In Vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

This study was supported by a Wellcome Trust-NIH PhD Studentship to SB, WDF and NV. Grant number 098252/Z/12/Z. SB, CHC and WDF are supported by the Intramural Research Program, NCI, NIH. NHG and WL are supported by the Intramural Research Program, NIA, NIH.Peer reviewedPublisher PD

Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice

<p>Abstract</p> <p>Background</p> <p>Imatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear.</p> <p>Objective</p> <p>To assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage.</p> <p>Methods</p> <p>Quantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. Results: Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected.</p> <p>Conclusion</p> <p>This study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens.</p

Vertebrate embryos as tools for anti-angiogenic drug screening and function

Shaunna Beedie is a recipient of a Wellcome Trust-NIH PhD Studentship (Grant number 098252/Z/12/Z). Alexandra J. Diamond is a recipient of a BBSRC EastBIO DTP PhD Scholarship. Lucas Rosa Fraga is a recepient of a PhD scholarship from the Science Without Borders program – CNPq Brazil – INAGEMP/ Grant CNPq 573993/2008-4 Shaunna Beedie and William D. Figg are supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.Peer reviewedPostprin

Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor

Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic. © 1999 Cancer Research Campaig

Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model

Acknowledgements The authors would like to thank Maria Kisakyamaria and Scott McMenemy for preliminary experimental data. This work was supported by a Wellcome Trust-NIH PhD Studentship awarded to SB, WDF and NV (Grant number 098252/Z/12/Z). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.Peer reviewedPublisher PD

First Results of Scanning Thermal Diffusivity Microscope (STDM) Measurements on Irradiated Monolithic and Dispersion Fuel

The thermal conductivity of the fuel material in a reactor before and during irradiation is a sensitive and fundamental parameter for thermal hydraulic calculations that are useds to correctly determine fuel heat fluxes and meat temperatures and to simulate performance of the fuel elements during operation. Several techniques have been developed to measure the thermal properties of fresh fuel to support these calculations, but it is crucial to also investigate the change of thermal properties during irradiation

The Role of Wild-Type p53 in Cisplatin-Induced Chk2 Phosphorylation and the Inhibition of Platinum Resistance with a Chk2 Inhibitor

The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis, and finally treatment failure. Our research goal is to determine and block the mechanisms of platinum resistance. Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin. These include ATM, p53, and Chk2. The increased Chk2 phosphorylation is modulated by p53 in a wild-type p53 model. Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient) cells doubled the amount of Chk2 phosphorylation 48 hours after cisplatin treatment. p53 knockdown by specific siRNA greatly reduced Chk2 phosphorylation. We conclude that wild-type p53, in response to cisplatin stimulation, plays a role in the upstream regulation of Chk2 phosphorylation at Thr-68. Cells without normal p53 function survive via an alternative pathway in response to the exogenous influence of cisplatin. We strongly suggest that it is very important to include the p53 mutational status in any p53 involved studies due to the functional differentiation of wt p53 and p53 mutant. Inhibition of Chk2 pathway with a Chk2 inhibitor (C3742) increased cisplatin efficacy, especially those with defective p53. Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy

Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities

Acknowledgements SB, NV, WDF funded by a Wellcome Trust-NIH PhD Scholarship (Grant number: 098252/Z/12/Z).Peer reviewedPostprin

Elevated InsP3R expression underlies enhanced calcium fluxes and spontaneous extra-systolic calcium release events in hypertrophic cardiac myocytes

Cardiac hypertrophy is associated with profound remodeling of Ca(2+) signaling pathways. During the early, compensated stages of hypertrophy, Ca(2+) fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca(2+) homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca(2+) release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca(2+) store are primarily responsible for the Ca(2+) flux that induces myocyte contraction, a role for Ca(2+) release via the inositol 1,4,5-trisphosphate receptor (InsP(3)R) in cardiac physiology has also emerged. Specifically, InsP(3)-induced Ca(2+) signals generated following myocyte stimulation with an InsP(3)-generating agonist (e.g., endothelin, ET-1), lead to modulation of Ca(2+) signals associated with excitation-contraction coupling (ECC) and the induction of spontaneous Ca(2+) release events that cause cellular arrhythmia. Using myocytes from spontaneously hypertensive rats (SHR), we recently reported that expression of the type 2 InsP(3)R (InsP(3)R2) is significantly increased during hypertrophy. Notably, this increased expression was restricted to the junctional SR in close proximity to RyRs. There, enhanced Ca(2+) release via InsP(3)Rs serves to sensitize neighboring RyRs causing an augmentation of Ca(2+) fluxes during ECC as well as an increase in non-triggered Ca(2+) release events. Although the sensitization of RyRs may be a beneficial consequence of elevated InsP(3)R expression during hypertrophy, the spontaneous Ca(2+) release events are potentially of pathological significance giving rise to cardiac arrhythmia. InsP(3)R2 expression was also increased in hypertrophic hearts from patients with ischemic dilated cardiomyopathy and aortically-banded mice demonstrating that increased InsP(3)R expression may be a general phenomenon that underlies Ca(2+) changes during hypertrophy