bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2178: Comparison and interpretation of variants in RNA and DNA from sarcoma cancer sample
Authors: Øster Bodil , Joecker Anika , Yip Rupert , Schacherer Frank , Basset Douglas , Salter Donald , Hayward Richard L. , Hupp Ted R. 
Published: August 2015

Abstract
Identification and interpretation of somatic variants using DNA from matched tumor/normal pairs is crucial for understanding the mechanisms behind cancer.
Studies have shown that a large proportion of variants present in the DNA are not present in the RNA and vice versa due to RNA-editing and other unknown molecular processes. In addition, recent publications show that RNA-editing plays an important role in cancer. These findings can have strong implications for clinical diagnostics where correct identification and interpretation of somatic variants from matched tumor/normal samples is essential.
In this study we will investigate somatic variants that are only present in the DNA or the RNA of pleomorphic undifferentiated sarcoma. For this approach we will first identify somatic variants in the DNA using Exome Sequencing data and in the RNA using RNA-Seq data from a matched tumor/normal pair. Somatic variants in DNA as well as RNA are then again filtered for germline variants using the DNA of the normal sample and the RNA of the normal sample. Somatic variants found in only DNA or only RNA are further investigated using Ingenuity's large Knowledge Base as well as HGMD and PGMD. We will show which class of proteins is mainly affected by the RNA editing events and which pathways are mainly affected. We will also highlight implications for clinical diagnostics using DNA only.
The complete analysis will be done using the new integrated QIAGEN tool suite of CLC Cancer Research Workbench, Ingenuity Variant Analysis and Biobase Genome Trax.
Citation Format: Bodil Øster, Anika Joecker, Rupert Yip, Frank Schacherer, Douglas Basset, Donald Salter, Richard L. Hayward, Ted R. Hupp. Comparison and interpretation of variants in RNA and DNA from sarcoma cancer sample. [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 2178. doi:10.1158/1538-7445.AM2015-2178
Abstract 2185: Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients
Authors: Jung Segun , Bi Yingtao , Davuluri Ramana V. 
Published: August 2015

Abstract
Stratification of cancer patients into different molecular groups is essential for developing targeted therapies. High-throughput technologies, such as microarrays and next-generation sequencing, have been extensively used for generating multi-omics data. Indeed, The Cancer Genome Atlas (TCGA) consortium, one of the most comprehensive and popular databases of cancer, has been accumulating large volumes of invaluable data for more than 30 cancer types, offering unprecedented opportunity to attain new insights in cancer biology. Despite the technological advances, analyzing, integrating and translating the gene signatures across different platforms remains a computationally challenging task.
Here, we developed a novel computational framework that integrates genomic and clinical data to stratify cancer patients into different molecular subgroups and predict clinically applicable phenotypes, such as survival. Application of this user-friendly framework derives platform-independent isoform-level gene signatures that can be translated from high-dimensional platforms (e.g., RNA-Seq) to clinically adaptable low-dimensional molecular assays (e.g., RT-PCR) for prognostic stratification. We applied the pipeline on two TCGA lung cancer datasets_Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC). Using independent test data, we achieved about 93% (LUAD) and 98% (LUSC) classification accuracy using less than 70 isoform-level gene signature. The proposed informatics platform is applicable to other cancer types in TCGA data portal.
Note: This abstract was not presented at the meeting.
Citation Format: Segun Jung, Yingtao Bi, Ramana V. Davuluri. Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients. [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 2185. doi:10.1158/1538-7445.AM2015-2185
Abstract 2195: A high-throughput chemical screen identifies synergistic activity between crizotinib and transcriptional CDK inhibitors in ALK-mutated neuroblastoma
Authors: Moore Nathan F. , Chipumuro Edmond , Hatheway Clark M. , Zhang Tinghu , Gray Nathanael S. , George Rani E. 
Published: August 2015

