bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4179: Quercetin inhibits growth of pancreatic cancer in vitro and in vivo
Authors: Angst Eliane , Park Jenny L. , Moro Aune , Lu Qing-Yi , King Jonathan C. , Go Vay Liang W. , Reber Howard A. , Eibl Guido , Hines O. Joe 
Published: February 2011

Abstract
Background and Aim: Polyphenols are common constituents of many fruits and vegetables, and have recently gained interest as potential therapeutic agents for various human malignancies. The most abundant of these polyphenols are flavonoids - quercetin being the most ubiquitous. The aim of this study was to assess the growth-inhibitory and anti-angiogenic properties of quercetin on pancreatic cancer (PaCa) cells in vitro and in vivo. Methods and Results: Using cell count and BrdU assay, we measured a dose-dependent inhibition of cell proliferation by quercetin (0-75µM) for MIA PaCa-2 (MP) and BxPC-3 (Bx) cells (p&lt;0.001 at 30µM). Quercetin (10 µM) increased apoptosis by 22% and 8% in MP and Bx, respectively (p&lt;0.05). Further, quercetin (10 µM) inhibited mRNA and protein expression of the pro-angiogenic chemokine CXCL8 (p&lt;0.05) in both cell lines as measured by ELISA and real-time PCR. Conditioned media from PaCa cells treated with 50 µM quercetin reduced endothelial cell tube formation by ∼50% compared to control (p&lt;0.05). A feeding study was conducted utilizing an orthotopic xenograft model of PaCa in nude mice. Luciferase-expressing MP (3×106) cells were injected subcutaneously into the flank of donor mice. After four weeks, 1 mm3 donor tumor sections were transplanted into the pancreatic tail of recipient mice. These animals were randomly allocated to control diet or 1% quercetin diet groups utilizing the AIN93G-based diet (n=12 per group). In addition, 6 mice from each group were injected weekly with gemcitabine (120 mg/kg mouse, i.p.). Animals were imaged weekly after tumor implantation until sacrifice at 6 weeks. Light emission was reduced in animals receiving quercetin, gemcitabine, and both treatments by 12%, 8%, and 16%, respectively at day 24. Furthermore, CXCL8 serum levels were significantly reduced in the quercetin/gemcitabine group (p&lt;0.001). Using HPLC analysis, quercetin and its metabolite, isorhamnetin, were detected in tumor tissues (2.6 ± 2.7 and 2.1 ± 0.9 nmol/gram, respectively). Conclusion: Quercetin significantly inhibits the growth of PaCa in vitro and in an orthotopic murine model. PaCa growth was inhibited utilizing a bioavailable quercetin preparation in the diet. Quercetin may, in part, be acting through a reduction of angiogenesis. From this data we surmise that quercetin may be useful as an adjunct to current treatment for pancreatic cancer.
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 4179.
Abstract 418: Introducing different genetic elements into human mesenchymal stem cells to transform into osteosarcoma
Authors: Austin-Page Lukas , Thein Sajida , Lam Matthrew , Park Amy , Li Nan , Yang Rui , Gorlick Richard 
Published: February 2011

Abstract
Despite Osteosarcoma (OS) being the most common primary malignant bone tumor in children and young adults, little clarity exists in where the cell of origin exists in the pathway of differentiation between a human mesenchymal stem cell (hMSC) and a mature osteoblast. It is similarly unclear the primary genetic alterations which initiate oteosarcoma formation in patients. Since high grade OS usually demonstrates histologic variability, and the potential for multilineage differentiation, along with some direct experimental observations some consider hMSC as the cell of origin of OS whereas others believe the pre-osteoblast or osteoblast to be the mot likely cell of origin. Our previous studies have shown that serially introducing 3 different viral constructs, hTERT, SV40TAg, and H-RAS, transforms hMSC into 2 distinct sarcomas cell lines, but not OS. This may be attributable to the fact that oncogenic H-Ras does not seem to play a direct role in the pathogenesis of OS. Therefore, the MSC-TS cell line, hMSC transfected with hTERT and SV40TAg can be used as a platform for further analysis of the impact of genetic transformation of hMSCs. The MSC-TS cells were transformed with lentivirus containing human β-catenin (β), and IGF-1R (I)
, separately. Both β-catenin and IGF-1R have been suggested to be involved in the pathogenesis of OS due to their proliferative and/or anti-apoptotic effects. Drug resistant colonies were picked up 21 days after selection to obtain stably transfected cell lines, MSC-TS-β, and MSC-TS-I, respectively. Western blots were carried out to detect the protein of β-catenin and IGF-1R, respectively. Clones, which have highest, lowest, and intermediate protein levels were selected, and comparison between the lines and characterizations are completed and underway. Further characterization includes: 1) Soft Agar Assays , 2)Subcutaneous/Orthotopic Tumorigenicity Assays,3) Routine histological examination and also staining with immunohistochemical markers, 4) Microarray Analysis, 5) Spectral Karyotyping / Comparative Genomic Hybridization, 6) Motility and Migration Assays, and 7) Differentiation Assays.
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 418.
Abstract 4182: A screen for genes that define the strong gender bias nature of hepatocellular carcinoma using a transposon mutagenesis murine model
Authors: Keng Vincent W. , Ryan Barbara J. , Silverstein Kevin A.T. , Sarver Aaron , Fan Danhua , Dupuy Adam J. , Jenkins Nancy A. , Copeland Neal G. , Largaespada David A. 
Published: February 2011

