bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5301: Development of CAIX and CAXII targeting imaging probes for non-invasive detection of metastatic breast cancer in axillary lymph nodes
Authors: Tafreshi Narges K. , Bui Marilyn M. , Bishop Kellsey , Lloyd Mark C. , Enkemann Steven A. , Vagner Josef , Grobmyer Stephen R. , Gillies Robert J. , Morse David L. 
Published: June 2012

Abstract
Axillary lymph node (ALN) status is the most important prognostic factor for staging breast cancer. ALNs are routinely excised for evaluation which is an invasive procedure associated with serious morbidities. The current study aims to develop a targeting platform for the non-invasive detection of metastatic breast cancer in lymph nodes. If successful, such an approach would decrease unnecessary surgery and significantly reduce associated morbidity.
Two cell surface carbonic anhydrase isozymes (CAIX and/or CAXII) were identified by comparison of the gene expression profiles of lesions from breast cancer patients and benign breast tissue and confirmed with public databases and literature. Protein expression was validated by immunohistochemistry of patient tissue samples in tissue microarray. Together, these two markers detect 100% of the metastatic breast cancer to lymph nodes surveyed (n = 37). Targeted probes were developed by conjugation of CAIX and CAXII specific monoclonal antibodies (mAbs) to a near-infrared fluorescent dye (VivoTag 680, VisEn). The selectivity of the probes were determined by comparing their binding to expressing and non-expressing breast cancer cells in vitro and by intravenous injection of the probes into nude mice bearing mammary fat pad (MFP) xenograft tumors of marker expressing cells, and non-expressing cells or by pre-injection of unlabeled antibody. To determine whether the probes can be delivered through the lymphatics and detect ALN metastases, luciferase expressing MDA-mb-231 cells that endogenously express CAIX, and luciferase expressing MDA-mb-231 engineered cells to express CAXII were used to form spontaneous ALN metastases from primary mammary fat pad tumors. Once ALN metastasis was observed by bioluminescence imaging, the probes were injected pri-tumorally into the MFP and observed to traverse through the MFP into the lymph node. A specific and durable fluorescence signal was observed in target positive metastases out to at least 48 h post-injection, long after completely clearing from the MFP. Sensitivity was determined by implanting varying numbers of CAIX and CAXII expressing cells into the ALN using ultrasound guidance. As few as 1000 cells were successfully detected indicating the high sensitivity of this method.
Hence, these imaging probes have potential use for clinical staging of breast cancer. In the future, this approach may be used to deliver nanoparticles for combined imaging and therapeutic applications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5301. doi:10.1158/1538-7445.AM2011-5301
Abstract 5310: Positron emission tomography imaging of endometrial cancer using an anti-EMP2 minibody
Authors: Fu Maoyong , Brewer Sarah , Braun Jonathan , Wadehra Madhuri 
Published: June 2012

