bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-156: A diet-derived sialic acid promotes inflammation and hepatocellular cancer
Authors: Samraj Annie N. , Laubli Heinz , Pearce Oliver , Secrest Patrick , Garcia-Bingman Andrea E. , Varki Nissi , Varki Ajit 
Published: May 2015

Abstract
N-glycolylneuraminic acid (Neu5Gc) is a non-human sialic acid derived from the diet (primarily red meat) that can be metabolically incorporated into human tissues despite being an antigen. Since this incorporation occurs in the face of circulating anti-Neu5Gc antibodies, we hypothesized that this generates an antibody-antigen reaction and leads to inflammation termed “xenosialitis”. Although red meat consumption is prominently associated with cancer development, pathological mechanisms behind this link are yet to be conclusively proven. The purpose of our research is to investigate the relationship between “xenosialitis”, inflammation and cancer. We used a Cmah null mouse model (mimicking the human lack of Neu5Gc) to provide evidence for such inflammation and cancer promotion. Anti-Neu5Gc antibodies were generated by immunizing Cmah null mice, with chimpanzee red blood cell membranes, or with human red blood cell membranes as controls. Pooled immune or control sera were repeatedly adsorbed with human red blood cells, and the resulting polyclonal antisera passively transferred into additional Cmah null mice that were on a diet with or without Neu5Gc. Mice fed with Neu5Gc and injected with anti-Neu5Gc antibodies showed dose-dependent elevation in acute phase proteins (Serum Amyloid A and Haptoglobin) in the serum as compared to controls. Such C57BL/6 mice are prone to developing hepatic adenomas and occasional carcinomas. Cmah null but not wild-type C57BL/6 mice immunized with chimpanzee red blood cell membranes and fed with Neu5Gc developed a higher frequency of hepatocellular cancer and liver histology showed Neu5Gc accumulation and foci of inflammation. In conclusion, Neu5Gc that has metabolically incorporated into tissues from the diet interacts with anti-Neu5Gc antibodies, generating xenosialitis. Potential correlations of human anti-Neu5Gc antibody levels with red meat consumption and cancer risk are being investigated. Methods to flush out the xenogenic Neu5Gc are being pursued. Similar mechanisms may be operative in other chronic inflammatory processes in diseases epidemiologically associated with red meat consumption, such as atherosclerosis.
Citation Format: Annie N. Samraj, Heinz Laubli, Oliver Pearce, Patrick Secrest, Andrea E. Garcia-Bingman, Nissi Varki, Ajit Varki. A diet-derived sialic acid promotes inflammation and hepatocellular cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-156. doi:10.1158/1538-7445.AM2014-LB-156
Abstract LB-173: Early detection of pancreatic cancer using a new 5-gene classifier
Authors: Bhasin Manoj , Bullock Andrea , Gu Xuesong , Bucur Octavian , Najarian Robert , Haines Jon Cody , Ruping Karl , Miksad Rebecca , Libermann Towia , Khosravi-Far Roya 
Published: May 2015

Abstract
Background: Largely due to late diagnosis when curative resection is no longer possible, Pancreatic Adenocarcinoma (PDAC) is a devastating disease marked by a mortality rate nearly equivalent to its incidence rate. While serum CA19-9 is associated with PDAC, it lacks the sensitivity and specificity needed for early and accurate diagnosis. Thus, early diagnosis of PDAC is critical to improving survival for PDAC patients and for accurate PDAC risk stratification.
Methods: We have identified key PDAC biomarkers through an optimized meta-analysis strategy of raw data (training sets). From this analysis, the top ranking genes that distinguish PDAC from normal pancreas were selected through statistical significance comparison of the consistency in differential PDAC gene expression across studies. The biomarker panel with the highest sensitivity and specificity in the training sets was chosen for assessment of predictive power in nine independent validation datasets. For a subset of genes in the panel, immunohistochemistry (IHC) analysis was performed in human PDAC and pancreatitis to validate our panel.
Results and Conclusions: We have identified a 5-gene classifier panel with specificity of 88.9% and sensitivity of 100% with an overall accuracy of 93.3% and AUC of 0.94 for discriminating PDAC from non-malignant (normal or pancreatitis) tissue. IHC analysis of two of the proteins confirmed enhanced expression in PDAC cells. Cell-based experiments demonstrated that both proteins enhance migration and invasion of PDAC cells as well as soft agar growth indicating that they may be causative in PDAC. The 5-gene predictor discriminated PDAC from healthy controls, as well as pancreatitis, with highest accuracy in nine independent validation sets. Our identified PDAC panel may facilitate early diagnosis and improve risk-stratification.
Citation Format: Manoj Bhasin, Andrea Bullock, Xuesong Gu, Octavian Bucur, Robert Najarian, Jon Cody Haines, Karl Ruping, Rebecca Miksad, Towia Libermann, Roya Khosravi-Far. Early detection of pancreatic cancer using a new 5-gene classifier. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-173. doi:10.1158/1538-7445.AM2014-LB-173
Abstract LB-18: Bcl2-associated athanogene 3 and major vault protein regulate cell survival and resistance to apoptosis in senescent cells by regulating ERK activation
Authors: Pasillas Martina , Shields Sarah , Reilly Rebecca , Mulrane Laoighse , Strnadnel Jan , Jirstrom Karin , Connor Darran O , Gallagher William , Gonias Steven , Coppinger Judith 
Published: May 2015

