bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4532: Nucleolin inhibits Hdm2-mediated p53 ubiquitination using multiple interactions
Authors: Bhatt Purvi , d'Avout Claire , Kane Naiomi S. , Borowiec James A. , Saxena Anjana 
Published: February 2011

Abstract
Nucleolin is a multifunctional abundant nucleolar protein whose transcriptional expression is trans-activated by the proto-oncogene c-myc during exponential cellular growth. This non-ribosomal protein has defined roles in ribosomal RNA processing and transcriptional regulation of various genes including rRNA. Following cellular stress, nucleolin has been shown to inhibit chromosomal replication and to relay nucleolar stress signals mediated by its sub-nuclear re-localization. Thus, nucleolin has been demonstrated to have both positive and negative effects on cell proliferation. We have previously demonstrated that nucleolin binds to the p53-antagonist Hdm2 and inhibits Hdm2-mediated degradation of p53 albeit independent of the ARF (Alternate Reading Frame) tumor suppressor protein. Nucleolin also reduces Hdm2 protein levels by an unknown mechanism when over-expressed in cells to levels found in a variety of cancer cells. Here we have delineated that multiple domains of both nucleolin and Hdm2 are involved in distinct nucleolin-Hdm2 interactions in unstressed cells. Our data indicates that the nucleolin N-terminus as well as the central RNA-binding domain (RBD) are predominantly involved in binding to Hdm2, as determined by Far-Western as well as GST-binding assays in vitro. While the N-terminus of nucleolin was found associated with the Hdm2 RING domain, the nucleolin RBDs robustly bound to the NLS/NES (nuclear localization and export signals) domain of Hdm2. The C-terminal GAR (Glycine-Arginine Rich) domain of nucleolin, shown previously to be essential for association with p53, did not bind Hdm2 yet was found to stimulate Hdm2-mediated p53-ubiquitination. Conversely, the nucleolin RBD that strongly interacted with Hdm2 was found to inhibit the Hdm2 E3 ligase activity against p53, leading to p53 stabilization. There was no significant effect of over-expression of nucleolin or its various domains on Hdm2-autoubiquitination in cells. Similarly, the phosphorylation status of nucleolin did not significantly influence its binding to Hdm2. As might be expected from a key rRNA processing factor, our findings suggest that the activity of nucleolin towards Hdm2 can be modulated to yield either p53 up- or down-regulation. Our studies can aid in the future design of small molecule-based cancer therapeutics that can stimulate the wild-type p53 checkpoint in variety of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4532.
Abstract 4534: A novel and potent small molecule antagonist of HDM2, SCH 1450206, activates the p53 pathway with mechanism-based activity
Authors: Liu Suxing , Mirza Asra , Wang Xiaoying , Lipari Philip , Lin Yinghui , Bogen Stephane , Ma Yao , Doll Ronald , Shipps Gerald , Seidel-Dugan Cynthia , Hicklin Daniel J. , Bishop W. Robert , Wang Yaolin 
Published: February 2011

Abstract
p53 is an attractive therapeutic target in oncology since aberrant regulation of p53 expression is associated with cancer development and progression. HDM2 is a primary negative regulator of p53 function in cells. The blockade of the p53-HDM2 interaction presents an attractive approach for development of drugs against tumors expressing wild-type p53. Here we report a novel and potent small molecule antagonist of HDM2, SCH 1450206. It binds selectively to the HDM2 protein with high affinity, with weak affinity to HDMX protein. SCH 1450206 induced dose- and time-dependent stabilization of p53 protein and its downstream targets in several human cancer cell lines with wild-type p53, but not in cell with p53 gene deletion. SCH 1450206-induced stabilization of p53 led to distinct changes in expression of p53 target genes regulating apoptosis and cell cycle checkpoints. Inhibition of cell proliferation and induction of apoptosis were surveyed in a panel of human tumor cell lines following SCH 1450206 treatment. Inactivation of p53 by shRNA in cell lines expressing wt-p53 abolished the inhibition of cell proliferation and appearance of senescence in response to SCH 1450206, suggesting the cellular activity of SCH 1450206 is p53 specific and mechanism-based. Taken together, our results demonstrated the mechanism of action of SCH 1450206, a novel HDM2 antagonist that can activate the p53 pathway, and offers a potential anti-tumor agent targeting tumors expressing wild-type p53.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4534.
Abstract 4540: Preclinical pharmacology and antitumor activity of CP-744809, a highly selective orally available small molecule inhibitor of aldose reductase
Authors: Griggs David W. , Shannon Kristen E. , Hauser Scott D. , Matulewic David A. , Baratta Michael T. , Pegg Jodi A. 
Published: February 2011