Abstract
Endometrial cancer is increasingly affecting pre-menopausal women, prompting a need to develop fertility-sparing therapy, and monitor response to treatment by quantitative non-invasive strategies. Epithelial membrane protein 2 (EMP2) is a tetraspan protein associated with surface localization and function of cancer-relevant integrin isoforms, and EMP2 expression in endometrial cancer correlates with increasing cancer stage and poor prognosis. As EMP2 is highly expressed in endometrial cancer, this pre-clinical study tested the feasibility of non-invasive detection of human endometrial tumor xenografts using a radiolabeled anti-EMP2 diabody and positron emission tomography (PET). EMP2 biodistribution in murine organ was determined by western blot and immunohistochemistry. Anti-EMP2 minibody (MB83) fragment was designed and transfected into CHO-K1 cells. Purified minibody was DOTA conjugated and the binding activity was tested by flow cytometry using endometrial cancer cell line, Hec-1A/EMP2 cells. Then conjugated minibody was chelated with Cu-64. In vivo biodistribution of Cu-64 labeled MB83 in Balb/c nu/nu mice were determined by microPET imaging and AMIDE sofeware. MB83 location was determined by microPET in mice bearing Hec1a/EMP2 xenograft. EMP2 expression was detectable in the lung but not other organs by either western or immunohistochemistry. The absence of detectable EMP2 protein in the organs reflects that the target tumor with high EMP2 protein could uptake anti-EMP2 antibody which could be observed by microPET. The specific uptake of MB83 minibody within the Hec1a/EMP2 tumor can be seen both visually and quantitatively. Selective tumor uptake became more specific over time. In contrast, 2-deoxy-2-[18F]fluoro-D- glucose (FDG) microPET uptake by HEC-1A/EMP2 was minimal, reflecting the poor detection of gynecologic cancer cell types by conventional FDG-PET imaging. These findings demonstrate the feasibility of imaging endometrial and other gynecological cancers which have upregulated EMP2 expression using recombinant anti-EMP2 antibodies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5310. doi:10.1158/1538-7445.AM2011-5310
Abstract 5321: Longitudinal high throughput CT imaging of orthotopic lung tumors in mice without using contrast media or respiratory gating
Authors: Bull Christopher M. , Li Li , Westmore Michael S. , Wolos Jeffrey A. 
Published: June 2012

Abstract
In the clinic, CT is the primary clinical imaging modality for diagnosing and staging tumors of the lungs because of its high speed, ability to differentiate between lung and tumor tissue, and relatively low cost. The high contrast between tumor and lung tissue provides accurate identification of tumors without the need for contrast agents.
The injection of cells from the pulmonary adenocarcinoma cell line NCI-441 directly into the lung results in localized tumor growth. Using this orthotopic model, we have developed a technique for imaging tumor growth in 12 mice simultaneously using the GE eXplore Locus Ultra CT scanner. Image acquisition requires only 8 seconds and delivers quantifiable data without the need for respiratory gating. Athymic nude mice were injected with NCI-H441 cells into the left lung. Lungs were imaged by CT every 7 days starting on day 7 post-inoculation. The images were analyzed using GE MicroView software by drawing contours on selected slices through the tumors and using the interpolation technique to generate a volumetric region defining the tumor. Twenty one days after inoculation the animals were imaged and mice with similar sized tumors were randomized into three groups (vehicle, gemcitabine 75 mg/kg, gemcitabine 150 mg/mg) and treated IP once every 3 days, through 4 cycles. CT analysis enabled the elimination of non-tumor bearing mice and mice with extremely large tumors. Substantial tumor growth was observed in the vehicle group, with nearly complete inhibition in the two gemcitabine groups. These results demonstrate the development of a robust, simple, and high-throughput model for quantifying orthotopic lung tumors in mice. Using CT for recruitment and longitudinal evaluation of tumor growth will reduce the numbers of animals needed per group while allowing rapid differentiation between compounds or doses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5321. doi:10.1158/1538-7445.AM2011-5321
Abstract 5324: Cathepsin E expression: A new potential target for pancreatic tumor imaging
Authors: Cruz-Monserrate Zobeida , Abd-Elgaliel Wael R. , Ji Baoan , Deng Defeng , Arumugan Thiruvengadam , Tung Ching H. , Logsdon Craig D. 
Published: June 2012

