bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Exercise on Cognitive Recovery after Acquired Brain Injury in Animal Models: A Systematic Review
Authors: Wogensen Elise , Malá Hana , Mogensen Jesper
Published: October 2015

The objective of the present paper is to review the current status of exercise as a tool to promote cognitive rehabilitation after acquired brain injury (ABI) in animal model-based research. Searches were conducted on thePubMed, Scopus, andpsycINFOdatabases in February 2014. Search strings used were: exercise (and) animal model (or) rodent (or) rat (and) traumatic brain injury (or) cerebral ischemia (or) brain irradiation. Studies were selected if they were (1) in English, (2) used adult animals subjected to acquired brain injury, (3) used exercise as an intervention tool after inflicted injury, (4) used exercise paradigms demanding movement of all extremities, (5) had exercise intervention effects that could be distinguished from other potential intervention effects, and (6) contained at least one measure of cognitive and/or emotional function. Out of 2308 hits, 22 publications fulfilled the criteria. The studies were examined relative to cognitive effects associated with three themes: exercise type (forced or voluntary), timing of exercise (early or late), and dose-related factors (intensity, duration, etc.). The studies indicate that exercise in many cases can promote cognitive recovery after brain injury. However, the optimal parameters to ensure cognitive rehabilitation efficacy still elude us, due to considerable methodological variations between studies.
Diagnostic Options and Challenges for Dengue and Chikungunya Viruses
Authors: Mardekian Stacey K. , Roberts Amity L.
Published: October 2015

Dengue virus (DENV) and Chikungunya virus (CHIKV) are arboviruses that share the sameAedesmosquito vectors and thus overlap in their endemic areas. These two viruses also cause similar clinical presentations, especially in the initial stages of infection, with neither virus possessing any specific distinguishing clinical features. Because the outcomes and management strategies for these two viruses are vastly different, early and accurate diagnosis is imperative. Diagnosis is also important for surveillance, outbreak control, and research related to vaccine and drug development. Available diagnostic tests are aimed at detection of the virus, its antigenic components, or the host immune antibody response. In this review, we describe the recent progress and continued challenges related to the diagnosis of DENV and CHIKV infections.
Naturally Occurring Extracellular Matrix Scaffolds for Dermal Regeneration: Do They Really Need Cells?
Authors: Eweida A. M. , Marei M. K.
Published: October 2015

The pronounced effect of extracellular matrix (ECM) scaffolds in supporting tissue regeneration is related mainly to their maintained 3D structure and their bioactive components. These decellularized matrix scaffolds could be revitalized before grafting via adding stem cells, fibroblasts, or keratinocytes to promote wound healing. We reviewed the online published literature in the last five years for the studies that performed ECM revitalization and discussed the results of these studies and the related literature. Eighteen articles met the search criteria. Twelve studies included adding cells to acellular dermal matrix (ADM), 3 studies were on small intestinal mucosa (SIS), one study was on urinary bladder matrix (UBM), one study was on amniotic membrane, and one study included both SIS and ADM loaded constructs. We believe that, in chronic and difficult-to-heal wounds, revitalizing the ECM scaffolds would be beneficial to overcome the defective host tissue interaction. This belief still has to be verified by high quality randomised clinical trials, which are still lacking in literature.
Performance on ICI Self-Cancellation in FFT-OFDM and DCT-OFDM System
Authors: Gupta Shilpi , Dalal Upena , Mishra Vishnu Narayan
Published: October 2015

In orthogonal frequency division multiplexing (OFDM) system, the existence of frequency offset in AWGN channel affects the orthogonality among the subcarriers and consequently introduces the intercarrier interference (ICI). The paper investigates new ICI self-cancellation technique to mitigate the effect of ICI in FFT-OFDM and compares it to DCT based OFDM system in terms of bit error rate (BER) and carrier to interference ratio (CIR). The proposed method for group size three results in a significant 20 dB improved CIR in FFT-OFDM. In terms of BER, proposed ICI self-cancellation technique outperforms the other self-cancellation techniques in FFT-OFDM. Also, this paper investigates outperforming BER and CIR improvement by using DCT-OFDM without applying self-cancellation techniques, due to its energy compaction property.
Overexpression of NTRK1 Promotes Differentiation of Neural Stem Cells into Cholinergic Neurons
Authors: Wang Limin , He Feng , Zhong Zhuoyuan , Lv Ruiyan , Xiao Songhua , Liu Zhonglin
Published: October 2015

