bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5092: Ziv-aflibercept treatment reduces intra-hepatic tumor growth of a preclinical colorectal carcinoma liver metastasis model, monitored using non-invasive micro-ultrasound and bioluminescent imaging.
Authors: Adler Alexander P. , Parveen Asma , Thurston Gavin , Eichten Alexandra 
Published: August 2014

Abstract
The liver is a frequent metastatic site for different types of cancers, including colorectal carcinomas (CRC). Therapies that inhibit the angiogenic growth factor VEGF, such as bevacizumab and ziv-aflibercept, are used in combination with chemotherapies to treat metastatic CRC. Ziv-aflibercept (also known as VEGF Trap) is being developed as a part of a collaboration between Sanofi and Regeneron Pharmaceuticals, Inc. and was recently approved by the FDA in metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. To better understand the role of VEGF in metastatic CRC, we aimed to assess the effects of ziv-aflibercept on intrahepatic CRC tumor growth, invasion and angiogenesis in a preclinical model. For that we developed and characterized a CRC liver metastasis model that would allow us to longitudinally assess the effects of ziv-aflibercept on CRC growth in the liver parenchyma using non-invasive high frequency micro-ultrasound and bioluminescent imaging modalities. Briefly, luciferase-expressing HCT116 (human colorectal carcinoma) tumor cells were implanted into the left liver lobe of male CB17 SCID mice using image-guided micro-ultrasound. Tumor growth was monitored using both micro-ultrasound and bioluminescent imaging. When tumors were established (approximately 70 mm3), mice were treated with either control protein (hFc, 25 mg/kg, 2x/wk) or ziv-aflibercept (25 mg/kg, 2x/wk) for up to 13 days. Ziv-aflibercept treatment inhibited tumor growth by 95% compared to control treatment. This inhibition of tumor growth was accompanied by significantly decreased cell proliferation (50-70%), as measured by Ki67 immunohistochemistry, and markedly decreased vessel density (approximately 50%), as revealed by CD31 immunohistochemistry. Ziv-aflibercept did not seem to increase tumor invasiveness, as H&E histology did not reveal dramatic differences at the tumor/stroma border between the ziv-aflibercept and control treated tumors. These experiments confirm that ziv-aflibercept reduces growth and vascularity of colorectal tumors growing in the liver in a preclinical model.
Citation Format: Alexander P. Adler, Asma Parveen, Gavin Thurston, Alexandra Eichten. Ziv-aflibercept treatment reduces intra-hepatic tumor growth of a preclinical colorectal carcinoma liver metastasis model, monitored using non-invasive micro-ultrasound and bioluminescent imaging. [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 5092. doi:10.1158/1538-7445.AM2013-5092
Abstract 5094: Angiopoietin-2 antagonist enhances the anti-angiogenic effect of sunitinib in a preclinical renal cell carcinoma model.
Authors: Molnar Nikolett , Siemann Dietmar W. 
Published: August 2014

Abstract
Angiogenesis, the formation of blood vessels from pre-existing ones, is an essential process in tumor growth and development. During angiogenesis, normal vessels consisting of endothelial and peri-endothelial cells are first destabilized via the Angiopoietin-2 (Ang-2)-Tie2 axis, and then endothelial cells are activated to proliferate and form new vessels mainly through the Vascular Endothelial Growth Factor (VEGF)-VEGFR2 axis. Currently there are several anti-angiogenic therapies targeting the VEGF-VEGFR pathway used in the clinic in various cancer settings. New therapies such as Ang-2 antagonists are also being pursued and have recently been shown to be valuable especially in combination with anti-VEGF therapies. Renal cell carcinoma (RCC) is a highly vascularized disease where anti-angiogenic therapies are used as both first and second line treatments. The present study focused on evaluating the effects of an Ang-2 antagonist in combination with the FDA approved Sunitinib, a first line treatment in RCC. An in vivo intradermal assay with VHL mutant, human renal cell carcinoma, Caki-2, cells was used to assess angiogenesis of either the Ang-2 antagonist, Sunitinib or the combination of the Ang-2 antagonist and Sunitinib. Results show a greater decrease in the number of tumor cell induced vessels in the Ang-2 and Sunitinib combination group compared to either Ang-2 antagonist or Sunitinib alone. Tumor growth was also impaired by these agents when used alone or in combination; however there was greater decrease in tumor volume in the Ang-2 and Sunitinib combination group compared to either Ang-2 antagonist or Sunitinib alone. These data show greater tumor vessel and tumor inhibition when an Ang-2 antagonist and Sunitinib are administered in combination.
Citation Format: Nikolett Molnar, Dietmar W. Siemann. Angiopoietin-2 antagonist enhances the anti-angiogenic effect of sunitinib in a preclinical renal cell carcinoma model. [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 5094. doi:10.1158/1538-7445.AM2013-5094
Abstract 5111: Protective effect of Traditional Chinese Medicine formula LQ against cyclophosphamide-induced renal damage in nude mice.
Authors: Zhang Lei , Wu Chengyu , Hoffman Robert M. 
Published: August 2014

Abstract
TCM formula LQ is an herbal cocktail. Cyclophosphamide (CYC) is widely used in cancer chemotherapy. However renal damage is a dose-limiting side effects of CYC. In the current study, we determined if LQ can protect against damage. The heart, liver, spleen, lung, kidney, and intestine of a mouse from control, LQ pretreatment, CYC pretreatment, and CYC+LQ treatment were stained with HE. The histology of each organ was observed under microscopy. The histology of the heart, liver, spleen, lung and intestine showed normal histopathological structure in all groups. The kidneys in the control mice, LQ pretreated mice, and CYC+LQ pretreated mice showed normal architecture of kidney cortex and medulla. The cortex showed normal renal corpuscle, proximal convoluted tubules, and distal convoluted tubules. The inner medulla and outer medulla all contained a thick ascending limb of the loop of Henle, and interstitial connective tissue. However, kidney of the CYC pretreatment mice showed damage in structures compare with other groups. The toxic effect of CYC on the kidney involved the glomeruli, the tubules, and the interstitium. The structures of the cortex in CYC pretreated group showed disconnection between glomeruli and tubules. The ducts in the medulla were destroyed. LQ also protected against weight loss and cachexia induced by CYC. LQ may be a promising drug for combination with CYC to improve its therapeutic index.
Citation Format: Lei Zhang, Chengyu Wu, Robert M. Hoffman. Protective effect of Traditional Chinese Medicine formula LQ against cyclophosphamide-induced renal damage in nude mice. [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 5111. doi:10.1158/1538-7445.AM2013-5111
Abstract 5112: Traditional Chinese medicine formula LQ inhibits spontaneous and cyclophosphamide-enhanced metastasis.
Authors: Zhang Lei , Wu Chengyu , Zhang Yong , Hoffman Robert M. 
Published: August 2014

Abstract
TCM (Traditional Chinese Medicine) formula LQ, an herbal cocktail, has shown anti-metastasis and anti-tumor efficacy without overt side-effects. In the present study, the human HT1080 fibrosarcoma cell line was labeled with both red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nucleus. Dual-color HT1080 cells were injected into the footpad of mice following LQ treatment. Dual-color HT1080 cells were also injected into epigastric cranialis vein of the mice pre-treated with cyclophosphamide (CYC) or a combination of CYC and LQ. The efficacy was monitored through dynamic subcellular imaging of trafficking of cancer cells in lymph nodes and blood vessels in live mice. LQ significantly inhibited HT1080 spontaneous metastases to their local lymph nodes in the foot pad injection model. In the control group, 100% of mice had lymph node metastasis, compared to 12.5% of the mice in the LQ group. LQ also inhibited cyclophosphamide-enhanced experimental metastasis in the epigastric cranialis vein injection model. LQ prolonged the overall survival of mice in the spontaneous lymph node metastatic model. LQ therefore shows promise as an antimetastatic agent.
Citation Format: Lei Zhang, Chengyu Wu, Yong Zhang, Robert M. Hoffman. Traditional Chinese medicine formula LQ inhibits spontaneous and cyclophosphamide-enhanced metastasis. [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 5112. doi:10.1158/1538-7445.AM2013-5112
Abstract 5121: Differential expression of CC chemokine receptor-9 in prostate cancer.
Authors: Singh Rajesh , Gupta Pranav , Grizzle William E. , Lillard James W. , Singh Shailesh 
Published: August 2014

Abstract
Despite recent advances in diagnosis and treatment, prostate cancer is the second leading cause of cancer-related deaths in US. Precise etiology and molecular target to treat prostate cancer is yet to be defined. In recent years, involvement of chemokines and their corresponding receptors in pathogenesis of prostate cancer has gained tremendous attention. We have previously shown that CC chemokines receptor-9 (CCR9) is significantly expressed in prostate cancer cell lines compared to normal epithelial cells derived from prostate. Furthermore, we have shown higher invasive and migratory potential of prostate cancer cells under the chemotactic gradient of CCL25, the only known natural ligand of CCR9. The aim of this study was to establish the clinical relevance of CCR9 in prostate cancer using tissue micro array (TMA). The TMAs were stained for CCR9 and virtual slides were created using an Aperio ScanScope scanning system to numerically analyze the Immuno-intensity of CCR9. The ScanScope generated true color digital images of each stained sample, which were viewed and analyzed using Aperio ImageScope (version 6.25 software). Our data show higher expression of CCR9 in prostate cancer tissues compared to match benign tissues. Interestingly, CCR9 immuno-intensity was stronger in tissues with Gleason grade 8 and above. This study suggests the potential involvement of CCR9 in pathogenesis of prostate cancer.
Citation Format: Rajesh Singh, Pranav Gupta, William E. Grizzle, James W. Lillard, Shailesh Singh. Differential expression of CC chemokine receptor-9 in prostate cancer. [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 5121. doi:10.1158/1538-7445.AM2013-5121
Abstract 513: Breast cancers are notched up with a proton pump at their leading edge.
Authors: Pamarthy Sahithi , Gilman-Sachs Alice , Beaman Kenneth 
Published: August 2014

Abstract
The H+ vacuolar ATPase is a multimeric complex, which acidifies intracellular vesicles and extracellular space. Notch signaling is a key signaling pathway regulating cell proliferation and differentiation during development and cancer. The expression of both V-ATPases and Notch signaling is aberrant in most cancers and hence, are potential targets for therapeutics. It is speculated that the vacuolar ATPases regulate Notch signaling directly by endosomal acidification and indirectly by endocytosis. Here, we studied the role of the a2 isoform of vacuolar ATPase (a2V) in regulating Notch Signaling in Breast cancer. Using confocal microscopy, we traced the location of a2V in MCF7, SKBR3 and MDA-MB231 breast cancer cell lines. We found that a2V is present on the plasma membrane and not on the early endosomes. The amount of a2V correlated with the invasiveness of the cancer. Most importantly, the expression of a2V was restricted to one side of the cells marking their leading edge. Also, no a2V expression was found when cells contacted each other on the inside. Next, we evaluated the effect of a2V knockdown in MDA-MB231 cells. Using siRNA, a2V was knocked down. We found that decrease of a2V enhances the expression of Notch2 and Notch 4 significantly (&gt;1.75 fold). Notch ligands (DLL family) and Notch targets also increased, supporting the finding. When we looked at Wnt pathway genes, we found a significant increase in Wnt4 (&gt;2 fold) and c-Myc(∼3 fold) expression although levels of β-catenin were unchanged. Since c-Myc is known to mediate apoptosis, we looked at apoptotic genes Bax and Bcl2 to after siRNA knockdown of a2V. Although Bax increased, there was no significant change in apoptosis, as seen in PI-annexin assay. Taken together, our data suggests that a2V is important for tumor growth and its presence on leading edge marks aggressiveness of tumors. Interestingly, a2V depletion results in the activation of Notch and several proliferative markers in breast cancer. We postulate that this is due to indirect effects of a2V in endocytosis or in regulating pH dependent enzymes responsible for Notch and Wnt signal transduction.
Citation Format: Sahithi Pamarthy, Alice Gilman-Sachs, Kenneth Beaman. Breast cancers are notched up with a proton pump at their leading edge. [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 513. doi:10.1158/1538-7445.AM2013-513
Abstract 5139: Molecular docking exploration of potential RET tyrosine kinase inhibitors at non ATP-binding sites.
Authors: Nicolescu Adrian C. , Gujral Taranjit S. , Zelt Jordan DS , Mulligan Lois M. 
Published: August 2014

Abstract
RET (REarranged during Transfection) tyrosine kinase receptor is a transmembrane protein required for the development of neural-crest-derived cells, the urogenital system, and the central and peripheral nervous systems, notably the enteric nervous system. The RET protein has an extracellular domain with a cysteine-rich region and four cadherin-like domains, a transmembrane domain, and an intracellular tyrosine kinase domain, required for RET phosphorylation and downstream signaling. The structure of the RET kinase shares with other tyrosine kinases many conserved functional motifs and regulatory residues that are important for the kinase enzyme function. RET activation requires binding of a glial cell-line-derived neurotrophic factor (GDNF) and a co-receptor of the GDNF family receptors α. Germline mutations of RET, leading to uncontrolled activation, are associated with thyroid cancer, and recently with colorectal and lung cancers, and chronic myelomonocytic leukemia. RET mutations that result in decreased receptor function have been linked to developmental defects, such as Hirschsprung disease and kidney anomalies. The design of receptor tyrosine kinase (RTK) inhibitors has traditionally targeted the enzymes’ highly conserved ATP binding pocket. This approach resulted in the discovery of potent small molecule inhibitors, but with relatively low selectivity. To date there are no RET-specific inhibitors available for therapy, although few small molecule inhibitors are undergoing clinical evaluations as potential RET inhibitors. Since there are important critical regions within the RET molecule (e.g., the substrate binding pocket and activation loop) that contain unique amino acids and structural features, we used the method of molecular docking to virtually screen a diverse library of compounds that potentially target non-ATP binding sites of RET. Known ligands of RET were used to test the success of docking before the library of compounds was screened, docking solutions were inspected and ranked, and best compounds selected for novel structural features and future testing. Multiple comparisons with other known structures of RTK-ligand complexes have been performed in order to identify molecular features that would characterize the discovery of potential RET-specific inhibitors.
Citation Format: Adrian C. Nicolescu, Taranjit S. Gujral, Jordan DS Zelt, Lois M. Mulligan. Molecular docking exploration of potential RET tyrosine kinase inhibitors at non ATP-binding sites. [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 5139. doi:10.1158/1538-7445.AM2013-5139
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5157: Ubiquitin-dependent regulation of AKT by NEDD4-1.
Authors: Wang Xinjiang , Fan Chuan-Dong , Lum Michelle A. , Xu Chao , Black Jennifer D. 
Published: August 2014

Abstract
Several E3 ligases have been reported to regulate AKT stability and activation through ubiquitination. We found that NEDD4-1 is a novel E3 ligase involved in ubiquitin-dependent regulation of AKT. NEDD4-1 physically interacts with AKT and mediates AKT ubiquitination in vitro and in vivo. NEDD4-1 catalyzes K63-type polyubiquitin chain formation on AKT in an in vitro ubiquitination assay. AKT ubiquitination by NEDD4-1 in vivo requires plasma membrane binding but not phosphorylation of AKT. Ubiquitination of AKT or pAKT by NEDD4-1 promotes AKT nucleus-oriented translocation. IGF-1 signaling stimulates NEDD4-1-mediated ubiquitination of pAKT but not total AKT. A cancer-derived plasma membrane-philic mutant AKT(E17K) is more effectively ubiquitinated by NEDD4-1 and more efficiently trafficked into the nucleus compared with AKT. This study revealed a novel function of AKT ubiquitination by NEDD4-1 in its nuclear trafficking, a step that contributes to AKT activation process in IGF-1 response.
Citation Format: Xinjiang Wang, Chuan-Dong Fan, Michelle A. Lum, Chao Xu, Jennifer D. Black. Ubiquitin-dependent regulation of AKT by NEDD4-1. [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 5157. doi:10.1158/1538-7445.AM2013-5157
Abstract 5165: Pathway oriented phospho-proteomics analysis with reverse phase protein array (RPPA) technology in cell growth and cancer therapy.
Authors: Inoue Takeomi , Iwata Naoko , Nishiwaki Eiji , Kirii Yasuyuki 
Published: August 2014