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) shows unique high expression of Cathepsin E (CTSE). Here we assessed the usefulness of detecting CTSE activity in vivo as a prognostic biomarker for PDAC using mouse xenografts and transgenic models of PDAC.
Procedures: CTSE expression in human and mouse pancreases with/without cancer were assessed by immunohistochemistry. Transgenic animal models of PDAC and xenografts of primary human PDAC tumors or establish pancreatic cancer cell lines in nude mice were injected with the CTSE selective fluorescent probe via tail vein. CTSE expressions in transgenic pancreatic tumors and xenografts were imaged using IVIS-100 optical imaging system. Negative control tumors were imaged in parallel. Tumors, organs and tissues of interest were imaged ex vivo for their associated Cath E expression.
Data: Results confirmed the over expression of CTSE in pancreatic cancer patients and transgenic mouse models of pancreatic cancer. Images illustrate the capability of detecting CTSE expression within pancreatic tumors in both transgenic and xenograft mice models. In vivo and ex vivo images of PDAC were possible by targeting CTSE expression.
Conclusions: Results represent the usefulness of CTSE as a potential molecular target for pancreatic cancer imaging. The elevated CTSE expression in pancreatic tumors allows in vivo detection of human PDAC xenografts and ex vivo imaging of transgenic PDAC tumors in mice. The study demonstrates CTSE as a promising target for tumor imaging.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5324. doi:10.1158/1538-7445.AM2011-5324
Abstract 5347: Inhibition of Notch3 signaling reduces tumorigenic properties of human rhabdomyosarcoma cells
Authors: Raimondi Lavinia , Ciarapica Roberta , Verginelli Federica , Gueguen Marie , Boldrini Renata , De Sio Luigi , Inserra Alessandro , Cortese Giancarlo , Locatelli Mattia , Dang Thao P. , Miele Lucio , Stifani Stefano , Limon Isabelle , Locatelli Franco , Rota Rossella 
Published: June 2012

Abstract
Rhabdomyosarcoma is a soft tissue sarcoma of childhood arising from impaired developmental processes involving skeletal muscle progenitors. Notch signaling is strictly implicated in muscle tissue determination and has been reported to be abnormally activated in rhabdomyosarcoma. The expression of a dominant negative form of the Notch target gene HES1 or the inhibition of the γ-secretase has been shown to arrest rhabdomyosarcoma cell growth and trigger differentiation in vitro. Nevertheless, the mechanism underlying the deregulation of Notch signaling in rhabdomyosarcoma remains unclear. Here, we show that Notch3 and Notch1 are aberrantly activated in primary rhabdomyosarcomas and cell lines compared to skeletal muscle tissues or cultured myoblasts. In the present study we provide evidence that Notch3 targeted down-regulation restrains cell proliferation in both alveolar and embryonal subtypes of rhabdomyosarcoma cell lines. This phenomenon is paralleled by a transcriptional down-regulation of HES1 and an increase in both the cell cycle inhibitor p21cip1 and the under-phosphorylated pRb. Further, cells in which Notch3 has been silenced are capable to form differentiated multinucleated fibers showing de novo expression of late markers of myogenesis. In addition, down-regulation of Notch3 results in p38 and Akt hyper-phosphorylation and over-expression of PTEN. Finally, sustained silencing of Notch3 in rhabdomyosarcoma cells hampers their tumorigenic properties in vitro and in vivo. These results support a pathogenetic role for Notch3 in rhabdomyosarcoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5347. doi:10.1158/1538-7445.AM2011-5347
Abstract 5445: Universal bioluminescent HTS-formatted assay for quantitation of ADP production in kinase and ATPase reactions
Authors: Goueli Said A. , Hsiao Kevin , Zdanovskaia Marina , Vidugiriene Jolanta , Zegzouti Hicham 
Published: June 2012

Abstract
Protein Kinases are implicated in metabolic and cellular disorders including cancer and thus they represent a very important target for the development of novel therapeutics. The process of developing new drug requires an innovative and low cost strategy to screen and identify compounds that can be used for lead optimization that incorporate the required desirable features. It will be idea to have a universal technology that can be used for the various stages of drug discovery such as assay development, compound screening, lead optimization, and enzyme profiling using the same technology platform. The technology should provide high sensitivity, robustness, and low cost. Towards that goal, we have expanded our luminescent platform for monitoring kinase activity to enable us to detect enzyme activity using low amount of enzymes, measure initial rates at very early substrate conversion, and generate reliable and robust data. This luminescent assay monitors enzyme activity by measuring ADP production using a homogenous and high through put formatted assay. The assay is also ideal for profiling compounds against various kinases since it detects ADP, the universal product of all kinases. Thus, the new homogenous assay is most suitable for drug discovery targeting kinases since it can be used in all various stages of drug development leading to animal or cellular studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2011-5445
Abstract 5472: Loss of TSC2 function predicts optimal therapeutic response to combinations of MEK and mTOR inhibitors
Authors: Conlon Beth A. , Legrier Marie-Emmanuelle , Rodriguez Gabin Alicia G. , Horwitz Susan Band , McDaid Hayley M. 
Published: June 2012