Neurotrophic tyrosine kinase type 1 (NTRK1) plays critical roles in proliferation, differentiation, and survival of cholinergic neurons; however, it remains unknown whether enhanced expression of NTRK1 in neural stem cells (NSCs) can promote their differentiation into mature neurons. In this study, a plasmid encoding the rat NTRK1 gene was constructed and transfected into C17.2 mouse neural stem cells (NSCs). NTRK1 overexpression in C17.2 cells was confirmed by western blot. The NSCs overexpressing NTRK1 and the C17.2 NSCs transfected by an empty plasmid vector were treated with or without 100 ng/mL nerve growth factor (NGF) for 7 days. Expression of the cholinergic cell marker, choline acetyltransferase (ChAT), was detected by florescent immunocytochemistry (ICC). In the presence of NGF induction, the NSCs overexpressing NTRK1 differentiated into ChAT-immunopositive cells at 3-fold higher than the NSCs transfected by the plasmid vector (26% versus 9%,P<0.05). The data suggest that elevated NTRK1 expression increases differentiation of NSCs into cholinergic neurons under stimulation of NGF. The approach also represents an efficient strategy for generation of cholinergic neurons.
Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling
Authors: Huang Chia-Wei , Huang Chao-Ching , Chen Yuh-Ling , Fan Shih-Chen , Hsueh Yuan-Yu , Ho Chien-Jung , Wu Chia-Ching
Published: October 2015

Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and followingin vivotherapeutic outcomes. Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.
Zn‐Doped LiNi1/3Co1/3Mn1/3O2 Composite as Cathode Material for Lithium Ion Battery: Preparation, Characterization, and Electrochemical Properties
Authors: Du Han , Zheng Yuying , Dou Zhengjie , Zhan Hengtong
Published: October 2015

Zn‐doped LiNi1/3Co1/3Mn1/3O2 composite, Li(Ni1/3Co1/3Mn1/3)1–xZnxO2 (x = 0.02; 0.05; 0.08), is synthesized by the sol‐gel method. The crystal structure, morphology, and electrochemical performance are investigated via X‐ray diffraction (XRD), scanning electron microscope (SEM), cyclic voltammetry (CV), and constant current charge/discharge experiment. The result reveals that Zn‐doping cathode material can reach the initial charge/discharge capacity of 188.8/162.9 mAh·g−1 for Li(Ni1/3Co1/3Mn1/3)0.98Zn0.02O2 and 179.0/154.1 mAh·g−1 for Li(Ni1/3Co1/3Mn1/3)0.95Zn0.05O2 with the high voltage of 4.4 V at 0.1 C. Furthermore, the capacity retention of Li(Ni1/3Co1/3Mn1/3)0.98Zn0.02O2 is 95.1% at 0.5 C after 50 cycles at room temperature. The improved electrochemical properties of Zn‐doped LiNi1/3Co1/3Mn1/3O2 are attributed to reduced electrode polarization, enhanced capacity reversibility, and excellent cyclic performance.
Enabling Cyber Physical Systems with Wireless Sensor Networking Technologies, Multiagent System Paradigm, and Natural Ecosystems
Authors: Jabeur Nafaâ , Sahli Nabil , Zeadally Sherali
Published: October 2015

Wireless sensor networks (WSNs) are key components in the emergent cyber physical systems (CPSs). They may include hundreds of spatially distributed sensors which interact to solve complex tasks going beyond their individual capabilities. Due to the limited capabilities of sensors, sensor actions cannot meet CPS requirements while controlling and coordinating the operations of physical and engineered systems. To overcome these constraints, we explore the ecosystem metaphor for WSNs with the aim of taking advantage of the efficient adaptation behavior and communication mechanisms of living organisms. By mapping these organisms onto sensors and ecosystems onto WSNs, we highlight shortcomings that prevent WSNs from delivering the capabilities of ecosystems at several levels, including structure, topology, goals, communications, and functions. We then propose an agent-based architecture that migrates complex processing tasks outside the physical sensor network while incorporating missing characteristics of autonomy, intelligence, and context awareness to the WSN. Unlike existing works, we use software agents to map WSNs to natural ecosystems and enhance WSN capabilities to take advantage of bioinspired algorithms. We extend our architecture and propose a new intelligent CPS framework where several control levels are embedded in the physical system, thereby allowing agents to support WSNs technologies in enabling CPSs.
New Architecture towards Ultrathin CdTe Solar Cells for High Conversion Efficiency
Authors: Teyou Ngoupo A. , Ouédraogo S. , Zougmoré F. , Ndjaka J. M. B.
Published: October 2015

