bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-002: Optimizing immunogenicity prediction of neoepitopes
Authors: Kosaloglu-Yalcin Zeynep , Lanka Manasa , Sidney John , Vaughan Kerrie , Greenbaum Jason , Sette Alessandro , Peters Bjoern 
Published: July 2017

Abstract
Epitopes that arise from a somatic mutation, so called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. It has however become evident that the vast majority of these neoepitope candidates do not induce a T cell response when tested in vivo or in vitro, i.e. they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. Several studies have used different combinations of immunoinformatic tools such as MHC binding predictions to prioritize the initial set of neoepitopes candidates. The tools to use and thresholds to apply for this prioritization has so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. To establish the appropriate tools and thresholds in the cancer setting, we here curated a set of immunogenic neoepitopes from the published literature and performed detailed analyses to detect what features discriminate immunogenic neoepitopes from a background set of mutated peptides. We experimentally measured the HLA binding affinity of all curated immunogenic neoepitopes. In doing so, we aimed to identify the optimal affinity threshold to effectively identify immunogenic neoepitopes. As a next step, we sought to assess the added value of different immunoinformatics tools, including various HLA binding prediction algorithms, processing prediction, stability prediction, and immunogenicity prediction, to most effectively detect immunogenic neoepitopes. The obtained results are now going to be used to facilitate the development of more accurate prediction algorithms.
Citation Format: Zeynep Kosaloglu-Yalcin, Manasa Lanka, John Sidney, Kerrie Vaughan, Jason Greenbaum, Alessandro Sette, Bjoern Peters. Optimizing immunogenicity prediction of neoepitopes [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-002. doi:10.1158/1538-7445.AM2017-LB-002
Abstract LB-003: Racial differences of intron retention and DNA methylation in breast cancer
Authors: Kim Dongwook , Shivakumar Manu , Lee Youngji , Olopade Olufunmilayo , Kim Dokyoon , Lee Younghee 
Published: July 2017

Abstract
Regulation of gene expression by DNA methylation in gene promoter regions is well-studied; however, the effects of methylation in the gene body (i.e., exons and introns) on gene expression are comparatively understudied. Recently, hyper-methylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hyper-methylated sites. In this study, we examined whether or not the level of methylation of an intron is correlated with how frequently that intron is retained during splicing using DNA methylation and RNA sequencing data from breast cancer tissue samples in The Cancer Genome Atlas (TCGA). We found that hypo-methylation of introns is correlated with higher levels of intron expression in mRNA and that most novel cancer-specific mRNA isoforms are due to intron retention. The methylation level of an intron is inversely correlated with its retention in mRNA transcripts from the gene in which it is located. Furthermore, we observed significant racial differences in the methylation level of retained introns: In samples from African-American donors, retained introns were not only less methylated compared to Caucasian donors, but also were more highly expressed. This underscores the need for Understanding racial epigenetic differences and their correlation with breast cancer is an important step toward achieving personalized cancer care.
Citation Format: Dongwook Kim, Manu Shivakumar, Youngji Lee, Olufunmilayo Olopade, Dokyoon Kim, Younghee Lee. Racial differences of intron retention and DNA methylation in 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-003. doi:10.1158/1538-7445.AM2017-LB-003
Abstract LB-005: Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees
Authors: Lehnert Erik D. , Freeman Eric , Salzman Julia 
Published: July 2017

Abstract
Public archives of sequencing data continue to grow at a rapid pace. (Re)analysis of large datasets can be both expensive and resource-intensive, and users are often only interested in the sample prevalence of a small subset of sequences. We have implemented a Sequence Bloom Tree data structure for the TCGA RNA-seq datasets, allowing researchers to rapidly test samples for the presence of sequences of interest. We demonstrate the ability to rapidly identify samples containing viral transcript sequences, estimate the sample prevalence of gene fusions and novel splice variants, and infer the presence of HeLa-cell contamination in a subset of TCGA data. We have implemented post-querying controls to mitigate false positives arising from the presence of genes with highly similar sequences. The tools are described using Common Workflow Language, allowing researchers to reproducibly generate and query the dataset.
Citation Format: Erik D. Lehnert, Eric Freeman, Julia Salzman. Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees [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-005. doi:10.1158/1538-7445.AM2017-LB-005
Abstract LB-010: Modeling the impact of mutations in ubiquitin pathway genes across human cancers
Authors: Osmanbeyoglu Hatice U. , Leslie Christina 
Published: July 2017

