bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3287: Targeting GSK-3: a new approach for the treatment of neuroblastoma
Authors: Dubrovskyi Oleksii , Ugolkov Andrey , Gaisina Irina , Bondarenko Gennadiy , Strizzi Luigi , Margaryan Naira , O'Halloran Thomas , Kozikowski Alan , Hendrix Mary , Mazar Andrew 
Published: August 2015

Abstract
Neuroblastoma is a devastating pediatric cancer and most patients older than 18 months present with multi-organ metastatic disease. High grade or recurrent disease is refractory to treatment with chemotherapy and almost uniformly fatal. Because GSK-3beta has been shown to be a positive regulator of NF-kappaB-mediated survival and chemoresistance in cancer cells, we hypothesize that the inhibition of GSK-3 may have potential therapeutic effects in neuroblastoma. To test this premise we used small molecule inhibitors, Western blotting, apoptotic and MTS assays to study the effect(s) of GSK-3 inactivation in neuroblastoma cell lines SK-N-DZ and SK-N-BE(2). Using chemically distinct GSK-3 inhibitors (AR-A014418, TDZD8 and 9-ING-41), we found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of neuroblastoma cells. We observed that inhibition of GSK-3 results in decreased expression of the anti-apoptotic molecules Bcl-XL and XIAP (NF-kappaB target genes) and a subsequent increase in neuroblastoma cell apoptosis. Moreover, we show that our novel GSK-3 inhibitor 9-ING-41 enhances the antitumor effects of irinotecan in neuroblastoma cells. Our results demonstrate that GSK-3 positively regulates neuroblastoma cell survival and proliferation and suggest that the inhibition of GSK-3 is a promising new approach for the treatment of neuroblastoma.
Citation Format: Oleksii Dubrovskyi, Andrey Ugolkov, Irina Gaisina, Gennadiy Bondarenko, Luigi Strizzi, Naira Margaryan, Thomas O'Halloran, Alan Kozikowski, Mary Hendrix, Andrew Mazar. Targeting GSK-3: a new approach for the treatment of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3287. doi:10.1158/1538-7445.AM2015-3287
Abstract 3288: The KCNA5 promoter is hypermethylated in Ewing sarcoma and silencing contributes to cell proliferation
Authors: Ryland Katherine , Hawkins Allegra , Weisenberger Daniel J. , Borinstein Scott , Laird Peter W. , Martens Jeffrey R. , Lawlor Elizabeth R. 
Published: August 2015

Abstract
Potassium channels regulate a variety of biological processes and dysfunction of these channels contributes to cancer initiation and progression. We recently showed that the KCNA5-encoded channel, Kv1.5, is a target of polycomb-group (PcG)-dependent repression in aggressive pediatric solid tumors and that this epigenetic silencing of the Kv1.5 channel contributes to cell survival under hypoxic stress. In human cancer, the promoters of PcG target genes are often subject to aberrant DNA hypermethylation. Therefore, in the current study we investigated whether the KCNA5 locus is hypermethylated in Ewing sarcoma. The methylation status of KCNA5 was determined in tumor samples, non-transformed cells and a panel of cancer cell lines using a custom Illumina GoldenGate® methylation array and by MethyLight. Promoter methylation and expression of KCNA5 were measured by MethyLight and qRT-PCR, respectively, before and after exposure to decitabine. Proliferation was assessed in untreated and decitabine treated cells in the presence or absence of the Kv1.5 channel blocker diphenyl phosphine oxide-1 (DPO-1). Methylation array studies of normal tissues and Ewing sarcoma tumors and cell lines showed that the KCNA5 promoter is hypermethylated in Ewing sarcoma compared to normal tissues. This hypermethylation was confirmed by MethyLight analysis in an independent set of primary tumors and cell lines. These studies also showed that methylation was relatively higher in cell lines than primary tumors. Exposure of Ewing sarcoma cells to decitabine led to demethylation of the KCNA5 promoter and directly correlated with increased expression of the KCNA5 transcript. Decitabine treatment did not affect the viability of Ewing sarcoma cell lines; however it led to a decreased proliferation. Significantly, pharmacologic inhibition of the Kv1.5 channel by DPO-1 partially reversed the decitabine-induced reduction in cell proliferation in three different cell lines (TC-71, A673 and A4573). Together these studies show that the KCNA5 promoter is hypermethylated in Ewing sarcoma and that inactivation of the Kv1.5 channel promotes cell proliferation. This work identifies DNA methylation as another epigenetic mechanism that regulates KCNA5 expression in cancer and further implicates epigenetic repression of the Kv1.5 potassium ion channel in tumor pathogenesis.
Citation Format: Katherine Ryland, Allegra Hawkins, Daniel J. Weisenberger, Scott Borinstein, Peter W. Laird, Jeffrey R. Martens, Elizabeth R. Lawlor. The KCNA5 promoter is hypermethylated in Ewing sarcoma and silencing contributes to cell proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2015-3288
Abstract 332: Extracellular matrix stiffness regulates metabolic state in metastatic, but not quiescent, breast carcinoma cells
Authors: Morris Brett A. , Burkel Brian , Ponik Suzanne , Eliceiri Kevin , Aguirre-Ghiso Julio , Condeelis John , Castracane James , Keely Patricia J. 
Published: August 2015

