bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4179: Expression profiling of zebrafish rb1- neuroectodermal-like brain tumors: A new model of CNS PNETs
Authors: McGrail Maura A. , Solin Staci L. , Haltom Jeffrey A. , Schultz Laura E. , Essner Jeffrey J. , Shive Heather R. 
Published: July 2016

Abstract
We examined the gene expression signature of zebrafish brain tumors induced by somatic inactivation of the retinoblastoma tumor suppressor rb1 to determine the similarity with human CNS primitive neuroectodermal tumors (PNETs). Childhood CNS PNETs are aggressive tumors characterized by undifferentiated cells with features of the embryonic neuroepithelium. Previously our histological analysis showed the majority of zebrafish rb1- lesions were proliferative neuroectodermal-like tumors composed of neoplastic cells with small hyperchromatic nuclei that form rosettes. To obtain the transcription profile of the zebrafish rb1- tumors, RNA-Seq was performed on 10 tumors from fish ranging in age from 3.5 to 10 months of age. Duplicate RNA-Seq libraries were synthesized for each tumor and multiplex sequenced on an Illumina HiSeq NextGen Sequencer at the Genome Sequencing Core, Kansas University. Our initial gene expression profiling of the zebrafish rb1- brain tumors revealed a molecular signature consistent with an undifferentiated tumor phenotype. In each zebrafish tumor sample, standard markers of neuronal differentiation (sypa, sypb, neurod1/2, neurog1/2) and glial differentiation (GFAP, S100β) were not significantly expressed. In contrast, the neural stem/progenitor marker sox2 was highly expressed in all tumors, consistent with the primitive neuroectodermal-like tumor histology. Comparison with human childhood CNS-PNET gene expression analysis revealed a similar profile. Four of the nine genes that define the human oligoneural (group 2) molecular subgroup (olig2, bcan, sox8b, sox10 and ascl1) described by Picard et al, 2012 were highly expressed in the zebrafish tumors. Together, the data indicate the zebrafish brain tumors induced by somatic inactivation of rb1 model human CNS PNETs. Additional gene expression, pathway, and cross-species comparative analyses are in progress. The zebrafish rb1- tumor model will be useful for investigating the molecular pathways driving the aggressive and undifferentiated features of CNS PNETs.
Citation Format: Maura A. McGrail, Staci L. Solin, Jeffrey A. Haltom, Laura E. Schultz, Jeffrey J. Essner, Heather R. Shive. Expression profiling of zebrafish rb1- neuroectodermal-like brain tumors: A new model of CNS PNETs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4179.
Abstract 4183: Targeting mTOR signaling during gliomagenesis
Authors: Torres Daniela , Mela Angelina , Peter Canoll D. 
Published: July 2016

Abstract
Diffusely infiltrating gliomas are the most common type of primary brain tumor seen in adults. In a subset of patients, these tumors present as low grade lesions that progress to high grade glioma (HGG). Conventional treatment for gliomas includes surgical resection followed by radiation and temozolomide. Glioma cells invade peripheral brain tissue making complete surgical resection impossible and despite aggressive treatment tumor recurrence is inevitable. Current research has focused on identifying new therapeutic targets, mainly in HGG. However, investigating the therapeutic targets at early stages of gliomagenesis could provide a novel approach for the treatment of low grade gliomas (LGG). Gliomas have been characterized by gene expression profiles and classified into distinct subtypes including proneural, classical and mesenchymal. Proneural gliomas, which account for the majority of LGG, show high expression of PDGFRα and frequently harbor p53 mutations. The resulting alterations in PDGFRα signaling and inactivation of p53 both induce an upregulation in mTOR signaling, which contributes to gliomagenesis via its regulation of cell growth and proliferation. Thus, inhibiting mTOR signaling should have a robust effect on glioma growth. However, inhibiting mTOR signaling in HGG has had limited success. This may be due to the accumulation of genetic alterations that occur during glioma progression resulting in loss of sensitivity to the anti-tumor effects of mTOR inhibitors. We hypothesize that inhibiting mTOR signaling at early stages of gliomagenesis will be more effective. To test this hypothesis we are characterizing the effects of mTOR inhibition at different stages of gliomagenesis in our proneural glioma mouse model. We assessed the effects of inhibiting mTOR with the ATP-competitive mTOR inhibitor (AZD8055) in vitro and in vivo. Our preliminary data show that AZD8055 inhibits mTOR activity and reduces glioma cell viability in vitro. Inhibition of mTOR in our proneural glioma model showed that AZD8055 crosses the blood brain barrier and effectively inhibits mTOR in glioma cells within the tumor, as well as in the surrounding brain tissue. In addition, we have characterized mTOR activity at different time points in glioma formation and show upregulation of mTOR activity during early stages of gliomagenesis. Our findings support the role of mTOR in early stages of gliomagenesis and motivate our ongoing studies to test the effects of AZD8055 for the treatment of LGG.
Citation Format: Daniela Torres, Angelina Mela, Canoll D. Peter. Targeting mTOR signaling during gliomagenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4183.
Abstract 42: A new type of drug resistance in cancer: extracellular ATP-induced resistance through ATP internalization and ATP-drug competition
Authors: Wang Xuan , Li Yunsheng , Qian Yanrong , Cao Yanyang , Chen Xiaozhuo 
Published: July 2016

