bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4304: Development of a new nucleoside triphosphate transporter (NTP) technology for rapid DNA labeling that measures cell cycle progression in live cancer cells
Authors: Asbrock Nick , Chu Vi , Su Kevin , Kraus Tomas 
Published: August 2018

Abstract
At its core, cancer is a disease of uncontrolled cell division. Mutations in different genes cause or accelerate cancer by increasing cell division rates or inhibiting cell proliferation control mechanisms such as apoptosis and tumor suppression. Traditional DNA incorporation cell proliferation assays that label nucleic acids (BrdU, EdU) have been popular but are limited by requiring cell fixation, high cost and lengthy protocols. Here, we have developed a new NTP transporter technology that allows the incorporation of Cyanine-3 fluorescently labeled dUTP's into DNA during the S-phase of the cell cycle to measure cell proliferation in live cancer cells (U2OS). Similar cell cycle profiles were produced using this new NTP transporter technology as analyzed by FACS analysis and live cell imaging vs. BrdU based cell proliferation assays. This technology will allow new insights into cancer cell proliferation and progression.
Citation Format: Nick Asbrock, Vi Chu, Kevin Su, Tomas Kraus. Development of a new nucleoside triphosphate transporter (NTP) technology for rapid DNA labeling that measures cell cycle progression in live cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4304.
Abstract 4313: Methylated BAF155 promotes cancer metastasis by cooperating with BRD4 to potentiate genes addicted to super-enhancers
Authors: Kim Eui-Jun , Wang Yidan , Lu Li , Rui Lixin , Zhong Xuehua , Wisinski Kari B. , Xu Wei 
Published: August 2018

Abstract
Triple-negative breast cancers (TNBC) lack the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC is the most aggressive breast cancer subtype and is often associated with distant metastasis, poor prognosis, and lack of targeted treatment options. The failure to identify a few genes driving metastasis through sequencing of paired tumors at primary and metastatic sites implies that epigenetic mechanisms may play important roles in TNBC metastasis. Recently, we found that an epigenetic enzyme coactivator associated arginine methyltransferase 1 (CARM1) is highly expressed in TNBC and its high expression correlates with poor prognosis. Subsequently we identified BRG1-Associated Factor 155 (BAF155), a component of SWI/SNF chromatin remodeling complex, as a novel CARM1 substrate. Transcriptome analyses of BAF155 methylation competent and defective cell lines identified many genes involved in regulating cancer metastasis are methyl-BAF155 targets. Methylation of BAF155 was found to promote metastasis in the TNBC xenografted mouse models. We generated a methyl-BAF155 antibody that could specifically detect methylated BAF155 (me-BAF155) by IHC and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We mapped global me-BAF155 genomic association sites using ChIP-seq and discovered that me-BAF155 was highly enriched in super-enhancers (SEs), regulatory elements on chromatin that are known to drive high transcription of many oncogenes. SEs are known to recruit BRD4, a BET family bromodomain protein. Indeed, global me-BAF155 binding peaks greatly overlap with those of BRD4 binding sites. Treatment of TNBC cells with either BRD4 inhibitor JQ1 or CARM1 inhibitor TP-064 significantly reduced the expression of me-BAF155 target genes. Together our data suggest that me-BAF155 is an important epigenetic target for treatment of cancer metastasis in TNBC cells.
Citation Format: Eui-Jun Kim, Yidan Wang, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Wei Xu. Methylated BAF155 promotes cancer metastasis by cooperating with BRD4 to potentiate genes addicted to super-enhancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4313.
Abstract 4319: Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling
Authors: Cardenas Horacio , Pepin Jessica Thomes , Jiang Guanglong , Condello Salvatore , Nephew Kenneth P. , Liu Yunlong , Matei Daniela 
Published: August 2018