Abstract
Introduction: Hepatocellular carcinoma (HCC) is a deadly disease where many of the underlying associated genetic mechanisms remain undiscovered. Although HCC has been relatively rare in the US, the growing number of patients with cirrhosis (due to hepatitis infection and/or obesity-related fatty liver) has accounted for a surge in the incidence of HCC. Using the conditional Sleeping Beauty (SB) transposon somatic insertional mutagenesis system in transgenic mice, a novel unbiased HCC genetic screen was performed to elucidate the important genes responsible for this disease1.
Methods: Triple transgenic (containing the conditional SB transposase, transposon mutagenic vector and liver-specific Cre transgenes) and quadruple transgenic (as above plus a conditional dominant negative p53 allele) mice were generated and aged for tumorigenesis1.
Results: Using this system combined with a conditional p53-deficient background, we were able to identify many HCC cancer candidate genes. In addition, liver tumor nodules were also isolated from experimental mice without a predisposed genetic background. Liver tumors were prevalent in male experimental mice, mimicking the strong gender bias in the incidence of HCC seen in humans. Liver tumors were isolated from female experimental mice with and without a p53-deficient background, only after a prolonged latency (&gt;432-days). From wild-type female liver tumors, we identified 17 candidate genes including the Pten tumor suppressor gene. From p53-deficient female liver tumors, we identified 6 candidate genes including some genes that are implicated in the miRNA18a pathway. This miRNA pathway has been associated with increased incidence of HCC in female patients.
Conclusion: SB system allows for the identification of putative genes involved in HCC development in female mice. Finally, our ultimate goal is that candidate genes will be useful in generating possible therapeutic agents for the treatment of HCC and increase our knowledge in defining the underlying genetic mechanisms associated with the strong gender bias nature of this deadly disease.
1. Keng, V.W., et al. (2009). A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nat Biotechnol. 27, 264-74.
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 4182.
Abstract 4184: Development of ixabepilone-induced CIPN is related to pre-treatment with paclitaxel in a mouse model
Authors: Carlson Karen-Sue B. , Ramnarain Anita , Strickland Sidney , Vahdat Linda T. 
Published: February 2011

Abstract
The mechanisms and underlying factors that predispose individuals to development of chemotherapy-induced peripheral neuropathy (CIPN) are not clearly understood. CIPN results in the dose attenuation, delay, or discontinuation of drug in patients otherwise responding to chemotherapy. Moderate to severe CIPN can interfere with function and activities of daily living. Microtubule-stabilizing agents, including taxanes and epothilones are strongly associated with development of CIPN. Ixabepilone, the first FDA-approved epothilone, is specifically used in taxane-resistant metastatic breast cancer. Any ixabepilone-induced CIPN may be as high as 71% depending on administration regimen. Specific risk factors for development of this side effect are unknown.
Here we present data using a murine model of sensory hyperalgesia that suggests pretreatment with paclitaxel, currently a labeling indication for use of ixabepilone in metastatic breast cancer, is itself a predisposing factor for development of ixabepilone-induced peripheral neuropathy. Wild type DB/A2 adult mice were treated with intraperitoneal 25 mg/kg paclitaxel, 2.5 mg/kg ixabepilone, or diluent (cremophor: ethanol) every other day for 4 doses. Mice were analyzed by rota-rod to test sensory-motor function and by hot and cold plate to test for temperature hyperalgesia. There was no difference in performance of either of the three treatment groups following the initial treatment cycle. Mice were then treated with a further cycle of chemotherapy, either the same as they received initially, except that half of the paclitaxel-treated group was crossed-over to ixabepilone. Rota-rod and hot plate testing again failed to show a difference between groups. However, cold-plate testing showed a statistically significant increase in cold hyperalgesia in mice treated first with paclitaxel followed by ixabepilone in comparison to all other treatment groups. EM and immunofluorescence analyses of dorsal root ganglia and sciatic nerve sections from mice in all four treatment groups are ongoing.
Although preliminary, these results suggest that prior chemotherapy regimens have a significant effect on development of CIPN in this model. The exact mechanisms of injury are under evaluation. A complementary clinical study is underway in women with breast cancer to understand the effect of ixabepilone on an ultrastructural level and its potential role in the development of peripheral neuropathy.
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 4184.
Abstract 4185: Isolation of cancer stem-like cells from a novel orthotopic xenograt model of supratentorial primitive neuroectodermal tumor that is susceptible to oncolytic Seneca Valley Virus
Authors: Liu Zhigang , Zhao Xiumei , Adesina Adenkunle M. , Baxter Patricia , Zhao Yijue , Rao Pulavalti , Su Jack M. , Perlaky Lazlo , Dauser Robert , Chintagumpala Murali , Lau Ching C. , Blaney Susan M. , Li Xiao-Nan 
Published: February 2011

