tbuckley/cabot-search huggingface dataset:
Abstract 650: B lymphocytes promote upregulation of an IL-1-NfkB dependent signaling and increase invasiveness of triple negative breast cancer
Authors: Nicole Flynn, Rajasekharan Somasundaram, Jennifer Sims-Mourtada
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that progresses quickly from a non-invasive carcinoma in situ to an invasive state. Chronic inflammation associated to humoral immune responses has been found to promote aggressiveness in a number of solid tumor types. In breast cancer, B lymphocytes are associated with microinvasive disease and correlate with expression of inflammatory genes. The purpose of our work is to study the impact of B lymphocytes on the tumor microenvironment and increased invasiveness of TNBC cells. Through real-time PCR, we demonstrate that co-culture of B lymphocytes and TNBC cells leads to increased mRNA levels of IL1β and its downstream target interleukin 8 (IL8) in both B lymphocytes and in TNBC cells. Western Blot analysis shows that co-culture also leads to increased phosphorylation of p65, indicating IL-1 β activation of NFκB signaling. Additionally, co-culture of B lymphocytes with TNBC cells leads to increased expression of matrix metalloproteinases (MMPs) and cellular invasion through a matrigel invasion chamber. Gelatin zymography reveals increased functional MMP2 and MMP9 in tumor cell supernatant following co-culture with B lymphocytes. To complement our in vitro studies, we examined the presence of CD20+ B cells and expression of inflammatory cytokines IL-1β and IL-8 by immunohistochemistry in serial sections of tissue microarrays from patients with estrogen receptor (ER) positive and negative ductal carcinoma in situ (DCIS) and invasive carcinoma. Large areas of densely populated B cells were observed in ER-DCIS and in invasive TNBC compared to ER+ DCIS. Furthermore, in ER- DCIS and TNBC, both B lymphocytes and tumor cells are found to express IL1β whereas IL8 is found more specifically to be expressed by tumor cells. Our findings support the hypothesis that B lymphocytes promote a chronic inflammatory environment leading to increased invasion of TNBC cells. Citation Format: Nicole Flynn, Rajasekharan Somasundaram, Jennifer Sims-Mourtada. B lymphocytes promote upregulation of an IL-1-NfkB dependent signaling and increase invasiveness of 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 650. doi:10.1158/1538-7445.AM2017-650
Abstract 2598: Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB)
Authors: Taofei Yin, Sara E. Patterson, Cara M. Statz, Anuradha Lakshminarayana, Daniel Durkin, Susan M. Mockus
Journal: Cancer Research (2017)

Abstract In the era of personalized medicine, comprehensive cancer genomic databases represent critical tools for interpreting gene variants and their relevant therapies. As the number of cancer genomic databases grow, it is challenging for users to compare and assess the data integrity and validity of such databases. The lack of disclosure of curation processes makes it difficult to cross reference different databases. The JAX Clinical Knowledgebase (CKB) is a comprehensive relational database providing evidence-based information on gene variants, targeted therapies, efficacy evidence, and clinical trials. At the Jackson Laboratory for Genomic Medicine, we have developed a curation paradigm to ensure curation transparency and consistency of the JAX-CKB. First, to ensure standardization of nomenclature, we have integrated standard nomenclature and ontologies, including HGNC approved nomenclatures for genes, HGVS guidelines for variants, and the Disease Ontology for indications/tumor types. Second, we implemented decision matrices to maintain uniformity of our evaluation of scientific and clinical data. For example, evaluation of the effect of gene variants on protein function is solely based on changes in the intrinsic activity of the protein instead of downstream pathway activation or the effects on pathogenesis; the response type of gene variants to therapies are classified based on the evidence of targeting specificity; and the efficacy evidence are further classified as actionable, diagnostic, prognostic, risk factor, emerging, or not active centered on the response type and the strength of the evidence. Third, to provide convenient evaluation of the clinical relevance of efficacy data, we further developed a tier ranking system based on emerging consensus guidelines, which takes response type, evidence type, and approval status into consideration. Finally, all decision matrices are clearly outlined on the JAX-CKB open access website for users’ reference. In summary, we have curated a highly structured and semantically consistent cancer genomic database following a set of specific curation guidelines. As a result, JAX-CKB open access has become a valuable resource for both the clinical and research communities, and is utilized by numerous independent groups for variant interpretation. Citation Format: Taofei Yin, Sara E. Patterson, Cara M. Statz, Anuradha Lakshminarayana, Daniel Durkin, Susan M. Mockus. Paradigm to ensure curation transparency and consistency of a cancer genomic database - the JAX Clinical Knowledgebase (CKB) [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 2598. doi:10.1158/1538-7445.AM2017-2598
Abstract 4535: Tumor cell division rate heterogeneity explains <i>in vitro</i> clonal dominance
Authors: Margriet M. Palm, Marjet Elemans, Joost B. Beltman
Journal: Cancer Research (2017)

