bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4798: Pilot study of plasma biomarker candidates for pancreatic cancer detection - a targeted proteomics approach
Authors: Pan Sheng , Chen Ru , Brand Randall , Hawley Sarah , Tamura Yasuko , Gafken Philip , Milless Brian , Goodlett David , Rush John , Brentnall Teresa 
Published: August 2012

Abstract
With the advances in genomics and proteomics, the number of biomarker candidates associated with pancreatic cancer has increased explosively in recent years. Many putative biomarkers have been discovered in pancreatic tumor tissue and pancreatic juice; such targets will need to be rigorously verified in plasma or serum for blood-based biomarker development. Currently, validation of putative biomarkers in blood largely relies on antibody creation for ELISA assays, and has been the bottleneck for biomarker development. Analytical techniques to robustly measure these proteins in plasma, which is arguably the most complex biological matrix with protein abundance exceeding 10 orders of magnitude, has been a challenge. In this study, we applied a mass spectrometry-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer diagnosis. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis and healthy age-matched controls. Based on the receiver operating characteristic (ROC) analysis, two of the five candidate proteins tested, demonstrated an Area Under Curve (AUC) value greater than 0.89 in the detection of pancreatic cancer from healthy controls and chronic pancreatitis controls. We further demonstrated that a composite biomarker by combining two complementary independent biomarkers improves the sensitivity for pancreatic cancer detection at 95% specificity. Based on this evidence, these biomarker candidates merit further validation in larger patient and control cohorts for their potential utility in clinical application. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the mass spectrometry-based targeted proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4798. doi:1538-7445.AM2012-4798
Abstract 48: Activation of c-Met receptor signaling by carcinoma-associated fibroblasts in the tumor microenvironment
Authors: Zillhardt Marion , Lengyel Ernst 
Published: August 2012

Abstract
Objective: Carcinoma-associated fibroblasts (CAFs) play a key role in tumorigenesis by promoting tumor growth, invasion, and metastasis. At sites of intra-abdominal ovarian cancer metastases, more than half of the tumor microenvironment is composed of CAFs, however, the mechanism for how CAFs promote metastatic disease in ovarian cancer is not known. Because of the prominent role that the receptor tyrosine kinase c-Met plays in metastasis, we hypothesized that CAFs within the metastatic tumor microenvironment may activate c-Met signaling in ovarian cancer cells leading to tumor progression at a metastatic site. Methods: Human cancer cell lines and primary human carcinoma-associated fibroblasts isolated from patients’ ovarian cancer metastases were used in multiple biochemical assays to analyze the role of CAFs in c-Met receptor signaling. Results: Using a receptor tyrosine kinase array to analyze phosphorylation of 42 different receptor tyrosine kinases (RTKs), we found that c-Met was the only RTK that was phosphorylated in cancer cells upon co-culture with CAFs. Further analysis of the co-culture revealed that direct contact between cancer cells and CAFs was required for activation of c-Met. Interestingly, the unique ligand for c-Met, hepatocyte growth factor (HGF), could not be detected in conditioned media from CAFs by ELISA and addition of HGF neutralizing antibodies to the co-culture did not prevent activation of the receptor. Furthermore, CAFs transiently transfected with HGF siRNA were still able to activate c-Met in the human ovarian cancer cell line SKOV3ip1 suggesting that c-Met activation by CAFs is HGF-independent. This effect was not limited to ovarian cancer cell lines as co-culture of CAFs with the cervical cancer cell line, HeLa, which expresses wild-type c-Met, and the breast cancer cell line, T47D, showed the same results as the two ovarian cancer cell lines, SKOV3ip1 and OVCAR-5. Remarkably, membrane fragments isolated from CAFs were sufficient to stimulate phosphorylation of c-Met in cancer cells in an HGF-independent manner. Several candidate factors were identified in the CAF membrane proteome which can activate c-Met signaling. Conclusions: Collectively, these results suggest a potentially novel mechanism whereby CAFs activate c-Met in cancer cells through direct contact which provides an additional rationale for the therapeutic targeting of c-Met in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 48. doi:1538-7445.AM2012-48
Abstract 4802: Metabolic distinctions in high grade epithelial ovarian cancer
Authors: Zand Behrouz , Bottsford-Miller Justin , Hu Wei , Stone Rebecca , Nick Alpa M. , Zhang Xinna , Geest Koen De , Lutgendorf Susan K. , Sood Anil K. 
Published: August 2012

