bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 546: Supporting neoantigen identification for personalized cancer vaccines trough analytical validation of an augmented content enhanced (ACE) transcriptome
Authors: Yen Jennifer L. , Boyle Sean , Alla Ravi , Harris Jason , Lefterova Martina , Chen Richard 
Published: July 2017

Abstract
The identification of neoantigens has become a critical step in the development of neoantigen-based personalized cancer vaccines and other immunotherapy applications. Since neoantigens can be generated from tumor specific mutations in any expressed gene, the first step in neoantigen identification typically involves deep sequencing of the tumor exome and transcriptome combined with exome sequencing of the matched normal. As personalized vaccines enter clinical trials, there is a growing need for strong analytical validation of these platforms.
To address this, we have developed the ACE Exome (~200X) and Transcriptome platforms for neoantigen identification which harness an augmented exome approach specifically designed to increase sensitivity for neoantigens in low complexity, difficult to sequence regions. To enable this platform for neoantigen based personalized cancer vaccines, we have performed a validation of both our ACE Exome (tumor and normal) and ACE transcriptome platforms for detecting DNA-based SNVs and Indels, as well as for RNA based small variant and fusion calls, variant types that are especially important for neoantigen identification. In this abstract, we describe the ACE Transcriptome validation.
To validate the ACE Transcriptome, we assessed analytical sensitivity (AS) and positive predictive accuracy (PPA). AS was calculated from a reference set of 894 SNVs and 19 indels across 11 tumor cancer cell lines with matched normals. The reference set was constructed based on previously observed variants in CCLE, COSMIC or had been validated by Sanger sequencing. PPA and limit of detection (LOD) were calculated in a series of tumor-normal dilutions representing allele frequencies ranging from 10% to 100%. For fusions, we further selected an additional 10 cell lines to test the detection of 16 previously characterized fusion events including several clinically actionable fusions (ALK and BCR-ABL1).
We report an analytical sensitivity for SNVs of &gt;99%, and a PPA of &gt;96% for small variants with &gt;=10% minor allele frequency (MAF). For fusion events, we report an analytical sensitivity of &gt;99%, with the detection of all 16 fusion events supported by at least 5 reads.
We demonstrate that our ACE Transcriptome assay and RNA cancer pipeline is a highly sensitive and robust platform for detecting small variants and fusions in the RNA.
Citation Format: Jennifer L. Yen, Sean Boyle, Ravi Alla, Jason Harris, Martina Lefterova, Richard Chen. Supporting neoantigen identification for personalized cancer vaccines trough analytical validation of an augmented content enhanced (ACE) transcriptome [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 546. doi:10.1158/1538-7445.AM2017-546
Abstract 5461: Nuclear localization of the caspase 3 cleaved form of p73 in anoikis
Authors: Alsafadi Samar , Tourpin Sophie , Salome-Desnoulez Sophie , Bessoltane Nadia , Andre Fabrice , Ahomadegbe Jean Charles 
Published: July 2017

Abstract
The transcription factor p73 is a homologue of p53 that can be expressed as pro- or anti-apoptotic isoforms. Unlike p53, p73 is rarely mutated or lost in cancers and it is found to replace defective p53 inducing apoptosis. Here, we investigated the p73 involvement in anoikis, a type of apoptosis caused by inadequate cell-matrix interactions. Breast cancer cell lines with different p53 status were treated with doxorubicin or docetaxel and cells detached from the extracellular matrix were analyzed. We demonstrate for the first time that doxorubicin-induced cell detachment is associated with p73 cleavage and caspase activation, independently of the p53 status. However, we did not detect p73 cleavage or caspase activation in detached cells under docetaxel treatment. Overexpressing the apoptotic isoform of p73 led to cell detachment associated with p73 cleavage and caspase activation. Interestingly, p73 cleaved forms localize to the nucleus during the late phase of cell death indicating an increase in the transcriptional activity. Our study suggests that the cleavage of p73 on specific sites may release its pro-apoptotic function and contribute to cell death.
Note: This abstract was not presented at the meeting.
Citation Format: Samar Alsafadi, Sophie Tourpin, Sophie Salome-Desnoulez, Nadia Bessoltane, Fabrice Andre, Jean Charles Ahomadegbe. Nuclear localization of the caspase 3 cleaved form of p73 in anoikis [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 5461. doi:10.1158/1538-7445.AM2017-5461
Abstract 5462: GTP cyclohydrolase in brain tumor stem cells is implicated in glioblastoma growth
Authors: Tran Anh N. , Walker Kiera , Harisson David , Chen Wei , Mobley James , Hocevar Lauren , Hackney James R. , Sedaka Randee S. , Pollock Jennifer S. , Cooper Sara J. , Gillespie George Y. , Hjelmeland Anita B. 
Published: July 2017

