bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of acute aerobic exercise and histamine receptor blockade on arterial stiffness in African Americans and Caucasians
Authors: Yan Huimin , Ranadive Sushant M. , Lane-Cordova Abbi D. , Kappus Rebecca M. , Behun Michael A. , Cook Marc D. , Woods Jeffrey A. , Wilund Kenneth R. , Baynard Tracy , Halliwill John R. , Fernhall Bo 
Published: December 2016

African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA. NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise compared with Caucasians, which may contribute to their higher risk of cardiovascular disease. Furthermore, African Americans exhibit attenuated vasodilator response compared with Caucasians.
Abstract A22: Targeting S100p Sensitizes Pancreatic Cancer Cells towards Gemcitabine
Authors: Tang Shing Chun , Chen Yangchao 
Published: December 2016

Abstract
Introduction: S100P (S100 Calcium Binding Protein P) is a member of S100 family proteins and plays important roles in cancers. S100p is up-regulated in Pancreatic Ductal Adenocarcinoma (PDAC). There is an up-regulation of S100p in pancreatic intraepithelial neoplasia (PanIN) tissue samples as well as a correlation of its expression with the grade of PanIN. S100p interacts with Receptor for Advanced Glycation End product (RAGE), whose downstream signaling pathways MAPK and NF-kB are responsible for the tumor progression and chemo resistance of PDAC. Thus, abrogation of the RAGE activation may be beneficial towards pancreatic cancer treatment. Therefore, we would like to investigate the growth and chemosensitivity of PDAC cells upon silencing S100p.
Methodology: The S100p in PDAC cell lines Capan2 and CFPAC1 was knocked down by lentiviral shRNA. Cell growth, wound healing, colonies formation ability and the tumorigenicity of the S100p knocked down cell lines were evaluated. Moreover, the chemosensitivity of PDAC cells with S100p knockdown towards gemcitabine was evaluated with cell viability assay.
Result: Knock-down of S100p inhibited PDAC cell growth and cell migration. RNAi targeting S100p in PDAC cells inhibited cell proliferation. Knock-down of S100p inhibited PDAC tumor growth in nude mice. Enhanced sensitization to gemcitabine on PDAC cells with S100p knock-down was also observed.
Conclusion: Our findings suggest that silencing S100p not only can inhibit the in vitro and in vivo growth of PDAC, but also can sensitize PDAC towards gemcitabine treatment. Our result provides a promising alternative by targeting S100p in combinatorial chemotherapy development for pancreatic cancer .
Financial support: The work described in this paper was supported by grants from the General Research Fund, Research Grants Council of Hong Kong (CUHK462109, CUHK462713 and 14102714), National Natural Science Foundation of China (81101888) and Direct Grant from CUHK to YC.
Citation Format: Shing Chun Tang, Yangchao Chen.{Authors}. Targeting S100p Sensitizes Pancreatic Cancer Cells towards Gemcitabine. [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 A22.
Abstract A42: The stem cell signal Musashi is required for pancreatic cancer progression and therapy resistance
Authors: Lytle Nikki K. , Fox Raymond G. , Jaquish Dawn V. , Pham Nhat-Long , Frederick Park D. , Lowy Andrew M. , Reya Tannishtha 
Published: December 2016

Abstract
Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States due to advanced stage at diagnosis and poor response to current therapies. There is an urgent need to identify factors that contribute to tumor progression and drug resistance in order to develop novel, more effective therapeutic strategies. Here we show that the RNA binding protein Musashi2 (Msi2) is critically important for pancreatic tumorigenesis: genetic deletion of Msi2 slowed progression of premalignant lesions to adenocarcinoma in the KPf/fC mouse model of pancreatic cancer and led to a profound increase in overall survival. To better understand how Msi2 contributes to tumor progression, we developed a Msi2 reporter mouse and crossed it into the KPf/fC model. We found that Msi2-reporter positive tumor cells are preferentially able to propagate adenocarcinoma growth, and are highly enriched among circulating tumor cells. Importantly, our studies reveal that tumor cells expressing Msi2 are exceptionally resistant to chemotherapy and radiation. Collectively, these studies identify Msi2 as a central regulator of pancreatic cancer and raise the possibility that targeting Msi could be a new approach for the treatment of pancreatic cancer.
Citation Format: Nikki K. Lytle, Raymond G. Fox, Dawn V. Jaquish, Nhat-Long Pham, Park D. Frederick, Andrew M. Lowy, Tannishtha Reya.{Authors}. The stem cell signal Musashi is required for pancreatic cancer progression and therapy resistance. [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 A42.
Abstract A45: Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression
Authors: Mello Stephano S. , Sinow Carolyn , Mazur Pawel K. , Vogel Hannes , Rinn John , Attardi Laura D. 
Published: December 2016

