bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5570: Targeted drug delivery system and magnetic resonance imaging with intrinsic ferromagnetic nano-particle compound.
Authors: Eguchi Haruki , Hirata Kunio , Kurotani Reiko , Fukumura Hidenobu , Singh David J. , Yamamoto Masahiro , Sato Itaru , Umemura Masanori , Yamamoto Masaki , Nagashima Yoji , Ishikawa Yoshihiro 
Published: August 2014

Abstract
First principles calculations based on structures obtained by X-ray crystallography analysis are applied to identifying the intrinsic ferromagnetic nano-particle compound. We have found that this organic based nano-particle compound (EI236) exhibits anti-cancer property and, more important, possesses a magnetic property as it was readily attached to a magnet. EI236 exhibited intrinsic ferromagnetic behaviors from -268 celcius degree to 37 celsius degree and inhibited melanoma expansion in mouse tails when delivered to the melanoma lesion using a commercially available magnet. The local accumulation of the compound, as induced by the magnet, was readily visualized by magnetic resonance imaging (MRI) in mice. (n=4) Thus, EI236 acted as both an anti-cancer drug and an MRI contrast, and had pharmacological effects that could be delivered in a controlled manner. The identification of such compounds can overcome the long-standing problems of controlled drug delivery by magnetic force and may dramatically alter our concept of pharmacotherapy in the future, i.e., drug-targeting using a magnet and drug-dosing using MRI.
Citation Format: Haruki Eguchi, Kunio Hirata, Reiko Kurotani, Hidenobu Fukumura, David J. Singh, Masahiro Yamamoto, Itaru Sato, Masanori Umemura, Masaki Yamamoto, Yoji Nagashima, Yoshihiro Ishikawa. Targeted drug delivery system and magnetic resonance imaging with intrinsic ferromagnetic nano-particle compound. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5570. doi:10.1158/1538-7445.AM2013-5570
Abstract 5579: Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor.
Authors: Miller Anna V. , Hicks Mark A. , Richardson Amanda C. , Windle Jolene J. , Harada Hisashi 
Published: August 2014

Abstract
Breast cancer is a leading cause of death among women. Understanding breast cancer at the molecular level is imperative for finding more effective approaches to successfully treat these patients. Microtubule inhibitors are among the most frequently used agents for breast cancer treatment, with proven efficacy in both localized and metastatic disease. Paclitaxel (Taxol) is a member of the taxane class of anti-neoplastic microtubule damaging agents and exhibits activity against a wide range of human malignancies including breast cancer. Paclitaxel stabilizes microtubules, resulting in G2/M cell cycle arrest, and continuous treatment with paclitaxel ultimately leads to cell death. However, the precise mechanisms of how this mitotic arrest triggers cell death are still unclear.
When cells undergo paclitaxel-induced cell death, the BCL-2 family-dependent mitochondrial apoptotic pathway is activated. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that cdk activation at mitotic arrest could induce MCL-1 phosphorylation and subsequent degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.
Citation Format: Anna V. Miller, Mark A. Hicks, Amanda C. Richardson, Jolene J. Windle, Hisashi Harada. Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5579. doi:10.1158/1538-7445.AM2013-5579
Abstract 558: MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers.
Authors: Rosa Carrasco A. , Wetzel Leslie , Kinner Krista , Chen Hong , Rothstein Raymond , Tice David , Hollingsworth Robert , Steiner Philipp , Xiao Zhan 
Published: August 2014

Abstract
HER3 (ErbB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Due to its unique kinase-deficient nature, HER3 needs to form heterodimers with EGFR, HER2 or other RTKs to be functionally active. Dimerization is induced by either HER3 ligand (Heregulin, HRG) binding, or overexpression of partner RTKs in a ligand-independent (LI) manner. In both settings, HER3 acts as a critical scaffold coupling the upstream RTKs to efficient PI3K/AKT pathway induction to drive tumor growth and survival.
We have developed a potent antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple cancer models with either ligand-dependent or ligand-independent HER3 activities. For ligand-dependent models, we have chosen MDA-MB-175VII, a breast cancer cell-line with known γ-HRG expression, and HMCB, a melanoma cell-line with β-HRG expression. Efficient suppression of cell proliferation by MEDI3379 or 2C2, a precursor of MEDI3379, was observed in both models. This anti-tumor effect is directly due to the abrogation of HER3 activation (as determined by pHER3 formation) and its downstream effector pAKT. Her2-amplified breast cancer models such as BT474 are known to display high ligand-independent HER3 activity that is due to constitutive dimerization of HER2 and HER3. Treatment of BT474 with MEDI3379 led to effective suppression of pHER3, pAKT, and cell-proliferation in vitro. We extended this observation in vivo by exploring the antitumor activity of MEDI3379 in several orthotopic HER2-amplified breast cancer xenografts in nude mice. Consistent with in vitro observations, the BT474 xenograft model responded to MEDI3379 treatment with 65% tumor growth inhibition. In contrast, two published HER3 mAbs (Ab #6 and U1-15) failed to display activity in this ligand-independent model. In conclusion, our findings demonstrated that MEDI3379 is a HER3 antagonist that is effective in models of human cancers driven by both ligand-dependent as well as ligand-independent HER3 activities.
Citation Format: Carrasco A. Rosa, Leslie Wetzel, Krista Kinner, Hong Chen, Raymond Rothstein, David Tice, Robert Hollingsworth, Philipp Steiner, Zhan Xiao. MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2013-558
Abstract 5580: Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC).
Authors: Huelsewig Carolin , Bernemann Christof , Ruckert Christian , Kiesel Ludwig , Pusztai Lajos , Liedtke Cornelia 
Published: August 2014