Abstract
Glioblastomas (GBMs) are the most common primary brain tumors in adults and one of the most aggressive cancers with high rates of recurrence and therapeutic resistance. In GBMs, subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have been characterized by their unique capacity to promote tumor maintenance, therapeutic resistance, and angiogenesis. BTIC maintenance is known to be regulated by reactive oxygen and nitrogen species. GTP cyclohydrolase, or GCH1, is a critical molecule regulating reactive species levels. We found that expression of GCH1 RNA and protein were upregulated in BTICs in comparison to non-BTICs. Overexpression of GCH1 in glioma cells increased cell growth in vitro and increased tumor formation and decreased survival in an intracranial GBM mouse model. In contrast, GCH1 depletion with short hairpin RNA in GBM cells led to growth inhibition in vitro as well as increased survival in animal orthotopic models. Furthermore, genetic modulation of GCH1 led to altered ROS levels in GBM xenolines. In silico analyses demonstrate that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence and worse survival. Together, our data suggest that upregulation of GCH1 in BTICs promotes tumor maintenance and is a key regulator of reactive oxygen species in glioblastoma.
Citation Format: Anh N. Tran, Kiera Walker, David Harisson, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee S. Sedaka, Jennifer S. Pollock, Sara J. Cooper, George Y. Gillespie, Anita B. Hjelmeland. GTP cyclohydrolase in brain tumor stem cells is implicated in glioblastoma growth [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 5462. doi:10.1158/1538-7445.AM2017-5462
Abstract 5472: Yeast Bax Inhibitor (BXI1) is involved in redox and calcium homeostasis of the ER in S. cerevisiae
Authors: Eagan David , Alisch Joseph , McDonough Liam , Benko Savannah , Jacob Walter , Ritzer Lukas , Mullin James , O'Reilly John , Austriaco Nicanor 
Published: July 2017

Abstract
In mammals, the Bax inhibitor (TMBIM) family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress. The canonical gene of the family called BI-1 has been linked to several human cancers. The crystal structure of a prokaryotic member of the family, BsYetJ, has revealed that the Bax inhibitor proteins are pH sensitive calcium leaks. Our published studies have shown that the yeast Bax Inhibitor, Bxi1p, is localized to the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by endoplasmic reticulum (ER) stress. We now show that cells lacking BXI1 have an altered redox microenvironment in the ER: The ER of Δbxi1 cells exposed to dithiothreitol (DTT) and tunicamycin, two drugs known to induce the unfolded protein response (UPR), become more reduced than their wildtype counterparts. Moreover, we also report that cells lacking BXI1 accumulate more calcium in the ER than wildtype cells. Together, our data suggests that Bxi1p is involved in regulating the ER microenvironment. Other members of the TMBIM family may have the same role in normal and cancer cells. [Our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.]
Note: This abstract was not presented at the meeting.
Citation Format: David Eagan, Joseph Alisch, Liam McDonough, Savannah Benko, Walter Jacob, Lukas Ritzer, James Mullin, John O'Reilly, Nicanor Austriaco. Yeast Bax Inhibitor (BXI1) is involved in redox and calcium homeostasis of the ER in S. cerevisiae [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 5472. doi:10.1158/1538-7445.AM2017-5472
Abstract 5476: CIP2A can be a therapeutic target of rapamycin in radioresistant head and neck cancer with P53 mutation
Authors: Kim Song Hee , Lee Won hyeok , Lee Myung Jin , Chang Hyo Won , Kim Ji Won , Kim Mi Ra , Park Jung Je , Han Myung Woul , Kim Sang Yoon 
Published: July 2017