Abstract
p53’s role as a critical tumor suppressor is well illustrated by the fact that it is found mutated in more than half of all human cancers. In addition, the highly penetrant cancer predisposition observed in Li-Fraumeni patients with germline mutations in p53 and in p53 null mice further highlight the importance of p53 in tumor suppression. p53 is a transcription factor, able to sense stress signals such as DNA damage and hyperproliferative signals, promoting in turn the expression of a network of target genes to induce anti-proliferative responses such as cell cycle arrest or apoptosis. Although studies of genes in the p53 network have largely focused on protein-coding genes, in recent years the role of p53-regulated non-coding (nc) RNAs in p53 biology has been increasingly recognized. To identify new p53-regulated ncRNAs that could contribute to tumor suppression, we leveraged chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing (RNA-seq) data we generated previously in p53 wild-type and p53-/- mouse embryonic fibroblasts (MEFs). This analysis uncovered the lincRNA Neat1 as a p53 target gene. We showed that Neat1 is induced by different DNA damaging agents in a p53-dependent manner in different mouse and human cell types, including pancreatic ductal cells. Although we found that Neat1 is not involved in DNA damage-induced p53-dependent cell cycle arrest or apoptosis responses, we found that it does play a role in p53-dependent transformation suppression in both oncogene-expressing fibroblasts and pancreatic cancer cells. Furthermore, using oncogene-expressing fibroblasts, we showed that Neat1 loss promotes cancer in vivo in a subcutaneous xenograft model. Preliminary evidence suggests also that Neat1 loss promotes acinar to ductal metaplasia, bolstering its importance in pancreatic cancer suppression. These findings highlight the importance of Neat1 for p53 tumor suppressor function. Detailed analyses of Neat1’s mechanism of action will provide insights in its function as a tumor suppressor.
Citation Format: Stephano S. Mello, Carolyn Sinow, Pawel K. Mazur, Hannes Vogel, John Rinn, Laura D. Attardi.{Authors}. Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression. [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 A45.
Abstract A56: Targeting eIF4A dependent translation as therapeutics in pancreatic cancer
Authors: Singh Kamini , Stark Stefan G. , Viale Agnes , Mohan Prathibha , Jiang Man , Rätsch Gunnar , Wendel Hans-Guido 
Published: December 2016

Abstract
Pancreatic cancer is one of the most aggressive cancers with no targeted therapy available. RNA translation is activated in aggressive pancreatic cancer and at the same time is also refractory to mTor inhibition. We have used a translation inhibitor for eIF4A, RNA helicase that is downstream of mTOR signaling and can be functionally targeted in pancreatic cancer. We establish that Silvestrol and its analog CR-31B showed potent anti-tumor activity in pancreatic cancer cell lines in vitro and in vivo. Silvestrol/CR-31B reduced pancreatic cancer cells and organoids growth derived from mouse model of pancreatic cancer and human patient samples in vitro. Further we identify the genome wide translational targets of Silvestrol in pancreatic cancer cell line that lacks response to mTOR signaling through loss of EIF4EBP1. Silvestrol down regulate translation of many key oncogenes and others cellular factors involved in oncogenic signaling in pancreatic cancer. Silvestrol targets were also enriched for G-quadruplex structure in their 5’UTR. With this study we establish a new mechanism of targeting pancreatic cancer cells through translation inhibition and identify more proteins as therapeutic targets that are regulated independent of mTOR signaling.
Citation Format: Kamini Singh, Stefan G. Stark, Agnes Viale, Prathibha Mohan, Man Jiang, Gunnar Rätsch, Hans-Guido Wendel.{Authors}. Targeting eIF4A dependent translation as therapeutics 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 A56.
Abstract A59: Crosstalk of different macrophage populations with pancreatic acinar or PanIN cells and contribution to development of pancreatic cancer
Authors: Liou Geou-Yarh , Doeppler Heike , Bastea Ligia , Storz Peter 
Published: December 2016

