bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4502: Molecular impact of in vitro exposure to electronic cigarette vapor in human bronchial epithelium
Authors: Moses Elizabeth , Wang Teresa , Jackson George R. , Corbett Sean , Drizik Eduard , Brooks Daniel , O’Connor George , Perdomo Catalina , Dubinett Steven , Hayden Patrick , Lenburg Marc E. , Spira Avrum 
Published: July 2016

Abstract
Electronic cigarettes (ECIGs) are an emerging alternative tobacco product thought by some to potentially be safer than traditional tobacco cigarettes (TCIGs). Despite the increasing prevalence of ECIG use, few studies have evaluated the potential physiological effects of ECIG exposure. In this study we aimed to determine the global gene expression effects of ECIG exposure on bronchial epithelium in vitro. Human bronchial epithelial cells (HBECs) grown at Air Liquid Interface (ALI) were exposed to TCIG smoke and ECIG vapor derived from tobacco or menthol flavored products with and without nicotine. We identified a number of gene expression alterations that were induced by both ECIG and TCIG exposure as well as a novel set of changes uniquely induced by ECIG exposure. ECIG exposure induced the expression of genes involved in oxidative and xenobiotic stress pathways and increased the production of reactive oxygen species, similar to, but generally lower in magnitude than, the effects of TCIGs. Furthermore, TCIG and ECIG exposure both decreased the expression of genes involved in cilia assembly and movement, suggesting that the integrity of the bronchial epithelium is concordantly impaired by both exposures. We additionally identified a number of ECIG-specific cell cycle and cell division pathway changes. Finally, we observed that ECIG-induced changes were dependent on both flavor and nicotine content. Together, these results indicate that ECIG vapor can induce cellular stress and molecular alterations within airway epithelium that share similarities with the effects of TCIG smoke. Based on these findings, further studies are warranted to determine whether ECIG use will lead to similar deleterious health outcomes as those caused by TCIGs.
Citation Format: Elizabeth Moses, Teresa Wang, George R. Jackson, Sean Corbett, Eduard Drizik, Daniel Brooks, George O’Connor, Catalina Perdomo, Steven Dubinett, Patrick Hayden, Marc E. Lenburg, Avrum Spira. Molecular impact of in vitro exposure to electronic cigarette vapor in human bronchial epithelium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4502.
Abstract 4505: Pan-cancer analysis of fusion gene druggability and neoantigen potential
Authors: Edgren Henrik , Ruusulehto Anja , Ojala Kalle , Laaksonen Maria 
Published: July 2016

Abstract
Fusion genes are a well known type of oncogenic mutation, in which a genomic rearrangement, such as e.g. a translocation, inversion or deletion, joins together parts of two genes, which normally are not located adjacent to each other. In the context of cancer driver mutations, the result of this rearrangement is a novel chimeric gene with oncogenic potential. While fusion genes have been known longest in hematological malignancies, over the last years they have been shown to occur in nearly all types of cancers studied. Notable examples include ETS-family fusions, such as TMPRSS2-ERG, in prostate cancer.
In previous work, we have used our FusionSCOUT fusion gene detection pipeline to analyze over 8000 cancer samples from 28 different TCGA cancer types. In this study, we extend this target discovery to further characterize the genomic alteration contexts in which gene fusions occur, both by examining the copy number states at inferred rearrangement breakpoints, as well as by correlating the numbers of fusion genes identified in tumors with the level of genomic instability in the tumors. We also analyze the frequency at which different druggable protein domains occur in fusion genes, comparing these to the expected random distribution. Finally, we predict, for each tumor, the neoantigen potential of the identified fusion proteins and compare this to the same predictions for simple somatic mutations, in order to characterize the contribution of fusion proteins to neoantigen load.
In summary, we extend our pan-cancer fusion gene identification analysis with a detailed characterization of the genomic alteration contexts at which fusion genes occur. We also report on the drug treatment potential of fusion genes, both in terms of small molecule drugs, as well as highlight the degree to which fusion gene derived chimeric proteins should be taken into account when estimating the neoantigen load of tumors.
Citation Format: Henrik Edgren, Anja Ruusulehto, Kalle Ojala, Maria Laaksonen. Pan-cancer analysis of fusion gene druggability and neoantigen potential. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4505.
Abstract 4513: A prognostic model for pulmonary carcinoid tumors based on large chromosomal alterations
Authors: Leventakos Konstantinos , Mansfield Aaron S. , Murphy Stephen J. , Johnson Sarah H. , Kerr Sarah E. , Aubry Marie Christine , Vasmatzis George , Molina Julian R. 
Published: July 2016