Abstract
A number of ubiquitin pathway genes show a strikingly high frequency of somatic alterations across diverse human cancers. While several ubiquitin ligase genes with recurrent mutations or copy number alterations been studied in individual cancers, their role in many malignancies remains poorly understood. To better model the impact of ubiquitin pathway alterations, we developed a computational strategy for exploiting parallel phosphoproteomics and mRNA sequencing data for large tumor sets to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Our modeling allows us to interpret the impact of mutations and copy number events in terms of altered signaling and transcription factor (TF) activity. We used a multi-task learning strategy to jointly train phosphoprotein-TF interaction models across 10 human cancers for which large reverse-phase protein array and RNA-seq data sets are available through TCGA. We then applied a novel algorithmic approach to extract networks of signaling proteins and TFs whose inferred activities are correlated across tumors and whose dysregulation is associated with specific somatically altered ubiquitin pathway genes. Our analysis revealed both known and novel interactions of ubiquitin ligase genes with signaling pathways and transcriptional programs in a pan-cancer context.
Citation Format: Hatice U. Osmanbeyoglu, Christina Leslie. Modeling the impact of mutations in ubiquitin pathway genes across human cancers [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-010. doi:10.1158/1538-7445.AM2017-LB-010
Abstract LB-012: Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions
Authors: Papineni Rao V. , Umar Shahid , Goltsov Alexey , Ahmed Ishfaq 
Published: July 2017

Abstract
We earlier showed with Systems Biology approach that the genotoxic stress response evoked by cancer, infection, and radiation injury have similarities, particularly at the gastrointestinal tract. This was made possible using biophotonics, and show promise in drug screening opportunities using each of these pathologies as a surrogate model for one another. Using similar molecular Imaging methodology, we showed for the first time binding of osteoporosis drug bisphosphonate to prostate and ovarian cancer tumors and potential drug repurposing candidature. Recently, we presented similar drug re-tasking potential of 2-Deoxyglucose (2-DG) in anti-infection. Here, our data demonstrating mitigation of citrobacter rodentium infection by dietary treatment by 2-DG (0.4%), were analyzed with the bisphosphonate anti-infection response to enteric bacterial pathogens data reported elsewhere. Based on these results, a systems approach analysis is developed and presented demonstrating cross-talk and communication between different cells and integrated responses to pathogens and disease by 2-DG and bisphosphonate in anticancer and anti-infection actions. A role in EGFR signaling and modulation in the infiltration immune response cells by these two dissimilar compounds play a profound bridging event in anticancer and anti-infection activities. These system biology strategies will provide opportunities for drug repurposing in personalized cancer therapy and in anti-microbial management during cancer treatment. Also pave way for safer drugs in prevention and therapy of HER family-driven cancers.
Citation Format: Rao V. Papineni, Shahid Umar, Alexey Goltsov, Ishfaq Ahmed. Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions [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-012. doi:10.1158/1538-7445.AM2017-LB-012
Abstract LB-022: PTP1B directed therapeutics for HER2 positive breast cancer
Authors: Krishnan Nava 
Published: July 2017

Abstract
PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state.
MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. Currently, we are testing MSI-1436 in a Phase 1 clinical trial in HER2-positive breast cancer patients, in collaboration with the Monter Cancer Center at Northwell Health formerly NS-LIJ.
Note: This abstract was not presented at the meeting.
Citation Format: Nava Krishnan. PTP1B directed therapeutics for HER2 positive 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-022. doi:10.1158/1538-7445.AM2017-LB-022
Abstract LB-023: STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin
Authors: Kida Taiki , Rogoff Harry A. , Li Chiang J. 
Published: July 2017

