bluuebunny/crossref_metadata_2025 huggingface dataset:
A Media and Clinic Intervention to Increase Colorectal Cancer Screening in Ohio Appalachia
Authors: Krok-Schoen Jessica L. , Katz Mira L. , Oliveri Jill M. , Young Gregory S. , Pennell Michael L. , Reiter Paul L. , Plascak Jesse J. , Slater Michael D. , Krieger Janice L. , Tatum Cathy M. , Paskett Electra D.
Published: October 2015

Objective. To test the effectiveness of a colorectal cancer (CRC) screening intervention among adults living in Ohio Appalachia.Methods. We conducted a group-randomized trial of a county-level intervention among adults living in 12 Ohio Appalachian counties who received a media campaign and clinic intervention focused on either CRC screening or fruits and vegetables. Participants’ percentage within CRC screening guidelines was assessed with cross-sectional surveys conducted annually for four years, and validated with medical record review of screening.Results. On average, screening data were obtained on 564 intervention and 559 comparison participants per year. There was no difference in the Wave 4 CRC screening rates of intervention and comparison counties (35.2% versus 31.4%). Multivariate analyses found that high perceived risk of CRC, willingness to have a CRC test if recommended by a doctor, doctor recommendation of a CRC screening test, and patient-physician communication about changes in bowel habits, family history of CRC, and eating fruits and vegetables were significant (p<0.05) predictors of being within CRC screening guidelines.Conclusions. The intervention was not effective in increasing CRC rates among Ohio Appalachian adults. Future research should determine how media and clinic-based interventions can be modified to improve CRC screening rates among this underserved population.
Green Synthesis, Characterization, and Antibacterial Activity of Silver/Polystyrene Nanocomposite
Authors: Awad Manal A. , Mekhamer W. K. , Merghani Nada M. , Hendi Awatif A. , Ortashi Khalid M. O. , Al-Abbas Fatimah , Eisa Nada E.
Published: October 2015

A novel, nontoxic, simple, cost‐effective and ecofriendly technique was used to synthesize green silver nanoparticles (AgNPs). The AgNPs were synthesized using orange peel extract as a reducing agent for silver nitrate salt (AgNO3). The particle size distribution of AgNPs was determined by Dynamic Light Scattering (DLS). The average size of silver nanoparticles was 98.43 nm. The stable dispersion of silver nanoparticles was added slowly to polystyrene solution in toluene maintaining the temperature at 70°C. The AgNPs/polystyrene (PS) nanocomposite solution was cast in a petri dish. The silver nanoparticles encapsulated within polymer chains were characterized by X‐ray diffraction (XRD) and Scanning Electron Microscopy (SEM) equipped with Energy Dispersive Spectroscopy (EDS) in addition to Transmission Electron Microscopy (TEM). The green AgNPs/PS nanocomposite film exhibited antimicrobial activity against Gram‐negative bacteria Escherichia coli, Klebsiella pneumoniae and Salmonella, and Gram‐positive bacteria Staphylococcus aureus. Thus, the key findings of the work include the use of a safe and simple AgNPs/PS nanocomposite which had a marked antibacterial activity which has a potential application in food packaging.
Biologic Agents for Periodontal Regeneration and Implant Site Development
Authors: Suárez-López del Amo Fernando , Monje Alberto , Padial-Molina Miguel , Tang ZhiHui , Wang Hom-Lay
Published: October 2015

