bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A78: Profiling of miRNA interactions in pancreatic adenocarcinoma by Argonaute CLIP-seq suggests a highly dynamic repertoire of targets
Authors: Quann Kevin , Loher Phillipe , Clark Peter , Delgrosso Kathleen , Fortina Paolo , Jing Yi , Brody Jonathan , Rigoutsos Isidore 
Published: October 2015

Abstract
MicroRNAs (miRNAs) are primary post-transcriptional regulators of gene expression which operate by degrading or otherwise repressing translation of target transcripts containing a corresponding miRNA recognition element (MRE). MiRNAs exert their effects through recruitment of the Argonaute (Ago) silencing complex to MRE sites. Although disruption of miRNA expression profiles is characteristic of many disease states, the inherent biological complexity of these regulatory networks has limited the ability to exhaustively catalog miRNA target repertoires and their associated functional phenotypes for a given tissue or cell type. To address these issues in the context of pancreatic adenocarcinoma, we performed next generation sequencing of both short and long RNA species to profile expression levels of both miRNAs and potential target transcripts, respectively, in hTERT-HPNE and MIA PaCa-2 cell lines. Additionally, we deep-sequenced Argonaute-bound RNAs (Ago CLIP-seq). Our results indicate that although the transcriptional profiles of both cell lines are stable across replicates, the subset of MREs that are engaged at any time with miRNAs is highly dynamic and not necessarily commensurate with relative transcript abundance. Additionally, we found that most MREs are located in intergenic and intronic regions. Moreover, of the MREs that are in protein-coding transcripts, the majority exist outside the 3′ untranslated regions (3′UTRs), in the coding regions and the 5′UTRs. These results further suggest that standard models for miRNA interactions that are commonly utilized may not adequately capture the interactions that are at work in pancreatic cells. Taken together, these results highlight a newfound complexity of miRNA regulatory networks and suggest their functional relevance in a model of pancreatic adenocarcinoma.
Citation Format: Kevin Quann, Phillipe Loher, Peter Clark, Kathleen Delgrosso, Paolo Fortina, Yi Jing, Jonathan Brody, Isidore Rigoutsos. Profiling of miRNA interactions in pancreatic adenocarcinoma by Argonaute CLIP-seq suggests a highly dynamic repertoire of targets. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A78.
Abstract A81: A microRNA signature identified for chemoresistance and mesenchymal phenotype is also found in advanced pancreatic cancer
Authors: Freeman James W. , Bera Alakesh , Kolaparthi Venkatasubbarao 
Published: October 2015

Abstract
Recent studies link cancer cells that possess an epithelial to mesenchymal transition (EMT) and cancer stem cell properties with chemoresistance and metastatic potential. Here, we investigated the molecular bases of the chemoresistant mesenchymal phenotype (CRMP) with emphasis on identifying a micro-RNA (miRNA) signature in advanced pancreatic ductal adenocarcinoma (PDAC). We developed a gemcitabine resistant cell model from a PDAC cell line, BxPC3. This gemcitabine resistant cell line (BxPC3-GZR) showed a pronounced mesenchymal phenotype and expressed high levels of CD44 a marker found on stem cells and showed a highly significant increase in expression of nine miRNAs and decrease in eight miRNAs. Based on relevance to cancer and on validation by q-RT-PCR we chose six of the miRNAs (miR-100, miR-125b, miR-21, miR-205, miR-27b and miR-455-3p) as a signature to determine whether they were similarly deregulated in 43 advanced PDAC tumor specimens previously analyzed as part of the Total Cancer Genome Atlas (TCGA). A strong correlation was observed for five of the six miRNAs in the tumor specimens compared to normal pancreas tissue.
To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both cellular CRMP and advanced PDAC. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. The results of this study suggests that CRMP is caused in part by deregulation of a specific set of miRNAs and that these miRNAs are also deregulated in advanced PDAC. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.