Solar Cell Capacitance Simulator in 1 Dimension (SCAPS-1D) is used to investigate the possibility of realizing ultrathin CdTe based solar cells with high and stable conversion efficiency. In the first step, we modified the conventional cell structure by substituting the CdS window layer with a CdS:O film having a wide band gap ranging from 2.42 to 3.17 eV. Thereafter, we simulated the quantum efficiency, as well as the parameters ofJ-Vcharacteristics, and showed how the thickness of CdS:O layer influences output parameters of Glass/SnO2/ZTO/CdS:O/CdTe1-xSx/CdTe/Ni reference cell. High conversion efficiency of 17.30% has been found using CdTe1-xSx(x=0.12) and CdTe layers of thickness 15 nm and 4 μm, respectively. Secondly, we introduced a BSR layer between the absorber layer and back metal contact, which led to Glass/SnO2/ZTO/CdS:O/CdTe1-xSx/CdTe/BSR/Ni configuration. We found that a few nanometers (about 5 nm) of CdTe1-xSxlayer is sufficient to obtain high conversion efficiency. For BSR layer, different materials with large band gap, such as ZnTe, Cu2Te, and p+-CdTe, have been used in order to reduce minority carrier recombination at the back contact. When ZnTe is used, high conversion efficiency of 21.65% and better stability are obtained, compared to other BSR.
Multiparameter Stochastic Dynamics of Ecological Tourism System with Continuous Visitor Education Interventions
Authors: Wei Dongping , Zheng Qunming , Wen Shouwen
Published: October 2015

Management of ecological tourism in protected areas faces many challenges, with visitation-related resource degradations and cultural impacts being two of them. To address those issues, several strategies including regulations, site managements, and visitor education programs have been commonly used in China and other countries. This paper presents a multiparameter stochastic differential equation model of an Ecological Tourism System to study how the populations of stakeholders vary in a finite time. The solution of Ordinary Differential Equation of Ecological Tourism System reveals that the system collapses when there is a lack of visitor educational intervention. Hence, the Stochastic Dynamic of Ecological Tourism System is introduced to suppress the explosion of the system. But the simulation results of the Stochastic Dynamic of Ecological Tourism System show that the system is still unstable and chaos in some small time interval. The Multiparameters Stochastic Dynamics of Ecological Tourism System is proposed to improve the performance in this paper. The Multiparameters Stochastic Dynamics of Ecological Tourism System not only suppresses the explosion of the system in a finite time, but also keeps the populations of stakeholders in an acceptable level. In conclusion, the Ecological Tourism System develops steadily and sustainably when land managers employ effective visitor education intervention programs to deal with recreation impacts.
Iterative Learning Control Approach for Signaling Split in Urban Traffic Networks with Macroscopic Fundamental Diagrams
Authors: Yan Fei , Tian Fu-li , Shi Zhong-ke
Published: October 2015

Recent analysis of field experiments in cities revealed that a macroscopic fundamental diagram (MFD) relating network outflow and network vehicle accumulation exists in the urban traffic networks. It has been further confirmed that an MFD is well defined if the network has regular network topology and homogeneous spatial distribution of vehicle accumulation. However, many real urban networks have different levels of heterogeneity in the spatial distribution of vehicle accumulation. In order to improve the mobility in heterogeneously congested networks, we propose an iterative learning control approach for signaling split, which aims at distributing the accumulation in the networks as homogeneously as possible and ensuring the networks have a larger outflow. The asymptotic convergence of the proposed approach is proved by rigorous analysis and the effectiveness is further demonstrated by extensive simulations.
Web-Based Data Integration and Interoperability for a Massive Spatial-Temporal Dataset of the Heihe River Basin EScience Framework
Authors: Guo Qingchun , Zhang Yaonan , He Zhenfang , Min Yufang
Published: October 2015

To solve the messy problem of data types and form a unified data-processing solution, data in the Heihe River Basin were first classified into five types to integrate them and achieve unified management of data and metadata, preventing the loss of metadata, in the data model of eScience framework. Considering many of the challenges that exist in the construction of the online spatial-temporal data integration and interoperability eScience platform, we used the open data interfaces and standards such as the Common DataModel (CDM) interface, common scientific data modelling (i.e., NetCDF, GRIB, and HDF), and Open Geospatial Consortium (OGC) standards. Through the eScience platform, we also provided online data processing tools by collecting free tools (e.g., NetCDF tool, quality control tool). This eScience platform enables researchers to make full use of scientific research information and results and facilitates collaboration, especially between the GIS community and other members of the earth science community, with the purpose of establishing an online platform of uniform spatial data from the Heihe River Basin via common scientific data modelling.
Error Checking for Chinese Query by Mining Web Log
Authors: Duan Jianyong , Mi Peng , Liu Hui
Published: October 2015

