bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 342: A hepatocyte growth factor antagonist engineered by disruption of heparan sulfate binding
Authors: Cecchi Fabiola , Pajalunga Deborah , Rabe Daniel C. , Peruzzi Benedetta , Fowler Andrew C. , Blackman Davida K. , MacDonald Nicholas , Stahl Stephen J. , Byrd Andrew R. , Bottaro Donald P. 
Published: February 2011

Abstract
Hepatocyte growth factor (HGF) stimulates cell proliferation, motility, and morphogenesis upon binding to the receptor tyrosine kinase Met and cell surface heparan sulfate (HS) glycans. NK1 is a truncated HGF isoform consisting of the N-terminal (N) and first kringle (K1) domains of full-length HGF that stimulates all major HGF biological activities. Within NK1, the N domain contains the HS binding site, while K1 contains the primary determinants of Met binding. To further define the role of HS in ligand-receptor interaction and biological signaling, we identified the primary HS binding residues in N domain (K60, K62, R73) and generated opposite charge mutations at these positions in NK1. Nuclear magnetic resonance analysis of recombinantly expressed mutant and wild type (WT) proteins revealed that both were folded normally. Mutant proteins displayed diminished binding to immobilized HS relative to WT, and the triple mutant protein (3M) also lacked intrinsic motogenic and mitogenic activity. Interestingly, 3M NK1 maintained Met binding and competitively inhibited DNA synthesis stimulated by WT NK1 as well as full-length HGF in normal cells.
Expression plasmids encoding 3M and WT NK1 proteins were transfected into the glioblastoma cell U87 MG, which is dependent on HGF/Met autocrine signaling for tumorigenicity in mice. 3M/U87 MG cells displayed a substantially lower rate of growth relative to WT/U87 MG or the parental cell line, suggestive of growth antagonism by 3M NK1. As anticipated, expression of WT NK1 significantly accelerated the growth of U87 MG tumor xenografts in mice, which reached maximal volume (1 ml) by 22 days post-implantation, compared to 45 days required by the parental cell line. In contrast, tumor growth in animals injected with 3M/U87 MG was dramatically impaired: at 60 days post implantation, average tumor volume for this group was &lt; 0.3 ml. Because both WT and 3M transfectants expressed equal amounts of their respective recombinant proteins, the HS binding site mutations delayed measurable tumor growth from one week to two months. Thus HS binding is critical for HGF-driven mitogenesis and tumor growth. We now show that HGF signaling requires specific HS binding interactions and that targeted disruption of these HS binding sites in HGF yields a potent and selective competitive inhibitor of normal and oncogenic HGF signaling. Our findings further define the role of HS in growth factor signaling and reveal a novel strategy for antagonist development which may be applicable to other HS-binding growth factors.
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 342.
Abstract 343: High-throughput screening of multiple protein kinase inhibitor using polymeric nanoparticles
Authors: Jun Eunsung , Kim Jong-Ho , So In-Seop , Kim In-San 
Published: February 2011