Abstract
Inactivating mutations of the breast cancer type 1 susceptibility protein (BRCA1) have been implicated in breast and ovarian cancer (OC) initiation. Having observed differential response of OC cells to histone deacetylase inhibitors (HDACi) dependent on the presence of a functional BRCA1, we mapped promoters marked by acetylation of lysine 9 or lysine 27 of histone H3 (H3K9ac, H3K27ac) by ChIP-sequencing, and measured gene expression by RNA-sequencing in the isogenic OC cell lines UWB1.289 carrying an inactivating mutation of BRCA1 (BRCA1-null) and UWB1.289 cells with restored BRCA1 gene (BRCA1+). Significant differences in promoter levels of H3K9 and H3K27 acetylation were associated with marked alteration of gene expression levels between BRCA-null and BRCA1+ cells and in response to the HDACi, entinostat. Pathway analyses revealed cellular movement, cellular development, cellular growth and proliferation, TGFβ1, TNF, and INF-γ among the top cellular/molecular functions and upstream regulators enriched by the absence of BRCA1 among H3K9ac differentially marked and differentially expressed genes. Importantly, the same pathways and regulators were enriched in response to entinostat in BRCA1+ cells, indicating that changes in gene expression affecting these functions and regulators in BRCA1-null cells depend on promoter-associated histone acetylation. Integrated analyses revealed that TGFβ1 and IFN-γ were also activated in BRCA1-null/or low vs. BRCA1-normal ovarian tumors in the TCGA database. IFN-γ target genes were upregulated at baseline and responded less to IFN-γ stimulation in BRCA1-null vs. BRCA1+ cells. Binding of HDAC1 to promoters of IFN-γ target genes was increased in BRCA1-null cells. Similarly, the BRCA1-null breast cancer cell line HCC1937 responded less to IFN-γ stimulation compared with HCC1937 cells in which BRCA1 was restored. The knockdown of STAT1, the main IFN-γ signaling transduction molecule, inhibited BRCA1+ cell proliferation, but did not affect BRCA1-null cells. We conclude that the transcriptome of BRCA1-null cells and tumors is altered through changes in histone acetylation affecting cancer-related pathways, including IFN-γ cellular responses. These changes could alter tumor progression in BRCA-null OC and impact response to immunotherapy.
Citation Format: Horacio Cardenas, Jessica Thomes Pepin, Guanglong Jiang, Salvatore Condello, Kenneth P. Nephew, Yunlong Liu, Daniela Matei. Epigenetic reprogramming associated with BRCA1 loss of function in ovarian cancer induces enhanced interferon gamma signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4319.
Abstract 4330: Pan-cancer analysis reveals m6A modification is functionally important in cancer
Authors: Zuo Zhixiang , Xie Yubin , Zheng Yueyuan , Nie Peng , Jiang Shuai , Zhao QI , Miao Yanyan , Ren Jian 
Published: August 2018

Abstract
N6-Methyladenosine (m6A) is the most abundant post-transcriptional modification in mammalian RNA molecules and has a critical role in many diseases, including cancer. However, the systematic investigation of the role of m6A in cancer is still lacking. We conducted a systematic analysis of the m6A-associated somatic mutations and expression of m6A writers and erasers in 3,401 cancer genomes of 12 cancer types from The Cancer Genome Atlas (TCGA) to find a potential role of the m6A machinery in cancer development. We revealed 1,973 genes with recurrent m6A-associated somatic mutations across multiple cancer types. We identified many known cancer genes, such as TP53, CTNNB1 and CDKN2A, as well as many candidate genes whose cancer-specific roles are less understood. Strikingly, liver cancer had the highest frequency of m6A-associated somatic mutations among the 12 cancer types, and these mutations were significantly enriched in metabolic pathways, such as retinol metabolism. In liver cancer, the abnormalities in m6A “writers” and m6A modification sites were significantly correlated with worse overall survival, independent of other clinical characteristics (e.g., tumor stage and race).
Implications: We for the first time consider somatic mutations relevant to the m6A modification sites to identify “driver” genes, thereby uncovering additional potential cancer “drivers” with rare mutations. Our study highlights m6A modifications as an important epigenetic mechanism of cancer development.
Citation Format: Zhixiang Zuo, Yubin Xie, Yueyuan Zheng, Peng Nie, Shuai Jiang, QI Zhao, Yanyan Miao, Jian Ren. Pan-cancer analysis reveals m6A modification is functionally important in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4330.
Abstract 4343: Molecular identification of bladder cancer gene expression subtypes
Authors: Chu In-Sun , Song Bic-Na , Leem Sun-Hee 
Published: August 2018