For the search engine, error-input query is a common phenomenon. This paper uses web log as the training set for the query error checking. Through then-gram language model that is trained by web log, the queries are analyzed and checked. Some features including query words and their number are introduced into the model. At the same time data smoothing algorithm is used to solve data sparseness problem. It will improve the overall accuracy of then-gram model. The experimental results show that it is effective.
Abstract A122: Case review for multi-targeted epigenetic therapy ( MTET) and its rationale in an integrative approach
Authors: Nezami Mohammad , Stobbe Daniel , Hager Steven
Published: October 2015

In 2012 there were 11,957,599 advanced cancer cases in the US reported by CDC and the incidence has been almost unchanged over the previous 8 years (482,000 cases in 2000 versus 456,000 cases in 2008). There has been an annual percentage change of only (-0.6) between years 1999 to 2008 in cancer incidence.

It is well described in the recent literature that epigenetic alterations are at least if not more important than genetic defects for the development and progression of malignant diseases. In the therapeutic field, transcriptional therapy is a very promising form of cancer treatment that is being extensively evaluated. It is speculated that inhibitors of DNA methylation and histone deacetylases can reactivate expression of tumor suppressor genes and induce histone hyperacetylation in the tumors of patients with solid cancers after treatment with these agents. Hypermethylation and transcription silencing of suppressor genes has been shown in 33% of breast cancers, 60% of prostate CA and 92% of colon CA.

Although the value of such combination therapy both in chemoprevention, as well as treatment in patients with cancer is extremely important and can cause a significant shift in the current practice of oncology and cancer prevention, unfortunately, the results in clinical studies have been poor as the target histone hyperacetylation does not correlate with survival (possibly due to P 16/21 resistance, onco promoter mutations and unselectiveness of the therapies).

To overcome such resistance we have developed a protocol using researched natural substances and off label drugs in a protocol called Multi targeted epigenetic therapy or MTET, currently tested in preclinical studies with promising results confirming apoptosis. This approach is shown to be clinically relevant in a set of cases treated and presented here.

Here we present thirty cases of advanced resistant stage four disease that were treated through this method successfully with three samples cases to be described in details. We conclude that further research is warranted in a larger spectrum and in clinical trial setting to evaluate the efficacy of such method.

Citation Format: Mohammad Nezami, Daniel Stobbe, Steven Hager. Case review for multi-targeted epigenetic therapy ( MTET) and its rationale in an integrative approach. [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 A122.
Abstract A18: Syndecan-1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance
Authors: Yao Wantong , Wang Wei , Taguchi Ayumu , Kapoor Avnish , Momin Amin , Jiang Hong , Rose Johnathon , Celiktas Muge , Deem Angela , Hanash Samir , DePinho Ronald , Ying Haoqiang , Draetta Giulio
Published: October 2015

Although the universal presence of KRAS mutations and their critical role in human pancreatic ductal adenocarcinoma (PDAC) designates it as an ideal therapeutic target, oncogenic KRAS (KRAS*) is still regarded as ‘undruggable’ to date. Therefore, to identify therapeutic points of intervention, it is critical to understand the impact of KRAS*-mediated pathways on in vivo tumor pathogenesis. We have recently generated an inducible KrasG12D-driven (iKRAS*) mouse PDAC model and established a critical role for sustained KRAS* activity in tumor maintenance, providing a model to characterize pathways required for KRAS*-dependent tumorigenicity. Cell surface proteins are relatively accessible and can provide candidates for biomarker discovery, as well as be utilized as therapeutic targets. To characterize the KRAS*-specific organization of cell surface proteins toward the development of possible diagnostic or therapeutic tools, we conducted an unbiased surfaceome analysis of tumor cells in the presence and absence of KRAS* signaling using the iKRAS* mouse PDAC model. Syndecans (SDC), a family of heparin sulfate proteoglycans, were identified as candidates whose membrane expression is correlated with KRAS* activity. Specifically, Syndecan-1 (SDC1) expression was upregulated in response to KRAS* induction in acinar-ductal metaplasia (ADM) and early pancreatic intraepithelial neoplasia (PanIN), but not in cerulein-induced chronic pancreatitis. Moreover, SDC1 membrane expression was abolished upon KRAS* extinction, and our data indicated that the MAPK pathway, but not the PI3K pathway, drives KRAS*-mediated SDC1 surface localization. Supportive of our findings, it has been shown that SDC1 expression is increased in premalignant and malignant pancreatic lesions of primary human PDAC, as well as in various other KRAS*-driven pancreatic cancer mouse models. To further study the role of SDC1 in KRAS*-driven pancreatic cancers, we generated an SDC1-knockout mouse model and crossed with LSL-KrasG12D-PDAC models. Our preliminary data indicate that genetic ablation of SDC1 expression effectively suppressed KRAS*-driven PDAC initiation and progression. The mechanisms of KRAS*-mediated SDC1 membrane localization and its impact on PDAC initiation and progression will be further explored.

