bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1796: Analysis of TCGA RNASeq data using SpliceSeq provides a survey of alternative splicing in cancer.
Authors: Ryan Michael C. , Weinstein John N. 
Published: August 2014

Abstract
The vast majority of human genes express more than one transcript isoform, and aberrant splicing patterns or changes in isoform expression ratios can lead to disease, notably cancer. Next generation sequencing platforms deliver the finest resolution yet of the transcriptome, and the wealth of sequencing data produced by TCGA provides an excellent basis for a broad study of alternative splicing in cancer. We have developed an interactive, exceptionally user-friendly tool, SpliceSeq, for investigation of alternative splicing in RNASeq data. The program is a follow-up to our SpliceCenter package (http://projects.insilico.us/SpliceCenter/SpliceOverview.jsp), which provides tools for use by the bench biologist in assessing experimental observations that may result from splice variation.
Our results from SpliceSeq for TCGA RNASeq data from several cancer types will be presented. We identify pervasive changes in splicing patterns across different cancer types by comparing tumor vs. normal and clinical subgroups (e.g. tumor stage, hyper-mutator status, and MSI designation). Interesting observations include striking splice variations in APP, the amyloid beta precursor protein, and in PKM, which is centrally involved in the balance between oxidative and glycolytic metabolism in tumors. SpliceSeq is freely available at http://bioinformatics.mdanderson.org/main/SpliceSeq:Overview.
1. Ryan MC, Cleland J, Kim R, Wong WC, Weinstein JN. SpliceSeq: A Resource for Analysis and Visualization of RNA-Seq Data on Alternative Splicing and Its Functional Impacts. Bioinformatics, 10.1093, 2012.
2. Ryan MC, Zeeberg BR, Caplen NJ, Cleland JA, Kahn AB, Liu H, and Weinstein JN. SpliceCenter: a suite of web-based bioinformatic applications for evaluating the impact of alternative splicing on RT-PCR, RNAi, microarray, and peptide-based studies. BMC Bioinformatics 9:313, 2008.
3. Kahn AB, Ryan MC, Liu H, Zeeberg BR, Jamison DC, Weinstein JN. SpliceMiner: a high-throughput database implementation of the NCBI Evidence Viewer for microarray splice variant analysis. BMC Bioinformatics 8:752, 2006.
Supported by NCI Grant No. U24CA143883. The content is solely the responsibility of the authors and does not necessarily represent official views of NCI or NIH. Also supported in part by a gift from the Mary K. Chapman Foundation and a grant from the Michael and Susan Dell Foundation honoring Lorraine Dell.
Citation Format: Michael C. Ryan, John N. Weinstein. Analysis of TCGA RNASeq data using SpliceSeq provides a survey of alternative splicing in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1796. doi:10.1158/1538-7445.AM2013-1796
Abstract 1829: Negative regulation of lncRNA GAS5 by miR-21.
Authors: Zhang Ziqiang , Mo Yin-yuan 
Published: August 2014

Abstract
Protein-coding genes account for only a small part of the human genome whereas the vast majority of transcripts make up the non-coding RNAs including microRNAs and long non-coding RNAs (lncRNAs). Both microRNAs and lncRNAs have been shown to play a critical role in regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. As master gene regulators, microRNAs can target a large number of protein-coding genes. However, it remains to be determined whether microRNAs can also target lncRNAs. In the present study, we determined whether miR-21 impacts lncRNA expression. Using lncRNA RT-PCR array carrying 83 human disease related lncRNAs, we showed that miR-21 was capable of repressing the growth arrest specific 5 (GAS5) lncRNA which was previously shown to be involved in growth arrest. This negative regulation between miR-21 and GAS5 was confirmed in breast tumor specimens. Of interest, GAS5 can also repress miR-21 expression. While ectopic expression of GAS5 suppressed, GAS5 siRNAs increased miR-21 expression. Importantly, there was a putative miR-21 binding site in exon 5 of GAS5; deletion of the miR-21 binding site abolished this activity. We further showed that biotin labeled GAS5 RNA probe was able to pull down the RNA-induced silencing complex (RISC) and subsequently identified miR-21 in this GAS5-RISC complex, implying that miR-21 and GAS5 may regulate each other in a way similar to the microRNA-mediated silencing of target mRNAs. Together, these results support the “endogenous competitive RNA” concept that microRNAs may regulate not only protein-coding genes, but also non-coding genes such as GAS5.
Citation Format: Ziqiang Zhang, Yin-yuan Mo. Negative regulation of lncRNA GAS5 by miR-21. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1829. doi:10.1158/1538-7445.AM2013-1829
Abstract 1875: A novel series of metabolic activators of PKM2 alter oncogene-meditated changes in tumor cell metabolism.
Authors: Bahr Brigham L. , Stevens Jenny , Squire Spencer , Moreno Christopher , Call Lee T. , Stephens Bret J. , Mollard Alexis , Warner Steven L. , Bearss David J. 
Published: August 2014

