bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5465: Persistent oxidative stress in mouse intestinal and colonic epithelial cells after exposure to 12C-ion radiation
Authors: Suman Shubhankar , Kumar Santosh , Fornace Albert J. , Datta Kamal 
Published: July 2017

Abstract
Purpose: 12C-ion radiotherapy is demonstrating favorable results compared to photon radiotherapy for select cancers. While normal tissue exposure is lower with 12C-ions relative to γ-rays, it cannot be completely eliminated and therefore, late tissue toxicity, inflammation and secondary carcinogenesis cannot be ruled out. The goal of this study was to assess the extent of persistent oxidative stress (POS) after 12C radiation exposure and compare the results to that after γ radiation exposure.
Methods and Materials: Mice (C57BL/6J; 6 to 8 weeks; male) were irradiated with 0.5 or 1.3 Gy of γ or 12C-ion, and intestinal (IEC), colonic (CEC) epithelial cells and tissues were collected 2 months after radiation exposure. In epithelial cells, intracellular ROS, mitochondrial superoxide, mitochondrial membrane potential (MMP), and cardiolipin oxidation were studied by flow-cytometry. Superoxide dismutase (SOD), catalase, and NADPH oxidase activity along with lipid oxidation were also assessed in epithelial cells using biochemical assays.
Results: Our results clearly showed radiation quality and dose-dependent induction of POS. Both intestine and colon showed a higher elevation of intracellular ROS, mitochondrial superoxide, NADPH oxidase activity, and mitochondrial cardiolipin oxidation after 12C relative to γ radiation. Moreover, antioxidant enzyme activity in intestine and colon was also significantly reduced in 12C-irradiated mice. Compared to γ radiation, membrane lipid damage was remarkably higher in both intestine and colon of 12C-ion irradiated mice. At 0.5 Gy, persistent oxidative damage indicated by 4-hydroxynonenal was 3-fold in colon and 1.6 fold in intestine after 12C relative γ radiation.
Conclusions: Mitochondrial deregulation, increased NADPH oxidase activity and loss of SOD and catalase activities were the major contributory events in 12C-ion-induced POS in mouse GI-tissues. Compared to intestine, colon was more susceptible to POS induction that might be due to progressive cell turnover in intestine resulting in faster elimination of initial damage signal in a given time than colon. Taken together, our data suggest that normal tissue exposure to 12C radiation carries higher long-term risk relative to γ-rays at comparable doses and further detail evaluation is warranted.
Citation Format: Shubhankar Suman, Santosh Kumar, Albert J. Fornace, Kamal Datta. Persistent oxidative stress in mouse intestinal and colonic epithelial cells after exposure to 12C-ion radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2017-5465
Abstract 5487: Identification of super-enhancer-associated cancer genes provides novel therapeutic targets in adult T-cell leukemia/lymphoma
Authors: Sanda Takaomi , Wong Regina WJ , Cao Phuong TN , Leong Wei Zhong , Yam Alice WY , Zhang Tinghu , Iida Shinsuke , Okamoto Takashi , Ueda Ryuzo , Gray Nathanael S. , Ishida Takashi 
Published: July 2017