Citation Format: Wantong Yao, Wei Wang, Ayumu Taguchi, Avnish Kapoor, Amin Momin, Hong Jiang, Johnathon Rose, Muge Celiktas, Angela Deem, Samir Hanash, Ronald DePinho, Haoqiang Ying, Giulio Draetta. Syndecan-1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance. [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 A18.
Abstract A24: CD133 initiates tumors, induces epithelial-mesenchymal transition, and increases metastasis in pancreatic cancer
Authors: Nomura Alice , Banerjee Sulagna , Sangwan Veena , Chugh Rohit , Dudeja Vikas , Vickers Selwyn M. , Saluja Ashok K.
Published: October 2015

CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer, however, the functional role in the cancer stem cell remains elusive. In this study, we overexpressed CD133 CSC marker in a cell line with minimal endogenous CD133 in order to determine its functional role within a cancer context. We determined that CD133 expression led to increased tumorigenicity down to 10 cells. Progression of tumors derived from cells overexpressing CD133 increased in volume quicker than controls. Additionally, the number of lesions and sites of metastasis were increased in the orthotopic tumors derived from CD133 overexpressing cells. In vitro, CD133 expression induced epithelial-mesenchymal transition (EMT). Mesenchymal marker genes such as SNAI1, ZEB1, CDH2, and VIM increased upon CD133 overexpression and led to increased in vitro invasion by Boyden chamber invasion assay. Furthermore, our results indicate EMT induction and increased invasiveness were mediated by increased NF-κB activation upon CD133 overexpression, as inhibition of NF-κB mitigated these effects. In conclusion, this study demonstrated a functional role of CD133 in pancreatic cancer: its expression increases tumorigenicity; induces EMT; and increases invasion and metastasis.

Citation Format: Alice Nomura, Sulagna Banerjee, Veena Sangwan, Rohit Chugh, Vikas Dudeja, Selwyn M. Vickers, Ashok K. Saluja. CD133 initiates tumors, induces epithelial-mesenchymal transition, and increases metastasis in 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 A24.
Abstract A37: MSI is not an important feature in early onset pancreatic carcinoma
Authors: Zanten Monica AJ Van , Kempers Marlies JE , Ligtenberg Marjolijn JL , Nagtegaal Iris D.
Published: October 2015

Background and Aim: There is scant information on pancreatic cancer occurring at young age. About 5 to 10 percent of patients with pancreatic cancer have a family history of pancreatic cancer, which is partially due to defined hereditary syndromes like Lynch syndrome. Recently, we have identified deletions of the 3’ end of the EPCAM gene as a novel cause of this hereditary syndrome. In the cohort of patients with EPCAM deletions a relatively high number of pancreatic cancers and duodenal cancers were observed. We therefore aimed to assess whether development of pancreatic or duodenal cancer at young age might be an indication of EPCAM-associated Lynch syndrome.

Methods: We searched the Dutch Pathology Registry (PALGA) to identify all patients who were diagnosed with pancreatic carcinoma (PC), ampulla of Vater carcinoma (VC) or duodenal carcinoma (DC) before the age of 50 in The Netherlands between January 2000 and December 2012. Immunohistochemical analysis was used to analyze mismatch repair (MMR)- and EPCAM-protein expression. MS-status was determined by a panel of 5 mononucleotide repeats in cases with an aberrant MMR protein pattern. Furthermore, multiplex ligation-dependent probe amplification will be performed in case of an absent EPCAM staining or loss of MSH2 and MSH6 protein expression.

Results: An aberrant MMR-IHC for PMS2 combined with microsatellite instability (MSI) was identified in 1 of 48 (2%) PC diagnosed before age 50. In 24 VC patients, one tumor (4%) showed MSI with absence of both MLH1 and PMS2 staining. This patient had a history of colon carcinoma at the age of 43 years. All patients showed a normal immunohistochemical staining for MSH2 and MSH6. EPCAM protein expression was present in all cases, except one case with an anaplastic pancreas carcinoma where EPCAM was absent in the vimentine-positive area of the tumor. Eight out of 22 DC tumors (36%) showed a MMR-defective phenotype with MSI, of which 2 with an aberrant MSH2 and MSH6 staining and a positive EPCAM protein expression. One of these two patients had a history of colon carcinoma at the age of 24 and 26 years.