Abstract
Aldose reductase (AKR1B1) mediates the first and rate limiting step in the conversion of glucose to polyols that contribute to redox imbalance, formation of reactive oxygen species, and activation of signal transduction pathways that can promote tumor formation and tumor growth. Aldose reductases are overexpressed in a variety of human tumors, and genetic or pharmacological blockade of AKR1B1 has been reported to attenuate these processes.
CP-744809 is a highly potent and selective aldose reductase enzyme inhibitor which has been previously shown to provide efficacy in an experimental model of diabetic retinopathy. The compound has properties of high oral bioavailability, very high protein binding, and a very long half life in vivo. In this study, we have characterized the activity of this agent in animal models of angiogenesis and tumor growth.
CP-744809 treatment significantly reduced VEGF-induced angiogenesis in a dose-dependent manner in the rat corneal micropocket assay, suggesting a heretofore unrecognized role for aldose reductase in this process. Interestingly, when the related aldose reductase inhibitor Zopolrestat was administered to normal rats, a significantly decreased level of the angiogenic lipid mediator sphingosine-1-phosphate was observed along with other lipid changes. In xenograft models, the CP-744809 treatment was associated with significant and reproducible reduction in tumor size that was dose dependent and superior to treatment with Zopolrestat. Final tumor mass in individual animals was highly correlated with the corresponding intratumoral drug concentration. In contrast, drug concentrations in serum were poorly correlated with drug concentrations in tumor or with tumor mass. Serum drug concentrations at every dose were consistently 7-10 fold higher than those observed in tumor, suggesting a barrier to optimal penetration of tumor tissue by the compound. Pooling data from multiple in vivo studies, the total intra-tumoral drug concentration (protein bound and unbound) required to achieve half maximal efficacy (EC50) was estimated to be 77 micrograms/ml.
These results confirm the therapeutic potential of aldose reductase as an interesting cancer target, and have uncovered a novel antiangiogenic activity. They also highlight the obstacle that adequate tumor tissue penetration may pose for clinical development of agents such as CP-744809. Combination treatments with other agents are being evaluated to assess the potential for synergistic activity with the vascular and inflammation modulating properties of aldose reductase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4540.
Abstract 4541: The design, synthesis and evaluation of selective FR α and β substrates with potent GARFTase inhibitory activity as antitumor agents
Authors: Zhou Xilin , Zhang Xin , Gang Aleem , Cherian Christina , Hou Zhanjun , Matherly Larry H. , Kisliuk Roy L. 
Published: February 2011

Abstract
Glycinamide ribonucleotide formyl transferase (GARFTase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway. Potent inhibitors of GARFTase and de novo purine biosynthesis have shown promise as antitumor drugs. However, a lack of selectivity and toxicity has been a major hurdle for GARFTase inhibitors as cancer chemotherapeutic agents. We recently reported a series of thieno[2,3-d]pyrimidine classical antifolates that are specifically taken up by the folate receptor (FR) and inhibit FR expressing tumor cells at nanomolar IC50 values (IC50= 4.9 nM in human KB tumor cells, IC50= 5.9 nM in human IGROV1 tumor cells,). GARFTase was confirmed as the target. Notably, the thieno[2,3-d]pyrimidine antifolates are unique and distinct from all other classical antifolates evaluated, including pemetrexed (PMX), raltitrexed (RTX), and methotrexate (MTX) in that they are neither substrates for reduced folate carrier (RFC) nor for the proton-coupled folate transporter (PCFT). This characteristic results in selective targeting of FR-expressing cells, without toxicity to normal cells that express RFC. To further investigate the structural requirements of antifolates with respect to FR substrate activity, a series of four 2-amino-4-oxo-6-substituted thieno[2,3-d]pyrimidines with different aryl side chains were synthesized. This afforded potent antitumor agents with increased inhibitory activity against FRα expressing tumor cells (IC50= 2 nM in human KB tumor cells) 2.5- fold more potent than the lead benzoyl compound. In addition, these thieno[2,3-d]pyrimidines were specific for FRα and were not transported by RFC or PCFT and indicated that the nature of the bicyclic scaffold is an important structural determinant for transport specificity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4541.
Abstract 4549: Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice
Authors: Beumer Jan H. , Eiseman Julie L. , Gilbert Judith A. , Holleran Julianne L. , Yellow-Duke Archibong E. , Clausen Dana M. , D'Argenio David Z. , Ames Matthew M. , Hershberger Pamela A. , Parise Robert A. , Bai Lihua , Covey Joseph M. , Egorin Merrill J. 
Published: February 2011

