bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1077: Use of the SVClassify algorithm to classify pediatric solid tumor translocation variant calls as likely true or false positives
Authors: Harenza Jo Lynne , Parikh Hemang M. , Wei Jun S. , Wen Xinyu , Sindiri Sivasish , Patidar Rajesh , Salit Marc , Meltzer Paul S. , Khan Javed , Zook Justin 
Published: August 2015

Abstract
With the advent of next-generation sequencing technologies, a variety of structural variant (SV) calling algorithms have been developed. However, these algorithms are generally not sensitive and specific, in part because they are biased toward identification of specific types or lengths of SVs. Thus, concordance among algorithms is often very low. At the National Institute of Standards and Technology (NIST), we have previously rigorously characterized sequencing biases across multiple sequencing platforms for the candidate NIST reference material, RM 8398 (the genome of individual NA12878). This yielded a high-confidence set of SNP and small indel (&lt;40 bp) variant calls. To extend our methods to SVs, we have developed SVClassify, which classifies SVs as likely true or false positive variants by combining evidence from one or more sequencing datasets. For NA12878, we were able to separate a set of validated deletions from random genomic regions with false positive and false negative rates less than 5%. We also found that the set of validated deletions clustered into different categories, including heterozygous Alu deletions, homozygous Alu deletions, and other heterozygous deletions. Until now, SVClassify has only been used for classification of large deletions on the non-cancerous genome, NA12878. In order to assess the sensitivity and specificity of SVClassify for correctly classifying translocations, we are using the RSVSim R package to simulate different numbers of translocations within repeat regions of the human genome. Furthermore, we will investigate the performance of SVClassify on cancer genomes, particularly pediatric solid tumors, which exhibit extensively rearranged genomes compared to their normal counterparts. To do so, pediatric tumor and normal datasets from multiple sequencing technologies will be integrated. To represent a spectrum of translocations, we will assess variant calls from cancer genomes with varying degrees of rearrangements: neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, we will use SVclassify to classify candidate SV calls made using the Complete Genomics pipeline, as well as those made on Illumina datasets using the recently developed SMUFIN algorithm.
Citation Format: Jo Lynne Harenza, Hemang M. Parikh, Jun S. Wei, Xinyu Wen, Sivasish Sindiri, Rajesh Patidar, Marc Salit, Paul S. Meltzer, Javed Khan, Justin Zook. Use of the SVClassify algorithm to classify pediatric solid tumor translocation variant calls as likely true or false positives. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2015-1077
Abstract 1079: Transcriptional profiling reveals uterine leiomyoma subtypes with distinct pathways and biomarkers of tumorigenesis
Authors: Mehine Miika , Kaasinen Eevi , Pitkänen Esa , Sarvilinna Nanna , Heinonen Hanna-Riikka , Mäkinen Netta , Sjöberg Jari , Aaltonen Lauri A. 
Published: August 2015