Conclusion: This nationwide study cohort suggests that early onset pancreatic cancer and ampulla of Vater cancer are at most rarely associated with (EPCAM-associated) Lynch syndrome, in contrast to early onset duodenal cancer.

Citation Format: Monica AJ Van Zanten, Marlies JE Kempers, Marjolijn JL Ligtenberg, Iris D. Nagtegaal. MSI is not an important feature in early onset pancreatic carcinoma. [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 A37.
Abstract A38: Adiponectin receptor agonists cause inhibition of pancreatic cancer proliferation
Authors: Mendonsa Alisha , Gorden Lee , VanSaun Michael Nathan
Published: October 2015

Adiponectin is an anti-atherogenic hormone which is typically decreased in the setting of obesity, diabetes, and pancreatitis. Adiponectin and/or its receptor levels have been inversely correlated with risk for pancreatic cancer. The purpose of this study was to determine the effect of adiponectin on pancreatic cancer cells and to investigate the primary molecular pathways that it regulates. We have previously shown that pancreatic cancer cells primarily produce adiponectin receptor 1. In our current studies, recombinant adiponectin and a novel small molecular adiponectin agonist, AdipoRon, were used to stimulate human and murine pancreatic cancer cell lines in vitro. Proliferation was assessed through an EdU incorporation assay, metabolism was measured through MTT, and apoptosis was assessed through Annexin V staining. Results demonstrate that adiponectin stimulation leads to a decrease in proliferation of pancreatic cancer cells. Further, AdipoRon elicits a more potent suppression of proliferation and an additional increase in apoptosis. To better understand the molecular mechanisms activated by adiponectin stimulation, we performed western blot analysis of treated cells. We were able to confirm that AMPK was a direct target of both adiponectin and AdipoRon. Further, we were able to show that FBS stimulated phosphorylation of Akt was diminished in the presence of AdipoRon. Our data demonstrate that adiponectin and adiponectin receptor agonists act in a suppressive manner against pancreatic cancer cell proliferation. Current studies will determine whether adiponectin agonists can additionally decrease proliferation in vivo.

Citation Format: Alisha Mendonsa, Lee Gorden, Michael Nathan VanSaun. Adiponectin receptor agonists cause inhibition of pancreatic cancer proliferation. [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 A38.
Abstract A42: Paracrine regulation of the pancreatic cancer epigenome
Authors: Sherman Mara H. , Collisson Eric , Downes Michael , Evans Ronald M.
Published: October 2015

Development of pancreatic ductal adenocarcinoma (PDAC) follows an increasingly well-defined series of genetic events in the pancreatic epithelium. Less well understood are the steps orchestrating the exuberant desmoplasia that accompanies every case of PDAC. This accumulation of stromal components arises from and is maintained by the reciprocal interactions between genetically altered tumor cells and adjacent stroma. Pancreatic stellate cells (PSCs) are myofibroblast-like cells activated by tissue damage and implicated in wound healing. Recent work suggests that PSCs are key primary drivers of the desmoplastic reaction that characterizes the disease, possibly through their established secretory capacity. We wished to explore the paracrine effects of PSC secreted factors on gene expression in pancreatic cancer cells. To investigate the global gene expression changes induced by stromal factors, PDAC cell lines were grown in “a-stromal” or “stromal” conditions. The addition of structural and diffusible PSC-derived factors significantly altered expression of thousands of genes in the cancer genome, suggesting that these factors exert genome-wide effects on the epigenetic state to so broadly affect transcription level. Stromal inputs lead to broad hyperacetylation of histones in the PDAC epigenome, particularly on gene-activating lysines on histone tails. These epigenetic events coincided with induction of genes implicated in anabolic metabolism, the glycosylation pathway, and inflammation. The gene expression changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental cues characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, we tested a small molecule inhibitor of a family of epigenetic readers for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by this small molecule, suggesting that acetyl-lysine readers serve as key transducers of stromal inputs to drive alterations in gene expression in pancreatic cancer cells. Inhibition of acetyl-lysine sensing 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 supports further investigation of epigenetic modulators, in combination with targeted drugs or immunotherapeutic approaches, for the treatment of PDAC.