Abstract
Objective: To identify differences in overall metabolite profile of human high grade serous epithelial ovarian cancers (EOC) compared to normal ovarian tissues. Methods: Forty-five patient tissues were obtained (n= 30 EOC, n= 15 normal). Samples were analyzed by Gas Chromatography (GC)/mass spectrometry (MS) and Liquid Chromatography (LC)/MS platforms. The difference between the groups was reported in fold change (FC). Welch's two sample t-tests were used to identify metabolites that differed significantly between cancer and normal ovarian tissues and p&lt;0.05 was defined as significant. Results: Using an existing library containing &gt;2000 metabolites, there were 315 metabolites that were identified between EOC and normal ovaries. Of these 315 metabolites, 204 were significantly altered with 180 up regulated metabolites, and 24 down regulated. EOC had altered metabolism in the glycolytic, amino acid, lipid, nucleotide and eicosanoid pathways. There was an increase dependence on glycolysis consistent with the “Warburg effect,” as noted by elevated glucose-6-phosphate (FC= 2.8, p&lt;0.003), fructose-6-phosphate (FC=2.9, p&lt;0.001) and lactate (FC= 1.7, p=0.013). Ovarian cancer cells showed significantly elevated levels of long-chain fatty acids (e.g, docosatrienoate (22:3n3) [FC= 9.06, p &lt; 0.001), including those derived from the diet (linoleate [FC=2.25, p&lt;0.001] and linolenate [FC=2.37, p&lt;0.001]). Furthermore, significantly high levels of components needed for phospholipid biosynthetic pathway (e.g. cytidine 5′-diphosphocholine [16.86, p &lt; 0.001], choline [FC = 1.5, p&lt;0.001]) were seen which along with the altered lipid metabolism supports membrane biosynthesis in cancer cells. The eicosanoid metabolism pathway had significantly higher levels of pro-inflammatory compounds such as prostaglandins E2 (FC= 17.11, p&lt;0.001), I2 (FC=16.35, p&lt;0.001) and 6-keto prostaglandin F1-α (FC= 16.77, p&lt;0.001). Interestingly, compounds best characterized only in the central nervous system, were also significantly elevated in ovarian cancer tissues. Conclusion: High grade EOC shows distinct metabolic alterations compared to normal ovarian tissues, forming the basis for targeting key metabolic pathways for biomarker and/or therapeutic approaches in ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4802. doi:1538-7445.AM2012-4802
Abstract 4806: Association of changes in 4-aminobutyrate aminotransferase (ABAT) and beta-alanine metabolism with breast cancer and the more aggressive estrogen receptor negative subtype
Authors: Budczies Jan , Lehmann Annika , Griffin Jules L. , Oresic Matej , Fiehn Oliver , Denkert Carsten 
Published: August 2012

Abstract
Metabolic changes are the final answer of the cell to environmental or genetic changes. While gene expression in breast cancer has extensively been studied, studies on the breast cancer metabolome and its correlation to transcriptional changes are rare. Therefore, a combined metabolomics and transcriptomics study was carried out by the METAcancer consortium. In this project, 275 breast cancer tissues collected as fresh-frozen samples in the METAcancer tumor bank were analyzed using gas chromatography combined with time of flight mass spectrometry (GC-TOF-MS). Out of these, 156 tumor samples were transcriptionally profiled using whole genome DASL. Before, we identified 10 increased and 9 decreased metabolites in the more aggressive estrogen receptor negative (ER-) compared to the estrogen receptor positive (ER+) breast cancer (poster #5573, AACR Annual Meeting 2010). Among these changes, the increase of beta-alanine (fold change = 2.4, p = 1.7E-20) was the strongest and most significant alteration. Comparing breast cancer and normal tissues, beta-alanine turned out to be strongly increased in the cancer tissues (fold change = 2.6, p = 1.1E-34). Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) we identified 135 enzymes that catalyze reactions of the 19 regulated metabolites. These enzymes were subjected to correlation analysis with their substrates and products. As most significant result, a negative relationship between 4-aminobutyrate aminotransferase (ABAT) expression and beta-alanine concentration was detected (Pearson correlation = –0.62, p = 1.1E-17). ABAT was significantly down-regulated in the more aggressive ER- subtype (fold change = –1.9, p = 1.6E-08). The differential expression of ABAT was confirmed in three publicly available breast cancer microarray data sets. The effect of ABAT inhibition was investigated in estrogen receptor positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. In both cell lines, treatment with vigabatrin, a small molecule that binds irreversibly to ABAT and inhibits the enzymatic activity, increased proliferation. In summary, we detected an accumulation of beta-alanine in breast cancer and an increase of beta-alanine and a down-regulation of ABAT in the more aggressive ER- subtype. The regulation of beta-alanine metabolism that underlies these changes is currently investigated in cell culture models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4806. doi:1538-7445.AM2012-4806
Abstract 4809: Elucidating acquired drug resistance in multiple myeloma using expression proteomics and phosphorylation profiling
Authors: Fang Bin , Xiang Yun , Mirza Sayeef , Remily-Wood Elizabeth , Mathews Linda , Dalton William , Shain Kenneth , Koomen John M. 
Published: August 2012

