Hypoxic hypometabolism in chicken embryos: conformism and downregulation.

Postnatally, during hypoxia the decrease in oxygen consumption ( [Formula: see text] ) can exceed what expected from the limitation in O2 availability, meaning that [Formula: see text] -downregulation exceeds O2-conformism. We questioned whether a similar phenomenon could occur prenatally, in chicken embryos at mid- (E11, out of 20.5 days) or near end- (E18) incubation. [Formula: see text] was measured with an open-flow system in the sequence of normoxia-normothermia (21% O2, 37 °C, 30 min), hypoxia in normothermia (Hx-NT, either 18, 15, 12 or 9% O2, 37 °C, 1 hour), hypoxia in hyperthermia (Hx-HT, up to 43 °C, 1 hour) and return to normoxia-normothermia (30 min). During Hx-NT [Formula: see text] invariably decreased in a [O2]-dependent fashion. The hypoxic drop in [Formula: see text] did not require a post-hypoxic payment of the O2-debt, implying that the decrease in [Formula: see text] reflected hypometabolism. [Formula: see text] did not differ significantly between Hx-HT and Hx-NT for [O2] = 15% or less, as expected by O2-conformism. Differently, with milder hypoxia (18% O2), [Formula: see text] during Hx-HT significantly exceeded that in Hx-NT, meaning that the value of [Formula: see text] in Hx-NT was not limited by O2 supply. We conclude that a phenomenon of hypoxic [Formula: see text] downregulation like that observed in postnatal mammals can occur also prenatally, in the chicken embryos. The mechanisms at the basis of the downregulation remain unresolved and could combine physiological and cellular processes.

Mathematical modelling of clonal reduction therapeutic strategies in acute myeloid leukemia.

Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies that rapidly eliminate dividing myeloblasts are used to induce remission, relapse can occur due to surviving therapy-resistant leukemic stem cells (LSCs). Hence, anti-LSC strategies have become a key target to cure AML. We have recently shown that previously approved cardiac glycosides and glucocorticoids target LSC-enriched CD34+ cells in the primary human AML 8227 model with more efficacy than normal hematopoietic stem cells (HSCs). To translate these in vitro findings into humans, we developed a mathematical model of stem cell dynamics that describes the stochastic evolution of LSCs in AML post-standard-of-care. To this, we integrated population pharmacokinetic-pharmacodynamic (PKPD) models to investigate the clonal reduction potential of several promising candidate drugs in comparison to cytarabine, which is commonly used in high doses for consolidation therapy in AML patients. Our results suggest that cardiac glycosides (proscillaridin A, digoxin and ouabain) and glucocorticoids (budesonide and mometasone) reduce the expansion of LSCs through a decrease in their viability. While our model predicts that effective doses of cardiac glycosides are potentially too toxic to use in patients, simulations show the possibility of mometasone to prevent relapse through the glucocorticoid's ability to drastically reduce LSC population size. This work therefore highlights the prospect of these treatments for anti-LSC strategies and underlines the use of quantitative approaches to preclinical drug translation in AML.