bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5292: An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets
Authors: Dumas Jasmine , Gargano Michael , Dancik Garrett M. 
Published: July 2016

Abstract
The Gene Expression Omnibus (GEO) is a public repository of gene expression and sequence-based datasets, that currently includes &gt;42,000 datasets with gene expression profiles obtained by microarray, and &gt;12,000 datasets containing the keyword “cancer”. Although GEO has its own analysis tool (GEO2R) for identifying differentially expressed genes, evaluation of a single gene is not straightforward, and GEO2R was not designed to identify prognostic biomarkers based on survival analyses. In this work, we describe an online, easy-to-use tool for biomarker analysis in GEO datasets.
shinyGEO is a web-based tool that allows a user to download the expression and sample data from a GEO dataset, select a gene of interest, and perform a survival or differential expression analysis in order to evaluate gene expression diagnostic or prognostic biomarkers. For both analyses, shinyGEO produces publication-ready graphics and generates R code ensuring that all analyses are reproducible. The tool is developed using shiny, a web application framework for R, a language for statistical computing and graphics.
The web application and source code is available at the following link: http://bioinformatics.easternct.edu/shinyGEO/
Citation Format: Jasmine Dumas, Michael Gargano, Garrett M. Dancik. An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets. [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 5292.
Abstract 58: Metformin impacts IGF-1R/ Akt signaling and energy metabolism in lung adenocarcinoma
Authors: Lobato Gabriela C. , Li Steve , Tarhoni Imad , Lie Wen-Rong , Borgia Jeffrey A. 
Published: July 2016

Abstract
Introduction: Clinical outcomes for type II diabetes patients diagnosed with NSCLC are superior for those receiving metformin relative to other diabetic medications, though the mechanism for this effect remains incompletely elucidated. We hypothesized that metformin induces changes in Akt-based signaling via AMPK that increases glycolytic flux, and adversely affects survival in cell-line models of lung adenocarcinoma. The objective for these studies is to investigate therapeutic strategies involving metformin that have the potential to synergize with strategies targeting IGF-1R/Akt signaling.
Methods: The lung adenocarcinoma cell lines, A549 and H358, were treated with 0, 1, 5, 10 mM metformin for 24, 48, and 72 hours and evaluated for changes in expression and activity of IGF-1R/Akt signaling, as well as the expression of 17 enzymes involved in glycolytic and oxidative energy metabolism, all using Luminex® immunobead assays. In parallel, MTT assays were performed for up to 5 days to document changes in cellular proliferation/ death rates. Extracellular acidification was also monitored as a measure of glycolytic flux. All findings were collated and statistically evaluated using SPSS v19 (Chicago, IL) using independent t-tests or one-way ANOVA.
Results: We observed that metformin decreased IGF-1R/Akt signaling while increasing the expression of the protein levels of the signaling intermediates. Treatment with metformin increased the expression of Akt, IRS-1, PTEN, GSK3alpha and TSC2 (p&lt;0.05 for all). Further, metformin treatment decreased the mean ratio of phospho-/total pyruvate dehydrogenase and increased the expression of ATP Synthase (both p&lt;0.05), and were associated (p&lt;0.05) with a dose-dependent increase in extracellular acidification. Lower doses (0.1 mM) of metformin did not have a significant impact on cell proliferation at 5 days, but a dose-dependent decrease in cell numbers was observed, with 37% and 29% reduction in cell numbers documented (p&lt;0.05) at 5 mM for the H358 and A549 cells, respectively.
Conclusion: This study links changes with Akt signaling with changes in glycolytic flux and oxidative metabolism. This study suggests metformin may make an attractive adjunct for advanced NSCLC patients receiving therapy that mechanistically involves targeting Akt signaling and metabolic control, such as IGF1R inhibition.
Citation Format: Gabriela C. Lobato, Steve Li, Imad Tarhoni, Wen-Rong Lie, Jeffrey A. Borgia. Metformin impacts IGF-1R/ Akt signaling and energy metabolism in lung adenocarcinoma. [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 58.
Abstract 608: Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer
Authors: Saeed Khalid , Rahkama Vesa , Eldfors Samuli , Bychkov Dmitrii , Mpindi John Patrick , Yadav Bhagwan , Aittokallio Tero , Horvath Peter , Peehl Donna , Paavolainen Lassi , Heckman Caroline , Wennerberg Krister , Mirtti Tuomas , Rannikko Antti , Kallioniemia Olli , Östling Päivi , af Hällström Taija 
Published: July 2016