Abstract
Rather than relying on oxidative phosphorylation for the generation of ATP, human tumor cells primarily utilize aerobic glycolysis to metabolize glucose (the Warburg effect). Pyruvate kinase is a metabolic enzyme that converts phosphoenolpyruvate (PEP) to pyruvate, catalyzing the rate-limiting step of glycolysis. The M1 isoform of pyruvate kinase (PKM1) that is the principal isoform in most adult differentiated tissues, while the PKM2 splice variant is the main isoform in embryonic tissues and in all cancer cells. Unlike the M1 splice form (PKM1), which is found in its tetrameric active form in cells, PKM2 is found in cells as an inactive dimer under normal physiological conditions. Tetramerization of PKM2 requires binding of the allosteric activator fructose-1,6-bisphosphate (FBP), an upstream glycolytic intermediate, resulting in a fully active enzyme. Regulation of PKM2 activity in cancer cells may allow glycolytic intermediates to be diverted into other biosynthetic pathways necessary for biomass production. PKM2 expression enhances tumorigenicity of cells while PKM1 expression represses it. This suggests that activators of PKM2 may have anti-tumor properties by forcing PKM2 to act more like PKM1. We have a series of small molecule PKM2 activators that exhibit low nM activation activity in biochemical and cell-based assays. These compounds increase pyruvate kinase activity in cancer cells and lead to an increase in pyruvate and ATP production. Our studies show that PKM2 activators inhibit the growth of lung cancer cell lines in vitro and in vivo and can reverse the metabolic changes induced by oncogenes such as k-Ras and c-Myc in lung cancer cells. The current lead compound was tested in established subcutaneously implanted A549 lung adenocarcinoma xenografts, where we observed a statistically significant 54% decrease in tumor growth, with no observable toxicity. These data suggest that this class of PKM2 activators is effective as tumor cell metabolic regulators with anti-tumor activity for lung cancer and potentially other malignancies.
Citation Format: Brigham L. Bahr, Jenny Stevens, Spencer Squire, Christopher Moreno, Lee T. Call, Bret J. Stephens, Alexis Mollard, Steven L. Warner, David J. Bearss. A novel series of metabolic activators of PKM2 alter oncogene-meditated changes in tumor cell metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1875. doi:10.1158/1538-7445.AM2013-1875
Abstract 1914: Molecular function of the long noncoding RNA SPRY4-IT1 in human melanomas.
Authors: Zhao Wei , Mazar Joseph , Li Jian-Liang , Brill Lawrence M. , Ratnam Maya , Khalil Ahmad M. , Mattick John S. , Dinger Marcel E. , Perera Ranjan J. 
Published: August 2014

