bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5155: Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter
Authors: Qu Xueping , Sandmann Thomas , Frierson Henry , Fu Ling , Fuentes Eloisa , Walter Kimberly , Okrah Kwame , Rumpel Craig , Moskaluk Christopher , Lu Shan , Wang Yulei , Bourgon Richard , Penuel Elicia , Pirzkall Andrea , Amler Lukas , Lackner Mark , Tabenero Josep , Hampton Garret , Kabbarah Omar 
Published: July 2016

Abstract
The molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) have been well described. However, the mechanisms through which some of the clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we employed an integrative genomics approach to examine CRC progression. Transcriptional profiling of laser capture microdissected colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas, and metastases, showed distinctive patterns in the activation of developmental and oncogenic pathways, including the clinically important EGFR axis. We observed a dramatic up-regulation of the EGFR ligand EREG in primary and metastatic cancer cells as compared to normal and adenomatous tissues that was indicative of autocrine tumor production, and confirmed this pattern of gene expression by in situ hybridization. Global methylation analysis indicated that up-regulation of EREG during the adenoma-carcinoma transition was associated with de-methylation of two key sites within the EREG promoter and this was accompanied by an increase in the levels of EGFR phosphorylation, as assessed by reverse phase protein analysis. In a clinical trial setting, we observed that low levels of EREG methylation in patients who received cetuximab as part of a Phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers from the TCGA datasets, including those of the head and neck, lung, and bladder. We propose that up-regulation of EREG expression through promoter de-methylation might be an important means of activating the EGFR pathway during the genesis of CRC and, potentially, other types of cancer.
Citation Format: Xueping Qu, Thomas Sandmann, Henry Frierson, Ling Fu, Eloisa Fuentes, Kimberly Walter, Kwame Okrah, Craig Rumpel, Christopher Moskaluk, Shan Lu, Yulei Wang, Richard Bourgon, Elicia Penuel, Andrea Pirzkall, Lukas Amler, Mark Lackner, Josep Tabenero, Garret Hampton, Omar Kabbarah. Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter. [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 5155.
Abstract 5157: Quantitative proteomic analysis identifying Krt17 plays a critical role in areca nut inducing oral carcinogenesis
Authors: Chiang Chang Hsu , Wu Chih-Ching , Cheng Ann-Joy 
Published: July 2016

Abstract
Areca nut is known a carcinogen for oral cancer in southeast Asia, however, the molecular mechanism leading to the malignancy is still unclear. To mimic the habit of areca nut chewing, our laboratory has established four oral cancer cell sublines (SAS, OECM1, K2, C9), chronically trained by areca nut extract (ANE). To elucidate the molecular basis of areca nut induced oral carcinogenesis, the differential proteomes between oral cancer cells and the ANE sublines were determined using the technique of isobaric mass tag (iTRAQ) labeling and multidimensional liquid chromatography- mass spectrometry (LC-MS/MS). Over thousand proteins were identified in four sublines, in which 194 proteins were found differential expressions in at least two ANE sublines. Bioinforatmic analysis revealed that these proteins participate in several pathways, with the regulation of epithelial to mesenchymal transition (EMT) most prominent. Fourteen proteins were confirmed differential expression in the ANE sublines, including Krt17. To shed more light on the mechanism of ANE induced carcinogenesis, Krt17 was further investigated. Knockdown Krt17 significantly suppressed ANE-induced cell growth, migration, and cell invasion, along with the modulation of EMT process. Furthermore, in a carcinogen-induced oral cancer mice model by 4NQO/arecoline, an active compound of ANE, Krt17 was found significantly up-regulated in all hyperplasia and carcinoma (p&lt;0.001). In conclusion, we have identified proteome associated with chronic areca nut exposure in oral cancer cells. Krt17 was demonstrated contributing to areca nut induced oral malignancy. This study should attribute to risk assessment, disease prevention or other clinical applications of areca nut-induced oral cancer.
Citation Format: Chang Hsu Chiang, Chih-Ching Wu, Ann-Joy Cheng. Quantitative proteomic analysis identifying Krt17 plays a critical role in areca nut inducing oral carcinogenesis. [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 5157.
Abstract 5174: Modeling mesothelioma initiation through disruption of the Hippo pathway revealed involvement of PLCB4 in YAP-driven mesothelioma cell proliferation
Authors: kakiuchi. tatsuo 
Published: July 2016