Abstract The cells that make up a tumor exhibit large phenotypic and genotypic variation, which strongly influences the effectiveness of cancer therapy. A typical manifestation of intratumor heterogeneity is the presence of a few clones that represent most of the tumor population, i.e. clonal dominance. Such heterogeneity could potentially be caused by the occurrence of different ratios of cancer stem cells and differentiated cells per clone, or, alternatively, clonal dominance may be caused by heterogeneity of division rates between clones. Previously published work, applying lineage tracing with genetic barcodes to in vitro iterated growth and passage experiments demonstrated that clonal dominance was accompanied by clone loss and partial overlap in dominant clones between biological replicates [1]. To identify the source of these observations, we build a computational model that simulates the iterated growth and passage experiments. By varying the 'division rules' in the model, we can quantitatively predict the evolution of the clone distribution for the aforementioned hypotheses. In this manner, we show that clonal dominance does not appear in simulations where all cells divide at a uniform rate, even when the population is subdivided in cancer stem cells and differentiated cells. However, when the division rates vary between clones and are inherited from parent cells, dominant clones appear. These simulations also closely match the in vitro evolution of clone loss and clonal overlap between biological replicates. Altogether, our findings suggest that tumor cells exhibit a heritable variability in the division rates of individual cells. References [1] Porter, S. et al. (2014). Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo. Genome Biology, 15(5), R75. Citation Format: Margriet M. Palm, Marjet Elemans, Joost B. Beltman. Tumor cell division rate heterogeneity explains in vitro clonal dominance [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 4535. doi:10.1158/1538-7445.AM2017-4535
Host modulation: controlling the inflammation to control the infection
Authors: P. Mark Bartold, Thomas E. Van Dyke
Journal: Periodontology 2000 (2017)

Abstract Historically, periodontal disease (gingivitis and periodontitis) has been recognized as being primarily of bacterial origin. However, recent evidence indicates that while bacteria are necessary for disease development they are not sufficient for the clinical manifestation of the many and varied forms of periodontal disease. It is becoming increasingly apparent that it is the host inflammatory response to the subgingival bacteria that is responsible for the tissue damage and, most likely, progression of the disease. We explore the concept that it is the subgingival microenvironment modified by the inflammatory response that leads to a change from a commensal to pathogenic microbiota. In this review, we examine the evidence for the emerging paradigm supporting the central role of inflammation rather than specific microbiota in the pathogenesis of periodontitis, and that by controlling the inflammation, it is possible to control the infection. As an extension of this, we propose a working model for the ongoing monitoring of periodontal patients using the medical model of ‘treat to target’.
Abstract 608: Augmenting and broadening T cell responses against mutated tumour neo-antigens
Authors: Bruce W. Robinson, Shaokang Ma, Jonathan Chee, Craig Rive, Paula Van Miert, Rob A. Holt, Jenette Creaney
Journal: Cancer Research (2017)

