Melting relations in the system FeCO3–MgCO3 and thermodynamic modelling of Fe–Mg carbonate melts

To constrain the thermodynamics and melting relations of the siderite\u2013magnesite (FeCO3\u2013MgCO3) system, 27 piston cylinder experiments were conducted at 3.5\ua0GPa and 1170\u20131575\ua0\ub0C. Fe-rich compositions were also investigated with 13 multi-anvil experiments at 10, 13.6 and 20\ua0GPa, 1500\u20131890\ua0\ub0C. At 3.5\ua0GPa, the solid solution siderite\u2013magnesite coexists with melt over a compositional range of XMg (=Mg/(Mg\ua0+\ua0Fetot))\ua0=\ua00.38\u20131.0, while at 6510\ua0GPa solid solution appears to be complete. At 3.5\ua0GPa, the system is pseudo-binary because of the limited stability of siderite or liquid FeCO3, Fe-rich carbonates decomposing at subsolidus conditions to magnetite\u2013magnesioferrite solid solution, graphite and CO2. Similar reactions also occur with liquid FeCO3 resulting in melt species with ferric iron components, but the decomposition of the liquid decreases in importance with pressure. At 3.5\ua0GPa, the metastable melting temperature of pure siderite is located at 1264\ua0\ub0C, whereas pure magnesite melts at 1629\ua0\ub0C. The melting loop is non-ideal on the Fe side where the dissociation reaction resulting in Fe3+ in the melt depresses melting temperatures and causes a minimum. Over the pressure range of 3.5\u201320\ua0GPa, this minimum is 20\u201335\ua0\ub0C lower than the (metastable) siderite melting temperature. By merging all present and previous experimental data, standard state (298.15\ua0K, 1\ua0bar) thermodynamic properties of the magnesite melt (MgCO3L) end member are calculated and the properties of (Fe,Mg)CO3 melt fit by a regular solution model with an interaction parameter of 127600\ua0J/mol. The solution model reproduces the asymmetric melting loop and predicts the thermal minimum at 1240\ua0\ub0C near the siderite side at XMg\ua0=\ua00.2 (3.5\ua0GPa). The solution model is applicable to pressures reaching to the bottom of the upper mantle and allows calculation of phase relations in the FeO\u2013MgO\u2013O2\u2013C system

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML