bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2480: Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism.
Authors: Millard Melissa , Neamati Nouri 
Published: August 2014

Abstract
Metabolic plasticity is an adaptive mechanism tumors rely upon for growth advantage. Without sufficient energy and biomass, cell replication cannot proceed. Therefore, interrupting cancer-specific metabolic processes presents a novel means to inhibit tumor growth. The clinical benefit of this approach has not yet been fully realized due to a lack of suitable agents targeting cancer cell metabolism. To address this unmet need we screened our in-house compound library for chemical scaffolds with potential metabolic activity. In the course of our studies we identified the small molecule AV220 as a potent metabolic antagonist suitable for preclinical development. In a panel of cancer cell lines, AV220 showed anti-proliferative activity in the low micromolar range. Mechanistic studies indicate a mode of action that involves energy sensing and regulatory pathways. AV220 treatment produced a rapid and sustained phosphorylation of AMPK and its substrate acetyl-CoA carboxylase. Prolonged treatment with AV220 resulted in profound intracellular vacuolation and increased autophagic flux followed by accumulation of Grp78, CHOP and ATF4. Additional early intracellular signaling events associated with AV220 treatment included phosphorylation of p38 and Erk 1/2 and Src and Akt inhibition. A structure-based search of our small molecule library led to the identification of additional analogs, many of which displayed similar cytotoxicities and a shared mechanism of action.
Citation Format: Melissa Millard, Nouri Neamati. Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism. [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 2480. doi:10.1158/1538-7445.AM2013-2480
Abstract 2482: Development of novel small-molecule inhibitors of androgen receptor variants lacking the ligand-binding domain.
Authors: Tian Xiaohong , Liu Weiguo , Geng Guoyan , Wu Jian Hui 
Published: August 2014

Abstract
Over 30,000 men die from prostate cancer in Canada and USA each year. Current therapeutic strategy for advanced prostate cancer is to suppress androgen receptor (AR) signaling by reducing level of androgens (via castration) and by antiandrogens to compete with endogenous androgens for binding in the AR ligand-binding domain (LBD). Despite of initial response, lethal ‘castration-resistant’ prostate cancer (CRPC) arises as a result of oncogenic reactivation of the AR. Current treatments for CRPC provide only a modest improvement in overall survival (a few months). It is now firmly established that reactivation of the AR signaling in CRPC is due to multiple mechanisms, including point mutations in the AR LBD and expression of AR variants lacking the LBD. Recently, a series of AR splice variants lacking the LBD, such as AR-v7, were identified from tissue specimen of CRPC patients. Significantly, AR-v7 is constitutively active even in the absence of androgens and it is thus no longer possible to be inhibited by conventional LBD-targeting antiandrogens (such as bicalutamide) or by androgen-depleting agents (such as Abirateron). This potentially provides a novel mechanism for the development of CRPC. Our recent work has identified a novel chemical compound that inhibits AR-v7 in reporter assays. We found this compound is also active against full-length ARs, including the wild type and multiple clinically-relevant mutant ARs, such as the T877A, H874Y and W741C mutants. Our study indicated this compound targets the N-terminal domain of the AR. We have obtained structure-activity relationship (SAR) of this compound.
Citation Format: Xiaohong Tian, Weiguo Liu, Guoyan Geng, Jian Hui Wu. Development of novel small-molecule inhibitors of androgen receptor variants lacking the ligand-binding domain. [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 2482. doi:10.1158/1538-7445.AM2013-2482
Abstract 2484: Proteomic identification of ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3 as potential biomarkers in colorectal cancer tissues.
Authors: Kang Kee R. , Kang Jung H. , Ju Young-Tae 
Published: August 2014

Abstract
Colorectal cancer (CRC) is the third most prevalent cancer worldwide and has poor prognosis. Recent improvement in methods for proteome analysis has offered the possibility of identifying disease-associated protein markers to assist in diagnosis or prognosis, and for selecting potential targets for specific drug therapy. In current study, the proteome of colorectal adenocarcinoma and the corresponding normal tissues was visualized and analyzed a number of proteins to isolate and identify tumor-specific proteins for CRC. Ten proteins were dominantly expressed and five proteins were largely repressed in CRC by the analysis of 2-DE and MALDI-TOF/mass spectrometry. Ubiquitin conjugating enzyme E2N, one of enzyme necessary for ubiquitination, and proteasome activator complex subunit 3 were focused to be increased in CRC tissues compared with normal colorectal tissues. The elevated expression of E2N and proteasome activator complex subunit 3 in CRC was confirmed by Western blot analysis and real time PCR. Immunohistochemistry also verified largely up-regulation of E2N and proteasome activator complex subunit 3 in 85 CRC patients. These findings suggest that ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3, which are involved in the ubiquitin-proteasome system, could be possible tumor biomarker candidates in CRC tissues. [Funding source: NRF grant (R13-2005-012-01003-0)].
Citation Format: Kee R. Kang, Jung H. Kang, Young-Tae Ju. Proteomic identification of ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3 as potential biomarkers in colorectal cancer tissues. [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 2484. doi:10.1158/1538-7445.AM2013-2484
Abstract 2486: Plasma proteomic changes induced by effective chemopreventive ratios of N-3:N-6 fatty acids against MNU-induced mammary carcinogenesis of the rat.
Authors: Skibinski Christine G. , Thompson Henry J. , Das Arunangshu , Manni Andrea , El-Bayoumy Karam 
Published: August 2014

Abstract
The development of sensitive, specific, and reliable biomarkers for early detection of breast cancer and the discovery of novel chemopreventive agents are two strategies with promising clinical applications. It has been postulated that the risk of breast cancer can be influenced by certain dietary compounds such as the type and amount of dietary fats ingested. We have shown that a diet high in an n-3:n-6 ratio (10:1 and 25:1), that provided 30% calories from fat (10% monounsaturated, 10% polyunsaturated, and 10% saturated fatty acids), significantly reduced rat mammary cancer induced by 1-methyl-1-nitrosourea(MNU). In the present study we used a proteomic approach to gain insights into the mechanisms of protection by a high n-3:n-6 ratio with the goal of identifying biomarkers that can be employed to monitor efficacy of chemopreventive agents. The plasma from six rats from each of three groups, a control group(n-3:n-6=1:1) and two groups fed a high n-3 diet(n-3:n-6=10:1 and 25:1) was pooled and submitted to the isobaric Tags for Relative and Absolute Quantitation(iTRAQ) method, which includes matrix-assisted laser desorption/ionization tandem mass spectroscopy(MALDITOF/TOF) to identify and quantify proteins that were regulated as a result of n-3 fatty acid supplementation. There were 148 proteins identified in our study with 95% confidence(unused score 1.3 or greater) by ProteinPilot 4.0. In plasma of rats fed 10:1 n-3:n-6, and 25:1 n-3:n-6 the number of proteins that met our criteria(p&lt;0.05, error factor≤2) were 10 and 14 proteins, respectively. Our results illustrated that many proteins were modified in a manner consistent with chemoprevention. Validation of the iTRAQ by Western Blotting showed up-regulation of vitamin D binding protein and gelsolin postulated to have a tumor suppressive effect through modulation of inflammation and actin depolarization, respectively. We also observed that 14-3-3 sigma, a well known tumor suppressor in breast tissue, was increased in a ratio dependent fashion. In contrast, we observed down-regulation of alpha-1b-glycoprotein which has been reported to be elevated in the serum of breast cancer patients. These proteins may serve in future studies as candidate biomarkers in early detection and clinical chemoprevention trials with well-defined ratios of n-3:n-6 fatty acids. Support: Susan G. Komen Foundation(KG081632)
Citation Format: Christine G. Skibinski, Henry J. Thompson, Arunangshu Das, Andrea Manni, Karam El-Bayoumy. Plasma proteomic changes induced by effective chemopreventive ratios of N-3:N-6 fatty acids against MNU-induced mammary carcinogenesis of the rat. [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 2486. doi:10.1158/1538-7445.AM2013-2486
Abstract 2488: Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung cancer.
Authors: Schaaij-Visser Tieneke B M , Nagel Remco , de Reus Inge , Piersma Sander R. , Pham Thang V. , Smit Egbert F. , Thunnissen Frederik B. , Brakenhoff Ruud H. , Berns Anton , Jimenez Connie R. 
Published: August 2014

Abstract
The five-year survival rate for non-small cell lung cancer (NSCLC) is still less than twenty percent in part due to treatment failure and lack of biomarkers for personalized therapy. Most NSCLC patients are treated by chemotherapy and cisplatin is still the major component of most chemotherapy regimens. However, resistance to cisplatin is a common phenomenon. Aim of this study was to identify protein biomarkers that can be used for cisplatin response prediction.
The proteomes and secretomes1 of a series of human NSCLC cell lines with a range of IC50-values for cisplatin (1.5 - 15 μM) were analyzed by label-free proteomics based on GeLC-MS/MS and quantified by spectral counting. Significant differential expression of proteins was determined by the in-house developed beta-binomial statistical test2. Network and gene ontology analysis was performed, with STRING and DAVID respectively, to reveal cellular and molecular functions associated with the differential proteins.
In total, 2885 and 2342 proteins were detected in the cell lysates and secretomes, respectively. The proteins with significantly higher expression in the resistant cell lines were associated RNA processing and vesicle transport, while the proteins with higher expression in the sensitive cell lines were known to be involved in RNA splicing, DNA damage repair and extracellular matrix organization. The most promising candidates are being validated in tissues and sputum of patients with known response to cisplatin.
1 Piersma SR et al. J Proteome Res. 2010 Apr 5;9(4):1913-22.
2 Pham TV et al. Bioinformatics. 2010 Feb 1;26(3):363-9.
Citation Format: Tieneke B M Schaaij-Visser, Remco Nagel, Inge de Reus, Sander R. Piersma, Thang V. Pham, Egbert F. Smit, Frederik B. Thunnissen, Ruud H. Brakenhoff, Anton Berns, Connie R. Jimenez. Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung 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 2488. doi:10.1158/1538-7445.AM2013-2488
Abstract 2491: Dynamics changes in antigen-autoantibody profiles involving glycolysis and spliceosome proteins precede a diagnosis of ER+ and triple negative breast cancer among post-menopausal women.
Authors: Ladd Jon , Johnson Melissa , Chao Timothy , Chin Alice , Pitteri Sharon , Mao Jianning , Amon Lynn M. , McIntosh Martin , Lampe Paul , Li Christopher , Prentice Ross , Disis Nora , Hanash Samir 
Published: August 2014

Abstract
We assessed the circulating autoantibody repertoire in breast cancer using genetically engineered mouse models and human plasmas collected at a pre-clinical time point and at the time of clinical diagnosis of breast cancer. We aimed to identify common pathways, networks and protein families associated with the humoral response to tumors and to elucidate the dynamic nature of tumor antigens and autoantibody interactions in ER+ and triple negative breast cancer. Lysate proteins from immortalized mouse cell lines from MMTV-neu and C3(1)-T mouse models and from the MCF7 and MDA-MB-231 human breast cancer cell lines were spotted onto nitrocellulose microarrays and hybridized with mouse and human plasma samples, respectively. Ig-based plasma immunoreactivity against glycolysis and spliceosome proteins was a predominant feature observed both in MMTV-neu tumor bearing mice and in pre-diagnostic ER+ human samples. A cytoskeletal signature was uniquely observed in C3(1)-T mice and in human patients with triple negative breast cancer. We provide evidence for dynamic changes in autoantibody reactivity and in antigen-antibody interactions with tumor development and progression.
Citation Format: Jon Ladd, Melissa Johnson, Timothy Chao, Alice Chin, Sharon Pitteri, Jianning Mao, Lynn M. Amon, Martin McIntosh, Paul Lampe, Christopher Li, Ross Prentice, Nora Disis, Samir Hanash. Dynamics changes in antigen-autoantibody profiles involving glycolysis and spliceosome proteins precede a diagnosis of ER+ and triple negative breast cancer among post-menopausal women. [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 2491. doi:10.1158/1538-7445.AM2013-2491
Abstract 2496: Identification and functional characterization of a novel oxidatively modified protein in the cardiac tissue after doxorubicin-induced cardiotoxicity.
Authors: Aryal Baikuntha P. , Jeong Jinsook , Rao V. Ashutosh 
Published: August 2014

Abstract
Doxorubicin (Dox) is an anthracycline drug that is effectively used as a chemotherapeutic agent for the treatment of a variety of cancers. Its dose-dependent cardiotoxicity, however, has limited its chemoprotective properties in clinical practice. One of the primary mechanisms of Dox-induced cardiotoxicity is the generation of intracellular reactive oxygen species (ROS) by an iron-catalyzed reaction. We hypothesized that the consequent protein oxidation under oxidative stress can be monitored and correlated with cellular outcome of survival or death. First, to understand how Dox-induced oxidative stress is related to the cardiotoxicity, we identified specific cardiac proteins that are oxidatively modified under Dox-induced oxidative stress in a spontaneously hypertensive rat model of acute toxicity. Next we characterized the type(s) of modifications and the amino acid residues within the protein that undergo modification under oxidative stress. Finally, we investigated the functional consequences of such oxidative modifications. Based on our findings, we focused on protein carbonylation as an indicator of severe oxidative damage. We detected a highly carbonylated protein in the cardiac tissue after Dox-treatment. The Dox-induced carbonylated protein was identified as a cardiac myosin binding protein C (MyBPC) using mass spectrometry. To determine the carbonylated sites and effect of such modification in the protein structure and function, we expressed MyBPC in E. coli and purified recombinant MyBPC. Consistent with the in vivo results, recombinant MyBPC showed an increase in carbonylation under excessive oxidative conditions. The degree of carbonylation was time- and concentration-dependent. Excessive carbonylation was associated with the degradation of MyBPC. Identification of carbonylated sites and the effect of such carbonylation in the protein functions will help to better understand the Dox-induced cardiac toxicity. Our findings also indicate the potential for an oxidative biomarker for monitoring the Dox-induced cardiotoxicity.
Citation Format: Baikuntha P. Aryal, Jinsook Jeong, V. Ashutosh Rao. Identification and functional characterization of a novel oxidatively modified protein in the cardiac tissue after doxorubicin-induced cardiotoxicity. [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 2496. doi:10.1158/1538-7445.AM2013-2496
Abstract 2497: Upregulation of annexin A8 is a common molecular phenotype of aberrant breast acinar morphogenesis induced by different genetic factors.
Authors: Rossetti Stefano , Corlazzoli Francesca , Sacchi Nicoletta 
Published: August 2014

