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Mark Cushman - One of the best experts on this subject based on the ideXlab platform.
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mechanism of the antiviral activity of new Aurintricarboxylic Acid analogues
Antiviral Chemistry & Chemotherapy, 1996Co-Authors: D. Reymen, Mark Cushman, José A. Esté, Myriam Witvrouw, Johan Neyts, Dominique Schols, Graciela Andrei, Robert Snoeck, E Hejchman, E. De ClercqAbstract:Various new Aurintricarboxylic Acid (ATA) polymer analogues have been evaluated for their antiviral activity against a wide array of DNA and RNA viruses, and their mechanism of action against human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1). Most of the polymers exhibited marked antiviral activity against a variety of enveloped viruses, but not against non-enveloped viruses. The ATA polymers displayed the most pronounced activity against HIV-1, HCMV and human herpesvirus type 6 (HHV-6). Their action against HCMV and HIV could be ascribed to inhibition of the initial attachment of virus particles to the cells. Using radiolabelled virus, we proved that the polymers inhibit the binding of HCMV to HEL fibroblasts. By flow cytometric analysis, we demonstrated that these new polymers interfere with (i) the binding of OKT4A monoclonal antibody (mAb) to the cellular CD4 receptor, (ii) the binding of anti-gp120 mAb to HIV-1 glycoprotein (gp) 120, and (iii) the adsorption of HIV-1 virion...
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Anti-HIV and anti-HCMV Activities of New Aurintricarboxylic Acid Analogues
Antiviral Chemistry and Chemotherapy, 1995Co-Authors: Mark Cushman, Pinglang Wang, D. Reymen, José A. Esté, Myriam Witvrouw, Johan Neyts, E. De ClercqAbstract:A variety of Aurintricarboxylic Acid (ATA) polymer analogues were prepared by substituting certain salicylic Acid derivatives and carbonyl compounds for salicylic Acid and formaldehyde in the ATA p...
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isolation and structure elucidation of low molecular weight components of Aurintricarboxylic Acid ata
Journal of Organic Chemistry, 1992Co-Authors: Pinglang Wang, John F Kozlowski, Mark CushmanAbstract:Nine low molecular weight components of Aurintricarboxylic Acid (ATA) have been isolated by silica gel column and thin-layer chromatography. The structures of these compounds have been elucidated by 1 H NMR and 13 C NMR spectroscopy in conjunction with COSY and HETCOR techniques for proton and carbon assignments. Four of the components afforded protection against the cytopathic effect of HIV-1 in CEM cell culture at relatively high concentrations that were near those resulting in cytotoxicity
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inhibition of hiv 1 integration protein by Aurintricarboxylic Acid monomers monomer analogs and polymer fractions
Biochemical and Biophysical Research Communications, 1992Co-Authors: Mark Cushman, Paula A ShermanAbstract:Several Aurintricarboxylic Acid (ATA) monomers, monomer analogs, and polymer fractions have been tested as inhibitors of HIV-1 integration protein (IN). Both of the ATA monomers and all of the ATA polymer fractions inhibited a selective DNA cleavage reaction catalyzed by IN. The ATA monomer analogs were inactive or had low activity. The activities of the substances as inhibitors of HIV IN correlated in a positive way with their activities as inhibitors of the cytopathic effect of HIV-1 in CEM and HIV-2 in MT4 cells. These results suggest that inhibition of HIV IN may contribute to the antiviral activity of the ATA monomers and monomer analogs in cell culture.