Abstract
Protein kinase play pivotal regulatory roles in most cell communication and metabolic pathways. Inhibitors of protein kinases not only hold great promise as therapeutic agents for many diseases, especially cancer, but are also of profound utility in the characterization of signaling pathways because of the centrality of protein phosphorylation as a regulatory process. Therefore, sensitive and widely applicable detection of protein kinase activity will provide a valuable tool to screen protein kinase inhibitors in drug discovery. We previously reported that self-assembled poly-ion complexes (PICs) containing kemptide, protein kinase A specific peptide motif, recognize the phosphorylation of kemptide by protein kinase A by recovery of fluorescence. In this research we found kinase specific substrate peptide with phage display which an efficient primary screening method to detect protein-protein interaction because of its relatively easy, rapid and massive recovery and analysis. Kinase substrate peptide library was made with phage and then library is displayed on capsid protein of phage. After kinase reaction, the phage clones are selected, recovered, and amplified for next round of bio-panning. The candidate clones are selected according for at least 4th round of bio-panning and the resultant peptides are analyzed for specificity. To prepare PICs, found peptide was conjugated with polyehtyleneimine (PEI) labeled with cyanine 5.5 (cy5.5). PICs consisting of peptide and cy5.5 chemically conjugated PEI and poly-L-aspartic acid showed significant fluorescent signal recovery in presence of protein kinase while they hardly showed fluorescent signal in absence of protein kinase. In addition, fluorescent signal did not recover with protein kinase inhibitor even though protein kinase was present. We tried to apply highthroughput screening to perform chemical library screening with 384-well plate. While wells without protein kinase showed strong fluorescent signal, wells containing protein kinase inhibitors represented no fluorescent signal, which is fully consistent with previous results and our expects. We conclude that this system is applied to highthroughput screening systems targeting protein kinase 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 343.
Abstract 3431: Role of tumor microenvironment in promoting tumor metastasis
Authors: Yadav Arti , Kumar Bhavna , Teknos Theodoros N. , Kumar Pawan 
Published: February 2011

Abstract
Metastatic spread of tumor cells to vital organs is the major cause of mortality in cancer patients. Tumor metastasis is a complex process involving multiple steps including detachment of tumor cells from the primary tumor, interaction with vascular endothelium and invasion of target organs. Although our understanding of the molecular and biological events that contribute to tumor cell progression has increased considerably over the last decade, we still know very little about the role of tumor-accessory cells in promoting tumor cell release from the primary tumor and metastasis to distal sites. It is well established that tumor angiogenesis plays a critical role in tumor progression. We have recently demonstrated that VEGF, in addition to its pro-angiogenic function, also induces the expression of Bcl-2 in the microvascular endothelial cells. Furthermore, tumor samples from head and neck cancer patients showed significantly higher Bcl-2 expression in tumor blood vessels and this enhanced Bcl-2 expression in tumor-associated endothelial cells was directly correlated with metastatic status of these patients. Upregulated Bcl-2 expression in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a SCID mouse model. While much is known about the role of Bcl-2 in cell survival, very little is known about the role of Bcl-2 in tumor metastasis. In this study, we examined the role and mechanism(s) by which Bcl-2 expression in tumor-associated endothelial cells may promote tumor metastasis. Our results suggest that endothelial cells expressing Bcl-2 (EC-Bcl-2) promote tumor metastasis via cell-cell interaction with tumor cells as well as by secreting chemokines including IL-6 and IL-8. EC-Bcl-2 secreted IL-6 induced EMT-related changes (downregulation of E-cadherin and upregulation of vimentin proteins) in the normal oral keratinocytes as well as head and neck tumor cells. IL-8 promoted tumor metastasis by enhancing tumor cell motility and invasiveness. In addition, EC-Bcl-2 cells exhibited significantly higher adhesion molecules expression and showed enhanced tumor cell binding. Tumor cells, when cultured alone in non-adherent conditions, showed marked increase in apoptosis (anoikis). In contrast, tumor cells showed a significant decrease in anoikis when co-cultured with EC-Bcl-2 in non-adherent conditions. Similarly, tumor cells when injected along with EC-Bcl-2 showed significantly higher lung metastasis as compared to tumor cell and EC-VC or tumor cell alone group. Taken together, these results suggest that endothelial cells expressing Bcl-2 promote tumor cell metastasis by enhancing tumor cell release and chaperoning them to distal sites.
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 3431.
Abstract 3433: A furin/MMP-14 signaling cascade processes BAI1 into a novel secreted anti-angiogenic and anti-tumorigenic factor, Vasculostatin-40 (Vstat40)
Authors: Cork Sarah , Sandberg Eric M. , Kaur Balveen , Mao Hui , Zhang Zhaobin , Olson Jeffrey , Van Meir Erwin G. 
Published: February 2011