The advancement of molecular mediators or biologic agents has increased tremendously during the last decade in periodontology and dental implantology. Implant site development and reconstruction of the lost periodontium represent main fields in which these molecular mediators have been employed and investigated. Different growth factors trigger different reactions in the tissues of the periodontium at various cellular levels. Proliferation, migration, and differentiation constitute the main target areas of these molecular mediators. It was the purpose of this comprehensive review to describe the origin and rationale, evidence, and the most current understanding of the following biologic agents: Recombinant Human Platelet-Derived Growth Factor-BB (rhPDGF-BB), Enamel Matrix Derivate (EMD), Platelet-Rich Plasma (PRP) and Platelet-Rich Fibrin (PRF), Recombinant Human Fibroblast Growth Factor-2 (rhFGF-2), Bone Morphogenic Proteins (BMPs, BMP-2 and BMP-7), Teriparatide PTH, and Growth Differential Factor-5 (GDF-5).
An Evaluation of Effects of Different Mydriatics on Choroidal Thickness by Examining Anterior Chamber Parameters: The Scheimpflug Imaging and Enhanced Depth Imaging-OCT Study
Authors: Yuvacı İsa , Pangal Emine , Yuvacı Sümeyra , Bayram Nurettin , Ataş Mustafa , Başkan Burhan , Demircan Süleyman , Akal Ali
Published: October 2015

Aim. To assess the effects of mydriatics commonly used in clinical practice on choroidal thickness and anterior chamber change.Methods. This was a prospective, randomized, controlled, double-blinded study including a single eye of the participants. The subjects were assigned into 4 groups to receive tropicamide 1%, phenylephrine 2.5%, cyclopentolate 1%, and artificial tears. At the baseline, anterior chamber parameters were assessed using a Pentacam Scheimpflug camera system, and choroidal thickness (CT) was measured using a spectral-domain OCT with Enhanced Depth Imaging (EDI) modality. All measurements were repeated again after drug administration.Results. Increases in pupil diameter, volume, and depth of anterior chamber were found to be significant (p=0.000,p=0.000, andp=0.000, resp.), while decreases in the choroidal thickness were found to be significant in subjects receiving mydriatics (p<0.05).Conclusions. The study has shown that while cyclopentolate, tropicamide, and phenylephrine cause a decrease in choroidal thickness, they also lead to an increase in the volume and depth of anterior chamber. However, no correlation was detected between anterior chamber parameters and choroidal changes after drug administration. These findings suggest that the mydriatics may affect the choroidal thickness regardless of anterior chamber parameters. This study was registered with trial registration number 2014/357.
Buckwheat Honey Attenuates Carbon Tetrachloride-Induced Liver and DNA Damage in Mice
Authors: Cheng Ni , Wu Liming , Zheng Jianbin , Cao Wei
Published: October 2015

Buckwheat honey, which is widely consumed in China, has a characteristic dark color. The objective of this study was to investigate the protective effects of buckwheat honey on liver and DNA damage induced by carbon tetrachloride in mice. The results revealed that buckwheat honey had high total phenolic content, and rutin, hesperetin, andp-coumaric acid were the main phenolic compounds present. Buckwheat honey possesses super DPPH radical scavenging activity and strong ferric reducing antioxidant power. Administration of buckwheat honey for 10 weeks significantly inhibited serum lipoprotein oxidation and increased serum oxygen radical absorbance capacity. Moreover, buckwheat honey significantly inhibited aspartate aminotransferase and alanine aminotransferase activities, which are enhanced by carbon tetrachloride. Hepatic malondialdehyde decreased and hepatic antioxidant enzymes (superoxide dismutase and glutathione peroxidase) increased in the presence of buckwheat honey. In a comet assay, lymphocyte DNA damage induced by carbon tetrachloride was significantly inhibited by buckwheat honey. Therefore, buckwheat honey has a hepatoprotective effect and inhibits DNA damage, activities that are primarily attributable to its high antioxidant capacity.
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

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

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

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

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

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

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

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

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

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.
Abstract A86: PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer
Authors: Ahmed Roshan Ara , Hopkins Benjamin , Palermo Carmine , Sastra Steve A. , Rapp Zachary , Parsons Ramon , Olive Kenneth P.
Published: October 2015

This abstract is also being presented as a short talk in Session 8: Clinical Science Trials. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.

