Using the past to constrain the future: how the palaeorecord can improve estimates of global warming

Climate sensitivity is defined as the change in global mean equilibrium temperature after a doubling of atmospheric CO2 concentration and provides a simple measure of global warming. An early estimate of climate sensitivity, 1.5-4.5{\deg}C, has changed little subsequently, including the latest assessment by the Intergovernmental Panel on Climate Change. The persistence of such large uncertainties in this simple measure casts doubt on our understanding of the mechanisms of climate change and our ability to predict the response of the climate system to future perturbations. This has motivated continued attempts to constrain the range with climate data, alone or in conjunction with models. The majority of studies use data from the instrumental period (post-1850) but recent work has made use of information about the large climate changes experienced in the geological past. In this review, we first outline approaches that estimate climate sensitivity using instrumental climate observations and then summarise attempts to use the record of climate change on geological timescales. We examine the limitations of these studies and suggest ways in which the power of the palaeoclimate record could be better used to reduce uncertainties in our predictions of climate sensitivity.Comment: The final, definitive version of this paper has been published in Progress in Physical Geography, 31(5), 2007 by SAGE Publications Ltd, All rights reserved. \c{opyright} 2007 Edwards, Crucifix and Harriso

Using a Build-and-Click Approach for Producing Structural and Functional Diversity in DNA-Targeted Hybrid Anticancer Agents

An efficient screening method was developed for functionalized DNA-targeted platinum-containing hybrid anticancer agents based on metal-mediated amine-to-nitrile addition, a form of “click” chemistry. The goal of the study was to generate platinum–acridine agents for their use as cytotoxic “warheads” in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to platinum. The assay, which was based on microscale reactions between 6 platinum–nitrile complexes and 10 acridine derivatives, yielded a small library of 60 platinum–acridines. Reactions were monitored, and product mixtures were quantitatively analyzed by automated in-line high-performance liquid chromatography–electrospray mass spectrometry (LC–ESMS) analysis and subjected to cell viability screening using a nonradioactive cell proliferation assay. The new prescreening methodology proves to be a powerful tool for establishing structure–activity relationships and for identifying target compounds

The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

<div><p>Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ ALL) is an aggressive cancer of the bone marrow. The addition of tyrosine kinase inhibitors (TKIs) has improved outcomes but many patients still suffer relapse and novel therapeutic agents are needed. KPC34 is an orally available, novel phospholipid conjugate of gemcitabine, rationally designed to overcome multiple mechanisms of resistance, inhibit the classical and novel isoforms of protein kinase C, is able to cross the blood brain barrier and is orally bioavailable. KPC34 had an IC₅₀ in the nanomolar range against multiple ALL cell lines tested but was lowest for Ph+ lines. In mice bearing either naïve or resistant Ph+ ALL, KPC34 treatment resulted in significantly improved survival compared to cytarabine and gemcitabine. Treatment with KPC34 and doxorubicin was more effective than doxorubicin and cytarabine. Mice with recurrence of their ALL after initial treatment with cytarabine and doxorubicin saw dramatic improvements in hind limb paralysis after treatment with KPC34 demonstrating activity against established CNS disease. Consistent with this KPC34 was better than gemcitabine at reducing CNS leukemic burden. These promising pre-clinical results justify the continued development of KPC34 for the treatment of Ph+ALL.</p></div

Oral administration of KPC34 induces DNA damage <i>in vivo</i>.

<p></p><p></p><p></p><p>A) Harvested cells were stained with antibodies for B220R and H2AX and analyzed by flow cytometry. Cells were initially gated by size, followed by B220R positivity. Dual-stained populations were then measured after gating saline treated cells.</p><p></p><p></p><p>B) Flow cytometry analyses of harvested bone marrow cells stained with B220R and H2AX. Representative dot plots are shown.</p><p></p><p></p><p>C) Quantified dual-stained populations averaged from 3 independent replicates. Values represent Mean + SEM. Tukey’s post t test was performed following one-way ANOVA. * = p value <0.05.</p><p></p><p></p><p></p> <p>A) Harvested cells were stained with antibodies for B220R and H2AX and analyzed by flow cytometry. Cells were initially gated by size, followed by B220R positivity. Dual-stained populations were then measured after gating saline treated cells.</p> <p>B) Flow cytometry analyses of harvested bone marrow cells stained with B220R and H2AX. Representative dot plots are shown.</p> <p>C) Quantified dual-stained populations averaged from 3 independent replicates. Values represent Mean + SEM. Tukey’s post t test was performed following one-way ANOVA. * = p value <0.05.</p