Abstract
Culture of human prostate cancer (PCa) progenitor cells would facilitate the discovery and testing of new, potentially curative therapies for PCa. Here, we established and characterized patient-derived conditionally reprogrammed cells (CRCs) from seven patients to determine their biological properties (genomic, transcriptomic, protein expression) and to apply these cells to test efficacies of 306 emerging and clinically approved drugs. The patient samples came from both primary prostate cancer as well as from advanced Castration-Resistant Prostate Cancer (CRPC).
Patients with primary prostate cancer generated six benign CRC cultures which all had an androgen receptor (AR)-negative, basal/transit-amplifying phenotype with few CNAs. In 3D cell culture, these cells could re-express AR. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Bcl-2 family inhibitor navitoclax emerged as the most potent cancer-specific drug for the CRCs from CRPC patient. Other drug efficacies observed included taxanes, mepacrine and retinoids, thus covering both existing (and clinically validated) as well as new drug efficacies.
In conclusion, comprehensive cancer-pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently tested in clinical trials of CRPC.
Citation Format: Khalid Saeed, Vesa Rahkama, Samuli Eldfors, Dmitrii Bychkov, John Patrick Mpindi, Bhagwan Yadav, Tero Aittokallio, Peter Horvath, Donna Peehl, Lassi Paavolainen, Caroline Heckman, Krister Wennerberg, Tuomas Mirtti, Antti Rannikko, Olli Kallioniemia, Päivi Östling, Taija af Hällström. Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant 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 608.
Abstract 823: Prevention of pancreatic cancer by cAMP control
Authors: Banerjee Jheelam , Papu John Arokya M. , Al-Wadei Mohammed H. , Schuller Hildegard M. 
Published: July 2016

Abstract
Smoking and alcoholism are risk factors for the development of pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). Using a hamster model of pancreatitis-associated PDAC induced by treatment with ethanol in the drinking water and the nicotine-derived nitrosamine 4-methylnitrosamino-(3-pyridyl)-1-butanone (NNK) by subcutaneous injection as well as immunohistochemistry of human PDAC tissue microarrays, we have previously shown that these cancers overexpressed stress neurotransmitters and cAMP while the inhibitory neurotransmitter ã-aminobutyric acid (GABA) was suppressed. Using our hamster model, the current study has tested the hypothesis that cAMP control by GABA supplementation in the drinking water prevents the development of pancreatitis-associated PDAC. Our data reveal strong preventive effects of GABA supplementation on the development of PDAC and pancreatic intraductal neoplasia (PanIN). ELISA assays and immunohistochemistry revealed significant decreases in the levels of cyclic adenosine monophosphate (cAMP) and interleukin 6 accompanied by reductions in the expression of several cancer stem cell markers, phosphorylated signaling proteins associated with cell proliferation and migration in pancreatic exocrine cells of GABA treated animals. We conclude that cAMP control by GABA supplementation inhibits multiple cancer supporting pathways at the level of cancer stem cells, differentiated cancer cells and the immune system, identifying this approach as promising novel tool for the prevention of PDAC in individuals with a history of smoking and alcoholism.
Citation Format: Jheelam Banerjee, Arokya M. Papu John, Mohammed H. Al-Wadei, Hildegard M. Schuller. Prevention of pancreatic cancer by cAMP control. [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 823.
Abstract 838: Natural plant extracts induced DNA damage and apoptosis through oxidative stress in transgenic mouse model
Authors: Yedjou Clement G. , Tchounwou Paul B. , Miele Lucio , Payton Marinelle 
Published: July 2016