Abstract
Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence (TIS) and discovered that Bcl2-associated athanogene 3 (Bag3) is upregulated after adriamycin treatment in MCF7 cells. Bag3 protein is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major signaling pathways. Mass Spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin in favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in TIS by activation of extracellular signal-regulated kinase1/2 (ERK1/2). Bag3 and MVP were required for ERK1/2 activation in response to adriamycin and silencing either gene product decreased cell survival in response to the drug. An increase in nuclear accumulation of MVP is observed during TIS and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We demonstrate that Bag3 and MVP are expressed in a panel of diverse breast cancer cell lines and human tumor samples from patients. Silencing of Bag3 and MVP shifts the response to apoptosis and regulates ERK1/2 signaling in ER positive MCF7, ZR751 cell lines and triple negative MDA-MB-231 and MDA-MB-468 cells. Overall this study highlights Bag3-MVP as an important complex that regulates a potent pro-survival signaling pathway in breast cancer.
Citation Format: Martina Pasillas, Sarah Shields, Rebecca Reilly, Laoighse Mulrane, Jan Strnadnel, Karin Jirstrom, Darran O Connor, William Gallagher, Steven Gonias, Judith Coppinger. Bcl2-associated athanogene 3 and major vault protein regulate cell survival and resistance to apoptosis in senescent cells by regulating ERK activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-18. doi:10.1158/1538-7445.AM2014-LB-18
Abstract LB-205: Genome-wide copy number analysis of pediatric hepatocellular carcinomas: Identification of characteristic aberrations
Authors: Pietsch Torsten , Carmichael A. , Vokuhl Christian , Leuschner Ivo 
Published: May 2015

Abstract
Hepatocellular carcinomas (HCC) of childhood are rare neoplams. Their pathogenesis is believed to be different from HCC in adulthood. The differential diagnosis from hepatoblastoma (HBL)is important because of worse prognosis of pediatric HCC (pHCC) and different treatment approaches. However, the diagnosis by conventional histological analysis may be difficult in some cases. Informations on chromosomal alterations in pHCC are lacking.
The aim of this study was to identify recurrent chromosomal aberrations in a larger cohort of pHCC and compare it to a previously published cohort of HBL (Weber et al., American Journal of Pathology, 2000) to identify characteristic chromosomal alterations of pHCC. Genomic DNA was extracted from FFPE samples of a cohort of 34 pHCC including 4 cases of the fibrolamellar subtype and 3 cases with partial fibrolamellar differentiation from the archives of the German Pediatric Tumor Registry, University of Kiel. Genome-wide copy analysis was performed by molecular inversion profiling. GISTIC analysis was done to identify significant large and focal aberrations.
Most frequent copy number alterations were gains of chromosome 1q (65%), 2q (35%), 6p (35%), 20 (35%), 19q (32%) and 8q (29%) and losses of chromosomal regions 1p (56%) and 4q (38%). In addition, GISTIC analysis identified several significant fokal alterations including losses of the AXIN1 tumor suppressor locus on 15q26 in 53% of cases. 6/34 pHCC lacked any larger chromosomal imbalances. Of note, 5 of these 6 genomically stable tumors showed fibrolamellar differentiation. When pHCC with fibrolamellar differentiation were compared to the other pHCC, loss of 1p and 4q and gains of 1q, 2q, 6q and 20 occurred significantly more frequent in the latter. When pHCC were compared to HBL, both entities shared similar alterations including gains if 1q and 2q, but losses of 1p (56% vs. 3%), and gains of 6p (35% vs. 3%) and 19q (32% vs. 0%) were significantly more frequent in pHCC.
In this genome-wide copy number analysis of a large cohort of pHCC we were able to identify for the first time characteristic alterations which may indicate a specific pathogenesis of these neoplasms, may help to subclassify pHCC and to differentiate these tumors from HBL.
Supported by the German Childhood Cancer Foundation.
Citation Format: Torsten Pietsch, A. Carmichael, Christian Vokuhl, Ivo Leuschner. Genome-wide copy number analysis of pediatric hepatocellular carcinomas: Identification of characteristic aberrations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-205. doi:10.1158/1538-7445.AM2014-LB-205
Abstract LB-215: The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab
Authors: Brand Toni Michel , Iida Mari , Corrigan Kelsey L. , Luthar Neha , Hornung Megan , Toulany Mahmoud , Gill Parkash , Salgia Ravi , Wheeler Deric L. 
Published: May 2015

