bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of dielectric behavior of water and thermally aged of XLPE/BaTiO3composites in the low-frequency range
Authors: Madani Lakhdar , Belkhiat Saad , Berrag Amine , Nemdili Saad 
Published: October 2015

Cross-Linked Polyethylene (XLPE) is widely used as insulation in electrical engineering, especially as cable insulation sheaths. In order to improve the dielectric properties susceptible to be modified under the effects of thermal aging and water in an absorption environment, polymers are mixed with ceramics. In this paper, the influence of barium titanate (BaTiO3), on the dielectric properties of XLPE has been studied. Dielectric parameters have been measured using an impedance analyzer RLC (WAYNE KERR 6420 type). Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy and X-ray diffraction were used as characterization techniques. The study has been carried out on two samples of XLPE. A pure sample of each were studied as a unloaded samples to be compared with samples of 5%wt, 10%wt, 15%wt and 20%wt. BaTiO3loaded XLPE. Afterwards, the composites were subject to humidity and to thermal aging. The incorporation of BaTiO31[Formula: see text]C does not modify the crystallinity and morphology of the XLPE and 2[Formula: see text]C reduces the space charges therefore the dielectric losses. [Formula: see text], [Formula: see text] and loss index are measured. Frequency response analysis has been followed in the frequency range (20–300 Hz). Experimental results show well that BaTiO3as nano-filler improves the dielectric properties of XLPE but in excessive content can drive to the cracking and therefore to absorption of water.
Abstract A04: PI3K regulation of RAC1 is required for Kras-induced pancreatic tumorigenesis
Authors: Takeuchi Kenneth K. , Carpenter Eileen , Wu Claire , Halbrook Christopher J. , Lin Richard Z. , Crawford Howard C. 
Published: October 2015

Abstract
Nearly all pancreatic ductal adenocarcinomas are caused by oncogenic mutations in the KRAS gene. Pharmacological inhibition of mutant KRAS has thus far been unsuccessful in the clinical setting, precipitating a need to understand the pathways downstream of KRAS which may prove more easily targeted with small molecule inhibitors. Here we show that PI3K p110α is absolutely required for pancreatic tumorigenesis while p110β is dispensable for this process. Surprisingly, ablation of p110α does not impair the ability of KRAS to activate AKT, demonstrating that AKT activation is not sufficient for transformation. Instead we find that p110α is required for robust activation of RAC1, a small GTPase required for pancreatic metaplasia. Consistent with this, our data show that p110α is necessary for regulating epithelial expression and activation of RAC-GEFs including Vav1, Tiam1 and Ect2. Ultimately, these results define the mechanistic role of p110α in pancreatic tumorigenesis and suggest selective inhibition of this PI3K isoform as a promising therapeutic approach to treating patients with pancreas cancer.
Citation Format: Kenneth K. Takeuchi, Eileen Carpenter, Claire Wu, Christopher J. Halbrook, Richard Z. Lin, Howard C. Crawford. PI3K regulation of RAC1 is required for Kras-induced 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 A04.
Abstract A102: Combination treatment with hypoxia-activated prodrug TH-302 and radiation reduce pancreatic tumor initiating cells and tumor growth in patient-derived xenografts
Authors: Lohse Ines , Rasowski Joanna , Cao Pinjian , Pintilie Melania , Do Trevor , Ibrahimov Emin , Tsao Ming-Sound , Hill Richard P. , Hedley David W. 
Published: October 2015

