bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2927: Gefitinib, an EGFR inhibitor, prevents progression of PanINs to pancreatic carcinoma in a preclinical conditional LSL-K-rasG12D transgenic mice model
Authors: Mohammed Altaf , Janakiram Naveena B. , Qian Li , Madka Venkateshwar , Ely Misty , Lightfoot Stan , Steele Vernon E. , Rao Chinthalapally V. 
Published: February 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy is a devastating disease with dismal prognosis (5-year survival rate of less than 5%), and is the fourth leading cause of cancer deaths in the USA. Developing novel strategies to prevent or delay the progression of pancreatic cancer is currently of intense interest. We studied chemopreventive efficacy of gefitinib, an EGFR inhibitor on pancreatic intraepithelial neoplasms (PanINs) and adenocarcinoma in conditional LSL-K-RasG12D transgenic mice. LSL-K-RasG12D and P48Cre mice were bred and offspring of activated K-rasG12D were generated. Six-week old male KrasG12D (20/group) and wild-type (12/group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm gefitinib for 35 weeks. At the time of sacrifice, pancreas were collected, weighed, and were evaluated histopathologically for PanINs and PDAC. To understand the molecular mechanisms, expression levels of PCNA, p38, cyclin D1, C2GNT, RhoA, β catenin, pERK, EGFR and Cav1, were determined in pancreatic tissues by IHC, immuno-fluorescence, immunoblotting and/or RT-PCR. Results suggest that mice fed with 100 and 200 ppm gefitinib had significantly reduced (p&lt;0.0001) ductal adenocarcinomas incidence than control diet fed mice. Importantly, significant reduction of pancreatic ducts with carcinoma (&gt;94%, p&lt; 0.0001) and suppression of PanIN 3 (∼34%) was observed in mice fed diet with gefitinib. We did find statistically significant dose dependent inhibition of PanIN 1 & 2 lesions between control and gefitinib fed groups. Also, mice fed gefitinib showed reduced pancreatic tumor weights (∼50%) compared to control diet fed mice. Furthermore, treated mice showed &gt;75% of pancreas free from carcinoma. Also, pancreas of mice fed gefitinib diets showed significantly reduced expressions of PCNA, p38, EGFR, RhoA, C2GNT, β-catenin, pERK, caveolin-1, and a significant increase in cyclin B1 (p&lt;0.005) levels compared to pancreas of control diet fed mice. In summary, our results suggest that gefitinib prevents the progression of pancreatic cancer precursor lesions in PanIN 1, 2 and 3 stages from further progressing to adenocarcinoma in a preclinical model. These data highlight the promise of chemoprevention in pancreatic cancer and administration of EGFR inhibitors represents an important strategy to prevent pancreatic cancer in high-risk patients.
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 2927.
Abstract 3001: MicroRNAs regulating wnt signaling are downregulated in malignant pleural mesothelioma
Authors: Gee Gretchen V. , Koestler Devin C. , Christensen Brock C. , Sugarbaker David J. , Ugolini Donatella , Ivaldi Giovanni P. , Resnick Murray B. , Houseman E. Andreas , Kelsey Karl T. , Marsit Carmen J. 
Published: February 2011

Abstract
Malignant pleural mesothelioma is a rapidly fatal disease whose diagnosis, particularly through less invasive techniques such as analysis of pleural effusion, can be challenging. Currently, a commercially available diagnostic test based on microRNA expression patterns is purported to distinguish between mesothelioma and lung adenocarcinoma. Yet, the biological basis of this technology has not been reported in the literature, and little research has been aimed at determining how differential miRNA expression contributes to the differences in pathogenesis between these diseases, both of which can be caused by asbestos exposure. We sought to illuminate the molecular differences between mesothelioma and lung adenocarcinoma by using microRNA microarrays to identify patterns in the most differentially expressed microRNAs. From this, we identified a panel of microRNAs, including members of the miR-200 gene family, that were all downregulated in malignant pleural mesothelioma compared to lung adenocarcinoma. Using the more sensitive detection method of quantitative RT-PCR on an independent series of tumors, we validated the specificity of these alterations in 100 malignant pleural mesotheliomas and 32 lung adenocarcinomas. Further examination of the relationship between these microRNAs revealed that they are predicted to act as redundant regulators of wnt signaling, and suggests a role for this pathway in tumor progression. This research points to novel approaches utilizing miRNAs whose decreased expression is unique to mesothelioma as potentially suitable for rapid diagnosis, and reveals important new targets for the treatment of this deadly disease.
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 3001.
Abstract 3030: An exosome isolation system for serum-based cancer biomarker discovery
Authors: Wu Fangting , Antes Travis J. 
Published: February 2011