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synthesis and anti hiv activities of low molecular weight Aurintricarboxylic Acid fragments and related compounds
Journal of Medicinal Chemistry, 1991Co-Authors: Mark Cushman, E. De Clercq, Dominique Schols, S Kanamathareddy, Mark E Goldman, J A BowenAbstract:Several compounds corresponding to fragments of the schematic representation of the polymeric structure of Aurintricarboxylic Acid (ATA) have been prepared and tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture and HIV-1 in CEM cell culture. Both the triphenylcarbinol 3 as well as the triphenylmethane 5 were found to afford protection against the cytopathogenicity of HIV-2 in MT-4 cells and HIV-1 in CEM cells, but they were inactive against HIV-1 in MT-4 cells. Both substances were also found to inhibit syncytium formation when MOLT-4 cells were cocultured with HIV-2-infected HUT-78 cells, but were inactive in this assay against HIV-1-infected cells. When observed, the activity is generally moderate in degree of protection and requires concentrations in the 10(-4) molar range. In contrast to ATA, both of these substances were inactive when tested for prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor and also for inhibition of HIV-1 reverse transcriptase. These substances therefore appear act by a mechanism that is distinct from that of polymeric ATA. Several active and inactive structural analogues of 3 and 5 were also synthesized. The anti-HIV activity in this series seems to depend on the presence of anionic carboxylate groups, since the methyl esters 4, 6, and 12 were uniformly inactive. The diphenylmethanes 8, 14, 18, and 19 also reproducibly inhibited the cytopathic effect of HIV-1 in CEM cell culture.
Shinru Shih - One of the best experts on this subject based on the ideXlab platform.
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inhibition of enterovirus 71 replication and the viral 3d polymerase by Aurintricarboxylic Acid
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Hui Chen Hung, Shinru Shih, John T A Hsu, Tzuchun Chen, Mingyu Fang, Kueijung Yen, Chingping TsengAbstract:Objectives Enterovirus 71 (EV71) causes serious diseases in humans. The aim of this study was to examine the effects of Aurintricarboxylic Acid (ATA) on EV71 replication and to explore the underlying mechanism. Methods To measure the activity of ATA in inhibiting the cytopathic effect (CPE) of EV71, a cell-based neutralization (inhibition of virus-induced CPE) assay was performed. The effect of ATA was further confirmed using plaque reduction and viral yield reduction assays. A time of addition assay was performed to identify the mechanisms of ATA's anti-EV71 activity. We examined the effects of ATA on the following key steps involved in virus replication: (i) translation of the internal ribosomal entry site (IRES)-mediated viral polyprotein; (ii) the proteolytic activity of viral proteases 2A and/or 3C; and (iii) the viral 3D RNA-dependent RNA polymerase (RdRp) activity. Results In this study, ATA was found to be a potent inhibitor of the replication of EV71. In the antiviral neutralization assay, ATA exhibited inhibitory activity against EV71 (TW/4643/98) and EV71 (TW/2231/98). Plaque assay further demonstrated that ATA inhibited EV71 replication with an EC(50) (effective concentration at which 50% of plaques were removed) of 2.9 microM. Studies on the mechanism of action revealed that ATA targets the early stage of the viral life cycle after viral entry. ATA was able to inhibit the RdRp activity of EV71, while neither the IRES-mediated translation of viral polyprotein nor the viral 3C protease activity was affected. Conclusions Overall, the findings in this study suggest that ATA is able to effectively inhibit EV71 replication through interfering with the viral 3D polymerase.
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Aurintricarboxylic Acid inhibits influenza virus neuraminidase
Antiviral Research, 2009Co-Authors: Hui Chen Hung, Chingping Tseng, Jinnmoon Yang, Sung Nain Tseng, Yen Fu Chen, Yusheng Chao, Hsing Pang Hsieh, Shinru Shih, John T A HsuAbstract:There is a continuing threat that the highly pathogenic avian influenza virus will cause future influenza pandemics. In this study, we screened a library of compounds that are biologically active and structurally diverse for inhibitory activity against influenza neuraminidase (NA). We found that Aurintricarboxylic Acid (ATA) is a potent inhibitor of NA activity of both group-1 and group-2 influenza viruses with IC50s (effective concentration to inhibit NA activity by 50%) values at low micromolar concentrations. ATA was equally potent in inhibiting the NA activity derived from wild-type NA and its H274Y mutant which renders NA resistance to inhibition by oseltamivir. Although ATA is structurally distinct from sialic Acid, molecular modeling experiments suggested that ATA binds to NA at the enzyme’s substrate binding site. These results indicate that ATA may be a good starting material for the design of a novel class of NA inhibitors for the treatment influenza viruses. © 2008 Elsevier B.V. All rights reserved.
Solon Thanos - One of the best experts on this subject based on the ideXlab platform.
