Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia

Nelarabine is the prodrug of 9-β-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine’s clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented

The Value of Emissions Trading

Abstract in HTML and technical report in PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).This paper estimates the value of international emissions trading, focusing attention on a here-to-fore neglected component: its value as a hedge against uncertainty. Much analysis has been done of the Kyoto Protocol and other potential international greenhouse gas mitigation policies comparing the costs of achieving greenhouse gas emission targets with and without trading. These studies often show large cost reductions for all Parties under trading compared to a no trading case. We investigate the welfare gains of including emissions trading in the presence of uncertainty in economic growth rates, using both a partial equilibrium model based on marginal abatement cost curves and a computable general equilibrium model that allows consideration of the interaction of emissions trading with existing energy taxes and changes in terms of trade. We find that the hedge value of international trading is small relative to its value in reallocating emissions reductions when, as in the Kyoto Protocol, the burden-sharing scheme does not resemble a least-cost allocation. The Kyoto Protocol also allocated excess allowances to Russia, so-called “hot air,” and much of the value often attributed to emissions trading stems from other Parties having access to these extra allowances, which has the effect of lowering the aggregate emissions target. We also find that the effects of preexisting tax distortions and terms of trade dominate the hedge value of trading. We conclude that the primary value of emissions trading in international agreements is as a burden-sharing or wealth transfer mechanism and should be judged accordingly.We gratefully acknowledge helpful comments from A.D. Ellerman. This research was supported by the US Department of Energy (DE-FG02-02ER63468, DE-FG04-04ER63929), US Environmental Protection Agency, US National Science Foundation, US National Aeronautics and Space Administration, US National Oceanographic and Atmospheric Administration; and the Industry and Foundation Sponsors of the MIT Joint Program on the Science and Policy of Global Change

Green House Gas Mitigation Policy, Bio-fuels and Land-use Change- a Dynamic Analysis

Research and Development/Tech Change/Emerging Technologies, Resource /Energy Economics and Policy,

Stabilization and Global Climate Policy

Abstract in HTML and technical report in PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).Academic and political debates over long-run climate policy often invoke “stabilization” of atmospheric concentrations of greenhouse gases (GHGs), but only rarely are non-CO2 greenhouse gases addressed explicitly. Even though the majority of short-term climate policies propose trading between gases on a global warming potential (GWP) basis, discussions of whether CO2 concentrations should be 450, 550, 650, or perhaps as much as 750 ppm leave unstated whether there should be no additional forcing from other GHGs beyond current levels or whether separate concentration targets should be established for each GHG. Here we use an integrated modeling framework to examine multi-gas stabilization in terms of temperature, economic costs, carbon uptake, and other important consequences. We show that there are significant differences in both costs and climate impacts between different "GWP equivalent" policies and demonstrate the importance of non-CO2 GHG reduction on timescales of up to several centuries.Sarofim was supported in part by a Martin Sustainability Fellowshi

Land carbon sequestration within the conterminous United States : regional- and state-level analyses

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Biogeosciences 120 (2015): 379–398, doi:10.1002/2014JG002818.A quantitative understanding of the rate at which land ecosystems are sequestering or losing carbon at national-, regional-, and state-level scales is needed to develop policies to mitigate climate change. In this study, a new improved historical land use and land cover change data set is developed and combined with a process-based ecosystem model to estimate carbon sources and sinks in land ecosystems of the conterminous United States for the contemporary period of 2001–2005 and over the last three centuries. We estimate that land ecosystems in the conterminous United States sequestered 323 Tg C yr−1 at the beginning of the 21st century with forests accounting for 97% of this sink. This land carbon sink varied substantially across the conterminous United States, with the largest sinks occurring in the Southeast. Land sinks are large enough to completely compensate fossil fuel emissions in Maine and Mississippi, but nationally, carbon sinks compensate for only 20% of U.S. fossil fuel emissions. We find that regions that are currently large carbon sinks (e.g., Southeast) tend to have been large carbon sources over the longer historical period. Both the land use history and fate of harvested products can be important in determining a region's overall impact on the atmospheric carbon budget. While there are numerous options for reducing fossil fuels (e.g., increase efficiency and displacement by renewable resources), new land management opportunities for sequestering carbon need to be explored. Opportunities include reforestation and managing forest age structure. These opportunities will vary from state to state and over time across the United States.This work was supported by NSF grants 104918, 1137306, and 1237491; EPA grant XA-83600001-1; and DOE grant DE-FG02-94ER61937.2015-08-2

Unintended Environmental Consequences of a Global Biofuels Program

Abstract and PDF report are also available on the MIT Joint Program on the Science and Policy of Global Change website (http://globalchange.mit.edu/).Biofuels are being promoted as an important part of the global energy mix to meet the climate change challenge. The environmental costs of biofuels produced with current technologies at small scales have been studied, but little research has been done on the consequences of an aggressive global biofuels program with advanced technologies using cellulosic feedstocks. Here, with simulation modeling, we explore two scenarios for cellulosic biofuels production and find that both could contribute substantially to future global-scale energy needs, but with significant unintended environmental consequences. As the land supply is squeezed to make way for vast areas of biofuels crops, the global landscape is defined by either the clearing of large swathes of natural forest, or the intensification of agricultural operations worldwide. The greenhouse gas implications of land-use conversion differ substantially between the two scenarios, but in both, numerous biodiversity hotspots suffer from serious habitat loss. Cellulosic biofuels may yet serve as a crucial wedge in the solution to the climate change problem, but must be deployed with caution so as not to jeopardize biodiversity, compromise ecosystems services, or undermine climate policy.This study received funding from the MIT Joint Program on the Science and Policy of Global Change, which is supported by a onsortium of government, industry and foundation sponsors

Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- and Palatability-Induced Binge Eating

While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding). In contrast, inhibition of the nucleus accumbens (NAc), through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive