bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4620: A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: A potential therapeutic agent in cancers
Authors: Francescone Ralph , Faibish Michael , Bentley Brooke , Yan Wei , Shao Rong 
Published: August 2012

Abstract
Recent studies have shown that YKL-40, a secreted glycoprotein, is highly expressed in patients with advanced cancers including breast cancer, colorectal cancer, ovarian cancer, lung cancer, and brain tumors. We have identified YKL-40 as an angiogenic molecule capable of stimulating endothelial cells in different types of cancers. Nevertheless, the therapeutic value of targeting YKL-40 in human cancers remains unknown. Therefore, it was the goal of this study to develop a monoclonal antibody against YKL-40 that could bind specifically and inhibit YKL-40 function with regard to cancer progression. A mouse monoclonal anti-YKL-40 antibody (mAY) was developed using hybridoma technology. mAY could specifically recognize recombinant YKL-40, as well as secreted YKL-40 from the media of two cancerous cell lines, MG63 and U87. Additionally, in functional testing, we demonstrated that mAY inhibited in vitro tube formation on Matrigel of endothelial cells induced by the conditioned media of MG63 and U87 cells. Recombinant YKL-40 treated endothelial cells displayed increased tube formation. mAY significantly abrogated tube formation by blocking recombinant YKL-40. Moreover, mAY reduced YKL-40 activated VEGF receptor 2 (Flk-1/KDR) and intracellular signaling MAP (mitogen-activated protein) kinase extracellular signal-regulated kinase (Erk) 1 and Erk 2. In relation to radiation therapy, treatment of gamma-irradiated U87 cells with mAY induced cell death through a down-regulation of p-AKT and AKT protein expression. Lastly, mAY treatment of U87 xenograft tumors diminished tumor volume, angiogenesis, and progression. These results demonstrate for the first time the therapeutic value of targeting YKL-40 in human cancers which highlights the potential benefits of anti-YKL-40 therapy in patients with a wide spectrum of cancers that over-produce YKL-40.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4620. doi:1538-7445.AM2012-4620
Abstract 4632: Phosphatidylserine-targeting ‘betabodies’ for the treatment of cancer
Authors: Huang Xianming , Ye Dan , Luster Troy , Thorpe Philip E. 
Published: August 2012

Abstract
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse β2-glycoprotein I (≥2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have advantages over bavituximab. They bind directly to PS, whereas bavituximab requires a cofactor protein (≥2GP1) for binding; they can be made fully human; they are smaller in size (100KDa versus 250KDa for the bavituximab: β2GP1 complexes); and they have slower blood clearance rates. Many different constructions of betabodies were tested, each having different orientations, domains, and glycosylation patterns. Constructs were identified that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had α-phase blood half-lives of approximately seven days after intravenous injection into mice as compared with two days for a murine version of bavituximab. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4632. doi:1538-7445.AM2012-4632
Abstract 4654: Docosahexaenoic acid induces autophagy through reactive oxygen species /mTOR pathway in p53 mutant cancer cells
Authors: Shin Soyeon , Jing Kaipeng , Kim Nayeong , Jeong Soyeon , Oh Hye-Rim , Cho Eun Ah , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Han Jeongsu , Park Jong-Il , Kweon Gi-Ryang , Park Seung-Kiel , Park Seung-Kiel , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: August 2012

Abstract
Our previous studies reported that docosahexaenoic acid (DHA) induces autophagy through p53 inhibition in the wild-type p53 cancer cells. This study attempts to elucidate the molecular mechanism underlying DHA-induced autophagy in PC3 and DU145 prostate cancer cells harboring mutant p53. DHA increased both the level of microtubule-associated protein light-chain 3 (LC3) and the number of autophagic vacuoles. Autophagic flux assay confirmed that DHA-induced increase in LC3-II and autophagic vesicles was an outcome of autophagic process activation, indicating that DHA also induces autophagy in p53 mutant cancer cells. DHA treatment also increased the level of reactive oxygen species (ROS) as measured by dihydroethidine staining, and pretreatment of an antioxidant, N-acetylcysteine (NAC), significantly inhibited the ROS production as well as autophagy induced by DHA, suggesting that ROS regulates the autophagic process triggered by DHA. Further experiments showed that the mechanism of DHA-induced autophagy associated with ROS production was related to a decrease in the activity of mammalian target of rapamycin (mTOR). NAC remarkably restored the decreases in the levels of phospho-mTOR and 4EBP, an mTOR downstream molecule, induced by DHA as analyzed by the Western blot assay. Furthermore, the level of phospho-AMPK, which negatively regulates mTOR was increased, while phospho-Akt was reduced during the DHA-induced autophagy, indicating the involvement of AMPK and Akt signalings. Collectively, our results demonstrate that DHA induces autophagy through the ROS-mediated mTOR inactivation in p53 mutant prostate cancer cells. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0006232].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4654. doi:1538-7445.AM2012-4654
Abstract 4661: Levels of C22:0- and C24:0-dihydroceramide correlate with cytotoxicity in T-cell acute lymphoblastic leukemia cell lines
Authors: Holliday Michael W. , Cox Steven B. , Kang Min H. , Maurer Barry J. 
Published: August 2012

Abstract
Fenretinide (4-HPR) is a synthetic retinoid that is cytotoxic to several T-cell acute lymphoblastic leukemia (ALL) cell lines, and has demonstrated activity in a variety of cancer cell lines in vitro. Reported mechanisms of action for fenretinide include both increased reactive oxygen species (ROS) generation in some cell lines and increased dihydroceramide levels. Dihydroceramides are the product of N-acylation of sphinganine with fatty acid chains varying in carbon length and degree of saturation. Although synthetic, short-acyl chain dihydroceramides have been reported to be non-cytotoxic in cell culture in vitro, the cytotoxic potencies of native-acyl chain dihydroceramides are unknown. In the current study, increased synthesis of specific native-acyl chain dihydroceramides was targeted through a novel cell culture method employing concurrent exogenous administration of sphinganine, GT-11, a dihydroceramide desaturase inhibitor, and specific individual fatty acids. Sphingolipids were analyzed using LC/MS/MS. Cytotoxicity was measured using the fluorescence-based cytotoxicity assay DIMSCAN. Non-parametric correlation analysis of cytotoxicity and absolute sphingolipid levels revealed a strong positive correlation between cytotoxicity and C22:0-dihydroceramide (α = 0.75, P &lt; 0.001) and C24:0-dihydroceramide (α = 0.84, P &lt; 0.001) in the CCRF-CEM ALL cell line, with similar results observed independently in MOLT-4, COG-LL-317 and COG-LL-332 ALL cell lines. Additionally, fenretinide cytotoxicity was significantly increased by co-treatment with C22:0-fatty acid in association with an increase of C22:0- and C24:0-dihydroceramides. These findings suggest that the addition of specific fatty acids, perhaps in a tumor-type specific manner, through simple dietary or intravenous supplementation, or via concurrent incorporation into drug delivery vehicles, may improve the clinical efficacy of dihydroceramide-increasing anticancer agents, such as fenretinide.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4661. doi:1538-7445.AM2012-4661
Abstract 4670: Identification of common genetic variants contributing to cisplatin-induced apoptosis and cytotoxicity in lymphoblastoid cell lines
Authors: Gorsic Lidija K. , Stark Amy L. , Wheeler Heather E. , Im Hae K. , Dolan M. Eileen 
Published: August 2012

Abstract
Cisplatin is a platinum agent effective against head and neck, ovarian, cervical, testicular, and lung cancers; however, severe toxicities and intrinsic/acquired resistance hinder its utility. Identifying genetic variants to predict patients at risk for toxicity or non-response would be highly beneficial. To this end, we utilized lymphoblastoid cell lines (LCLs) to identify variants associated with cisplatin-induced cytotoxicity (cell growth inhibition) and apoptosis (caspase 3/7 activity). International HapMap LCLs derived from populations of Northern and Western European (CEU), African (YRI), and African-American (ASW) ancestry were phenotyped for cell growth inhibition and caspase 3/7 activity followed by Genome Wide Association Studies (GWAS). Analysis revealed expression quantitative trait loci (eQTL) enrichment in cytotoxicity-associated SNPs (p&lt;0.001) and in apoptosis-associated SNPs (p&lt;0.001) for all population sets. Applying a threshold of p&lt;0.001 resulted in 19, 14, 0, and 1 SNP(s) overlapping in CEU, YRI, ASW, and meta analysis combining the 3 populations respectively. Furthermore, we found that 16/19 and 9/14 overlapping SNPs for CEU and YRI are eQTLs. Of the 16 eQTLs in CEU, rs4343077 correlated with cisplatin-induced cytotoxicity (p=0.0007) and apoptosis (p=0.0007) and is intronic of epidermal growth factor receptor pathway substrate 8 (EPS8). Given that EPS8 encodes an oncoprotein participating in malignant transformation of tumor cells and has been formerly linked to cisplatin-induced drug response, we evaluated cellular sensitivity to cisplatin following siRNA knockdown in 5 CEU LCLs. Successful knockdown of greater than 70% of endogenous EPS8 resulted in a 7% increase in percent survival (p=1e-6) and a 6.6% decrease for caspase 3/7 activity (p=0.033) across cell lines. We also evaluated expression levels of 6 target genes of rs4343077 and found that 5 significantly (p&lt;0.01) changed following EPS8 knockdown. Our genome wide approach evaluating both cytotoxicity and apoptosis led to the identification of EPS8, a gene that confers sensitivity to cisplatin. Identification of genetic variants contributing to cisplatin-induced cell death through apoptosis is necessary for a better mechanistic understanding of the drug and ultimately to identify patients most likely to respond.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4670. doi:1538-7445.AM2012-4670
Abstract 4673: The anti-proliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and indomethacin in ovarian cancer cells
Authors: Valle Blanca L. , D'Souza Theresa , Becker Kevin G. , Wood William H. , Wersto Robert P. , Morin Patrice J. 
Published: August 2012

Abstract
Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and preclinical mouse model experiments have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. In an attempt to clarify the mechanisms of tumor prevention by NSAIDs, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in several ovarian cancer cell lines. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and/or apoptosis. To identify the possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, ovarian cancer cell lines were treated with diclofenac or indomethacin and microarray analysis was performed. Among the genes differentially expressed in the different cell lines were genes involved in signaling, metabolism, and cell cycle regulation. Some of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1 and E2F4, suggesting involvement of these transcription factors in the response of ovarian cancer cells to NSAID treatment. In addition, E2F1 was found downregulated at the protein level upon treatment with diclofenac and indomethacin. The levels of phosphorylated Rb protein also decreased upon treatment with NSAIDs, suggesting activation of Rb and involvement of the Rb/E2F pathway in the effects of NSAID treatment in ovarian cancer cells. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer cells and we have identified a number of target genes and pathways that may be important for the NSAID-induced cell cycle arrest and apoptosis. Current efforts are focused on determining the exact roles of these genes and pathways in NSAID-mediated cancer growth inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4673. doi:1538-7445.AM2012-4673
Abstract 4797: Global phosphotyrosine survey reveals the evidence of activation of multiple tyrosine kinase signaling pathways in basal-like breast cancer cells
Authors: Wu Xinyan , Renuse Santosh , Chen Lily , Chaerkady Raghothama , Kim Min-Sik , Zahari Saddiq , Sahasrabuddhe Nandini , Zhong Jun , Yang Yi , Kashyap Manoj , Marimuthu Arivusudar , Ling Min , Fackler Mary Jo , Merino Vanessa , Zhang Zhen , Sukumar Saraswati , Pandey Akhilesh 
Published: August 2012

Abstract
About 10-15% of all breast cancers are basal-like breast cancers (BLBCs) that are highly aggressive and lack effective targeted therapeutic options as they lack ER, PR and Her-2. Reversible phosphorylation of proteins is one the most important post-translational modifications and is involved in almost all kinds of cellular processes. Tyrosine phosphorylation (pY) accounts for a minority of total phosphorylation, less than 0.1% by overall abundance. However, pY plays a disproportionately large role in diseases especially in cancer. More than half of the 90 tyrosine kinases identified in the human proteome have been implicated in cancer through gain-of-function mutations, gene amplification, overexpression, or as tumor suppressors and become attractive therapeutic targets. To assess activated tyrosine kinase signaling pathways in TNBCs, we collected a panel of 28 publicly available triple-negative breast cancer cell lines and systematically analyzed the invasiveness and anchorage independent growth of this panel of cell lines. We carried out global quantitative phosphotyrosine profiling using high resolution Fourier transform mass spectrometry. In all, we identified 2,133 tyrosine-phosphorylated peptides from more than 800 proteins. A number of tyrosine kinases were found to be differentially phosphorylated in different sets of breast cancer cells. Pathway analysis revealed that phosphorylation level of certain oncogenic kinases including EGFR, MET, FAK1 and SRC was elevated in a majority of basal-like breast cancer cells. Notably, multiple members of EPH receptor family, EPHA1, EPHA2, EPHA3, EPHB3 and EPHB4, were hyper-phosphorylated in multiple basal-like breast cancer cells. Supervised clustering analysis of phosphorylated proteins identified specific phospho-signatures that correlated with invasiveness and anti-anoikis colony formation ability. One of these hyper-phosphorylated proteins was DYRK2, a dual specificity tyrosine kinase. We observed that DYRK2 had an effect on colony formation and invasive ability on a subset of TNBC cell lines. Overall, our global phosphoproteomic study confirms high heterogeneity in the activation status of tyrosine kinases across triple negative breast cancer cells and suggests that some of them are attractive candidates as therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4797. doi:1538-7445.AM2012-4797
Abstract 4804: Glycoproteomic analysis of lung cancer malignant pleural effusions identify glycosylated proteins being produced by metastatic tumor cells
Authors: Miyamoto Suzanne , Yoneda Ken , Ruhaak Renee , Stroble Carol , Lebrilla Carlito B. , Gandara David 
Published: August 2012

Abstract
Malignant pleural effusions are produced in late stage metastatic lung cancer. We have obtained malignant pleural effusions from lung cancer patients. The specimens are separated into fluid and cells and the cells are grown in culture in a non-adherent manner. The original pleural effusion fluid and the conditioned media harvested from the tumor cells growing in culture are analyzed by glycoproteomic methods to identify glycosylated proteins being produced by the tumor cells. The cells are grown in culture with defined media in a non-adherent manner for an extended period of time to enrich for the tumor cell populations. These cells are phenotypically characterized for lung, epithelial and tumor markers by immunohistochemistry and/or flow cytometry. Conditioned media is collected from the growing cells and along with the original pleural effusion fluid and the tumor cells analyzed for glycosylated proteins using lectin chromatography followed by the use of glycomic and proteomic methods to analyze N- and O-linked glycans and proteins present in these samples. Our early results indicate that cancer glycosylated proteins CA125 (MUC16), MUC1 and fibronectin are present in the conditioned media samples obtained from the different pleural effusion tumor cell cultures that can also be measured in the original pleural effusion fluids. Not all pleural effusion tumor cells produce the same cancer biomolecules. Interestingly if the tumor cells produced CA125 (MUC16) in their culture media, CA125 was also detected in the original pleural effusion fluid confirming that the biomolecules in the fluid originated from the tumor cells. Another patient sample produced mostly MUC1, but much CA125. Fibronectin was also produced by these cells. Glycomic analysis of the samples shows an enrichment of certain glycan groups (high mannose, fucosylated and sialytic acid) in the conditioned media samples when compared with the original pleural effusion fluid samples showing that these glycan groups and the proteins to which they are attached originate from the tumor cells present in the malignant pleural effusions. The use of malignant pleural effusions from lung cancer patients provides us with an excellent opportunity to study metastatic tumor cells and their local environment without the need for scarce tissue specimens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4804. doi:1538-7445.AM2012-4804
Abstract 4808: Discovery of a phospho-signature predicting response to dasatinib in non-small cell lung cancer
Authors: Klammer Martin , Kaminski Marc , Zedler Alexandra , Oppermann Felix , Müller Stefan , Tebbe Andreas , Whittaker Mark , Godl Klaus , Schaab Christoph 
Published: August 2012

Abstract
Since targeted drugs selectively block molecular pathways that are typically over-activated in tumour cells, they are more precise and show fewer adverse effects than traditional chemotherapeutic agents. At the same time the proportion of patients that benefit from targeted drugs is smaller. Therefore, predictive molecular markers are needed to confidently predict the patient's response to a specific therapy. Such markers would facilitate therapy personalization, where the selected therapy is based on the molecular profile of the patient. We sought to identify a signature of protein phosphorylations that predicts the response to dasatinb in non-small cell lung cancer cell lines. A panel of cell lines were profiled in a global, unbiased, phosphoproteomics study yielding quantitative information for roughly 25,000 phosphorylation sites. The identical cell lines were tested for their response to dasatinib. From the phosphoproteome profiles, we identified a signature of twelve phosphorylation sites that can accurately predict dasatinib sensitivity. Four of the phosphorylation sites belong to integrin α4, a protein that mediates cell-matrix or cell-cell adhesion. We evaluated the performance of this signature in a cross-validation set-up and investigated the robustness of the selected predictive features. Finally, we confirmed the predictive power of the signature in an independent set of breast cancer cell lines. We showed that the phosphorylations of integrin β4 as well as eight further proteins are candidate biomarkers for predicting response to dasatinib in solid tumours. Furthermore, we demonstrated that identifying predictive phosphorylation signatures from global, quantitative phosphoproteomic data is possible, and opens a new path to discovering molecular markers for response prediction.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4808. doi:1538-7445.AM2012-4808