Abstract
Increased breast density is associated with a 4-6 fold increased risk of developing breast cancer, and is associated with an increase in deposition of extracellular matrix (ECM) proteins, most abundantly collagen I. Collagen, like other ECM proteins, plays a structural role fundamental to tissue organization. High levels of collagen deposition correspond with a stiffer ECM, which is emerging as an important regulator of cell proliferation and tumor progression. Our previously reported microarray implicated changes in mammary epithelial cell metabolism in response to increased matrix stiffness, consistent with the expanding role of the ECM in tumor cell signaling. Here we report that increased matrix stiffness regulates the expression of pyruvate dehydrogenase kinase 1, a key regulator between lactic acid production and pyruvate entry into the mitochondria, in highly metastatic 4T1 breast carcinoma cells. Interestingly, we do not observe this same metabolic regulation in quiescent (dormant) 4T07 tumor cells of the same lineage. These alterations in protein expression correlated to changes in cellular NADH metabolism observed by several independent approaches, including metabolic flux analysis and quantitative imaging fluorescence lifetime microscopy. Thus, we find that alterations in collagen stiffness cause metabolic shifts between oxidative phosphorylation and aerobic glycolysis in highly metastatic cells, but not in quiescent cells. These findings identify stiffness of the ECM as an important regulator of metabolic state, and further identify quiescence as a dominant trait that is not overcome by ECM stiffness.
Citation Format: Brett A. Morris, Brian Burkel, Suzanne Ponik, Kevin Eliceiri, Julio Aguirre-Ghiso, John Condeelis, James Castracane, Patricia J. Keely. Extracellular matrix stiffness regulates metabolic state in metastatic, but not quiescent, breast carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2015-332
Abstract 3324: A novel role for PAK4 in the regulation of EMT and stemness in glioblastoma
Authors: Kesanakurti Divya , Xu Jihong , Jasti Rao S. , Puduvalli Vinay K. 
Published: August 2015

Abstract
Glioblastomas (GB) are the most aggressive of primary brain tumors with high rates of tumor recurrence and poor prognosis. Epithelial-mesenchymal transition (EMT) is the dynamic transdifferentiation process which leads to acquisition of invasiveness, stem-like characteristics and drug resistance in tumor cells. A small fraction of radio- and chemo-resistant cancer stem cells (CSC) with a capacity of self-renewal is considered to be crucial for tumor recurrence. Our previous studies indicated high levels of expression of p21-activated kinase 4 (PAK4) in GBs and confirmed its role in the regulation of proliferation, migration and invasion. Here, we aimed to determine whether PAK4-regulated invasiveness was associated with mesenchymal transition of glioma cells and to delineate the essential signaling events that governed EMT and maintenance of stemness in GBs. PAK4 overexpression in glioma cells resulted in loss of E-cadherin and Zo-1 and a significant increase in N-cadherin and vimentin levels. Conversely, shRNA-mediated PAK4 downregulation led to loss of mesenchymal phenotype and markers in glioma cell lines. Further, irradiation (IR, 8 Gy) treatments significantly elevated PAK4 expression and nuclear localization in correlation with increased EMT in glioma cells. FACS analysis and western blotting indicated an enrichment of CD133+ CSCs with high expression of CD133 and Nestin in IR-treated cells. In order to study the significance IR-induced EMT and stemness with PAK4 nuclear translocation, we performed a transcription factor (TF) interaction array with immunoprecipitated PAK4 as bait, which revealed nuclear-PAK4 association with PPARγ and other TFs. Moreover, immunoprecipitation, ChIP and re-ChIP experiments showed IR-induced PAK4 binding with PPARγ nuclear receptor complex and recruitment on the PPREs of NADPH oxidase-1 promoter and elevated Nox1 expression in IR-treated cells. PAK4-knockdown suppressed the IR-induced EMT and stemness in the glioma cells lines. In line with these in vitro results, mouse orthotopic intracranial xenograft experiments showed decreased tumor growth and N-cadherin expression in tumors from PAK4-shRNA expressing cells when compared with controls. These results strongly support a role for PAK4 in the regulation of IR-induced EMT and stemness via PPARγ/Nox1 signaling and provide a rationale for PAK4 as a new therapeutic target against glioblastoma and suggest a potential for overcoming radioresistance in these tumors.
Citation Format: Divya Kesanakurti, Jihong Xu, Rao S. Jasti, Vinay K. Puduvalli. A novel role for PAK4 in the regulation of EMT and stemness in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3324. doi:10.1158/1538-7445.AM2015-3324
Abstract 3328: Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation
Authors: Rosen Elliot T. , Kryndushkin Dmitry , Gonzalez Yanira , Aryal Baikuntha , Chehab Leena , Dickey Jennifer , Rao Ashutosh 
Published: August 2015

