bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4340: Development of short peptide probe to detect ovarian tumors in mouse xenograph model
Authors: Lee Chung-Wein , Guo Lili , Stantz Keith M. 
Published: February 2011

Abstract
Ovarian cancer is the leading gynecological cancer in women with five year survival rate less than 45%. Ovarian epithelial cancer (OEC) is responsible for 80 to 90% of all ovarian cancers. Postmenopausal women have high level of gonadotropin in blood circulation and high occurrence of OEC. Therefore, the elevated gonadotropin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), was proposed to contribute to transforming normal ovarian surface epithelium to neoplastic ovarian surface epithelium. The studies on gonadotropin theory have shown both supporting and conflicting epidemiological and animal model data. Therefore an alternative marker for ovarian tumor detection is beneficial. Follicule Stimulating Hormone Receptor (FSHR) belongs to G protein-coupled receptor with substantial extracellular domains. FSHR normally is expressed on normal ovarian epithelium, fallopian tubal epithelium and similar to LHR. Recent studies showed that FSHR is not only highly expressed on many ovarian cancer cells but is involved in the development and progression of ovarian cancer influencing a variety of oncogenes (MAPK, EGFR, c-myc, and HER-2/neu). FSHR expression increases in the following order: ovarian epithelial inclusions (OEIs) to benigh ovarian epithelial tumor (OET), and to borderline OETs. Our objective is to develop a small molecular weight ligand to image in vivo the differential expression of FSHR associated with OEC, possibility to image OEC in different stages with associated binding molecules to FSHR. D.W. Lee et. al. identified a deca peptide (BI-10) from FSH binding inhibitor of bovine serum. We conjugated the BI-10 peptide with fluorescein to quantify the binding affinity of OVCAR3 cells in flow cytometry. The cells were incubated with BI-10 at various concentrations for 30 mins before removing from six-well culture plates and washing off free peptides. The EC50 of BI-10 binding peptides to OVCAR3 was measured to be 160 μM, with an average number of FSHR receptors per cell to be 1.7×107. After conjugating a NIR fluorochrome (Alexa Fluoro 750) to this peptide and and injection (i.v.) into a mouse xenograft model of ovarian cancer, OEC tumors were clearly detected by optical imaging. A tumor-to-reference tissue update ratio was measured to be 1.20, 1.26, and 1.43 with respect to injected dose 15, 30, and 120 μg probe, respectively. We are currently testing techniques to further increase the BI-10 peptide binding to various ovarian cancer cell lines both in vitro and in vivo by constructing multimeric forms including the BI-10 peptide with various flexible linkers.
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 4340.
Abstract 4341: Tumor imaging via β-galactosidase fragment complementation with a multifunctional targeted-reporter complex
Authors: Broome Ann-Marie , Lavik Kari , Ramamurthy Gopalakrishnan , Liggett Luther A. , Agnes Richard S. , Basilion James P. 
Published: February 2011

Abstract
Determining the status of cell surface receptors has become routine in the care of patients with cancer and has proven to be helpful in guiding treatment. Mutational events that drive a normal cell to become a cancer cell require the coordinated overexpression of not just one receptor at a time, but rather multiple biomarkers. A growing body of evidence from genomic and proteomic research asserts that several receptors contribute to tumor behavior and these expression patterns are referred to as the cancer signature. Many cancers are characterized by an abnormal increase in the activity of epidermal growth factor receptors (EGFR) and transferrin receptors (TfR). Our data of representative human cancer cell lines demonstrate unique, observable expression patterns for the two receptors. Targeted-reporter imaging agent platforms have real application for noninvasive imaging of the multi-step progression of cancer growth, creating the next frontier in in vivo imaging. To develop imaging tools that take advantage of the diagnostic molecular signature, new technologies must employ a contrast agent or signal-amplifying material conjugated to a targeting agent. By linking a reporter enzyme, such as β-gal, to a targeting moiety, either ligand or a short peptide, signal-amplification at the molecular level is achieved. We divided β-gal into unique, independent polypeptides that reassemble and complement enzymatic activity in bacteria and in mammalian cells. We created two sets of complementing pairs that individually have no enzymatic activity. However, when brought into close proximity, complementing pairs associate, resulting in detectable enzymatic activity. We then constructed a targeting complex composed of reporter fragment, linker, and targeting moiety. Our studies demonstrate a time course- and dose-dependent uptake in vitro. Further, we were able to simultaneously visualize the two cell surface receptors implicated in cancer development, EGFR and TfR, using complementing pairs of the targeted-reporter fragment complex. In addition, we are able to image tumor localization in vivo of the targeted-complexes when a fluorescence reporter is added to the complex, as well as immunohistochemical staining of the β-gal reporter complex ex 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 4341.
Abstract 4342: Multimodal contrast agent development using imprint lithography based techniques: New tools for examining biodistribution
Authors: Herlihy Kevin P. , Merkel Timothy , DeSimone Joseph M. 
Published: February 2011