Abstract
Uterine leiomyomas, also known as fibroids, are benign smooth muscle tumors with an estimated prevalence of 77% among women of reproductive age. Although benign, they frequently cause a variety of health complications and are the leading cause of hysterectomy worldwide. Recent studies utilizing high-throughput sequencing have revealed recurrent and mutually exclusive mutations in a variety of genes, suggesting that distinct molecular pathways are involved in the initiation of leiomyoma tumorigenesis. The consequences of these mutations are poorly understood and expression signatures associated with these driver mutations may provide further insights. The aim of this study was to explore transcriptional differences between genetic subgroups of leiomyomas utilizing Affymetrix exon arrays and RNA-sequencing. We performed transcriptional profiling of ∼100 leiomyomas harboring different genetic drivers; these included leiomyomas harboring MED12 mutations, HMGA2/HMGA1 rearrangements, biallelic inactivation of FH and COL4A5-COL4A6 deletions. We identified a long non-coding transcript of RAD51B to be specifically upregulated in MED12 mutant leiomyomas. Genes involved in key metabolic pathways, including pentose phosphate pathway and glutathione biosynthesis, were specifically upregulated in FH-deficient leiomyomas. AKR1B10 was the most significantly upregulated gene in leiomyomas of the FH type. This gene was not expressed in other leiomyomas and may serve as a robust biomarker for FH-deficient leiomyomas. Overexpression of the proto-oncogene PLAG1 was specifically seen in leiomyomas harboring HMGA2 or HMGA1 aberrations, suggesting that these tumors exert their tumorigenic effect through dysregulation of PLAG1. This was supported by identification of one uterine leiomyoma harboring a translocation of PLAG1 resulting in a similar overexpression. While this study highlights the importance of stratifying each leiomyoma into a specific subgroup, it also shows that several genes are commonly dysregulated among all leiomyomas. Targeting these genes would be ideal in developing treatments for this disease.
Citation Format: Miika Mehine, Eevi Kaasinen, Esa Pitkänen, Nanna Sarvilinna, Hanna-Riikka Heinonen, Netta Mäkinen, Jari Sjöberg, Lauri A. Aaltonen. Transcriptional profiling reveals uterine leiomyoma subtypes with distinct pathways and biomarkers of tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1079. doi:10.1158/1538-7445.AM2015-1079
Abstract 1106: Genome-wide CRISPR-Cas9 screens reveal candidate therapeutic targets and tumor suppressor genes for human glioma
Authors: Ding Yu , Toledo Chad , Hoellerbauer Pia , Basom Ryan , Girad Emily , Lee Eunjee , Corrin Philip , Lin Qi , Li Xiao-Nan , Nam Do-Hyun , Lee Jeongwu , Zhu Jun , Pollard Steven , Delrow Jeffery , Olson Jim , Paddison Patrick J. 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is the most aggressive and common form of brain cancer in adults. There are currently no effective therapies for GBM. Even with standard of care treatments, such as surgery, radiation, and chemotherapy, ∼90% of adult patients die within 2 years of diagnosis. Our inability to develop new more effective therapies may arise from pre-clinical models that inadequately predict therapeutic window and the fact that many new GBM drugs are “hand-me-downs” from other cancers, not specifically developed for treating brain tumors. To identify patient-tailored drug targets for GBM, our group has performed a series of functional genetic screens in patient derived GBM stem-like cells (GSCs) and also non-transformed human neural stem cells (NSCs). GSCs retain tumor-initiating potential and tumor-specific genetic and epigenetic signatures, even during extended outgrowth in serum-free culture. NSCs represent non-transformed candidate cell of origin controls, which share similar gene expression signatures and identical in vitro growth conditions. Using these systems along with RNAi or CRISPR/Cas9 platforms, we have identified multiple molecular vulnerabilities specific to GSCs, which appear to be largely driven by oncogenic transformation, in processes ranging from kinetochore regulation to 3′ pre-mRNA splice site recognition. At this meeting, we present our latest findings from genome-wide CRISPR-Cas9 gene knockout screens in multiple GSC and NSC isolates. These include validation studies of patient tumor-lethal genes using gene knockout rather than gene knockdown technology. In addition, we will present validation studies of gene products growth limiting for NSC expansion/self-renewal from these screens, a subset of which are candidate tumor suppressors for glioma. Strengths and weaknesses of using gene editing technology and GSC isolates for identification of therapeutic targets will be discussed.
Citation Format: Yu Ding, Chad Toledo, Pia Hoellerbauer, Ryan Basom, Emily Girad, Eunjee Lee, Philip Corrin, Qi Lin, Xiao-Nan Li, Do-Hyun Nam, Jeongwu Lee, Jun Zhu, Steven Pollard, Jeffery Delrow, Jim Olson, Patrick J. Paddison. Genome-wide CRISPR-Cas9 screens reveal candidate therapeutic targets and tumor suppressor genes for human glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2015-1106
Abstract 112: FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer
Authors: Hait Nitai C. , Avni Dorit , Yamada Akimitsu , Milstien Sheldon , Takabe Kazuaki , Spiegel Sarah 
Published: August 2015