Citation Format: Mara H. Sherman, Eric Collisson, Michael Downes, Ronald M. Evans. Paracrine regulation of the pancreatic cancer epigenome. [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 A42.
Abstract A45: Understanding the roles of extracellular matrix proteins in pancreatic ductal adenocarcinoma progression and metastasis
Authors: Tian Chenxi , Olund Daniel , Tuveson David , Hynes Richard O.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related death, and is characterized by accumulation of excessive extracellular matrix (ECM). Although the ECM of tumors, such as PDAC, has long been known to have major effects on behavior of both tumor and stromal cells, including invasion, angiogenesis, metastasis, and resistance to therapy, the detailed composition of the ECM in PDAC tumor progression and metastasis are not understood. To study the involvement of ECM proteins in PDAC primary tumor growth and the tissue-specific metastasis program, I modified the comprehensive ECM proteomic approach by Mass Spectrometry (MS) recently developed in our lab to profile the ECM changes during PDAC progression in both the LSL-KrasG12D/+; LSL-Trp53R127H/+; Pdx-1-Cre (KPC) mouse models of PDAC and human patient samples. We will compare ECM profiles from normal pancreas, pancreatitis, early and late pancreatic intraepithelial neoplasia (PanIN) stages, and PDAC. Initial MS identified between 100 and 140 ECM proteins in samples representing each stage. The combination of mouse models and human samples will allow me to uncover critical ECM changes during PDAC progression and metastasis and, furthermore, to investigate and understand the functional consequences of such changes. The ongoing studies will characterize the ECM of PDAC in detail and provide novel insights into diagnosis, prognosis and treatments of this very difficult disease.

Citation Format: Chenxi Tian, Daniel Olund, David Tuveson, Richard O. Hynes. Understanding the roles of extracellular matrix proteins in pancreatic ductal adenocarcinoma progression and metastasis. [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 A45.
Abstract A67: Defining signaling pathways governing metastatic potential in pancreas cancer
Authors: Whittle Martin C. , Carlson Markus , Hingorani Sunil R.
Published: October 2015

Pancreas cancer is an aggressively metastatic disease in which circulating tumor cells (CTC) often colonize distant organs long before diagnosis. Approximately 45% of patients present at diagnosis with metastatic disease, and this increases to 90% at the time of death. Even after surgical resection of the primary tumor, local and distant recurrence develops in approximately two thirds of cases. These sobering statistics highlight the need to define mechanisms and vulnerabilities of metastasis that can be targeted to improve patient outcomes. To better understand the process of pancreatic cancer metastasis, we study the KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre (KPC) model of autochthonous pancreas cancer. KPC mice spontaneously develop invasive and metastatic disease to numerous sites, including the liver and lungs, at rates similar to those seen in humans. Lineage tracing, performed by selectively expressing fluorescent reporters in pancreatic cells of KPC mice, has revealed a rare population of CTC that may be precursors to these metastatic foci. Building on this model, we show that alteration of TGFβ pathway components significantly affects the metastatic potential of autochthonous tumors, and that the timing and balance of signaling is critical in the metastatic process. These differences in metastatic potential are reflected in the numbers and functional properties of the respective CTC. Our distinct models with drastically different metastatic potentials provide clues to understanding the signaling mechanisms driving metastasis in pancreas cancer.

Citation Format: Martin C. Whittle, Markus Carlson, Sunil R. Hingorani. Defining signaling pathways governing metastatic potential in pancreas 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 A67.
Abstract A76: Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model
Authors: Mills Lisa D. , Zhang Lizhi , Marler Ronald J. , Svingen Phyllis A. , Fernandez-Barena Maite , Dave Maneesh , Bamlet William , McWilliams Robert , Faubion William A. , Fernandez-Zapico Martin E.
Published: October 2015

The role of the transcription factor GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the GLI1 knockout animal (GKO) with cre-dependent pancreatic activation of oncogenic KRAS concomitant with loss of the tumor suppressor TP53 (KPC). Interestingly, in this model, GLI1 played a tumor protective function, where survival of GKO/KPC mice was reduced compared to KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time-points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and leukopenia. Expression studies identified FAS and FAS ligand as potential mediators of this phenomenon. The FAS /FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation assays identified FAS and FASL as direct targets of GLI1 where GKO/KPC mice showed lower levels of this ligand compared to KPC animals. Furthermore, GLI1 overexpression and knockdown studies demonstrate a key regulatory role for GLI1 in both FAS and FASL expression. Finally, decreased levels of apoptosis were detected in the tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help the design and analysis of trials targeting GLI1-related pathways.

