bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-216: Stroma-induced up-regulation of discoidin domain receptor 1 enhances peritoneal metastasis of gastric carcinomas
Authors: Jin Hyejin , Ham In-Hye , Oh Hye Jung , Lee Dakeun , Han Sang-Uk , Brekken Rolf A. , Hur Hoon 
Published: July 2017

Abstract
Introduction: Discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase, is expressed by about 50% of gastric tumor cells in previous our study and is activated by fibrillar collagens, which are major components of tumor stroma. Further, it has been proposed that peritoneal metastasis is associated with high stroma content in gastric carcinomas (GCs). In this study we investigated the contribution of DDR1 activity to peritoneal metastasis of GCs.
Methods: We performed the immunohistochemistry for DDR1 and Masson’s trichrome staining for accumulation of collagen bundles in 202 human GC tissues. The human GC cell lines (MKN-28 and KATO-III) were co-cultured with GCs-associated fibroblasts (CAFs), and the expression of DDR1 and signal transduction pathways were investigated by Western blot. We evaluated CAF-induced tumorigenesis of GCs cell lines and the effects of DDR1 specific inhibitor in 3D co-culture system and peritoneal seeding in xenograft animal models.
Results: High stromal collagen correlated with peritoneal recurrence (P=0.004) and was positively associated with expression of DDR1 in GC tissues (P&lt;0.001). We confirmed that co-culture with CAFs elevated the expression of DDR1 in GC cell lines. CAFs also enhanced GC cell line spheroid formation in vitro in a tumor cell DDR1-dependent manner. Co-implantation of CAFs with GC cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1.
Conclusion: Our findings suggest that CAF-induced elevation of tumor cells DDR1 enhances peritoneal tumorigenesis of GCs and the inhibition of DDR1 signaling is an attractive strategy for the treatment of GC peritoneal metastasis.
Citation Format: Hyejin Jin, In-Hye Ham, Hye Jung Oh, Dakeun Lee, Sang-Uk Han, Rolf A. Brekken, Hoon Hur. Stroma-induced up-regulation of discoidin domain receptor 1 enhances peritoneal metastasis of gastric carcinomas [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 LB-216. doi:10.1158/1538-7445.AM2017-LB-216
Abstract LB-222: A nanoscale optical reporter implant for miRNA biomarkers in vivo
Authors: Heller Daniel A. , Harvey Jackson D. , Jena Prakrit V. , Williams Ryan M. , Galassi Thomas V. , Baker Hanan A. , Roxbury Daniel , Zerze Gül , Mittal Jeetain 
Published: July 2017

Abstract
MicroRNAs and other small oligonucleotides in biofluids are promising biomarkers, but conventional assays require complex processing steps unsuitable for point-of-care assays or implantable/wearable sensors. Single-walled carbon nanotubes are an ideal material for implantable sensors due to emission in the near-infrared spectral region, photostability, and exquisite sensitivity. We engineered a carbon nanotube-based platform capable of real-time optical quantification of hybridization events of microRNA and other oligonucleotides for use in vivo. The sensor mechanism derived from competitive effects between displacement of both oligonucleotide charge groups and water from the nanotube surface, resulting in a solvatochromism-like response. The platform allowed detection via single molecule sensor elements and multiplexing using multiple nanotube species. The sensor monitored toehold-based strand displacement events, reversing the sensor response and regenerating the sensor complex. The sensor functioned in whole urine and serum, and it non-invasively measured DNA and microRNA biomarkers after implantation into live mice.
Citation Format: Daniel A. Heller, Jackson D. Harvey, Prakrit V. Jena, Ryan M. Williams, Thomas V. Galassi, Hanan A. Baker, Daniel Roxbury, Gül Zerze, Jeetain Mittal. A nanoscale optical reporter implant for miRNA biomarkers in vivo [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 LB-222. doi:10.1158/1538-7445.AM2017-LB-222
Abstract LB-227: Combined treatment with radiation and epigenetic regulation improve to targeting cancer stem cells in pancreatic cancer
Authors: Yi Joo Mi , Kwon Hyun-Mi , Kang Eun-Jin , Yang Kwangmo 
Published: July 2017