Abstract
Introduction: Multiple myeloma (MM) is an incurable malignancy of the plasma cell. While patients may initially respond to treatment, the development of acquired drug resistance (ADR) is a consistent feature of the disease. In order to understand the processes involved in ADR, proteomics is used to examine multiple phenotypic outcomes associated with drug resistance in cell line models. Both protein expression and phosphorylation data will be mined for biological mechanisms and candidate biomarkers for detection of ADR in MM patients. Experimental Procedures: Using cell line models of melphalan and doxorubicin resistance, protein expression is compared using spectral counts and extracted ion chromatograms from GeLC-MS/MS data. In addition, phosphorylation profiles are created using SCX peptide fractionation with IMAC phosphopeptide enrichment prior to LC-MS/MS cataloging. Additional hypothesis-driven experiments are conducted using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) for targeted quantification. In addition to steady state comparisons between naïve and drug resistant cells, initial responses to therapy are also evaluated. Assays developed for interrogation of cell line models can be translated to patient specimens. Data Summary: GeLC-MS/MS expression measurements typically produce semi-quantitative data for &gt; 2,000 proteins (2+ peptides per protein). Phosphorylation analysis has produced a catalog of &gt; 1,000 sites across the entire group of cell lines. Data are manually evaluated for proteins relevant to MM and mapped to pathways using Metacore GeneGO. Because both melphalan and doxorubicin produce DNA damage, common processes include DNA damage repair, cell cycle regulation, and apoptosis. Each drug also produces unique phenotypes. For example, doxorubicin resistance is mediated in large part by multidrug resistance proteins; melphalan resistance is marked by increases in redox proteins. LC-MRM of heat shock proteins and Bcl-2 family apoptosis regulators supplements existing data. LC-MRM is also used to examine the response in the expression of proteins involved in ADR at the onset of treatment in naïve MM cells. Conclusions: Proteomics can further elucidate the biological processes involved with ADR in MM to generate candidate biomarkers. LC-MRM is used in cell line models to develop a platform for assessing panels of proteins related to ADR, which can ultimately be translated to assist in clinical decisions for tailoring therapy to the individual patient.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4809. doi:1538-7445.AM2012-4809
Abstract 4810: Multiplexed immunoprecipitation-liquid chromatography-multiple reaction monitoring mass spectrometry quantification of protein expression and phosphorylation for breast cancer biomarkers
Authors: Chen Yi , Britton David J. , Wood Elizabeth R. , Pike Ian , Koomen John M. 
Published: August 2012

Abstract
Introduction: Estrogen receptor alpha (ER alpha), progesterone receptor B (PR B), and the receptor tyrosine kinase, Her2, are tumor markers classified by the American Society of Clinical Oncology (ASCO) as level of evidence I in breast cancer. The quantitative evaluation of protein expression and phosphorylation status of these targets in tumor tissues will enable subtype classification and support clinical decision-making and selection of targeted therapy in breast cancer. Experimental Procedures: Breast cancer cell lines were used to develop peptide-based quantitative assays for protein expression and phosphorylation using immunoprecipitation (IP) and liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM). Stable isotope-labeled standard peptides were synthesized and developed as internal standards. Multiplexed IP for ER alpha, PR B, and HER2 will be developed to enable the enrichment of the proteins to enable quantification of the expression and phosphorylation of these biomarkers in the same sample. The sensitivity of each assay will be tested using serial dilutions of cell lysate to evaluate requirements for analysis of clinical specimens. Data Summary: LC-MRM assays for both unmodified and phosphorylated peptides have been developed and characterized for each protein. Recovery using multiplexed IP for these proteins is similar to recovery of individual IP. Data have been generated for cell line models of stimulation and treatment. For example, LC-MRM quantification of HER2 in cell line models stimulated with EGF or Heregulin shows that protein expression is unchanged, but phosphorylation increases; on the other hand, LC-MRM shows clearly that phosphorylation of Her2 is inhibited with Lapatinib. Conclusions: The ability to examine the protein expression as well as the phosphorylation status in these biomarkers with quantitative mass spectrometry will produce improved understanding of their role in the development and progression of breast cancer and has the potential to improve the selection of targeted therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4810. doi:1538-7445.AM2012-4810
Abstract 4811: Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis in telomerase-proficient mice
Authors: Hartmann Daniel , Begus-Nahrmann Yvonne , Eshraghi Parisa , Rasche Volker , Schirmacher Peter , Lee Han-Woong , Lechel André , Rudolph K. Lenhard 
Published: August 2012