Abstract
The presence of p53 mutation was associated with poor survival in various tumors. The involvement of p53 in apoptosis and cell-cycle control makes it a plausible biomarker of prognosis . Classifying TP53 mutations in HNSCC described disruptive TP53 mutation in either the L2 or L3 loop of the DNA binding domain, resulting in polarity change within the protein, or stop cordon. Disruptive TP53 mutation in HNSCC tumors predicts for locoregional recurrence, due to increased radioresistance via the inhibition of senescence. Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we found that overexpression CIP2A (cancerous inhibitor of protein phosphatase 2A) positively correlated with presence of p53 mutation in head and neck cancer and mediates radioresistance through suppression of radiation induced senescence. And we demonstrated that rapamycin could induce senescence via CIP2A downregulation and increase radiosensitivity in p53 disruptive mutation cell line. This is the first investigation to analyze the role of CI2A in resistance to the radiotherapy of head and neck cancer. As a consequence, a greater understanding of radioresistance mechanisms through our results in head and neck cancer with p53 mutation will enable the rational design of combination regimens and sequential treatment algorithms to improve clinical outcomes and points to the usefulness of CIP2A as a biomarker to predict clinical response to rapamycin in head and neck cancer.
Citation Format: Song Hee Kim, Won hyeok Lee, Myung Jin Lee, Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Jung Je Park, Myung Woul Han, Sang Yoon Kim. CIP2A can be a therapeutic target of rapamycin in radioresistant head and neck cancer with P53 mutation [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 5476. doi:10.1158/1538-7445.AM2017-5476
Abstract 5478: The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in cancer cells
Authors: Takahashi Nobuaki , Chen Hsing-Yu , Harris Isaac , Stover Daniel , Bronson Roderick , Deraedt Thomas , Cichowski Karen , Welm Alana , Mills Gordon , Brugge Joan 
Published: July 2017

Abstract
Generation of reactive oxygen species (ROS), a natural byproduct of oxygen metabolism, occurs in all aerobic organisms at a controlled rate. Cancer cells are subjected to numerous cellular insults, including dysregulated oncogenes and dissociation from their natural extracellular matrix (ECM) niches, leading to the generation of high levels of ROS. Although cancer cells possess enhanced canonical antioxidant programs that neutralize ROS, they nevertheless exhibit prominent ROS levels in response to these insults, suggesting the existence of additional programs that allow cancer cells to tolerate elevated ROS.
In this study, we provide evidence for an unconventional mechanism for redox adaptation involving the ROS-activated, Ca2+-permeable TRPA1 channel, which normally functions as an irritant receptor in sensory neurons but is highly upregulated in breast, lung, malignant neural sheath, and other tumors. We found that TRPA1 overexpression enhances survival and proliferation of MCF-10A cells under conditions of matrix-detachment and this effect was dependent on TRPA1 activation by ROS generated as loss of matrix anchorage. In MCF-10A acini, TRPA1 expression induced Ca2+ entry in ECM-deprived cells in the luminal space and promoted their survival and proliferation. Conversely, TRPA1 knockdown inhibited Ca2+ responses to ROS generated through ECM detachment and induced clearance of cells from the luminal space in breast cancer spheroids. TRPA1 was also activated by ROS-inducing chemotherapies and drove chemoresistance in breast, lung and malignant peripheral nerve sheath tumor cells, and its downregulation suppressed breast xenograft tumor growth and enhanced chemosensitivity. TRPA1 mediated these effects independent of antioxidant responses, but through activation of cellular survival and anti-apoptotic programs involving the RAS-ERK/AKT/mTOR pathways.
Together, our findings describe an unexpected mechanism whereby cancer cells co-opt the neuronal TRPA1 channel in order to adapt to oxidative environments. This TRPA1-induced response is distinct from canonical redox adaptation mechanisms that rely on antioxidant program. As TRPA1 inhibitors are currently in clinical trials for pain and respiratory therapies, these studies raise the possibility of using these inhibitors as therapeutic chemosensitizers in TRPA1-enriched tumors.
Citation Format: Nobuaki Takahashi, Hsing-Yu Chen, Isaac Harris, Daniel Stover, Roderick Bronson, Thomas Deraedt, Karen Cichowski, Alana Welm, Gordon Mills, Joan Brugge. The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in 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 5478. doi:10.1158/1538-7445.AM2017-5478
Abstract 5482: Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival
Authors: Peng Dunfa , Hu Tianling , Zhu Shoumin , El-Rifai Wael 
Published: July 2017