Citation Format: Roshan Ara Ahmed, Benjamin Hopkins, Carmine Palermo, Steve A. Sastra, Zachary Rapp, Ramon Parsons, Kenneth P. Olive. PTEN-Long and gemcitabine combination treatment as a therapeutic for 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 A86.
Abstract B08: The role of periostin in pancreatic carcinogenesis and metastatic spread
Authors: Hausmann Simone , Regel Ivonne , Federlein Anna , Mazur Pawel K. , Steiger Katja , Michalski Christoph W. , Erkan Mert , Kleeff Jörg
Published: October 2015

Background: Excessive desmoplasia is a typical feature of pancreatic ductal adenocarcinoma (PDAC) and is highly associated with an aggressive tumor phenotype. The main cell population contributing to the stromal response consists of pancreatic stellate cells (PSCs). Periostin, an extracellular matrix protein (ECM), produced by activated PSCs has been shown to have anti-apoptotic and growth-stimulatory effects on pancreatic tumor cells as well as the ability to create a metastatic niche in the secondary target organ. The main signaling route by which periostin mediates its effects is the integrin signaling pathway. Through binding to different integrin subunits the focal adhesion kinase (FAK) gets phosphorylated and downstream signaling pathways such as RAS/ERK/MEK become additionally activated.

Aim: Analyzing the function of periostin in early pancreatic carcinogenesis as well as metastatic spread.

Methods: A conditional tumor mouse model, expressing oncogenic KrasG12D under the control of a pancreas specific Ptf1a promoter was crossbred with Postn global knockout mice (p48Cre/+;LSL-KrasG12D/+;Postn-/-) and early tumor development was analyzed at two, three and six months of age. In a second approach, a tumor-promoting inflammatory stromal reaction was induced by cerulein injections in p48Cre/+;LSL-KrasG12D/+ mice whereby one group of mice was additionally treated with a daily dose (30mg/kg) of FAK inhibitor. All mice were sacrificed after 7 days and HE staining was performed. Thirdly, to study metastasis formation, murine pancreatic tumor cells were injected into the tail vein of wild type, Postn+/- and Postn-/- mice. After 6 weeks target organs were collected for subsequent analyses.

Results: In the early phases, p48Cre/+;LSL-KrasG12D/+;Postn-/- mice displayed less PanIN lesions, fewer atypical ductal structures and reduced proliferating cells. The inhibition of FAK-signaling blocked pancreatic tumorigenesis and absence of periostin abrogated metastatic spread.

Conclusion: Periostin produced by the pancreatic stellate cell is necessary both for early carcinogenesis and metastatic spread. The effects of periostin can be antagonized by blocking its downstream pathway using FAK inhibitors.

Citation Format: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff. The role of periostin in pancreatic carcinogenesis and metastatic spread. [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 B08.
Abstract B09: Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma
Authors: Long Kristen B. , Luque Santiago L. , Beatty Gregory L.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDA) is commonly resistant to chemotherapy due to extensive stromal fibrosis and poor vascularity which combine to inhibit chemotherapy diffusion into tumor tissue. Strategies that target tumor-associated fibrosis have shown promise in preclinical and early clinical trials. We have previously shown that treatment with an agonist CD40 monoclonal antibody (mAb) can induce macrophages to facilitate degradation of tumor-associated fibrosis in PDA, resulting in tumor regressions. Here, we investigated the mechanism by which macrophages facilitate stromal degradation using the KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model of PDA. By immunofluorescence imaging, we first characterized the extracellular matrix that surrounds PDA tumors in the KPC model. We found high levels of fibronectin, hyaluronic acid and type I collagen present within the surrounding PDA stroma. Treatment with a CD40 mAb resulted in macrophage dependent degradation of both fibronectin and type I collagen, but had no effect on hyaluronic acid. To examine the ability of macrophages to degrade type I collagen, we developed an in vitro colorimetric collagen degradation assay. We found that neither CD40 activation nor classical activation with IFN-γ and LPS were sufficient to induce macrophages to degrade type I collagen. In contrast, classical activation of macrophages in the presence of tumor cells led to >50% collagen degradation in vitro. This effect was correlated with the ability of classically activated macrophages to eliminate tumor cells. Our findings suggest that macrophages acquire the capacity to degrade tumor-associated stromal fibrosis only after activation and successful elimination of tumor cells. This finding has important implications for the design of novel strategies that exploit the anti-fibrotic potential of macrophages for potentially improving drug delivery in PDA.