Citation Format: Lisa D. Mills, Lizhi Zhang, Ronald J. Marler, Phyllis A. Svingen, Maite Fernandez-Barena, Maneesh Dave, William Bamlet, Robert McWilliams, William A. Faubion, Martin E. Fernandez-Zapico. Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model. [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 A76.
Abstract A85: Collagen triple helix repeat containing-1 enhances the aggressiveness of pancreatic tumor by increased cancer cell motility and adhesiveness
Authors: Sun-Hee Leem , Tae-Hong Kang , Woong Chung Jin , Yeonsil Hwang , Seokho Kim , Seok Koh Sang
Published: October 2015

Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein involved in vascular remodeling, bone formation and developmental morphogenesis. CTHRC1 is expressed in human cancers such as breast cancer and melanoma. In this study, we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease. CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models. Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness. CTHRC1 activated several key signaling molecules, including Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase and Rac1. Treatment of xenograft mice of pancreatic cancer cells with a CTHRC1-specific monoclonal antibody led to significantly smaller tumor sizes compared with those of untreated control mice. Collectively, our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells.

Citation Format: Leem Sun-Hee, Kang Tae-Hong, Chung Jin Woong, Hwang Yeonsil, Kim Seokho, Koh Sang Seok. Collagen triple helix repeat containing-1 enhances the aggressiveness of pancreatic tumor by increased cancer cell motility and adhesiveness. [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 A85.
Abstract A91: IKBKE signaling in pancreatic tumorigenesis
Authors: Rajurkar Mihir , Mao Junhao
Published: October 2015

Oncogenic activation of Kras is an important event in Pancreatic Ductal Adenocarcinoma (PDAC), that leads to activation of multiple signaling pathways. Although Kras is conceptually an attractive therapeutic target for PDAC, attempts made to target Kras using small molecules have been mostly unsuccessful. Another approach in treating pancreatic cancer is to target downstream effectors of Kras. We have previously shown that non-canonical activity of the Gli transcription factors downstream of Kras is required for the initiation and progression of pancreatic tumors, and that Gli drives a unique pancreas specific transcriptional program in the context of oncogenic Kras. Here, we demonstrate that the IkB Kinase Epsilon (IKBKE) is a novel transcriptional target of Gli that is essential for pancreatic transformation. Using genetically modified mouse models, we show that IKBKE activity, while dispensable for pancreatic development, is required for oncogenic transformation in the pancreas. We find that the genetic knockout of IKBKE leads to a dramatic inhibition of initiation and progression of pancreatic intraepithelial neoplasia (PanIN) precursor lesions in mice carrying pancreas specific activation of oncogenic Kras. Furthermore, we find that although IKBKE is a known NF-kB activator, it only modestly regulates NF-kB activity in PDAC. In contrast we find that IKBKE strongly promotes Akt phosphorylation in PDAC in vitro and in vivo, indicating that this may be the primary mechanism of IKBKE induced tumorigenesis. Our findings support the evaluation of IKBKE as a novel therapeutic target in treatment of pancreatic cancer.

Citation Format: Mihir Rajurkar, Junhao Mao. IKBKE signaling in pancreatic tumorigenesis. [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 A91.
Abstract A94: Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer
Authors: Kapoor Avnish , Yao Wantong , Ying Haoqiang , Hua Sujun , Liewen Alison , Sadanandam Anguraj , Al-Khalil Ramsey , Viale Andrea , Pettazzoni Piergiorgio , Sanchez Nora , Protopopov Alexei , Zhang Jianhua , Heffernan Timothy , Johnson Randy L. , Chin Lynda , Wang Y. Alan , Draetta Giulio , DePinho Ronald A.
Published: October 2015

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12D–independent PDAC recurrence. We utilized MRI imaging to monitor regression of advanced pancreatic tumors measuring at least 8 mm in diameter at time of doxycycline withdrawal. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression, downstream canonical MAPK signaling but instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Enforced Yap1 expression can substitute for oncogenic Kras-driven tumor maintenance and associated tumor cell proliferation without activation of canonical Kras signaling surrogates. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models indicates that the oncogenic Kras-independent relapse tumors generated in response to KrasG12D extinction closely resemble the quasimesenchymal-subtype of human PDAC and rely on alternative oncogenic mechanisms including Yap1 for their growth.

Citation Format: Avnish Kapoor, Wantong Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Anguraj Sadanandam, Ramsey Al-Khalil, Andrea Viale, Piergiorgio Pettazzoni, Nora Sanchez, Alexei Protopopov, Jianhua Zhang, Timothy Heffernan, Randy L. Johnson, Lynda Chin, Y. Alan Wang, Giulio Draetta, Ronald A. DePinho. Yap1 activation enables bypass of oncogenic Kras addiction in 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 A94.