Abstract
It is estimated that up to 90% of women have benign breast lesions, some of which are pre-malignant. In situ lesions, particularly the ones that involve the ducts (ductal carcinoma in situ, DCIS), have the potential to progress into invasive malignant lesions and become life threatening. These breast premalignant states are identified because of specific morphological tissue abnormalities. Three-dimensional (3D) cultures of human mammary epithelial cells closely recapitulate breast acinar morphogenesis. While untransformed mammary epithelial cells form hollow acini, lined by polarized, non-proliferating cells, breast cancer cells form acini filled with non-polarized, actively proliferating cells, similar to DCIS. By using a proteomic approach in a panel of morphologically aberrant acini derived from human breast epithelial cells, we found that the disruption of acinar morphogenesis by different genetic factors generates a common proteomic signature. Among the proteins that we found consistently upregulated, we identified Annexin A8 (ANXA8), a member of the annexin family of calcium and membrane-binding proteins with a wide range of cellular functions, including cell division, apoptosis, and cell growth regulation. We tested ANXA8 expression in tissue samples from patients with atypical ductal hyperplasia (ADH), and tissue microarrays of DCIS, with or without, history of invasive breast cancer. Interestingly, this analysis detected ANXA8 increased expression in atypical proliferating ducts relative to non-proliferative ducts, making ANXA8 a potential marker of breast pre-malignancies.
Acknowledgments: this study was funded by grants of the Susan Komen Foundation, the Breast Cancer Coalition of Rochester, the Friends for an Earlier Test of Breast Cancer Foundation.
Citation Format: Stefano Rossetti, Francesca Corlazzoli, Nicoletta Sacchi. Upregulation of annexin A8 is a common molecular phenotype of aberrant breast acinar morphogenesis induced by different genetic factors. [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 2497. doi:10.1158/1538-7445.AM2013-2497
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 250: Growth characteristics of breast cancer stem cells in vitro and in vivo.
Authors: Lee Carnella M. , Sawant Anandi , Cha Ha-Ram , Ponnazhagan Selvarangan 
Published: August 2014

Abstract
Breast cancer (BCa) is the most common malignancy in United States women, accounting for greater than 40,000 deaths each year. Studies have attributed the presence of cancer stem cells (CSC) with resistance to chemotherapy as a key component of refractories of treatments in BCa. Breast cancer stem cells (BCa-SC) are characterized by CD24lo and CD44hi phenotype with mesenchymal properties, which differ from the epithelial CD24hi and CD44hi phenotype expressed in the majority of BCa cells. Thus, further understanding properties of BCa-SC may lead to the development of novel treatment options towards treating refractory cancer cells. Fundamental to this, further characterization of BCa-SC will be needed to identify therapeutic targets based CSC biology. To this end, we sought to characterize the plasticity of BCa-SC based on cell cycle in vitro and growth kinetics in vivo. A murine BCa cell line, 4T1, was cultured in CSC medium and analyzed every 6 hrs for CD24 and CD44 expression by flow cytometry. Results of this analysis indicated that specific BCa-SC markers peaked every 24 hours. This data supports a possible reprogramming of BCa-SC based on cell cycle regulation, suggesting the use of cell cycle inhibitors to block cells in particular stages of the cell cycle, which may improve therapeutic approaches to induce cell death. The stemness of these cells was further confirmed by real-time PCR. BCa-SC showed increased expression of ALDH1, TWIST, and TGF-β3 with decreased E-Cadherin and CD24 levels correlating to the phenotypic changes observed with CD24 and CD44 expression. To further examine the role of BCa-SC in tumor growth in vivo, BALB/c mice were subcutaneously implanted with populations of 4T1 cells that constituted CSC and non- cancer stem cells (NCSC) in different combinations and tumor growth was analyzed. Results showed that the growth kinetics CSC and NCSC when used alone was significantly lower in vivo compared to mixed populations containing both CSC and NCSC, suggesting CSC may attribute for the repopulation of the disease but an aggressive growth requires differentiated non-stem cells in the tumor microenvironment.
Citation Format: Carnella M. Lee, Anandi Sawant, Ha-Ram Cha, Selvarangan Ponnazhagan. Growth characteristics of breast cancer stem cells in vitro and in vivo. [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 250. doi:10.1158/1538-7445.AM2013-250