Abstract
Increasing evidences suggests that various cancer types contain a population of cells that display stem cell properties. These cells are called cancer stem cells (CSCs). They are virtually resistant to radiation, and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. We therefore investigated the combination effect of a DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine (5-aza-dC), and radiation treatment in pancreatic cancer. Pancreatic cancer cell lines were initially tested for radiation sensitivity by ionizing radiation (IR) in vitro and were treated with 5-aza-dC. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation or 5-aza-dC treatment alone. To understand whether combination treatment can target to pancreatic cancer stem cells, we observed that combination treatment can significantly reduce Oct4, Nanog, Sox2, CD133, and CD44 levels which are key factors for self-renewal pathway or cancer stem cell surface markers in pancreatic cancer cells, respectively. Using transcriptome analysis, OCT4 target genes showed differential expression pattern between irradiation or 5-aza-dC treatment alone and combination treatment. In addition, sphere forming assay supports these data in vitro and in vivo, describing that combination effect of IR and 5-aza-dC can reduce significantly sphere forming ability and proportion of side population (putative CSCs) significantly decreased in combination treated cells compared to control or single treatment. Therefore combined treatment of IR and 5-aza-dC is capable of eliminating pancreatic CSCs. Further investigation of this useful approach may lead to the development of a novel intervention for the cancer therapeutic strategy.
Citation Format: Joo Mi Yi, Hyun-Mi Kwon, Eun-Jin Kang, Kwangmo Yang. Combined treatment with radiation and epigenetic regulation improve to targeting cancer stem cells in pancreatic 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 LB-227. doi:10.1158/1538-7445.AM2017-LB-227
Abstract LB-243: Precision medicine: Lung biomarkers
Authors: Harris Curtis C. 
Published: July 2017

Abstract
More than half of all new lung cancer diagnoses are made in patients with locally advanced or metastatic disease, at which point therapeutic options are scarce. It is anticipated, however, that the widespread use of Low-Dose Computed Tomography (LDCT) screening, will lead to a greater proportion of lung cancers being diagnosed at an early, operable, stage. Still, the overall rate of recurrence for surgically treated Stage I lung cancer patients is up to 30% within 5 years of diagnosis. Thus, the identification and clinical application of biomarkers of early stage lung cancer are a pressing medical need. The integrative analysis of "omic," clinical and epidemiological data for single patients is a core principle of precision medicine. Through rigorous bioinformatics and statistical analyses we have identified biomarkers of early-stage lung cancer based on DNA methylation, expression of mRNA and miRNA, inflammatory cytokines, and urinary metabolites. Beyond a more comprehensive understanding of the molecular taxonomy of lung cancer, these biomarkers can have very practical implications in the context of unmet clinical needs of early stage lung cancer patients: First, current guidelines for LDCT screening broadly include individuals based on age and history of heavy smoking. Tumor-derived circulating biomarkers in the blood and urine associated with lung cancer risk could narrow and prioritize individuals for LDCT screening. Second, a high number of nodules are identified by LDCT, of which fewer than 5% are finally diagnosed as lung cancer. Biomarkers may help discriminate malignant nodules from benign or indolent lesions. Third, the expected rise in the numbers of lung cancer patients diagnosed at an early stage will necessitate new treatment options. Circulating, urinary and tissue-based biomarkers that molecularly categorize Stage I patients after tumor resection can help identify high-risk patients who may benefit from adjuvant chemotherapy or innovative immunotherapy regimens.
References
1. Vargas, A.J. and C.C. Harris, Biomarker development in the precision medicine era: lung cancer as a case study. Nat Rev Cancer, 2016. 16(8): p. 525-37.
2. Robles, A.I. and C.C. Harris, Integration of multiple "OMIC" biomarkers: A precision medicine strategy for lung cancer. Lung Cancer, 14 June 2016: p. [Epub ahead of print].
3. Robles, A.I., et al., An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers. J Thorac Oncol, 2015. 10(7): p. 1037-48.
Citation Format: Curtis C. Harris. Precision medicine: Lung biomarkers [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 LB-243. doi:10.1158/1538-7445.AM2017-LB-243
Abstract LB-249: Examination of analytical factors impacting concordance of plasma-tumor testing by next-generation sequencing (NGS)
Authors: Stetson Daniel , Dougherty Brian , Ahmed Ambar , Lubinski Tristan , Markovets Aleksandra , Thress Kenneth , McEwen Robert , Schiavon Gaia , Whitston David , Nuttall Barrett , Barrett J. Carl 
Published: July 2017