Abstract
Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that has shown efficacy in metastatic colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Clinical data suggests that patients whom initially respond to cetuximab eventually acquire resistance, highlighting the importance of understanding resistant mechanisms for the development of better treatment regimes for cancer patients. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, and more specifically the Axl receptor as playing a key role in promoting tumor growth and metastasis. In the current study, we utilized NSCLC and HNSCC models of acquired resistance to cetuximab and found that Axl was overexpressed, activated, and highly associated with EGFR as compared parental controls. Further, using siRNA technology and novel Axl targeting agents (antibody and tyrosine kinase inhibitor), Axl was found to regulate proliferation, EGFR activation, and MAPK signaling in cetuximab resistant clones (CtxR). Additionally, Axl mRNA expression was regulated by EGFR induced MAPK activation in resistant cells. To investigate the role of Axl in in vivo models of acquired resistance to cetuximab, de novo acquired resistance was created by prolonged treatment of cetuximab sensitive (CtxS) tumor xenografts with cetuximab. Analysis of resultant CtxR tumors demonstrated that Axl was hyperactivated and highly associated with EGFR as compared to vehicle treated tumors. In addition, CtxR tumors expressing the highest levels of phosphorylated Axl also expressed hyperactivated EGFR, supporting the role of Axl in EGFR activation. Finally, to expand these findings to other members of the TAM family, Tyro, Axl, or Mer were stably overexpressed in CtxS parental NSCLC cells and tested for cetuximab response. The results of this experimentation indicated that stable overexpression of each TAM receptor rendered CtxS cells resistant to cetuximab therapy. Collectively, the studies presented herein identify the TAM family of receptors as key players in acquired resistance to cetuximab and provide rationale for the clinical evaluation of anti-TAM receptor therapeutics in the resistant setting.
Citation Format: Toni Michel Brand, Mari Iida, Kelsey L. Corrigan, Neha Luthar, Megan Hornung, Mahmoud Toulany, Parkash Gill, Ravi Salgia, Deric L. Wheeler. The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2014-LB-215
Abstract LB-217: CK2 protein kinase promotes resistance to MAPK pathway inhibition
Authors: Zhou Bingying , Kassner Michelle , Yin Holly , Der Channing J. , Cox Adrienne D. 
Published: May 2015

Abstract
Small molecule kinase inhibitors have opened potential new avenues for treating cancers dependent on the RAS-RAF-MEK-ERK MAPK pathway, yet identification of both de novo/innate/intrinsic and acquired resistance mechanisms will be critical for the successful application of these inhibitors in the clinic. We interrogated the kinome to identify resistance mechanisms towards the novel ERK1/2-selective inhibitor SCH772984. We first utilized a kinome-focused RNAi screen to identify genes that, when silenced, sensitized KRAS-dependent pancreatic cancer cells to SCH772984. In our drug dose-response screen of 711 kinases (QIAGEN library), we used 4 independent siRNA duplexes to knock down each gene, treated at 5 different drug doses, then evaluated viability with a standard CellTiter-Glo assay. Nineteen kinases enhanced sensitivity to SCH772984 (where at least 2 siRNAs for each target decreased IC50) at least 5-fold, indicating that they could drive ERK1/2 inhibitor resistance. Among these were 4 of the 9 protein kinases (Cot, Raf-1, PAK3 and PRKCH) identified in a cDNA expression screen for kinases that caused resistance of BRAF-mutant melanoma to the BRAF inhibitor vemurafenib. We therefore hypothesized that at least some of the kinases that scored positive in this screen might be conserved both across the MAPK pathway and across different cancer types. The tetrameric protein kinase CK2 (formerly casein kinase II) has crucial roles in cell survival, proliferation and differentiation, and its expression and/or activity is dysregulated in cancers including melanoma. In very recent studies, we have now determined that the alpha subunit of CK2 is sufficient to cause resistance to each of the three ERK MAPK pathway inhibitors currently approved for treatment of melanoma: vemurafenib (BRAFi), dabrafenib (BRAFi) and trametinib (MEKi). Co-inhibition of the MAPK pathway and CK2 (e.g., with CX-4945, currently in phase I trials) further enhanced sensitivity. Thus, this combination may offer an effective regimen to forestall or delay tumor relapse. We also observed that CK2alpha maintains ERK phosphorylation in the presence of MAPK inhibitors, and that it posttranslationally reduces abundance of the ERK phosphatase DUSP6/MKP-3, in a kinase-dependent manner. The relationship of these findings to CK2-mediated mechanisms of drug resistance will be discussed.
Citation Format: Bingying Zhou, Michelle Kassner, Holly Yin, Channing J. Der, Adrienne D. Cox. CK2 protein kinase promotes resistance to MAPK pathway inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2014-LB-217
Abstract LB-238: Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3
Authors: Godeau François , Leneuve Patricia , Costa Laetitia D. , Bouc Yves L. , Renoir Jack-Michel 
Published: May 2015