Abstract
Pancreatic cancer is characterized by an inflammatory environment. Here we delineate the crosstalk between different macrophage populations with pancreatic cells carrying oncogenic Kras mutations. First, we show that pancreatic acinar cells that undergo oncogenic transformation by mutant Kras upregulate chemoattractants that attract inflammatory macrophages. These inflammatory macrophages contribute to acinar cell dedifferentiation to a progenitor-like cell type (acinar-to-ductal metaplasia; ADM). Resulting cells can give rise to PanIN lesions. We then provide insight at which stage of PanIN formation a switch between inflammatory and alternatively-activated macrophages occurs; and define one mechanism by which this can be mediated. Eventually, we provide insight of how alternatively-activated macrophages facilitate the further progression of PanIN lesions to a more aggressive phenotype.
Citation Format: Geou-Yarh Liou, Heike Doeppler, Ligia Bastea, Peter Storz.{Authors}. Crosstalk of different macrophage populations with pancreatic acinar or PanIN cells and contribution to development of 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 A59.
Abstract A66: Runx3 drives metastatic programs in pancreas cancer
Authors: Whittle Martin C. , Feng Libing , Dotson Ashley , Pakiam Fiona , Hingorani Sunil R. 
Published: December 2016

Abstract
The extreme proclivity of pancreatic ductal adenocarcinoma (PDA) for metastatic spread is the principal cause of mortality for this disease, even for patients who successfully undergo surgical resection of the primary tumor. We have engaged in a concerted effort to define the fundamental molecular and cellular drivers of PDA through the use of cognate genetically engineered mouse models that recapitulate the spectrum of human PDA. Recently, we incorporated conditional deletion of Smad4 into the KPC mouse model and noted a significant attenuation of metastatic burden in the resultant KPDC mice. Gene expression analysis identified the Runt family transcription factor Runx3 as highly expressed in metastatic KPC tumors, but minimally expressed in PDA from KPDC mice. We showed that aberrant expression of Runx3 strongly enhanced the metastatic potential of PDA through an orchestrated program that stimulated cancer cell invasion and migration and also helped generate a niche for disseminated cells to establish themselves in foreign tissues (such as the liver or lung) and form metastases. Runx3 expression additionally inhibited proliferation by upregulating expression of the cell cycle inhibitor Cdkn1a (p21), initiating a metastatic switch that favored PDA dissemination over local outgrowth. We have also identified influences of Runx3 expression on key developmental and immune-regulatory signaling pathways that are known to be aberrantly regulated in PDA. Because Runx3 has been shown to interact with Smad4 and p53, the genomic context of PDA expressing Runx3 critically modulates its function through de novo or altered protein complex formation. Defining the dichotomous, contextual roles of Runx3 as both a tumor “suppressor” and “promoter” may provide insight into the proximal cause of lethality in patients, thereby informing clinical prioritization of local versus systemic therapies for individual patients with PDA.
Citation Format: Martin C. Whittle, Libing Feng, Ashley Dotson, Fiona Pakiam, Sunil R. Hingorani.{Authors}. Runx3 drives metastatic programs in pancreas 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 A66.
Abstract A91: Stage-specific transcriptome analysis of human pancreatic cancer progression
Authors: Kim Jungsun , Donahue Greg , Yang Wenli , Zaret Kenneth S. 
Published: December 2016