Abstract
Recently, we reported that the long noncoding RNA (lncRNA) SPRY4-IT1, which lies within the intronic region of the Sprouty4 gene, is upregulated in human melanomas and influences cell growth, proliferation, and motility, suggesting it may play an important role in the molecular etiology of human melanomas. Here, we report the identification of the full-length of SPRY4-IT1 transcript and its molecular function in human melanoma cells. SPRY4-IT1 transcripts are predominantly found in cytoplasm and accumulate in the polysome fraction of the cell suggests that they may interact with cellular proteins and/or interact with mRNAs to modulate the protein translation. We have identified a group of SPRY4-IT1 interacting proteins by isolating SPRY4-IT1 and protein binding complex and further characterization by mass spectrometry analysis. When SPRY4-IT1 ectopically expressed in melanocytes, it induced formation of multinucleated giant cells and modulates the expression of many genes including a subset of anti-apoptotic, cell cycle regulatory, DNA packaging, chromosome organization and chromatin architecture genes. Notably, the downregulation of the tumor suppressor gene dipeptidyl peptidase IV (DPPIV) and the upregulation the cellular proliferation marker Ki67 indicates the relevance of SPRY4-IT1 in the transition of melanocytes to melanomas.
Citation Format: Wei Zhao, Joseph Mazar, Jian-Liang Li, Lawrence M. Brill, Maya Ratnam, Ahmad M. Khalil, John S. Mattick, Marcel E. Dinger, Ranjan J. Perera. Molecular function of the long noncoding RNA SPRY4-IT1 in human melanomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1914. doi:10.1158/1538-7445.AM2013-1914
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2025: Prevention of mammary tumor progression via intraductal injection of nanoparticle-formulated siRNA.
Authors: Krause Silva , Brock Amy , Goldberg Michael , Ingber Donald E. 
Published: August 2014

Abstract
The contribution of specific genes to the development and progression of mammary tumors has been hampered by the inability to silence these genes locally in the mammary gland. Localized intraductal chemotherapy treatments have been explored and offer significant advantages in terms of reduced toxicity and side effects. Therefore, we wanted to explore the possibility of gene knockdown using siRNA delivery via intraductal injection. FVB C3(1)-SV40Tag transgenic female mice spontaneously develop hyperplastic mammary lesions that progress to invasive mammary tumors. Hyperplastic ducts form as early as 12 weeks of age and progress into DCIS-resembling tumors by 16 weeks of age. These further develop into invasive tumors that invade locally into adipose tissue and muscle and occasionally form metastases to lung by 18 to 20 weeks of age. We intraductally injected nanoparticle-formulated siRNA targeted to the SV40 T-antigen transgene beginning at 8 weeks of age through 23 weeks of age into the mammary gland twice a month. As controls, transgenic females were either left untreated or intraductally injected with a non-targeting siRNA. Tumor formation was monitored using ultrasound technology that allows for tumor detection as early as 0.4mm in diameter. At 23 weeks of age, when 100% of the control mice developed tumors, only 1 of 8 mice that received siRNA to the transgene had developed a small tumor. Histological analysis of the mammary glands confirmed development of early lesions but tumor progression was successfully prevented. Mammary lesions were analyzed for proliferation, apoptosis and expression of various markers of differentiation, including hormone receptor status. We showed that siRNA was not detectable in any other organs of the mouse, including the liver. Furthermore, we confirmed that frequent intraductal siRNA injection did not interfere with subsequent pregnancy or lactation, a period in which the mammary gland undergoes extensive remodeling to allow for milk production. Our long-term goal is to leverage the information we uncovered through this effort to target key genes we identified through gene network analysis aiming to prevent the progression of DCIS to invasive tumors. Moreover, this new technology can be utilized to explore the role of genes during specific times during development and tumor formation.
Citation Format: Silva Krause, Amy Brock, Michael Goldberg, Donald E. Ingber. Prevention of mammary tumor progression via intraductal injection of nanoparticle-formulated siRNA. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2025. doi:10.1158/1538-7445.AM2013-2025
Abstract 2185: Development and characterization of the fully human chimeric protein GrB-TWEAK targeting Fn14-positive solid tumor cells.
Authors: Zhou Hong , Migliorini Mary , Cao Yu , Cheung Lawrence H. , Hittelman Walter N. , Winkles Jeffrey A. , Rosenblum Michael G. 
Published: August 2014

