bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2448: Development of a red fluorescent labeled agent for assessing HER2 expression in vitro and in vivo
Authors: Narayanan Nara , Cuneo Garry , Morin Jeff , Vasquez Kristine , Rajopadhye Milind , Yared Wael , Peterson Jeffrey D. , Kossodo Sylvie C. 
Published: August 2012

Abstract
Upregulation of tumor HER2 occurs in approximately 25% women with breast cancer and is often associated with poor prognosis. We developed a red fluorescent imaging agent to non-invasively image and quantify tumor-associated HER2 expression in vivo. A red fluorescent dye (VivoTag 645; α=210,000 μ/cm; abs/em max 643/660 nm) was used to label trastuzumab, which is currently used to treat breast and stomach cancer. The red-labeled trastuzumab (VM4003) preferentially labeled HER2+ SKOV-3 human ovarian adenocarcinoma cells over HER2− human colorectal adenocarcinoma Colo-205 cells (10 fold), and the specificity of binding was confirmed by control experiments using free dye, labeled non-specific IgG, and competitive blockade with unlabeled excess trastuzumab. Fluorescence microscopy confirmed the expected membrane localization of fluorescence. In vivo and ex vivo imaging by fluorescence molecular tomography (FMT), showed significantly higher signal within the tumors, peaking at 6-72 hours following intravenous injection of 2 mg/kg VM4003, decreasing thereafter with a tissue half-life of 3 days. In vivo quantification of tumor signal in nude mice showed significantly higher tumor signal in HER2+ than in HER2− tumors (14.36 + 4 versus 2.39+ 0.74 pmol, at 6h imaging time, p=0.007; 18.77 + 4.45 versus 3.50+ 0.98 pmol, at 24h, p=0.001). Specificity of targeting was confirmed by competition with excess intravenous unlabeled trastuzumab, which achieved 70% signal inhibition in the tumors (tumor signal 16.12 + 3.03 versus 4.72 + 1.96 pmol, p=0.022 at 24h). Tumor volumes, as determined by direct measurements of tumor size, were comparable between both groups of mice (p=0.193). Fluorescence microscopy of ex vivo frozen tissue sections confirmed tumor fluorescence and signal localization associated to cell membranes and cytoplasm. In summary, red fluorescent-labeled trastuzumab selectively targets αER2, allowing both imaging in vitro and the non-invasive real-time tomographic imaging and quantification in vivo of HER-2 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2448. doi:1538-7445.AM2012-2448
Abstract 2457: Laminin receptor cross-talk stimulates receptor internalization and migration of human prostate cancer cells
Authors: Anderson Todd A. , Gard Jaime MC , Sroka Isis C. , Strautman Stephanie R. , Morrissey Colm , Knudsen Beatrice S. , Cress Anne E. 
Published: August 2012

Abstract
Integrin cell adhesion receptors are internalized and recycled to the plasma membrane during cellular migration. The laminin binding A3B1 and A6B1 integrin receptors are differentially expressed on prostate tumor cells in Gleason grades 3-5 as detected in biopsy and prostatectomy specimens. The A6 integrin exists as a full length form or as a pro-metastatic variant, A6pB1, a receptor form missing the extracellular laminin binding domain via the action of the serine protease, uPA. The objective of this study is to determine whether internalization of the A6 integrin occurs in human bone metastatic lesions and whether cross-talk between the laminin receptors A6B1, A6pB1 and A3B1 modifies their respective internalization rates. In a tissue microarray of 185 metastatic prostate cancers from 45 patients, approximately 70% of bone metastases expressed A6B1 on tumor plasma membrane and/or within the cytoplasm. The A6 and A6p integrins in DU145 cells are constitutively internalized with a biological half life of approximately 30 minutes as compared to 60 minutes for A3 or 20 minutes for the unrelated transferrin receptor. Increasing production of A6pB1 by supplying exogenous uPA stimulated A3 internalization. Conversely, blockage of A6pB1 production using an A6 specific antibody (J8H) decreased A3 internalization. Targeted depletion of the A3 integrin increased DU145 cell migration that was dependent upon A6 integrin as detected by antibody blocking experiments using J8H (A6 specific) and AIIB2 (B1 specific). Analysis of transcriptomic data from prostate cancer xenografts, revealed three different candidate receptor recycling genes that significantly correlated with the loss of membrane and increase in cytoplasmic expression. Taken together, these data indicate that cross-talk between A6B1 and A3B1 modifies their internalization rates and prostate tumor cell migration. This suggests that successful therapeutic targeting of metastasizing prostate cancer cells may depend upon coordinated targeting of both receptors and the recycling machinery. Current work is to determine the involvement of candidate recycling genes in the biological control of laminin binding integrins in human prostate cancer. (Supported in part by NIH grants P30CA023074, 1RO1 CA159406 and the TACMASS core service of the University of Arizona Cancer Center).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2457. doi:1538-7445.AM2012-2457
Abstract 2539: The PARP inhibitor AZD2281 induces autophagy and complete cell death in BRCA mutant breast cancer cell lines
Authors: Akar Ugur , Barrera Angelica Gutierrez , Hortobagyi Gabriel N , Arun Banu 
Published: August 2012