Citation Format: James W. Freeman, Alakesh Bera, Venkatasubbarao Kolaparthi. A microRNA signature identified for chemoresistance and mesenchymal phenotype is also found in advanced pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A81.
Abstract A87: Pancreatic tumor stem cells resistant to inhibition of oncogenic signaling are dependent on mitochondrial function
Authors: Viale Andrea , Pettazzoni Piergiorgio , Lyssiotis Costas , Ying Haoqiang , Sánchez Nora , Marchesini Matteo , Carugo Alessandro , Green Tessa , Seth Sahil , Giuliani Virginia , Heffernan Timothy , Kimmelman Alec , Wang Huamin , Fleming Jason , Cantley Lewis , DePinho Ronald , Draetta Giulio 
Published: October 2015

Abstract
This abstract is also being presented as a short talk in Session 7: New Therapies. A full abstract is printed in the Proffered Abstracts section (PR13) of the Conference Proceedings.
Citation Format: Andrea Viale, Piergiorgio Pettazzoni, Costas Lyssiotis, Haoqiang Ying, Nora Sánchez, Matteo Marchesini, Alessandro Carugo, Tessa Green, Sahil Seth, Virginia Giuliani, Timothy Heffernan, Alec Kimmelman, Huamin Wang, Jason Fleming, Lewis Cantley, Ronald DePinho, Giulio Draetta. Pancreatic tumor stem cells resistant to inhibition of oncogenic signaling are dependent on mitochondrial function. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A87.
Abstract A90: Non-canonical effects of PTEN restoration therapy contribute to improved survival in a GEM model of pancreatic ductal adenocarcinoma
Authors: Hopkins Benjamin , Palermo Carmine , Ahmed Roshan A. , Sastra Stephen A. , Parsons Ramon , Olive Kenneth P. 
Published: October 2015

Abstract
Expression of the PTEN tumor suppressor protein is frequently altered in human pancreatic tumors, and deletion of PTEN in genetically engineered mouse (GEM) models accelerates pancreatic tumorigenesis. However, efforts to target components of the PTEN pathway, through inhibitors of PI3-Kinases, AKT, or mTOR, have failed to provide significant survival benefit to date. We utilized a naturally occurring, membrane-permeable variant of the PTEN protein, called PTEN-Long, to restore PTEN-function in trans to established pancreatic tumors in the KPC GEM model of pancreatic ductal adenocarcinoma (PDA). Combination PTEN-Long + gemcitabine therapy prolonged overall survival by 2-fold in this model and led to frank regressions of varying duration in a subset of tumors.
In order to study the mechanisms of response to PTEN-Long therapy, we utilized variants of the PTEN-Long protein that are functionally mutated in different ways. A phosphatase-dead variant of PTEN-Long failed to have any effect on tumor growth in KPC mice. Interestingly, a variant of PTEN-Long that is no longer membrane permeable actually reduced overall survival in combination with gemcitabine, perhaps indicating a role for the protein in the extracellular matrix. Finally, we compared the effect of PTEN-Long in KPC mice to that of the pan-PI3K inhibitor GDC-0449. In contrast to PTEN-Long + gemcitabine, GDC-0449 + gemcitabine failed to extend survival or produce tumor regressions. Investigating the distinctions between pan-PI3K inhibition and PTEN restoration, we noted disparate, indeed opposite, effects of these two therapies on blood glucose maintenance and insulin levels, strongly that PTEN can function though additional, non-canonical intermediates beyond phospho-inositides. With the development of a clinical grade PTEN-Long material under way, we believe that these studies highlight the potential therapeutic utility of PTEN restoration therapy in PDA. These experiments provide the opportunity to dissect non-canonical aspects of PTEN signalling through in vivo structure/function analysis in GEM models of pancreatic cancer.
