bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A90: Mesothelin confers tumor cell vulnerabilities for gefitinib treatment
Authors: Poteet Ethan , Liang Zhengdong , Wang Youwen , Chen Changyi , Yao Qizhi 
Published: December 2016

Abstract
Combination therapy for pancreatic adenocarcinoma (PDAC) has recently had two successful stage III trials with FOLFIRINOX (combination folinic acid, fluorouracil, irinotecan, and oxalplatin) and combination gemcitabine and paclitaxel. Because of the heterogeneity of PDAC, the benefits of combination therapy are immediately apparent since it targets multiple facets of cancer simultaneously. However, FOLFIRINOX and gemcitabine + paclitaxel are highly toxic and affect all dividing cells, making apparent the need for better understanding of the cell profiles in PDAC. The epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many cancers, with EGFR or its ligands often overexpressed or mutated. Recently we have found that EGFR expression is correlated to mesothelin (MSLN) expression in PDAC. MSLN, a cell surface glycoprotein, has been shown by us and other labs to be overexpressed in 80 to 90% of all PDAC cases. To examine the relationship between MSLN and EGFR, we modulated MSLN expression by generating a MSLN overexpressing cell line from MIA-PaCa2 cells, and a MSLN knockdown cell line from CAPAN-2 cells. The change in EGFR signaling mimicked that of MSLN, with MSLN overexpression significantly increasing EGFR expression and MSLN knockdown significantly decreasing EGFR expression. Furthermore, high MSLN (and therefore high EGFR expression) showed increased sensitivity to gefitinib, an EGFR ATP binding site inhibitor, at concentrations as low as 100 nM, while MSLN low expressing cells did not exhibit any effect from gefitinib at concentrations below 10 µM. Cell Cycle analysis demonstrated that gefitinib increased the number of cells in G1 phase after 24 hours in MSLN high expressing cells, but had no effect on MSLN low expressing cells. In addition, western blot analysis of EGFR downstream pathways showed an increase in phosphorylated phospholipase C-Υ (PLC-Υ) in MSLN high expressing cells, which could be mitigated by treatment with gefitinib. Finally, combination therapy with gemcitabine and 100 nM gefitinib showed an additive effect in MSLN high expressing cells, while in MSLN low expressing cells combination gemcitabine and gefitinib had no additional effect over gemcitabine alone. This study demonstrates the correlation between MSLN expression and EGFR expression and indicates that gefitinib could be a potential addition to combination therapy for PDAC in patients with high MSLN expression.
Citation Format: Ethan Poteet, Zhengdong Liang, Youwen Wang, Changyi Chen, Qizhi Yao.{Authors}. Mesothelin confers tumor cell vulnerabilities for gefitinib treatment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A90.
Abstract B03: Pancreatic cancer stem cells: can it be restrained?
Authors: Chopra Neha , Choudhury Sangeeta , Wajid Saima , Jain Kriti , Mirza Rizwana 
Published: December 2016

Abstract
Over the past decades world-wide, research towards not only understanding the biology, but also attempting to decrease the mortality rate in pancreatic carcinoma has become the forefront in cancers of solid tumor. Recent evidences suggest that pancreatic carcinomas harbour a distinct subpopulation of putative cancer stem cells defined by their self-renewal capacity, differentiation ability, tumorigenicity and ability to drive towards metastasis. Therefore, there is not only a need to identify this population, and also design newer approaches to target these chemo-resistant cell populations, especially in pancreatic cancer which till date shows 5-year survival rate to be below 5%.
Our study identified the potential of CD44hiCD24lo MiaPaCa2/PanC1 cells to possess lower capability to generate spheroids whereas CD44hiCD24hi MiaPaCa2/PanC1 showed higher spheroid forming capacity. Spheroids obtained from both cell-lines showed similar metastatic cancer gene expression pattern. However, a distinctive CXCR4 expression levels were observed between CD44hiCD24lo PanC1-spheroids and CD44hiCD24hi PanC1-spheroids. It was also observed that EMT, CXCR4 and Muc1 were highly expressed in MiaPaCa2-spheroids. Hence, suggesting only a sub-population of tumor cells behave as “cancer initiating cells/stem-like cells” which are associated with cell-cell adhesion and cell matrix interaction.
In order to determine the role of cancer stem-like cells (spheroids/CSCs) to migrate and invade to metastasize particularly in pancreatic carcinoma, experiments were designed to evaluate their self-renewal capability and epithelial to mesenchymal transition (EMT) and their association with developmental genes. An exponential spheroid formation was observed along with stem cell transcriptional genes (Oct4 and Nanog). Interestingly, MiaPaCa2-spheroids exhibited higher expression levels of Sox-2, MMP-9 and Vimentin in comparison to PanC1-spheroids suggesting that MiaPaCa2-spheroids may be more aggressive or has higher invasive potential. It appears that pancreatic CSCs undergoing EMT probably express higher levels of Sox-9, Ngn-3, Pdx-1 and c-Myc genes which attributes to its embryonic stemness.
The results from the study clearly project the role of CSCs in pancreatic carcinoma and thus further studies to delineate the mechanism which might lead to suppression of pancreatic CSCs is crucial. In this direction, a pilot study has been initiated to explore the potential of Mesenchymal Stem Cells to target the pancreatic CSCs.
Citation Format: Neha Chopra, Sangeeta Choudhury, Saima Wajid, Kriti Jain, Rizwana Mirza.{Authors}. Pancreatic cancer stem cells: can it be restrained? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B03.
Abstract B53: The integrin αvβ6 is a promising therapeutic target for treating PDAC
Authors: Vallath Sabari , Reader Claire , Morton Jennifer , Sansom Owen , Evans Jeff , Biankin Andrew , Barry Simon T. , Kocher Hemant , Marshall John F. 
Published: December 2016