Abstract
One of the most frightening events that women will ever face is being diagnosed with breast cancer. One in eight women in the United States will be diagnosed with this life-threatening disease during her lifetime. Even with all the advances in pharmaceutical technology, mortality rates for breast cancer have remained stagnant for the past few decades. The development of new drugs from natural products is considered important. The specific aim of the present study was to use transgenic mouse mammary tumors as a test model to explore the therapeutic mechanisms of a novel natural product as anti-cancer agent in the treatment of breast cancer. To achieve our specific aim, we performed both in vitro and in vivo studies. Acridine orange and propidium iodide (AO/PI) staining were used to visualize live and dead cells with the means of Cellometer Vision. Tumor volume and weight were measured. Tumor histology was assessed by immunohistochemistry, and enzymatic activities were determined by spectrophotometry. The extent of DNA damage was evaluated by the Comet assay. Cell/tissue apoptosis was measured by the flow cytometry. Data obtained from the AO/PI dye assessment indicated that the tested natural product significantly reduced the number of live cells in a dose-dependent manner, showing a gradual increase in the loss of viability in treated cells. We observed tumor growth inhibition after 4 weeks of daily intraperitoneal administration of plant extracts to trangenic mice. There was a significant increase in DNA damage in treated mice compared to the control mice. Flow cytometry data showed a strong dose-response relationship between plant extracts treatment and annexin V/PI positive cells. Similarly, a statistically significant and dose-dependent increase (p&lt; 0.05) was recorded with regard to caspase 3 activity. Data from enzyme analysis (alaninine transaminase, aspartate transaminase, and creatinine) revealed that plant extract administration is not toxic to treated mice. These results suggest that induction of cell death, DNA damage, and cell/tissue apoptosis may be involved in the therapeutic mechanisms of plant extracts in breast cancer. Collectively, the findings from this study provide convincing evidence that the tested plant extracts may represent a potential anticancer candidate against breast cancer. Research supported by NIH Grant No. NIMHD-G12MD007581) and Grant No. P20GM103476.
Citation Format: Clement G. Yedjou, Paul B. Tchounwou, Lucio Miele, Marinelle Payton. Natural plant extracts induced DNA damage and apoptosis through oxidative stress in transgenic mouse model. [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 838.
Abstract 925: IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress
Authors: Uygur Berna , Leikina Evgenia , Chernomordik Leonid 
Published: July 2016

Abstract
Poorly understood interactions between prostate cancer (PCa) cells and their microenvironment direct the epithelial to mesenchymal transition (EMT) during disease progression. Cell-to-cell fusion, such as cell fusion in muscles and placenta, is one of the ways in which cells can drastically change their properties. Cell fusion has been proposed to promote tumor cell diversity and the ability to metastasize. Metastatic disease has been also suggested to depend on the interleukin 4 (IL-4) signaling. Patients with hormone-refractory PCa have elevated levels of IL-4 and it has been proposed that targeting IL4 -receptor interactions limits metastatic disease. Here, to mimic conditions at the interphase between rhabdosphincter myofibers and apical anterior regions of prostatic gland we explored interactions of PC3 cells (human PCa cell line) with skeletal muscle cells. Co-culturing of these cells resulted in an elevated concentration of related cytokines IL-4 and/or IL-13 in the tissue culture medium from the co-cultured cells but not from muscle cells cultured on their own. The co-culturing (i); the application of the conditioned medium from the co-cultured cells (ii); and treating PC3 cells with recombinant IL-4 (iii) resulted in a robust fusion between PC3 cells, in a significant increase in the percentage of PC3 cells expressing stem cell marker CD133, in the drug resistance, in an increase of the expression of mesenchymal-characteristic markers pAKT, MMP9, desmin, and in the loss of E-cadherin that is another marker for EMT. The described effects required co-culturing of the PC3 cells and muscle cells. Moreover, the co-culturing and recombinant IL-4 application also upregulated the expression of the two proteins - annexin A5 and syncytin that play important role in several cell-cell fusion processes. Significantly, application of either (i) IL-4-neutralizing antibodies or (ii) peptide inhibitors of syncytin; and (iii) lowering annexin A5 expression suppressed cell proliferation and fusion. Our findings substantiate a hypothesis that IL-4 and IL-13 in the microenvironment of PCa cells promote the EMT and raise metastatic potential of PCa cells by their fusion mediated by upregulated syncytin- and annexin A5.
Citation Format: Berna Uygur, Evgenia Leikina, Leonid Chernomordik. IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress. [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 925.
Abstract CT004: KEYNOTE-006: PD-L1 expression and efficacy in patients (Pts) treated with pembrolizumab (pembro) vs ipilimumab (IPI) for advanced melanoma
Authors: Carlino Matteo , Ribas Antoni , Gonzalez Rene , Hoeller Christoph , Bar-Sela Gil , Barrow Catherine , Chao David , Wolter Pascal , Berking Carola , Straume Oddbjørn , Berrocal Alfonso , Holgado Esther , Gangadhar Tara C. , Weiss Geoffrey , Zhou Honghong , Emancipator Kenneth , Ibrahim Nageatte , Schadendorf Dirk 
Published: July 2016