Citation Format: Kristen B. Long, Santiago L. Luque, Gregory L. Beatty. Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B09.
Abstract B11: Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma
Authors: Thomas Dafydd H. , Lee Albert K. , Sastra Stephen A. , Palermo Carmine F. , Rabadan Raul , Kenneth P Olive
Published: October 2015

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers partly due to its profound primary chemoresistance. Previous work from this laboratory found that the prominent desmoplastic stroma observed in PDA is a significant factor in the tumor chemoresistance. We reported that, in established tumors, inhibition of the Hedgehog (Hh) pathway in tumor fibroblasts caused a loss of tumor stroma including α-smooth muscle actin positive (α-SMA) cells. This resulted in an increase in drug delivery to the tumor and subsequent reduction in tumor volume, leading to prolonged survival in a clinically relevant mouse model of PDA. However, the mechanisms by which Hh signaling contributes to the desmoplastic stroma in PDA remain unknown.

In this study we have attempted to identify the target genes of the Hh pathway in the stroma of pancreatic tumors. Using a novel tumor biopsy procedure coupled with RNA-SEQ analysis we have identified genes acutely sensitive to Hh pathway inhibition in the KPC mouse model of PDA. Following 2 days of post biopsy treatment with the Smoothened inhibitor IPI926 the Hh pathway genes Gli1 and Ptch2 were significantly down-regulated. In addition, the Hh target gene, wnt inhibitory factor 1 (Wif1) and other novel genes which may be promoting stromal desmoplasia were significantly down-regulated due to Hh pathway inhibition.

In addition to studying the target genes of the Hh-pathway in the stroma we have utilized a Gli1-GFP reporter mouse to study the Hh target cells in the stroma. Previous work has suggested that Hh target cells in pancreatic tumors are myofibroblasts and thus α-SMA positive. However, we observed that while some Gli1 positive stromal cells are α-SMA positive a significant proportion are α-SMA negative. In addition, costaining KPC-Gli1-GFP tumors for other stromal markers, including Fibroblast specific protein-1 (FSP-1), Glial Fibrillic Acidic Protein (GFAP), zinc finger E-box binding homeobox 1 (Zeb1) and Neuron-Glial Antigen 2 (NG-2) reveals subsets of Hh target cells in the tumor stroma. These data suggest a complex mechanism of Hh-regulated development of the desmoplastic stroma.

To date the mechanisms of Hh-mediated stromal desmoplasia remain refractory. Taken together, these studies attempt to uncover the Hh target genes and cell types in the stroma of pancreatic tumors and provide an explanation for Hh-mediated stromal desmoplasia in PDA.

Citation Format: Dafydd H. Thomas, Albert K. Lee, Stephen A. Sastra, Carmine F. Palermo, Raul Rabadan, P Olive Kenneth. Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma. [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 B11.
Abstract B112: Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A
Authors: Hoskins Jason W. , Flandez Marta , Jia Jinping , Parikh Hemang , Collins Irene , Emmanuel Mickey , Ibrahim Abdisamad , Xiao Wenming , Powell John , Malats Nuria , Petersen Gloria M. , Real Fransisco X. , Amundadottir Laufey T.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC), as with all cancer, is driven by dysregulation of genetic programs due to accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. Holistic views of perturbations in gene expression networks could illuminate key regulators and pathways for this highly lethal cancer. Toward this end, we performed massively-parallel mRNA-sequencing in normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples as well as pancreatic cancer cell lines (n = 9), and determined differential gene expression (DE) patterns. Sub-network enrichment analyses of all expressed genes based on magnitude of DE identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in our pancreatic tumor samples (median P = 7.56 x 10-7, median rank = 1, range = 1-25). To explore the effect of HNF1A expression in pancreatic tumor-derived cells we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines. Induction of HNF1A overexpression caused severe growth inhibition (5.3-fold, P = 4.5x10-5 for MIA PaCa-2 clones; 7.2-fold, P = 2.2x10-5 for PANC-1 clones), and G0/G1 cell cycle arrest. This was accompanied by down-regulation of 49 out of 84 assayed cell cycle genes, while only 1 displayed increased expression. These data, combined with HNF1A’s direct regulation of pancreatic development and homeostasis genes (i.e. PDX1, PTF1A and NR5A2), suggest it may be an important tumor suppressor in pancreatic cells.

