Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

International audienceBackground: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood.Methods: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by "reverse phase protein array" (RPPA) and western blotting experiments conducted on selected proteins to confirm the results.Results: We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia.Conclusions: Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson’s disease?

In Parkinson’s disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7 days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia

International Science Foresight Workshop: Global Challenges and Research Gaps. The Royaumont process.

How scientists might better contribute to SDGs in the land sector? At the invitation of INRAE, a group of high-level international experts delivers a comprehensive and systemic approach

Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis?

Iron accumulation has been observed in mouse models and both sporadic and familial forms of Amyotrophic lateral sclerosis. Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e. chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span as compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index (BMI) were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata and motor cortex (according to MRI), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS

An Overview of the Ethics of Eating and Drinking

Eating and drinking are ethical acts. When we make decisions about what to eat and what not to, we are making decisions that impact our own health, the well-being of those who work in the food system, animal welfare, and the environment. Food ethics is the interdisciplinary study of how what we eat – including the way it is produced, distributed, marketed, prepared, and ultimately consumed – impacts human, animal, and planetary health and well-being. Food ethics also analyses the justice or fairness of these impacts. Food ethics raises many difficult questions that do not always have clear or easy answers, such as how do we produce enough food to feed everyone well and equitably; how do we ensure that everyone has access to high-quality, nutritious food that is culturally appropriate; how do we do this in a way that treats workers fairly and respectfully, is considerate of animal welfare, and is environmentally sustainable; and how do we shift power across the food system in favor of the public good over multinational food companies. This chapter will explore these questions and more, hopefully encouraging thoughtful discussions and potential solutions for the future

Instabilité des prix agricoles et politiques optimales de stabilisation

This thesis proposes an analysis of food price stabilisation policies in poor countries. In order to represent the conditions in these countries, we introduce in a rational expectations storage model the assumption that consumers cannot insure against price risk and are risk averse. The market incompleteness justifies public intervention and various stabilisation policies are analysed. An optimal storage policy implies a storage level higher than without intervention. This additional storage crowds out private storers by removing the profit opportunity from speculation. Since the use of complex intervention rules is unlikely in poor countries, we compare state-contingent optimal food storage policies, with and without commitment, to simple storage rules such as a constant private storage subsidy or a price-band defended by public storage. The ability of government to commit to a policy rule brings additional welfare gains in comparison with a discretionary policy. These gains stem from the possibility of manipulating producers' expectations and, thus, of inducing them to promote stabilisation. Simple stabilisation rules can achieve, when designed optimally, gains closed to those of state-contingent policies. Finally, the analysis of stabilisation policies is extended to an open economy framework in which the stabilisation instruments are trade and storage policies. An optimal storage policy alone fails to protect consumers, since most additional storage is actually used to serve the world market. In contrast, an optimal trade policy strongly decreases price volatility by exploiting the world market.Cette thèse propose une analyse des politiques de stabilisation des prix alimentaires dans les pays pauvres. Afin de représenter la situation dans ces pays, l'auteur considére dans un modèle de stockage à anticipations rationnelles que les consommateurs ne peuvent pas s'assurer contre le risque prix et qu'ils sont averses au risque. L'incomplétude de marché justifie l'intervention publique et des politiques optimales de stabilisation sont analysées. Une politique optimale de stockage publique implique une augmentation du niveau de stockage. Ce stockage additionnel entraîne l'évincement de tous les stockeurs privés en supprimant les opportunités de profit spéculatif. L'usage de règles complexes d'intervention publique étant peu probable dans des pays pauvres, l'auteur compare des politiques optimales de stockage alimentaire à des règles simples comme une subvention au stockage privé ou une bande de prix défendue par du stockage public. L'engagement du gouvernement entraîne des gains de bien-être par rapport à une politique discrétionnaire liés à la possibilité de manipuler les anticipations des producteurs et donc de les induire à stabiliser les prix. Les règles simples de stabilisation permettent d'obtenir des gains proches de ceux obtenus avec des politiques optimales. Dans un cadre d'économie ouverte, les instruments de stabilisation sont la politique commerciale et le stockage. Une politique de stockage non accompagnée d'une politique commerciale ne profite pas aux consommateurs, car les bénéfices de la stabilisation se dissipent sur le marché mondial. Au contraire, une politique commerciale optimale permet d'augmenter la stabilisation en exploitant le marché mondial

Additional file 6: Figure S5. of Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

RPPA analysis of Reh cell lines treated with PRD. Signal intensities were normalized by Z-score and signals were used for a hierarchical cluster analysis. A black color indicates that protein from Reh cells treated with several concentrations of PRD in normoxia versus hypoxia, matches the medium expression level calculated for a specific protein in a particular experimental condition. Higher level expression than mean is shown as a red color, and a green color refers to a lower level expression than mean. Protein names are listed below and experimental conditions are mentioned on the right-hand side. All antibodies used for RPPA were validated by Western blot. All antibodies are listed in Additional file 7: Table S1. (DOCX 148 kb