Transfusion sanguine

thumb|Poche de sang pour transfusion Une transfusion sanguine est une opération consistant à injecter, par perfusion intraveineuse, du sang ou des dérivés sanguins. Histoire La transfusion sanguine (jusqu'en 1918 cf. ci-dessous, on ne peut pas vraiment parler de transfusion : il s'agit alors de ce qu'on pourrait appeler des « dons de sang ») est très ancienne : l'histoire des anciens Égyptiens et le Traité d’anatomie d'Hérophile en font mention. Dans la plupart de ces tentatives, le sang employé était d’origine animale. En 1492 : le pape Innocent VIII aurait subi le premier traitement de cellules vivantes. Persuadé par un médecin que le seul traitement était une transfusion, il se serait fait injecter successivement le sang de trois garçons de dix ans qui en moururent. Le traitement lui aurait apporté la mort. Cependant, selon le médecin et essayiste Gérard Tobelem, « aucun récit historique fiable ne permet d'authentifier » l'événement (Histoires du sang, Plon, 2013).

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Modelling the Intracellular Environment under Uncertainty, from Post-translational Modification to Metabolic Networks

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Modelling and analysis of biological systems is crucial in order to quantitatively explain and predict their behaviour. The importance of modelling in systems biology becomes even more evident when tackling complex, large systems. Approaches that rely on modelling can be used to tackle a range of problems, such as cellular signalling or using genetically modified bacteria to synthesize human proteins for medical purposes. These phenomena range across different spatiotemporal scales, whether it is predicting the decay of red blood cells for blood transfusion or finding engineering targets in order to increase the productivity of bioprocesses. Reconciling models with experimental data and quantifying how uncertainty propagates through these models is crucial to exploiting them to their full potential. Uncertainty impacts not only the calibration and validation of a model, but also the predictions extracted from it. Developing and implementing uncertainty quantification methods into these models is a key step in exploring their behaviour and accelerating the adoption of such methods in metabolic engineering. In this thesis I firstly propose to implement and explore uncertainty quantification methods on control coefficients obtained by Metabolic Control Analysis (MCA) of Genome Scale Metabolic Models (GEMs), with the goal of quantifying uncertainty propagation from model parameters to control coefficients. I additionally want to build Single Protein Models that describe the effects of Post Translational Modifications (PTMs). The nature of the experimental data available to calibrate these models makes uncertainty an inherent property, and therefore Global Sensitivty Analysis (GSA) techniques are well suited to describing the links between parameter uncertainty and model behaviour.

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Targeted antibody and cytokine cancer immunotherapies through collagen affinity

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Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T lymphocyte antigen 4 antibody (alpha CTLA4) + anti-programmed death ligand 1 antibody (alpha PD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both alpha CTLA4+alpha PD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8(+) T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise.

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Stored red blood cells: A changing universe waiting for its map(s)

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The availability of stored red blood cells (RBCs) for transfusion remains an important aspect of the treatment of polytrauma, acute anemia or major bleedings. RBCs are prepared by blood banks from whole blood donations and stored in the cold in additive solutions for typically six weeks. These far from physiological storage conditions result in the so-called red cell storage lesion that is of importance both to blood bankers and to clinical practitioners. Here we review the current state of knowledge about the red cell storage lesion from a proteomic perspective. in particular, we describe the current models accounting for RBC aging and response to lethal stresses, review the published proteomic studies carried out to uncover the molecular basis of the RBC storage lesion, and conclude by suggesting a few possible proteomic studies that would provide further knowledge of the molecular alterations carried by RBCs stored in the cold for six weeks. (C) 2009 Published by Elsevier B.V.

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