bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-267: GRB7: A novel target in basal breast cancer
Authors: Giricz Orsi , Pero Stephanie C. , Krag David N. , Sparano Joseph A. , Kenny Paraic A. 
Published: February 2011

Abstract
Basal breast cancers lack expression of estrogen and progesterone receptors and HER2, rendering them non-responsive to the most commonly used targeted therapies in breast cancer. These tumors are typically more aggressive, more locally invasive and more likely to metastasize to the brain than other breast cancer subtypes and, consequently, have a poor prognosis. GRB7 is a cytoplasmic adaptor protein that interacts with receptor tyrosine kinases, relaying information to their downstream signaling cascades. It also plays a role in integrin signaling and cell migration by binding focal adhesion kinase (FAK) and ephrin receptors. It is a part of the HER2 amplicon and is frequently overexpressed in HER2-amplified breast tumors. Breast tumors in which HER2 and GRB7 are both co-amplified and co-overexpressed have a poor prognosis.
We and others have recently determined that high levels of GRB7 are associated with recurrence in women with triple-negative breast cancer treated with anthracyclines (Sparano et al. J Clin Oncol 27(15s) 500). In this study, we have tested the hypothesis that triple-negative breast cancer cell lines are dependent on GRB7 for proliferation, migration and invasion. We have utilized a highly specific cell-penetrating peptide inhibitor of GRB7 (G7-18NATE) and tested its effects on a panel of 5 basal breast cancer cell lines in a series of culture assays: monolayer wound healing assays (motility on 2D substrates), transwell invasion assays (in vitro invasiveness) and 3D Matrigel cultures (morphogenesis in 3D environment). In all cases evaluated, the Grb7 inhibitory peptide impaired the proliferation, migration and invasion of these cell lines, even though these cells express low levels of GRB7 compared to HER2-amplified cell lines.
These data implicate GRB7 as a key mediator of several important phenotypes of basal breast cancer cells and suggest that GRB7 itself, or GRB7-dependent pathways, may prove to be important targets for the development of specific therapies for this disease.
This work was supported in part by Susan G. Komen for the Cure (KG091136).
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 LB-267.
Abstract LB-268: RTVP-1 regulates glioma cell migration and podosome formation via interaction with N-WASP
Authors: Lee Jae Kyung , Av Amotz Ziv , Xiang Cunli , Cazacu Simona , Finniss Susan , Giladi Nis , Barda-Saad Mira , Brodie Chaya 
Published: February 2011

Abstract
Gliomas, the most frequent primary brain tumor are characterized by increased proliferation and invasion into the surrounding normal brain tissue. In a recent study we reported that RTVP-1 is highly expressed in gliomas and that its expression is correlated with the degree of malignancy of astrocytic tumors. In addition, RTVP-1 is involved in the regulation of the growth, survival, and migration of glioma cells. To further delineate the molecular mechanisms underlying the effect of RTVP-1 in glioma cells we performed a pull down assay using His-tagged RTVP-1 followed by mass spectroscopy, and found that RTVP-1 was associated with the actin polymerization regulator, N-WASP. The association of RTVP-1 and N-WASP was further validated by co-immunoprecipitation and FRET analysis. Since N-WASP regulates cell spreading and migration we examined the role of RTVP-1 in these processes. We found that overexpression of RTVP-1 increased, whereas silencing of this protein decreased cell spreading and migration of glioma cells. The effect of RTVP-1 was mediated by N-WASP since silencing of N-WASP abolished RTVP-1 effects. In addition, RTVP-1 increased podosome formation in glioma cells and this effect was also mediated via its interaction with N-WASP. Moreover, the association of RTVP-1 and N-WASP was increased during cell spreading and appeared to be localized to contact areas of the spreading cells with the extracellular matrix. Another protein which was found by the pull down assay to interact with RTVP-1 is hnRNPK. This protein has been recently reported to associate with and to inhibit the effect of N-WASP on cell spreading. Using co-immunoprecipitation and FRET analysis we validated the interactions of hnRNPK with N-WASP and RTVP-1 in glioma cells. In addition, using co-immunoprecipitation studies, we found that overexpression of RTVP-1 decreased the association of N-WASP and hnRNPK, therefore suggesting that RTVP-1 may activate N-WASP by decreasing its association with hnRNPK. In summary, we report that RTVP-1 regulates glioma cell spreading, migration and invasion and that these effects are mediated via interaction with N-WASP and by interfering with the inhibitory effect of hnRNPK on the function of N-WASP.
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 LB-268.
Abstract LB-276: A novel approach using the telomerase-selective adenoviral marker (OBP-401) for detection of circulation tumor cells in breast cancer patients
Authors: Kim Seung Jin , Sato Jun , Taguchi Tetsuya , Tamaki Yasuhiro , Tsukamoto Fumine , Akazawa Kenji , Masago Akinori , Tsujino Yukio , Urata Yasuo , Noguchi Shinzaburo 
Published: February 2011