Abstract
The TNFR superfamily member Fn14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), has emerged as a potentially clinically valuable target for cancer therapy. Specifically, Fn14 expression is relatively low in normal tissues but elevated in various human solid tumor types, including brain, breast, lung and melanoma, and can be a negative prognostic indicator. To target Fn14-overexpressing cancer cells, we constructed via PCR a novel chimeric protein designated granzyme B (GrB)-TWEAK, using the human TWEAK receptor-binding domain as the targeting moiety and the human pro-apoptotic serine protease GrB as the cytotoxic agent. The fusion construct was expressed in mammalian cells and purified to homogeneity from conditioned media. BiaCore analysis of TWEAK and GrB-TWEAK binding to the Fn14 extracellular domain indicated that these proteins bound to Fn14 with similar affinity, with Kds of ∼ 3 nM and ∼ 8 nM, respectively. Confocal immunofluoresence studies showed that GrB-TWEAK specifically and rapidly (within 3 hrs) internalized into Fn14-expressing MDA-MB-231 breast cancer and HT-29 colorectal adenocarcinoma cells. GrB-TWEAK activity was assessed using a panel of 26 human cancer cell lines and it demonstrated impressive and selective cytotoxicity to Fn14-expressing cells in the low nanomolar range (IC50 ranged from 0.4 nM-330 nM), which was 6- to 1117-fold more potent than free GrB. Treatment of cells expressing the multidrug resistance protein MDR1 showed no cross-resistance to the fusion construct in vitro. Mechanistic studies demonstrated that GrB-TWEAK activated caspase cascades and cytochrome C-related pro-apoptotic mechanisms consistent with the known intracellular functions of GrB in target cells. Preliminary mouse xenograft tumor model studies are ongoing. This work was conducted, in part, by the Clayton Foundation for Research (MGR) and supported by NIH grant NS055126 (JAW).
Citation Format: Hong Zhou, Mary Migliorini, Yu Cao, Lawrence H. Cheung, Walter N. Hittelman, Jeffrey A. Winkles, Michael G. Rosenblum. Development and characterization of the fully human chimeric protein GrB-TWEAK targeting Fn14-positive solid tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2185. doi:10.1158/1538-7445.AM2013-2185
Abstract 2348: Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients.
Authors: Jones Clifford D. , Blades Kevin , Foote Kevin M. , Guichard Sylvie M. , Jewsbury Philip J. , McGuire Thomas , Nissink Johannes W. , Odedra Rajesh , Tam Kin , Thommes Pia , Turner Paul , Wilkinson Gary , Wood Christine , Yates James W. 
Published: August 2014

Abstract
AZD6738 is a potent and selective inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase with the potential to be used in the clinic. We report the discovery of a morpholino-pyrimidine series and its subsequent optimisation to the pre-clinical candidate AZD6738 which has a good overall balance of potency, selectivity, pharmacokinetic and biopharmaceutical properties suitable for oral dosing. ATR is a serine/threonine protein kinase involved in DNA damage response signalling caused by DNA replication associated stress. Activation of ATR at stalled replication forks leads to suppression of replication fork origin firing, promotes repair and S/G2-cell cycle checkpoints to prevent premature mitosis and maintain genomic integrity. Failure to resolve damage leads to genomic instability and if sufficiently high, cell death. Stalled replication forks may collapse leading to formation of DNA double stranded breaks and activation of the ataxia telangiectasia mutated (ATM) kinase. ATM works in conjunction with ATR to efficiently resolve replication associated DNA damage creating a co-dependency with loss of one leading to a greater reliance on the other to maintain genomic stability. ATM is frequently inactivated across B-cell malignancies, head and neck, breast and lung cancers through chromosomal deletion, promoter hypermethylation or mutation. ATM-deficient tumours are hypothesised to be more reliant on ATR for survival and specific inhibition of ATR may lead enhanced anti-tumour activity while minimizing normal tissue toxicity. AZD6378 has the potential to test the clinical efficacy of ATR inhibition in cancer patients as monotherapy against ATM-deficient tumours or in combination with chemo or radiotherapy.
Citation Format: Clifford D. Jones, Kevin Blades, Kevin M. Foote, Sylvie M. Guichard, Philip J. Jewsbury, Thomas McGuire, Johannes W. Nissink, Rajesh Odedra, Kin Tam, Pia Thommes, Paul Turner, Gary Wilkinson, Christine Wood, James W. Yates. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2348. doi:10.1158/1538-7445.AM2013-2348
Abstract 247: ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.
Authors: Jiang Qingfei , Crews Leslie A. , Barrett Christian L. , Court-Recart Angela , Goff Daniel , Sadarangani Anil , Rusert Jessica , Morris Sheldon , Goldstein Lawrence , Chun Hye-Jung , Marra Marco , Fraser Kelly , Dao Kim-Hien , Minden Mark , Jamieson Catriona 
Published: August 2014