Abstract
Purpose: Supratentorial primitive neuroectodermal tumor (PNET) accounts for 2-3% of all pediatric brain tumors. Despite multimodality therapies, the clinical outcome remains poor, and the 5-year progression free survival rate is less than 40%. Clinically relevant animal models are needed for understanding tumor biology and developing more effective therapies. Here we report our recent development of a clinically relevant animal model, isolation and characterization of cancer stem-like cells in the xenograft tumors, and preclinical investigation of the antitumor efficacy of a novel picorna oncolytic virus Seneca Valley Virus-001 (SVV-001) both in vitro and vivo, especially in cancer stem-like cells.
Experimental Design: Orthotopic xenograft mouse model was developed by direct injection of 105 tumor cells from a freshly resected brain PNET tumor specimen into the right cerebrum of Rag2/severe combined immunodeficient mice. CD133+ cells were quantitatively analyzed and isolated with FACS using human-specific antibodies against CD133. Antitumor activity of SVV-001was evaluated in vitro in cultured xenograft tumor cells and in vivo in mice bearing pre-formed xenograft tumors.
Results: A novel transplantable PNET xenograft model IC-2664PNT was established. The xenograft tumors not only replicate the biologic phenotypes but also preserve cancer stem-like cell pools. The IC-2664PNET neurospheres, which expressed high levels of CD133 and nestin, were efficiently infected and killed by SVV-001 (0.5-25 virus particle/ cell). A single tail vein injection of SVV-001 (5×1012 virus particle/kg) prolonged survival time of PNET xenograft model.
Conclusions: We have established the first clinically relevant animal model for childhood supratentorial PNET. It replicated the major histopathological features of the original patient tumor, and preserved a CD133+ stem cells pool during serial subtransplantations. SVV-001 has potent antitumor efficacy in PNET, especially selectively kill cancer stem-like cells, and prolong survival in vivo.
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 4185.
Abstract 4187: A rapid and robust transgenic high-grade glioma mouse model for therapy-intervention studies
Authors: de Vries Nienke A. , Bruggeman Sophia W. , de Vries Hilda I. , Zevenhoven John , Buckle Tessa , Hamans Bob C. , Leenders William P. , Beijnen Jos H. , van Lohuizen Maarten , Berns Anton J.M. , van Tellingen Olaf 
Published: February 2011

Abstract
High-grade glioma is a devastating and uniformly fatal disease for which better therapy is urgently needed. Glioma cells extensively infiltrate into surrounding pivotal brain structures, thereby rendering current treatments largely ineffective. Evaluation of novel therapies requires the availability of appropriate glioma mouse models. We here present a novel transgenic mouse model of high-grade glioma that can be conveniently used for testing therapy-intervention strategies.
High-grade gliomas were induced by stereotactic intracranial injection of self-deleting lentiviral GFAP-Cre or CMV-Cre vectors into adult immune-competent compound LoxP-conditional mice, resulting in localized expression of K-Rasv12 in conjunction with loss of p16Ink4a/p19Arf with or without concomitant loss of p53 or Pten. Tumors have been characterized by histology, immune-histochemistry and magnetic resonance imaging and reproduced many of the features that are characteristic for human high-grade gliomas, including invasiveness and blood-brain barrier functionality. We are currently assessing which molecular alterations in cell signaling pathways have occurred.
Especially CMV-Cre injection into p53;Ink4a/Arf;K-Rasv12 mice resulted in grade IV (glioblastoma multiforme) with a short tumor latency (2-3 weeks) and full penetrance. Early detection and follow-up of tumor growth can be accomplished conveniently by non-invasive bioluminescence imaging and the practical utility for therapy-intervention has been demonstrated in a study with temozolomide. Temozolomide delayed tumor progression modestly but significantly in line with what is observed in patients. Importantly, this novel model can be used with almost the same convenience as traditional xenograft models, thus allowing the implementation of realistic high grade glioma models at the forefront of preclinical evaluation. We expect that this model will be particularly useful to assess the potential clinical utility of agents that may augment temozolomide cytotoxicity, such as PARP-inhibitors or Wee1 kinase inhibitors, but also for agents targeting activated RAS and/or PI3K-Akt-mTor signaling pathways.
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 4187.
Abstract 4188: Protein profiling of the first genetically engineered murine model of brainstem glioma
Authors: Nazarian Javad , Becher Oren J. , Hathout Yetrib , MacDonald Tobey J. 
Published: February 2011

