bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 882: Copy number variation analysis identified multiple genetic variants related to nasopharyngeal carcinoma predisposition
Authors: Su Wen-Hui , Tse Ka-Po , Yang Min-lee , Shugart Yin Yao , Chang Yu-Sun 
Published: June 2012

Abstract
Nasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. Recently, we have conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3 in the major histocompatibility complex region. In addition to HLA-A gene, we detected novel significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 and HLA-F. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Following the GWAS study, we made an effort to search systematically for copy number variations (CNVs) that confer increased risk to NPC using the same dataset. We generated CNV calls using four different softwares and used 15 internal duplicated samples to look for best filtering criteria. CNVs were selected if same CNVs were identified from two independent softwares to increase credibility of prediction. We identified eight CNVs that overrepresented in NPC patients compared to healthy controls. Six deletions on chromosomes 3, 6, 7, 8 and 19, as well as 2 duplications on chromosomes 7 and 12 were found. One of the most significant CNV on chromosome 6p21.3 was further replicated in an independent case-control dataset, using a deletion-specific polymerase-chain reaction. To the best of our knowledge, it is the first study of genome-wide constitutional CNV in NPC.
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 882. doi:10.1158/1538-7445.AM2011-882
Abstract 896: A systematic search in tumor interstitial fluid identifying a tumor-specific interleukin-hypoxia-glycolysis-DNA repair pathway and a novel serum marker RBB3 for human hepatoma
Authors: Hsieh Sen-Yung 
Published: June 2012

Abstract
The long-term outcome of patients with hepatocellular carcinoma (HCC) remains undesirable, primarily due to late diagnosis and high recurrence. We aimed to discover new markers for early detection and prediction of recurrence. We initiated our search by comparing the proteomes of the interstitial fluid of HCC (TIF) and nonHCC liver tissues by using proteomic approaches. About 150 proteins were found to be dysregulated in TIF. Gene ontology analysis and biofunction reconstruction revealed the involvement of “interleukin-hypoxia-glycolysis-DNA repair pathway” in HCC. To search for novel serum markers, we identified secreted RBB3 (sRBB3) significantly increased their amount in TIF. Further studies disclosed that the serum sRBB3 level was significantly higher in HCC (113 cases) than in cirrhosis (47 cases)(p &lt; 0.001) and chronic hepatitis (64 cases)(p &lt; 0.001). The accuracy of serum sRBB3 in detection of HCC was further validated in 2 independent sets (92 cases in each set) of patients by using receiver operating characteristic (ROC) curve. A sensitivity of 89.3% and a specificity of 99.7% were obtained. Moreover, serum srbb3 had a better performance than serum alpha-fetoprotein (AFP) in discrimination of early HCC from chronic hepatitis [areas under the ROC curves (AUC) for srbb3 vs. AFP = 0.931 vs. 0.810] and from cirrhosis (AUCs: serbb3 vs. AFP = 0.709 vs. 0.627). The serum sRBB3 level was strongly associated with portal vein invasion and extrahepatic metastasis of HCC (p = 0.017). The performance of the combination of serum srbb3 and AFP was similar to that of srbb3 but better than that of AFP in discrimination of HCC from non-HCC. Conclusion: Interstitial fluid of tumor tissues is a good source in the search for novel tumor markers. An immune-mediated tumor microenvironment plays roles in genome damage and possibly tumorigenesis of HCC. Serum srbb3 is a better HCC marker than AFP, particularly for detection of early HCC and for portal vein invasion and extrahepatic metastatsis.
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 896. doi:10.1158/1538-7445.AM2011-896
Abstract 899: TMPRSS2:ERG urine test identifies Gleason score upgrading and significant prostate cancer
Authors: Aubin Sheila M. , Tomlins Scott , Meyer Sarah , Penabella Yvonne , Siddiqui Javed , Wei John , Chinnaiyan Arul , Rittenhouse Harry , Groskopf Jack 
Published: June 2012