Abstract
Integrins are expressed on the surface of all nucleated cells and permit bi-directional communication for cells with their extracellular environment. The integrin αvβ6 is not usually expressed on adult cells unless they are undergoing tissue remodeling, as αvβ6 activates TGFβ, the cytokine that orchestrates wound healing. We find that αvβ6 is not expressed by normal pancreas but is upregulated on over 90% of PDAC. In vitro experiments show αvβ6 promotes cell survival, adhesion, migration and invasion through Matrigel. Treatment with αvβ6-blocking antibody 264RAD of xenografts of human PDAC cell line CfPac1 co-injected with stellate cells stopped tumor growth. In combination with Gemcitabine 264RAD shrank established (100mm3) tumors significantly (p&lt;0.001). In separate studies we treated novel transgenic mice (Pdx1-Cre; LSL-KRasG12D/+; LSL-Dusp6-/-; developed by Prof. S. Keays) with Gemcitabine or 264RAD+Gemcitabine once they had developed PDAC. The Gemcitabine alone group all died within 17 days but the combination therapy group lived significantly longer, the last animal dying at 59 days. Immunohistological analysis shows that the 264RAD-treated tumors had significantly reduced pErk and Ki67 suggesting reduced growth signaling and proliferation. Additionally strongly reduced endomucin and SMA suggest reduction in angiogenesis and myofibroblast activity in the microenvironment. This may be due to reduced TGFβ signaling since pSMAD3 and nuclear SMAD4 levels were also strongly suppressed. Thus 264RAD suppressed PDAC development by targeting both the pancreatic cancer cells and the microenvironment. These studies have resulted in the funding of a Phase I trial for 264RAD therapy of PDAC patients, sponsored by Cancer Research UK in collaboration with AstraZeneca-Medimmune.
Citation Format: Sabari Vallath, Claire Reader, Jennifer Morton, Owen Sansom, Jeff Evans, Andrew Biankin, Simon T. Barry, Hemant Kocher, John F. Marshall.{Authors}. The integrin αvβ6 is a promising therapeutic target for treating PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B53.
Abstract B68: Role of CD44 in pancreatic cancer cell plasticity
Authors: Freeman James W. , Zhao Shujie , Chen Chen , Karnad Anand 
Published: December 2016

Abstract
Two subpopulations of pancreatic adenocarcinoma (PDAC) cells were separated from different cell lines on the basis of CD44 expression level. CD44 high and CD44 low expressing cells were compared for their invasive potential, epithelial/mesenchymal phenotype, in vitro response and in vivo development of resistance to gemcitabine. CD44 high cells showed a mesenchymal phenotype, formed tumor spheres, were more invasive and were less responsive to gemcitabine. In contrast, CD44 low cells had an epithelial phenotype, were weakly invasive, did not grow as tumor spheres and showed greater response to gemcitabine. CD44 high cells showed a predominant expression of CD44 standard isoform with lower levels of various CD44 variant isoforms. Interestingly, gemcitabine treatment of CD44 low cells induced a phenotypic switch, loss of ESRP1 expression with concurrent up regulation in expression of CD44 standard. In an orthotopic mouse model, tumors from CD44 high cells had a selective growth advantage and formed metastases more rapidly. Gemcitabine treatment continuously suppressed tumor growth in animals implanted with CD44 low cells during the 22 weeks of the experiment; whereas, tumors from CD44 high cells initially showed some response to gemcitabine but developed resistance by weeks 10-12. Knockdown of CD44 in CD44 high cells from two different PDAC cell lines, inhibited invasion and increased their response to gemcitabine similar to that seen for CD44 low cells. Collectively this study suggests that a subpopulation of CD44 high expressing PDAC cells with a mesenchymal-like phenotype tends to be highly invasive, more resistant to gemcitabine in vitro and to develop gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response of PDAC.
Citation Format: James W. Freeman, Shujie Zhao, Chen Chen, Anand Karnad.{Authors}. Role of CD44 in pancreatic cancer cell plasticity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B68.
Abstract IA08: Drugging undruggable kras: will myc do the trick?
Authors: Der Channing J. 
Published: December 2016