Abstract
The increased usage of circulating tumor DNA (ctDNA) sequencing for oncology clinical research demonstrates a critical need for sensitive and specific testing. While we have observed a high degree of concordance between single tumor mutations in tumor and plasma, several recent studies have highlighted a lack of concordance between plasma and tumor panel NGS gene panel testing due to biological and technical factors. To explore further these factors and benchmark ctDNA NGS testing services, a set of matched plasma, tumor, and normal samples from 24 subjects were acquired from three biobanking companies. Replicate 2 ml-plasma samples were tested by four ctDNA sequencing companies, and matching tumor/normal samples were tested by two tumor sequencing companies. Concordance was measured by comparing plasma mutations to tumor mutations as well as comparing mutations among the same plasma tested by the ctDNA companies. While our experience with NGS of matched samples from clinical trials typically identifies ~30% of patients with no detectable mutation and therefore likely not shedding tumor DNA, with the retrospectively collected commercial samples ~60% lacked detectable high confidence mutations, likely due to quality control issues with sample collection. We also found variation in the concordance of ctDNA mutation detection rates among the four vendors, due to significant differences in DNA yield and assay sensitivity. While factors such as tumor heterogeneity and timing of plasma-tumor collection can lower concordance rates, the majority of discordance in our study was due to technical rather than biological variation. Assay analytical variance and the impact of reporting false positive variants are key factors that need to be addressed as plasma-based NGS testing is more widely incorporated into translational and clinical research. Examples illustrating the complexity of the analyses and giving support for confidence in ctDNA testing results will be given.
Citation Format: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Tristan Lubinski, Aleksandra Markovets, Kenneth Thress, Robert McEwen, Gaia Schiavon, David Whitston, Barrett Nuttall, J. Carl Barrett. Examination of analytical factors impacting concordance of plasma-tumor testing by next-generation sequencing (NGS) [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 LB-249. doi:10.1158/1538-7445.AM2017-LB-249
Abstract LB-262: A somatic-mutational process in breast cancer genomes recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers
Authors: Glodzik Dominik , Morganella Sandro , Davies Helen , Nik-Zainal Serena ,   ICGC Breast Cancer Consortium
Published: July 2017

Abstract
Somatic rearrangements are a part of mutational landscape of human cancer genomes. We systematically investigated the distribution of the somatic rearrangements in 560 breast cancer genomes and highlight 33 rearrangement hotspots associated with a signature of Homologous Recombinational repair deficiency, characterized mainly by large (&gt;100kb) tandem duplications.
Remarkably, these tandem duplication hotspots are enriched for breast cancer germline susceptibility loci (OR 4.28) and breast-specific “super-enhancer” regulatory elements (OR 3.54). They likely represent sites of selective susceptibility to double-strand break damage due to high transcriptional activity. However, through incrementally increasing the number of copies of these functionally active loci, they could inadvertently come under some level of selective pressure. Indeed, transcriptomic consequences range from strong individual oncogene effects through to weak but quantifiable multigene expression effects.
We thus present a passenger somatic rearrangement mutational process that has the ability to create secondary driver events. It exerts its influence through coding sequences and non-coding regulatory elements, contributing a continuum of driver consequences, from modest through to strong effects, making this mutational process a particularly deleterious one.
Citation Format: Dominik Glodzik, Sandro Morganella, Helen Davies, Serena Nik-Zainal, ICGC Breast Cancer Consortium. A somatic-mutational process in breast cancer genomes recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers [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 LB-262. doi:10.1158/1538-7445.AM2017-LB-262
Abstract LB-265: 5’ gap-mediated long patch base excision repair
Authors: Woodrick Jordan , Camacho Sharon , Parvathaneni Swetha , Sharma Sudha , Roy Rabindra 
Published: July 2017