Citation Format: Benjamin Hopkins, Carmine Palermo, Roshan A. Ahmed, Stephen A. Sastra, Ramon Parsons, Kenneth P. Olive. Non-canonical effects of PTEN restoration therapy contribute to improved survival in a GEM model of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A90.
Abstract B05: Assessing and removing biophysical barriers to treatment
Authors: DelGiorno Kathleen E. , Carlson Markus , Provenzano Paolo P. , Brockenbough Scott , Hingorani Sunil R. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a confounding cancer with a penchant for metastasis and resistance to therapy. Cell autonomous events, such as mutations in the Kras proto-oncogene, are essential for the initiation and maintenance of PDA; however non-malignant cells as well as non-cellular components have been shown to contribute to tumor growth, immunosuppression, and chemotherapeutic resistance. The stromal compartment can comprise more than 80% of tumor content and is characterized by a dynamic and deregulated extracellular matrix (ECM). In addition to a role in tissue structure, the ECM provides biophysical and biochemical cues that determine cell responses. PDA presents its own characteristic ECM signature including large deposits of the negatively charged glycosaminoglycan (GAG) hyaluronan (HA), as well as fibrillary collagens which increases matrix stiffness. We have previously demonstrated that high levels of HA in PDA contribute to extraordinary interstitial fluid pressures (IFP) and vascular collapse. We show here that IFP is comprised of both freely mobile and immobile fluid phases. Due to its highly charged nature, HA binds large amounts of water to create an immobile-fluid phase with a significant swelling pressure. This pressure is not detected by conventional methods that can measure only free fluid pressure. The swelling pressure stresses abundant collagen fibrils which contract through cellular efforts to maintain homeostasis, further contributing to IFP. Targeting HA through systemic administration of pegylated hyaluronidase (PEGPH20) liberates the immobile fluid phase and dramatically reduces IFP, increasing vessel patency and bioavailability of systemically delivered agents. We present results on the effects of targeting additional ECM components and signaling pathways to help remove biophysical barriers to chemotherapeutic access. We also compare the abilities of different methodologies to measure interstitial pressures associated with the distinct fluid phases in a variety of experimental contexts.
Citation Format: Kathleen E. DelGiorno, Markus Carlson, Paolo P. Provenzano, Scott Brockenbough, Sunil R. Hingorani. Assessing and removing biophysical barriers to treatment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B05.
Abstract B10: Function and therapeutic implications of p53 in the stroma of pancreatic cancer
Authors: Ridinger Maya , Kraus Annabelle , Cox Miranda , Wade Mark , Liddle Christopher , Downes Michael , Evans Ron , Wahl Geoffrey 
Published: October 2015

Abstract
Pancreatic ductal adenocarninoma (PDA) is one of the most aggressive human cancers and is characterized by a predominant stromal compartment mainly composed of fibroblastic and immune cells. Pancreatic stellate cells (PSCs) are the main fibroblastic cells in the pancreatic tumor microenvironment. During tumor progression, they evolve into activated and proliferative myofibroblast-like cells that synthesize copious amounts of extracellular matrix (ECM) proteins and have diminished lipid storage capacity. They produce a dense fibrous stroma that obstructs intratumoral vasculature to create physical and biological therapeutic barriers. These observations suggest that strategies that normalize the stroma may enhance anti-tumor treatment strategies.
Activated PSCs in pancreatic cancers encode wild type p53, raising the possibilities that p53 activation could prevent their proliferation, and induce other paracrine anti-tumor effects. Nutlin-3a is a small-molecule p53 agonist that blocks the binding of its major negative regulator, Mdm2. As Nutlin derivatives are currently in clinical trials, we tested the consequences of activating p53 by Nutlin-3a in PSCs.
The data to be presented show that Nutlin-3a induces transcriptional regulation of genes that induce multiple changes consistent with quiescence. Using PSCs from patient samples, we show that p53 activation induces lipid droplet formation, decreases expression of αSMA (ACTA2), and produces growth arrest. We also observed that p53 activation inhibits TGFβ-induced transcription of genes involved in PSC activation.