Abstract
KRAS oncogene mutations are found in ~95% of pancreatic ductal adenocarcinoma (PDAC) and are well validated drivers of PDAC initiation and maintenance. Consequently, a major goal for the field is the development of effective anti-KRAS therapies. However, despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the KRAS have reached the clinic, prompting the widely held perception that KRAS is “undruggable”. However, with more advanced knowledge of KRAS function and new technological approaches, there is renewed hope that the time is ripe to revisit targeting KRAS. I will present our studies focused on the RAF-MEK-ERK mitogen-activated protein kinase cascade. This effector signaling network is a well-validated driver of KRAS-dependent cancer growth. Despite this key role, pharmacologic inhibitors of RAF and MEK have been ineffective in inhibiting growth of KRAS-mutated cancers, in large part due to dynamic signal reprogramming leading to ERK reactivation and bypass of inhibitor action. We therefore addressed whether direct ERK inhibition may be a more effective therapeutic approach. We identified a growth suppression mechanism due to pharmacologic inhibition of ERK that involves degradation of the MYC oncoprotein, activation of the p16INK4A-RB1 tumor suppressor pathway and induction of a senescence-like phenotype. We also applied unbiased genetic and chemical functional screens, as well as reverse phase protein array analyses, and identified the PI3K-AKT-mTOR signalling network as a key driver of pancreatic cancer resistance to ERK inhibition. Novel combination inhibitor approaches that synergistically enhanced ERK inhibitor anti-tumor activity were also identified. Finally, we determined that continued expression of KRAS was required for maintenance of MYC protein expression. We determined that previously identified mechanisms of RAS effector signaling alone did not account for MYC protein regulation in PDAC, prompting our search for novel protein kinases that regulate MYC protein degradation. Our efforts are centered defining pharmacologic strategies to accelerate MYC protein degradation as a novel approach for blocking mutant KRAS in PDAC.
Citation Format: Channing J. Der.{Authors}. Drugging undruggable kras: will myc do the trick? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA08.
Abstract IA13: Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome
Authors: Sherman Mara H. , Evans Ronald M. 
Published: December 2016

Abstract
Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.
Citation Format: Mara H. Sherman, Ronald M. Evans.{Authors}. Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA13.
Abstract IA18: Probing tumor heterogeneity with mouse models
Authors: Stanger Ben Z. 
Published: December 2016

Abstract
Although the majority of pancreatic cancers harbor mutations in a small set of cancer genes, individual tumors vary widely with respect to histology, gene expression patterns, and response to therapy. This inter-tumoral heterogeneity is likely due to mutations or epigenetic events affecting less commonly-mutated cancer genes, resulting in tumors that can be broadly grouped into three or four categories based upon transcriptional profiling. To determine the extent to which the KPC model captures the inter-tumoral heterogeneity of pancreatic cancer, we performed RNA-sequencing on isolated tumor cells from 11 murine pancreatic tumors. Using unsupervised clustering, tumors fell into two broad categories: cluster 1 tumors, which were poorly-differentiated and well-vascularized, and cluster 2 tumors, which were moderately- to well-differentiated and poorly-vascularized. Differences in gene expression could account for some of these differences; for example, cluster 1 tumor cells exhibited low levels of Shh expression, consistent with the paucity of stroma. Moreover, mechanisms of EMT differed between the two classes of tumors. Gene set variation analysis with whole transcriptome data from human PDA revealed a correlation between cluster 1 tumors and the squamous or quasi-mesenchymal subtype. Likewise, cluster 2 tumors were correlated with the classical, ADEX, and pancreatic progenitor subtypes of human PDA. These data suggest that the KPC mouse model, despite its foundation on Kras and p53 mutations alone, captures the heterogeneity of human PDA and may therefore be useful for understanding heterogeneous responses to therapy.
Citation Format: Ben Z. Stanger.{Authors}. Probing tumor heterogeneity with mouse models. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA18.
Abstract PR10: CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer
Authors: Steele Colin , Karim Saadia , Leach Josh , Bailey Peter , Biankin Andrew , Nibbs Rob , Barry Simon , Sansom Owen , Morton Jen 
Published: December 2016