Abstract
Disruption of the Hippo pathway as a result of deletion and/or mutation of the involved genes (e.g., neurofibromin 2 [NF2]) is frequently observed in mesothelioma. The disruption results in reduced phosphorylation of yes-associated protein (YAP), and the non-phosphorylated YAP translocates to the nucleus and regulates gene expression. While the roles of the disrupted Hippo pathway in the maintenance of established tumors have been investigated using mesothelioma cell lines, its involvement in the initiation of mesothelioma remains unclear.
We used immortalized human mesothelial cells to study the transformation process, and found that NF2 knockdown led to transformation of the cells concurrently with reduction in YAP phosphorylation. The cells exhibited enhanced growth in vitro, and formed tumors following transplantation into nude mice. Similar results to those obtained by NF2 knockdown were also obtained using enforced expression of wild-type (wt) or constitutively active (S127A) YAP. Although enforced expression of YAPwt or YAPS127A was insufficient to transform primary (unimmortalized) human mesothelial cells, our findings provide evidence for the crucial roles of activated YAP in the transformation of mesothelial cells.
To identify YAP-regulated genes critical for mesothelial tumorigenesis, we conducted gene expression analysis comparing control- and YAP-transduced immortalized human mesothelial cells. Gene Set Enrichment Analysis (GSEA) using a gene set down-regulated by YAP knock-down in mesothelioma cell lines revealed phospholipase C beta 4 (PLCB4) to be among the top-ranking genes up-regulated by YAP in our experiments. PLCB4 was up-regulated by YAP in immortalized human mesothelial cells, and down-regulated by YAP knock-down in YAP-driven mesothelioma cells. shRNA-mediated silencing of PLCB4 attenuated the growth of YAP-transduced mesothelial cells and Hippo-disrupted, but not -proficient, mesothelioma cell lines.
Our model system thus provides a versatile tool to investigate the mechanisms underlying mesothelioma development. We suggest that PLCB4 may be an attractive drug target for the treatment of malignant mesothelioma.
Citation Format: tatsuo kakiuchi. Modeling mesothelioma initiation through disruption of the Hippo pathway revealed involvement of PLCB4 in YAP-driven mesothelioma cell proliferation. [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 5174.
Abstract 5181: Dual inhibition of RNA Pol I transcription and PIM kinase as a new therapy to treat prostate cancer
Authors: Rebello Richard J. , Kusnadi Eric , Cameron Don , Lesmana Analia , Drygin Denis , Clark Ashlee K. , Porter Laura , Sandhu Shahneen , Risbridger Gail P. , Pearson Richard B. , Hannan Ross D. , Furic Luc 
Published: July 2016

Abstract
Background: The MYC oncogene is commonly over-expressed in prostate cancer (PC). Upregulation of ribosome biogenesis and function is a characteristic feature of MYC-driven tumors. Accordingly, inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically in models of hematological malignancy characterized by elevated MYC expression. Additionally, PIM kinases activate MYC signaling and mRNA translation in PC and cooperate with MYC to accelerate tumorigenesis. Here we investigate the efficacy of a dual approach targeting ribosome biogenesis and function to treat PC by combining CX-5461 with the pan-PIM kinase inhibitor CX-6258 in murine and human models
Methods: The efficacy of CX-5461 and CX-6258, alone and in combination, was tested in PC cell lines, in the Hi-MYC mouse model of PC (n = 8-11 per group) and in PC metastatic tissues. Primary cell lines derived from Hi-MYC mice were used to analyze signaling events underpinning therapeutic efficacy. Triplicate experiments were analyzed with ANOVA followed by Dunnett's post hoc test. All statistical tests were two-sided.
Results: CX-5461 reduced anchorage independent growth and induced cell cycle arrest in human PC cell lines and in primary prostatic epithelial cells from Hi-MYC mice (P&lt;0.001). CX-5461 treatment of Hi-MYC mice induced p53 expression and activity and significantly reduced prostate epithelial cell proliferation (P = 0.02) and invasion. While CX-6258 showed little effect alone, its combination with CX-5461 further suppressed proliferation (P = 0.01), dramatically reduced the incidence of large invasive lesions from 64% to 9% and preserved prostate ductal architecture.
This promising combination strategy prevented the growth of PDX tissue characterized by elevated MYC and resistance to conventional therapy (P = 0.04).
Conclusions: Our results demonstrate preclinical efficacy of combination therapies targeting the ribosome at multiple levels and provide a new approach for treatment of PC with high MYC activity.
Citation Format: Richard J. Rebello, Eric Kusnadi, Don Cameron, Analia Lesmana, Denis Drygin, Ashlee K. Clark, Laura Porter, Shahneen Sandhu, Gail P. Risbridger, Richard B. Pearson, Ross D. Hannan, Luc Furic. Dual inhibition of RNA Pol I transcription and PIM kinase as a new therapy to treat prostate cancer. [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 5181.
Abstract 5186: Using HuTrial™ to aid in predicting a patient population of responders
Authors: Thatte Jayant , Ricono Jill , Scott Colleen , Broudy Thomas B. 
Published: July 2016