Abstract
Background: The anti-PD-1 antibody pembro and the anti-CTLA-4 antibody IPI have shown efficacy in advanced melanoma. In KEYNOTE-006 (NCT01866319), pembro significantly improved PFS, ORR, and OS compared with IPI. Here, we present data on PD-L1 expression and efficacy at the second interim analysis.
Methods: IPI-naive pts were randomly assigned in a 1:1:1 ratio to pembro 10 mg/kg Q2W or Q3W or 4 cycles of IPI. Randomization was stratified by PD-L1 expression using Dako's PD-L1 IHC 22C3 pharmDx assay (positive [membranous PD-L1 staining in ?1% of tumor and adjacent immune cells] vs negative), ECOG PS (0 vs 1), and line of therapy (1st vs 2nd). IHC scores of 0 (0% staining), 1 (&lt;1%), 2 (1%-9%), 3 (10%-32%), 4 (33%-65%), and 5 (?66%) were used to score PD-L1 expression. Response was assessed per central RECIST v1.1. Efficacy end points, PFS, OS, and ORR, were compared based on PD-L1 status and IHC score. Data cutoff date was March 3, 2015.
Results: Overall, 834 pts enrolled. Of the 821 PD-L1 evaluable pts, 671 (82%) were PD-L1 positive. Pembro significantly improved PFS (P &lt; .00001 for both arms), OS (P = .0005 for Q2W and P = .0036 for Q3W), and ORR (P = .00003 for Q2W and P = .00001 for Q3W) compared with IPI. Improved efficacy in pts with PD-L1-positive (PFS: HR = 0.52; 95% CI, 0.43-0.64; OS: HR = 0.56; 95% CI, 0.43-0.74; ORR: P &lt; .00001) vs PD-L1-negative tumors (PFS: HR = 0.83; 95% CI, 0.55-1.26; OS: HR = 0.94; 95% CI, 0.56-1.6; ORR: P &lt; .00001) was observed in combined pembro arms compared with IPI. There was a correlation between degree of PD-L1 positivity and improved PFS, OS, and ORR in pembro compared with IPI (Table). Efficacy between the 2 pembro arms was comparable.
Conclusions: PD-L1 positivity is associated with improved efficacy with pembro compared with IPI. Higher degree of PD-L1 positivity correlated with greater improvement in PFS, OS, and ORR. As evidenced by treatment effect in all groups, pembro monotherapy is appropriate in pts regardless of PD-L1 status.
Citation Format: Matteo Carlino, Antoni Ribas, Rene Gonzalez, Christoph Hoeller, Gil Bar-Sela, Catherine Barrow, David Chao, Pascal Wolter, Carola Berking, Oddbjørn Straume, Alfonso Berrocal, Esther Holgado, Tara C. Gangadhar, Geoffrey Weiss, Honghong Zhou, Kenneth Emancipator, Nageatte Ibrahim, Dirk Schadendorf. KEYNOTE-006: PD-L1 expression and efficacy in patients (Pts) treated with pembrolizumab (pembro) vs ipilimumab (IPI) for advanced melanoma. [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 CT004.
Abstract CT125: A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404
Authors: Grossmann Kenneth F. , Sondak Vernon K. , Othus Megan , Tarhini Ahmad , Patel Sapna , Kirkwood John M. , Ribas Antoni , Moon James 
Published: July 2016