Abstract
Activating mutations in the anaplastic lymphoma receptor tyrosine kinase (ALK) represent important therapeutic targets in neuroblastoma (NB). One of the more common mutations, ALKF1174L, is sensitive to the FDA-approved ALK inhibitor, crizotinib, only at high doses and mediates acquired resistance to crizotinib in ALK-rearranged cancers. To identify compounds that would potentiate the effect of crizotinib, we performed a high-throughput compound screen using ALKF1174L-dependent human NB SH-SY5Y cells and compared viability between cells treated with the screen compound alone and in combination with crizotinib. The strongest “hits” among the ∼8,000 compounds screened were inhibitors of cyclin dependent kinases (CDKs). The combination of crizotinib and two candidate pan-selective CDK inhibitors, AT7519 and SNS-032 resulted in synergistic activity with significantly increased apoptosis over that of either single agent alone. This effect was observed in NB cells expressing not only ALKF1174L, but also in those expressing ALKR1275Q, the most common NB-associated ALK mutation. Synergy was also seen with ceritinib (LDK378), a structurally unrelated ALK inhibitor, in combination with both AT7519 and SNS-032. We determined that the synergistic effect was mediated preferentially through the transcriptional, rather than the cell cycle activity of these CDK inhibitors, denoted by absence of cell cycle arrest, stalling of RNA polymerase II at representative gene promoters, and loss of Pol II phosphorylation at the transcription elongation marker serine 2 in treated cells. These findings were comparable with results obtained using agents that were highly selective for CDK9 or CDK7, CDKs with roles in transcription regulation. Finally, in murine xenogaft models of ALK-mutated NB, the combination resulted in inhibition of tumor growth and prolongation of survival compared to single agents alone. Together, these data support further pre-clinical and clinical efforts to explore the therapeutic potential of combining ALK inhibitors with transcriptional CDK inhibitors in ALK-mutated NB.
Citation Format: Nathan F. Moore, Edmond Chipumuro, Clark M. Hatheway, Tinghu Zhang, Nathanael S. Gray, Rani E. George. A high-throughput chemical screen identifies synergistic activity between crizotinib and transcriptional CDK inhibitors in ALK-mutated neuroblastoma. [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 2195. doi:10.1158/1538-7445.AM2015-2195
Abstract 2213: Evaluation of bias associated with high-multiplex, target-specific pre-amplification
Authors: Okino Steven T. , Kong Michelle , Wang Yan T. 
Published: August 2015

Abstract
We developed a novel PCR-based pre-amplification (PreAmp) technology that can increase the abundance of over 350 target genes one million-fold. To assess potential bias introduced by PreAmp we utilized ERCC RNA reference standards, a model system that quantifies measurement error in RNA analysis. We assessed three types of bias: amplification bias, dynamic range bias and fold-change bias. We show that our PreAmp workflow does not introduce significant amplification and fold-change bias under stringent conditions. We do detect dynamic range bias if a target gene is highly abundant and PreAmp occurred for 16 or more PCR cycles; however, this type of bias is correctable. To validate PreAmp performance in an actual gene expression profiling experiment, we analyzed a panel of genes that are regulated during differentiation using the NTera2 stem cell model system. We find that results generated using PreAmp are statistically equivalent to results obtained using standard qPCR without the pre-amplification step. Importantly, PreAmp maintains patterns of gene expression changes across samples; the same biological insights would be derived from a PreAmp experiment as with a standard gene expression profiling experiment. Our PreAmp technology can facilitate accurate analysis of extremely limited samples in gene expression profiling experiments.
Citation Format: Steven T. Okino, Michelle Kong, Yan T. Wang. Evaluation of bias associated with high-multiplex, target-specific pre-amplification. [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 2213. doi:10.1158/1538-7445.AM2015-2213
Abstract 2214: Dynamic transcriptome analysis of DNA damage pathways under hypoxia
Authors: Lo Winnie W. , Zafarana Gaetano , Bristow Robert G. 
Published: August 2015

Abstract
During the outgrowth of tumor, gradients of hypoxic regions develop due to reduced oxygen diffusion. Intratumoral hypoxia is a prognostic factor associated with decreased disease-free survival and increased resistance to radiotherapy and chemotherapy in different solid cancers. We have previously shown that chronic hypoxia suppresses DNA damage repair pathways partly through decreased protein translation efficiency. The RNA levels of repair pathway genes have also been shown to be downregulated in hypoxia; however, most of the RNA studies do not distinguish between RNA synthesis and degradation. Here, we use novel metabolic labeling of newly synthesized RNA to investigate the dynamic changes in transcription rates of DNA damage repair pathways under hypoxia.
4-thiouridine (4sU), a uridine analogue, was added to the media of DU145 cells (prostate cancer cell line) that have been cultured in 21% or 0.2% oxygen concentrations for 72 hours. Total RNA was extracted and 4sU-tagged RNA was biotinylated and separated from untagged pre-existing RNA using streptavidin coated magnetic beads. Real-time RT-PCR was used to quantify the expression of repair pathways in three RNA subsets (total, pre-existing, and newly synthesized). Parallel experiments were performed in RNA harvested from the cytoplasmic and nuclear factions of cells.
We found that with 30-minute 4sU incubation, most 4sU-tagged RNA is still in the nucleus, and is subjected to little degradation, thus reflecting the average transcription rate. The percentage of newly synthesized RNA is lower in hypoxic than in normoxic cells. Importantly, the transcript levels of homologous recombination (HR) repair pathway regulators, RAD51, BRCA1 and BRCA2, are decreased in both total and newly-synthesized RNA of hypoxic cells. Our results demonstrate that in addition to translational regulation, hypoxia may also downregulate repair pathways through suppression of transcription. This 4sU assay provides opportunities for further analysis of differential RNA synthesis and decay of DNA damage repair pathways between hypoxia and normoxia.
Citation Format: Winnie W. Lo, Gaetano Zafarana, Robert G. Bristow. Dynamic transcriptome analysis of DNA damage pathways under hypoxia. [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 2214. doi:10.1158/1538-7445.AM2015-2214
Abstract 228: A novel device to perform rapid high-throughput in vivo drug sensitivity testing and identify optimal drug therapy for personalized cancer treatment
Authors: Jonas Oliver 
Published: August 2015