Abstract
BRCA1 and BRCA2 are well-known DNA repair proteins that are usually mutated or deleted in breast tumors. According to the literature, 5 (12%) of 41 breast cancer cell lines have BRCA mutations and 28 (68%) of the 41 cell lines have BRCA1 allelic loss. PARP inhibitors are known to inhibit tumor growth in BRCA mutant tumors. The purpose of this study was to investigate the effects of PARP inhibitors in BRCA mutant breast cancer cell lines. We found that AZD2281 as a single agent induced complete cell death in BRCA1 mutant (HCC-1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 induced an average growth inhibition of 33% in BRCA wild-type cell lines with BRCA1 allelic loss. Downregulation of BRCA1 or BRCA2 by shRNA sensitized the triple-negative breast cancer cell lines BT-20 and MDA-MB-231 to AZD2281 treatment. We also investigated whether autophagy is induced in response to PARP inhibition. AZD2281 treatment induced LC3-II expression, an indication of autophagy. Transmission electron micrographs demonstrated autophagosome formation after AZD2281 treatment. On transmission electron micrographs, we observed a decrease in mitochondria related to autophagosome formation after AZD2281 treatment. To show AZD2281 induced autophagy is targeting mitochondria, we labeled mitochondria with yellow fluorescein protein using lentiviral stable transfection. Flow cytometry measurement demonstrated a decrease in fluorescein-labeled mitochondria after AZD2281 treatment. Inhibition of autophagy in a AZD2281-treated BRCA mutant breast cancer cell line rescued mitochondrial degradation and partially inhibited apoptosis. In conclusion, we showed that autophagy plays an important role in AZD2281-induced cell death in BRCA mutant breast cancer cell lines by degradation of mitochondria besides DNA degradation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2539. doi:1538-7445.AM2012-2539
Abstract 2540: Identification of factors governing sensitivity of NSCLC cell lines to inhibition of Poly (ADP-Ribose) Polymerase (PARP)
Authors: Kommajosyula Naveen , Moreau Lisa , D'Andrea Alan D. , Shapiro Geoffrey I. 
Published: August 2012