Abstract
Background: The detection of circulating tumor cells (CTCs) is a potential method to predict survival of metastatic breast cancer patients as well as outcomes of early breast cancer patients. However, no method for CTCs has yet proven to be the golden standard. We developed a new approach for detecting CTCs using the telomerase-selective adenoviral marker (OBP-401, Oncolys Biopharma). This marker contains the replication cassette, in which the human telomerase reverse transcriptase promoter drives expression of E1 genes, and the green fluorescent protein (GFP) gene for monitoring viral replication. Thus, OBP-401 infects viable cancer cells and replicates in them under the telomerase activity, and we can detect viable CTCs as GFP-positive cells.
Methods: This system is consisted of the following steps; (1) virus-infection for 7.5 ml whole blood (incubated with 4 × 10sup8 Plaque Forming Unit OBP-401 virus for 24 hours at 37 Celsius), (2) dead cell staining using L23102 (invitrogen), (3) virus-inactivation and RBC elimination, and (4) detection of GFP expressing cells using fluorescence microscopy. In a preclinical study, the sensitivity of this system was assessed using cell lines. Next, we conducted feasibility studies for CTCs detection in 80 healthy individuals, 70 metastatic, and 27 early breast cancer patients. In metastatic and early breast cancer patients, we compared the sensitivity of this system with that of CellSearch® (Veridex). GFP-positive cells (viable CTCs) and L23102 expressing cells measuring ≥ 20 m in diameter (dead CTCs) were considered as CTCs in this system.
Preliminary data: The sensitivity of this system, which was determined by a serial dilution of MDA-MB-468 cells against healthy volunteer's blood, was 1 cell per 7.5 ml. Neither viable nor dead CTCs were detected in any of healthy controls. Of 50 metastatic patients, 12% were primary breast cancers with stage IV disease, 24% were in the 1st line chemotherapy setting, and 42 % were heavily pretreated with chemotherapy. The sensitivities of tumor markers (CEA and CA15-3), CellSearch, and OBP-401 were 78%, 54%, and 66%, respectively.
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 LB-276.
Abstract LB-295: Identification of the first class of proteasome inhibitors that impair 26S proteasome assembly in vitro.
Authors: Etievant Chantal , Riquet William , Roullet Nicolas , Knibiehler Martine , Vandenberghe Isabelle , Carletti Isabelle , Gairin Jean Edouard 
Published: February 2011