Citation Format: Jason W. Hoskins, Marta Flandez, Jinping Jia, Hemang Parikh, Irene Collins, Mickey Emmanuel, Abdisamad Ibrahim, Wenming Xiao, John Powell, Nuria Malats, Gloria M. Petersen, Fransisco X. Real, Laufey T. Amundadottir. Transcriptome analysis in pancreatic cancer reveals a tumor suppressor function for HNF1A. [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 B112.
Abstract B114: c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells
Authors: Geismann Claudia , Grohmann Frauke , Häsler Robert , Rosenstiel Philip , Schneider Günter , Zeissig Sebastian , Schreiber Stefan , Schäfer Heiner , Arlt Alexander
Published: October 2015

NF-κB has been shown to be critical for resistance of pancreatic ductal adenocarcinoma (PDAC) against chemotherapeutic drug and death receptor induced apoptosis, but little is known about the role of the c-Rel subunit.

In the present study, by analysis of genome-wide patterns of c-Rel dependent gene expression we were able to establish c-Rel as a critical regulator of TRAIL induced apoptosis in PDAC. Transfection with siRNA against c-Rel sensitized the TRAIL resistant PDAC cells and EMSA revealed that c-Rel is part of the TRAIL inducible NF-κB complex. Array analysis identified NFATc2 as a critical downstream target of c-Rel in PDAC. In line, siRNA targeting c-Rel strongly reduced TRAIL induced NFATc2 activity and siRNA targeting NFATc2 sensitized PDAC cells against TRAIL induced apoptosis. Finally, TRAIL induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacological inhibition of COX-2 with celecoxib enhanced TRAIL apoptosis.

In conclusion, we were able to delineate a novel c-Rel, NFATc2 and COX-2 dependent anti-apoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.

Citation Format: Claudia Geismann, Frauke Grohmann, Robert Häsler, Philip Rosenstiel, Günter Schneider, Sebastian Zeissig, Stefan Schreiber, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells. [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 B114.
Abstract B116: Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma
Authors: Kim Jungsun , Zaret Kenneth S.
Published: October 2015

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of any human malignancy. When human PDAC cells are injected into immunodeficient animals, they create tumors of the late stage from which they were derived. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC) lines that we generated from PDAC were not of the expected cancer genotype, one PDAC iPS-like line, 10–22 cells, conferred the highly disrupted cancer genome of the starting tumor epithelial population. When 10-22 iPS-like cells are injected into immunodeficient mice, they generate pancreatic intraepithelial neoplasia (PanIN) precursors that progress to the invasive stage PDAC. Using this unique system, we established serum-free cultures of human PanIN lesions from immunodeficient mice injected with 10-22 cells and analyzed the proteome of secreted and released proteins. The live human PanIN explants secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4a network achieved in intermediate-stage lesions from new clinical samples. Recent studies show that the PanIN cells progress to metastases at longer time. The 10-22 cell line is being engineered with near-infrared fluorescent protein under the control of the ductal K19 promoter so that populations can be retrieved by FACS for transcriptome analysis as well as tumor progression and regression in response to drugs can be monitored in vivo. We are now assessing the secreted or released proteins from early lesions grown in mice as diagnostic markers for human PDAC prognosis. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.

Citation Format: Jungsun Kim, Kenneth S. Zaret. Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B116.