Abstract
Recently, Poly (ADP Ribose) Polymerase-1 (PARP-1) has been shown to be an important target in subsets of breast and ovarian cancers. PARP inhibitors are emerging as important new anticancer agents, especially in cancers defective in homologous recombination (HR) repair, such as those lacking BRCA1 or BRCA2. To date, the potential role of PARP inhibition in NSCLC has not been extensively studied. BRCA1 or BRCA2 promoter hypermethylation and ATM mutation have been described in primary NSCLCs, alterations that may sensitize cells to PARP inhibition. We have examined a panel of 26 genotypically-defined NSCLC cell lines for sensitivity to the PARP-1 inhibitor AG014699 using colony formation assays. We have identified 5cell lines that are exquisitely sensitive (IC50 ≤ 50nM), 9 cell lines that are moderately sensitive (IC50 ≤ 60-500nM) and 12 cell lines that are resistant (IC50 &gt; 5 µM). To determine whether sensitive cell lines have defective HR compared to resistant cell lines, we examined the formation of Rad51 foci following exposure to PARP inhibition, as well as to gamma-irradiation and cisplatin. Both sensitive and resistant cell lines demonstrated efficient formation of Rad51 foci as well as gamma-H2AX foci in response to DNA damaging treatments, suggesting correct initiation of HR. In resistant cell lines, the repair process following PARP inhibition is completed within 24 hours, with resolution of Rad51 and gamma H2AX foci. No alterations in cell cycle distribution were detected in these cell lines, suggesting that the efficiency of repair allows proliferation to continue largely unabated. However, in sensitive cell lines, these foci persist greater than 30 hours following DNA damaging treatments. These results suggest that although sensitive lines are able to initiate HR repair, they are unable to complete the process, so that Rad51 foci are not resolved. The persistence of DNA damage in these cell lines is confirmed by persistent gamma H2AX focus formation as well as S/G2 arrest, the latter representing intact checkpoint control. We are currently investigating whether PARP inhibitor-sensitive cell lines have a deficiency in one of the helicases or resolvases required for resolution of the complex Holliday junctions formed during HR repair. Our results may define a novel subset of NSCLCs with a late-step defect in HR that can be approached with PARP inhibition as a novel treatment strategy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2540. doi:1538-7445.AM2012-2540
Abstract 2541: Effect of carcinogen acrolein on DNA repair and mutagenic susceptibility.
Authors: Wang Hsiang-Tsui 
Published: August 2012

Abstract
Lung cancer death is the number one cause of cancer death in the United States. Cigarette smoking is the major cause of lung cancer. Cigarette smoke (CS) contains more than 60 human carcinogens. Our early work has demonstrated that acrolein (Acr), one of the most abundant aldehydes in CS, reacts with DNA to form α- and α-hydroxy-1, N2-cyclic propano-dG adducts (α-Acr-dG and α-Acr-dG). The distribution of Acr-dG in the p53 gene coincides with lung cancer p53 mutational spectrum. Acr-dG adducts induce mainly G to T and G to A mutations that are similar to the mutation signature found in the p53 gene in lung cancer. We have also found that Acr inhibits DNA repair. Therefore, we concluded that Acr is a major etiological agent for CS related lung cancer. In this study, we found that Acr-dG adducts are poorly repaired in Acr treated normal human bronchial epithelial (NHBE) cells. Intriguingly, NHBE cell lysates are competent in carrying out in vitro repair synthesis assay using Acr-modified as well as UV-irradiated DNA as substrates. These results indicate that Acr treatment impairs DNA repair function. We found that Acr not only inhibits nucleotide excision repair (NER), it also inhibits base excision repair (BER) and mismatch repair (MMR). Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes. However, Acr causes a reduction of XPA, XPC, hOGG1, PMS2 and MLH1 proteins and that this effect can be neutralized by the proteosome inhibitor, MG132. We further found that Acr treatment enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA, but can also modify DNA repair proteins and further cause degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2541. doi:1538-7445.AM2012-2541
Abstract 2544: Associations between RET/PTC rearrangements, BRAF and RAS mutations and radiation dose, age at exposure, and latency in post-Chernobyl thyroid cancer
Authors: Leeman-Neill Rebecca J. , Brenner Alina V. , Little Mark P. , Bouville Andre C. , Bogdanova Tetyana I. , Hatch Maureen , Mabuchi Kiyohiko , Tronko Mykola D. , Nikiforov Yuri E. 
Published: August 2012