Abstract
Super-enhancers are often enriched at cancer genes in various malignancies. Identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive lymphoproliferative disorder that arises from CD4+ mature T-lymphocytes. A recent genome-wide sequencing study revealed a large number of genetic and chromosomal abnormalities. However, there is still a lack of functional evidence for these genetic abnormalities in ATL pathogenesis due to the large mutational burden and the considerable genetic heterogeneity. Here, we performed super-enhancer profiling combined with gene expression analysis in primary ATL samples and cell lines. Super-enhancers are frequently enriched at genes involved in T-cell activation and T-cell receptor signaling pathway in both ATL and normal CD4+ T-cells, reflecting the origin of leukemia cells. Super-enhancers at the CCR4 gene, a known therapeutic target in ATL, were observed in all ATL cases. Additionally, we identified previously-uncharacterized genes that were highly activated in ATL cells and required for cell growth. A small-molecule inhibitor of CDK7 efficiently downregulated the expression of these genes and inhibited cell growth. Our study provides a novel strategy to identify critical cancer genes in cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Takaomi Sanda, Regina WJ Wong, Phuong TN Cao, Wei Zhong Leong, Alice WY Yam, Tinghu Zhang, Shinsuke Iida, Takashi Okamoto, Ryuzo Ueda, Nathanael S. Gray, Takashi Ishida. Identification of super-enhancer-associated cancer genes provides novel therapeutic targets in adult T-cell leukemia/lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2017-5487
Abstract 5488: APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
Authors: Li Zhaodong , Abraham Brian , Berezovskaya Alla , Farah Nadine , Liu Yu , Leon Theresa , Fielding Adele , Tan Shi Hao , Sanda Takaomi , Weintraub Abraham , Li Benshang , Shen Shuhong , Zhang Jinghui , Mansour Marc , Young Richard , Look Thomas 
Published: July 2017

Abstract
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells resulting in clonal selection. Although most cancer causing mutations have been detected in the protein-coding regions of the cancer genome, driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.
Citation Format: Zhaodong Li, Brian Abraham, Alla Berezovskaya, Nadine Farah, Yu Liu, Theresa Leon, Adele Fielding, Shi Hao Tan, Takaomi Sanda, Abraham Weintraub, Benshang Li, Shuhong Shen, Jinghui Zhang, Marc Mansour, Richard Young, Thomas Look. APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2017-5488
Abstract 5530: Evidence linking aquaporin-3 loss to increased invasiveness in bladder cancer
Authors: Roy Arpita , DeSilva Dinuka M. , Bottaro Donald P. 
Published: July 2017

Abstract
Bladder cancer (BCa) is the most common type of urothelial cancer (UC). According to American Cancer Society, in 2016, diagnoses of 76,960 new cases of bladder cancer (BCa) and 16,390 BCa associated deaths have been estimated. More than 90% of bladder cancer starts in the innermost transitional epithelium (urothelium) of the bladder. Aquaporin 3 (AQP3), one of 13 members of a transmembrane channel forming protein family (AQP0-12), has an N-terminal basolateral sorting signal and localizes to the basolateral membrane in epithelial tissues. Recent studies have shown that AQP3 expression is decreased in UC thus supporting a new hypothesis that alteration of the expression of AQP3 plays a role in the pathogenesis of UC. However, it remains to be determined whether AQP3 is involved in the invasion and metastasis of UC cells. In the present study, human bladder cancer cell lines of different grades, SW780 (G1) and TCCSUP (G4) were studied. Transcript and protein levels of AQP3 expression were significantly higher in low grade, SW780 cells when compared to the higher-grade TCCSUP cells. Inhibition of AQP3 by CuSO4 or siRNA specific knockdown of AQP3 resulted in increased migration in the wound-healing scratch assay. Over-expression of AQP3 plasmid resulted in reduced migration. It is known that epithelial cell polarity contributes to tumor suppression and that loss of E-cadherin is a crucial step in epithelial-to-mesenchymal transition (EMT). Our results indicate that AQP3 overexpression induced expression of E-cadherin, consistent with a role for AQP3 as a tumor suppressor by maintaining epithelial cell polarity and inhibiting EMT in BCa. Conversely, reduced AQP3 levels leading to reduced E-cadherin levels in high-grade BCa cells may result in loss of cell polarity, increased invasiveness and increased EMT.
Citation Format: Arpita Roy, Dinuka M. DeSilva, Donald P. Bottaro. Evidence linking aquaporin-3 loss to increased invasiveness in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5530. doi:10.1158/1538-7445.AM2017-5530
Abstract 554: Accurately identifying neoantigens utilizing both DNA and RNA somatic variants in an enhanced platform
Authors: Boyle Sean M. , Harris Jason , Bartha Gabor , Alla Ravi , Karbelashvili Mirian , Chervitz Steve , Montana Aldrin , Rowell Craig , Jonganeel Patrick , Kirk Scott , McClory Rena , West John , Chen Rich 
Published: July 2017