Abstract
The base excision repair (BER) pathway is one of the most frequently used DNA repair mechanisms in the cell and modulates many human pathophysiological conditions related to DNA damage. Through live cell and in vitro reconstitution experiments, we have discovered a novel step in a sub-pathway of the conventional long-patch BER that involves formation of a 9 nt gap 5’ to the lesion, which is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 and RPA. The novel step is employed during repair of a variety of DNA lesions, including oxidative and alkylation damage. Moreover, RECQ1 regulates the autoribosylation status of PARP1 and the choice between long-patch and single-nucleotide BER, which regulates cellular toxicity to DNA damage. Taken together, our results propose a revised model of the long-patch BER pathway and characterize a crucial regulation point for pathway choice in BER.
Citation Format: Jordan Woodrick, Sharon Camacho, Swetha Parvathaneni, Sudha Sharma, Rabindra Roy. 5’ gap-mediated long patch base excision repair [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 LB-265. doi:10.1158/1538-7445.AM2017-LB-265
Abstract LB-266: DAXX promotes de novo lipogenesis in triple-negative breast cancer
Authors: Mahmud Iqbal , Garrett Timothy J. , Liao Daiqing 
Published: July 2017

Abstract
Triple-negative breast cancers (TNBCs), defined by the absence of ER and PR expression and the lack of HER2 amplification, have no targeted treatment options, are highly aggressive, and exhibit poor prognosis. Identification of drivers and associated signaling pathways, particularly for TNBCs, is needed to assist the development of targeted therapies, to prolong disease-free survival, and to improve clinical outcome for cancer patients. Using high-throughput microarray-based global transcriptome profiling, we found that transcriptional regulator DAXX depletion strikingly impaired while DAXX overexpression enhanced the expression of genes in the de novo lipogenesis pathways in TNBCs cell line. Consistently, unbiased global metabolomics and lipidomics profiling by Ultra-High performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS) also revealed that DAXX promotes de novo lipogenesis in both TNBC cell line as well as in corresponding xenograft tumors. In analyzing large number of genomic datasets including The Cancer Genome Atlas (TCGA), MolEcular Taxonomy of BReast cancer International Consortium (METABRIC), and The Cancer Cell Line Encyclopedia (CCLE) dataset, we found that DAXX expression is significantly higher in TNBC tumor samples and cell lines, and also DAXX gene expression positively correlates with that of key lipogenesis enzymes. The role of DAXX in cancer metabolism is previously unknown. Our integrated OMICs data analysis thus indicates that DAXX promotes de novo lipogenesis in TNBC. The mechanism through which DAXX regulates lipid metabolism is being investigated in our laboratory. Overall, our study identifies a potentially important pathway driving TNBC progression and suggests potential therapeutic targets for treating this aggressive form of breast cancer that still lacks curative treatment options.
Citation Format: Iqbal Mahmud, Timothy J. Garrett, Daiqing Liao. DAXX promotes de novo lipogenesis in triple-negative breast 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 LB-266. doi:10.1158/1538-7445.AM2017-LB-266
Abstract LB-271: SplashRNA, a sequential classification algorithm for ultra-potent RNAi
Authors: Pelossof Raphael , Fairchild Lauren , Leslie Christina S. , Fellmann Christof 
Published: July 2017