Abstract
The MAPK-RAS-PI3K signaling network is oncogenic in many human malignancies. The plasticity of cancer cell ‘circuitry’ is an important consideration in the rational design of drug combinations, particularly those targeting this signaling network. Therapies directed at MEK, a downstream RAS effector, have been in various stages of clinical development and shown to exhibit single-agent activity in RAF-mutant tumors. However, there is significant redundancy in the MAPK-PI3K pathway that mediates acute resistance to drugs that target either axis of this network, therefore the optimal use for MEK inhibitors will be in combination.
We have previously demonstrated that the combination of MEK and mTOR inhibitors is synergistic in a broad range of tumor cell lines and xenofrafts and mechanistically this is mediated via potent suppression of cap-dependent translation. To better define which cohort of patients would best benefit from this combination modality, we have evaluated the efficacy of MEK and rapalog combinations in TSC2 defective cells. The TSC1/2 complex integrates AKT/mTOR and MAPK circuitry and normally inhibits mTOR via Rheb. However disruption of the TSC complex occurs by mutational inactivation, LOH and inactivating phosphorylation via various kinases, including ERK. Loss of TSC2 function hyperactivates mTOR signaling and confers increased sensitivity to mTOR-directed therapies, including rapalogs. In spite of the known participation of MAPK signaling in TSC function, pharmacological inhibitors of MAPK or other components have not been evaluated in TSC2 null tumors.
Cells defective in TSC2 had increased sensitivity to both single agent MEK or rapalog therapies, relative to TSC2 WT cells, and had a much more synergistic interaction that was associated with potent dephosphorylation of the translational repressor, 4E-BP1. Synergy was associated with autophagy induction in TSC2 null cells followed by profound growth arrest that did not respond to growth factor stimulation. Cells with intact TSC2 function did not undergo autophagy after combined MEK and rapalog-inhibitor treatment and did not exhibit the same degree of growth arrest. Bioenergetic profiling indicated that TSC2 null cells had increased levels of oxygen consumption relative to WT cells, indicating changes in metabolic output associated with mTOR activation. In conclusion, these data support the use of combined MEK and rapalog-inhibitor therapy in tumors with defective TSC2 signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5472. doi:10.1158/1538-7445.AM2011-5472
Abstract 5503: Anti-proliferative role of MMP-9 and uPAR/cathepsin B knockdown in negative regulation of DNA repair mechanisms in human glioma xenografts
Authors: Ponnala Shivani , Veeravalli Krishna Kumar , Chetty Chandramu , Rao Jasti S. 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is one of the most lethal forms of brain tumors. Efficient repair of DNA damage, especially double strand breaks (DSBs) and anti-apoptotic mechanisms associated with GBM, makes treating GBM challenging. In the present study, siRNA-mediated transcriptional silencing of MMP-9 and uPAR (MU) and MMP-9 and cathepsin B (MC) in 4910 and 5310 glioma xenograft cells had significant anti-proliferative effect as assessed by BrdU, MTT and clonogenic assays. FACS analysis revealed cells were in sub-G0-G1 phase after xenograft cells were treated with MU or MC. We also investigated the role of MU or MC knockdown in reducing DNA damage response (DDR), which eventually leads to apoptosis in glioma xenograft cells. RT-PCR and Western blot analyses revealed downregulation of DNA PKcs and Ku70/80 levels, which are responsible for non-homologous end joining (NHEJ) DNA repair. Elevated γH2AX protein expression and increased comet tail length indicated that the reduced NHEJ DNA repair led to accumulation of DSBs in MU and MC knocked down cells. The binding efficiency of Ku70 and Ku80 to DSB was significantly reduced in glioma cells treated with MU or MC. In addition, we noticed a reduced γH2AX and Ku70/Ku80 colocalization at DSBs in MU- and MC-treated xenograft cells. Moreover, MU and MC knockdown in these xenograft cells resulted in the downregulation of several other proteins involved in DNA damage response and the survival pathway (e.g., ATM, Rad 51, CHK2, EGFR, Akt, and ERK). Immunohistochemistry of the brain sections of xenografts injected into nude mice showed a reduced expression of DNA PKcs in animals treated with MU and MC siRNA. Taken together, our results clearly demonstrate that silencing via MU and MC not only negatively regulates DNA damage response, but also downregulates the proteins associated with the survival pathway. Based on these findings, it appears that silencing MU or MC in addition to radiation could be an effective strategy to treat radioresistant high-grade gliomas, where treatment usually fails due to the enhanced repair of DSBs induced by radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5503. doi:10.1158/1538-7445.AM2011-5503
Abstract 5524: Generation of cellular immune responses to MUC1-C to target the portion of MUC1 that is most biologically relevant to the transformation process
Authors: Jochems Caroline , Poole Diane J. , Vergati Matteo , Gulley James L. , Schlom Jeffrey , Tsang Kwong Yok 
Published: June 2012