Abstract
The identification of neoantigens is a crucial step in the development of neoantigen-based personalized cancer vaccines and other immunotherapies. Accurately predicting which neoantigens are likely to be immunogenic remains a key challenge owing to the complex processes involved in determining neoantigen immunogenicity including the antigen presenting machinery, likelihood of MHC class I and II binding, similarity to self, and ability to interact with the TCR.
We have developed a neoantigen detection pipeline built upon our analytically validated Accuracy and Content Enhanced (ACE) Exome and Transcriptome sequencing platform and somatic variants calling pipeline through combined DNA and RNA analysis. The analytical performance of these pipelines is greater than &gt;97% sensitivity for small variants (RNA and DNA) with a specificity of &gt;98% (DNA) and a fusion sensitivity of &gt;99% (RNA).
Within our neoantigen pipeline, variants that are detected by our DNA and RNA cancer analysis pipelines are processed for antigen identification, including SNVs, indels, and fusion events. Importantly, both in-frame and out-of-frame events are accurately considered by transcript, allowing for detection of a wealth of candidate neoantigens. Our pipeline includes assessment of important immunologic components including HLA prediction, MHC binding (class I and II), immunogenicity, similarity to self, and similarity to known antigens. Additionally, peptides are evaluated for variant allele frequency in both the RNA and DNA of the tumor sample and gene expression level is considered. Collectively, our ImmunoID product provides a comprehensive assessment of features that may be used for identifying and ranking potentially immunogenic neoantigens.
To assess the effectiveness of this pipeline in predicting immunogenic neoantigens, we assembled a gold-set of 23 known, previously experimentally-validated immunogenic neoantigens from the literature. We spiked in these neoepitopes into exome data and assessed the ability of our neoantigen pipeline to find and rank these immunogenic known neoantigens. Preliminary results show our neoantigen pipeline is able to accurately identify 22 out of 23 (~96%) of the spiked in neoantigens as being potentially immunogenic.
Citation Format: Sean M. Boyle, Jason Harris, Gabor Bartha, Ravi Alla, Mirian Karbelashvili, Steve Chervitz, Aldrin Montana, Craig Rowell, Patrick Jonganeel, Scott Kirk, Rena McClory, John West, Rich Chen. Accurately identifying neoantigens utilizing both DNA and RNA somatic variants in an enhanced platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 554. doi:10.1158/1538-7445.AM2017-554
Abstract 5540: Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor
Authors: Hu Tommy , Soliman Mario , Kapadia Malika , Dovat Elanora , Payne Jonathan , Song Chunhua , Dovat Sinisa 
Published: July 2017