To assess the genome-wide effects of p53, we performed transcriptome analysis of PSCs grown in the presence or absence of Nutlin-3a. This analysis revealed that p53 inhibits the expression of genes associated with the activation of PSCs such as ECM components and induces the expression of genes implicated in lipid metabolism characteristic of the quiescent state. P53 activation also decreased expression of genes with tumor-supporting potential including cytokines, growth factors and signaling molecules.
Ongoing investigations are designed to determine the consequences of stromal p53 activation on cancer cells using in vitro co-culture systems and mouse models of pancreatic cancer.
Citation Format: Maya Ridinger, Annabelle Kraus, Miranda Cox, Mark Wade, Christopher Liddle, Michael Downes, Ron Evans, Geoffrey Wahl. Function and therapeutic implications of p53 in the stroma of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B10.
Abstract B105: Significance of BRCA mutation for the patients with pancreatic cancer
Authors: Kashintsev Alexey , Imyanitov Evgeny , Kokhanenko Nikolai , Ievleva Aglaya 
Published: October 2015

Abstract
Background: Several independent reports have indicated the efficacy of DNA damaging therapy for the oncological patients with loss of homolog recombination in consequence of BRCA 1,2 or PALB2 germiline mutation. There are similar works about pancreatic cancer but the frequency and localization of defects in these genes and the results of chemotherapy are variable.
Methods: From 2009 to 2012 years 257 patients with PAC were included in the study. The analysis of the Russian founder mutation BRCA1 5382insC is performed in 150 PAC: 116 pacients included accidentally and 34 – by the presence of kindred’s with oncology. We had compared our results with the control group of 1007 healthy people. Prevalence of BRCA2 6174delT were analyzed in 22 cases. For these two genes we used allele specific real-time PCR. Full exon sequencing of coding region of BRCA2, PALB2 was conducted on DNA samples extracted from 8 patients by the HRM-analysis. For the administration of chemotherapy (ChT) we estimated a performance status by ECOG scale and efficacy by the RECIST criteria.
Results: Two patients had carriers of BRCA1 mutation and one – BRCA2 5197_5198delTC. In the control group only 1/1007 had BRCA1 allele. All patients with founder mutations had 2 or more kindred’s with oncology and 1 had carriers of BRCA1 5382insC. Defects in the PALB 2 were not identified. ChT was administered only for 1 patients with BRCA2 allele because only he had a 1 score for ECOG scale. He had a 4 line of ChT (FOLFIRINOX, cisplatin, chlorambucil, mitomicin) and only in last one there was stabilization of the process by RECIST criteria and decrease the level of CA 19-9 from 3810 to 547 U/ml. FTP was a 4,1 months and overall survival – 8,1.
Conclusion: The frequency of BRCA1/2mutation carriers was rare for PAC but higher than in the general population and probability of detection was depended on familial history. It means that samples from patients with PAC whom had 2 or more relatives or kindred carrier of BRCA mutation should be selected for DNA analysis. The DNA crosslink agents are preferable for patients with BRCA mutation.
Note: This abstract was not presented at the conference.
Citation Format: Alexey Kashintsev, Evgeny Imyanitov, Nikolai Kokhanenko, Aglaya Ievleva. Significance of BRCA mutation for the patients with pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B105.
