bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2589: Sulfated hyaluronic acid: A possible targeted therapy for prostate cancer
Authors: Yates Travis , Benitez Anaid , Lopez Luis E. , Lokeshwar Vinata B. 
Published: June 2012

Abstract
Tumor cell-derived hyaluronidase HYAL1, which degrades hyaluronic acid (HA), promotes tumor growth and metastasis. In prostate cancer (CaP), HYAL1 expression in biopsy and prostatectomy specimens is an independent prognostic marker for predicting disease progression. Sulfated hyaluronic acid (sHA) inhibits HYAL1 activity through a mixed inhibition mechanism. Antitumor activity of sHA has not been evaluated. In this study we evaluated effects of sHA on CaP cells. The effect of sHA (0-40 ug/ml) on cell proliferation and apoptosis was examined in CaP cells (PC3-ML, LNCaP, LNAI, C4-2B, LAPC-4, DU145, RWPE1) by cell counting and Cell Death ELISA kit. Matrigel invasion and Boyden chamber assays were used to test the effect of sHA on invasive activity. Effect of sHA on signaling, apoptosis cascade, androgen receptor activity, VEGF, NFkB activity, and HA receptor levels, was evaluated by immunoblotting, Q-PCR and reporter assays. Athymic mice bearing LNAI xenografts were treated with sHA (25 and 50 mg/kg) by i.p. injection. sHA inhibited proliferation, motility and invasion in CaP cells. At IC50 for HAase activity inhibition (∼ 10-μg/ml), sHA induced &gt; 3-fold apoptosis and inhibited invasive activity of CaP cells, which could be partially reversed by HA-fragments. sHA induced caspase-3, -8, -9 activation, up-regulation of Fas, Fas-L, FADD, and DR4 and down regulated bcl-2, phospho-bad, bcl-XL, phospho-Akt, phospho-IkB, and phospho-AR. At IC50, sHA caused &gt; 90% inhibition of NFKB-reporter activity, PSA-promoter activity and transcriptionally down regulated HA-receptors (CD44 and RHAMM) and VEGF. Effect of sHA could be reversed by overexpression of m-Akt. Down regulation of CD44 and RHAMM, together with sHA synergistically inhibited cell proliferation and Akt activation. sHA significantly inhibited LNAI tumor growth. The majority of the animals did not form palpable tumors at 50-mg/kg dose even after 70 days when the treatment was stopped on 42nd day. No weight loss or serum and organ toxicity was observed in sHA treated animals. Tumors showed reduced microvessel density (∼3-fold) and increased TUNEL positive cells (&gt; 5-fold). This is the first study that shows targeting HYAL1 (by sHA – a novel non-toxic agent), may control CaP growth and progression.
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 2589. doi:10.1158/1538-7445.AM2011-2589
Abstract 2603: Inhibition of Notch and mTOR by nelfinavir as a novel approach for T cell acute lymphoblastic leukemia (T-ALL)
Authors: Chang Yoon Soo , Meza Leah M. , Onozawa Masahiro , Gills Joell J. , Aplan Peter D. , Dennis Phillip A. 
Published: June 2012