Abstract
Cellular proliferation in T-cell acute lymphoblastic leukemia is regulated by multiple signaling pathways. The Phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently dysregulated in T-ALL. Targeting the PI3K pathway has shown promise as a novel therapeutic approach for T-ALL. However, regulation of the PI3K pathway is still not well understood. Here, we report that PI3K activity in T-ALL can be controlled by transcriptional regulation of key members of this pathway, PIK3CD and PIKFYVE. DNA binding analysis of primary T-ALL using qChIP revealed that the tumor suppressor protein, Ikaros, binds the promoter regions of PIK3CD and PIKFYVE. Since Ikaros acts as a regulator of transcription, we tested whether Ikaros binding to PIK3CD and PIKFYVE affects their expression. Overexpression of Ikaros results in reduced transcription of PIK3CD and PIKFYVE in T-ALL. Targeting Ikaros with a specific shRNA, resulted in increased transcription of PIK3CD and PIKFYVE in T-ALL. Together, these results demonstrate that Ikaros functions as a transcriptional repressor of both PIK3CD and PIKFYVE, and suggest that Ikaros can regulate the PI3K pathway in T-ALL. It has been previously shown that Ikaros function in B-cell acute lymphoblastic leukemia is regulated by oncogenic Casein Kinase II (CK2). We tested whether Ikaros ability to repress transcription of PIK3CD and PIKFYVE is regulated by CK2. Inhibition of CK2 by a specific pharmacological inhibitor, CX-4945, resulted in increased Ikaros binding to the promoters of PIK3CD and PIKFYVE, as well as in transcriptional repression of both of these genes. These results suggest that Ikaros function as a repressor of PIK3CD and PIKFYVE transcription is impaired by CK2 in T-ALL. CK2 inhibition restores Ikaros-mediated transcriptional repression of PIK3CD and PIKFYVE, which results in downregulation of the PI3K pathway. In conclusion, the presented data demonstrate that the PI3K signaling pathway is regulated by transcriptional repression of PIK3CD and PIKFYVE by Ikaros in T-ALL. Results reveal interplay between two signaling pathways in T-ALL, CK2 and PI3K, where CK2 positively regulates the PI3K pathway by inhibiting Ikaros function. These data reveal novel mechanisms that regulate cellular proliferation in T-ALL.
Citation Format: Tommy Hu, Mario Soliman, Malika Kapadia, Elanora Dovat, Jonathan Payne, Chunhua Song, Sinisa Dovat. Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2017-5540
Abstract 5547: A computational approach to predict tissue level cell cycle regulatory network for normal proliferating and cancer cells
Authors: Sheng Tao , Cao Sha , Zhang Chi , Xu Ying 
Published: July 2017

Abstract
Cell cycle control and regulation has been widely studied in terms of cyclin-dependent kinases (CDKs) activities, while only limited information are available on tissue contexts and signaling. In this study, we adopted a systems biology approach aiming to comprehensively capture how tissue level signaling events orchestrate cell cycle phases in a CDKs activities independent manner in both of normal and tumor tissues. We have applied our in house gene co-expression and bi-clustering analysis on a collection of 8 single cell transcriptomic sequencing datasets of normal proliferating human embryonic cells, 17 RNA-seq transcriptomic datasets of inflammatory tissues and 30 microarray data sets of chronic inflammatory diseases as normal proliferating reference and TCGA RNA-seq data for 20 cancer types aiming to identify cell cycle associated gene co-expression modules. Our results suggest that the tissue level signaling events are generally show distinct regulatory structures between tumor and normal tissues: 1) the Rho GTPase signaling pathways that control cell polarity, activate in G2/M transition phase in normal tissue, while mainly in G1 and S phases in tumor. 2) Focal adhesion kinases (FAK) drives G1/S transition in normal tissues, while activated in multiple phases in tumor. 3) Hippo signaling for cell size control activates at G2/M transition phase in normal tissue while in multiple phases in tumor. In addition, we have also generated tissue level regulatory networks for cell cycle controls by predicting possible collective effects of extra- and intra-cellular signaling for both normal proliferating and cancer cells.
Citation Format: Tao Sheng, Sha Cao, Chi Zhang, Ying Xu. A computational approach to predict tissue level cell cycle regulatory network for normal proliferating and cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5547. doi:10.1158/1538-7445.AM2017-5547
Abstract 5559: Using cancer dependency data to discover tumor suppressive and oncogenic functional modules
Authors: Pan Joshua , Meyers Robin M. , Michel Brittany C. , Sizemore Ann E. , Vazquez Francisca , Weir Barbara A. , Hahn William C. , Tsherniak Aviad , Kadoch Cigall 
Published: July 2017