Abstract Cytotoxic T lymphocytes (CTLs) recognize mutated tumor proteins (neo-antigens) and are important for anti-tumor immunity, especially in the context of immune checkpoint blockade immunotherapy (ICPB). Positive outcomes to ICPB are associated with high neo-antigen loads and with neo-antigen specific CTL responses. However only around 20% of patients respond to ICPB. In order to examine ways in which the non-responders might become responders we examined several strategies to improve response rates, using anti-CTLA4 initially as the ICPB therapy in BALB/c mice in which Uqcrc2 has been defined as a DNA/RNAseq-identified neo-antigen in AB1 tumor lines induced by a relevant human carcinogen(1). a) We first examined therapy-induced changes in T-cell responses against Uqcrc2. Anti-CTLA4 alone increased the magnitude of responses against Uqcrc2. Anti-CTLA4 combined with anti-GITR induced determinant spreading, unmasked responses against a new neo-antigen UNC45A that was undetectable during normal tumour growth. Immunogenic chemotherapy also unmasked responses against UNC45A, suggesting that subdominant neo-antigens can be unmasked by the appropriate immunotherapy. b) We then evaluated neo-antigen vaccination strategies. Uqcrc2 vaccination only protected against tumor growth when administered in combination with partial Treg depletion (Foxp3.DTR mice), suggesting that neo-antigen vaccination will only be maximally effective when administered in combination with therapies that modulate existing immune restraints, including Tregs. c) We determined optimal anatomical location for tracking neo-antigen CTL responses and identified the draining lymph node as an optimal, though not exclusive, location for response testing compared to blood or tumor. We are currently examining these observations using sequencing-defined neo-antigens in our patients and will present data on changes in human neo-antigen responses to therapy. These observations have important translational implications for identification of key neo-antigens, choice of therapy and monitoring of anti-tumor responses. 1. J. Creaney et al., Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen. Oncoimmunology 4, e1011492 (2015). Citation Format: Bruce W. Robinson, Shaokang Ma, Jonathan Chee, Craig Rive, Paula Van Miert, Rob A. Holt, Jenette Creaney. Augmenting and broadening T cell responses against mutated tumour neo-antigens [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 608. doi:10.1158/1538-7445.AM2017-608
Abstract 998: OPeN: the oncology precision network data sharing consortium
Authors: Lincoln Nadauld, Derrick Haslem, Paul D. Tittel, Mariko Tameishi, Thomas Brown, James Ford
Journal: Cancer Research (2017)

Abstract Background: The advent of Next-Generation Sequencing (NGS), and other molecular diagnostic technologies, has enabled the use of genomic information to guide targeted treatment in cancer patients. While this precision oncology approach can yield exciting clinical outcomes, the innumerable genomic variants identified in individual tumors effectively establishes each case as a unique N=1 clinical presentation. This scenario is contrary to a basic dogma of medical practice where historical cases and treatment outcomes guide future management and therapeutic decisions. Aggregation of large data sets, on a multi-institutional basis, has the potential to overcome the N=1 paradox and yield management insights in the implementation of precision oncology. Methods: We have formed the Oncology Precision Network (OPeN), an oncology data sharing consortium, to aggregate big data sets consisting of clinical, genomic, pharmacological, and treatment response data from diverse patient cases. Data from Intermountain Healthcare, Stanford University, and Swedish Cancer Institute-Providence St. Joseph Health, as well as other institutions, comprises the database and is derived from 79 hospitals, over 800 physician clinics and more than 50,000 annual cases. Results: The OPeN database can be interrogated by variant type, specific therapeutics, clinical outcomes, and by grouped variables, in a structured data format. The overarching IT platform is a cloud based, open source, triple store precision oncology solution, Syapse. These data are yielding valuable insights, including tumor mutational burden (TMB) scores and their correlation to immunotherapy response, clinical response in various drug-gene combinations, and therapy-specific adverse events. Conclusions: We anticipate this resource will be used by the Molecular Tumor Boards of contributing institutions for clinical interpretation, and by treating providers to overcome the N=1 challenge associated with precision oncology. Citation Format: Lincoln Nadauld, Derrick Haslem, Paul D. Tittel, Mariko Tameishi, Thomas Brown, James Ford. OPeN: the oncology precision network data sharing consortium [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 998. doi:10.1158/1538-7445.AM2017-998
Abstract 3425: MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9
Authors: Petra Faltejskova-Vychytilova, Jana Merhautova, Pablo Conesa-Zamora, Katerina Slaba, Tana Machackova, Marek Svoboda, Marek Vecera, Jitka Mlcochova, Jaroslav Juracek, Jiri Sana, Parwez Ahmad, Natalia Gablo, Ondrej Slaby
Journal: Cancer Research (2017)

