tbuckley/cabot-search huggingface dataset:
Abstract 3374: APA isoform diversity in triple negative breast cancers
Authors: Ayse Elif Erson-Bensan, Begum H. Akman, Merve Oyken, Hizlan H. Agus, Esra Yavuz, Murat Erdem, Tolga Can
Journal: Cancer Research (2017)

Abstract Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs and relieving microRNA-mediated repression. Therefore, APA is gaining increased attention as a potential mechanism to activate oncogenes. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 3'UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 3'UTR length alterations where the significant majority was shortening events (70%, 113 of 165) of mostly proliferation-related transcripts in over 500 TNBC patients compared with normal breast tissue. Representative shortening events correlated with increased protein levels and relapse free survival of patients, suggesting functional significance of isoform variability. To begin addressing the underlying mechanisms of 3’UTR shortening, we turned to APA machinery proteins. We detected variable expression of APA machinery proteins in different breast cancer subtypes but CSTF2 (cleavage stimulation factor 2) has the most prominent overexpression in breast cancer cells. Therefore, among potential regulators of 3’UTR shortening, we further investigated the role of CSTF2 in proximal polyA signal selection. Because some of the TNBC patients are EGFR positive, we found EGF treatment to cause increased CSTF2 levels. Higher CSTF2 levels indeed correlated with further shortening of the 3'UTRs. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our integrated approach revealed a pattern of 3'UTR length changes in TNBC patients and a potential link between APA and EGF signaling. Further studies are underway to investigate the mechanistic link between EGF signaling and regulation of 3’UTR lengths. (This work is funded by TUBITAK 112S478 and 114Z884) Citation Format: Ayse Elif Erson-Bensan, Begum H. Akman, Merve Oyken, Hizlan H. Agus, Esra Yavuz, Murat Erdem, Tolga Can. APA isoform diversity in triple negative breast 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 3374. doi:10.1158/1538-7445.AM2017-3374
Abstract 83: Irinotecan resistance in type 2 interleukin-1 receptor overexpressed colorectal cancer cells is overcome by inhibitor of MEK
Authors: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee
Journal: Cancer Research (2017)

Abstract We have previously demonstrated that the expression of interleukin-1 receptor type II (IL1R2) is closely associated with the advanced staging and distant metastasis in patients with CRC. We also found that enhanced expression of IL1R2 played certain roles to resist the targeted therapeutics, regorafenib, in CRC cells. Whether IL1R2 expression is associated with the resistance to chemotherapeutics is unclear. Irinotecan, a water-soluble and semisynthetic derivative of camptothecin, is one of widely used first- and second-line chemotherapeutics for treatment of patients with metastatic colorectal cancer (CRC). Herein, we first demonstrated that enhanced expression of IL1R2 resulted in increased resistance of CRC cells to irinotecan using IL1R2 ectopically expressed HCT116 and DLD-1 cells, which were IL1R2 low expressing CRC cells, and IL1R2 silenced HT29 cells, which were IL1R2 high expressing CRC cells. Since we have shown that IL1R2 may activate MEK/ERK signaling by inhibition of PP2A, we further revealed that a specific inhibitor of MEK, CI-1040, could overcome the irinotecan resistance in IL1R2-overexpressing DLD-1 and HT29 cells. Our result showed that the combination of irinotecan and CI-1040 synergistically suppressed the cell growth in high IL1R2 expressing CRC cells but less significant in low IL1R2 expressing cells. We also confirmed that treatment of IL1R2-overexpressing CRC cells with CI-1040 significantly suppressed the pERK, a downstream target of MEK. These results support that IL1R2 mediates through activation of MEK/ERK signaling to cause irinotecan resistance in human CRC cells. The investigation how IL1R2 induces irinotecan resistance is ongoing. Accordingly, we may suggest that combined treatment of irinotecan and MEK-ERK inhibitor is a potential therapeutic strategy against IL1R2 overexpression related irinotecan resistant CRC. Citation Format: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee. Irinotecan resistance in type 2 interleukin-1 receptor overexpressed colorectal cancer cells is overcome by inhibitor of MEK [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 83. doi:10.1158/1538-7445.AM2017-83
A “sense of magnitude” requires a new alternative for learning numerical symbols
Authors: Delphine Sasanguie, Bert Reynvoet
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. proposed that the processing of numerosities is based primarily on a “sense of magnitude.” The consequences of this proposal for how numerical symbols acquire their meaning are, however, neglected. We argue that symbols cannot be learned by associating them with a system that is not yet able to derive discrete numbers accurately because of immature cognitive control.
Abstract 3589: A systematic approach toward gene annotation of the hallmarks of cancer
Authors: Jeff Kiefer, Sara Nasser, John Graf, Chinnappa Kodira, Fiona Ginty, Lee Newberg, Anup Sood, Michael E. Berens
Journal: Cancer Research (2017)