Abstract
Background: T-ALL accounts for 10-15% of childhood ALL and 25% of adult ALL. Although intensive chemotherapy improves disease free survival, patients who relapse or progress have a dismal prognosis. Notch1 is a promising target in T-ALL because it is commonly activated, and inhibitors of γ-secretase (GSI), an aspartic protease that processes Notch1, are in clinical trials. Nelfinavir is an HIV protease inhibitor with anti-cancer activity through its inhibition of the Akt/mTOR pathway as well as unknown mechanisms. Because the HIV protease is an aspartic protease, we hypothesized that a target for nelfinavir in cancer cells could be γ-secretase.
Methods: Nelfinavir was compared to compound E, a commercially available GSI, in in vitro studies. Notch1 and mTOR signalling was evaluated in human and murine T-ALL cell lines by immunoblotting. γ-secretase activity was assessed in cell-free in vitro assays. Cell death was measured by flow cytometry after annexin V and propidium iodide staining. Nelfinavir was also tested in a transgenic model of T-ALL (established by overexpression of SCL and LMO1 in the mouse thymus) using microCT scans, flow cytometry and IHC.
Results: Among 7 HIV protease inhibitors evaluated, only nelfinavir inhibited expression of the Notch1 transmembrane and intracellular domains as well as Hes1 and survivin, well-established downstream targets of Notch1. At clinically achievable concentrations, nelfinavir rapidly inhibited Notch1, which was sustained to 16 hr when death was evident. Cell-free assays showed that although compound E was a more potent inhibitor of γ-secretase, the maximal enzymatic inhibition by nelfinavir was equivalent at higher doses. Nelfinavir was far more effective than compound E in reducing expression of Notch targets such as phospho-Rb, c-Myc, and Hrb, Hes1, and survivin. Nelfinavir induced apoptosis to levels equivalent to 20 µM etoposide, but compound E was only cytostatic. To explore other mechanisms that could explain the decreased protein expression and higher levels of cell death with nelfinavir, we assessed the Akt/mTOR pathway. Nelfinavir rapidly induced AMPK activation and mTOR inhibition, coincident with Notch1 inhibition. In SCL-LMO1 double transgenic mice, nelfinavir decreased thymic size and markedly increased apoptotic cells in the thymus. It also decreased the CD3+ populations in spleen and bone marrow and decreased CD4+CD8+ double positive leukemic cells.
Conclusion: These studies show that nelfinavir is superior to a GSI and highly active in preclinical studies of T-ALL. Clinical testing of nelfinavir in T-ALL patients is planned.
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 2603. doi:10.1158/1538-7445.AM2011-2603
Abstract 2667: L1CAM neural adhesion molecule is overexpressed in human brain metastases of breast cancer and contributes to colony formation efficiency
Authors: Evans Lynda M. , Woditschka Stephan , Fitzgerald Daniel P. , Palmieri Diane , Badve Sunil , Sledge George W. , Steeg Patricia S. 
Published: June 2012

Abstract
To investigate the molecular mechanisms responsible for breast cancer metastasis to the brain, a gene expression analysis was performed using formalin-fixed, paraffin embedded sections of matched primary breast tumors and resected brain metastases. The neuronal cell adhesion molecule L1CAM was upregulated by approximately 1.57 fold in the brain metastases relative to the primary tumors (p=0.037). This trend was most apparent in Her-2+ tumors (p=0.044) and did not extend to ER+ patients (p=0.42). L1CAM has been correlated to decreased patient survival in breast cancer. MDA-MB-231 breast cancer cells selected to grow in the brain (231-BR) expressed 6.4 fold greater L1CAM on western blots than the parental cell line (231-P). Using three shRNA constructs, L1CAM expression was decreased by 1.76, 3.82, and 63.3 fold in the 231-BR cell line. Decreased L1CAM expression inhibited the clonogenic formation of 231-BR cells by 40-50% (p&lt;0.002); however, increased proliferation by MTT assay by 30-60% (p&lt;0.002). The most efficient L1CAM knockdown also showed a 30% decrease in migration via scratch assay relative to the non-targeting control, suggesting that L1CAM may be involved in 231-BR cell migration (p&lt;0.03). Studies are underway to determine the effect of L1CAM down-regulation on the development of breast cancer brain metastases. These results suggest L1CAM may be a potential novel therapeutic target for metastatic breast cancer in the brain.
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 2667. doi:10.1158/1538-7445.AM2011-2667
Abstract 2688: Establishment of high avidity CTL clones induced by HLA-A2 restricted glypican-3 (GPC3) peptide vaccine
Authors: Yoshikawa Toshiaki , Suzuki Shiro , Nakatsugawa Munehide , Shirakawa Hirofumi , Nobuoka Daisuke , Sakemura Noriko , Motomura Yutaka , Nakatsura Tetsuya 
Published: June 2012