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cortisol promotes survival and regeneration of axotomised retinal ganglion cells and enhances effects of Aurintricarboxylic Acid
Graefes Archive for Clinical and Experimental Ophthalmology, 2006Co-Authors: Peter Heiduschka, Solon ThanosAbstract:Neuroprotection is essential for repair processes after a traumatic insult in the central nervous system. We have demonstrated previously significant neuroprotective properties of the anti-apoptotic drug Aurintricarboxylic Acid in the model of axotomised retinal ganglion cells. Glucocorticoids are widely used to treat injuries of the nervous system. Due to the anti-inflammatory and microglia-inhibiting properties of glucocorticoids, we studied the neuroprotective effects of intravitreally administered cortisol after an optic nerve cut. Ninety-eight adult Sprague–Dawley rats were used in this study. The optic nerve was cut intra-orbitally. Either vehicle or compound solution was injected intravitreally. Fluorescent dye was put onto the optic nerve stump to label retinal ganglion cells retrogradely. Retinal whole mounts were prepared 2 weeks after axotomy, and surviving retinal ganglion cells were counted. Two weeks after axotomy, up to 50±7% of all retinal ganglion cells survived if cortisol was injected into the eye compared with 17±5% survival if only vehicle solution was injected. The neuroprotective effects of Aurintricarboxylic Acid (43±5% survival) could be further enhanced if combined with cortisol (up to 61±5% survival). Regeneration of cut retinal ganglion cell axons into a peripheral nerve graft could also be enhanced by an intravitreal injection of cortisol (169±42 regenerating retinal ganglion cells per mm2 vs. 73±12 cells per mm2 after vehicle injection). The increase was not as high as with Aurintricarboxylic Acid (192±40 cells per mm2), although more retinal ganglion cells survived with cortisol. This indicates that neuronal survival alone is not sufficient for subsequent axonal regeneration. Nevertheless, regeneration could be markedly increased if Aurintricarboxylic Acid and cortisol were combined (308±72 cells per mm2). Whereas Aurintricarboxylic Acid seems to act directly on lesioned retinal ganglion cells, cortisol seems to act on the glial environment, as indicated by microglial cell morphology and enhanced glial fibrillary Acidic protein expression. The results show that both neuroprotection and regeneration can be enhanced by the combination of two simple compounds acting on different sites.
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Aurintricarboxylic Acid promotes survival and regeneration of axotomised retinal ganglion cells in vivo
Neuropharmacology, 2000Co-Authors: Peter Heiduschka, Solon ThanosAbstract:Aurintricarboxylic Acid (ATA) has been used as an anti-apoptotic drug to counteract ischemic or cytotoxic injury to neurons. We investigated whether ATA has a neuroprotective effect on axotomized, adult retinal ganglion cells (RGC) as a model for traumatic neuronal cell death. A solution of ATA was injected into the vitreous body of rat eyes whose optic nerves had been cut. In controls, 14% of RGC survived 14 days after axotomy, whereas 44% of RGC survived after a single injection of ATA solution, and 59% survived when the injection was repeated after 7 days. A single injection of ATA 1 day after axotomy rescued 58% of RGC. However, injection of ATA 4 days after axotomy did not influence the survival of RGC, indicating that crucial, irreversible cascades of death are initiated prior to this point in time. The TUNEL technique was used to visualise apoptotic ganglion cells and revealed that 4 days after axotomy their number was significantly less in retinas whose optic nerves were axotomized and treated with ATA, than those of controls. As a consequence of neuroprotection, more RGC were recruited to regenerate into a peripheral nerve graft used to replace the cut optic nerve. In this paradigm, ATA-treated RGC extended significantly more axons within the graft than control RGC. This number could be increased by a second injection of ATA 7 days after axotomy. These data show that ATA is not only able to delay post-traumatic neuronal death but also enhances the extent of axonal regeneration in vivo.
Nhan L Tran - One of the best experts on this subject based on the ideXlab platform.