Abstract
PURPOSE: Previous mutational analyses have failed to identify a predictive or prognostic marker for pulmonary carcinoid tumors (PCT). The heterogeneity of PCTs coupled with a lack of detailed information about the tumor biology, impedes patient stratification into groups based on tumor phenotypes or treatment response. We sought to use high-throughput next-generation sequencing to improve prognostication.
METHODS: We stratified 37 patients with resected PCTs as low risk (n = 17) and high risk (n = 20) based on a 5 year long follow up for recurrence. Patients with no recurrence within 5 years from initial treatment were deemed low risk. Macrodissection was followed by genomic DNA isolation and next-generation sequencing was performed using an Illumina Mate Pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction.
RESULTS:
Carcinoids commonly harbor rearrangements (median 3.5, range 1-167). Large chromosomal gains or losses were found in 24 of the cases (64.8%). We developed a prognostic score that included the total amount of genetic alterations (deletions and translocations). ROC analysis revealed an AUC of 0.76. High risk patients had a mean score of 20 and low risk patients had a mean score of 5.45 (p value = 0.03, Welch Two Sample t-test). Further analysis of the specific genetic alterations harbored by high and low risk PCTs and correlation with the pathologic and immunohistochemical information is currently underway.
CONCLUSION:
Large chromosomal rearrangements and aneuploidy portend a poor prognosis for patients with PCTs. Mate Pair sequencing of PCTs provides valuable prognostic information for this highly heterogeneous group of cancers.
Citation Format: Konstantinos Leventakos, Aaron S. Mansfield, Stephen J. Murphy, Sarah H. Johnson, Sarah E. Kerr, Marie Christine Aubry, George Vasmatzis, Julian R. Molina. A prognostic model for pulmonary carcinoid tumors based on large chromosomal alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4513.
Abstract 4524: A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma
Authors: Fromond Claudia , Espanel Xavier , Estevez Severine , Adarbes Vanessa , Bocart Stephanie , Loillier Bruno , Soude Anne , Urban Nathalie , Bell Frederic , Masson Philippe , Boubia Benaïssa , Broqua Pierre , Montalbetti Christian 
Published: July 2016

Abstract
Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. Thus, NSD2 inhibitors are potential therapeutics for this devastating cancer
Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay was based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox or metal contamination activity were excluded. For confirmation purposes, an orthogonal counter-screen based on 3H SAM incorporation was performed. The IC50 obtained for one of the best compounds across the AlphaLisa and 3H SAM incorporation are very similar, showing values of 0.15 μM and 0.29 μM respectively for compound 1.
Binding affinities measured by MST and SPR for compound 1 were consistent with the IC50 observed in the biochemical assays KD = 0.19 μM for MST and 1.7 μM by SPR. This compound was also shown to be a good binder by NMR (STD), and further experiments are planned to elucidate the selectivity and MOA of this series.
To our knowledge, no NSD2 inhibitor have been identified to date despite several screening efforts performed by other groups. We believe that our hits are promising starting points to generate potent and selective NSD2 inhibitors.
Citation Format: Claudia Fromond, Xavier Espanel, Severine Estevez, Vanessa Adarbes, Stephanie Bocart, Bruno Loillier, Anne Soude, Nathalie Urban, Frederic Bell, Philippe Masson, Benaïssa Boubia, Pierre Broqua, Christian Montalbetti. A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4524.
Abstract 4525: Distinctive chromatin organization of p53 binding sites in normal and cancer cells
Authors: Cui Feng , LoVerso Peter , Bao Feifei 
Published: July 2016

Abstract
The tumor suppressor p53 is arguably one of best known proteins in humans, which induces or represses hundreds of genes to prevent tumor development. Now, it becomes clear where p53 binds across the human genome and how it regulates gene expression. Recent studies have established that p53 can access its target sites on the nucleosomal DNA and the rotational positioning of a nucleosome is critical to determine the accessibility of p53 sites. We have found that p53 response elements (REs) associate with cell cycle arrest such as p21 REs are likely to be exposed on the nuclesomal surface. However, it remains unclear if other chromatin elements such as histone modifications and DNA methylation affect p53 in vivo binding and if such chromatin organization differs in normal cells versus cancer cells.
We analyzed the pre-existing chromatin landscape of thousands of p53 binding sites identified so far in normal (GM12878) and cancer (K562) cells. The p53 sites derived from the normal cells are often found in the vicinity of the transcription start sites (TSSs) of nearby genes, characterized with relative low nucleosome occupancy, high levels of transcriptionally active histone marks such as H3K4me3 and low levels of DNA methylation. By contrast, the p53 sites found in the cancer cells are located remotely from TSSs, with relatively high nucleosome occupancy, low levels of H3K4me3 and DNA methylation. The shift in p53 genomic binding patterns in the normal and cancer cells reflects the cancer-associated epigenetic dysregulation. Overall, in contrast to most of DNA-binding transcriptional factors, p53 binding sites occur in nucleosome-enriched regions. These findings indicate that p53 belong to a set of transcription factors including the pluripotency factors Oct4, Sox2 and Klf4 that can directly interact with nucleosomes in the context of chromatin.
Citation Format: Feng Cui, Peter LoVerso, Feifei Bao. Distinctive chromatin organization of p53 binding sites in normal and cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4525.
Abstract 4532: Deregulation of retinoic acid (RA) epigenetic control of sphingolipid signaling
Authors: Rossetti Stefano , Gagliostro Vincenzo , Sacchi Nicoletta 
Published: July 2016

