bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5329: Glycyl-tRNA Synthetase is a novel target for cancer therapeutics
Authors: Mo Zhongying , Liu Ze , Yang Xiang-Lei 
Published: July 2017

Abstract
Neddylation, an ubiquitination-like, post-translational modification that controls cell cycle and proliferation, is strongly associated with cancer. Interestingly, we recently identified that glycyl-tRNA synthetase (GlyRS) as a critical chaperone for neddylation1. GlyRS is also an essential enzyme for protein synthesis, which is required for tumor growth. Therefore, the dual functional GlyRS may be a novel target for anti-cancer therapy. Consistent with this idea, we found strong positive correlation between the level of GlyRS and tumor progression in breast cancer. A proof-of-concept inhibitor of GlyRS for aminoacylation was able to suppress neddylation in breast cancer cells, and reduce their lung metastasis in a mouse model. Taken together, we propose that GlyRS is a novel and promising target for cancer treatment.
Reference:1. ZY Mo, Q Zhang, J Laurer, Z Liu, LT Sun, Y Shi, P Griffin, XL Yang. Nature Structural and Molecular biology. 2016 Jun 27. doi: 10.1038/nsmb.3250.
Citation Format: Zhongying Mo, Ze Liu, Xiang-Lei Yang. Glycyl-tRNA Synthetase is a novel target for cancer therapeutics [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 5329. doi:10.1158/1538-7445.AM2017-5329
Abstract 5334: Destabilization of EWS-Fli1 protein by deubiquitinase inhibition in Ewing Sarcoma
Authors: Wang Shan , Kittler Ralf 
Published: July 2017

Abstract
Background: Ewing Sarcoma is a malignant tumor in bone or soft tissue, and typically in teenagers and young adults. Genetically, 85% of Ewing’s Sarcoma contains the chromosomal translocation [t(11;22)(q24;q12)], which fuses EWSR1 gene from chromosome 11 and Fli1 gene from chromosome 22 and generates an aberrant chimeric protein EWS-Fli1. EWS-Fli1 is essential for cell growth and development in EWS-Fli1 positive Ewing Sarcoma cells. Therefore, targeting EWS-Fli1 could be a promising therapeutic strategy for Ewing Sarcoma.
Methods and Results: Currently, the compounds of targeting EWS-Fli1 mainly interfere its interaction with partner or DNA. However, it could be a more potent way to manipulate its protein stability. Firstly, the proteasome inhibitor MG132 could retard the degradation of EWS-Fli1 protein in EWS502 cells and A673 cells, and increase its ubiquitination, which hints the degradation of EWS-Fli1 is through the ubiquitin (Ub)-proteasome pathway (UPP). Then, to identify the protein that interact with EWS-Fli1 and modulate its stability, we selected the candidate deubiquitinase according to literatures and the protein homology. And by co-immunoprecipitation assay, we identified a deubiquitinating enzyme (DUB) binding to EWS-Fli1. RNAi-mediated knockdown or inhibition of EWS-Fli1-DUB with a small molecule compound caused a marked increase in EWS-Fli1 ubiquitination, decreased levels of EWS-Fli1 in a proteasome-dependent manner, and further inhibited the growth of Ewing Sarcoma cells.
Conclusion: The findings indicate that EWS-Fli1 could be ablated by inhibiting its specific deubiquitinase in Ewing Sarcoma, which could be a novel treatment approach for Ewing Sarcoma.
Citation Format: Shan Wang, Ralf Kittler. Destabilization of EWS-Fli1 protein by deubiquitinase inhibition in Ewing Sarcoma [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 5334. doi:10.1158/1538-7445.AM2017-5334
Abstract 5338: Transcriptional elongation mediates human papillomavirus type 16 late promoter activation
Authors: Songock William , Bodily Jason 
Published: July 2017