Abstract
Cancer stem cells (CSCs) are considered to play an important role in cancer therapy resistance, metastasis, and recurrence. Wnt/β-catenin is one of key signaling pathways that confer cancer stemness properties to a portion of the heterogeneous cancer cell population. Dysregulation of the Wnt/β-catenin pathway may lead to accumulation of β-catenin and aberrant activation of its target gene transcription. However, it has been proven difficult to design a therapeutic targeting β-catenin. Identification of a drugguble target for the β-catenin pathway is highly desirable given the importance of β-catenin in promoting cancer stemness.
Here, we demonstrate that Serine Threonine Kinase 17A (STK17A), a novel member of the death-associated protein family of serine/threonine kinases, promotes cancer stemness phenotypes via β-catenin. Over-expression of STK17A resulted in increased anchorage-independent spherogenesis and invasive phenotype of cancer cells, whereas STK17A gene silencing reduced these malignant phenotypes. Overexpression of STK17A led to increased transcriptional activity of β-catenin and upregulation of its target genes. These changes were accompanied by increased phosphorylation of β-catenin at ser675. Cell-free in vitro kinase assay revealed that STK17A directly phosphorylates β-catenin at ser675 in an ATP-dependent manner. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness kinase inhibitor, was found to potently inhibit STK17A, leading to inhibition of β-catenin phosphorylation at ser675. These results suggest that inhibition of STK17A is a promising approach for targeting cancer stemness.
Citation Format: Taiki Kida, Harry A. Rogoff, Chiang J. Li. STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin [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-023. doi:10.1158/1538-7445.AM2017-LB-023
Abstract LB-030: Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression
Authors: McCann Jennifer J. , Dean Jeffry L. , Leeuw Renee De , Schiewer Matthew J. , McNair Christopher M. , Knudsen Karen E. 
Published: July 2017

Abstract
Prostatic adenocarcinoma (PCa) remains the most frequently diagnosed cancer type and the third leading cause of cancer death in men in the United States. While organ-confined disease is manageable, treatment options for disseminated PCa remain limited. First-line therapy for metastatic PCa functions through targeting the androgen receptor (AR) signaling axis, as AR activity is required for tumor maintenance. However, while treatment is initially effective, these tumors invariably recur, displaying reactivation of AR signaling despite continued therapeutic targeting. Moreover, no durable treatment currently exists for this ultimately fatal disease stage, termed castrate-resistant PCa (CRPC). Significantly, recent high profile, genome-wide studies have revealed that missense mutations in the TP53 gene occur in nearly all cancer types, and these mutations frequently occur at specific TP53 “hotspots”. Interestingly, enrichment of certain hotspot p53 mutants specifically occurs in PCa. While the underlying causes of PCa-enriched mutations remain undefined, their presence elicits contrasting, pro-oncogenic biochemical and biological phenotypes. Unpublished data suggests that mutant p53 isoforms act in a mutation-specific fashion to drive PCa progression through alterations in the canonical activity of p53, identified through characterization of their related transcriptomes and cistromes. Biologically, these mutant p53 isoforms also confer differential proliferative and survival phenotypes. Moreover they act in a mutation-dependent fashion in response to castration therapy both in vitro and in vivo. Mechanistically, pro-oncogenic mutant p53 appears to manipulate both conventional and novel pathways leading to PCa progression. These findings both corroborate and expand the recent findings that mutations in p53 drive cancer progression, and further suggest a critical role for p53 mutations as regulators of disease progression in PCa.
Citation Format: Jennifer J. McCann, Jeffry L. Dean, Renee De Leeuw, Matthew J. Schiewer, Christopher M. McNair, Karen E. Knudsen. Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression [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-030. doi:10.1158/1538-7445.AM2017-LB-030
Abstract LB-031: Deciphering distinct roles of RASA2 in melanomagenesis
Authors: Arafeh Rand , Qutob Nouar , Emmanuel Rafi Rafi , Madore Jason , Elkahloun Abdel , Wilmott James S. James S. , Gartner Jared J. , Pizio Antonella Di , Rotkopf Ron , Dutton-Regester Ken , Hill Victoria , Pritchard Antonia , Lin Jimmy C. , Rosenberg Steven A , Khan Javed , Ben-Dor Shifra , Niv Masha Y. Masha Y. , Ulitsky Igor , Mann Graham J , Scolyer Richard A. , Hayward Nicholas K. , Samuels Yardena 
Published: July 2017