Abstract
Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. Patients who receive acute doses of irradiation to the thoracic cavity for Hodgkin's Lymphoma and breast cancer are subject to an elevated risk of RIHD. The ability to mitigate the long-term cardiac effects of radiation exposure in these populations by modulating protein oxidation and the process of autophagy in the heart has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate radiation-induced heart disease. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at various time points up to one year. Echocardiography and electrocardiography were performed to evaluate functional changes in cardiac performance. Four weeks following ionizing radiation, both males and females showed decreased heart mass and decreased whole body mass in the groups exposed to medium and high doses of radiation. A marked difference in both heart and whole body mass was observed in the high dose group after one year. Anemic conditions were noted by low red blood cell counts observed in both males and females at all three time points in the animals receiving the highest dose of irradiation. Cardiac troponin T analysis revealed cardiotoxicity in both the medium and high dose groups at early time points. Echocardiography revealed that left ventricular volume at diastole was increased in males following high dose irradiation, and that left ventricular mass decreased following high irradiation exposures. Finally, it should also be noted that after one year, multiple animals receiving radiation developed spontaneous tumors. We are currently exploring the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage and the subsequent, protective autophagic response.
Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Yanira Gonzalez, Baikuntha Aryal, Leena Chehab, Jennifer Dickey, Ashutosh Rao. Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3328. doi:10.1158/1538-7445.AM2015-3328
Abstract 3349: Optimizing radioimmunotherapy techniques for the alpha-emitter 225Actinium
Authors: Julian Ricklie A. , Kang Chi Soo , Sun Xiang , Song Hyun A. , Revskaya Ekaterina , Chong Hyun-Soon , Dadachova Ekaterina 
Published: August 2015

Abstract
Introduction: Radioimmunotherapy (RIT) is a potent therapeutic technique that may be applicable to the treatment of numerous human cancers. Currently available RIT therapies employ beta- and alpha-emitting radionuclides. Alpha-emitters, such as 225Actinium (225Ac), have promising advantages over beta-emitters RIT such high linear energy transfer and independence of the tumor oxygenation status. RIT using 225Ac radionuclide directed by the monoclonal antibodies trastuzumab or panitumumab may provide effective, targeted antineoplastic effects.
Methods: Antibodies trastuzumab to HER2/neu and panitumumab to EGFR were conjugated to the bifunctional ligands NETA, DOTA, DECA, DEPA and DETA. The conjugates were labeled with 225Ac at room temperature and 37°C. At selected time points, the mixture was analyzed by instant thin layer chromatography (ITLC). Radiolabeling reaction kinetics and yields were calculated for 225Ac and for its daughter isotopes 221Francium (221Fr) and 213Bismuth (213Bi) using the energy discrimination function of the multichannel analyzer in the gamma counter. Summary of the new data: Radiolabeling with Actinium was effective for several ligand-antibody combinations and completed within 30 min. Radiolabeling yields for 225Ac and it daughters 221Fr and 213Bi were most robust for NETA and DECA conjugates to trastuzumab and panitumumab, labeled at 37°C.
Conclusion: Several novel ligands were evaluated for radiolabeling of monocloncal antibodies trastuzumab or panitumumab with 225Ac radionuclide and demonstrated fast kinetics of radiolabeling. Potential for targeted therapeutic applications will be explored in future experiments.
Citation Format: Ricklie A. Julian, Chi Soo Kang, Xiang Sun, Hyun A. Song, Ekaterina Revskaya, Hyun-Soon Chong, Ekaterina Dadachova. Optimizing radioimmunotherapy techniques for the alpha-emitter 225Actinium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3349. doi:10.1158/1538-7445.AM2015-3349
Abstract 3352: Identification of factors that recruit tumor-associated neutrophils to head and neck squamous cell cancer
Authors: Niaz Hanan A. 
Published: August 2015