Abstract
Objective: In men diagnosed with prostate cancer (PCa) at biopsy, a major challenge is correctly stratifying those with indolent versus significant PCa for treatment selection. The extent and grade of PCa is assessed in part based on standard risk factors, biopsy Gleason score (bx GS) and the number of positive biopsy cores. However, due to under-sampling at biopsy, upgrading in Gleason score is often seen from biopsy to prostatectomy. In this study we evaluated a TMPRSS2:ERG (T2:ERG) urine test for its ability to identify significant cancer and upgrading at prostatectomy.
Methods: Post-DRE urine specimens were prospectively collected from 218 men referred for prostatectomy. T2:ERG mRNA copies were quantified using a transcription-mediated amplification assay and normalized to PSA mRNA copies to calculate a T2:ERG score. The prototype T2:ERG urine assay detects the gene fusion mRNA isoform TMPRSS2 exon 1 to ERG exon 4. T2:ERG score was correlated to prostatectomy Gleason score (px GS) and significant cancer as defined by the Epstein criteria at prostatectomy.
Results: Of 185 men scheduled for radical prostatectomy, 61 had low risk of significant cancer based on having bx GS&lt;6 and % positive biopsy cores&lt;33%, yet upon prostatectomy, 57% of these men were found to harbor a significant PCa. The T2:ERG assay identified an additional 31% prostatectomy significant cancer in the biopsy low-risk disease cancer group. In a multivariate model, adding T2:ERG to bx GS and % positive cores significantly increased the accuracy for predicting significant PCa at prostatectomy from 0.84 to 0.89 (p=0.0002). Sensitivity increased by 8% for detecting prostatectomy significant cancer when T2:ERG was added to these biopsy criteria (sens/spec=85%/87% vs 77%/87%). T2:ERG also significantly correlated with Gleason score upgrading from biopsy to prostatectomy (bx GS/px GS = 6/ 6 vs bx GS/px GS = 6/&gt;7, p = 0.0076). At biopsy, 70 men were found to have low-grade cancer (bx GS&lt;6), but upon prostatectomy, upgrading was seen in 50% of these men. T2:ERG was able to identify 40% of men with bx GS&lt;6 that were later upgraded.
Conclusions: A T2:ERG urine test may help identify significant cancers and Gleason score upgrading, and increase predictive accuracy when used in combination with currently available methods.
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 899. doi:10.1158/1538-7445.AM2011-899
Abstract 9: 2-deoxyglucose caused toxicity is regulated by the Bcl-2 family and is enhanced by Bcl-2 antagonist in lymphoma cell lines
Authors: Zagorodna Oksana , Martin Sean , Kuwana Tomomi , Spitz Douglas , Knudson C. Michael 
Published: June 2012

Abstract
Introduction. 2-deoxyglucose (2DG) is a glucose analog and inhibitor of glycolysis that has been shown to have anti-cancer activity, proposed to be due to altered metabolism of cancer cells. 2DG has also been reported to induce ER stress through inhibition of N-linked glycosylation. Whether 2DG is effective in lymphoma and the mechanisms of cell death are not known.
Materials and Methods. Five tumor cell lines were independently derived from Lck-Bax driven murine T cell lymphomas (TCLs). The sensitivity of these cell lines to 2DG was determined by plasma membrane integrity and clonogenic survival. Caspase inhibitors, overexpression of Bcl-2, downregulation of Bim, the Bcl-2 antagonist ABT-737, and mannose were utilized to determine the molecular mechanism of 2DG-caused death in lymphoma cell lines.
Results and Conclusions. TCLs are uniformly sensitive to physiologically relevant concentrations of 2DG treatment. The cell death pathway involves Bax “activation” and Caspase cleavage following 2DG treatment. However, qVD-OPh effectively inhibited caspase activity while providing minimal protection from death. In contrast, expression of Bcl-2 enhanced both short term and clonogenic survival of 2DG treated cells. A Bcl-2 antagonist, ABT-737, sensitized TCLs to 2DG-induced cell death. Examination of BH3-only members demonstrated that both Bim and Bmf were upregulated following 2DG treatment. Importantly, downregulation of Bim with shRNAs protected from 2DG treatment, demonstrating that Bim is a critical mediator of 2DG toxicity. We also observed that 2DG led to CHOP induction, a transcription factor shown to directly mediate Bim upregulation following ER stress. Mannose, a reagent known to alleviate ER stress induced by 2DG, also transiently protected from cell death. While mannose effectively blocked CHOP upregulation, Bim upregulation was delayed but not blocked indicating that 2DG upregulated BIM and induced cell death by ER stress dependent and independent mechanism. However, both pathways converge at a step that involves the activation of Bax and is blocked by Bcl-2. We conclude that 2DG toxicity is regulated by the Bcl-2 family, and the combination of Bcl-2 inhibition and 2DG is a candidate for effective therapeutic strategy for lymphoma.
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 9. doi:10.1158/1538-7445.AM2011-9
Abstract 921: HER3 reactivation: A compensatory shift between Akt-mediated positive and negative feedback loops in HER2-overexpressed human breast cancer cells
Authors: Tang Patrick Ming Kuen , Leung Fenix , Gijsen Merel , Harris Adrian L. , Kong Anthony 
Published: June 2012