Abstract
Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic properties that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. Consequently, targeting the IGF axis has become an area of intense preclinical and clinical research through the development of 3 major classes of therapeutic compounds: antibodies that target IGF-IR, dual IGF-IR and IR tyrosine kinase inhibitors (TKI), and IGF ligands (IGF-I and IGF-II) neutralizing antibodies.
Due to their high affinities for IGF-I and IGF-II, six IGFBPs regulate IGF bioavailability and IGFBP-3 is the main carrier of circulating IGFs in postnatal serum. In order to efficiently neutralize the excess of free IGF ligand maintaining tumor progression, we have produced, using the baculovirus insect cell system, a protease-resistant mutein of human IGFBP-3 with conserved affinities towards both IGF-I and IGF-II that was fused to the human IgG1 Fc fragment. In vitro, the resulting immunoadhesin (mIGFBP-3-Fc), evaluated in both regular and 3D culture, was found to block proliferation, arrest cell cycle and induce apoptosis in various types of cancer cell lines (Colon Adenocarcinoma, Ewing's Sarcoma, Adrenocortical Carcinoma and Multiple Myeloma (MM). mIGFBP-3-Fc antitumor activity was evaluated in vivo using RPMI-8226 luciferase-expressing MM cells xenografts. When MM cells were grafted subcutaneouly, daily mIGFBP-3-Fc injections drastically reduced tumor growth and induced tumor cell apoptosis. Similarly, after iv tumor cell injection, bone marrow localization of MM cells was substantially reduced in the mIGFBP-3-Fc-treated group. Furthermore, when used in association with the proteasome inhibitor Bortezomib, mIGFBP-3-Fc was shown to enhance the antitumor effect of Bortezomib used as single agent. Altogether, these data support the concept that mIGFBP-3-Fc could improve MM treatment either as a single agent or in association with proteasome inhibitors.
Citation Format: François Godeau, Patricia Leneuve, Laetitia Da Costa, Yves Le Bouc, Jack-Michel Renoir. Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2014-LB-238
Abstract LB-247: Circulating proteolytic products of tumor-resident enzyme as potential biomarkers for early detection of breast cancer
Authors: Hu Ye 
Published: May 2015

Abstract
In theory, any or all of tumor-secreted proteins can serve as cancer biomarkers. However, the reality is challenging to monitor because of the large degree of fluctuation in abundance and localization of these tumor-secreted proteins, especially in the early stage of tumor development and/or metastasis. As such, it seems feasible that we might take advantage of the fact that secreted proteases/peptidases in the tumor microenvironment generate proteolytic products, also referred to as “circulating peptides”, which are detectable in bloodstream and provide ample information about the body, “coded” in the patterns and quantity of these peptides. Herein we clearly link the catalytic activity of Carboxypeptidase N (CPN) to its proteolytic products during breast tumor progression in mouse model and clinical samples. CPN plays important roles in regulating vasoactive peptide hormones, growth factors, and cytokines by specifically cleaving their C-terminal basic residues. Circulating fragment profiling, by an approach combining nanopore fractionation and mass spectrometry, revealed the nature and extent of cleavage by CPN. These results correlated with the level of CPN-catalyzed peptides in blood taken from the tumor-bearing mice, healthy women and breast cancer patients. We showed that generation of C3f_R1310-L1319 specifically correlated with the CPN expression level. In both mouse and clinical patient samples, the amount of CPN was increased in tumor tissues compared to that seen in normal breast tissue, while its counterpart in blood remained constant. The amount of 6 CPN-catalyzed peptides predominantly increased in sera taken from both the mice at 2 weeks after orthotropic implantation and the patients’ plasma as early as the first pathologic stage of breast cancer. In conclusion, the circulating level of the selected 6 CPN-catalyzed proteolytic products reflects the extent of this enzyme's activity in tumors, and our results clearly indicate their strong potential as biomarkers for non-invasive early diagnosis of breast cancer.
Citation Format: Ye Hu. Circulating proteolytic products of tumor-resident enzyme as potential biomarkers for early detection of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2014-LB-247