Abstract
The Ubiquitin-Proteasome System (UPS) is the main non-lysosomial proteolytic machinery in the eukaryotic cells. Prior to their degradation proteins are adressed to the catalytic 26S proteasome complex composed of a 20S “core” that contains proteolytic activities, assembled with one or two 19S regulatory particles that bind proteins to be degraded. Due to its central role of in regulating cell cycle progression and signal transduction the UPS has been proposed as a suitable target for antineoplastic strategies. To date only catalytic inhibitors of proteasome, targeting proteolytic activities of the 20S core particle, have been characterized and/or have emerged as potent anticancer drugs (1).
However, the capacity of the UPS to degrade proteins not only depends of the catalytic activities of the 20S core, but also of the 26S proteasome assembly, a dynamic and tightly controlled cellular process. Thus, compounds impairing 26S proteasome assembly could represent a novel class of proteasome inhibitors.
With the aim of identifying such molecules we first set up a robust biochemical screening assay allowing us to follow 26S proteasome assembly in vitro. First, 26S proteasome was purified from Hela cells using affinity chromatography followed by gel filtration. Then, experimental conditions were determined for in vitro 26S disassembly into its constitutive sub-complexes (19S+20S) ands its re-assembly as an active and functional 26S entity. The differential CTL-activity between 26S and 20S proteasomes (2) was then used as the readout to follow the reassembly of 26S in vitro, prior to be confirmed using in gel overlay experiments and western-blotting. Using this biochemical assay:
1) we screened naturals compounds endowed with antiproliferative properties and described as inhibitors of the ubiquitine-proteasome pathway (3).
2) we identified structurally-related natural molecules, epidithiodioxopiperazine and diketodithiopiperazine derivatives, as the first class of molecules inhibiting proteasome assembly without significantly affecting neither 26S nor 20S catalytic activity in vitro.
Our research efforts now concentrate in showing that: 1) these molecules inhibit proteasome assembly in cells, and that 2) this inhibition can be correlated with their antiproliferative effects.
References
Sterz J. et al. Extert Opin. Invest. Drugs, 2008, 17
Rivett AJ et al., Experimental Gerontology, 2002, 37
Vandenberghe I. et al., Biochem. Pharmacol., 2008, 76
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 LB-295.
Abstract LB-305: Why two are better than one: Suppression of carcinoma cell growth in vitro and in human HGF/SF transgenic SCID by inhibitors of MET (SGX523) and EGFR (erlotinib)
Authors: Zhang Yu-Wen , Staal Ben , Essenburg Curt , Su Yanli , Kang Liang , West Rich , Kaufman Dafna , DeKoning Tom , Eagleson Bryn , Buchanan Sean , Vande Woude George 
Published: February 2011

Abstract
The signaling cascade originating from hepatocyte growth factor/scatter factor (HGF/SF)-MET ligand-receptor pair is frequently observed in a broad spectrum of human cancers. Inappropriate activation of this pathway has been shown to occur via: paracrine/autocrine activation; by amplification or mutation in the MET gene; or through ligand independent mechanisms (www.vai.org/met). Various MET drugs targeting this pathway are under development and in need of relevant in vivo tumor models to allow assessment of drug efficacy alone or in combination against human MET expressing tumors. Conventional mouse models post a significant limitation on fulfilling such demand as mouse HGF/SF has low affinity/activity on the human MET. Such limitations are abrogated in human HGF/SF transgenic SCIDs (designated hHGFtg-SCID), which, unlike its non-transgenic littermates, produce human HGF/SF to allow human MET signaling on cells of human cancer xenografts. Here, we show that the hHGFtg-SCID mouse significantly enhances tumor xenograft growth of many MET-expressing human carcinoma cell lines including lung, breast, kidney, colon, gastric and pancreatic cancers. Using the hHGFtg-SCID mouse model systems, we demonstrated that SGX523, a MET small molecule kinase inhibitor which suppressed MET phosphorylation and downstream signaling activation in vitro, partially inhibits the growth of xenografts derived from NCI-H596 lung cancer cells, HCC1954 breast cancer cells and HPAF II pancreatic cancer cells. Furthermore, we found that the partial tumor growth inhibition by SGX523 was significantly enhanced by co-administration of erlotinib, the EGFR small molecule kinase inhibitor. In vitro, erlotinib also enhanced SGX523 inhibitory activity in cell proliferation and G1/S cell cycle progression assays. Our data suggest that the hHGFtg-SCID mouse is a valuable system for evaluating MET drugs, and simultaneously targeting MET and EGFR pathways may provide a better treatment for cancers harboring inappropriate activation of both pathways.
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 LB-305.
Abstract LB-31: Drug combination studies: theory and analysis
Authors: Hixon Mark S. 
Published: February 2011