Abstract
Introduction
Cytidine drugs, such as gemcitabine, undergo rapid, inactivating catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine drug metabolism. However, p.o. THU is at most 20% bioavailable (Beumer et al.), which limits its preclinical evaluation and clinical use. Therefore, the more lipophilic prodrug triacetyl THU (taTHU) was developed. We characterized THU pharmacokinetics after administration of taTHU to mice.
Methods
Mice were dosed 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters and p.o. bioavailability were calculated non-compartmentally and compartmentally. We assessed taTHU inhibition of metabolism of gemcitabine by recombinant CD.
ResultsTHU parameterstaTHU i.v. 150 mg/kgtaTHU p.o. 150 mg/kgCmax (µg/mL)10611.8Tmax (min)560Half-life (min)235122AUC0-inf (mg/mL*min)7.553.36Vd/F (L/kg)4.495.26Cl/F (mL/min/kg)13.229.8F-THUi.v. (%)68.030.3% dose in 0-16 h urine405.6% dose in 0-24 h urine5512
THU, after 150 mg/kg taTHU i.v., had a 235 min terminal half-life and produced plasma THU concentrations &gt;1 µg/mL, the concentration shown to inhibit CD, for 10 h. A multi-compartment model fit the data best. 150 mg/kg p.o. taTHU produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5-2 h, followed by a decline with a 122 min half-life. Approximately 68% of i.v. taTHU was converted to THU. Approximately 30% of p.o. taTHU reached the systemic circulation as THU. After i.v dosing, renal excretion accounted for 40-55% of the taTHU dose, 26-35% as THU and an additional 14-19% as acetylated forms of THU. After p.o. dosing, the renal excretion percentages were 6-12%, 5.2-11%, and 0.42-0.71%, respectively. taTHU did not inhibit recombinant CD.
Conclusion
The availability of THU after p.o. taTHU in mice is 30%, as compared to the 20% achieved after p.o. THU. Clinical studies are warranted to evaluate availability of THU from taTHU in humans.
Support: N01-CM07106, N01-CM52202, P30-CA47904 from the NCI and P41-EB001978.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4549.
Abstract 4555: Remote sensing image dtection; a new tool for evaluation the tumor thickness in tongue SCC
Authors: Chang Kuo-Wei Chang , Wong Yong Kie , Wong Mark , Chang Chein-I 
Published: February 2011

Abstract
A preoperative predictor of the risk of subclinical nodal metastasis would be useful. Studies have shown a strong correlation between histological tumor depth and the risk of nodal metastasis. To assess if preoperatively measured tumor depth predicts an increased risk of subclinical metastatic neck disease and thus the need for elective neck dissection. To further pin-point the boundary between normal to infective tissues, biopsy is generally performed. However, the similarity and the general nature of tissue substances between normal and cancer cells are sometimes hard to distinguish by human eyes. This is also true for experienced radiologist. Therefore, computer aided cancer cell classification is highly beneficial for such diagnoses. In this presentation, we implemented methods that are found highly successfully in satellite remote sensing image detection and classification. These methods can be grouped into two major categories, supervised and unsupervised classification. The supervised methods, Least Squares Orthogonal Subspace Projection (LSOSP), Non-negative Constraint Least Squares (NCLS) and Fully Constraint Least Squares (FCLS), require a detail library of every possible tissue signatures consist in the MR image. But, the classification results can be generally more accurate. On the other hand, the unsupervised methods, Automatic Target Detection (ATGP), Unsupervised Non-negative Constraint Least Squares (UNCLS), and Unsupervised Fully Constraint Least Squares (UFCLS), can automatically generate tissue classification results. However, parameters for these techniques such as the number of tissues need to be predefined. Also, the cancer cell classification still needs human intervention to justify the location of infectious region. Based on our experiments, both category of methods are show promising results.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4555.
Abstract 4572: Comparison of proteomic profiles in human plasma of smokers and nonsmokers using the iTRAQ approach
Authors: Bortner James D. , Richie John , Das Arunangshu , Liao Jason , Umstead Todd , Stanley Anne , Stanley Bruce , Belani Chandra , El-Bayoumy Karam 
Published: February 2011