Abstract
Modern medicine stands to benefit greatly from recent advances in polymer science. Many state of the art therapeutics suffer from a poor therapeutic index because of poor biodistribution characteristics. To solve this problem, researchers are turning to new methods for therapeutic delivery. Herein we employ a top-down particle fabrication technique called Particle Replication In Non-wetting Templates (PRINT®) to fabricate unique biocompatible particles with distinct therapeutic properties based on their composition, size and shape. The particles are easily tagged with a variety of imaging beacons and radioisotopes making them effective as contrast agents for magnetic resonance imaging, positron emission tomography and fluorescence imaging and as radiotherapeutics. We employ this technique to design particles that will target or de-target specific organs and tissues as a function of their size and shape and therefore more effectively deliver their cargo. To our knowledge this work represents the first example of imprint lithography-based multimodal contrast agents and the first in-depth study of biodistribution of nanometer scale shape and size specific particles.
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 4342.
Abstract 4346: Genome-wide analysis of alternative splicing in pediatric medulloblastoma
Authors: Menghi Francesca , Jacques Thomas S. , Barenco Martino , Hubank Mike , Clifford Steven C. , Ham Jonathan 
Published: February 2011

Abstract
Background
Alternative pre-mRNA splicing (AS) is a key post-transcriptional mechanism for the generation of protein diversity. Abnormal alternative splicing can occur in cancer, and it results in the production of novel transcript variants or in an imbalance between normal mRNA isoforms. In both cases it can affect the global pattern of protein expression within a cell in ways that have the potential to sustain tumour growth.
To investigate patterns of alternative splicing in human pediatric medulloblastoma, we used the Affymetrix Human Exon 1.0 ST array, and measured gene expression at the level of individual exons on a genome-wide scale for 14 medulloblastoma specimens and 5 samples of normal cerebellum.
Results
Through statistical analysis of differential splicing we identified 1260 genes potentially undergoing AS between normal cerebellum and medulloblastoma. We selected 9 examples of differential splicing of cassette exons and validated them by semi-quantitative RT-PCR and sequencing. Interestingly, 3 of the validated genes showed a pattern of AS specific for the molecular subgroup of medulloblastomas characterized by hyper-activation of the Sonic Hedgehog (Shh) signalling pathway. In an in vitro mouse granule cell progenitor (GCP) culture model in which cells depend on Shh for the maintenance of their progenitor state, the pattern of AS in the presence of Shh for 5 out of the 6 genes analyzed recapitulated the pattern observed in the tumor samples, suggesting that the preferential expression of specific transcript forms is regulated during normal cerebellar development. Similarly, by analyzing different stages of post-natal mouse cerebellar development, we observed that the switch between the two alternative transcript forms occurred between P7 and P14, at the time when GCPs mature into post-mitotic neurons.
Conclusions
We identified and validated AS events between normal cerebellum and medulloblastoma and showed that medulloblastomas display patterns of AS which are observed during the normal development of the mouse cerebellum. Further studies will investigate the regulation and biological role of AS events in cerebellar development and tumorigenesis.
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 4346.
Abstract 4348: PDGF-Rα expression and activation of the MAPK pathway in disseminated pilocytic astrocytomas
Authors: Engels Alexander C. , Denkhaus Dorota , Gnekow Astrid , Pietsch Torsten 
Published: February 2011

Abstract
Background: Pilocytic astrocytomas (PA) are the most common pediatric tumors of the central nervous system. Approximately 5 % of patients with PA present a tumor dissemination. Although the disseminated growth is associated with severe clinical problems, the genetic alterations associated with this biological behaviour have never been investigated. As the histology of the disseminated PAs does not differ significantly to sporadic PAs, we analyzed the mitogen-activated protein kinase (MAPK) pathway for aberrations because genetic alterations of members of this pathway as BRAF and NF-1 have been found to be involved in the pathogenesis of non-disseminated PAs.
Methods: Immunohistochemical analysis of the platelet-derived growth factor receptors alpha (PDGF-Rα) and beta (PDGF-Rβ), the epidermal growth factor receptor (EGF-R), and the downstream activated (phosphorylated) extracellular signal-regulated kinase (p-ERK) was performed in a cohort of 18 patients suffering disseminated PAs. In three patients, material of the primary tumor and of relapses could be studied. The BRAF gene was analyzed for mutations by single strand conformation analysis (SSCP) and for gene copy numbers by semiquantitative PCR with fluorescence labelled primers. Mutational hotspots of the K-RAS, H-RAS and N-RAS genes were also analyzed by SSCP.
Results: Immunohistochemical analysis showed an increased PDGF-Rα expression in 71.4% of disseminated Pas, but no significant overexpression of EGF-R or PDGF-Rβ. A constitutive ERK phosphorylation was demonstrated in all disseminated PAs investigated. Molecular genetic analysis revealed V600E BRAF mutations in two tumors and an increased BRAF gene copy level in the majority of cases. No RAS mutations were found.
Conclusions: This is the first report of molecular genetic analysis of the MAPK pathway in disseminated pilocytic astrocytomas. It underlines the important role of the upstream PDGF-Rα receptor and subsequent MAPK pathway in these gliomas. Its activation represents a potential target for novel strategies in the therapy of disseminated PAs.
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 4348.
Abstract 4361: Retinoblastoma (RB) genomic progression analysis using Tissue Microarrays (TMA) comprising 121 RB patient tumors
Authors: D'Silva Crystal N. , Yoshimoto Maisa , Natalino Renato , Soares Fernando , Antoneli Celia , Ribeiro Karina , Halliday William , Gallie Brenda L. , Squire Jeremy A. 
Published: February 2011