Abstract
Background: Esophageal adenocarcinoma (EAC) is the major type of malignant cancer of esophagus in the USA. The incidence rate has increased 4-10% per year among men since 1976 in the USA, more rapidly than for any other type of cancer. EAC is known to originate from premalignant Barrett’s esophagus (BE) through BE-dysplasia-EAC process. Normal cells have intact anti-oxidative mechanisms, among which NFE2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular response to various stimuli. Cancer cells have high levels of reactive oxygen species and oxidative stress due to activation of oncogenes, inflammatory microenvironment, and dysfunction of anti-oxidative mechanisms. However, the role of NRF2 in Barrett’s related esophageal carcinogenesis is barely known.
Methods and Results: We have found that Nrf2 protein expression is significantly upregulated in EAC cell lines as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines. We detected a similar overexpression of NRF2 in primary EAC tissue samples. Using luciferase reporter assay, we demonstrated significant induction of NRF2 transcription activity in EAC cells in response to exposure to acidic bile acids, as compared to controls (P&lt;.01). We detected significant increase in the expression of Heme Oxygenase 1 (HO-1) and Glutathione Reductase (GR) in these cells (P&lt;.01). Knockdown of NRF2 by siRNA or crisp/cas9, significantly increased cellular ROS level, oxidative DNA damage (8-oxoguanine), and double strand DNA breaks (p-H2AX). Knockdown of NRF2 sensitized cells to apoptosis following exposure to bile acids and CDDP. Concordant with these results, the use of NRF2 inhibitor, Brusatol, sensitized EAC cells to CDDP treatment with a significant increase in cell death, as compared to single agent treatment (P&lt;.01). Conclusion: These results indicate that constitutive overexpression of NRF2 in EAC cells protects cancer cells from high level of ROS and promotes cancer cell survival. Inhibition of NRF2 through its specific inhibitor may have therapeutic value in EAC.
Citation Format: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai. Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival [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 5482. doi:10.1158/1538-7445.AM2017-5482
Abstract 5499: The reprogramming of the steroid receptor binding landscape at active enhancers is associated with a fast DNA residence time through a mechanism termed dynamic assisted loading in breast cancer cells
Authors: Swinstead Erin , Miranda Tina , Paakinaho Ville , Beak Songjoon , Hager Gordon 
Published: July 2017