Abstract
Rationale: Using orthotopically-grown primary pancreatic cancer xenografts we recently identified an association between hypoxia and spontaneous metastasis formation, and we hypothesized that metastatic potential is conferred by the presence of tumor-initiating cells (TIC). We therefore investigated the relationship between hypoxia, tumor growth and TIC, and examined the effect of the hypoxia-activated prodrug TH-302 and ionizing radiation (IR) on pancreatic TIC and tumor growth.
Methods: Eleven patient-derived pancreatic cancer xenograft models were used to examine tumor-initiation potential in relation to the tumor phenotype. To examine the effect of TH-302 and IR on TIC, tumor-bearing mice were treated with 50 mg/kg or 150 mg/kg TH-302, 10Gy of IR, or with the combination of TH-302 and IR. To examine the effect of TH-302 and IR on tumor growth, mice were treated with either TH-302 or IR alone, or with the combination treatment according to a clinically relevant schedule. Animals were treated with 50mg/kg TH-302 injected ip on days 1, 5 and 9 and/or 2Gy irradiation per day on days 2, 3 and 4. Tumor hypoxia was measured by EF5 administration and immunostaining.
Results: TIC frequency varied across the patient-derived xenograft models and rapid tumor growth was strongly correlated with high TIC frequency but not hypoxia. Treatment with TH-302 in combination with IR led to a significant reduction in TIC frequency compared with either treatment alone in all models tested. Treatment-induced reduction in TIC frequency was independent of the magnitude of tumor hypoxia. Treatment-induced reduction of tumor growth was only observed in fast-growing hypoxic models. Additionally, TH-302 treatment also induced DNA damage in tumor tissue adjacent to the hypoxic zone which is consistent with the previously demonstrated bystander effect of TH-302.
Conclusions: These results suggest that TIC can reside in both the oxic and the hypoxic microenvironment and that the combination of TH-302 and IR may present a novel therapeutic strategy to reduce the frequency of TIC and tumor growth rate of pancreatic tumors.
Citation Format: Ines Lohse, Joanna Rasowski, Pinjian Cao, Melania Pintilie, Trevor Do, Emin Ibrahimov, Ming-Sound Tsao, Richard P. Hill, David W. Hedley. Combination treatment with hypoxia-activated prodrug TH-302 and radiation reduce pancreatic tumor initiating cells and tumor growth in patient-derived xenografts. [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 A102.
Abstract A105: Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through redox modulation
Authors: Ju Huaiqiang , Gocho Takshi , Aguilar Mitzi , Zhuang Zhuo-Nan , Fu Jie , Wu Min , Yanaga Katsuhiko , Huang Peng , Chiao Paul 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) usually develops intrinsic and extrinsic resistances to gemcitabine, and the mechanisms are not well understood. Here we found gemcitabine treatment induced NOX-derived ROS generation through the increase of p22-phox expression via NF-kappaB activation. As ROS levels increased, nuclear translocation of Nrf2 stimulated transcription of cytoprotective antioxidant genes, specially, those encoding enzymes that catalyze glutathione production to reduce elevated ROS as one of intrinsic resistance counter measures. RNAi depletion of Nrf2 enhanced the sensitivity to gemcitabine in multiple PDAC cells. The addition of beta–phenylethyl isothiocyanate (PEITC) inhibited the ROS detoxification process by reducing glutathione levels; this, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our results provide novel pre-clinical knowledge in pancreatic cancer chemoresistance, and combination with a redoxmodulating compound to deplete antioxidants can overcome intrinsic gemcitabine resistance. Our study suggests that a redox-mediated pathway that contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC demonstrates a coordinated and selective cytotoxic effect against pancreatic cancer cells and a new avenue for further clinical studies of this deadly disease. Thus, this combination strategy could prove valuable as a cancer treatment.
Note: These results were published in Molecular Cancer Therapeutics as a full-length article before the online publication of this abstract. Citation information: Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation. Huai-Qiang Ju, Takeshi Gocho, Mitzi Aguilar, Min Wu, Zhuo-Nan Zhuang, Jie Fu, Katsuhiko Yanaga, Peng Huang, and Paul J. Chiao. Mol Cancer Ther March 2015 14:788-798. doi:10.1158/1535-7163.MCT-14-0420.
Citation Format: Huaiqiang Ju, Takshi Gocho, Mitzi Aguilar, Zhuo-Nan Zhuang, Jie Fu, Min Wu, Katsuhiko Yanaga, Peng Huang, Paul Chiao. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through redox modulation. [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 A105.
Abstract A118: An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281)
Authors: Weinberg Uri , Kirson Eilon , Farber Ori , Palti Yoram 
Published: October 2015

Abstract
Background: NovoTTF Therapy is a non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. Tumor Treating Fields (TTFields) interfere with two steps during mitosis: The formation of the mitotic spindle (metaphase), and the translocation of charged organelles (anaphase). TTFields inhibit proliferation of pancreatic cell lines in vitro, and inhibit pancreatic tumor growth in vivo, alone and in combination with gemcitabine. NovoTTF Therapy applied to the brain in recurrent GBM patients demonstrated an anti-tumoral effect with minimal toxicity and better quality of life, compared to chemotherapy (Stupp et al, 2012). Being a regional treatment, TTFields can potentially inhibit the primary tumor as well as major metastatic sites of pancreatic adenocarcinoma.
Methods:
Objectives: the current trial is designed to study the safety, tolerability and efficacy of NovoTTF therapy applied to the abdomen concomitant to the standard care gemcitabine treatment, in patients suffering from advanced pancreatic adenocarcinoma.
Endpoints: severity and frequency of adverse events associated with the experimental treatment (primary), progression free survival (PFS), 6-month PFS rate, overall survival, overall response rate, compliance with NovoTTF Therapy (secondary)
Treatments: Gemcitabine 1000 mg/m2 over 30 minute infusion once weekly for up to 7 weeks, followed by a week rest from treatment. Subsequent cycles will consist of once weekly infusions on days 1, 8, 15 every 28 days. Continuous NovoTTF Therapy at a frequency of 150 kHz will be administered to the abdomen, in order to cover the region of primary tumor and main metastatic sites. The fields will be applied in two perpendicular directions at a maximal intensity of 1414 mA RMS, using highly insulated Transducer Arrays connected to a portable, battery-operated electric field generator. TTFields will be administered for at least 18 hours a day until radiological disease progression.
Major eligibility criteria: unresectable, pathologically confirmed, locally advanced/metastatic pancreatic adenocarcinoma, measurable/assessable disease, ECOG score 0-1, no prior chemotherapy or radiation, no implantable electronic medical devices.
Citation Format: Uri Weinberg, Eilon Kirson, Ori Farber, Yoram Palti. An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281). [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 A118.
Abstract A12: Establishing in vitro and in vivo models of pancreatic ductal adenocarcinoma (PDA) utilizing both acinar and ductal lineages
Authors: Handler Jesse , Bar-Sagi Dafna 
Published: October 2015