Abstract
MUC1 is overexpressed in diverse human carcinomas and hematological cancers, and therefore serves as a potential target for immunotherapy. The MUC1 molecule has two distinctive subunits, formed by autocleavage with a SEA domain. The N-terminal (MUC1-N) is the large extracellular domain, and the C-terminal (MUC1-C) has three subunits: a small extracellular domain that is covalently bound to MUC1-N, a single transmembrane domain and a cytoplasmic tail. It has been reported by Kufe et al that the MUC1-C subunit transduces signals that confer growth and survival responses. The MUC1-C cytoplasmic tail located downstream of the SEA domain is sufficient for the induction of anchorage independent growth and tumorigenicity. MUC1-C overexpression is also highly associated with poor prognosis in patients with lung cancer and breast cancer. We and others have previously reported on HLA-A2 binding agonist epitopes to MUC1-N. The objective of this investigation is to identify and characterize HLA-A3 binding cytotoxic T-lymphocyte (CTL) epitopes and agonist epitopes of the MUC1-C subunit. The intention is to add these peptides to vaccines against MUC1 positive carcinomas, as well as using them for monitoring patients’ immune responses in clinical MUC1 vaccine trials. The generation of cellular immune responses to MUC1-C would thus target the portion of MUC1 that is most biologically relevant to the transformation process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5524. doi:10.1158/1538-7445.AM2011-5524
Abstract 5553: Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21Cip/WAF1
Authors: Wei Min , Kakehashi Anna , Yamano Shotaro , Fukushima Shoji , Wanibuchi Hideki 
Published: June 2012

Abstract
The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into 7 groups and administered IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 ppm in the diet for 16 weeks. We found that IQ doses of 1 ppm and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 ppm induced preneoplastic lesions in both these organs. These results demonstrate the presence of no effect levels of IQ for both liver and colon carcinogenicity in rats and indicate that the dose-response relationship for IQ carcinogenicity is nonlinear. The finding that p21Cip/WAF1 was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects, suggests that induction of p21Cip/WAF1 is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01 to 10 ppm, but administration of 100 ppm IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results argue for the existence of a practical carcinogenic threshold for this genotoxic compound.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5553. doi:10.1158/1538-7445.AM2011-5553