Abstract
Drug resistance is a major problem in cancer therapies and responsible for most relapse, one of the major causes of death in cancer. Several cancer drug resistance mechanisms are known, including genetic mutations in protooncogenes or tumor suppressor genes, cancer stem cells, and multi-drug resistance (MDR). Among these mechanisms, MDR is ATP-dependent. Intratumoral (extracellular) ATP levels of various cancer types are 10⁁3 to 10⁁4 times higher than those in their corresponding normal tissues but the biological significance of the high intratumoral ATP concentrations is unknown. We recently reported that extracellular ATP is internalized by cancer cells via macropinocytosis and enhances their growth and survival (1). Based on these results, we hypothesized that the internalized ATP also promotes drug resistance. Here we report that extracellular ATP, at concentrations in or below the range of reported intratumoral ATP levels, substantially increased intracellular ATP levels and promoted cancer cell drug resistance to tyrosine kinase inhibitor (TKI) sunitinib in human NSCLC A549 cells. The ATP increase and the drug resistance were mediated, at least in part, by macropinocytosis, clathrin- and caveolae-mediated endocytoses. The elevated intracellular ATP induced upregulated phosphorylation of PDGFR and proteins/enzymes in the PDGFR-mediated signaling pathways, such as Akt, mTOR, Raf and MEK, resulting in augmented cell growth and reduced apoptosis induced by sunitinib. The upregulated phosphorylation was not mediated by purinergic receptor signaling. Furthermore, in vitro, ex vivo, and in vivo, extracellular ATP partially restored phosphorylation levels of PDGRF and its downstream proteins/enzymes inhibited by sunitinib, a PDGFR inhibitor (TKI). These results strongly suggest that the extracellular ATP-increased intracellular ATP reversed the inhibition of TKIs by competing with the inhibitors for the ATP-binding site of PDGFR, enhancing the Akt-mTOR and Raf-MEK signaling pathways and promoting cancer cell survival. All these findings significantly expand our understanding of the roles of extracellular ATP in the Warburg effect (2) and drug resistance in cancer and indentify a new anti-drug resistance target.
1. Qian Y, Wang X, et al., Cancer Lett. 351(2014): 242-5.
2. Chen X, Qian Y, Wu S. Free. Radic. Biol. Med. 79(2015): 253-263.
Citation Format: Xuan Wang, Yunsheng Li, Yanrong Qian, Yanyang Cao, Xiaozhuo Chen. A new type of drug resistance in cancer: extracellular ATP-induced resistance through ATP internalization and ATP-drug competition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 42.
Abstract 4207: microPET/CT imaging of the mobilization of CD11b+ cells
Authors: Cao Qizhen , Huang Qian , Li Chun 
Published: July 2016

Abstract
Objectives: Mobilization of immune cells is often associated with prognosis and treatment response for many diseases. The objective of this study was to test whether mobilization of CD11b+ myeloid cells could be noninvasively imaged by PET/CT. Methods: Anti-mouse CD11b antibody was labeled with 64Cu. Immunocompetent mice with 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in the ears, lipopolysaccharide (LPS)-induced inflammation in the lung, mice bearing 3 different syngeneic murine tumors (4T1 mammary carcinoma, CMS4 sarcoma, and CT26 colon carcinoma), and mice bearing ID8 ovarian cancer undergoing photothermal therapy were imaged with [64Cu]-labeled anti-CD11b. microPET-CT imaging and biodistribution were obtained at 24 h after intravenous injection of the radiotracer. Subpopulations of bone marrow cells, cells from spleen, and cells from the disease sites were analyzed by flow cytometry and/or immunohistochemistry (IHC) staining. Results: 64Cu-labeled anti-CD11b bound specifically to CD11b+ myeloid cells. microPET-CT images showed significantly higher uptake of 64Cu-DOTA-anti-CD11b antibody at the inflammatory sites and tumors undergoing photothermal therapy. In addition, microPET-CT images also revealed mobilization of CD11b+ cells from bone marrow to secondary lymphoid organs (spleen and/or lymph nodes). Interestingly, mice bearing 4T1 carcinoma displayed a markedly different imaging/distribution pattern compared to mice bearing CMS4 and CT26 tumors, characterized by a significant increase in blood pool and liver activities with corresponding reduction in the uptake of the radiotracer in the bone marrow and the spleen in different stages of tumor development. These findings were evaluated in the context of flow cytometry and IHC analyses. Conclusions: The differential distribution pattern of 64Cu-labeled anti-CD11b in different disease models could be attributed to mobilization of CD11b+ cells. PET/CT may be used to image systems response of immune cells to disease development and treatments. (Supported in part by the John S. Dunn Foundation)
Citation Format: Qizhen Cao, Qian Huang, Chun Li. microPET/CT imaging of the mobilization of CD11b+ cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4207.
Abstract 4224: Multiplexing single cell time lapse imaging of intra-cellular oxygen in cancer cells
Authors: Düssmann Heiko , Perez Sergio , Kumar Ujval Anil , Papkovsky Dmitri B. , Prehn Jochen HM 
Published: July 2016