Abstract
One of the biggest challenges in drug discovery is directing drug treatment to the correct population. Crown Bioscience currently has over 1,800 Patient derived xenograft models in &gt;70 indications. These models, HuPrime® human surrogate mouse models, are reflective of the diversity of genetics, tumor heterogeneity and response in patient populations. HuPrime® models are searchable in the HuBase™ database by the expression data, copy number, mutational analysis as well as patient clinical data including diagnosis, pathology and IHC information. The vast number of models available allows one to perform surrogate clinical trials in a Phase II-like trial utilizing one patient sample per tumor bearing animal per treatment group (n = 1 studies). In this study we show reproducibility of n = 1 studies compared to the traditional preclinical mouse studies with multiple animals with the same tumor being treating with the same test agent. Further we show, the use of one patient sample per treatment allows for the expansion of the study utilizing multiple patient samples thereby reducing cost of preclinical studies. One can leverage the HuPrime® models to discover biomarkers, identify patient responder and non-responder profiles to accelerate drug development and improve chances of success in the clinic.
Citation Format: Jayant Thatte, Jill Ricono, Colleen Scott, Thomas B. Broudy. Using HuTrial™ to aid in predicting a patient population of responders. [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 5186.
Abstract 520: The role of the calpain pathway in early response and acquired resistance to radiation in glioblastoma
Authors: Bassett Emily A. , Chakravarti Arnab 
Published: July 2016

Abstract
Glioblastoma (GBM) is the most aggressive, malignant brain tumor that is highly heterogeneous and often develops resistance to conventional chemotherapy and radiation treatments. The median survival time of GBM patients is 12-15 months despite aggressive treatment modalities, and there is an urgent need for the development of novel treatment strategies. The goal of this study is to identify novel mechanisms of radioresistance in GBM through mass spectrometry-based phosphoproteomic profiling, with the objective that more effective therapies can be rationally developed in the future. We and others have previously reported that GBMs are characterized by deregulated signaling pathways that control critical cellular processes including survival, migration, and proliferation. Very little is known about acquired resistance mechanisms to radiation, specifically how radiation alters protein phosphorylation patterns in tumors on a global level, or how radiation-induced changes in protein phosphorylation contribute to treatment resistance. In order to identify radiation-induced changes in protein phosphorylation, we performed phosphoproteomic profiling of 6 GBM cell lines and 1 normal human astrocyte cell line both before and after radiation treatment in 3 independent experiments. Specifically, cells were collected before treatment and at 2 time-points following a 10 Gy radiation treatment. Following protein isolation and phosphopeptide enrichment, global phosphoproteomic analysis was performed by mass spectrometry. Relative quantitation and statistical analysis were performed to determine fold changes in phosphorylation at both post-radiation time-points. An average of 3,971 phosphopeptides mapping to 1,649 phosphoproteins were quantified for each independent experiment, and a total of 621 phosphoproteins were quantified across all 3 datasets. We identified a major component of the calpain signaling pathway that consistently shows an increase in phosphorylation following radiation treatment in GBM cell lines. The post-radiation increase in phosphorylation was confirmed in 2 independent experiments and observed across all 6 GBM cell lines. This is the first study linking the calpain signaling pathway to radiation response in GBM. Mechanistic studies using phosphomimetic and nonphosphorylatable mutants of the protein of interest will determine the effect of phosphorylation on calpain activity and radiation resistance. Results of this work will contribute to our understanding of how GBM tumors become resistant to radiation therapy, and may identify a novel target to overcome radiation resistance in GBM.
Citation Format: Emily A. Bassett, Arnab Chakravarti. The role of the calpain pathway in early response and acquired resistance to radiation in glioblastoma. [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 520.
Abstract 5200: Preclinical model of patient-derived tumor xenograft in humanized mice
Authors: Wulf-Goldenberg Annika , Stecklum Maria , Fichtner Iduna , Hoffmann Jens 
Published: July 2016