Abstract
We present SplashRNA, a sequential classifier - analogous to face detection algorithms - to predict ultra-potent microRNA-based short hairpin RNAs (shRNAs) for virtually any gene. Trained on existing and novel large-scale datasets, SplashRNA outperforms previous algorithms and reliably predicts the most efficient shRNAs for a given gene. Combined with the optimized miR-E backbone, &gt;90% of high-scoring SplashRNA predictions trigger &gt;85% protein knockdown when expressed from a single genomic integration. SplashRNA can significantly improve the accuracy of loss-of-function genetics studies and facilitates the generation of compact shRNA libraries. The open source SplashRNA platform completes the RNAi toolkit to harness microRNA-based shRNAs for robust single-gene and multiplexed inducible and reversible target inhibition.
Citation Format: Raphael Pelossof, Lauren Fairchild, Christina S. Leslie, Christof Fellmann. SplashRNA, a sequential classification algorithm for ultra-potent RNAi [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 LB-271. doi:10.1158/1538-7445.AM2017-LB-271
Abstract LB-280: The landscape of somatic microsatellite indels across cancer: detection and identification of driver events
Authors: Maruvka Yosef E. , Mouw Kent W. , Karlic Rosa , Parasuraman Rasanna , Kamburov Atanas , Polak Paz , Haradhvala Nicholas J. , Hess Julian M. , Rheinbay Esther , Brody Yehuda , Braunstein Lior Z. , D’Andrea Alan , Lawrence Michael S. , Bass Adam , Bernards Andre , Michor Franziska , Getz Gad 
Published: July 2017

Abstract
Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that are abundant in the human genome and exhibit high rates of mutations in the form of insertions or deletions of the repeated motif (MS indels). Despite their prevalence, the contribution of somatic MS indels to cancer is largely unexplored due to difficulties in detecting them and assessing their significance. Here, we present a comprehensive analysis of MS indels across 20 tumor types. We characterize the overall MS indel landscape and detect genes with candidate driver MS indel events. We present two novel tools: MSMuTect for accurate detection of somatic MS indels and MSMutSig for identifying candidate cancer genes containing events at higher frequency than expected by chance. We observe high variability of the frequency of MS indels across tumors and demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite stable (MSS) tumors from tumors with microsatellite instability (MSI). Applying MSMutSig across 6,788 tumors from 20 different tumor types identified 7 genes with significant MS indel hotspots: ACVR2A, RNF43, DOCK3, MSH3, ESRP1, PRDM2 and JAK1. In the four genes that have been previously implicated in cancer (ACVR2A, RNF43, JAK1 and MSH3), we identified previously unreported MS indels events. Three of the genes with significant loci - DOCK3, PRDM2 and ESRP1- had not been previously listed as cancer genes. MS indels in DOCK3, a negative regulator of the WNT pathway, were mutually exclusive with mutations in CTNNB1. MS indels in ESRP1, an RNA processing gene, correlated with alternative splicing of FGFR2, an event associated with the epithelial-to-mesenchymal transition. Overall, our comprehensive analysis of somatic MS indels across cancer highlights their importance, particularly in
MSI tumors, significantly contributes to the ongoing global efforts to detect cancer genes, and may improve classification of patients into clinically-relevant subgroups.
Citation Format: Yosef E. Maruvka, Kent W. Mouw, Rosa Karlic, Rasanna Parasuraman, Atanas Kamburov, Paz Polak, Nicholas J. Haradhvala, Julian M. Hess, Esther Rheinbay, Yehuda Brody, Lior Z. Braunstein, Alan D’Andrea, Michael S. Lawrence, Adam Bass, Andre Bernards, Franziska Michor, Gad Getz. The landscape of somatic microsatellite indels across cancer: detection and identification of driver events [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 LB-280. doi:10.1158/1538-7445.AM2017-LB-280