détermine la dynamique des populations cellulaires et, par conséquent, l'efficacité de différents protocoles de traitement.This PhD thesis is devoted to mathematical modelling of haematopoiesis and blood diseases. We investigate several models, which deal with different and complementary aspects of haematopoiesis.The first part of the thesis concerns a multi-scale model of erythropoiesis where intracellular regulatory networks, which determine cell choice between self-renewal, differentiation and apoptosis, are coupled with dynamics of cell populations. Using experimental data on anemia in mice, we evaluate the roles of different feedback mechanisms in response to stress situations. At the next stage of modelling, spatial cell distribution in the bone marrow is taken into account, the question which has not been studied before. We describe normal haematopoiesis with a system of reaction-diffusion-convection equations and prove existence of a stationary cell distribution. We then introduce malignant cells into the model. For some parameter values the disease free solution becomes unstable and another one, which corresponds to leukaemia, appears. This leads to the formation of tumour which spreads in the bone marrow as a travelling wave. The speed of its propagation is studied analytically and numerically. Bone marrow cells exchange different signals that regulate cell behaviour. We study, next, an integro-differential equation which describes cell communication and prove the existence of travelling wave solutions using topological degree and the Leray-Schauder method. Individual based approach is used to study distribution of different cell types in the bone marrow. Finally, we investigate a Physiologically Based Pharmacokinetics-Pharmacodynamics model of leukaemia treatment with AraC drug. AraC acts as chemotherapy, inducing apoptosis of all proliferating cells, normal and malignant. Pharmacokinetics provides the evolution of intracellular AraC. This, in turn, determines cell population dynamics and, consequently, efficacy of treatment with different protocols

THE PHILOSOPHICAL-THEORETICAL FRAMEWORK OF RUSSIAN CONSERVATISM

В статье анализируются концептуальные основы такого сложного феномена, как русский консерватизм, с особым акцентом на его онтологических и социально-философских рамках. Подчеркивается актуальность философско-теоретического изучения русского консерватизма ввиду преобладания эмпирических исследований в этой области и общего недостатка работ комплексного характера. С использованием историко-философских источников и современных работ виднейших представителей и критиков русского консерватизма, на базе системного, компаративного и диалектического методов изучены исторические формы и философские основания русского консерватизма. Отправляясь от двух подходов к сущности консерватизма - содержательного и ситуативного, автор предлагает две трактовки философско-теоретических рамок русского консерватизма - расширительную и минималистскую. Обнаружено, что в контексте эвристически более эффективной минималистской трактовки выделяются следующие три этапа эволюции русского консерватизма: классический, неклассический и постнеклассический. На классическом этапе (XIX - начало XX в.) сформировались четыре основных направления (типа) русского консерватизма, впоследствии лишь углублявшиеся, - это государственный, социальный, либеральный и революционный консерватизм. Каждый из этих типов имел соответствующие аналоги в западноевропейском консерватизме. В статье показываются специфические особенности всех форм русского консерватизма: метафизичность, антирационализм, религиозный традиционализм, органицизм, приоритет эволюционного типа социальных изменений, партикуляризм и антииндивидуализм, самобытные версии «русского пути», социальный корпоративизм, духовно-аристократический иерархизм, идеократия, антибуржуазный характер. Полученные результаты могут выступать исходной концептуальной системой для проведения дальнейших исследований как в сфере социальной философии русского консерватизма, так и прикладного изучения его отдельных этапов, направлений и персоналий. Кроме того, перспективы исследования связаны с нахождением более глубокой корреляции между русскими и западными типами консервативной философии.The article analyzes the conceptual framework of such a complicated phenomenon as Russian conservatism, with a particular accent on its ontological and socio-philosophical boun-daries. The topicality of philosophical-theoretical investigation of Russian conservatism is stressed considering the prevalence of empirical studies in this field and the general lack of complex research works. The historical forms and philosophical underpinnings of Russian conservatism have been examined with the use of historical philosophical sources and contemporary li-terature of the prominent representatives and critics of Russian conservatism, and on the basis of systematic, comparative and dialectical methods. Starting from the two main approaches to the essence of conservatism - substantial and situational, the author proposes two interpretations of the philosophical-theoretical framework of Russian conservatism - widening and minimalistic ones. It has been discovered that in the context of a minimalistic interpretation (heuristically more effective) the following three stages of evolution of Russian conservatism are marked out: classical, non-classical and post-non-classical. At the classical stage (XIX - early XXth century) four fundamental trends (types) of Russian conservatism, afterwards only beco-ming deeper, were formed, - these are state, social, liberal and revolutionary types of conservatism. Each of them had adequate analogues in West European conservatism. Specific peculiarities of all types of Russian conservatism are demonstrated in the article: metaphysical nature, anti-rationalism, religious traditionalism, organicism, a priority of evolutionary societal changes, particularism, anti-individualism, original versions of «Russian Path», social corporatism, spiritual-aristocratic hierarchism, ideocracy, antibourgeois character. These results can be used as an initial conceptual system for further studies both in the sphere of social philosophy of Russian conservatism and applied research of its separate stages, trends and personalities. Besides the perspectives of the study are connected with the determination of a deeper correlation between Russian and Occidental types of conservative philosophy

spatial distribution of cell populations in the process of erythropoiesis

International audienc