Abstract
The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. While DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity may also be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole transcriptome sequencing of normal, chronic phase (CP) and serially transplantable blast crisis (BC) chronic myeloid leukemia (CML) progenitors revealed increased interferon-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the interferon responsive ADAR1 p150 isoform and a propensity for increased A-to-I RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promoted expression of the myeloid transcription factor PU.1 and induced malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a mis-spliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of BC CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
Citation Format: Qingfei Jiang, Leslie A. Crews, Christian L. Barrett, Angela Court-Recart, Daniel Goff, Anil Sadarangani, Jessica Rusert, Sheldon Morris, Lawrence Goldstein, Hye-Jung Chun, Marco Marra, Kelly Fraser, Kim-Hien Dao, Mark Minden, Catriona Jamieson. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 247. doi:10.1158/1538-7445.AM2013-247
Abstract 2640A: Cell stiffness as a new indicator of diagnosis for human lung cancer cells and their metastasis.
Authors: Suganuma Masami , Takahashi Atsushi , Watanabe Tatsuro , Akiyama Hirohiko , Nakajima Yuki , Mondal Anupom , Fujiki Hirota 
Published: August 2014

Abstract
Our previous study with atomic force microscopy (AFM) revealed that highly metastatic B16-F10 cells have lower cell stiffness than low metastatic B16-F1 cells, and that treatment of the cells with a green tea polyphenol, EGCG, increased cell stiffness, associated with inhibition of metastasis. Since cell stiffness measured by Young's modulus (Pa) using AFM is attracted the attention as a new indicator of cancer diagnosis, we expanded the study to human lung cancer cell lines, comparing with primary cultured normal bronchial epithelial cells.
We found that cell stiffness of lung cancer cell lines was significantly lower than that of human immortalized peripheral lung epithelial cells (HPL1D): Young's moduli for two adenocarcinoma cell lines (A549 and H322) were 2.4 kPa and 2.2 kPa; that of squamous cell carcinoma cell line (H1703): 0.6 kPa; a large cell carcinoma cell line (H1299): 0.8 kPa; and HPL1D: 4.9 kPa. Furthermore, primary cultured normal bronchial epithelial cells (NBEC) established from ten lung cancer patients showed high Young's moduli from 3.0 kPa to 7.4 kPa. These data indicate that soft cell stiffness is a new indicator of diagnosis for lung cancer. Furthermore, it is important to note that H1703 and H1299 cells with low cell stiffness had high motile activity, compared with A549 and H322 cells with high cell stiffness. This indicates that low cell stiffness of lung cancer cell lines was associated with high motility, suggesting high metastatic ability. Treatments with EGF significantly induced transformation of HPL1D cells with morphological change, resulting in significant reduction of cell stiffness from 3.4 kPa to 1.5 kPa. These data suggest that low cell stiffness is induced in carcinogenic process. A histogram of Young's moduli indicates that a cancer cell line is a conglomerate of various cells with varying cell stiffness. In order to study the change of cell stiffness during cell-cycle, we established H1299/Fucci cells by introducing fluorescent-cell-cycle-indicator (Fucci) gene into H1299 cells. Young's moduli for each cell-cycle phase of H1299/Fucci cells were 1.71 kPa for G1, 1.64 kPa for G1→S, 1.55 kPa for S/G2 and 1.64 kPa for M→G1. Thus, changes in cell stiffness were observed depending on cell-cycle regulation, but the difference was small. Based on all data, we think cell stiffness is a dynamic feature of cancer cells, associated with motility and metastasis of lung cancer.
Citation Format: Masami Suganuma, Atsushi Takahashi, Tatsuro Watanabe, Hirohiko Akiyama, Yuki Nakajima, Anupom Mondal, Hirota Fujiki. Cell stiffness as a new indicator of diagnosis for human lung cancer cells and their metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2640A. doi:10.1158/1538-7445.AM2013-2640A