Abstract
Exosomes are 40-100 nm membrane vesicles secreted by most cell types, including all cancer cells. While the exact biological functions of exosomes remain unclear, exosomes can mediate communication between cells, facilitating processes such as antigen presentation and in trans signaling to neighboring cells. The abundance of exosomes present in the circulation of cancer patients increases with tumor grade. Studies identifying protein and microRNA biomarkers in these circulating exosomes can reveal the tumor type and origin. These recent studies highlight the growing use and need of standardized exosome enrichment. What is missing in this research area is a method for simple, rapid and reproducible exosome purification to facilitate research into the role of exosome in both physiological and pathological process, as well as possible diagnostic and therapeutic potentials. In this study, SBI utilizes proprietary polymer mixture (ExoQuick) to precipitate exosome from human serum samples. Using ExoQuick, we successfully observe small RNAs in the exosome pellets and detect microRNAs by qPCR. Exosome precipitation from serum samples was verified using Western blot analysis on the ExoQuick supernatant and pellet fractions and probed with antibodies against two commonly found exosome biomarker proteins, CD63 and CD9. Robust signals for CD63 and for CD9 were observed only in the exosome pellet fractions but not in the serum supernatant. These preliminary data provide proof-of-concept for our approach in using polymer-based, one-step exosome purification method from human serum samples. The technologies developed in this study will advance the exosome research field by providing a simple and standardized exosome isolation method that will allow high-throughput exosome analysis to enable major strides forward in serum-based microRNA biomarker discoveries for cancer diagnostics and prognostics tools.
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 3030.
Abstract 3051: mRNA and microRNA expression profiles integrated with drug sensitivities of the NCI-60 human cancer cell lines
Authors: Liu Hongfang , D'Andrade Petula , Fulmer-Smentek Stephanie , Lorenzi Philip , Kohn Kurt , Weinstein John , Pommier Yves G. , Reinhold William C. 
Published: February 2011

Abstract
We present here new NCI-60 profiling studies of mRNA and miRNA expression using the 41,000-probe Agilent Whole Human Genome Oligo Microarray and the 15,000-feature Agilent Human miRNA Microarray V2. Expression levels were determined for ∼21,000 genes and 723 human miRNAs. The resulting data sets are freely available and searchable online at http://discover.nci.nih.gov in our CellMiner relational database package. The profiling included technical replicates, with six and eight cell lines assayed in quadruplicate for mRNA and miRNA, respectively. The remaining cell lines were assayed in duplicate. Our analysis indicates high reproducibility for both platforms and an essential biological similarity across the various cell types. The expression levels were integrated with our previously published 1,429-compound database of anticancer activity in the NCI screen. Large blocks of both mRNAs (∼2000) and miRNAs (∼200) with unidirectional correlation to ∼1300 drugs including 121 drugs with known mechanisms of action were identified. The data sets presented here will facilitate recognition of the groups of mRNAs, miRNAs and drugs that potentially affect and interact with one another.
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 3051.
Abstract 3095: JMJDX interacts with DEAH (Asp-Glu-Ala-His) box polypeptide 9 (DHX9)
Authors: Unoki Motoko , Nakamura Yusuke , Hamamoto Ryuji 
Published: February 2011

Abstract
We identified JMJDX as a candidate oncogene. Expression of JMJDX was up-regulated in various cancers including bladder cancer. Knockdown of JMJDX suppressed cell growth, suggesting that the protein may be involved in cancer cell growth. The protein possesses a JmjC domain. The domain is often found in lysine demethylases. To identify substrates of JMJDX, we performed immunoprecipitation and subsequent mass spectrometric analysis. In the result, we found that JMJDX physically associated with DHX9, which is also known as RNA helicase A. DHX9 is a DNA helicase and also works as an RNA helicase. DHX9 has a nuclear transport domain (NTD), which is known to necessary and sufficient for its bi-directional nuclear trafficking. It was reported that arginine methylation at the NTD domain is required for the NTD-mediated nuclear import. Thus, JMJDX may demethylate the methylated arginines at the domain and control its transportation between nucleus and cytoplasm. If our hypothesis is true, JMJDX will be the first arginine demethylase, because JMJD6, which was reported as the first arginine demethylase, was recently turned out that it is actually a lysine hydroxylase. DHX9 is thought to have oncogenic functions in cancer cells. In addition, expression levels of JMJDX are very low in normal tissues. Therefore, we think that JMJDX can be an anti-drug target with less adverse reactions.
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 3095.
Abstract 3124: Platelet-derived growth factor receptor α cooperates with loss of p16/INK4a and p19/ARF to enhance tumorigenesis through the PI3K- and SHP-2-mediated signaling in the brain
Authors: Liu Kunwei , Hu Bo , Feng Haizhong , Kazlauskas Andrius , Smith Erin , Symed Karen , Bachoo Robert , Cheng Shi-Yuan 
Published: February 2011