Abstract The hallmarks of cancer consist of ten categories that serve as an organizing principle and framework for understanding neoplastic disease. The ten hallmarks include activating invasion and metastasis, avoiding immune destruction, deregulating cellular energetics, enabling replicative immortality, evading growth suppressors, genome instability and mutation, inducing angiogenesis, resisting cell death, sustaining proliferative signaling, and tumor-promoting inflammation. In order to facilitate the use of the hallmarks of cancer in genomic studies, we have undertaken a systematic methodology to map genes to each individual hallmark of cancer. Assignment of genes to the individual hallmarks was performed leveraging gene ontology (GO) annotations. Specifically, for each hallmark, a term list was generated by cancer research experts, with biological terms associated with each hallmark. This term list was used to search and identify matching GO terms. Matched terms were then mapped to the highest, most specific, representative, non-redundant GO term in the GO hierarchy. Genes for each term were restricted by selecting only human taxon, and high confidence experimental evidence codes. For specific GO terms, where present, the Regulation of ‘GO term’ category was included. The genes for each GO term for each hallmark were combined in a non-redundant list of genes for each hallmark. In the case of the evading growth suppressors category, a different strategy was employed. In this instance, genes were identified through ‘tumor suppressor’ gene/protein annotation in the DGIdb resource and UniProt. Additionally, text-mining methods on biomedical research literature were used to defined a high confidence list of genes for this hallmark. As an example use case of the hallmarks we applied them to the analysis of the TCGA Pan-Cancer RNAseq data set. Clustering across the individual hallmarks led to interesting differences within particular tumor tissue types, as well as shared hallmarks for other tumor types. For example, use of the genome instability and mutation hallmark for Pan-Cancer clustering, revealed a tight tissue-based cluster of low-grade gliomas and GBMs. This result suggests the importance of this hallmark expression in this tumor type. This high confidence mapping of genes to hallmarks of cancer provides a unique dataset to facilitate analyses of cancer genome data. Citation Format: Jeff Kiefer, Sara Nasser, John Graf, Chinnappa Kodira, Fiona Ginty, Lee Newberg, Anup Sood, Michael E. Berens. A systematic approach toward gene annotation of the hallmarks of 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 3589. doi:10.1158/1538-7445.AM2017-3589
Internet Searches for Suicide Following the Release of <i>13 Reasons Why</i>
Authors: John W. Ayers, Benjamin M. Althouse, Eric C. Leas, Mark Dredze, Jon-Patrick Allem
Journal: JAMA Internal Medicine (2017)

This quasiexperimental examination of internet search results determines that the Netflix series 13 Reasons Why has both increased suicide awareness while unintentionally increasing suicidal ideation.
Abstract 2410: Toward mutation analysis of regulatory elements: Epigenetic profiling of primary breast tumors
Authors: Samah El Ghamrasni, Paul Guilhamon, Rene Quevedo, Cindy Yang, Mathieu Lupien, Trevor Pugh
Journal: Cancer Research (2017)