Abstract
Background: Adjuvant therapy for melanoma has centered on high dose interferon for now almost 20 years. Recently, the FDA approved ipilimumab dosed at 10 mg/kg (10/kg ipi) for use in high risk resected melanoma. Though these two treatment options are available they still have limits in terms of efficacy with approximately 1 year of relapse free survival benefit (HDI and 10/kg ipi) and a modest overall survival benefit (HDI). Toxicity remains an issue as well with both therapies. S1404 is a Phase III, open label trial which seeks to compare currently available FDA approved treatments to one year of pembrolizumab in patients at high risk of relapse and death after surgery.
Study Design: 1,378 patients will be randomized 1:1 to an FDA approved standard therapy, or pembrolizumab. Stratification factors include PD-L1 staining status, clinical stage, and pre-randomization selected standard treatment option.
Patients: Patients must be 18 or older, and have Stage IIIA (n2), IIIB, IIIC or IV (M1a, b and c) resected melanoma to be eligible. Exclusion factors include brain metastases, ocular primary, and auto-immune disease. Prior therapy is not allowed, but radiation as adjuvant treatment is considered an option available to patients prior to treatment.
Current status: As of January 2016, 30 sites are registered and 5 patients are randomized. An amendment to include 10 mg/kg ipilimumab as a treatment option is under review and will likely be finalized by the time of the meeting.
Support: NIH/NCI NCTN grants CA180888, CA180819, CA180818, CA180826, CA180858, CA180820, CA180844
Citation Format: Kenneth F. Grossmann, Vernon K. Sondak, Megan Othus, Ahmad Tarhini, Sapna Patel, John M. Kirkwood, Antoni Ribas, James Moon. A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404. [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 CT125.
Abstract LB-017: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to marked dependence on PRMT5
Authors: Mavrakis Konstantinos , McDonald E Robert , Schlabach Michael R. , Billy Eric , Hoffman Gregory R. , deWeck Antoine , Ruddy David A. , Venkatesan Kavitha , McAllister Greg , deBeaumont Rosalie , Ho Samuel , Liu Yue , Yan-Neale Yan , Yang Guizhi , Lin Fallon , Yin Hong , Gao Hui , Kipp David Randal , Zhao Songping , McNamara Joshua T. , Sprague Elizabeth R. , Cho Young Shin , Gu Justin , Crawford Ken , Capka Vladimir , Hurov Kristen , Porter Jeffrey A. , Tallarico John , Mickanin Craig , Lees Emma , Pagliarini Raymond , Keen Nicholas , Schmelzle Tobias , Hofmann Francesco , Stegmeier Frank , Sellers William R. 
Published: July 2016

Abstract
Metabolic genes are increasingly recognized as targets of somatic genetic alteration in human cancer often leading to profound changes in intracellular metabolite concentrations. 5-Methylthioadenosine Phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway that metabolizes methylthioadenosine (MTA) to adenine and methionine. Its chromosomal position proximal to CDKN2A results in frequent collateral homozygous deletion in a wide range of human cancers. By interrogating data from a large scale deep-coverage pooled shRNA screen across 390 cancer cell line models we found that the viability of MTAP null cancer cells is strongly impaired upon shRNA-mediated depletion of the protein arginine methyltransferase PRMT5. In MTAP deleted cells there is marked accumulation of the substrate MTA and surprisingly, we find that MTA is a specific inhibitor of the catalytic activity of PRMT5. In keeping with these data, knockout of MTAP in an MTAP-proficient cell line led to increased MTA levels and rendered them sensitive to PRMT5 depletion. Moreover, reconstitution of MTAP in an MTAP-deficient cell line fully rescued PRMT5 dependence. Collectively, these findings indicate that the collateral loss of MTAP in CDNK2A deleted cancers leads to accumulation of MTA that thereby creates a hypomorphic PRMT5 state that is selectively sensitized towards further PRMT5 inhibition.
Citation Format: Konstantinos Mavrakis, E Robert McDonald III, Michael R. Schlabach, Eric Billy, Gregory R. Hoffman, Antoine deWeck, David A. Ruddy, Kavitha Venkatesan, Greg McAllister, Rosalie deBeaumont, Samuel Ho, Yue Liu, Yan Yan-Neale, Guizhi Yang, Fallon Lin, Hong Yin, Hui Gao, David Randal Kipp, Songping Zhao, Joshua T. McNamara, Elizabeth R. Sprague, Young Shin Cho, Justin Gu, Ken Crawford, Vladimir Capka, Kristen Hurov, Jeffrey A. Porter, John Tallarico, Craig Mickanin, Emma Lees, Raymond Pagliarini, Nicholas Keen, Tobias Schmelzle, Francesco Hofmann, Frank Stegmeier, William R. Sellers. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to marked dependence on PRMT5. [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 LB-017.