Abstract
Glioblastomas are the most common and lethal cancer in the central nervous system. Comprehensive genetic studies showed that in high-grade gliomas, overexpression of platelet-derived growth factor receptor alpha (PDGFRα) ranks third among top amplified genes and frequently co-occurs with loss of tumor suppressor genes, p16/INK4a and p14/ARF (p19/ARF in mice), in these high-grade glioblastomas. However, the biological consequences of PDGFRα overexpression in INK4a/ARF-deficient glial cells and glioma cells remain elusive. Here we show that activation of PDGFRα signaling by overexpressing PDGFRα and/or PDGF-A transformed Ink4a/Arf-deficient mouse astrocytes in vitro and rendered these cells highly tumorigenic in the brain of mice. Consistently, in INK4a/ARF null but not wild-type human glioma cell lines that express endogenous PDGFRα, overexpression of PDGF-A significantly enhances glioma formation in the brain. Re-introduction of p16/INK4a into Ink4a/Arf-null astrocytes suppressed PDGFRα-induced cell transformation in vitro and glioma formation in the brain. Conversely, cellular depletion of endogenous p16/INK4a by RNA interference in human glioma cells markedly enhances colony formation in vitro when compared to the controls. Mechanistically, abrogation of intrinsic tyrosine kinase activity of PDGFRα or interruptions of signaling modules at PDGFRα (Y to F mutations at specific tyrosine residues) that lost binding capacity for PI3K or Shp-2, but not PLC gamma or c-Src, significantly diminished PDGFRα-induced glioma formation in the brain. In vitro, specific YF mutations or inhibitors of PI3K or Shp-2 attenuated Akt activation and PDGFRα-induced colony formation. Furthermore, inhibition of Shp-2 by its inhibitors and siRNAs disrupts the interaction of PI3K with PDGFRα that is critical for gliomagenesis of Ink4a/Arf null cells. In summary, our data suggests that activation of PDGFRα signaling, particularly through the PI3K and Shp-2 pathways, in INK4a/ARF deficient astrocytes and glioma cells induce gliomagenesis in the brain. Our findings provide critical insights into interactions of genetic lesions frequently found in clinical glioma specimens and will be useful for identification of new therapeutic targets for treatments of patients with malignant gliomas.
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 3124.
Abstract 3198: Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis
Authors: Qiu Wei , Leibowitz Brian , Zhang Lin , Yu Jian 
Published: February 2011

Abstract
Gastrointestinal toxicity is the primary limiting factor in abdominal and pelvic radiotherapy, but has no effective treatment currently. We recently showed a critical role of the BH3-only protein PUMA in acute radiation-induced GI damage and GI syndrome in mice. Growth factors such as IGF-I and bFGF have been shown to protect against radiation-induced intestinal injury, though the underlying mechanisms remain to be identified. We report here the suppression of PUMA through the PI3K/AKT/p53 axis in the intestinal stem cells (ISCs) as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. IGF-I or bFGF impaired radiation-induced apoptosis, and the expression of PUMA and p53 in the crypt cells and intestinal stem cells. Using colonic epithelial cells that undergo PUMA-dependent and radiation-induced apoptosis, we found that a PI3K inhibitor, dominant-negative PI3K, or Mdm2 antagonist restored the induction of PUMA, p53 and apoptosis in the presence of growth factors. In contrast, overexpression of AKT suppressed the induction of PUMA and p53 by radiation. Furthermore, inhibiting PI3K or activating p53 abrogated growth factor-mediated suppression of apoptosis and PUMA expression in the intestinal crypts and stem cells following radiation.
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 3198.
Abstract 3212: Development of a chemiluminescence-based single telomere length analysis (STELA) method
Authors: Heaphy Christopher M. , Haffner Michael C. , Meeker Alan K. 
Published: February 2011