Abstract
Efforts to define protein complexes and their functional networks are critical for systems-level understanding of the pathways involved in human cancer. Current methods to catalog human protein complexes via physical interaction are often unable to resolve functional differences between complex members or infer relationships governed by sub-stoichiometric interactions. While functional wiring maps in yeast have been generated by measuring epistatic interactions between pairs of genes, efforts to scale this concept in individual human cell lines have been met with challenges and have only been able to characterize limited numbers of genes at a time.
We have developed a scalable approach that can measure functional similarity without the constraints of pairwise genetic interaction experiments. Using data from genome-wide RNAi and CRISPR dropout screens performed in hundreds of cancer cell lines, we leveraged the heterogeneity of gene dependencies across cancer types to measure functional similarity between thousands of genes at once, which in turn allowed us to recreate known inter- and intra-complex functional relationships and to uncover tumor suppressive and oncogenic functional modules in cancer-relevant pathways such as proteolysis, metabolism and transcription.
Applying these approaches to the mammalian SWI/SNF (BAF) chromatin remodeling complex, which is mutated in over 20% of human cancer, revealed three functional modules that arose separately during metazoan evolution, one of which is entirely novel and uncharacterized. We then performed biochemical experiments that fully support three specialized complex configurations, each with distinct size, subunit composition, and function. These data reorganize the BAF complex into previously unrecognized modules that better explain mutational burden in human cancer. Notably, we observe that that all known BAF-driven, highly penetrant rare cancers and neurodevelopmental disorders involve disruption within a single functional module we defined, underscoring the value of evaluating disease genomics through the lens of functional modularity.
Citation Format: Joshua Pan, Robin M. Meyers, Brittany C. Michel, Ann E. Sizemore, Francisca Vazquez, Barbara A. Weir, William C. Hahn, Aviad Tsherniak, Cigall Kadoch. Using cancer dependency data to discover tumor suppressive and oncogenic functional modules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5559. doi:10.1158/1538-7445.AM2017-5559
Abstract 5567: A scalable and integrated computational and experimental workflow to identify new driver genes in cancer genome data
Authors: Horn Heiko , Lawrence Michael S. , Chouinard Candace R. , Shrestha Yashaswi , Hu Jessica Xin , Worstell Elizabeth , Shea Emily , Ilic Nina , Kim Eejung , Kamburov Atanas , Kashani Alireza , Hahn William C. , Campbell Joshua D. , Boehm Jesse S. , Getz Gad , Lage Kasper 
Published: July 2017

Abstract
High throughput sequencing has revolutionized the study of the cancer genome, enabling numerous discoveries in basic and clinical research. However, considerable sample sizes are required to find cancer driver genes with intermediate and low mutation frequencies, and for a large proportion of patients the molecular cause (e.g. driver gene(s)) of disease is unknown. Here, we describe an integrated computational and experimental workflow that combines cancer genome data, molecular network information, multiplexed in vivo tumorigenesis assays, and reanalysis of driver-gene-negative cancer patients to predict and validate new driver genes. We develop a statistic, network mutation burden, that combines molecular network information with data from 4,742 cancer genomes to accurately classify known driver genes across 21 tumor types and predict 62 driver gene candidates.Of these, 35 gene candidates were tested in multiplexed in vivo tumorigenesis cell assays using sensitized immortalized human embryonic kidney (HA1E-M) and immortalized human lung epithelial (SALE-Y) cell lines.Tumor formation in vivo was observed for 11 genes (2 in HA1E-M, 3 in SALE-Y, 6 in both). By reanalyzing 242 lung adenocarcinoma patients with an unknown molecular cause of disease we show that two of these candidates, TFDP2 and AKT2, are significantly amplified in multiple samples.Overall, we describe a scalable combined computational and experimental framework to predict and validate driver genes across many tumor types. Our proof-of-concept approach should become increasingly useful as the number of cancer genomes continues to grow.
Citation Format: Heiko Horn, Michael S. Lawrence, Candace R. Chouinard, Yashaswi Shrestha, Jessica Xin Hu, Elizabeth Worstell, Emily Shea, Nina Ilic, Eejung Kim, Atanas Kamburov, Alireza Kashani, William C. Hahn, Joshua D. Campbell, Jesse S. Boehm, Gad Getz, Kasper Lage. A scalable and integrated computational and experimental workflow to identify new driver genes in cancer genome data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5567. doi:10.1158/1538-7445.AM2017-5567