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nt 10identification of Aurintricarboxylic Acid ata as an inhibitor of tweak fn14 signaling in glioblastoma cells
Neuro-oncology, 2014Co-Authors: Harshil Dhruv, Donald Chow, Holly Yin, Michael E Berens, Ian T Mathews, Nhan L TranAbstract:The long-term survival of patients with glioblastoma (GB) is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. In order to discover a small molecule inhibitors that disrupt Fn14-TWEAK signaling axis and subsequently glioma cell invasion, we developed a cell-based drug screening assay using HEK293 cells that overexpresses Fn14 and harbors NF-κB driven Firefly luciferase protein expression. In preliminary drug screening assay using LOPAC1280 library of 1280 pharmacologically active compound, Aurintricarboxylic Acid (ATA) showed suppression of NF-κB driven Firefly Luciferase activity downstreatm of TWEAK-Fn14 signaling. Conversely, ATA did not show any suppression in NF-κB driven Firefly Luciferase activity downstream of TNFα-TNFR1 signaling, suggesting that ATA is a specific inhibitor of TWEAK-Fn14-NFκB signaling. In vitro, we demonstrated that ATA suppresses TWEAK induced chemotactic migration of glioma cells (T98G and A172) by inhibiting Rac1 and Akt activation. In addition, glioma cells treated with ATA showed increased susceptibility to standard treatment including temozolomide and radiation. In summary, this work reports a new small molecule inhibitor of TWEAK-Fn14 signaling that could be useful in enhancing the therapeutic targeting of this deadly disease.
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abstract 2709 identification of Aurintricarboxylic Acid ata as an inhibitor of tweak fn14 signaling in glioblastoma cells
Cancer Research, 2014Co-Authors: Harshil Dhruv, Ethan Holiday, Donald Chow, Holly Yin, Michael E Berens, Nhan L TranAbstract:The long-term survival of patients with glioblastoma (GB) is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. In order to discover a small molecule inhibitors that disrupt Fn14-TWEAK signaling axis and subsequently glioma cell invasion, we developed a cell-based drug screening assay using HEK293 cells that overexpresses Fn14 and harbors NF-κB driven Firefly luciferase protein expression. In preliminary drug screening assay using LOPAC1280 library of 1280 pharmacologically active compound, Aurintricarboxylic Acid (ATA) showed suppression of NF-κB driven Firefly Luciferase activity downstreatm of TWEAK-Fn14 signaling. Conversely, ATA did not show any suppression in NF-κB driven Firefly Luciferase activity downstream of TNFα-TNFR1 signaling, suggesting that ATA is a specific inhibitor of TWEAK-Fn14-NF-κB signaling. In vitro, we demonstrated that ATA suppresses TWEAK induced chemotactic migration of glioma cells (T98G and A172) and display no general cytotoxicity. In summary, this work reports a new small molecule inhibitor of TWEAK-Fn14 signaling that could be useful in enhancing the therapeutic targeting of this deadly disease. Citation Format: Harshil D. Dhruv, Ethan Holiday, Donald Chow, Holly Yin, Michael E. Berens, Nhan L. Tran. Identification of Aurintricarboxylic Acid (ATA) as an inhibitor of TWEAK-Fn14 signaling in glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2709. doi:10.1158/1538-7445.AM2014-2709
Harshil Dhruv - One of the best experts on this subject based on the ideXlab platform.
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identification of Aurintricarboxylic Acid as a selective inhibitor of the tweak fn14 signaling pathway in glioblastoma cells
Oncotarget, 2017Co-Authors: Alison Roos, Harshil Dhruv, Donald Chow, Holly Yin, Ian T Mathews, Landon J Inge, Serdar Tuncali, Lauren Hartman, Nghia Millard, Jean KlossAbstract:// Alison Roos 1, * , Harshil D. Dhruv 2, * , Ian T. Mathews 2 , Landon J. Inge 3 , Serdar Tuncali 1 , Lauren K. Hartman 2 , Donald Chow 2 , Nghia Millard 2 , Holly H. Yin 2 , Jean Kloss 4 , Joseph C. Loftus 4 , Jeffrey A. Winkles 5 , Michael E. Berens 2 , Nhan L. Tran 1 1 Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA 2 Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA 3 Norton Thoracic Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85004, USA 4 Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA 5 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA * These authors have contributed equally to this work Correspondence to: Nhan L. Tran, email: tran.nhan@mayo.edu Keywords: glioblastoma, survival, invasion, Fn14, Aurintricarboxylic Acid Received: August 15, 2016 Accepted: December 26, 2016 Published: January 17, 2017 ABSTRACT The survival of patients diagnosed with glioblastoma (GBM), the most deadly form of brain cancer, is compromised by the proclivity for local invasion into the surrounding normal brain, which prevents complete surgical resection and contributes to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. To discover small molecule inhibitors that disrupt the TWEAK-Fn14 signaling axis, we utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-κB-driven firefly luciferase reporter protein. Focusing on the LOPAC1280 library of 1280 pharmacologically active compounds, we identified Aurintricarboxylic Acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-κB dependent signaling, but not TNFα-TNFR-NF-κB driven signaling. We demonstrated that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both the chemotherapeutic agent temozolomide (TMZ) and radiation-induced cell death. In summary, this work reports a repurposed use of a small molecule inhibitor that targets the TWEAK-Fn14 signaling axis, which could potentially be developed as a new therapeutic agent for treatment of GBM patients.