Abstract
Recent immunohistological studies have shown that abundant tumour-associated neutrophils (TAN) are present within malignant tumours. TAN can have a significant impact on the tumour microenvironment via release of potent growth factots, chemokines and proteinases that influence tumour progression. The presence of TAN has been associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to identify which factors are responsible for neutrophil recruitment into HNSCC.
The number of TAN within human HNSCC tissue was evaluated by immunohistochemical staining for the neutrophil marker, myeloperoxidase (MPO). The factors secreted by FaDu HNSCC multi-cellular tumour spheroids (MCTS) were analysed by cytokine array and ELISA. Neutrophils isolated from the peripheral blood of healthy volunteers were used to measure neutrophil migration to factors identified from the array. Then the recruitment of neutrophils to MCTS was assessed overtime by flow cytometry in the absence and presence of small molecule inhibitors. FaDu xenograft mouse models were used to confirm the effect of these inhibitors on neutrophil recruitment in-vivo.
MPO staining confirmed the presence of marked numbers of TAN in HNSCC compared to normal oral epithelium. HNSCC MCTS resemble in-vivo tumours, displaying areas of hypoxia, necrosis and cell proliferation. Neutrophils migrated to recombinant CXCL8, CXCL1 and MIF and these chemoattractants were found in the conditioned medium of FaDu MCTS. The recruitment of neutrophils to FaDu MCTS was significantly inhibited when neutrophils were pre-treated with antagonists for CXCR2 and CXCR4, the receptors for CXCL8, CXCL1 and MIF respectively. Moreover, use of the MIF inhibitor, ISO-1caused a dramatic reduction in the number of neutrophils recruited into FaDu MCTS. In-vivo, ISO-1 significantly reduced the number of TAN in xenograft FaDu tumours. Collectively, these data suggest that CXCL8, CXCL1 and MIF in particular are important in the recruitment of TAN into HNSCC.
Citation Format: Hanan A. Niaz. Identification of factors that recruit tumor-associated neutrophils to head and neck squamous cell cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3352. doi:10.1158/1538-7445.AM2015-3352
Abstract 3358: SOCS3 deficiency in myeloid cells promotes tumor development: Involvement of STAT3 activation and myeloid-derived suppressor cells
Authors: Yu Hao , Qin Hongwei , Benveniste Etty (Tika) 
Published: August 2015

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing anti-tumor immunity. We report for the first time that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T-cell infiltration in tumors. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSC via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSC and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation.
Note: This abstract was not presented at the meeting.
Citation Format: Hao Yu, Hongwei Qin, Etty (Tika) Benveniste. SOCS3 deficiency in myeloid cells promotes tumor development: Involvement of STAT3 activation and myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3358. doi:10.1158/1538-7445.AM2015-3358
Abstract 3362: Systematic evaluation of immune checkpoint inhibitors
Authors: Barnes Sheri , Miliani de Marval Paula , Hauser Jacob , Brainard Tracy , Small Daniel , Synnott Aidan J. , Mullin Robert J. 
Published: August 2015

Abstract
With the increasing success and subsequent interest in tumor immunology, we recognized a growing need for well-characterized preclinical models. While the literature contains many different experimental models, the available data includes a variety of reagents and the side by side comparative evaluation of therapeutics in multiple models is relatively rare. Lechner et al., (J. Immunother. 36:477-489, 2013) addressed this issue and reported on a comparative analysis of a set of six syngeneic models. Our effort looked to expand this paradigm towards a comparative evaluation of the responsiveness of a collection of syngeneic models to antibody based checkpoint inhibitor therapeutics. Specifically, we examined the response of the Colon26, MC38, B16F10, Lewis Lung, Madison109, EMT-6, and 4T1 models to anti-CTLA-4, anti-PD-1 and anti-PDL-1 monotherapies as well as capturing the response to combination therapies of anti-CTLA-4 with anti-PD-1 or anti-PDL-1.. Our results clearly show a differential response across this set of models both in regard to CTLA-4 targeted therapy as well as PD-1/PDL-1 therapy. In an attempt to expand the number of checkpoint inhibitor responsive models, we are performing a second phase of work evaluating the impact of immuno-modulatory radiation therapy upon these baseline responses.
In initiating these studies and evaluating the literature, it became clear that there were multiple choices in regard to anti-CTLA-4 preclinical reagents. We have also performed a series of studies evaluating the efficacy of multiple anti-CTLA-4 clones as an extension of previously published work which described the variable ability of anti-CTLA-4 clones to deplete tumor Treg populations (Simpson et al. J. Exp. Med. 210(9) 1695-1710, 2013). Our anti-tumor data correlates well with these cell based observations. This differential allows one to match efficacy with model and expands the reagents available for evaluating combination therapies.
Citation Format: Sheri Barnes, Paula Miliani de Marval, Jacob Hauser, Tracy Brainard, Daniel Small, Aidan J. Synnott, Robert J. Mullin. Systematic evaluation of immune checkpoint inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2015-3362