Abstract
Hormonal therapies, including ovarian ablation, ER antagonists, and aromatase inhibitors, are the standards of care for treatment of ERα positive breast cancer. However, development of resistance to hormone therapies in advanced breast cancer is a major obstacle. Moreover, estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional estrogen targeted therapies. Strategies that lead to re-expression of ERα could sensitize breast cancers to selective ER modulators. FTY720/Fingolimod, a sphingosine analog, is an FDA-approved pro-drug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We have now found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P in turn is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and gene expression independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. In ERα negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, oral administration of clinically relevant doses of FTY720 to mice bearing ERα negative syngeneic breast tumors also re-expressed ERα and increased therapeutic sensitivity to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that FTY720 is a promising strategy for effective treatment of conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer. Supported by NIH grant RO1CA061774 and the Department of Defense BCRP program award W81XWH-14-1-0086 (S. Spiegel).
Citation Format: Nitai C. Hait, Dorit Avni, Akimitsu Yamada, Sheldon Milstien, Kazuaki Takabe, Sarah Spiegel. FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2015-112
Abstract 1125: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers
Authors: Hao Yujun , Samuels Yardena , Li Qingling , Krokowski Dawid , Brunengraber Henri , Hatzoglou Maria , Zhang Guo-Fang , Vogelstein Bert , Wang Zhenghe 
Published: August 2015

Abstract
Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations reprogram glutamine metabolism by up-regulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, thereby rendering them addicted to glutamine. We demonstrated that induction of GPT2 by mutant p110α is necessary and sufficient to render CRC cells addicted to glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of CRCs with PIK3CA mutations, but not CRCs with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harboring PIK3CA mutations. Mutant p110α up-regulates GPT2 gene expression through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110α activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant CRCs convert more glutamine to α-keto-glutarate to replenish the tricarboxylic acid (TCA) cycle to generate ATP. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs.
Citation Format: Yujun Hao, Yardena Samuels, Qingling Li, Dawid Krokowski, Henri Brunengraber, Maria Hatzoglou, Guo-Fang Zhang, Bert Vogelstein, Zhenghe Wang. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1125. doi:10.1158/1538-7445.AM2015-1125
Abstract 1133: Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state
Authors: li zhiguo , jie li , xiaoqi Liu 
Published: August 2015

Abstract
One outcome of activation of the PI3K pathway is increased aerobic glycolysis, but the upstream signaling events that regulate the PI3K pathway, thus the Warburg effect, are elusive. Increasing evidence suggests that Plk1, a cell cycle regulator, is also involved in cellular events in addition to mitosis. To test whether Plk1 contributes to activation of the PI3K pathway, thus aerobic glycolysis, we have identified PTEN as a Plk1 substrate. We hypothesize that Plk1 phosphorylation of PTEN contributes to activation of the PI3K pathway and the Warburg effect. Our data show that overexpression of Plk1 leads to activation of the PI3K pathway and enhanced aerobic glycolysis. In contrast, inhibition of Plk1 causes markedly reduced glucose metabolism in mice. Mechanistically, we show that Plk1 phosphorylation of PTEN and Nedd4-1 results in PTEN inactivation. Finally, we show that Plk1 phosphorylation of PTEN promotes tumorigenesis in both its phosphatase-dependent and -independent pathways.
Note: This abstract was not presented at the meeting.
Citation Format: zhiguo li, li jie, Liu xiaoqi. Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1133. doi:10.1158/1538-7445.AM2015-1133
Abstract 1146: Global profiling of SPARC-regulated metabolic pathways in ovarian cancer
Authors: Taylor Sherine , Sanchez Christian , Adrees Amna , Ozbek Hale Nur , Sahni Harjapjit , Said Neveen A. 
Published: August 2015