Abstract
A novel method for the graphical analysis of drug combination studies is presented. This method, Delta Plot Analysis, addresses the shortcomings of Isobolograms and Combination Index determinations. By use of this method, one may choose either a Bliss Independence or Loewe Additivity model and conduct the analysis. The method is comparative in nature, plotted as a function of cell survival (tracking other observables is also possible), and most importantly contains confidence intervals for determining significance above/below an additive effect line. In short, assay data with much scatter require greater differentiation from additivity to be interpreted as anything other than additive while data with less scatter allow one to conclude synergy or antagonism with less deviation from theoretical additive. Notably, the method handles partial response curves and makes use of single agent dose response curves to incorporate experimental uncertainty. A great advantage of the method is that synergistic and antagonistic interactions produce signature patterns in addition to providing data points falling outside of the additive effect confidence interval - something of great utility to the analyst. Also intriguingly, when accounting for experimental uncertainty (through simulations or with empirical data), a synergistic interaction is revealed to be synergistic regardless of the choice of Bliss or Loewe models. Delta Plot Analysis has been validated with published data and confirmed with in-house drug combination studies. The method is robust, requires no specialized software and easily depicts a multidrug combination study. This presentation also includes a look at the theory behind multiple drug interactions from a first principles perspective and provides a useful way of connecting drug action with drug effect.
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 LB-31.
Abstract LB-313: Soluble UL16 binding protein 2 is elevated in the sera of lung cancer patients
Authors: Yamaguchi Kosuke , Chikumi Hiroki , Kinoshita Naoki , Shimizu Asuka , Hashimoto Kiyoshi , Kurai Jun , Yamasaki Akira , Nakamoto Masaki , Matsumoto Shingo , Takata Miyako , Igishi Tadashi , Burioka Naoto , Shimizu Eiji 
Published: February 2011

Abstract
NKG2D ligands are the surface molecules which induce expression on transformed cells. Specifically they bind to NKG2D on NK cells, and this binding induces activation of NK cells. In humans, NKG2D ligands are described as MICA, MICB and ULBP1, 2, 3, and 4. In this study, we explored the clinical and immunological significance of NKG2D ligands on lung cancer. We evaluated the expression of each NKG2D ligand on the cell surface of various lung cancer cell lines by flow cytometory. The soluble form of ULBP2 was measured in culture supernatant and in sera of lung cancer patients by an original developed ELISA system. Immunological effects of cell surface ULBP2 and soluble form of ULBP2 were examined by 3.5-h 51Cr release assay.
We found that ULBP2 was the most widely and strongly expressed NKG2D ligand in lung cancer cell lines. Soluble form of ULBP2 was increased in culture supernatant of the lung cancer cell lines with high expression of cell surface ULBP2. In addition, soluble form of ULBP2 was detectable in the sera of lung cancer patients and increased amount of soluble ULBP2 in sera significantly correlated with poor prognosis lung cancer patients. We evaluated the the immunological effect of soluble ULBP2 separately using human peripheral blood mononuclear cells (PBMCs), and found that soluble ULBP2 suppressed NK activity.
In conclusion, ULBP2 is the most significant NKG2D ligand in lung cancer and its soluble form was detectable and elevated in sera of lung cancer patients. Because soluble form of ULBP2 is one of the determinant factor of the anti-tumor immunity of the cancer patients, the development of intervention in this effect would be a candidate for the promising immuno-modulatory therapy
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 LB-313.
Abstract LB-320: Inhibition of TGFß1 improves the therapeutic efficacy of non-immunologic tumor cell based vaccine
Authors: Liu Pu , Jaffar Jade , Swisher Elizabeth , Hellstrom Karl Erik , Hellström Ingegerd 
Published: February 2011