Abstract
Background: Triple negative breast cancer is characterized by an unfavorable prognosis. While patients do not benefit from endocrine or Her2 targeted therapies except chemotherapy, there is an increased response (pCR) to taxane-/anthracycline-containing therapy compared to other breast cancers. However, molecular determinants of chemotherapy specifically in TNBC remain largely unknown. Current research suggests an increased Wnt Pathway activity in TNBC while Wnt pathway activity has been shown to play an important role in breast cancer pathogenesis. Material and Methods: Differentially expressed genes in TN vs. non-TN breast cancers of patients treated with neoadjuvant taxane-/anthracycline-containing chemotherapy were identified and validated in an independent AffymetrixU133A gene chip dataset (Hess et al. 2006). Genes were tested for correlation with relapse-free survival, response to neoadjuvant chemotherapy and Ki67 expression. The effects of siRNA mediated knockdown of SFRP1 and treatment with small molecule XAV939 (specific inhibitor of Wnt signaling) were analyzed in TNBC cell lines MDA-MB 468, MDA-MB 231, HCC 1806 and luminal cell line MCF7 on chemo sensitivity. Results: Our list of over expressed genes in TNBC vs. non-TNBC contains several genes which are already discussed as potential markers for TNBC like αB-crystallin and transcription factor FOXC1. Furthermore, a few Wnt pathway associated genes (i.e. SFRP1, TCF7L1, TCF7L2, SOX10) occur in this list, which was validated in an independent dataset. While SFRP1 expression was not associated with relapse-free survival in TNBC, it was significantly correlated with a pCR. Importantly, no correlation to Ki67 expression could be demonstrated. mRNA knockdown of Wnt pathway inhibitor SFRP1 in two different TNBC cell lines (MDA-MB 468 and HCC 1806) resulted in an increased resistance to paclitaxel, doxorubicin and cisplatin. Treatment with Wnt inhibitor XAV939 resulted in TNBC cell lines MDA-MB 231, MDA-MB 468 and in luminal cell line MCF7 increased chemo sensitivity to paclitaxel and doxorubicin. Conclusion: We suggest Wnt Signaling and/or SFRP1 expression as a novel maker of chemotherapy sensitivity to taxane-, anthracycline and/or platinum-containing chemotherapy in TNBC in vitro that is independent of Ki67 expression.
Citation Format: Carolin Huelsewig, Christof Bernemann, Christian Ruckert, Ludwig Kiesel, Lajos Pusztai, Cornelia Liedtke. Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2013-5580
Abstract 560: Mechanical stress activates a mitotic checkpoint in multicellular tumor spheroids.
Authors: Desmaison Annaïck , Grenier Katia , Frongia Celine , Lorenzo Corinne , Ducommun Bernard , Lobjois Valerie 
Published: August 2014

Abstract
Expanding solid tumors are subjected to mechanical stress that impact on their growth rate and development. However little is known on the mechanisms by which mechanical cues are acting on tumor cell biology.
To address that issue, we used MultiCellular Tumor Spheroid (MCTS), a 3D model recapitulating the microenvironment, the proliferative gradient and cell-cell interactions found in a tumor. To test the impact of mechanical stress on tumor cell proliferation, we first designed, produced and used dedicated polymer microdevices in which MCTS engineered to express fluorescent biomarkers were confined to apply mechanical constraints. We observe that under constraints, MCTS display a high proportion of mitotic cells in low proliferative regions of confined spheroids. We show that these cells are being arrested in mitosis for at least 24 hours (EdU incorporation neg.) and that mitotic arrest is not caused by impairment of rounding.
We next used live SPIM (Selective Plane Illumination Microscopy) 3D imaging to monitor mitosis progression in isotropically constrained MCTS. We show that constraint impairs bipolar spindle assembly and delays progression toward metaphase-anaphase transition.
Our data indicate that in a multicellular structure mechanical constraints are responsible for a defect in cell cycle progression associated with a mitotic arrest.
Citation Format: Annaïck Desmaison, Katia Grenier, Celine Frongia, Corinne Lorenzo, Bernard Ducommun, Valerie Lobjois. Mechanical stress activates a mitotic checkpoint in multicellular tumor spheroids. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2013-560
Abstract 5601: Efficient tumor therapy by anthrax toxin fusion proteins that contain cytolethal distending toxin B.
Authors: Bachran Christopher , Abdelazim Suzanne , Hasikova Radka , Liu Shihui , Leppla Stephen H. 
Published: August 2014