Abstract
Human patient-derived xenografts (PDX) from different tumor indications transplanted on immunodeficient mice have demonstrated strong predictive power for many drug development programs in cancer research. However, one caveat of PDX models is that they lack a functional immune system, which allows tumor engraftment in the xenogenic host mice.
Immunotherapy has emerged as one of the most promising avenues for cancer therapy. For translating immunotherapies into the clinics preclinical animal models are needed which harbor human immune cell repertoire for rising an immune response.
To overcome these constraints our aim is the development of PDX models on mice with a functional human immune system to improve predictability of drug efficacy and safety.
We reconstituted a human immune system in mice by engrafting human hematopoietic stem cells in immunodeficient mice. We were able to demonstrate that in the mice a full set of human immune cells, including T cells, B cells, NK cells, monocytes and dendritic cells can be analyzed by flow cytometry.
At the time when the human immune system was developed, established patient-derived tumors were transplanted on these reconstituted humanized mice. PDX from different tumor entities were transplanted. The tumors are growing on these humanized mice either similar to non humanized mice or slightly slower. During the observation period no rejections by the human immune cells were evident, although tumor growth was accompanied by an increase of human T cells in the peripheral blood. Ex vivo analysis will be performed demonstrating the cytotoxicity of these T cells and the functionality of the human immune cells.
Humanized mice bearing various PDX tumors were treated with therapeutic checkpoint inhibitors. Ipilimumab that target the CTLA-4 receptor lead to a slight tumor growth delay and an increased percentage of T cells in the blood and in the tumor. Nivolumab that targets the PD-1 receptor showed similar results. The combination of both inhibitors showed a synergistic effect which lead to a greater tumor growth inhibition.
Our humanized mouse models enable appropriate preclinical assessment of immune-based therapeutic anti-tumor strategies especially when combing the humanized mouse with patient-derived tumor xenografts.
Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Iduna Fichtner, Jens Hoffmann. Preclinical model of patient-derived tumor xenograft in humanized mice. [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 5200.
Abstract 5211: Trends in the incidence of retinoblastoma in the United States from 1973-2012
Authors: Fernandes Arthur G. , Pollock Benjamin D. , Hoffman Aaron E. 
Published: July 2016

Abstract
Background: Retinoblastoma is a rare form of eye cancer that usually develops in early childhood, typically before the age of 5. This study aims to determine the incidence of retinoblastoma in the United States over a 40-year period from 1973 to 2012 using a review of existing databases.
Methods: 882 patients with retinoblastoma (International Classification of Diseases for Oncology (ICD-O-3) codes C69.2 (retina) and C69.9 (eye, NOS)) were derived from the Surveillance, Epidemiology, and End Results (SEER) program database in the United States from 1973 to 2012, using the nine historical SEER registries with the earliest observation collections. Incidence rates were calculated per 1,000,000 children and age-adjusted using the United States Census Bureau data as the standard population. The significance of trend in the incidence rate over time was determined using the Chi-Square test, and 95% CIs were calculated. Descriptive statistics evaluated differences in incidence in terms of age group, gender, race and laterality. Surveillance was evaluated by analysis of diagnosis confirmation and reporting source.
Results: There were a total of 882 cases of retinoblastoma, representing 6.1% of all childhood cancers under age 5 years. 49.1% of cases were males and 96% of all cases were children aged 0-4 years. The mean incidence of retinoblastoma was 12.14 cases per million children aged 0-4 years (95% CI 11.32 to 12.96) and 0.49 cases per million children aged 5-9 years (95% CI 0.36 to 0.65). There was no significant trend in the incidence for children aged 0-4 years old (Xsup2 = 35.455 p = 0.6324) or 5-9 years old (Xsup2 = 32.247 p = 0.7695) for all races/genders. The proportion of bilateral cases (28.9%) versus unilateral cases (71.1%) remained stable over the 40-year period. 85.6% of the cases were confirmed microscopically and hospitals represent 98.8% of the reporting sources.
Conclusions: The incidence rate of retinoblastoma in the United States has remained stable for the last 40 years. The majority of the cases are unilateral, and hospitals are the main reporting source.
Citation Format: Arthur G. Fernandes, Benjamin D. Pollock, Aaron E. Hoffman. Trends in the incidence of retinoblastoma in the United States from 1973-2012. [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 5211.