Abstract
Our goals are to discover gene networks that control the progression of pancreatic intraepithelial neoplasias (PanINs) to invasive stage pancreatic ductal adenocarcinoma (PDAC) and to understand how the pluripotency regulatory network can temporarily suppress the transition. Certain cancer cells are amenable to reprogramming to pluripotency by somatic cell nuclear transfer (SCNT) or defined transcription factors (iPS). Prior work showed that SCNT-cancer cells develop into normal appearing blastocysts, but later the cancer genome in SCNT-chimeric mice was reactivated during embryogenesis, re-expressing the cancer phenotype of the lineage from which they originated. We previously showed that when an iPS-like line, designated 10-22, derived from human pancreatic ductal adenocarcinoma (PDAC), was injected into immunodeficient mice, they consistently recapitulated pre-invasive, PanIN to invasive stages of PDAC (Kim et al., 2013 Cell Reports). Specifically, the PDAC-iPS cells differentiated into a ductal, PanIN2/3 epithelium with a collagen basement membrane, followed by progression to an invasive stage phenotype with basement membrane breakdown. Furthermore, the ductal cell lesions were surrounded by stroma that co-differentiated from the pluripotent 10-22 cells, indicative of signaling interactions with the epithelium. With this system, we now ask: 1) What gene regulatory networks for pluripotency can transiently attenuate the cancer genome; 2) Upon loss of pluripotency and differentiation, what are the regulatory network transitions during human PDAC progression? 3) What are the reciprocal signals between the PDAC epithelial cells and their surrounding stromal cells during pancreatic cancer progression? To address these questions, we have genetically tagged the PDAC-iPS 10-22 line with a lentiviral vector expressing a ubiquitous promoter driving GFP and a ductal K19 promoter driving infrared protein (iRFP), so that cells can be retrieved by FACS. While GFP+iRFP- cells include stroma derived from the 10-22 cells, GFP+iRFP+ allows isolation of precursor and invasive stages of PDAC. The tagged lines were injected into immunodeficient mice, the lesions were monitored in vivo by iRFP flourescence, and RNA was isolated in triplicate at multiple time points and subjected to RNA-Seq analysis. The human PDAC 10-22 cell system is being used to discover effectors and networks whereby pluripotency can dominate over cancer and new features of human PDAC progression, which would be ultimately used for developing novel cancer therapies.
Citation Format: Jungsun Kim, Greg Donahue, Wenli Yang, Kenneth S. Zaret.{Authors}. Stage-specific transcriptome analysis of human pancreatic cancer progression. [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 A91.
Abstract B12: CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K
Authors: James Michael 
Published: December 2016

Abstract
Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. Tumor cells must endure ER stress caused by microenvironmental, oxidative, energetic, and therapeutic stresses to survive. However, the role of ER stress survival signaling in pancreatic tumorigenesis has not been elucidated. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related target in pancreatic cancer. We recently demonstrated that CRR9/CLPTM1L is overexpressed in 90% of pancreatic ductal adenocarcinomas and associated with poor outcome, while it is not expressed in normal pancreatic ductal epithelium. Furthermore, we have shown that CLPTM1L can confer resistance to chemotherapeutic killing, apoptosis, and anoikis, and is critical for KRas transformation and tumorigenesis. Here, we demonstrate that CLPTM1L interacts with phosphoinositol-3-kinase (PI3K) and the ER stress protein Glucose Related Protein 78 (GRP78) at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt survival signaling. Surface accumulation of both CLPTM1L and GRP78 are induced by ER stress and by chemotherapy in vitro. Subsequent to our recent discovery of the presence of CLPTM1L at the cell surface, we have developed antibody inhibitors of CLPTM1L, which deplete chemotherapy-inducible surface accumulation of CLPTM1L and GRP78, as well as downstream survival signaling through the Akt pathway and Bcl-xL expression. These agents have shown striking anti-tumorigenic efficacy in preclinical models of pancreatic cancer and present a promising therapeutic and chemosensitization approach.
Citation Format: Michael James.{Authors}. CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K. [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 B12.
Abstract B34: A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Cancer
Authors: Yang Shouhui , He Peijun , Wang Jian , Schetter Aaron , Tang Wei , Funamizu Naotake , Yanaga Katsuhiko , Uwagawa Tadashi , Satoskar Abhay R. , Gaedcke Jochen , Bernhardt Markus , Ghadimi B. Michael , Gaida Matthias M. , Bergmann Frank , Werner Jens , Ried Thomas , Hanna Nader , Alexander H. Richard , Hussain S. Perwez 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Pancreatic tumors with aberrant expression of macrophage migration inhibitory factor (MIF) are highly aggressive, and an increased MIF predicts poorer patient survival. We analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of PDAC patients to identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression. The identified key genes and pathways were linked to patients’ survival and were mechanistically, functionally and clinically characterized using cell lines, genetically engineered mouse model and PDAC patient cohorts. Here, we report mechanistic, functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor, nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2), leading to enhanced disease aggressiveness and poorer survival in PDAC. MIF upregulated miR-301b, which then targeted and suppressed NR3C2 expression. Tumors with high MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally, patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to chemotherapeutic drug gemcitabine. Furthermore, genetic deletion of MIF disrupted MIF-mir-301b-NR3C2 axis, which resulted in reduced metastasis and prolonged survival in genetically engineered mouse model of PDAC. These findings provide proof-of-principle that therapies targeting MIF-miR-301b-NR3C2 axis may improve disease outcome in PDAC
Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain.{Authors}. A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 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 B34.