Abstract
Lung cancer is a potentially preventable disease because it is strongly related to tobacco smoke. Although there have been great strides taken to inform the population of the severity of the risks associated with smoking, there are currently 43.4 million Americans that smoke and 1.3 billion smokers worldwide. Therefore, it is important to develop biomarkers that can identify individual smokers and ex-smokers who are at especially high risk for lung cancer. Relative changes that take place in the human plasma proteome as a result of smoking may be playing an important role in the etiology of lung cancer. Thus, in this study we used a proteomic approach utilizing isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to compare the plasma protein expression levels between healthy smokers and non-smokers. With this multi-plex non-gel based technique, up to 8 samples can be simultaneously labeled with isobaric tagging reagents, 113-119 and 121, for quantitation and identification by mass spectrometry. Plasma samples from seven white male smokers and seven white male non-smokers were distributed into two 8-plex iTRAQ sets. The 113 label in each set was used to label a pool consisting of each sample in the study in order to compare between the two 8-plex sets. Plasma from each subject was depleted of the 14 most abundant plasma proteins using an immunoaffinity column to search for lower abundant proteins. Based on our results, we identified 18 significant (p&lt;0.05) differentially expressed proteins between smokers and non-smokers. The proteins that were down-regulated in smokers include sex hormone-binding globulin (SHBG), inter-α (globulin) inhibitor H3 (HC3), and vitronectin. The proteins that were up-regulated in smokers include the complement component 8, α, β and γ polypeptides, gelsolin, and mannose-binding protein C (MBP-C). Among those identified, SHBG, HC3, and gelsolin protein have been previously identified in smokers and have been suggested to be candidate markers for lung cancer. The results of this study show that cigarette smoking can influence the relative expression profile of plasma proteins. However, the relationship of these proteins to the development of lung cancer needs to be determined so that they can be further developed as biomarkers of disease risk.
Support: NCI PO1 70972
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4572.
Abstract 4585: Verification of prostate cancer biomarker candidates by nanoparticle-capture MRM
Authors: Fredolini Claudia , Luchini Alessandra , Meani Francesco , Russo Paul , Tamburro Davide , Douglas Temple , Longo Caterina , Gambara Guido , Zhou Weidong , Ross Mark , Novelli Francesco , Collura Devis , Muto Giovanni , Espina Virginia , Ornstein David , Liotta Lance A. , Petricoin Emanuel F. 
Published: February 2011

Abstract
Prostate adenocarcinoma (PCa) is highly diffuse between older men, and biomarkers that allow discrimination of cancerous pathologies from benign diseases, identification of clinical aggressive cancer with high specificity and monitor cancer progression are required. Recently we applied a new workflow for the discovery of candidate biomarkers based on hydrogel nanoparticle capture of LMW serum borne analytes. Comparing serum from pre and post prostatectomy patients we identified 112 candidates biomarkers. Our novel nanoparticle technology provides a rapid and near 100% efficient means to capture and greatly amplify the resting concentration of LMW protein analytes. Since most of these markers do not have well performing specific antibodies commercially available, we utilized MRM to verify their differential expression as first identified by Orbitrap-MS/MS.
Hydrogel nanoparticle serum pre-processing was used for both Orbitrap-LTQ based discovery and MRM verification such that the same analyte fractionation workflow was used but different downstream mass spectrometry. MRM was performed on a Thermo Quantum triple quadrupole-MS using the nanoparticle trapped analyte archive as the input for analysis. The following biomarker candidates were selected for MRM verification: Apolipoprotein E, Diacylglycerol kinase alpha, complement 1 subcomponent q B chain precursor, complement component 1 q subcomponent gamma polypeptide, serpin peptidase inhibitor, vitronectin precursor, angiotensinogen preproprotein, H4 histone family member J, fibronectin 1 isoform 2, orosomucoid 1 precursor, alpha-2-HS-glycoprotein, annexin I.
Several prostate candidate biomarkers were verified by Nanoparticle capture-MRM, thus providing data supporting the use and continued improvement of this novel biomarker discovery system for the identification of protein biomarker panels for early disease detection and therapeutic monitoring.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4585.
Abstract 4589: Changes in proteomic profiles with age in male rats using the iTRAQ approach
Authors: Das Arunangshu , Richie John , Bortner James , Aliaga Cesar , Stanley Anne , Stanley Bruce A. , El-Bayoumy Karam 
Published: February 2011

Abstract
Aging is an important risk factor for many diseases including prostate cancer (PC). Enhanced risk for disease may, in part, be due to aging-related changes in the proteome. Thus, a better knowledge of the changes in protein levels occurring with age would help in the early detection of the disease, as well as in monitoring chemopreventive intervention. In the present study we used male F344 rats, a commonly used aging and PC model, and compared protein levels in the blood plasma of young (4 months), mature (12 months), old (18 months) and very old (24 months) rats by a proteomic approach known as isobaric Tag for Relative and Absolute Quantitation (iTRAQ). In this multi-plex non-gel based technique samples can be simultaneously labeled with isobaric tagging reagents for quantitation and identification by mass spectrometry. Plasma samples were pooled from three animals and 50 μg of protein from each group was labeled for a 4-plex iTRAQ analysis. A total of seventy nine proteins were identified, thirty one with &gt;99% confidence. Among those, the levels of thirteen proteins were changed significantly (p&lt;0.05) with age and five of which with &gt;99% confidence including serotransferrin, hemopexin, fetuin-A, fetuin-B and α-1-acid glycoprotein. Both age-specific and growth-development related changes were observed throughout the life span with maximum changes (either increases or decreases) being observed at 18 months. The results of this study show that age indeed can influence the expression profile of plasma proteins. The relationship of these proteins to PC is currently being investigated by analyzing their levels in different lobes of the prostate gland. Supported in part by R01 CA 127729-01
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4589.