Abstract
Introduction: Childhood exposure to I-131 from the Chernobyl accident was associated with a dramatic increase in incidence of papillary thyroid cancer (PTC). PTCs are characterized by several genetic alterations including RET/PTC rearrangements and point mutations of BRAF and RAS. Association between mutations and radiation doses has not been studied in post-Chernobyl tumors. Design: We analyzed 70 PTCs diagnosed in a Ukrainian-American cohort who were &lt; 18 y.o. at the time of Chernobyl and received 0.008-8.6 Gy of I-131 to the thyroid. Thyroid doses were estimated based on radioactivity measurements taken shortly after the accident, environmental transport models, and interview data. BRAF and RAS mutations were identified by melting curve analysis and RET/PTC1 and RET/PTC3 by real-time RT-PCR. All mutations were confirmed by sequencing. Results: Identified mutations and patient characteristics are shown in Table 1. Logistic regression analysis demonstrated a significant decrease in I-131 dose for both BRAF and RAS mutations (p=0.005 and 0.026). There were highly statistically significant (p&lt;0.001) differences between the trends with dose for BRAF and RAS vs RET/PTC. Comparing with BRAF and RAS mutations, the age at exposure was lower in cases with RET/PTC (p=0.001). RET/PTC3 was associated with a shorter latency period as compared to other mutations (p&lt;0.02). Table 1. Genetic alterations and corresponding patient characteristics Conclusions: Our results demonstrate for the first time that prevalence of BRAF or RAS point mutations in post-Chernobyl tumors significantly decreases with increasing radiation dose, in contrast to the lack of decrease for RET/PTC. RET/PTC rearrangements are associated with younger age at exposure than point mutations of BRAF and RAS. These data provide support for the potential relationship between chromosomal rearrangements, but not point mutations, and radiation exposure.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2544. doi:1538-7445.AM2012-2544
Abstract 2545: FLT3-driven redox signalling in acute myeloid leukemia
Authors: Corcoran Aoife , Cotter Thomas G. 
Published: August 2012

Abstract
The concept of reactive oxygen species (ROS) being produced via the activation of specific oncogenes provides a basis for generating genomic instability and pro-survival signalling in tumor cells. The purpose of this study was to identify downstream targets of NADPH oxidase (Nox)-derived ROS signalling in acute myeloid leukemia cells, by performing a proteomic analysis utilizing two-dimensional phosphotyrosine immnoblotting. The majority of the targets identified were cytoskeletal-associated proteins including Ezrin, a known regulator of the cytoskeleton, which was examined further. The study demonstrated that inhibition of Nox enzymes, using diphenyleneiodonium chloride in the acute myeloid leukemia cell line MOLM-13, resulted in a decrease in Ezrin tyrosine phosphorylation and also triggered a shift in Ezrin sub-cellular localization as detected by immunofluorescence. The change in Ezrin localization coincided with altered cell morphology, observed using scanning electron microscopy and a decreased ability to migrate through a polycarbonate transwell membrane. Similar effects were observed upon inhibition of the oncogenic receptor tyrosine kinase FLT3 using the staurosporine derivate PKC412, implicating a role for FLT3 as an upstream regulator of Ezrin. Our results indicate that FLT3 drives production of ROS by Nox, which stimulates changes in Ezrin tyrosine phosphorylation and localization via redox regulation of Src. Furthermore, the modulation of Ezrin by FLT3 leads to subsequent alterations of MOLM-13 cell morphology and a significant influence on cell motility.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2545. doi:1538-7445.AM2012-2545
Abstract 2552: Detection of PIGO-deficient cells using proaerolysin: a valuable tool to investigate mechanisms of mutagenesis in the DT40 cell system
Authors: Nakamura Jun , Tian Xu , Bultman Scott , Swenberg James A. 
Published: August 2012

Abstract
A DNA damage response analysis makes use of the chicken DT40 isogenic cell line and its dozens of available mutants knocked out in various DNA repair and cell cycle pathways. While this DT40 cell system is valuable for understanding the DNA damage response to genotoxic agents, no convenient mutation assay for mutagens currently exists for this reverse-genetic system. Here we establish a proaerolysin (PA) selection-based mutation assay in DT40 cells to identify glycosylphosphatidylinositol (GPI)-anchor deficient cells. Using PA, we detected an increase in the number of PA-resistant DT40 cells exposed to MMS for 24 hours followed by a 5-day period of phenotype expression. GPI anchor synthesis is catalyzed by a series of phosphatidylinositol glycan complementation groups (PIGs). The PIG-O gene is on the sex chromosome (Chromosome Z) in chicken cells and is critical for GPI anchor synthesis at the intermediate step. We identified that all PA-resistant DT40 cells analyzed have mutations in the PIG-O gene. This novel assay for DT40 cells provides a valuable tool to investigate the mode of action of mutations caused by reactive agents using a series of isogenic mutant DT40 cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2552. doi:1538-7445.AM2012-2552
Abstract 2554: HSP90 inhibition induced cytotoxicity via downregulation of Rad51 expression and DNA repair capacity in non-small cell lung cancer cells
Authors: Lin Yun-Wei , Weng Shao-Hsing , Ko Jen-Chung , Chen Huang-Jen , Tseng Sheng-Chieh , Huang Yu-Ching , Tsai Min-Shao , Chiou Robin Y.-Y. 
Published: August 2012