Abstract
A number of molecularly targeted drugs have been successfully launched as anti-cancer agents, and intensive efforts are underway to discover new targets and their modifiers. Nevertheless, many compounds selected by enzyme screening methodology demonstrated unexpected effects in intact cells or animal models. Since recent efforts from signaling pathway analysis have revealed that complexity of signaling networks, homeostatic controls and off-target effects can lead to unexpected cellular/in vivo consequences, profiling the effects of drug candidates on a wide range of intracellular signaling pathways is becoming an attractive strategy.
Many proteomics approaches, especially in the area of phospho-proteomics, have been developed, and their applications are rapidly growing for the purpose of cellular signal profiling. Among these approaches, reverse phase protein array (RPPA) is one of the most powerful technologies because of its high sensitivity and reliability. We have developed a signal transduction oriented RPPA system that focuses on phospho-protein profiles in samples. Thus far, our system utilizes approximately 180 phospho-protein specific antibodies and can profile the phosphorylation status of more than 100 Gene Ontology processes covering more than 10 components in each process. Our current studies on modification of cellular signals induced by tyrosine kinase inhibitors (TKIs) in several cancer cell types are elucidating novel mechanisms for TKI actions. For example, our studies on Erlotinib and Gefitinib treated cells have resulted in very similar profiles as EGF-stimulated cancer cells. However, several differences in the signaling profiles between them may suggest differences of efficacy and toxicity.
Independently, we have developed a nearly comprehensive in vitro kinase inhibitor profiling system, and we already have complete inhibition profiles for nine kinase inhibitors such as Erlotinib or Gefitinib. This allows us to combine in vitro profiling results with pathway intervention profiles to build a database integrating kinase-inhibition-potencies and cellular-signaling-profiles. Our aim is to expand this database to obtain new information to guide strategies for effective targeting in drug discovery. In this presentation, we present the novel targeting discovery strategy based on this database analysis.
Citation Format: Takeomi Inoue, Naoko Iwata, Eiji Nishiwaki, Yasuyuki Kirii. Pathway oriented phospho-proteomics analysis with reverse phase protein array (RPPA) technology in cell growth and cancer therapy. [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 5165. doi:10.1158/1538-7445.AM2013-5165
Abstract 5167: Profiling GTPases in native proteomes with a GTP acyl phosphate probe.
Authors: Nomanbhoy Tyzoon K. , Shih Ann , Aban Arwin 
Published: August 2014

Abstract
GTPases constitute an important class of regulatory proteins that participate as signal transducers in the capacity of molecular switches. The GTPase superfamily consists of 250 members in the human genome. These fall into several families, including the small GTPases (Ras Rho, Arf, Rab and Ran), heterotrimeric GTPases, elongation and initiation factors, and dynamins. In order to profile the distribution of GTPases in various cell lines and tissues, we have developed a chemical probe comprised of GTP linked to desthiobiotin through an acyl-phosphate bond. By treating complex proteomes with the probe, we are able to isolate probe-labeled peptides with streptavidin, and subsequently, identify the probe-labeled peptides by mass spectrometry. GTPases were identified from almost all known GTPase families indicating that this approach can be used to globally profile GTPases in various proteomes. The most common labeling site occurs at the conserved lysine residue in the phosphate binding loop (GXXXXGK) of the GTP-binding site. Significantly, the probe-labeled peptide for H-,K- and N-RAS includes amino acid positions 12 and 13, which are frequently mutated in cancers. Thus, the GTP probe can be used to directly quantify mutant RAS isoforms at the protein level.
Citation Format: Tyzoon K. Nomanbhoy, Ann Shih, Arwin Aban. Profiling GTPases in native proteomes with a GTP acyl phosphate probe. [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 5167. doi:10.1158/1538-7445.AM2013-5167