Abstract
All-trans retinoic acid (RA), the bioactive derivative of vitamin A, can paradoxically exert both anti-cancer and cancer-promoting actions. According to our studies, RA promotes breast cancer cell growth and invasion whenever it fails to exert its genome-wide epigenetic control of transcription via the RA receptor alpha (RARA). Factors that negatively affect RARA genomic function lead to genome-wide deregulation of the transcriptome epigenetically regulated by RA, including RARA-target genes controlling critical sphingolipid functions. We show here that functional inhibition of genomic RARA concomitantly leads to epigenetic repression of neutral sphingomyelinase 2 (nSMase2/SMDP3), a critical enzyme involved in the synthesis of pro-apoptotic ceramide, and upregulation of S1PR1, a key receptor of sphingosine-1-phosphate (S1P), a sphingolipid with pro-proliferative and pro-invasive activity. Selective activation of S1PR1 recapitulates RA pro-proliferative/pro-invasive action, while selective inhibition of S1PR1 counteracts it. Apparently, activation of the S1P-S1PR1 axis, combined with lack of RARA-mediated epigenetic control of SMPD3-ceramide axis, contributes to determine RA tumorigenic action.
This study was supported by the NCI R01 CA127614 grant (NS).
Citation Format: Stefano Rossetti, Vincenzo Gagliostro, Nicoletta Sacchi. Deregulation of retinoic acid (RA) epigenetic control of sphingolipid signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4532.
Abstract 4533: Disruption of intrachromosomal interactions by deficient cohesin initiate epithelial-mesenchymal transition and stemness in cancer
Authors: Yun Jiyeon 
Published: July 2016

Abstract
PURPOSE
Although EMT-MET process is a crucial reversible event in development of human tumorigenesis controlled by complex networks, very little is known about how EMT-MET occurs reversibly and timely in cancer. Recently, different levels of Rad21 protein, a subunit of cohesin high-order-chromatin-architectural complex, between mesenchymal and epithelial cancers have been described.
METHODS
To elucidate how Rad21 determines EMT states, we silenced Rad21 in epithelial cancers using lentiviral shRNAs. We performed microarray to compare transcriptional changes by Rad21-KD. Additionally, we measured cell cycles and mitotic chromosome segregations to rule out the role of Rad21 as a sister chromatid segregation molecule. We observed cell morphology through confocal microscopy and checked high-order-chromatin structures using Chromosome-Conformation-Capture (3C) and Chromatin immunoprecipitation (ChIP) assay.
RESULTS
We identified high-order-chromatin structures mediated by Rad21 plays critical regulatory roles in transcription of EMT related genes for the first time. Rad21-KD in epithelial cancers caused reduction of Rad21 enrichment on TGFB1 and ITGA5 genes, leading to disruption of the-gene-specific-chromatin-looping structures. This dramatically recruited PolII and AcH3, active transcription marks, causing rapid induction of the gene transcriptions. Indeed, induced EMT-related genes directly led to morphological changes with EMT traits. We ultimately found that cancer stem cell-like cells showed same results with mesenchymal cancer and Rad21-KD epithelial cells.
These findings indicate that the initiation of EMT in cancer might crucially require changes in high-order-chromatin structures of EMT-related genes mediated by cohesin, contributing to rapid and precise reversible changes in EMT or MET state to adapt to phenotypes of human cancer development.
Citation Format: Jiyeon Yun. Disruption of intrachromosomal interactions by deficient cohesin initiate epithelial-mesenchymal transition and stemness in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4533.
Abstract 4540: Use of SIAH E3 ubiquitin ligase as a biomarker in pancreatic adenocarcinoma
Authors: Svyatova Elizaevta 
Published: July 2016