Abstract
Glypican-3 (GPC3) is an onco-fetal antigen which is overexpressed in human hepatocellular carcinoma (HCC) and that among normal tissues it is slightly expressed in placenta and embryonic liver. Previously, we have identified a HLA-A2-restricted GPC3144-152 (FVGEFFTDV) peptide which can induce GPC3-reactive cytotoxic T lymphocytes (CTLs) without inducing autoimmunity. In the present study, we performed phase I clinical trial of HLA-A2 restricted GPC3-derived peptide vaccine to the 14 patients with advanced HCC. Immunological responses were analyzed by ex vivo IFN-γ Enzyme-linked immunospot (ELISPOT) assay. The frequency of GPC3 peptide specific CTLs after vaccinations (mean, 96; range, 5-441) was statistically significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P &lt; 0.01). An increase of the GPC3 peptide specific CTL frequency was detected in 12 (86%) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3 peptide specific CTLs after vaccination and dose of peptide injected (P = 0.0166, r = 0.665). Moreover, we established some GPC3 peptide specific CTL clones from PBMCs of patients vaccinated with GPC3 peptide by single cell sort using Dextramer and CD107a antibody. These CTL clones were high avidity CTLs (10−10M and 10−11M) and could recognize HCC cell lines expressing GPC3 in a HLA-class I-restricted manner. These results suggest that tumor-cytolytic T cells are indeed elicited in patients after vaccination. Now we investigate whether the GPC3 based immunotherapy have possibility of the application for other GPC3 expressing cancers including melanoma, clear cell carcinoma of the ovary, pediatric cancer or not, using established GPC3 peptide specific CTL clone.
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 2688. doi:10.1158/1538-7445.AM2011-2688
Abstract 2712: Inflammation in the background cirrhotic tissue might accelerate the promotion in the HCC development from HCV-associated cirrhosis
Authors: Tarao Kazuo , Miyakawa Kaoru , Endoh Yuichi , Kobayashi Satoshi , Ueno Makoto , Ohkawa Shinichi , Morinaga Soichiro , Nakamura Yoshiyasu , Miyagi Yohei , Kameda Yoichi , Okudaira Masahiko 
Published: June 2012

Abstract
Aim: Hamada et al. succeeded in converting ER-1, a weakly tumorigenic cloned cell line of a rat mammary carcinoma, into a highly tumorigenic and metastatic cell line by interaction with host cell reactive to a foreign body (plastic plates). They attributed these phenomenon to the cytokines such as LL-6 derived from host reactive inflammatory cells crowded around the foreign body. It is possible that the same mechanism is involved in the development of human HCC, and that inflammation in the background cirrhotic tissue might accelerate the process of promotion. Methods: Curative hepatic resection for HCC with LC was performed in 223 patients during the past 8 years in Kanagawa Cancer Center hospital. Of 223 patients 182 patients were anti-HCV-positive or HCV-RNA positive without habitual alcohol intake. Out of 182 patients, 32 patents whose HCC revealed only one small HCC nodule of less than 3 centimeter in diameter were selected for this study. For the evaluation of inflammation in the background LC, modified Knodell's histology activity index (HAI) was used. (for the evaluation of pure inflammation, items of fibrosis was omitted); piece meal necrosis (1-4), intra lobular cellular degeneration and focal necrosis (1-4), portal cellular inflammation (1-4), were estimated by two well experienced pathologist. In each case, the HAI score was estimated in five field and average HAI score was calculated. All the sections of resected HCC tissue was examined pathologically in all patients for determining the grade of malignancy according to Edmondson Steiner's classification; Ed I (well differentiated), Ed II (moderately diff.), Ed III (poorly diff.) Results: The average HAI score in the non-cancerous cirrhotic portion in HCC patients with Ed III was 5.50 ± 0.98 (mean ± SD), and was significantly larger than that in HCC patients without Ed III (4.18 ± 0.70, p &lt; 0.001).
Furthermore, the occurence rate of HCC containing Ed III component in the HCC patients whose HAI score was more than 5.0 was as high as 88.9% (16 out of 18), and was highly significant as compared with those in HCC patients whose HAI score was less than 5.0% (3 out of 14, 21.4%, p &lt; 0.005).Conclusions: It is suggested that inflammation in the surrounding non-cancerous cirrhotic tissue would accelerate the process of promotion in the HCC development.
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 2712. doi:10.1158/1538-7445.AM2011-2712
Abstract 2730: Role of Stat1 in skin tumor promotion
Authors: Bozeman Ronald , DiGiovanni John , Abel Erika 
Published: June 2012