Abstract Non-coding mutations found in regulatory elements can function as driver mutations in breast cancer by changing the binding affinity of transcription factors for DNA, thereby resulting in direct change of expression of genes that promote cancer development. Identifying such additional driver mutations can reveal the molecular mechanisms favorable to breast cancer development and progression, as well as reveal new biomarkers to better tailor personalized/precision cancer medicine. In this study we have collected 20 primary luminal breast tumors and optimized experimental workflow to dissociate solid tumors and map open chromatin using ATAC-seq. In our initial experiments using ATAC-seq profiling of bulk tumor tissues, we were able to call an average of 15x103 peaks. Subsequently, flow cytometry analysis showed the presence of 15-25% of immune cells in our primary tumors. Therefore, we have optimized a workflow to eliminate immune cells and focus mainly on epithelial tumor cells. Primary breast tumors were digested using collagenase and further dissociated with dispase. Cells were sorted into two populations (mammary epithelial and immune cells) using anti-CD45, anti-CD49f and anti-EpCAM antibodies. Sorted mammary epithelial cells were then used for ATAC- and RNA-seq library preparation as well as for generation of patient derived organoids. Our new workflow resulted in an increased number of called peaks (40x103 vs 15x103), as well as a significant increase in the percentage of unique peaks compared to bulk sequencing (45% vs 15%). By refining our workflow to enrich for tumour content, we will continue our ongoing effort to profile these open chromatin regions and contextualize the mutations within in a large cohort of luminal breast cancers using targeted sequencing. These data will be compared with large-scale whole genome data generated by our group and made publicly available by others. Citation Format: Samah El Ghamrasni, Paul Guilhamon, Rene Quevedo, Cindy Yang, Mathieu Lupien, Trevor Pugh. Toward mutation analysis of regulatory elements: Epigenetic profiling of primary breast tumors [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 2410. doi:10.1158/1538-7445.AM2017-2410
Abstract 5372: Alterations in the chromatin accessibility in nonalcoholic steatohepatitis-associated hepatocellular carcinoma
Authors: Mekonnen Lemma Dechassa
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Accumulated evidence in the past decade has stablished that NASH, in addition to other well-identified risk factors, is becoming a major cause of HCC in United States. In the present study, we investigated cancer-associated chromatin alterations in the Stelic Animal Model (STAM) of NASH-related HCC. Using Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq), we identified 1666 differentially opened chromatin regions in HCC tumor tissue as compared to normal livers. Annotation of these regions showed that they were associated with 1773 differentially expressed genes, which were enriched in lipid and steroid metabolism, obesity, and cancer. Among the differentially opened chromatin regions, 10% resided within 5 kb from the transcription start site (TSS), while the remaining 90% were located distal to the TSS (&amp;gt; 5 kb). By combining ATAC-seq and transcriptomic profiles, we demonstrated that 182 of the up-regulated genes were associated with open chromatin regions in tumor tissue. Furthermore, 24 of these up-regulated genes, including Apoa4, Nupr1, Anxa2, and Igfbp1, had accessible chromatin regions located proximal to the TSS. Importantly, analysis of histone modifications at the open chromatin regions of the over-expressed cancer-related Apoa4 and Anxa2 genes demonstrated enrichment by H3K4 mono-methylation (H3H4me1) and H3K27 acetylation (H3K27ac), histone marks that associated with the active gene promoters (H3K27ac) and enhancers (H3Kme1 and H3K27ac). In conclusion, these data provide evidence for alterations in the chromatin accessibility in tumor tissue and potential role of open chromatin regions in the over-expression of critical cancer-related genes in HCC. Citation Format: Mekonnen Lemma Dechassa. Alterations in the chromatin accessibility in nonalcoholic steatohepatitis-associated hepatocellular 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 5372. doi:10.1158/1538-7445.AM2017-5372
Abstract 2065: Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma
Authors: Rossella Rota, Cristina Cossetti, Silvia Pomella, Alberto Gualtieri, Elena Carcarino, Carola Ponzetto, Riccardo Taulli, Lucio Miele, Franco Locatelli
Journal: Cancer Research (2017)

Abstract Rhabdomyosarcoma (RMS) in a pediatric soft tissue sarcoma expressing myogenic markers. RMS includes two histological subtypes, embryonal and alveolar, which differ clinically and molecularly. The majority of alveolar RMS expresses fusion oncoproteins such as PAX3/7-FOXO1. Fusion positive (FP) RMS are at high risk showing a dismal prognosis while fusion negative (FN) ones have a better outcome. The MET protooncogene is a target gene of PAX3-FOXO1 and is overexpressed in FP RMS. However, it is upregulated/overactivated in FN RMS as well. It concurs to disease pathogenesis and is a potential target of therapy. We have shown that MET is down-regulated by the myomiR cluster miR-1/206 that promotes myogenic-like differentiation and inhibits proliferation of RMS cells. Notch signaling is also deregulated in RMS and inhibition of either Notch1 in FN or Notch3 in both subtypes leads to tumor growth blockade. Some preliminary data from our lab indicate that the expression of miR-1/206 is induced in Notch3-silenced RMS cells. Therefore, we sought to investigate the crosstalk between MET and Notch signaling in RMS. We detected a down-regulation of MET transcript and protein in Notch3 knocked down RMS cells. In turn, MET silencing reduced Notch1 and Notch3 activation together with the levels of Notch ligands, JAG1 and DLL1. In line with this, forced expression of an activated form of MET (Tpr) resulted in Notch1 over-activation and up-regulation in FN RMS cells. Notably, a FN cell line treated for long time (more than 6 months) with growing doses of EMD, a clinically relevant MET inhibitor, showed resistance to treatment, over-activation of MET, i.e., hyperphosphorylation, and Notch1 signaling hyperactivation. These preliminary results suggest that MET and Notch signaling could crosstalk in RMS and that their co-targeting could be used to overcome drug resistance to single agent therapy. To this end, combination treatments of MET inhibitors with clinically relevant gamma-secretase inhibitors are in course. The work is supported by Associazione Italiana Ricerca sul Cancro project IG15312 to RR. Citation Format: Rossella Rota, Cristina Cossetti, Silvia Pomella, Alberto Gualtieri, Elena Carcarino, Carola Ponzetto, Riccardo Taulli, Lucio Miele, Franco Locatelli. Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma [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 2065. doi:10.1158/1538-7445.AM2017-2065
Abstract 4181: Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening
Authors: Hwani Ryu, Ah-young Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn
Journal: Cancer Research (2017)