Abstract
The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS pathway activation is commonly detected in pancreatic cancer. These activations confer drug resistance, drive aggressive tumor growth and metastasis, and ultimately contribute to poor clinical outcome. Currently, there is no curative treatments for pancreatic cancers. Thus, early detection, biomarker discovery, and identifying novel means of countervailing hyperactive K-RAS signals are urgently needed.
Seven-In-Absentia Homolog (SIAH), E3 ubiquitin ligase, is an essential downstream component of the RAS signal transduction pathway. SIAH is a member of a highly evolutionarily conserved family of RING finger E3 ubiquitin ligases.
Our previous immunohistochemistry (IHC) studies have shown SIAH is a tumor-specific biomarker and SIAH expression is progressively increased as pancreatic tumor progresses from pancreatic intraepithelial neoplasia (PanIN) to pancreatic adenocarcinoma (PDCA) at late stages. In this study, we expand our observations by comparing the expression patterns of SIAH and several newly identified SIAH-interacting proteins using Mayo clinic pancreatic cancer SPORE tissue microarrays (TMA) in a hope of identifying new vulnerability and novel prognostic biomarkers in pancreatic cancer. We hypothesized that SIAH and SIAH-interacting proteins may serve as useful biomarkers and will help to assess effectiveness of anticancer treatment, disease progress, predict clinical outcome and patient survival in the clinical settings. Moreover, we are evaluating SIAH's role in the regulation of the SIAH-interacting proteins and validating the potential mechanisms of these dynamic interactions identified in vitro using pancreatic cancer patients TMA. Ultimately, we aim to explore the new cancer vulnerability, develop new therapeutic strategies, and validate novel prognostic biomarkers for pancreatic cancer patients.
This study is performed in a double blind control settings and we are currently awaiting the disclosure of the clinical information from the pathologist.
Citation Format: Elizaevta Svyatova. Use of SIAH E3 ubiquitin ligase as a biomarker in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4540.
Abstract 4543: Substrate trapping proteomics reveals novel mechanism for regulation of mTORC1 signaling by βTrCP-FNIP1/2-FLCN axis
Authors: Kim Tai Young , Chang Jee Yun , Ku Jin Mo , Hong Se Hyang , Kim ji Hye , Choi Hyeong Sim , Lee Kangwook , Kim Myeong-Sun , Woo Sang Mi , Major Michael B. , Ko Seong-Gyu 
Published: July 2016

Abstract
Defining the full complement of substrates for each ubiquitin ligase remains an important challenge. Improvements in mass spectrometry instrumentation and computation and in protein biochemistry methods have resulted in several new methods for ubiquitin ligase substrate identification. Here we used the parallel adapter capture (PAC) proteomics approach to study βTrCP2, a substrate adaptor for the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. The processivity of the ubiquitylation reaction necessitates transient physical interactions between βTrCP2 and its substrates, thus making biochemical purification of FBXW11-bound substrates difficult. Using the PAC-based approach, we inhibited the proteasome to “trap” ubiquitylated substrates on the SCF (βTrCP2) E3 complex. Comparative mass spectrometry analysis of immunopurified βTrCP2 protein complexes before and after proteasome inhibition revealed 21 known and 23 putatively novel substrates. Interestingly, many novel substrates for βTrCP2, including TBC1D4, HCFC1, DENND4C, FNIP1, and FLCN are related to cell metabolism. TBC1D4 encodes a GTPase activating protein for the small GTPase Rab that controls insulin-dependent trafficking of the GLUT4 glucose transporter in adipocytes. DENND4C acts as a guanine nucleotide exchange factor for Rab10 and its activity is required for insulin-stimulated GLUT4 translocation to plasma membrane in adipocytes. HCFC1 is a member of the host cell factor family, affecting gluconeogenesis by modulating PGC-1α stability. These suggest βTrCP2 might play important roles in glucose homeostasis by regulating stability of several different target proteins. Here, in focused study, we found that βTrCP1/2 bound, polyubiquitylated, and destabilized FNIP1, FLCN interacting protein 1. We further demonstrated that FNIP1 degradation was promoted by AMPK activation after glucose depletion and expression of a degradation-resistant FNIP1 mutant results in sustained activation of mTORC1 signaling. Hence, our findings reveal that βTrCP1/2 is involved in nutrient sensing through the AMPK-FLCN-FNIP1 and mTORC1 signaling pathways.
Citation Format: Tai Young Kim, Jee Yun Chang, Jin Mo Ku, Se Hyang Hong, ji Hye Kim, Hyeong Sim Choi, Kangwook Lee, Myeong-Sun Kim, Sang Mi Woo, Michael B. Major, Seong-Gyu Ko. Substrate trapping proteomics reveals novel mechanism for regulation of mTORC1 signaling by βTrCP-FNIP1/2-FLCN axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4543.