Abstract
The activated serine/threonine protein kinase Akt (or Protein Kinase B, PKB) regulates cell survival and metabolism by phosphorylation of numerous adaptor proteins and kinases. Akt is known as a key downstream target of HER3 signaling axis. It is also suggested to be an important modulator for the HER3 reactivation via a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium during TKI-induced drug resistance. However, the mechanism of Akt-mediated HER3 reactivation during TKI treatment is still unclear. Interestingly, HER3 was rapidly dephosphorylated when an Akt inhibitor (Akt inhibitor VIII, Akti) was applied to mimic the inhibitory effect of TKI on the PI3K/Akt axis. The same phenomenon was also found when PI3K inhibitor was utilized instead. This positive feedback within the HER3 signaling axis was shown to be mediated by PTPN9, a phosphatase that is known to negatively regulate the EGFR activation state. We showed that PTPN9 was upregulated once Akt was inhibited. This lead to EGFR deactivation and eventually caused the dephosphorylation of HER3, which was reversed when PTPN9 was locked down. Furthermore, reactivation of HER3 was also found in the Akti-treated cells at 24h. This was shown to be due to a negative feedback loop via the ADAM17-mediated heregulin release, which could be suppressed by ADAM17 inhibitor INCB4298. Our results are crucial in advancing our knowledge in HER3/PI3K/Akt axis, where the positive loop revealed the mechanism of Akt suppression in regulating HER3 phosphorylation; and the negative loop is implicated in resistance mechanisms to various targeted therapies that affect Akt activity.
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 921. doi:10.1158/1538-7445.AM2011-921
Abstract 928: Species and cell type independent core MYC target genes in cancer and stem cells
Authors: Ji Hongkai , Wu George , Zhan Xiangcan , Nolan Alexandra , Koh Cheryl , De Marzo Angelo , Fan Jinshui , Cheadle Chris , Fallahi Mohammad , Cleveland John , Dang Chi V. , Zeller Karen 
Published: June 2012

Abstract
The c-Myc (hereafter Myc) transcription factor augments the induction of pluripotency of somatic cells and contributes to human tumorigenesis, but the mechanisms by which Myc mediates these phenotypes remain only partially understood. To decipher Myc's biological functions, it is essential to define its target genes. To date, numerous Myc target gene lists have been constructed in various cellular contexts from several species but no study has rigorously defined species and cell type independent core Myc targets. Using a model of human B lymphoma cells bearing inducible MYC, we identified direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified, for the first time, direct Myc targets in human embryonic stem cells (ESCs). Here we report that Myc regulates a core set of target genes that are shared in mouse and human ESCs as well as in four other human cancer cell types. The expression of this gene set is increased in Myc-expressing premalignant B lymphocytes and is highly elevated in lymphoma cells from Eμ-Myc transgenic mice. Remarkably, the expression of the core gene set significantly correlates with MYC expression across 8,129 microarray samples in Gene Expression Omnibus (GEO), which represent 312 cell and tissue types. Expression profiles of B cell lymphomas, acute leukemia, lung cancers and Ewing sarcomas are among those with the highest correlation. Annotation of this gene signature highlights Myc's primordial function in ribosomal biogenesis as one of its key roles in cancer and stem cells.
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 928. doi:10.1158/1538-7445.AM2011-928
Abstract 94: Wnt signaling antagonists are progressively hypermethylated during colorectal neoplastic progression
Authors: Silva Ana-Luisa , Arends Mark J. , Wyllie Andrew H. , Ibrahim Ashraf EK 
Published: June 2012

Abstract
Background: Colorectal cancer (CRC) is the third most common type of cancer. The Wnt signaling pathway is known to play an important role in initiation and progression of CRC. Suppression of Wnt antagonists by promoter hypermethylation has been proposed to increase Wnt activity. DNA methylation changes of Wnt antagonists during CRC progression through the preinvasive adenoma stage have not been previously characterized. We analyzed promoter methylation changes of selected Wnt antagonists in a set of synchronous normal, hyperplastic or adenomatous polyps and adenocarcinoma tissue samples obtained from colectomy specimens.
Method: We profiled methylation changes in CpG islands associated with the Wnt signaling antagonists DKK1, DKK2, DKK3, WIF1, SFRP1, SFRP2, SFRP4, SFRP5, and SOX17 using pyrosequencing assays. We also examined methylation changes of two members of the β-catenin destruction complex, APC and AXIN2, and two non-antagonist genes (CDH1 and DVL2) involved in Wnt signaling. The sample set included 48 cases comprising matched normal (n=73), hyperplastic polyp (n=9), adenoma (n=42) and adenocarcinoma (n=48) tissue samples.
Results: Our samples showed significant widespread hypermethylation changes of a subset of the analyzed Wnt antagonists in the transition from normal to hyperplastic polyp to carcinoma and from normal to adenoma to carcinoma, mostly in an increasing stepwise pattern (p&lt;0.05, Wilcoxon rank sum test). DKK1 showed no significant change during CRC progression, DKK3 did not show significant methylation changes during the hyperplastic polyp to carcinoma stage and SFRP4 was not significantly hypermethylated during adenoma to adenocarcinoma progression. APC was hypermethylated in a small subset of carcinomas, however, these changes were not statistically significant. AXIN2 and the non-antagonist Wnt genes, CDH1 and DVL2 showed consistent normal levels of methylation throughout CRC progression.
Conclusion: Wnt antagonists are progressively hypermethylation during CRC neoplastic development. We propose that CpG island hypermethylation of Wnt antagonists could be used as biomarkers for early detection of CRC.
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 94. doi:10.1158/1538-7445.AM2011-94
Abstract 960: Ceramide-dependent release of nanovesicles is a class effect oflipid-based Akt inhibitors
Authors: Gills Joell J. , Zhang Chunyu , Abu-Asab Mones S. , Castillo S. Sianna , Marceau Caleb , Kozikowski Alan , Tsokos Maria , Goldkorn Tzipora , Dennis Phillip A. 
Published: June 2012