Abstract
Mechanisms of vascular development and maintenance in the brain are not well-understood, but vascular integrity is compromised in many neurological diseases, particularly highly aggressive glioblastoma multiforme (GBM), which co-opts the existing vasculature and induces extensive angiogenesis. Brain angiogenesis inhibitor 1 (BAI1), a brain-enriched transmembrane receptor, has been proposed to be an endogenous regulator of brain angiostasis, but its mechanisms of action are largely unknown. In the present work, we investigate the proteolysis of extracellular BAI1 using genetic and molecular biology techniques to show that the large extracellular domain of BAI1 is proteolytically cleaved to generate an abundant product of 40 kDa we named Vasculostatin-40 (Vstat40). We demonstrate that cleavage of Vstat40 from BAI1 is dependent on a two-step process of proteolytic activation. In the final step of the cascade, Vstat40 is directly processed from extracellular BAI1 by membrane type-matrix metalloproteinase 1 (MMP-14). We show that the upstream activity of proprotein convertases, primarily furin, plays an important role in facilitating this processing event. We confirm the significance of Vstat40 as an important angio-regulatory factor by demonstrating that it inhibits angiogenesis in culture in a CD36-dependent manner. Finally, we present data on the effect of Vstat40 on intracranial glioma growth using an orthotopic xenograft model in order to illustrate its potential as a future therapeutic.
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 3433.
Abstract 3440: Activation of hedgehog pathway in tumor vasculature is a late event of pancreatic tumorigenesis
Authors: SASAJIMA JUNPEI , Mizukami Yusuke , Nakamura Kazumasa , Sugiyama Yoshiaki , Kawamoto Toru , Koizumi Kazuya , Sato Kazuya , Tanno Satoshi , Fujiya Mikihiro , Shimizu Norihiko , Hidenori Karasaki , Kono Toru , Ii Masaaki , Chung Daniel C. , Bardeesy Nabeel , Kohgo Yutaka 
Published: February 2011

Abstract
Bone marrow cells can be activated to function as instigators of tumor growth by systemic tumor-derived signals. We have identified subsets of BM cells that regulate neovascularization in pancreatic ductal adenocarcinoma (PDAC). Notably, blockade of Hedgehog (Hh) signaling markedly destabilized neovessels in PDAC xenografts by attenuating the homing and incorporation of the BM-derived cells into the neovasculature. We found IGF-1 production in the tumor stroma was regulated by the Hh ligand, Shh, and played a key role during this process. In vitro co-culture experiments demonstrated that human PDAC cell lines induced IGF-1 in c-Kit+ BM derived mononuclear cells utilized as pro-angiogenic cells, and that the induction was attenuated either by cyclopamine or expression of shRNA targeting Smo in the mononuclear cells. Shh secreted from PDAC cells induced tube formation by the mouse endothelial line MS-1, suggesting an important role for Shh in migration and capillary formation of the BM-derived pro-angiogenic cells; this induction of capillary morphogenesis was blocked by anti-IGF-1 neutralizing antibody. The “paracrine” effect of Hh seems to be a late event during pancreatic tumorigenesis, as full length Gli2 expression in neovasculatures was detected within PDAC lesions, but not in precursor PanIN lesions using a genetically engineered mouse models. We also observed upregulation of VE-cadherin, Id1, and Ptch1 mRNA in lineage-/c-Kit+ fraction of BM mononuclear cells from PDAC mice as compared to control mice or mice with PanIN, suggesting that pro-angiogenic conditions induced at the level of the BM in cancer-bearing hosts. The primitive progenitors derived from ‘activated BM’ are imported to the tumor microenvironment where they become fully activated. Overall, these studies provide insights into the cellular and molecular mechanisms by which BM-derived cells promote tumor growth and angiogenesis and have implications for the design of anti-angiogenesis therapies.
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 3440.
Abstract 3445: Helicobacter pylori increases the risk of colorectal polyps in African Americans
Authors: Zahaf Marwah , Nouraie Mehdi , Brim Hassan , Smoot Duane T. , Adeyinka Laiyemo , Lee Edward L. , Ashktorab Hassan 
Published: February 2011