Abstract
Human papillomaviruses (HPVs) are small DNA viruses that infect keratinocytes of squamous epithelia and cause benign lesions that can progress to several malignancies, including cervical cancer. Upregulation of viral transcripts by the HPV16 late promoter is dependent on host cellular differentiation. We sought to investigate the main cellular transcription regulators that correlate with differentiation-dependent increase in the late viral transcripts. Here, we show evidence that the step in transcription cycle that is responsible for late promoter activation is transcriptional elongation.
We began by establishing that the increase in viral transcripts originating from the late promoter is primarily regulated at the transcript synthesis level rather than post-transcription level. Based on this observation, we investigated whether there is a correlation between late promoter activation and activities that occur during the initiation, pausing or elongation steps of transcription cycle. Using chromatin immunoprecipitation (ChIP), we did not observed a differentiation-dependent increase of RNA Polymerase II (RNAP II) in the late promoter region. However, there was a significant increase of RNAP II at downstream sites of late promoter suggesting elongation is regulated by differentiation.
We then sought to investigate the cyclin dependent kinases (CDKs) that are known to regulate transcription elongation. ChIP did not show a significant increase of the elongation factor CDK9 in the late promoter; however, the enrichment of CDK9 at downstream sites of the viral genome significantly increased upon differentiation, suggesting that differentiation induces recruitment of CDK9 to facilitate elongation. Additionally, CDK8, a component of the Mediator complex that recruits CDK9 to the RNAP II, was increased upon differentiation. Kinase inhibitors against CDK8 did not affect late viral transcripts; however, knocking down CDK8 resulted in significant reduction of viral transcripts, suggesting that CDK8 could be involved in protein-protein interactions that are required for the synthesis of late viral transcripts.
These findings suggest that HPV has evolved to utilize cellular transcriptional elongation machinery as a way of regulating its late gene expression. This mechanism allows the virus to persistently infect host cells and cause HPV-associated malignancies.
Citation Format: William Songock, Jason Bodily. Transcriptional elongation mediates human papillomavirus type 16 late promoter activation [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 5338. doi:10.1158/1538-7445.AM2017-5338
Abstract 5342: Epigenetic polymorphisms and human papillomavirus E6/E7 oncoproteins transfection: Induce ATM gene deletion11q22-23 and chromosomal instability
Authors: McGhee Eva , Zarate Liliana , Opara Chiamaka , Alugbue Antoinette , Tyler Meidrah , Wissa Bileko , Ballard Billy , Pattillo Roland 
Published: July 2017

Abstract
Persistent infections involving high-risk types 16 and 18 of Human Papillomavirus (HPV) have been established as the etiological agent of cervical cancer. Recent data indicate that several polymorphisms of key regulators from the DNA damage repair pathways are associated with cancer development susceptibility. The long arm of chromosome 11 has received much attention as a high frequency of epigenetic deletions of various sites, observed in HPV-long term infection that lead to cervical cancer, indicating the presence of putative tumor suppressor genes and its association with disease progression. To better understand the importance of chromosome 11q22-23 region in the development of cervical cancer, we investigated genetic and epigenetic alterations of the tumor suppressor ATM gene in human keratinocytes transfected with HPV E6/E7 oncoproteins (16-MT). In the present study we examined 16-MT cells for epigenetic changes and chromosome imbalances, using FISH, and arrayCGH. We used several FISH probes, mapping to region 11q22-23 where the ATM gene is located. Our study revealed that the ATM gene located on chromosome 11q is deleted, relating to chromosome deletions, that are recurrent abnormalities in cervical cancer, implicating the loss of tumor suppressor genes as a significant mechanism that drive cells to become cancerous. This study was designed to investigate genetic instability using HPV16 E6/E7 oncoproteins to better understand the importance of chromosome 11q epigenetic changes. Deletion of 11q22-23 was observed in all metaphases scored. With restricted areas of deletions, two chromosomal regions of possible importance in cervical carcinomas could be distinguished. The first region is D11S1325 and the second region is D11S2179. The second region may contain part of the ATM gene. The results indicate that a tumor suppressor gene on chromosome 11q22-23 may be involved in the carcinogenesis of the cervix and the involvement of the ATM gene, as the driving factor remains a possibility.
Citation Format: Eva McGhee, Liliana Zarate, Chiamaka Opara, Antoinette Alugbue, Meidrah Tyler, Bileko Wissa, Billy Ballard, Roland Pattillo. Epigenetic polymorphisms and human papillomavirus E6/E7 oncoproteins transfection: Induce ATM gene deletion11q22-23 and chromosomal instability [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 5342. doi:10.1158/1538-7445.AM2017-5342
Abstract 5346: Combining droplet tagged short read sequencing with optical DNA mapping technology for improved assembly of cancer genomes
Authors: Jiang Yuan , Bilke Sven , Meltzer Paul S. 
Published: July 2017