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nt 10identification of Aurintricarboxylic Acid ata as an inhibitor of tweak fn14 signaling in glioblastoma cells
Neuro-oncology, 2014Co-Authors: Harshil Dhruv, Donald Chow, Holly Yin, Michael E Berens, Ian T Mathews, Nhan L TranAbstract:The long-term survival of patients with glioblastoma (GB) is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. In order to discover a small molecule inhibitors that disrupt Fn14-TWEAK signaling axis and subsequently glioma cell invasion, we developed a cell-based drug screening assay using HEK293 cells that overexpresses Fn14 and harbors NF-κB driven Firefly luciferase protein expression. In preliminary drug screening assay using LOPAC1280 library of 1280 pharmacologically active compound, Aurintricarboxylic Acid (ATA) showed suppression of NF-κB driven Firefly Luciferase activity downstreatm of TWEAK-Fn14 signaling. Conversely, ATA did not show any suppression in NF-κB driven Firefly Luciferase activity downstream of TNFα-TNFR1 signaling, suggesting that ATA is a specific inhibitor of TWEAK-Fn14-NFκB signaling. In vitro, we demonstrated that ATA suppresses TWEAK induced chemotactic migration of glioma cells (T98G and A172) by inhibiting Rac1 and Akt activation. In addition, glioma cells treated with ATA showed increased susceptibility to standard treatment including temozolomide and radiation. In summary, this work reports a new small molecule inhibitor of TWEAK-Fn14 signaling that could be useful in enhancing the therapeutic targeting of this deadly disease.
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abstract 2709 identification of Aurintricarboxylic Acid ata as an inhibitor of tweak fn14 signaling in glioblastoma cells
Cancer Research, 2014Co-Authors: Harshil Dhruv, Ethan Holiday, Donald Chow, Holly Yin, Michael E Berens, Nhan L TranAbstract:The long-term survival of patients with glioblastoma (GB) is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. In order to discover a small molecule inhibitors that disrupt Fn14-TWEAK signaling axis and subsequently glioma cell invasion, we developed a cell-based drug screening assay using HEK293 cells that overexpresses Fn14 and harbors NF-κB driven Firefly luciferase protein expression. In preliminary drug screening assay using LOPAC1280 library of 1280 pharmacologically active compound, Aurintricarboxylic Acid (ATA) showed suppression of NF-κB driven Firefly Luciferase activity downstreatm of TWEAK-Fn14 signaling. Conversely, ATA did not show any suppression in NF-κB driven Firefly Luciferase activity downstream of TNFα-TNFR1 signaling, suggesting that ATA is a specific inhibitor of TWEAK-Fn14-NF-κB signaling. In vitro, we demonstrated that ATA suppresses TWEAK induced chemotactic migration of glioma cells (T98G and A172) and display no general cytotoxicity. In summary, this work reports a new small molecule inhibitor of TWEAK-Fn14 signaling that could be useful in enhancing the therapeutic targeting of this deadly disease. Citation Format: Harshil D. Dhruv, Ethan Holiday, Donald Chow, Holly Yin, Michael E. Berens, Nhan L. Tran. Identification of Aurintricarboxylic Acid (ATA) as an inhibitor of TWEAK-Fn14 signaling in glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2709. doi:10.1158/1538-7445.AM2014-2709