Abstract
Retinoblastoma is the second most common childhood intraocular malignancy and development of the tumor is initiated by bi-allelic loss of the RB1 gene. Bi-allelic RB1 loss may not always directly lead to malignant retinoblastoma, rather other genetic changes are likely involved. Subsequent mutational events, specifically gain and loss of chromosomal regions harboring key oncogenes and tumor suppressor genes, appear to underlie the progression of precursor lesions such as retinoma to retinoblastoma. Research thus far has implicated several cytogenetic aberrations in this sequence of molecular events, the two most recurrent and notable being the augmented copy number status of KIF14 and MDM4 on 1q and of DEK and E2F3 on 6p. A small subset of retinoblastoma also exhibits high-level amplification of the MYCN gene on chromosome 2p. KIF14, MDM4, DEK, E2F3 and MYCN have been widely characterized as oncogenes in a variety of cancers. The functional roles of the proteins encoded by these genes would also confer tumor cells manifesting these genomic changes with a selective survival and proliferative advantage. Our project is testing the hypothesis that 1q and 6p gain and 2p amplification - defined by extra copies of KIF14 and MDM4, DEK and E2F3 and MYCN respectively - are associated with clinical parameters of progression. The study comprises formalin-fixed paraffin-embedded fluorescence in situ hybridization (FFPE-FISH) analysis of pre-constructed tissue microarrays comprising 121 patient tumours, in order to determine the genomic copy number status of the five aforementioned genes. Results show 1q gain (3-10 copies) in 102/121 (84%), 6p gain in 115/121 (95%), MYCN gain in 14/121 (12%) and MYCN amplification (&gt;10 copies) in 16/121 (14%) patient tumors. Assessment of potential correlations between the copy number status of these genes and clinical variables of disease progression include patient age, pathology at the time of diagnosis, optic nerve invasion, choroid involvement, laterality of the disease, number of tumor foci present at the time of diagnosis and histopathological parameters. To our knowledge, there has been no recent study associating genomic change of these five genes with clinical parameters of progression in a sample size of statistical significance. The large cohort and consequent statistical power of our results will facilitate a better understanding of the biological role of these genes in the progression from retinoma to retinoblastoma.
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 4361.
Abstract 4362: Plk1 is overexpressed in retinoblastoma and its inhibition by siRNA or small-molecule inhibitor results in growth arrest and apoptosis
Authors: Berglund Andrew , Dalgard Clifton L. 
Published: February 2011

Abstract
Retinoblastoma (RB) is a pediatric cancer of the retina where current chemotherapeutic regimens are broad spectrum with significant side effects. Molecular target-based approaches for RB therapy are absent and may be rational for this disease. We performed a siRNA library screen for growth inhibition of human Y79 RB cells. Knockdown of Plk1 or AURKA (but not other mitotic regulatory factors) lead to greater than 90% cell growth inhibition and prompted further investigation. We determined Plk1 expression in retinoblastoma and normal retina tissue by immunohistochemistry. We also determined the effects of siRNA-mediated Plk1 knockdown and small molecule-mediated Plk1 inhibition on Y79 and Weri-Rb1 cell growth using a tetrazolium dye-based assay. Effects on proliferation and cell cycle distribution were determined by flow cytometric analysis of EdU incorporation and DNA content. Activation of DNA damage response and apoptosis was determined by western blot analysis of phospho-H2AX, cleaved caspase-3, and PARP. We observed moderate and high Plk1 protein expression in several human retinoblastoma tumor samples as compared to minimal or low expression found in normal retinal tissue. Increased Plk1 expression was observed in RB cell lines as compared to normal retina cells. 10 nM Plk1 siRNA and 30 nM BI-2536 potently inhibited Y79 and Weri-Rb1 cell growth and significantly decreased cell viability. A decrease in S phase EdU incorporation and proliferation and an increase in G1 phase population was observed in flow cytometric analysis of Plk1 inhibited RB cells. A significant increase in phospho-H2AX, cleaved caspase-3, and cleaved PARP protein levels was observed in Y79 and Weri-Rb1 cells treated with Plk1 siRNA or BI-2536. These results suggest that Plk1 may be a rational target for RB therapy and encourages preclinical studies in animal models of RB.
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 4362.
Abstract 4369: MMP9, MMP14, and MMP15 genes are induced by nicotine in an E2F-dependent manner
Authors: Johnson Jackie L. , Pillai Smitha , Chellappan Srikumar 
Published: February 2011