Abstract
Kataegis, chromothripsis, chromoplexy and forms of structural hyper-mutation generically described as chromoanagenesis are found in many cancer types. Structural rearrangements can result in deletions, translocations, inversions and insertions, and gene amplification with important functional consequenes as cancer drivers and clonal diversity. Whole genome sequencing is increasingly used to sensitively detect strucutural rearrangements. Yet, it remains difficult to detect these events reliably without an excessive number of false positives. This is largely a consequence of the still relatively short read-length of commonly used sequencing platforms. As a result, in larger cohorts, PCR based methods are generally not feasible for validating all predicted structural rearrangements. Accordingly, new approaches for robust mapping of both simple and complex rearrangements are needed. Here we used a hybrid of two technologies, 10X genomics droplet tagged Illumina sequencing (10X Genomics ) and DNA fiber molecular imaging (BioNano Irys) for high throughput validation. First, utilizing a sequencing-assisted synthetic genome: for each rearrangement predicted by NGS, we build a “pseudo-chromosome” offering this structure as one alternative to the BioNano aligner. This combination compensates for the weaknesses of each platform resulting in a more robust result. In this way, even short reads can validate structural rearrangements, as the requirement for split reads is obviated. Provided that sufficient coverage is achieved, statistical analysis can be used to confidently recognize NGS false positive predictions. This allows the cataloging of complex repetitive regions and large-scale rearrangements. In our study we have evaluated this combined approach to large scale genome mapping to identify hallmark fusions and other rearrangements from the highly complex genomes of osteosarcoma cancer cell lines.
Citation Format: Yuan Jiang, Sven Bilke, Paul S. Meltzer. Combining droplet tagged short read sequencing with optical DNA mapping technology for improved assembly of cancer genomes [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 5346. doi:10.1158/1538-7445.AM2017-5346
Abstract 5350: A comprehensive and integrated approach to genomic and proteomic analysis of FFPE NSCLC tumor specimens
Authors: Hinerfield Douglas , Mellen Jennifer , Geiss Gary , Webster Philippa , Merritt Chris , Barker Kristi , Demirkan Gokhan , Filanoski Brian , Polakiewicz Roberto , Crosby Katherine 
Published: July 2017

Abstract
This poster describes a novel fully integrated method for the multiplexed DNA, RNA and Protein analysis of formalin fixed paraffin embedded tumor specimens. Cancer progression is typically a result of aberrations in the molecular pathways that regulate cell growth. Identifying and understanding these changes is necessary for the detection of drug targets as well as the identification of novel biomarkers that can predict response to such drugs. Deep molecular profiling of clinical tumor samples is challenged by limited material and the compromised quality resulting from variable handling and the fixation processes that are commonly employed in the clinical laboratories. While multiplexed gene expression and mutational analysis of such samples has become well established, we describe a new method that enables multiplexed DNA, RNA and protein analysis from a single formalin fixed paraffin embedded (FFPE) tumor specimen on the NanoString nCounter system. We have adapted the sample preparation methods to enable the multi-analyte analysis of FFPE samples and have demonstrated concordance with the clinical gold standard immunohistochemistry (IHC) methodology. As a proof-of-concept, five FFPE non-small cell lung cancer (NSCLC) specimens were simultaneously stained with a panel of antibodies specific to a variety of cancer-relevant proteins, five of which were validated on serial sections by IHC using antibodies from Cell Signaling Technology. In addition to the protein analysis, from the same specimen, expression of 770 cancer-related genes and &gt;100 single nucleotide variants (SNVs) were also analyzed on the nCounter platform. By integrating the analysis of DNA SNV’s, as well as RNA and protein expression from single FFPE specimens, it is now possible to reveal the molecular mechanisms of tumor progression, uncover novel drug targets and identify biomarkers from precious specimens.
Citation Format: Douglas Hinerfield, Jennifer Mellen, Gary Geiss, Philippa Webster, Chris Merritt, Kristi Barker, Gokhan Demirkan, Brian Filanoski, Roberto Polakiewicz, Katherine Crosby. A comprehensive and integrated approach to genomic and proteomic analysis of FFPE NSCLC tumor specimens [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 5350. doi:10.1158/1538-7445.AM2017-5350
Abstract 5357: OncoGxSelectTM - a beneficial supplement to comprehensive cancer genetic test
Authors: Han Yang , Yu Pengfei , Song Qingxuan , Wei Min , Hu Guanghui 
Published: July 2017

Abstract
Genetic profiling of tumor has been widely accepted both in oncology research and clinical field. However, clinical doctors are sometimes overwhelmed by tremendous and complicated information provided by comprehensive genetic tests, although they are welcomed by research-oriented oncologists. In order to provide accurate key findings to aid diagnosis and treatment in clinical practice, a careful tailored NGS based test - OncoGxSelectTM was developed and validated. Targeting 7 popular cancer types (NSCLC, Colorectal cancer, Breast cancer, Melanoma, Thyroid cancer, Esophageal and GIST cancer), OncoGxSelectTM detects all 4 types of genomic alterations including single nucleotide mutation, insertion/deletion, copy number variation and gene rearrangement in tumor tissue for 12 well-characterized clinical actionable genes strictly following NCCN (National Comprehensive Cancer Network) guidelines. OncoGxSelectTM offers high sensitivity and specificity greater than 99%, low cost and fast turnaround time using both DNA and RNA as starting material from FFPE samples with as low as 10% tumor cell content. This CLIA certified and CAP accredited genetic test panel is a valuable supplement to clinical oncologists to further facilitate diagnosis and treatment choosing.
Citation Format: Yang Han, Pengfei Yu, Qingxuan Song, Min Wei, Guanghui Hu. OncoGxSelectTM - a beneficial supplement to comprehensive cancer genetic test [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 5357. doi:10.1158/1538-7445.AM2017-5357
Abstract 5359: An ultrasensitive and highly reproducible hybridization capture-based Next-Generation Sequencing clinical assay to enable precision oncology in patients with solid tumors
Authors: Hernandez Moises , King Sara , Raghunath Sharanya , Johnson Christopher , Loughmiller David , Nadauld Lincoln , Mishra Pravin J. 
Published: July 2017