Abstract
Inflammation is a key component of cancer development in many tissues. Emerging clinical observations support the idea of a strong association of chronic inflammation and cancer. The JAK-STAT pathway is one of the major signaling pathways involved in modulating both pro- and anti-inflammatory responses. Aberrant expression of STATs has been reported in multiple human cancers and in animal models of tumorigenesis. Previous work performed in our lab demonstrated a role for Stat1 in mediating the promotion stage of epithelial multi-stage carcinogenesis in mouse skin when chrysarobin was used as the promoting agent. To further investigate the role of Stat1 in chrysarobin-mediated skin tumor promotion, Stat1 knockout (KO) mice and wild-type controls were treated with chrysarobin and the inflammatory response was assessed. Stat1 deficiency caused a reduction in the dermal inflammatory response following a single topical application of chrysarobin. In this regard, Stat1 KO mice had reduced dermal immune cell influx following chrysarobin treatment. In particular, Stat1 KO mice exhibited reduced influx of macrophages following a single application. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Mice deficient in Stat1 displayed an attenuated induction of Cox-2 mRNA and protein compared to wild-type controls following a single application of chrysarobin (200 nmol per mouse). This latter data suggest that Stat1 may be involved in the regulation of Cox-2 in keratinocytes. Collectively, these findings suggest that Stat1 may contribute to chrysarobin-mediated skin tumor promotion by regulating, in part, levels of Cox-2, PGE2 and ultimately skin inflammation. These and other ongoing studies aimed at identifying the mechanistic basis for the role of Stat1 in chrysarobin-mediated tumor promotion will be presented.
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 2730. doi:10.1158/1538-7445.AM2011-2730
Abstract 2739: DNA repair genotype-phenotype correlation and interplay between different DNA repair pathways
Authors: Allione Alessandra , Guarrera Simonetta , Polidoro Silvia , Rosa Fabio , Ricceri Fulvio , Voglino Floriana , Russo Alessia , Gaetano Cornelia Di , Simonelli Valeria , Mazzei Filomena , Porcedda Paola , Giachino Claudia , Vineis Paolo , Dogliotti Eugenia , Matullo Giuseppe 
Published: June 2012

Abstract
Individual DNA repair capacity is modulated by the genetic background to which hundreds of single nucleotide polymorphisms (SNPs) or haplotype combinations in DNA repair genes are likely to contribute. A large number of studies have been published on the association between DNA repair gene polymorphisms and cancer risk, whereas only few small studies investigated the relation between DNA repair phenotypic assays and cancer risk or DNA repair polymorphisms. In order to identify functional SNPs/haplotypes modulating DNA repair phenotypes and to investigate their potential impact on cancer risk, we have performed a genotype-phenotype correlation study evaluating levels of DNA damage and DNA repair capacity in blood cells treated at low doses of different DNA damaging agents. We investigated the association between genotypes/haplotypes and the DNA repair capacity measured with the following DNA repair phenotypic assays on cryopreserved lymphocytes from 225 healthy individuals: Comet assay after treatment with BPDE, phosphorylation of histone H2AX after treatment with γ-rays, OGG1 glycosylase activity, OGG1 and ERCC1 expression levels. Sixty-five DNA repair genes and a total of 768 SNPs have been selected and analysed on the 225 DNA samples by using a custom GoldenGate SNP chip (Illumina). Genotype-phenotype correlation analysis identified some new possible functional variants and haplotypes. We also tested gene-gene interactions, comparing results with existing prior knowledge from different publicly available databases and crossing functional evidence with information on gene expression levels and protein-protein interaction. A confirmation of some already described interplays between different DNA repair pathways have been obtained from SNP analysis and a suggestion of new possible cross-talks have been identified that need further experimental validation. Our results can contribute to identify subjects carrying combinations of less efficient DNA repair variants/haplotypes possibly at increased cancer risk or who can better benefit from anti-cancer therapies.
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 2739. doi:10.1158/1538-7445.AM2011-2739
Abstract 2741: Applying a biological pathway-based approach to interrogate the genome-wide association data on prostate cancer
Authors: Feng Junjie , Sun Jielin , Zhang Zheng , Zhu Yi , Xu Jianfeng 
Published: June 2012