Abstract
Introduction: A current concept of carcinogenesis indicates that telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. So far, this concept has not been proven in vivo since appropriate mouse models were lacking. Methods: Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Results: Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Conclusion: Together, these data provide the first in vivo evidence that telomere dysfunction can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional, genetic checkpoint defects at germline level.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4811. doi:1538-7445.AM2012-4811
Abstract 4812: p53 acts during total-body irradiation to promote lymphomagenesis
Authors: Lee Chang-Lung , Blum Jordan M. , Moding Everett J. , Sullivan Julie M. , Jeffords Laura B. , Rodrigues Rafaela C. , Ma Yan , Kim Yongbaek , Kirsch David G. 
Published: August 2012

Abstract
Radiation therapy can cause acute toxicity and long-term side effects including radiation-induced cancer. Because some of the short-term side effects of radiation are due to p53-mediated apoptosis, blocking p53 during radiation can protect some normal tissues from acute radiation injury and might improve the therapeutic ratio of radiation therapy. However, temporarily blocking p53 could also increase late effects of radiation because mice in which p53 is permanently deleted are sensitized to radiation-induced carcinogenesis. Experiments using a mouse model where p53 can be temporarily turned on during irradiation suggest that radiation-induced apoptosis does not contribute to p53-mediated tumor suppression. Here, we perform reciprocal experiments and temporarily turn p53 off during total-body irradiation (TBI) using transgenic mice with reversible RNA interference (shp53). Our results show that temporary p53 knockdown during TBI suppressed death from bone marrow failure by protecting hematopoietic stem and progenitor cells (HSPCs) against radiation. Remarkably, we found that temporary knockdown of p53 during TBI not only ameliorated acute hematological toxicity, but also prevented lymphoma development. In contrast, p53 knockdown during and permanently after TBI sensitized mice to radiation-induced carcinogenesis, which recapitulates the tumor spectrum of p53+/− mice exposed to irradiation. Mechanistic studies show that, by blocking apoptosis in hematopoietic cells, p53 knockdown during TBI suppressed accelerated repopulation of HSPCs, a critical step that facilitates expansion of pre-malignant clones with mutations after irradiation. Taken together, our results demonstrate that, although p53 is indispensible to suppress tumor formation after radiation, p53 functions during TBI to promote lymphoma formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4812. doi:1538-7445.AM2012-4812
Abstract 4814: Hepatocarcinogenesis induced by transgenic expression of hepatitis B virus in mice
Authors: Na Bing , Huang Zhiming , Sun Bing , Wang Qian , Ou J.-H. James , Liu Limin 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and chronic hepatitis B virus (HBV) infection is the most important risk factor of HCC. However, it remains unclear whether HBV plays any direct role in carcinogenesis. We have established two independent transgenic mouse lines expressing a mutant HBV (“preS2 mutant”) that is found at a significant higher frequency in people with HCC than those without. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice developed hepatocellular neoplasms, including HCC. We also found a significant increase in hepatocarcinogenesis independent of inflammation in a transgenic mouse line expressing wildtype HBV. The significant increase of HCC incidence in all three HBV transgenic lines argues that HBV contributes directly to the development of HCC in the absence of chronic inflammation. Endoplasmic reticulum stress-induced unfolded protein response activation and β-catenin truncation/mutation were found in the HCC samples, which may contribute to the hepatocacinogenesis. To screen other candidate genes critical in the HCC development, we performed mouse whole genome microarray analysis and identified a group of genes whose expression levels increased in the livers of the HBV transgenic mice and often further increased in HCC compared to that of the non-transgenic littermates. Using quantitative RT-PCR, we confirmed the expression pattern in 8 out of 10 selected genes that are known to involve in the control of cell survival/proliferation, mobility and intercellular signaling. Among the eight genes, Fabp5 encodes a retinoic acid-binding protein that is known to be overexpressed in various types of human tumors, including HCC, and is implicated in tumor cell survival and proliferation. We also found that Fabp5 is highly expressed in HCC cell lines and in the HCC of our HBV transgenic mice by Western Blot. Immunohistochemistry/immunofluorescence staining confirmed that hepatocytes in HCC overexpress Fabp5. More importantly, Fabp5 expression is significantly elevated in the liver of 4-month old HBV transgenic mice long before HCC development. Therefore our findings suggest that HBV expression may disrupt regulation of proteins important for cell survival and proliferation and contribute directly to hepatocarcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4814. doi:1538-7445.AM2012-4814