Abstract
Heat shock protein 90 (HSP90) is an exciting target in cancer therapy. Our previous studies indicated that repair protein Rad51 involved in protecting non-small lung cancer (NSCLC) cell lines against chemotherapeutic agents induced cytotoxicity. In this study, the role of Rad51 expression in HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) induced cytotoxicity in two NSCLC cell lines, A549 and H1975, were investigated. 17-AAG treatment decreased cellular Rad51 protein and mRNA levels and phosphorylated MKK1/2-ERK1/2 protein levels. 17-AAG treatment disrupted the HSP90 and Rad51 interaction and triggered Rad51 protein degradation through 26S proteasome pathway. Moreover, 17-AAG treatment decreased DNA repair capacity in NSCLC cells, which could restore by enforced expression of Flag-Rad51 vector. Specific inhibition of Rad51 expression by siRNA could further enhance the 17-AAG-induced cytotoxicity. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) vector significantly restored the 17-AAG-reduced Rad51 protein levels as well as cell viability. Moreover, arachidin-1, antioxidant stilbenoids, has demonstrated beneficial effects on human health. It could further decrease Rad51 expression and augment the cytotoxic effect and growth inhibition by 17-AAG. Moreover, 17-AAG and arachidin-1-induced synergistic cytotoxic effect and DNA repair capacity decrease could be abrogated in lung cancer cells with MKK1/2-CA or Flag-Rad51 expression vector transfection. Our results suggested that HSP90 inhibition induced cytotoxicity via downregulation of Rad51 expression and DNA repair capacity in NSCLC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2554. doi:1538-7445.AM2012-2554
Abstract 2557: Exploring the contribution of ubiquitin binding domain of Bcr-Abl in chronic myelogenous leukemia
Authors: Chen Ru , Mahon Gwen , Tala Ilona , Chen Qing , Hu Tinghui , Li Dan , Ozer Harvey , Whitehead Ian 
Published: August 2012

Abstract
Chronic myelogenous leukemia (CML) is invariably associated with the expression of the p210 Bcr-Abl fusion protein. Although the Abl-encoded tyrosine kinase activity is important for leukemogenesis, the emerging problems of acquired resistance and minimal residual disease highlight the need for new complementary targets for pharmacological intervention. In our previous studies, we had identified a non-classical ubiquitin binding domain (UBD) within the NH2-terminal of p210 Bcr-Abl. Deletion of the UBD (p210 Bcr-Abl(≥UBD)) impairs the interaction between p210 Bcr-Abl and p-β-catenin (ser33). Over-expression of p210 Bcr-Abl, but not p210 Bcr-Abl(≥UBD), leads to an accumulation of phosphorylated β-catenin, and at least two of its known transcriptional targets, cyclin D1 and c-Myc. The interaction between p210 Bcr-Abl and β-catenin is ubiquitination dependent. β-catenin is a central component of the Wnt pathway which plays a critical role in the regulation of hematopoiesis. In a murine bone marrow transplantation model for CML, mice transplanted with hematopoietic cells that express p210 Bcr-Abl(≥UBD) have significantly increased life spans compared to mice transplanted with p210 Bcr-Abl expressing cells. Delayed disease progression is associated with decreased levels of β-catenin, and reduced numbers of granulocyte macrophage progenitors (GMPs), in the bone marrow. Deletion of UBD also impairs the transplantability of CML cells. Based on these observations we propose a model in which p210 Bcr-Abl may influence the Wnt signaling pathway, and leukemic expansion, by binding ubiquitinated β-catenin, and stabilizing it against degradation. Stabilized β-catenin leads to increased self-renewal of CML stem cells and progenitors. Importantly, this activity is contained within Bcr sequences, and is independent of tyrosine kinase activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2557. doi:1538-7445.AM2012-2557