Abstract
Genome-wide association studies (GWAS) have been successful in identifying common susceptibility loci for several complex diseases, yet the massive amounts of data generated from GWAS have not been maximally leveraged. We have applied a previously reported pathway-based approach to analyze the prostate cancer (PCa) GWAS data from the Cancer Genetic Markers of Susceptibility (CGEMS) project. This approach examines whether the cumulative contribution of a set of SNPs that occur on genes within a predefined biological pathway is greater than expected by chance, and thus may provide important novel biological insights that have been missed by most current GWAS. Out of the 555 pathways analyzed from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology, and BioCarta databases, a total of 32 pathways reached a nominal P &lt; 0.05 in their associations with PCa. Among these notably include six KEGG-defined cancer pathways (thyroid, prostate, renal, and pancreatic cancer, non-small cell lung cancer, and acute myeloid leukemia), three well-established cancer-related molecular pathways (ATR-BRCA, ionizing radiation response, and apoptosis), and three pathways that have cancer implications (glycolysis, calcium-dependent cell-cell adhesion, and regulation of actin cytoskeleton), which together constitute more than one third of the top-ranked pathways. Of closest relevance is the prostate cancer pathway (hsa05215), which was ranked the third highest (nominal P = 0.01) in our analysis. However, no associations of these top pathways remained significant after correction for multiple testing, indicating that the common variants involved in PCa risk are likely to occur in genes from multiple pathways. This genome-wide pathway analysis supports a model that alterations from multiple pathways may combinatorially contribute to the etiology of PCa.
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 2741. doi:10.1158/1538-7445.AM2011-2741
Abstract 2747: Application of a novel multi-locus test for genetic association incorporating gene-gene interaction suggests functionality for multiple susceptibility loci for prostate cancer
Authors: Ciampa Julia G. , Holmes Chris , Chatterjee Nilanjan 
Published: June 2012

Abstract
The discovery of gene-gene interactions in genome-wide association studies (GWAS) can generate hypotheses about the biologic process through which multiple susceptibility loci influence the pathogenesis of disease. We present an extension of a previously proposed score-test for disease association that allows for interaction between sets of biologically similar single nucleotide polymorphism (SNPs). The score-test gains power over alternative methods by incorporating a parsimonious one-degree-of-freedom model for gene-gene interaction. Our proposed extension allows for additional power gains in case-control studies via use of a retrospective likelihood that can exploit an assumption of gene-gene independence for the underlying population between unlinked sets of SNPs. Simulation studies were used to validate the performance of this method. It was found to maintain type I error and to gain power over alternative methods. We used it in a prostate cancer (PRCA) application with data from Stage II of the Cancer Genetic Markers of Susceptibility GWAS that includes 27,383 SNPs in 3941 cases and 3964 controls. We performed two genome scans, conditioning on established susceptibility SNPs for PRCA. Both analyses identified a high-ranking SNP notable for its biology and worthy of follow-up study. The first scan involved a sub-region of 8q24 that contains independent susceptibility loci specific to PRCA, as well as androgen-receptor (AR) binding sites and androgen-responsive enhancer elements. The analysis highlights rs748120 intronic to NR2C2 which produces an AR co-regulator such that, when NR2C2 binds AR, expression of their target genes decreases. The observed interaction suggests NR2C2 may contribute to the androgen sensitivity of this 8q24 gene desert in the etiology of PRCA. The second scan involved the JAZF1 and HNF1B genes regions that are associated with both PRCA and type 2 diabetes, which itself is associated with PRCA risk. The analysis highlights rs4810671 intronic to SULF2 which has demonstrated oncogenic properties in several cancers. It is regulated by insulin, the hormone thought to mediate the association of type 2 diabetes with PRCA. The observed interaction suggests abnormal insulin function may affect PRCA risk through dysregulation of SULF2. In summary, we propose an innovative multi-locus test for disease association that gains power over alternative methods and we describe promising results from a PRCA GWAS that suggest functionality for susceptibility regions.
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 2747. doi:10.1158/1538-7445.AM2011-2747