Abstract
The transcription factor (TF), FoxA1 has been described as a pioneer factor, implicated in steroid receptor (SR) binding patterns. Classically it has been proposed that the pioneer factor model is a slow and static binding event. However, it has recently been described that the estrogen and glucocorticoid receptors (ER and GR), can regulate the binding patterns of each other in a mouse mammary cell line defined as dynamic assisted loading. Further, this phenomenon has been extending demonstrating that both ER and GR can recruit FoxA1 to specific binding sites associated with an increase in chromatin accessibility and fast DNA residence times. This was also associated with the absence of a DNaseI footprint for the initiating and secondary factor supporting the assisted loading model. To further investigate the molecular mechanism behind the dynamic assisted loading model we have characterized the binding and transcriptional landscape of ER and GR in a number of breast cancer cell line models. Genome wide analysis of ChIP and DNaseI hypersensitivity assays upon single and dual activation show that both SRs can recruit each other to a specific subset of binding sites associated with an increase in chromatin accessibility. Therefore, depending on the chromatin landscape, one factor functions as the initiating factor and the other the secondary factor. Further, RNA polymerase II (RNAP II), p300, and H3K27ac binding patterns are associated with the newly programed ER or GR binding sites. Together this suggests chromatin reorganization upon dual activation of either ER or GR (the initiating factors) and recruitment of the secondary factor (ER or GR) through an assisted loading mechanism. Further, we have demonstrated an association of the transcriptional machinery at these newly acquired binding sites at active enhancers. These results propose that many TFs in a given cell have the potential to affect the binding landscape of other TFs, depending on the chromatin context. In addition, this study has shifted our classical understanding of pioneer factors in breast cancer, demonstrating that not only can SRs alter the response of FoxA1 but also each other though highly dynamic and fast DNA interactions associated with active enhancers and transcription.
Citation Format: Erin Swinstead, Tina Miranda, Ville Paakinaho, Songjoon Beak, Gordon Hager. The reprogramming of the steroid receptor binding landscape at active enhancers is associated with a fast DNA residence time through a mechanism termed dynamic assisted loading in breast 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 5499. doi:10.1158/1538-7445.AM2017-5499
Abstract 551: Assessment of computational approaches for quantification of immune cell infiltration from gene expression profiles of complex biological samples
Authors: Hodkinson Brendan P. , Schaffer Michael E. , Gormley Michael 
Published: July 2017

Abstract
Anticancer immunotherapies target immune cells to block immune suppression and/or promote immune activation in order to eliminate cancer cells. Ipilumumab and Nivolumab, targeting CTLA4 and PD1 respectively, have demonstrated dramatic responses in melanoma and lung cancer (Hodi et al. 2010; Risvi et al. 2015). However, poor response rates in other types of cancer underscore the need to better understand immunomodulatory mechanisms (Topalian et al. 2012). Examination of immune cell specific signals, in either the tumor microenvironment or the periphery, has proven to be a useful tool in developing prognostic biomarkers (Chi et al. 2014; Gentles et al. 2015), inferring mechanisms of action (Krejcik et al. 2016), and discerning immune-based predictors of drug response (Tumeh et al. 2014). In this study we evaluate various gene expression-based computational approaches for inferring immune cell identity in complex cellular mixtures in order to rank their relative utility for illuminating the details of the tumor microenvironment and potentially revealing new biomarkers for prognosis and response prediction.
Immune cell identity has been inferred by previous researchers using a variety of mathematical approaches, including least squares (Abbas et al. 2009), quadratic programming (Gong et al. 2011; Zhong et al. 2013), maximum likelihood (Qiao et al. 2012; Liebner et al. 2013), machine learning (Newman et al. 2015), and enrichment type approaches (Angelova et al. 2015). We used publically-available gene expression microarray data from blood, normal tissue, and tumor samples to assess the effectiveness of these methods in sample types relevant to oncology research. The results from comparisons of these different methods demonstrate that certain approaches are significantly more robust to noise, and are therefore more suitable for complex cellular mixtures such as tumor samples. The discerning use of methods to infer immune cell type proportions from gene expression profiles may lead to improved prognosis, predictive biomarkers for immunotherapy to assist in patient stratification, and new immunoncology targets by indicating immunosuppressive mechanisms.
Citation Format: Brendan P. Hodkinson, Michael E. Schaffer, Michael Gormley. Assessment of computational approaches for quantification of immune cell infiltration from gene expression profiles of complex biological samples [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 551. doi:10.1158/1538-7445.AM2017-551