Abstract
Oxygen plays an important role in aerobic energy metabolism and signal transduction. The detection of intracellular or subcellular molecular oxygen (O2) levels is important for the understanding of cell physiology and mitochondrial energy metabolism, and the alterations correlated with cancer. Detection of O2 has recently been improved significantly with the development of live cell time lapse microscopy compatible oxygen sensitive probes.
We here utilized nanoparticle probe MitoImageTM-MM2 with embedded poly(9,9-dioctylfluorene) (PFO) as an O2-independent component and Pt(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorophenyl)-porphyrin (PtTFPP) to perform time lapse ratiometric measurements of intra-cellular oxygen levels. Loading of HeLa cervical cancer cells with MM2 enables us to image kinetics of intracellular O2 concentration in response to the mitochondrial respiratory chain inhibitors Antimycin A (complex III) or sodium azide (complex IV). These changes were detected in respiration-supporting medium equilibrated with 5% (53 μM) and 20% (225 μM)O2. Also exposing cells to varying extracellular oxygen concentrations (21 - 225 μM) showed strong dependence of the intracellular oxygen levels. The mitochondrial membrane potential was monitored by simultaneous imaging of Tetra-Methyl-Rhodamine-Methyl ester (TMRM) in the same sample. Multiplexing with GFP finally allowed us to monitor intracellular O2 during the apoptotic signaling process of mitochondrial outer membrane permeabilisation (MOMP) in HeLa expressing cytochrome-c-eGFP and stained with TMRM.
In conclusion, the MitoImageTM-MM2 nanoparticle probe enables single-cell, time-lapse imaging of alterations in intracellular oxygen levels in cancer cells, and can be employed in multiplex assays to investigate alterations in intracellular oxygen levels relative to protein dynamics and mitochondrial function.
Keywords: Intracellular oxygen; phosphorescent oxygen-sensitive nanoparticles; HeLa cells; MitoImage ratiometric probes; confocal microscopy.
Citation Format: Heiko Düssmann, Sergio Perez, Ujval Anil Kumar, Dmitri B. Papkovsky, Jochen HM Prehn. Multiplexing single cell time lapse imaging of intra-cellular oxygen in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4224.
Abstract 4236: SUPR-PET: Nuclear imaging of Her2-positieve breast cancer with SUPR peptides
Authors: Kelderhouse Lindsay E. , Hardy Amanda , Pisaneschi Federica , Gray Joshua P. , Gammon Seth , Roberts Richard W. , Takahashi Terry T. , Fiacco Steve , Millward Steven W. 
Published: July 2016

