The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53–442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 >8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL

Post-2020 climate agreements in the major economies assessed in the light of global models

Integrated assessment models can help in quantifying the implications of international climate agreements and regional climate action. This paper reviews scenario results from model intercomparison projects to explore different possible outcomes of post-2020 climate negotiations, recently announced pledges and their relation to the 2 °C target. We provide key information for all the major economies, such as the year of emission peaking, regional carbon budgets and emissions allowances. We highlight the distributional consequences of climate policies, and discuss the role of carbon markets for financing clean energy investments, and achieving efficiency and equity

Extinction and survivorship of southern Tethyan benthic foraminifera across the Cretaceous/Palaeogene boundary

The benthic foraminiferal record from the Cretaceous/Palaeogene boundary stratotype of E1 Kef, Tunisia, shows a succession of three distinct assemblages. The late Maastrichtian upper bathyal assemblage is highly diversified and shows no prominent signs of gradual change towards the boundary. The earliest Palaeocene is marked by the disappearance of more than 50% of the taxa, resulting in a strongly impoverished fauna, tolerant to low oxygen conditions and with a shallower water affinity. Sequential (re-) appearance of many taxa in the early Palaeocene signifies the restoration towards normal Palaeocene upper bathyal faunas. The faunal changes reflect major perturbations in redox and trophic conditions at the sea-floor. At least locally, and perhaps even on a regional Tethyan scale, the extinctions can be related to a sharp decrease in oxygen supply, in combination with strongly reduced nutrient resources. It is suggested that a prolonged reduction in surface fertility and food flux to the sea-floor invoked worldwide (but diachronous) benthic extinctions. In particular endobenthic deposit feeders and other taxa adapted to high and perhaps heterogeneous nutrient resources suffered extinction.status: publishe

Learning curves for hydrogen production technology: An assessment of observed cost reductions

At present three key energy carriers have the potential to allow a transition towards a sustainable energy system: electricity, biofuels and hydrogen. All three offer great opportunity, but equally true is that each is limited in different ways. In this article we focus on the latter and develop learning curves using cost data observed during the period 1940–2007 for two essential constituents of a possible ‘hydrogen economy’: the construction of hydrogen production facilities and the production process of hydrogen with these facilities. Three hydrogen production methods are examined, in decreasing order of importance with regards to their current market share: steam methane reforming, coal gasification and electrolysis of water. The fact that we have to include data in our analysis that go far back in time, as well as the uncertainties that especially the older data are characterized by, render the development of reliable learning curves challenging. We find only limited learning at best in a couple of cases, and no cost reductions can be detected for the overall hydrogen production process. Of the six activities investigated, statistically meaningful learning curves can only be determined for the investment costs required for the construction of steam methane reforming facilities, with a learning rate of 11±6%, and water electrolysis equipment, with a learning rate of 18±13%. For past coal gasification facility construction costs no learning rate can be discerned. The learning rates calculated for steam methane reforming and water electrolysis equipment construction costs have large error margins, but lie well in the range of the learning reported in the literature for other technologies in the energy sector