Abstract
We have previously reported the tumor suppressor effect of SPARC in ovarian cancer through inhibiting cancer cell growth and their interactions within the peritoneal milieu. In the present study, we sought to determine the effect of SPARC on metabolic perturbations associated with ovarian cancer using a syngeneic murine ovarian cancer model in SPARC knockout (KO) mice and their wildtype (WT) counterparts. Murine ID8 ovarian cancer cell line were injected intraperitoneally in SPARC KO and WT mice. Matched intraperitoneal tumor tissue, and ascitic fluid were harvested 6 weeks post-injection of ID8 cells and were subjected to global biochemical metabolomic profiling. In tandem, WT and KO tumors were dissected by LCM-microdissected and were subjected to gene expression profiling. Metabolomic profiling of SPARC KO tumors and ascites revealed significantly altered metabolites associated with glucose, energy, amino acid, and lipid metabolism, as well as redox homeostasis. Integrated transcriptome and metabolome analysis of the top significantly upregulated genes and metabolites in the KO compared to WT tumors and ascitic fluid revealed that the major pathways upregulated in absence of SPARC are those involved in: conversion of glucose to acetyl CoA and entry into the citric acid (TCA) cycle, respiratory electron transport and oxidative phosphorylation (SUCLG2; NDUFAB1; ATP5F1; UQCRH; ATP5H; COX5B; NDUFV1; ATP5O; IDH3B/ succinate, fumarate and pyruvate), protein metabolism (EIF5A; PREB; EIF4H; DAD1; STT3A; RPL4; SUMO1; CCT4; CCT2; IGFBP5; HSPA5; EIF3A; EIF4B; RPS19; EIF3E/ mannose; N-acetylneuraminate; N-glycolylneuraminate; glutamate; spermidine), fatty acid beta oxidation (HADH; TPI1; LPL/glycerol), purine nucleotides de novo biosynthesis and salvage (ATP5F1; ATP5H; PAICS; ATP6V1G1/ aspartate; glycine; glutamate; fumarate). Together, these data provide novel insight on the molecular mechanisms of the SPARC-induced metabolic perturbation associated with ovarian cancer that can be translated into diagnostic and prognostic biomarkers of the disease.
Citation Format: Sherine Taylor, Christian Sanchez, Amna Adrees, Hale Nur Ozbek, Harjapjit Sahni, Neveen A. Said. Global profiling of SPARC-regulated metabolic pathways in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2015-1146
Abstract 1153: Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody
Authors: Lerner Lorena , Tao Nianjun , Krieger Brian , Nicoletti Richard , Feng Bin , Ismail Nesreen , Winston William , Zhang Yanyu , Jiang Jinwei , Weiler Solly , Gyuris Jeno 
Published: August 2015

Abstract
Background:
One of the most lethal and debilitating effects of cancer is the development of cancer-related anorexia-cachexia syndrome (CACS). It affects the majority of advanced cancer patients and is thought to be responsible for up to ∼30% of all cancer deaths. CACS is a complex metabolic syndrome associated with malnutrition and severe involuntary weight loss due to the loss of muscle and fat tissue, as well as the clinical manifestation of anemia, inflammation and suppression of immune functions. The precise molecular mechanisms responsible for cancer cachexia are poorly understood, thus limiting the development of effective therapeutics. Current evidence suggests that a pro-inflammatory state may be responsible for many of the symptoms associated with CACS. Growth Differentiation Factor 15 (GDF15) is a pro-inflammatory cytokine whose circulating levels are significantly increased in cachectic cancer patients and several animal models of cancer cachexia. Here we demonstrate that the inhibition of GDF15 function results in the compete reversion of the phenotypic and metabolic changes associated with CASC.
Methods:
Mice bearing HT-1080 human fibrosarcoma xenografts have increased plasma GDF15 levels and develop cachexia were used in this study. Tumor bearing animals were treated either with AV-380, a GDF15 neutralizing antibody or IgG1 control. The effect on body weight, muscle/fat mass and organ sizes were assessed. Metabolic changes induced by the treatment were measured by a comprehensive laboratory animal monitoring system (CLAMS).
Results:
Treatment with AV-380 restored body weight, muscle and fat mass as well as normal organ sizes. Analyses of the CLAMS data demonstrated that mice receiving AV-380 reversed the phenotypic and metabolic changes associated with the cachexia induced by this tumor model. Moreover, AV-380 treated mice showed an increase in locomotor activity and energy expenditure, achieving levels similar to non tumor bearing control animals.
Conclusions:
Inhibition of GDF15 function completely reverted body weight loss, restored normal body composition and triggered a catabolic to anabolic metabolic switch in this cancer cachexia model. The data highlights the therapeutic potential of the GDF15 inhibitory antibody AV-380 for the treatment for CACS.
Citation Format: Lorena Lerner, Nianjun Tao, Brian Krieger, Richard Nicoletti, Bin Feng, Nesreen Ismail, William Winston, Yanyu Zhang, Jinwei Jiang, Solly Weiler, Jeno Gyuris. Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2015-1153