Abstract
We have developed an implantable device that can perform drug sensitivity testing of a large number of anti-cancer agents inside the living tumor. This device contains reservoirs that release microdoses of single agents or drug combinations into distinct spatial regions of the tumor in local concentrations that are representative of concentrations achieved during systemic drug treatment. Local efficacy and drug concentration profile are evaluated for each drug or combination on the device, and the local efficacy was confirmed to be an excellent predictor of systemic efficacy across multiple drugs and tumor models.
Currently up to 16 individual drugs or combinations can be assessed independently, without systemic drug exposure, through minimally invasive biopsy of a small region of a single tumor. Moreover, this assay takes into consideration physiologic effects that contribute to drug response by allowing drugs to interact with the living tumor in its native microenvironment. Because these effects are crucial to predicting drug response we envision that these devices will help identify optimal drug therapy before systemic treatment is initiated and could significantly extend drug response prediction beyond the predictive biomarkers used today. These devices may also potentially be used in clinical drug development to safely gather efficacy data on new compounds before pharmacological optimization.
Note: This abstract was not presented at the meeting.
Citation Format: Oliver Jonas. A novel device to perform rapid high-throughput in vivo drug sensitivity testing and identify optimal drug therapy for personalized cancer treatment. [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 228. doi:10.1158/1538-7445.AM2015-228
Abstract 2287: A model system to treat T-cell acute lymphoblastic leukemia with JAK inhibitors
Authors: Senkevitch Emilee , Hixon Julie , Li Wenqing , Durum Scott 
Published: August 2015

Abstract
The IL-7 Receptor signaling pathway is necessary for the proliferation and survival of T cells. Together with collaborators, we have shown that 9% of patients with T cell acute lymphoblastic leukemia (T-ALL) have gain of function mutations in IL-7R exon 6. These mutations promote homodimerization of IL-7Rα subunits, resulting in constitutive activation of this pathway via JAK1. Approximately 20% of T-ALL patients fail to respond to conventional chemotherapy, so there is a need for additional options for these patients. We hypothesized that JAK inhibitors could be used to treat T-ALL patients, particularly those with IL-7R mutations. We established a cell line model of T-ALL driven by constitutive IL-7R signaling which grew as a leukemia in RAG1-/- mice. The model cells were established by transforming the D1 thymocyte cell line with a mutated IL-7Rα derived from a patient sequence. These cells termed D1_hIL7R_P1 are also GFP+ which allows us to monitor the proliferation of the cells in vivo. D1_hIL7R_P1 cells delivered intravenously result in an aggressive leukemia with morbidity within 18-21 days. Currently we are studying the chemotherapeutic effects of two JAK inhibitors, Ruxolitinib and Tofacitinib on T-ALL. The maximum tolerated doses for Tofacitinib and Ruxolitinib are 50 mg/kg and 150 mg/kg, respectively. Ruxolitinib appears to be the most effective, showing a reduction of leukemogenesis detected in blood and tissues after just three days of oral treatment. Additionally, we have obtained samples derived from pediatric T-ALL patients. Once growth kinetics in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice is established, we will proceed to study the efficacy of the JAK inhibitors with human leukemia cells.
Citation Format: Emilee Senkevitch, Julie Hixon, Wenqing Li, Scott Durum. A model system to treat T-cell acute lymphoblastic leukemia with JAK inhibitors. [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 2287. doi:10.1158/1538-7445.AM2015-2287
Abstract 2290: More than a biomarker: Studying the role of vimentin in lung cancer metastasis
Authors: Salgueiro Alessandra M. , Gilbert-Ross Melissa , Havel Lauren S. , Shupe John , Marcus Adam I. 
Published: August 2015