Abstract
Akt regulates many cellular processes and Akt inhibitors are being developed as cancer therapeutics. The mechanism of action of lipid-based Akt inhibitors (LBAIs) such as perifosine and phosphatidylinositol ether lipid analogues (PIAs) is incompletely understood. Here, we show that LBAIs quickly deplete cells of proteins such as EGFR, IGFR and p-Akt that can be recovered in tetraspanin-enriched 100,000 xg pellets from conditioned media. Electron micrographs of these pellets exhibited heterogenous vesicular structures whose diameter was less than 1 µM. In vitro, LBAI treatment increased vesicle shedding as revealed by live cell microscopy. In vivo, LBAIs increased plasma levels of nanovesicles derived from tumor xenografts. Several lines of evidence show that release of nanovesicles by LBAI depends upon ceramide generation. LBAIs increased levels of cellular ceramide, and addition of exogenous ceramide stimulated nanovesicle release. GW4869, an inhibitor of sphingomyelinase, an enzyme that generates ceramide by cleavage of sphingomyelin, blocked release of nanovesicles induced by LBAI. When transferred in vitro, purified nanovesicles increased ceramide levels and inhibited proliferation of naïve recipient cells, suggesting these contain residual LBAIs. Pre-treatment with GW4869 blocked ceramide induction in recipient cells and yielded greater retention of the donor nanovesicles. These studies identify ceramide-dependent release of cellular nanovesicles as a class effect of LBAI and a novel means to shed EGFR, IGF-IR and p-Akt from tumors that could perpetuate the cytotoxicity of LBAIs. We believe this is the first report of secondary pharmacologic effects via cell-mediated drug transfer in nanovesicles.
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 960. doi:10.1158/1538-7445.AM2011-960
Abstract 97: Chronic nicotine and NNK exposure causes promoter hypermethylation of GAD2 in human pancreatic duct epithelial cells
Authors: Bernert Heike , Plummer Howard K. , Schuller Hildegard M. 
Published: June 2012

Abstract
Epigenetic alterations are present at early stages of carcinogenesis, and DNA promoter hypermethylation in precursor lesions potentially affects transcriptional regulation. Previous studies by our laboratory have shown that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) inhibits the proliferation of human pancreatic cancer cells grown both in vitro and in mouse xenografts. To test the hypothesis that nicotine as well as the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce changes in methylation status of the GABA synthesizing enzymes GAD1 (GAD67) and GAD2 (GAD65), the human pancreatic duct epithelial cell line clone HPDE6-E6E7c7 has been exposed to daily treatment of either nicotine or NNK over a course of five days. This initial screen of the methylation status of the promoter region of GAD1 and GAD2 by bisulfate genomic sequencing in HPDE6-E6E7c7 indicates aberrant methylation of GAD2 by either nicotine or NNK. Quantitative methylation-specific PCR as well as gene expression studies by real-time PCR after 5-aza-2’-deoxycytidine treatment, alone or in combination with trichostatin A on the last day of treatment along with concurrent five day treatment with nicotine or NNK confirm these observations that aberrant methylation of GAD2 may be an important factor in the pathogenesis of pancreatic cancer. Quantitative methylation-specific PCR indicates aberrant methylation in six out of ten human matched normal versus cancerous pancreatic tissue samples, which corroborates the in vitro results. In conclusion, exposure to nicotine and NNK leads to significant epigenetic alterations of the GAD2 promoter region. Consecutive silencing of GAD2 with suppression of GABA synthesis may represent an important mechanism by which nicotine and related compounds induce disturbances in inhibitory neurotransmitter circuits which may contribute to the pathogenesis of ductal adenocarcinoma of the pancreas. Supported by grants 1RO1CA130888 and 2RO1CA042829 with the National Cancer Institute.
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 97. doi:10.1158/1538-7445.AM2011-97