Abstract
PDAC is predicted to become the second commonest cause of cancer death in the western world by 2030. Aggressive invasion and early metastases are characteristic of the disease, and even the few patients eligible for potentially curative resection inevitably develop recurrent or metastatic disease.
We now show that CXCR2 signalling is upregulated in human pancreatic cancer, predominantly in neutrophils at the tumour invasive edge. In mouse models, genetic ablation or inhibition of CXCR2 abrogated metastasis while inhibition also slowed tumorigenesis, particularly when combined with chemotherapy. Depletion of neutrophils also suppressed metastasis, suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche.
Indications from trials thus far suggest that immunotherapy will not work as a single agent strategy in pancreatic cancer patients. Importantly, we find that loss or inhibition of CXCR2 improved T-cell entry and combined inhibition of CXCR2 and PD1 in mice with established disease caused a significant extension of survival.
Thus, our data highlight two novel therapeutic opportunities for PDAC: first the use of CXCR2 inhibitors in surgically-resected patients to prevent recurrence at distant sites, and second, the use of CXCR2 inhibition in combination with immunotherapy in surgically unresectable advanced disease.
This abstract is also being presented as Poster B55
Citation Format: Colin Steele, Saadia Karim, Josh Leach, Peter Bailey, Andrew Biankin, Rob Nibbs, Simon Barry, Owen Sansom, Jen Morton.{Authors}. CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr PR10.
Juggling the Balance between Preventive Security and Human Rights in Europe
Authors: Den Boer Monica 
Published: December 2016

Within the European Union (eu), security issues are increasingly framed as risks and threats that can be controlled bypreventive measures. Theeuhas established several agencies, legal instruments and databases to facilitate the prevention of crime, terrorism and irregular migration. This article takes stock of the way in which theeuseeks to balance the preventive security logic with its own human rights framework. While human rights can jointly be considered an evolving normative framework in theeu, there is a need to identify which human rights are at risk and how (non-) compliance ought to be monitored.The article states some concerns about equal access to human rights as well as the lack of a strong general oversight mechanism. Continued structural attention should be given toex antehuman-rights impact assessments and there needs to be more emphasis on regular external evaluations of human rights complianceex post facto. In relation to the external action of theeu, theeumust practice what it preaches and needs to reflect critically on the necessity and proportionality of precautionary security measures.
Doppler Radar Analysis of a Tornadic Miniature Supercell during the Landfall of Typhoon Mujigae (2015) in South China
Authors: Zhao Kun , Wang Mingjun , Xue Ming , Fu Peiling , Yang Zhonglin , Chen Xiaomin , Zhang Yi , Lee Wen-Chau , Zhang Fuqing , Lin Qing , Li Zhaohui 
Published: December 2016

AbstractOn 4 October 2015, a miniature supercell embedded in an outer rainband of Typhoon Mujigae produced a major tornado in Guangdong province of China, leading to 4 deaths and up to 80 injuries. This study documents the structure and evolution of the tornadic miniature supercell using coastal Doppler radars, a sounding, videos, and a damage survey. This tornado is rated at least EF3 on the enhanced Fujita scale. It is by far the strongest typhoon rainband tornado yet documented in China, and possessed double funnels near its peak intensity.Radar analysis indicates that this tornadic miniature supercell exhibited characteristics similar to those found in United States landfalling hurricanes, including a hook echo, low-level inf low notches, an echo top below 10 km, a small and shallow mesocyclone, and a long lifespan (3 h). The environmental conditions—which consisted of moderate convective available potential energy (CAPE), a low lifting condensation level, a small surface dewpoint depression, a large veering low-level vertical wind shear, and a large cell-relative helicity—are favorable for producing miniature supercells. The mesocyclone, with its maximum intensity at 2 km above ground level (AGL), formed an hour before tornadogenesis. A tornado vortex signature (TVS) was identified between 1 and 3 km AGL, when the parent mesocyclone reached its peak radar-indicated intensity of 30 m s−1. The TVS was located between the updraft and forward-flank downdraft, near the center of the mesocyclone. Dual-Doppler wind analysis reveals that tilting of the low-level vorticity into the vertical direction and subsequent stretching by a strong updraft were the main contributors to the mesocyclone intensification.