Abstract B107: BET proteins are key mediators of pancreatic cancer cell growth and its tumor microenvironment
Authors: Liss Andrew S. , Nahar Sabikun , Mertz Jennifer A. , Bryant Barbara , Sims Robert J. , Castillo Carlos Fernandez-del , Lillemoe Keith D. , Warshaw Andrew L. , Thayer Sarah P. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. While the genetic alterations of PDAC have been well characterized, the epigenetic pathways regulating PDAC remain, for the most part, elusive. Employing an in vivo shRNA screen targeting 150 epigenetic regulators we identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC cell growth and maintenance of the tumor stroma. PDAC cells are broadly dependent on the activity of BET proteins, as the growth of 17/20 cell lines was sensitive to the BET inhibitor CPI203. BET family members contribute to PDAC cell growth by modulating the expression of MYC and the activity of GLI, two key transcriptional programs. Xenograft tumors in mice treated with BET inhibitor exhibited little to no growth, while tumors in control mice grew to 5 times their starting size. In addition to diminishing the proliferation of cells in these tumors, BET inhibition also effects the tumor stroma. A four-fold reduction in fibroblast content of tumors was observed which correlated with a 60-90% down-regulation of a key mediator of the tumor microenvironment, SHH, within the cancer cells. Taken together, these results suggest that therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC.
Citation Format: Andrew S. Liss, Sabikun Nahar, Jennifer A. Mertz, Barbara Bryant, Robert J. Sims, III, Carlos Fernandez-del Castillo, Keith D. Lillemoe, Andrew L. Warshaw, Sarah P. Thayer. BET proteins are key mediators of pancreatic cancer cell growth and its tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B107.
Abstract B111: Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression with prognostic implications
Authors: Hoskins Jason W. , Ibrahim Abdisamad , Emmanuel Mickey , Parikh Hemang , Jia Jinping , Collins Irene , Ylaya Kris , Altekruse Sean F. , Hewitt Stephen M. , Petersen Gloria M. , Amundadottir Laufey T. 
Published: October 2015

Abstract
A genome-wide association study (GWAS) of pancreatic cancer conducted within the NCI Cohort Consortium (PanScan I and II) identified pancreatic cancer susceptibility loci on chromosomes 1q32.1/NR5A2, 5p15.33/CLPTM1L/TERT, 9q34.2/ABO, and 13q22.1. The most significant single-nucleotide polymorphism (SNP) identified on 13q22.1, rs9543325, lies in a 600 kb gene desert; the nearest genes are KLF5, KLF12, PIBF1, DIS3, and BORA (265–586 kb). Imputation using the 1000 Genomes and DCEG reference datasets did not improve the GWAS signal, but produced a set of highly correlated SNPs for functional follow-up. We performed eQTL analysis to test for association between the genotypes of these functional candidate variants and expression of nearby genes. Among 100 normal derived pancreatic tissue samples, DIS3 expression showed the strongest association with a novel 30 bp indel variant in the risk locus (P = 4.0 × 104), indicating risk alleles associate with reduced DIS3 expression. Mutations in DIS3 have previously been identified in acute myeloid leukemia and multiple myeloma, and its expression has been correlated with metastatic potential in colorectal cancer, suggesting DIS3 is relevant to cancer biology. Chromosome conformation capture identified a physical interaction between the indel-containing locus and a region near the DIS3 promoter. Luciferase assay for regulatory function of this indel-containing locus revealed allele-specific silencer activity for the insertion allele. Supershift electromobility shift assay (EMSA) demonstrated binding of LEF1 specifically to the insertion allele of the indel, which contains two in silico predicted LEF1 binding elements. Finally, through immunohistochemical analysis, high DIS3 protein levels associated with better survival for pancreatic cancer patients (hazard ratio = 2.87, 95% CI = 1.49–5.53, P = 0.001). Our results suggest that at least one target gene for the pancreatic cancer risk variants on chr13q22.1 may be DIS3, and that the underlying biology may be mediated by the novel indel through a long-range repressive effect on DIS3 expression.
Citation Format: Jason W. Hoskins, Abdisamad Ibrahim, Mickey Emmanuel, Hemang Parikh, Jinping Jia, Irene Collins, Kris Ylaya, Sean F. Altekruse, Stephen M. Hewitt, Gloria M. Petersen, Laufey T. Amundadottir. Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression with prognostic implications. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B111.