Abstract
Carcinogenesis is a multistep process characterized by the accumulation of genetic alterations that drive the transformation of normal cells to malignant cells. Telomeres are specialized nucleoprotein structures that function to protect and stabilize the ends of eukaryotic chromosomes by preventing chromosome fusions, masking double strand DNA break damage signals and preventing exonucleolytic chromosomal degradation. It is well established that telomere shortening is present in precursor and invasive stages of many carcinomas. Additionally, numerous investigations have demonstrated that altered telomere length predisposes cells to possess the properties necessary for metastasis formation, and therefore represents a predictor of clinical outcome. However, most of these studies have used assays that measure the average telomere length of all the cells in a particular population. To circumvent this problem, Baird et al. (Nature Genetics, 2003) previously described a PCR-based single telomere length analysis (STELA) method that could accurately measure the full spectrum of telomere lengths from a specific chromosomal arm. Although this method represents a substantial improvement over existing methods, the assay requires the use of radioactive material. Here, we describe a modification of the STELA assay which uses chemiluminescence instead of radioisotopes for product visualization, while maintaining the overall sensitivity of the detection of a wide range of telomere lengths. This new methodology has tremendous potential to illuminate the mechanisms that support the initiation of cancer and may provide an avenue for investigators to address the full extent and significance of telomere shortening in the tumorigenic process at the single chromosome level. The modified assay described here will allow for more widespread use of this technique among cancer researchers.
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 3212.
Abstract 3216: CREG1, an epigenetically regulated gene, cooperates with p16INK4a in cellular senescence
Authors: Moolmuang Benchamart , Tainsky Michael A. 
Published: February 2011

Abstract
By passing cellular senescence, an irreversible growth arrest of cells that is activated in normal cells upon shortening of telomere and other cellular stress, to become immortal is one of the prerequisites for carcinogenesis. Using spontaneously immortal Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes1) is one of the genes whose expression fit the criteria of senescence-associated genes, decrease expression during immortalization and increase in senescence. Moreover, we found that epigenetic mechanism regulates CREG1 expression. CREG1 is a secreted glycoprotein that was shown to bind RB-family pocket proteins and inhibits E2F transactivation activity. Therefore, we hypothesize that CREG1 plays a role in cellular senescence involving p16INK4a/Rb pathway.
Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines commonly seen in Li-Fraumeni Syndrome. Because CREG1 was shown to interact with RB pocket proteins in vitro, we tested that growth suppression by CREG1 may depend on the phosphorylation status of Rb. We found that p16INK4a is also downregulated in immortal cells and that coexpression of CREG1 and p16INK4a, and inhibitor of CDK and Rb phosphorylation, has a greater effect than CREG1 and p16INK4a alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16INK4a inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition. Whether CREG1 directly involved in transcriptional repression of cyclin A and B mediated by p16INK4a will be confirmed by ChIP assay. In conclusion, we are the first to find that CREG1 enhances p16INK4a-induced senescence by transcriptional repression of cell cycle mediated genes.
Analysis of how CREG1 and its cooperation with p16INK4a regulate cell cycle and cellular senescence may provide better understanding of cellular immortalization, an early step in human tumorigenesis.
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 3216.
Abstract 3228: Dual HER2 and EGFR inhibitor BIBW2992 have dramatic activity in a HER2 wild type/EGFR L858R murine lung cancer model
Authors: Li Danan , Chen Zhao , Chen Liang , Liang Mei-chih , Walton Zandra , Sanofsky Benjamin , Janne Pasi , Wong Kwok-Kin 
Published: February 2011

Abstract
Dual HER2 and EGFR inhibitor BIBW2992 have dramatic activity in a HER2 wild type/EGFR L858R murine lung cancer model
HER2 (ERBB2) is a proto-oncogene that belongs to EGFR tyrosine kinase receptor family. HER2 genomic locus amplification and HER2 protein over-expression detected by IHC have been identified in many human cancer types including breast, brain and lung cancer. Simultaneous over-expression of both HER2 and EGFR occurs in a subpopulation of lung cancer patients. Here we developed a transgenic mouse model with inducible wild type HER2 expression in type II pneumocyte. Continual HER2 over-expression in the lung epithelial compartment leads to peripheral lung adenocarcinoma that responds dramatically to targeted anti-HER2 therapeutics. Mice over-expressing both EGFR L858R and the wild type HER2 alleles do not significant accelerate tumorigenesis or alter of tumor histology as compared to tumors generated by the wild type HER2 single alleles. The HER2/EGFR driven murine lung tumors showed mild and transient response to the EGFR inhibitor, gefitinib. This result mimics the observation from clinical patients. However, the dual HER2/EGFR inhibitor, BIBW2992, is much more effective against these HER2/EGFR driven lung cancers as measured by tumor regression and over all survival. Our data suggested that targeting therapy against both EGFR and HER2 is a better strategy in lung cancer patients with co-expression of EGFR and HER2 when compared with treatment against EGFR alone. Clinical trial for dual HER2/EGFR inhibitors in this population should be considered.
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 3228.