Abstract
In recent years, patients with Her2-positive breast cancer have benefitted greatly from targeted therapies such as Trastuzumab and Pertuzumab. However, there are currently no FDA-approved Her2-targeted imaging agents to diagnose and monitor Her2-positive breast cancer leaving physicians to rely on biopsies to determine Her2 status. Whole-body visualization of Her2 would allow the noninvasive identification of all Her2 primary and metastatic lesions as well as serve as a powerful tool to monitor the effectiveness of Her2-targeted therapeutics. We recently described the generation of Her2-targeted SUPR (Scanning Unnatural Protease Resistant) peptides that selectively bind the Her2 receptor in vitro with low nanomolar affinity. Cy5-labeled SUPR peptides showed rapid and Her2-specific tumor uptake and minimal retention in non-tumor tissues after 24 hours of washout. In this study, we describe 18F radiolabeling of Her2-targeted SUPR peptides and their evaluation as PET radiotracers to visualize Her2 expression in vivo. The lead compound, SUPR4, was labeled with 18F-fluoroethylazide in high radiochemical yield and specific activity on an automated radiochemical synthesis platform. The resulting radiotracer (SUPR-18F) showed rapid and Her2-selective tumor uptake between 30-60 minutes post-injection with minimal liver uptake. The majority of the tracer was cleared by the kidneys at 2 hours post-injection although some activity was observed in the GI tract suggesting hepatobiliary excretion. No significant uptake was observed in the brain. 90 minute dynamic PET scans were performed to estimate the rate of tumor uptake and clearance in major organ systems and the biodistribution quantified by autoradiography post-mortem. Pre-injection of unlabeled SUPR peptide, Trastuzumab, and Pertuzumab followed by PET imaging with SUPR-18F was used to confirm tumor uptake as a function of specific binding to the Her2 receptor. Having established the utility of SUPR-18F in pre-clinical mouse models, we anticipate that this class of PET tracers could be employed in same-day imaging procedures throughout the administration of Her2-targeted therapy.
Citation Format: Lindsay E. Kelderhouse, Amanda Hardy, Federica Pisaneschi, Joshua P. Gray, Seth Gammon, Richard W. Roberts, Terry T. Takahashi, Steve Fiacco, Steven W. Millward. SUPR-PET: Nuclear imaging of Her2-positieve breast cancer with SUPR peptides. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4236.
Abstract 4274: Porcine ovarian matrix supports maintenance of human intestinal organoid cultures
Authors: George Jay , De Gese Sol , Benton Gabriel 
Published: July 2016

Abstract
Currently, extracellular matrix hydrogels derived from the Engelbreth-Holmes-Swarm murine tumor (Cultrex BME, Matrigel) are used for stem cell maintenance and differentiation of both normal and tumor organoid culture models. While this matrix is suitable for many in vitro applications, there is increasing demand for a 3D organoid culture platform that is more suitable for clinical applications. Here, we have developed a soluble extracellular matrix derived from normal porcine ovaries that forms a hydrogel polymer at physiological temperature and that supports maintenance of human small intestine organoids in culture. This matrix supports expansion of LGR5+ human stem cell populations using Wnt, EGF, Noggin, and R-Spondin 1 cell culture medium. The matrix also supports differentiation of stem cells into mini organs by removing Wnt which is characterized by the formation of intestinal crypts which exhibit immunostaining for lineage specific markers. This new extracellular matrix hydrogel represents a non-tumor sourced, normal extracellular matrix for evaluating both development and cancer progression.
Citation Format: Jay George, Sol De Gese, Gabriel Benton. Porcine ovarian matrix supports maintenance of human intestinal organoid cultures. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4274.
Abstract 4284: Exploratory plasma proteomic analysis in a randomized cross-over trial of aspirin among healthy individuals
Authors: Wang Xiaoliang , Zhang Yuzheng , Shojaie Ali , Lampe Paul D. , Levy Lisa , Peters Ulrike , Potter John D. , White Emily , Lampe Johanna W. 
Published: July 2016

Abstract
Background: Long-term use of aspirin is associated with lower colorectal cancer (CRC) incidence; however, the mechanism of the chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Methods: We assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized, double-blinded, placebo-controlled, cross-over trial of 44 healthy non-smoking men and women, aged 21-45 years. Plasma proteomics was analyzed on an antibody microarray with ∼3,000 full-length antibodies, printed in triplicate. Moderated paired t-test was performed on individual antibodies, and gene set analyses were performed for KEGG and GO pathways. Results: Among the 3,387 antibodies, significant differences in plasma protein levels were observed for 267 antibodies (p&lt;0.05), the most significant protein being a transcription-factor regulator belonging to a steroid receptor family and found to be differentially expressed in colon cancer cells. Other significant proteins are involved in multiple oncogenic pathways related to colon tumorigenesis. In the pathway analysis, 4 KEGG (among 138) and 69 GO (among 1,089) pathways were found to be significant (p&lt;0.05), including natural killer (NK) cell-mediated cytotoxicity, butanoate metabolism and Wnt signaling pathways. Pathways that modulate cellular protein binding to steroid receptors were also significantly different between aspirin treatment and placebo (p&lt;0.05). None of the results remained statistically significant after correction for multiple testing. Conclusion: Several proteins and pathways, which have previously been reported as playing a role in colorectal carcinogenesis in vitro were found to be differentially expressed after aspirin treatment vs. placebo in healthy human subjects. This study suggests several chemopreventive mechanisms of aspirin; however, larger, confirmatory studies are needed.
Citation Format: Xiaoliang Wang, Yuzheng Zhang, Ali Shojaie, Paul D. Lampe, Lisa Levy, Ulrike Peters, John D. Potter, Emily White, Johanna W. Lampe. Exploratory plasma proteomic analysis in a randomized cross-over trial of aspirin among healthy individuals. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4284.