Abstract
Background: H. Pylori infection have linked to colorectal polyps, mainly through hypergastrinemia and its trophic effect on colon mucosa. African Americans were under represented despite both common diseases are more prevalent in them.
Aim: The aim of this study was to investigate whether H. Pylori infection has a role in development of colorectal polyps in Africans Americans.
Methods: Retrospectively, Africans Americans (n=1262) greater than 40 years old who underwent bidirectional gastrointestinal endoscopy on the same day were enrolled. The pre-procedure indication and post-procedure diagnosis were recorded (n=1262). H. Pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of biopsies from complete colonoscopy. Multivariable logistic regression was used to assess the independent risk factors of polyp occurrence.
Results: Colorectal polyps (regardless polyp pathology) were more prevalent in H. Pylori-infected subjects (43%; 160/368) compared to (34%; 302/894) uninfected subjects (OR=1.5; 95 %CI=1.2-1.9). Furthermore, there was a trend toward larger polyp size ≥ 1cm in H. Pylori positive patients (P=0.07). There was no difference in histopathology or location of polyps in regard to H. Pylori status. Among the participants, 21 (2%) were defined with baseline above average risk for colorectal polyps justifying colonoscopy and of those; the polyps were detected in 62% (OR; 95%CI=2.9; 1.2-7.1). Age and male gender were independent risk factors for colorectal polyps.
Conclusion: H. Pylori increases the risk of developing colorectal polyps and may increase the chances for having a larger size polyp in Africans Americans. These findings suggest that H. Pylori might have a role in the initiation and/or promotion of polyps. Further studies are needed to explore its mechanisms.
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 3445.
Abstract 3449: Tungsten induces DNA damage and alters growth of developing B lymphocytes
Authors: Guilbert Cynthia , Petruccelli Luca A. , Mann Koren K. 
Published: February 2011

Abstract
Tungsten is used widely in modern life in everything from household goods to technologically advanced material. However, little is known about the consequences of tungsten exposure. The lack of information concerning the toxicities associated with tungsten has been highlighted recently when high tungsten levels were discovered at the sites of several pediatric leukemia clusters. In these clusters, the majority of the children developed acute lymphoblastoid leukemia of the preB lymphocyte subtype. Thus, we investigated whether tungsten exposure alters the growth of preB cells and defined signaling pathways induced by tungsten. We exposed a co-culture system of the BU-11 preB cell line grown on BMS2 stromal cells to tungsten at doses found at the sites of the leukemia clusters. Growth, cell cycle, and apoptosis were determined in both cell types. While no significant changes in any of these parameters were observed in the BMS2 stromal cells, tungsten treatment for 48 hours decreased the BU-11 cell number, which correlated with an accumulation of cells in G0/G1 and increased apoptosis. Unlike polycyclic aromatic hydrocarbons, tungsten induced apoptosis in BU-11 cells grown in rIL-7 and therefore, is independent of the stromal cell layer. These results were confirmed in primary murine bone marrow cultures and in human peripheral blood mononuclear cells. Tungsten can polymerize forming polytungstates in water and soil. Interestingly, these polytungstates are significantly more effective at inhibiting growth in BU-11 and BMS2 cells. In order to begin analysis of signaling pathways induced by tungsten, cDNA microarrays were performed in a leukemic cell line following 24 hours of tungsten treatment and integrated pathway analyses were performed. Genes involved in DNA damage and ER stress were highly upregulated following tungsten exposure and validated by qPCR. An increase in DNA damage was confirmed by COMET assay. These results suggest that the developing B lymphocyte population is sensitive to tungsten-induced toxicities and that tungsten exposure may contribute to leukemogenesis.
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 3449.
Abstract 3458: Benzo[a]pyrene (BP)-induced DNA damage is elevated in mice lacking Xeroderma pigmentosum complementation group A (Xpa) and heterozygous for the tumor suppressor gene p53
Authors: John Kaarthik , Pratt Margaret M. , Churchwell Mona I. , Beland Frederick A. , McMullen Gail , Poirier Miriam C. 
Published: February 2011