Abstract
Cigarette smoking is strongly correlated with the onset of non-small cell lung cancer (NSCLC). Nicotine, the addictive component of cigarettes, has been found to induce proliferation, confer resistance to apoptosis, and induce EMT like changes in breast, pancreatic, and lung cancer cell lines. In addition, nicotine also induces morphological changes characteristic of a migratory, mesenchymal phenotype in NSCLCs. Correspondingly, the exact molecular mechanism for this acquired invasiveness in NSCLCs has been partially elucidated, but still remains somewhat unclear. To determine whether this increased invasion is due to up-regulation of proteolytic proteins, we first examined the mRNA levels of matrix metalloproteinase genes, which are crucial proteins for the mechanical degradation of the ECM, after exposure to nicotine. MMP9, MMP14, and MMP15 mRNA levels were significantly induced by treatment with nicotine when compared to serum starved A549 lung adenocarcinoma cells. Transient transfection experiments in H1650, A549, and MDA-MB-231 cell lines also show that a 2kb MMP9-luc promoter is induced by treatment with nicotine. In order to identify a possible factor responsible for this induction, we next analyzed the promoters of MMP genes. Chip assays show that these MMPs had multiple functional E2F binding sites. Wound healing assays on these cells showed that cells lacking E2F1 were impaired in their ability to migrate on plastic. In addition, cells lacking E2F1 showed a lower capacity for invasion, as determined by Boyden Chamber assays. The effect of depleting E2F1 on MMP expression was assessed by Real-time PCR assays. It was found that MMP 9, 14, and 15 were down-regulated in A549 cells lacking E2F1. Furthermore, these MMP9, 14, and 15 promoter reporters were induced upon co-transfection with either E2F1 or E2F3, both classical E2F activators. These data suggest that the Rb/E2F pathway is a likely downstream target of nicotine and mediates invasion by enhancing the levels of MMPs.
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 4369.
Abstract 4370: Arsenite stabilizes HIF-1α protein through p85α-mediated upregulation of inducible Hsp70 protein expression
Authors: Guo Wei , Zuo Zhenghong , Yang Zhuo , Xia Qing , Liu Jinyi , Li Jingxia , Zhang Dongyun , Shi Xianglin , Huang Chuanshu 
Published: February 2011

Abstract
Arsenite has long been known as a human carcinogen. The hypoxia-inducible factor-1 (HIF-1) is an important transcription factor upon hypoxia and other stresses, which is proved to be associated with the pathogenesis of several cancers. Although hypoxia-inducible factor-1α (HIF-1α) has been reported to be activated by arsenite both in vivo and in vitro, the detailed molecular mechanisms leading to HIF-1α expression and activation due to arsenite exposure have not been well understood. In the present study, we found that arsenite is able to induce HIF-1α protein accumulation in both mouse epidermal Cl41 cells and mouse embryonic fibroblasts (MEFs). Knockout of p85α in MEFs (p85α−/−) led to the deficiency of HIF-1α protein accumulation induced by arsenite exposure, suggesting that p85α is crucial for arsenite-induced stabilization of HIF-1α protein. At the same time, our studies also show that p85a exhibited an inhibition of HIF-1α protein degradation via PI-3K/Akt-dependent pathway in cellular response to arsenite exposure. Our further studies revealed that arsenite exposure was able to induce inducible Hsp70 expression, and the deficiency of HIF-1α protein in p85α−/− MEF cells could be restored by introduction of inducible Hsp70 into p85α−/− MEF (p85α−/− (Hsp70)). Moreover, our results also indicated that p85α is crucial for arsenite-induced activation of heat shock transcription factor 1 (HSF-1), which is responsible for the transcription of inducible Hsp70. The transcriptional up-regulation of hsp70 by activated PI-3K/Akt pathway is strictly mediated by heat shock transcription factor-1 (HSF-1). Taken together, our studies demonstrated that p85α-mediated HIF-1α stabilization due to arsenite exposure is specific through p85α mediation of HSF-1 activation and subsequently transcriptional up-regulation of the inducible Hsp70. During this course, p85 regulated inducible Hsp70 expression transcription through PI-3K/Akt/HSF-1 pathway upon arsenite exposure.
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 4370.