Abstract The Wnt/β-catenin signaling pathway is critical for colorectal cancer (CRC) development, progression and metastasis. Tankyrase enzymes (TNKS1 and TANKS2), members of the PARP (Poly(ADP-ribose)polymerases) superfamily, PARsylate and target Axin for degradation via ubiquitin-proteasome pathway, leading to accumulation of β-catenin into nucleus. In addition, aberrant YAP/TAZ singling contributes to anticancer drug resistance, but inhibition of TNKS suppresses YAP/TAZ signaling through stabilizing Angiomotin (AMOT). Therefore, inhibition of TNKS has emerged as an attractive strategy for treatment of cancers. To identify potent and selective small molecule inhibitors of TNKS1, a TNKS1-ligand docking was used for computational-based virtual screen of a chemical library containing 1.6 million compounds and 24 virtual hits were further subjected to in vitro evaluation for TNKS1 inhibition. Using an in vitro TNKS1 enzyme assay, we identified a novel pyridine derivative (AZ236106) significantly inhibited TNKS1 enzyme activity in a concentration-dependent manner, but not PARP1/2. Treatment of AZ236106 stabilized Axin, reduced β-catenin in nucleus and downregulated β-catenin target genes in DLD-1 cells harboring adenomatous polyposis coli (APC) mutation. Moreover, we observed that AZ236106 inhibited accumulation of YAP in the nucleus and expression of YAP garget genes. Combination treatment of AZ236106 with either radiation or PLX4032, a BRAF inhibitor, decreased cell proliferation and increased apoptotic cell death in DLD-1 and SK-MEL28 cells, compare to AZ236106, radiation or PLX4032 alone. Our findings suggest that AZ236106 may have therapeutic potential in cancers, and could be further refined for efficacy and safety to develop a lead compound. Citation Format: Hwani Ryu, Ah-young Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening [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 4181. doi:10.1158/1538-7445.AM2017-4181
Abstract 3133: NF-κB-dependent inflammatory responses offset sorafenib cytotoxicity in hepatocellular carcinoma via TIFA
Authors: Tong-You Wade Wei, Pei-Yu Wu, Ting-Jung Wu, Ming-Daw Tsai
Journal: Cancer Research (2017)

Abstract Sorafenib is the promising first-line drug to treat advanced hepatocellular carcinoma (HCC), with the acquired resistance within 6 months in most treated patients. The epithelial-mesenchymal transition (EMT)-driven cancer metastasis contributes to sorafenib resistance via multiple signaling pathways, but the underlying molecular mechanism remains elusive. Recent studies showed that inflammatory cytokines TNF-α functionally initiates EMT through NF-κB mediated Snail activation in HCC, and that TRAF-interacting protein TIFA sustains the positive feedback loop between TNF-α and NF-κB that enhances chemoresistance in AML. Here we investigated the functional link between TIFA-regulated NF-κB inflammatory signaling and sorafenib resistance as a potential therapeutic target in the treatment of HCC. We showed that severe hepatitis induced in HCC mice promoted intrahepatic metastasis concurrently with NF-κB-driven EMT via Snail, and that HCC patients with hepatitis displayed poorer responses to sorafenib and unfavorable clinical outcome. In support, inflammatory TNF-α stimulation promoted levels of TIFA, NF-κB signaling factors, and EMT axis independent of sorafenib treatment, while silencing of TIFA or RelA perturbed sorafenib-dependent cytokine secretion in HCC cells. In addition, silencing of TIFA or RelA suppressed pro-survival factors Bcl-2 and Bcl-XL, and promoted pro-apoptotic factor BAX in response to sorafenib treatment in vitro. Consequently, HCC cells regained sorafenib chemosensitivity upon silencing of TIFA or RelA through promoted apoptosis. To further explore the therapeutic relevance, shRNAs were delivered using the liver-tropic adeno-associated virus serotype 8 in mice with orthotopic HCC xenografts, and results showed that targeting TIFA or RelA specifically enhanced sorafenib chemotoxicity resulting in more prominent tumor regression. Our results collectively showed that TIFA and NF-κB support inflammatory responses to offset sorafenib cytotoxicity, and that their targeting are therapeutically effective concomitant with sorafenib treatment in HCC. Citation Format: Tong-You Wade Wei, Pei-Yu Wu, Ting-Jung Wu, Ming-Daw Tsai. NF-κB-dependent inflammatory responses offset sorafenib cytotoxicity in hepatocellular carcinoma via TIFA [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 3133. doi:10.1158/1538-7445.AM2017-3133