Abstract
As it seems that both acinar and ductal cells can give rise to PDA and that the developmental pathways for these two lineages differ, it is essential that we have models to study the biology of these cells both in vitro and in vivo. To facilitate this, we have developed in vitro organoid models using both acinoductal and ductal cells. These models involve isolation of primary acinar or ductal cells from the mouse pancreas and subsequent 3D culture in Matrigel. Importantly, these models allow us to study both WT, KRAS transformed, or otherwise manipulated primary cells in a physiologically relevant context. We have gone on to perform orthotopic allografts using these cells to study their behavior in vivo. KRAS transformed acinoductal and ductal cells exhibit markedly different phenotypes within these allografts. Ductal cells form large cystic lesions, while acinoductal cells form small, well differentiated ductal lesions within the context of a residual Matrigel plug. Preliminary data suggest that these differences may be due to differential activation of pancreatic stellate cells (PSCs).
Citation Format: Jesse Handler, Dafna Bar-Sagi. Establishing in vitro and in vivo models of pancreatic ductal adenocarcinoma (PDA) utilizing both acinar and ductal lineages. [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 A12.
Abstract A16: Mutant Kras associated protein oxidation in pancreatic neoplasia
Authors: Schultz Michelle A. , Shah Rital , DeCant Brian , Bentrem David , Grippo Paul 
Published: October 2015

Abstract
Recent studies have suggested that mutant Kras associated activation of the Nrf2 pathway may have a significant role in pancreatic cancer tumorigenesis. Nrf2 regulates a battery of antioxidant genes, including peroxiredoxin-1 (Prdx-1), that are responsible for maintaining redox homeostasis in the cell. While ROS detoxification may have significant roles in cancer, several non-classical mechanisms of redox signaling associated with protein oxidation and phosphorylation are also important in tumorigenesis. Prdx-1 can regulate transcription as a cofactor in multiple oxidation states, represses tumorigenesis in its reduced state, and can act as a nuclear chaperone in elevated states of oxidation and when phosphorylated. We are therefore investigating the role of Prdx-1 and its oxidation states in oncogenic signaling pathways in mutant Kras models of pancreatic tumorigenesis and neoplasia. Our data demonstrate that Prdx1 is localized to the nucleus in normal c57-BL6 mice and exclusively located in the cytoplasm in normal pancreatic cells in the EL-Kras model of pancreatic neoplasia. Moreover, in acinar to ductal metaplatic pancreatic cells in EL-Kras mice, there is an increase in cytoplasmic Prdx1 expression and evidence of nuclear staining. Papillary cells in lesions of EL-Kras mice have apical Prdx-1 expression and ductal cells lining these lesions have higher cytoplasmic Prdx-1 expression and some nuclear Prdx-1 localization. This suggests that throughout tumor progression, Prdx-1 is differentially regulated. In vitro, neoplastic and tumorigenic pancreatic cell lines have more total Prdx-1 and oxidized Prdx-1 expression than non-tumorigenic cell lines. Moreover, cells that have mutant Kras were associated with higher levels of protein oxidation than those with wildtype Kras expression. Interestingly, mutant Kras was also associated with differences in pERK interaction with Prdx-1, which was also differentially regulated by fatty acids that control pancreatic neoplasia. In addition, ERK phosphorylation was also modified by fatty acid treatment in wildtype and mutant Kras normal, neoplastic, and tumorigenic cell lines. Our data therefore suggests that mutant Kras is associated with elevated levels of Prdx-1 oxidation and that Kras mediated activation of ERK could be associated with changes in Prdx-1 signaling in pancreatic neoplasia.
Citation Format: Michelle A. Schultz, Rital Shah, Brian DeCant, David Bentrem, Paul Grippo. Mutant Kras associated protein oxidation in pancreatic neoplasia. [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 A16.
Abstract A23: SMYD3 links methylation of MAP3K2 to Ras-driven tumors
Authors: Mazur Pawel K. , Reynoird Nicolas , Khatri Purvesh , Butte Atul J. , Wilkinson Alex , Garcia Benjamin , Liu Shichong , Vermeulen Michiel , Jansen Pascal W.T.C. , Tummino Peter J. , Kruger Ryan G. , Aller Glenn S. Van , Barbash Olena , Huddleston Michael , Gozani Or , Sage Julien 
Published: October 2015