Abstract
Melanoma is the deadliest form of human skin cancer. The incidence of melanoma continues to rise. Recent advances in knowledge of melanoma genetics, genomics and biology has led to an optimistic view of the therapeutic outlook for melanoma patients. We analyzed sequence data from &gt;500 melanoma genomes/exomes to identify novel tumor suppressor genes in melanoma. RASA2 was identified as the most highly somatically mutated novel tumor suppressor gene. RASA2 was mutated in 5% of melanomas and deleted in an additional 16.4% of cases. RASA2 is a GTPase Activating Protein (GAP) that regulates RAS; which is one of the most highly mutated oncogenes in melanoma but drugs targeting RAS have as yet shown poor efficacy. The role of RASA2 has not been investigated in melanoma. NF1, which encodes another RAS- specific GAP, was found to be frequently mutated in melanoma. Interestingly, mutations in RASA2 and NF1 co-occur in the same patients with high frequency. We plan to elucidate the roles of RASA2 in melanomagenesis and to understand why RASA2 and NF1 mutations co-occur despite the fact that both proteins are RasGAPs. Ras includes three isoforms: NRas, KRas and HRas. Our preliminary data show that RASA2 is more specific to NRAS and that NF1 is more specific to KRAS and HRAS. This finding highlights the existence of a paradigm of cooperativity in which combined loss of multiple negative regulators (RASA2 and NF1) of the RAS pathway is required for melanoma development. Therefore, this type of enhancement of RAS signaling is possibly selected for in some melanomas. We will apply a proteomic screen using BioID to identify RASA2 and NF1 binding partners to provide insights into the functional effects and consequences of alterations in RASA2 and NF1. We expect that these studies will not only identify the cellular components that contribute to the Ras signaling pathway but will also identify potential novel therapeutic targets.
Citation Format: Rand Arafeh, Nouar Qutob, Rafi Rafi Emmanuel, Jason Madore, Abdel Elkahloun, James S. James S. Wilmott, Jared J. Gartner, Antonella Di Pizio, Ron Rotkopf, Ken Dutton-Regester, Victoria Hill, Antonia Pritchard, Jimmy C. Lin, Steven A Rosenberg, Javed Khan, Shifra Ben-Dor, Masha Y. Masha Y. Niv, Igor Ulitsky, Graham J Mann, Richard A. Scolyer, Nicholas K. Hayward, Yardena Samuels. Deciphering distinct roles of RASA2 in melanomagenesis [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-031. doi:10.1158/1538-7445.AM2017-LB-031
Abstract LB-032: Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma
Authors: Wang Qing , Zhu Jiang , Yang Hsin-Sheng 
Published: July 2017

Abstract
Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in many types of cancer including colorectal cancer. In this study, we found that knockdown/knockout of Pdcd4 increased the activity of mammalian target of rapamycin complex 2 (mTORC2). Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which was resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the sin1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the sin1 5’UTR, suggesting that sin1 5’UTR mediated Pdcd4’s inhibition on Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157-469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited the Sin1 translation, and thus inhibited mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157-469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and as a result failed to inhibit mTORC2 activity and invasion. In addition, treating cells with an eIF4A inhibitor also efficiently inhibits Sin1 expression and invasion. These results suggest that Pdcd4-inhibited Sin1 translation is through eIF4A, and is functionally important for suppression of mTORC2 activity and invasion. In colorectal cancer tissues, Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuate mTORC2 activity and thereby suppress invasion.
Citation Format: Qing Wang, Jiang Zhu, Hsin-Sheng Yang. Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma [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-032. doi:10.1158/1538-7445.AM2017-LB-032
Abstract LB-035: Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis
Authors: Ro Seung-Hyun , Xue Xiang , Shah Yatrik , Lee Jun Hee 
Published: July 2017

Abstract
The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.
Citation Format: Seung-Hyun Ro, Xiang Xue, Yatrik Shah, Jun Hee Lee. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis [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-035. doi:10.1158/1538-7445.AM2017-LB-035