Abstract
Cytolethal distending toxin (Cdt) is produced by several Gram-negative bacterial species. It is composed of three subunits, CdtA, CdtB, and CdtC, with CdtB being the catalytic subunit. We fused CdtB from Haemophilus ducreyi with the N-terminal 254 amino acids of Bacillus anthracis toxin lethal factor (LFn) to produce a novel, potent anti-tumor drug. CdtB is transported into the cytosol of targeted cells via the efficient delivery mechanism of anthrax toxin. The fusion protein efficiently killed various human tumor cell lines by inducing a complete cell cycle arrest in the G2/M phase and subsequently inducing apoptosis. Despite the described role of CdtB as a DNase, we detected a prominent phosphatase activity of CdtB, similar to phosphatase and tensin homolog (PTEN) activity. Animal studies showed very low toxicity of a systemically-applied tumor-specific treatment and impressive anti-tumor effects, resulting in a 90% cure rate. This study demonstrates the great potential of a combination of efficient drug delivery by a modified anthrax toxin system and the enzymatic activity of CdtB, and argues for the continued development of this novel anti-cancer drug.
Citation Format: Christopher Bachran, Suzanne Abdelazim, Radka Hasikova, Shihui Liu, Stephen H. Leppla. Efficient tumor therapy by anthrax toxin fusion proteins that contain cytolethal distending toxin B. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5601. doi:10.1158/1538-7445.AM2013-5601
Abstract 5639: hsa-miR-200a regulates VEGF-C to induce epithelial-mesenchymal transition in sorafenib resistance hepatocellular carcinoma cells.
Authors: Chiou Jean , Su Jen-Liang , Hsiao Michael 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Although treatment and perioperative management have evolved in recent years with dramatic advances in diagnostic techniques, operative methods, and combined chemoradiotherapy, the prognosis of patients with liver cancer remains dissolve. Sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance. It has been reported that Vascular endothelial growth factor (VEGF)-C signaling through VEGFR-3 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. In this study, we will elucidated the molecular mechanisms of VEGF-C with sorafenib-resistance in hepatocellular carcinoma. Our results showed that recombinant VEGF-C protein protected Huh-7/WT cell from sorafenib treatment. Knockdown of VEGF-C in Huh7/SR (sorafenib-resistance) cells decreased the cell survival in sorafenib treatment. The sorafenib-resistant cells changed their appearance from epithelial type to mesenchymal type compared to control. In Affymetrix microarray and microRNA microarray assays, we also found significant differences between Huh7/WT and Huh7/SR cell lines. hsa-miR-200a was found down-regulated in Huh7/SR cells which was found to be associated with epithelial-mesenchymal transition (EMT). Overexpression of hsa-miR-200a was found to regulate VEGF-C to alter EMT status in Sorafenib-resistance HCC. In conclusion, EMT may induce VEGF-C and downstream signaling pathways which resulted in sorafenib-resistance in HCC and hsa-miR-200a was found to be playing an important role in this process.
Citation Format: Jean Chiou, Jen-Liang Su, Michael Hsiao. hsa-miR-200a regulates VEGF-C to induce epithelial-mesenchymal transition in sorafenib resistance hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5639. doi:10.1158/1538-7445.AM2013-5639
Abstract 5641: Sunitinib inhibits AXL phosphorylation in tumor cells.
Authors: Van der Mijn Johannes C. , Gotink Kristy J. , de Haas Richard R. , Dekker Henk , Jimenez Connie R. , Broxterman Henk J. , Verheul Henk M.w. 
Published: August 2014