Abstract
Sequencing whole cancer exome and whole genome provides useful information to study cancer evolution. However, cost and amount of data may become overwhelming. Enrichment capture-based methods to design custom targeted gene panel have rapidly evolved recently in cancer genomics arena. Custom targeted gene sequencing entails several advantages (i.e., better quality, ethical, affordable, technically suitable, personalized and reimbursable) for cancer patients over whole exome and whole genome sequencing. With this in mind, and to enable precision oncology in patients with solid tumors, we developed ICG100 2.0 panel, a hybridization capture-based next-generation sequencing assay for targeted sequencing of all exons and flanking introns of 162 commonly mutated cancer genes in formalin-fixed, paraffin-embedded (FFPE) tumors. To establish ICG100 2.0 panel, we compared three commercially available capture based technologies and evaluated reproducibility, sensitivity, specificity and the detection limit for low-frequency variants using internally developed bioinformatics pipeline. Cell lines, reference standards/synthetic DNA and solid tumor samples with the known genetic information was utilized in this analysis. Results were derived from MiSeq and NextSeq platforms and cross-compared on other platforms, including MassArray and ddPCR for establishing concordance and uniformity. Intra and interrun replicates were utilized to assess the quality, precision and reproducibility of variant calling. Mean depth of coverage was observed at &gt;300X with &gt;99% sensitivity and specificity. These findings and observations will guide other clinical laboratories to establish new assay that require less DNA input, enzyme based fragmentation and reduced preparation time. While we show that the three capture based methods (after comparison) had an overall accuracy in SNP and CNV detection similar to each other with minor differences, we describe an approach to assess and establish the best assay from the clinical standpoint to guide treatment decisions and match cancer patients to the most appropriate clinical trials.
Citation Format: Moises Hernandez, Sara King, Sharanya Raghunath, Christopher Johnson, David Loughmiller, Lincoln Nadauld, Pravin J. Mishra. An ultrasensitive and highly reproducible hybridization capture-based Next-Generation Sequencing clinical assay to enable precision oncology in patients with solid tumors [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 5359. doi:10.1158/1538-7445.AM2017-5359
Abstract 5368: Comparative analysis of multiple copy number alteration tools in the detection of amplifications and deletions on both whole-exome and targeted NGS panel platforms
Authors: Virk Selene M. , Boyle Sean Michael , Alla Ravi , Yen Jennifer , Chen Richard 
Published: July 2017

Abstract
Somatic copy number alterations, or CNAs, are frequent occurrences in the tumor landscape and can present in the form of focal alterations or as chromosome level events. Reliable detection of CNAs is crucial to understanding the impact of these events on a wide range of factors including tumor progression and treatment outcomes. The clinical use of NGS panels, and more recently exomes, continues to expand in cancer but the reliable detection of CNAs remains a challenge. A major factor contributing to the challenge is the availability of reliable tools that have been well tested and validated.
We sought to characterize the sensitivity and specificity of multiple CNA detection tools with a focus on clinically relevant genes in NGS panel and whole-exome. Our approach utilized a variety of publicly available CNA tools to identify whole gene amplifications and deletions in a set clinically relevant genes identified in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. The tested CNA tools included two that supported both whole exome and panel NGS data, allowing cross platform in addition to cross tool comparisons. This work involved more than 20 well characterized cell lines derived from a broad spectrum of tumor types, including breast, lung, melanoma, and prostate cancers. The cell lines were analyzed in both tumor/normal and tumor only (which utilizes a proxy normal) modes. Analyses of patient-matched and proxy-normal data were performed with both assays.
Using our approach, we were able to identify clinically relevant CNAs on both platforms. The performance of the tools tested varied, with some tools performing best on either amplification or deletion events. These results represent a comprehensive comparison of recent copy number alteration tools and provides data that can be utilized to make the tools even more robust and reliable.
Citation Format: Selene M. Virk, Sean Michael Boyle, Ravi Alla, Jennifer Yen, Richard Chen. Comparative analysis of multiple copy number alteration tools in the detection of amplifications and deletions on both whole-exome and targeted NGS panel platforms [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 5368. doi:10.1158/1538-7445.AM2017-5368