Abstract
In developing countries, esophageal cancer is the third most common cancer in men. We have employed a mouse model of esophageal cancer using DNA repair deficient mice. Unlike their wild type counterparts, C57BL/6J mice lacking Xpa and heterozygous for p53 [Xpa(−/−) p53(+/−)] have previously been shown to develop forestomach and esophageal tumors when fed BP (Hoogervorst et al., Carcinogenesis, 2003). Two methodologies were employed to examine BP-induced steady-state levels of DNA damage in esophagi of male mice fed 0 or 100 ppm BP for 4 weeks. HPLC, in conjunction with tandem mass spectrometry (HPLC-MS/MS), was used to measure 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPdG) and a chemiluminiscence immunoassay (CIA), using antiserum elicited against r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-modified DNA was used to evaluate BP-DNA adducts. In the esophagi of Xpa(−/−) p53(+/−) mice, there were 38.7 ± 4.8 BPdG adducts/108 nucleotides (mean ± SE, n=5), as measured by HPLC-MS/MS, while in the wild type mice there were 28.0 ± 1.8 BPdG adducts/108 nucleotides (mean ± SE, n=5). Furthermore, complete loss of p53 resulted in the greatest accumulation of BPdG adducts, with 58.1 ± 8.6 BPdG adducts/108 nucleotides (n=5) in Xpa(−/−) p53(−/−) mice (p&lt;0.05 vs. wild type mice). Esophageal BP-DNA adduct values, as measured by CIA, were 23.3 ± 1.7 adducts/108 nucleotides (n=3) in the Xpa(−/−) p53(+/−) mice, compared to 14.6 ± 3.0 adducts/108 nucleotides (n=3) in the wild type mice. Since similar adduct levels were determined using both HPLC-MS/MS and CIA, this indicates that BPdG is the major adduct resulting from BP in mouse esophagus. The higher levels of DNA damage in DNA repair-deficient p53-deficient mice, compared to their wild type counterparts, may contribute to the enhanced susceptibility of these mice to esophageal tumor induction by BP. Currently we are examining the role of chlorophyllin, a chemopreventive agent, in reducing BP-induced DNA damage levels and tumor formation in this model.
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 3458.
Abstract 3459: Loss of p16INK4a gene renders mice more susceptible to DMBA-induced mammary carcinogenesis
Authors: Naseemuddin Mohammed , Nasti Tahseen H. , Yusuf Nabiha 
Published: February 2011

Abstract
Breast cancer is the most common type of cancer diagnosed in women. The incidence of breast cancer varies with environmental influences, including carcinogen exposure. Polyaromatic hydrocarbons (PAH), have been implicated as etiologic agents in breast cancer. Exposure occurs primarily through the smoking of tobacco, inhalation of polluted air, and ingestion of charred foods. One such example of a carcinogenic polyaromatic hydrocarbon is 7,12-dimethylbenz(a)anthracene (DMBA) which in animal models, induces mammary adenocarcinoma. p16, a low molecular weight tumor suppressor protein, and a major CDK inhibitor, is the product of a tumor suppressor p16/INK4a gene. It is frequently inactivated in the human tumors. In the present study, we were interested to evaluate the role of p16INK4a in DMBA-induced mammary carcinogenesis. Tumor latency was higher in p16INK4a−/− compared to WT (C3H/HeN) counterparts. Tumors from p16INK4a−/− mice were very aggressive as revealed by PCNA and Ki67 staining and qRT-PCR analysis. The levels of angiogeneic markers CD31 and VEGF were also higher in the tumors of p16INK4a−/− mice as compared to WT mice. These results indicate that restoration of p16INK4a−/− function can be helpful in reducing mammary tumors caused by environmental pollutants like DMBA.
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 3459.