Abstract
A major mechanism of metastasis is the epithelial to mesenchymal transition (EMT) where epithelial cells from the primary site undergo genetic and epigenetic alterations to become motile and mesenchymal. A canonical marker of EMT and a clinical marker of metastasis is the intermediate filament protein, vimentin. Vimentin expression correlates with increased metastatic potential and poor patient prognosis across most solid tumor types including lung, prostate, and breast cancers; however little is known about how vimentin functions to promote the metastatic cascade. Here we use a lung cancer mouse model to study the role of vimentin in lung cancer metastasis in vivo. We have re-developed an LSL-KrasG12D,LKB1fl/fl mouse model whereby intranasal administration of lentiviral Cre recombinase causes a KrasG12D mutation and LKB1 knockout in the lungs. Consequently, about half of the mice that develop primary lung tumors after 10 weeks also develop metastasis to the mediastinal lymph nodes by week 16. We crossed this mouse with a Vim-/- mouse to create a LSL-KrasG12D,LKB1fl/fl, Vim-/- (termed here KLV) mouse to determine if loss of vimentin prevents lung cancer metastasis in this model. Our findings show that the KLV mouse exhibits significantly less metastasis to the mediastinal lymph nodes (12%) as compared with its vimentin wild type counterpart but does not show a decrease in primary tumor formation. These knockout mice also exhibit less focal invasion at the primary tumor site while maintaining a well-differentiated adenocarcinoma histology independent of vimentin genotype. Taken together, our work indicates that vimentin is critical for lung cancer metastasis but not primary tumor formation.
Citation Format: Alessandra M. Salgueiro, Melissa Gilbert-Ross, Lauren S. Havel, John Shupe, Adam I. Marcus. More than a biomarker: Studying the role of vimentin in lung cancer metastasis. [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 2290. doi:10.1158/1538-7445.AM2015-2290
Abstract 2303: Impact of synbiotics administration on tumorigenesis of colon cancer mouse model
Authors: Saito Yasufumi , Hinoi Takao , Adachi Tomohiro , Shimomura Manabu , Miguchi Masashi , Niitsu Hiroaki , Kochi Masatoshi , Ohdan Hideki , Sentani Kazuhiro , Oue Naohide , Yasui Wataru 
Published: August 2015

Abstract
Introduction:
Previous study showed that Synbiotics might have beneficial effect in human and animal colitis like ulcerative colitis. However, it is not well known that the influence of Synbiotics for tumorigenesis in colon cancer. The aim of present study was to investigate the influence of Synbiotics in colon cancer mouse model and colitis associated cancer mouse model.
Methods:
Mouse stains carrying colon epithelium-preferential Apc mutation (CPC;Apc mice), that show sporadic colorectal adenomas and carcinomas are used in this study. We also used CPC;Apc mice consumed 1%Dextran Sulfate Sodium (DSS) as colitis associated colon cancer model, developing apploximately fourfold more adenomas and adenocarcinomas than CPC;Apc not consumed. At first, 9 of CPC;Apc mice were administerated symbiotics (Probiotics (Lactobacillus) 0.1g + Prebiotics (Oligosaccharide) 10mg/0.3ml/body) between 7 and 20 age in weeks and 10 was not administerated. Secondaly, using 9 of CPC;Apc consumed 1%DSS was administrated Symbiotics, 8 of not administrated, 7 of only Probiotics, and 7 of only Prebiotics. Body weight was measured weekly. Fecal microbial analysis was performed. At sacrifice in 21 age in weeks, the small and large bowel were histologically assessed.
Results:
Synbiotics administration group has no differences of tumorigenesis comparing to control group (tumor incidence rate(88.9%(8/9) vs. 62.5% (5 / 8); control vs. Synbiotics; p = 0.21)average tumor number(3.2 vs. 2.1; p = 0.38), average tumor greatest diameter 5.8 vs. 5.1 mm; p = 0.51). Using CPC;Apc consumed 1%DSS, Symbiotics administration group showed inhibiting morbidity (50% (8 / 16) vs. 80% (8 / 10); control vs. Synbiotics; p = 0.04) and weight loss, and less tumor incidence than control (18.8 vs. 9.6; control vs. Synbiotics; p = 0.01). On the other hands, administration of probiotics or prebiotics alone had no significant differences of tumorigeneis.
Conclusion:
This data suggest that Synbiotics administration may have influence of inhibiting tumorigenesis in the colitis associated colon cancer.
Citation Format: Yasufumi Saito, Takao Hinoi, Tomohiro Adachi, Manabu Shimomura, Masashi Miguchi, Hiroaki Niitsu, Masatoshi Kochi, Hideki Ohdan, Kazuhiro Sentani, Naohide Oue, Wataru Yasui. Impact of synbiotics administration on tumorigenesis of colon cancer mouse model. [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 2303. doi:10.1158/1538-7445.AM2015-2303