Abstract Growing evidence suggests that microRNAs (miRNAs) are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues have been used for miRNA expression analyses. We proved that miR-215-5p is significantly down-regulated in tumor tissues compared to non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. To identify specific cellular processes affected by ectopic expression of miR-215-5p, a series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines. Increased levels of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo by use of NSG mice model and stable cell line over-expressing miR-215-5p. Finally, we proved epiregulin and HOXB9 to be the direct targets of miR-215-5p by luciferase assay and western blot analyses. Since epiregulin is EGFR ligand and HOXB9, is its transcriptional inducer, we suggest, that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC. This work was supported by Ministry of Health of the Czech Republic, grant nr. 15-33158A, 15-34553A, 15-31627A, 15-34678A, 16-31314A, 16-31765A and by grant of Czech Grant Agency nr. 16-18257S. Citation Format: Petra Faltejskova-Vychytilova, Jana Merhautova, Pablo Conesa-Zamora, Katerina Slaba, Tana Machackova, Marek Svoboda, Marek Vecera, Jitka Mlcochova, Jaroslav Juracek, Jiri Sana, Parwez Ahmad, Natalia Gablo, Ondrej Slaby. MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9 [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 3425. doi:10.1158/1538-7445.AM2017-3425
Abstract LB-262: A somatic-mutational process in breast cancer genomes recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers
Authors: Dominik Glodzik, Sandro Morganella, Helen Davies, Serena Nik-Zainal
Journal: Cancer Research (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 (&amp;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 3537: Otx2 and c-Myc association drives tumor progression in medulloblastoma molecular subtypes 3/4
Authors: Yining Lu, Maheedhara R. Guda, Swapna Asuthkar, Ian Purvis, Collin M. Labak, Neha Jain, David J. Daniels, Sarah E. Martin, Andrew J. Tsung, Kiran K. Velpula
Journal: Cancer Research (2017)

Abstract Medulloblastoma (MB) is a pediatric brain tumor comprising of four molecular subgroups, with Group 3 and 4 tumors characterized by particularly poor prognosis. While research has advanced our understanding of MB, there is still a pressing need for new knowledge of the functional processes underlying its progression due to a scarcity of therapeutics. Recent studies have identified Orthodenticle homeobox 2 (Otx2), a cerebellar transcription factor, to be highly expressed in MB Group 3/4 subtypes. Datamining studies from Northcott and Robinson datasets revealed co-expression of Otx2 and c-Myc in Group 3/4 tumors. DAB staining conducted in human MB specimens showed increased expression of Otx2 and c-Myc. Colocalization studies confirmed datamining results. Next, we used a clinical Otx2 inhibitor, all-trans retinoic acid (ATRA), in a PDX cell line, P9, and in UW228 cells. Western blot analysis demonstrated reduced levels of c-Myc along with Otx2. In another experiment, we used the c-Myc/Max inhibitor 10058-F4 and observed comparable results to Otx2 inhibition. Real time PCR and immunocytochemistry experiments confirmed the aforementioned results. Further, treatment with ATRA and 10058-F4 showed reduced proliferation and migratory abilities in p9 and UW228 when compared to their respective controls. Mass spectrometry conducted on immune-precipitated Otx2 in P9 cells revealed a plethora of novel interaction partners that drive tumor growth and progression. In addition, western blot analysis in ATRA treated cells showed reduced expression of Max, suggestive of the existence of a feedback loop that link with Otx2 and c-Myc. Collectively our studies highlight Otx2 as a potential contributor to the malignant phenotype and describe its role in mediating the aggressiveness of Group 3/4 medulloblastoma. Citation Format: Yining Lu, Maheedhara R. Guda, Swapna Asuthkar, Ian Purvis, Collin M. Labak, Neha Jain, David J. Daniels, Sarah E. Martin, Andrew J. Tsung, Kiran K. Velpula. Otx2 and c-Myc association drives tumor progression in medulloblastoma molecular subtypes 3/4 [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 3537. doi:10.1158/1538-7445.AM2017-3537