Abstract
Background Sunitinib is a multi-targeted tyrosine kinase inhibitor (TKI), that is used for treatment of patients with advanced renal cell cancer (RCC) Drug resistance to sunitinib is a major clinical problem. We recently reported that continuous exposure to sunitinib causes acquired resistance of tumor cells. The receptor tyrosine kinase Axl has been implicated in acquired resistance to multiple TKIs, including erlotinib and lapatinib. In addition, sunitinib was previously reported to be a potential inhibitor of Axl catalytic activity. We therefore investigated the potential role of Axl in sunitinib resistance. Methods 786-O cells resistant to sunitinib were obtained by continuous exposure to the drug as previously published (Gotink et al. Clin Cancer Res 2011). AXL expression was studied in 786-O cell lines and EC-RF24 endothelial cells by RT-PCR and Western blot. Sunitinib and AXL inhibitor R428 sensitivity of cells transfected with siRNAs against AXL or scrambled siRNAs was determined by MTT cell viability assays. For kinase activity experiments recombinant AXL and tyrosine peptide arrays (PamGene, ‘s Hertogenbosch, the Netherlands) were used. Phospho-AXL and total AXL in cell lysates were measured by ELISA. Results Axl phosphorylation in vitro in both 786-O and EC-RF24 cells was dose-dependently inhibited by sunitinib, with a 50% inhibitory concentration of 5 μM. Activity of recombinant Axl kinase was measured on tyrosine containing peptide arrays in presence of 0, 1 or 4 μM sunitinib or 2 μM R428. Sunitinib induced dose-dependent inhibition of Axl activity, where 2 μM R428 blocked all peptide phosphorylations. In addition, 786-O sunitinib resistant cells (786-O SUN) showed a 4-fold overexpression of Axl protein compared to 786-O parental cells. However, gene silencing of AXL in 786-O SUN cells by RNA interference did not sensitize the cells to sunitinib. Sunitinib resistant cells were shown to be cross-resistant to the Axl inhibitor R428 with respective IC50 values of 0.9 μM (±0.1 μM) and 1.8 μM (±0.1 μM). Conclusion Phosphorylation of Axl is inhibited by sunitinib in both 786-O RCC and EC-RF24 endothelial cells. Despite its overexpression in sunitinib resistant cells, gene silencing of AXL did not sensitize 786-O resistant cells to sunitinib, indicating that sunitinib resistance is not mediated by AXL.
Citation Format: Johannes C. Van der Mijn, Kristy J. Gotink, Richard R. de Haas, Henk Dekker, Connie R. Jimenez, Henk J. Broxterman, Henk M.w. Verheul. Sunitinib inhibits AXL phosphorylation in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5641. doi:10.1158/1538-7445.AM2013-5641
Abstract 5664: The antiangiogenic effect of two drugs loaded nanocarriers and its potential application for cancer metronomic treatment.
Authors: Alani Adam G. , Mishra Gyan 
Published: August 2014

Abstract
Purpose: To synthesize and evaluate the antiangiogenic effect of individual and mixed paclitaxel (PTX) and rapamycin (RAP) conjugated micelles
Methods: RAP or PTX were conjugated to poly(ethyleneglycol)-block-poly(aspartate-hydrazide) utilizing a pH-sensitive linker based on hydrazone prodrug strategy. The synthesized drug-polymer conjugates were characterized using NMR and gel permeation chromatography (GPC). RAP and PTX polymer conjugates, PEG-RAP and PEG-PTX respectively were assembled into individual and mixed micelles. The size of these micelles was determined using dynamic light scattering. The micelle drug content was quantified by RP-HPLC. The antiangiogenic effect of individual and mixed micelles was evaluated in in vitro Human Umbilical Vein Endothelial Cells (HUVEC) model through proliferation, tube formation and migration assays. The HUVEC cell proliferation was evaluated by the CellTiter-Blue® Cell Viability Assay, the tube formation was evaluated by measuring the total area covered by the HUVEC capiliary formation while the HUVEC cell migration was determined by xCELLigence System.
Results: PEG-RAP and PEG-PTX were successfully synthesized and the molecular weight of the polymers was determined by GPC and NMR. The number of drug molecules attached to the polymer for RAP and PTX were 22 and 25 respectively. PEG-RAP and PEG-PTX were assembled into individual and mixed micelles as mono dispersed populations in the range of 40-100nm. The IC50 of PEG-RAP and PEG-PTX individual micelles were 12μM and 2nM respectively. The mixed micelles showed synergistic effect in inhibiting the HUVEC cell proliferation. Individual and mixed micelles inhibited HUVEC tube formation and migration with the mixed micelles showing a synergistic effect.
Conclusions: We were successful in synthesizing new conjugates of RAP and PTX with a pH-sensitive linker. These polymers were formulated into individual and mixed micelles. Antiangiogenic effect was observed with individual and mixed micelles. The antiangiogenic effect was synergistically enhanced with the use of mixed micelles.
Citation Format: Adam G. Alani, Gyan Mishra. The antiangiogenic effect of two drugs loaded nanocarriers and its potential application for cancer metronomic treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5664. doi:10.1158/1538-7445.AM2013-5664