Abstract
Background and objectives of the study: Many cancers, including ovarian cancer, over-express transforming growth factor-beta (TGF-ß), which helps them evade immune control through a variety of mechanisms. We investigated whether the efficacy of tumor cells to induce an immune response, when used intact or as part of a dendritic cell (DC)-based vaccine can be enhanced by inhibiting their production of TGFß1 via anti-sense.
Methodology: The TGFß1 expression by two ovarian cancer cell lines was silenced by transfection with a non-replicating lentivirus shRNA. Autologous PBMC were co-cultivated, in the presense of IL-2, with Mitomycin-C (MMC) treated cancer cells or mature dendritic DC that had been pulsed with tumor lysates. The in vitro sensitized lymphoid cells were evaluated by ELISPOT for production of IFN-γ and by flow cytometry.
Preliminary data: Quanitative ELISA showed that TGFß1 production in the two ovarian cancer lines was signficantly inhibited by transfection with shRNA. In vitro sensitization of autologous PBMC with either tumor cells where the TGFß1 gene had been silenced or with DC that had been pulsed with homogenates of tumor cells with a silencd TGFß1 gene induced a stronger IFNγ release and increased the frequency of NK cells and DC while it decreased the population of Treg cells. We are presently investigating the anti-tumor response in a mouse melanoma model after vaccination with murine bone-marrow derived DC which have benn pulsed with TGFß silenced tumor lysates.
Conclusions: The production, by many tumors, of TGFß1 interferes with their ability to induce an anti-tumor response. This is true both when intact tumor cells and DC pulsed with tumor homogenate are used as immunogen.
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 LB-320.
Abstract LB-344: Senescence-related genes signature in high grade gliomas
Authors: Coppola Domenico , Balducci Lodovico , Chen Dung-Tsa , Brem Steven , Egan Kathy , Dalton William , Yeatman Timothy 
Published: February 2011

Abstract
Background: The prognosis of high grade gliomas (HGG) worsens with the age of the patients. We hypothesized that overexpression of senescence-related genes indicates a poorer prognosis.
Materials and Methods: Frozen tumor samples from 60 patients of different ages (32 to 88 years) with the histologic diagnosis of HGG were macrodissected and arrayed on a custom version of the Affymetrix HG-U133 + GeneChip. There were 29 events (deaths) with a median survival time of 20 months. A set of 14 known senescence-associated genes (SAGs) including CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM1, IGFBP3, IL6, IL8, SAA4, TNFRSF11B, TNFSF11 and TP53 were the focus of the study (Campisi J. et al. PLoS Biology, 2008). An overall senescence score was generated using principal component analysis to reflect the combined effect of the senescence-associated gene signature. Pearson correlation and Cox proportional hazards regression were used to examine the association of each SAG and the senescence score with age at onset and overall patient survival. False discovery rate was used to adjust for multiple comparisons.
Results: We found an age-related gradient in the senescence score representation of the combined SAGs (r = 0.40; p=0.0014). Ten SAGs were significantly correlated with age (false discovery rate at 5%): IGFBP3 (r=0.44), ICAM1 (r=0.40), IL6 (r=0.38), CDKN1A (r=0.35), TNFSF11 (r=0.34), TP53 (r=0.34), CXCL1 (r=0.31), CCL7 (r=0.30), COPG (r=0.29), and CSF2RB (r=0.29). The SAG signature was also correlated with poor prognosis (p=0.0098; median survival: 13 and 28 months, respectively, for high versus low senescence score). Two SAGs were significantly associated with patient survival: IL6 (14 versus 38 months) and COPG (13 versus 38 months).
Conclusion: We report for the first time an SAG signature in HGG associated with age at onset and patient outcome. This signature composed of genes involved in cell cycle regulation, apoptosis, cell proliferation, and angiogenesis may define a more aggressive subtype of high-grade glioma.
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 LB-344.