Abstract
Brainstem gliomas account for about 15% of all pediatric brain tumors and are the leading cause of death for pediatric brain cancers. The PDGFB induced mouse model of brainstem glioma (BSG) uses the RCAS/t-va system and is the first genetically engineered murine model of the disease. Tumors of these mice exhibit histopathological characteristics of pediatrics BSGs. Tumorigenesis is driven by overexpression of PDGFB in nestin expressing progenitors and accelerated by deletion of INK4A-ARF. Although PDGFB is known to be highly expressed both in these mice and a subset of pediatric BSGs, the exact mechanisms of disease formation and progression is not well understood.
In an attempt to explore the molecular mechanisms of PDGFB-mediated tumor formation, we generated the complete protein profiles of brainstem samples obtained from normal (n=3) and PDGFB-induced BSG (N=3) mice. Total proteins were extracted, tryspin digested and resulting peptides were analyzed by shotgun proteomics (LC-MS/MS) and proteins were identified using Sequest algorithm. Label-free analysis was performed using ProteoIQ software.
A total of 1,363 proteins were confidently identified by using the following stringent filtration criteria: &gt; 2 peptides/protein, &gt;10 spectra/protein, minimum peptide probability of 0.95, and a minimum peptide length of 5 amino acids. Our analysis identified overlap in several molecular pathways that we had previously reported in proteomic profiling of pediatric formalin fixed autopsy specimens. Some of the proteins that showed similar dysregulation included: ALDOC, EEF1A1, GPI, PKM2, and SPTBN1. Furthermore, the list of proteins and their expression values were analyzed by the Ingenuity Pathway Assist (IPA). IPA derives molecular interactions based on published data and peer-reviewed manuscripts. Our analysis showed that 228 of these proteins have been reported to play a role brain tumor or other types of cancer. Together, our protein analysis of the first murine model of BSG has provided significant additional insights regarding into PDGFB-induced oncogenesis and molecular perturbations.
Our analysis is the first report of the comprehensive protein profile of this novel BSG murine model. Pathways and molecular interactions identified by this combined comparative proteomic approach will require further validation both using additional samples obtained from the murine BSG model as well as human postmortem BSG specimens. Such validations may lead to the identification of therapeutic targets and improve our understanding of the biology of BSG.
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 4188.
Abstract 4191: Thymidylate synthase accelerates development of pituitary tumors in Men1 knockout mice
Authors: Lee Hye Seung , Chen Min , Hwang Jin Hyeok , Sarfaraz Sami , Giaccone Giuseppe , Zajac-Kaye Maria 
Published: February 2011

Abstract
Thymidylate synthase (TS) is a key enzyme for DNA biosynthesis during cellular proliferation. Studies from our laboratory have demonstrated oncogenic activity of TS in mammalian cells (Cancer Cell, 5 p341, 2004) and in transgenic mice that overexpress human TS (hTS) (Oncogene v26 p4814, 2007). To investigate the in vivo role of TS in pituitary tumorigenesis, we crossed hTS transgenic mice with conditional Men1 knockout mice. We found that overexpression of hTS in fMen1−/− mice significantly decreased the age of onset and increased the incidence of pituitary tumors. fMen1−/−hTS mice developed adenoma and carcinoma as early as 6 and 7 month respectively, while the development of these tumor was not observed in fMen1−/− mice until after 8 month of age. By 8 months of age, 12.1% fMen1−/−hTS mice developed adenoma while no adenoma was observed in fMen1−/− mice. At 10 month of age, progression of pituitary adenoma to carcinoma occurred with higher incidence (51.6%) in fMen1−/−hTS as compared to fMen1−/− mice (18.2%) (p=0.013). Using immunohistochemistry and immunoblotting analysis we confirmed expression of ectopic hTS protein in pituitary tumors of fMen1−/−hTS mice. Our results demonstrated that TS enhances the development and progression of pituitary tumors and suggested that this transgenic model can be use to study the in vivo consequences of elevated hTS on DNA stability, to test how this relates to tumorigenesis, and to improve the use of hTS as a biomarker and therapeutic target. The impact of this work is that it would show that elevated hTS is playing an active role in promoting tumor cell proliferation and is not a simply a passive target for chemotherapy agents to induce cellular toxicity.
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 4191.