Abstract
The Ras family of oncogenes is activated in a large fraction of human cancers. Treatment of Ras-driven tumors with inhibitors of protein kinases in the Ras signaling network, such as Raf or MEK is a promising therapeutic strategy. However, toxicity issues and the emergence of tumor cells that are resistant to these drugs underscore the need for a better understanding of the Ras pathway and for the development of novel therapeutic options to improve the survival of cancer patients.
Deregulation in lysine methylation signaling has emerged as a common etiologic factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumors. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown.
Here we show that methylation of MAP3K2 by SMYD3 increases MAP Kinase signaling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LAC), we found that abrogating SMYD3 catalytic activity inhibits tumor development in response to oncogenic Ras. We employed protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signaling module. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP Kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation.
Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signaling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling.
Citation Format: Pawel K. Mazur, Nicolas Reynoird, Purvesh Khatri, Atul J. Butte, Alex Wilkinson, Benjamin Garcia, Shichong Liu, Michiel Vermeulen, Pascal W.T.C. Jansen, Peter J. Tummino, Ryan G. Kruger, Glenn S. Van Aller, Olena Barbash, Michael Huddleston, Or Gozani, Julien Sage. SMYD3 links methylation of MAP3K2 to Ras-driven tumors. [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 A23.
Abstract A52: Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment
Authors: Sodir Nicole M. , Soucek Laura , Littlewood Trevor D. , Arends Mark J. , Evan Gerard I. 
Published: October 2015

Abstract
The frequent occurrence of Myc deregulation in human cancers makes Myc an intriguing potential therapeutic target. This is supported by recent studies demonstrating that Myc inhibition (via expression of a dominant negative Myc mutant) triggers regression of SV40-driven pancreatic islet tumors and KRasG12D-driven lung tumors in mice. In the case of insulinoma, regression is presaged by collapse of the tumor microenvironment and involution of the tumor vasculature. One feature of human pancreatic ductal adenocarcinoma (PDAC) is its extensive stromal component (desmoplasia) that is thought to contribute to the resistance of PDAC to current therapies. We show that systemic Myc inhibition in the well-established KRasG12D-driven PDAC mouse model triggers regression of both tumor and its associated desmoplastic stroma, indicating that endogenous Myc function in the tumor cells is required for maintenance of the desmoplastic reaction. Consistent with this, ectopic expression of physiological levels of deregulated Myc enhances pancreatic tumor progression and drives stromal desmoplasia, and this reverses upon cessation of deregulated Myc. That systemic Myc inhibition causes regression of both tumor and its associated stroma, while ectopic activation of Myc in tumor cells drives both tumor progression and desmoplasia, confirm that Myc serves an essential and non-redundant role, coupling diverse intracellular oncogenic pathways to the tumor microenvironment, and underscoring its credentials as a pharmacological target in cancers driven by different oncogenes and arising in different tissues.
Citation Format: Nicole M. Sodir, Laura Soucek, Trevor D. Littlewood, Mark J. Arends, Gerard I. Evan. Myc is required for maintenance of KRasG12D-driven pancreatic cancer and its associated microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A52.
Abstract A57: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Authors: Zhou Shu , McCann Thalia , French Randall , Lowy Andrew , Insel Paul 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts/stellate cells, inflammatory cells and other cell types. This unique tumor microenvironment has been increasingly recognized as a key mediator of PDAC progression and drug resistance. Thus, targeting the tumor stroma may be a novel therapeutic approach for PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic cancer-associated fibroblasts (CAFs) may be potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We found 104 GPCRs, whose expression was shared in CAFs obtained from the primary tumors of five patients. Among those GPCRs, 35 had at least two-fold higher expression in the CAFs compared to normal pancreatic fibroblasts and included GPCRs that link to each of the major classes of G proteins. RT-PCR analysis of the 10 most up-regulated GPCRs correlated well (r2=0.82) with the data from the GPCR array. We conclude that: 1) GPCRomic array analysis can identify and quantify the profile of GPCRs expressed by pancreatic CAFs; 2) the CAF-expressed profile differs from that of normal pancreatic fibroblasts and 3) GPCRs expressed by CAFs may have functional roles and be novel therapeutic targets for PDAC.
Citation Format: Shu Zhou, Thalia McCann, Randall French, Andrew Lowy, Paul Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [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 A57.