Abstract
Bladder urothelial carcinoma (BLCA) comprises two main types: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). To discovery the subtype of BLCA, we used gene expression data from 165 patient cohort (102 NMIBC, 63 MIBC). Three other gene expression data sets including the Sweden 1 cohort (97 NMIBC, 45 MIBC), the Sweden 2 cohort (213 NMIBC, 93 MIBC), and 408 MIBC sample from The Cancer Genome Atlas (TCGA) and 476 sample (460 NMIBC, 16 MIBC, the multicenter European UROMOL consortium). For selection of subtype-specific gene set, we used significance analysis of microarrays (SAM). Then, subtype-specific genes were trained by prediction analysis for microarrays (PAM) to build a classifier. Clustering analyses were applied to gene expression data of training set identified four molecular subtypes with different clinical outcomes. The majority of patients with class 1 were the low-grade NMIBC and associated with the prognosis of NMIBC, for cancer-specific survival (P =0.003, log-rank test). Class 2 patients, characterized by FGFR3 overexpression and downregulated immune pathways, showed the intermediate prognosis. Class 3 tumors showed high expression of cell-cycle genes and downregulated notch signaling pathway. Furthermore, high-grade NMIBC were predominantly found in class 3, indicating that NMIBC patients classified as class 3 would be more likely to progress to MIBC. Class 4 tumors, mainly composed of MIBC, were characterized by high expression of immune-related genes which is positively associated with potential response to immunotherapy. We further validated the BLCA subtypes in four independent data sets (n = 1,471), including the RNA-seq data set, by applying the 786-gene classifier onto the data sets. As expected, the progression rate of NMIBC patients classified as class 3 was significantly increased compared with other three classes in the RNA-seq data set (P &lt; 0.001, log-rank test).
Citation Format: In-Sun Chu, Bic-Na Song, Sun-Hee Leem. Molecular identification of bladder cancer gene expression subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4343.
Abstract 4363: Pharmacologic targeting of Gq reveals new pathways in uveal melanoma
Authors: Onken Michael D. , Makepeace Carol M. , Wang Shiqi , Kaltenbronn Kevin M. , Kanai Stanley M. , Broekelmann Tom J. , Cooper John A. , Blumer Kendall J. 
Published: August 2018

Abstract
Constitutively active G protein α-subunits are oncogenic drivers of several cancers, most notably in uveal (eye) melanoma (UM), which have constitutively activating mutations in GNAQ(Gαq) or GNA11(Gα11) in over 90% of tumors. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in cancer has yet to be achieved. Here we show that constitutively active Gαq in UM cells can be targeted by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically to trap constitutively active Gαq in inactive GDP-bound Gαβγ heterotrimers, and allosteric inhibition of other Gα subunits can be achieved by introduction of an FR binding site. In UM cells driven by constitutively active Gαq, FR inhibits second messenger signaling, arrests proliferation and reinstates melanocytic differentiation. At higher doses, FR also induces apoptosis. FR has no effect on BRAF-driven UM cells. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, antagonized by a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide important therapeutic targets for UM. Further, the development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors where targeting a single receptor is ineffective.
Citation Format: Michael D. Onken, Carol M. Makepeace, Shiqi Wang, Kevin M. Kaltenbronn, Stanley M. Kanai, Tom J. Broekelmann, John A. Cooper, Kendall J. Blumer. Pharmacologic targeting of Gq reveals new pathways in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4363.
Abstract 440: Single-cell whole-genome sequencing reveals somatic mutation signatures in normal somatic cells predictive of cancer later in life
Authors: Dong Xiao , Zhang Lei , Lee Moonsook , Maslov Alexander Y. , Vijg Jan 
Published: August 2018

Abstract
Single-cell sequencing for analyzing DNA mutations across the genome in somatic tissues is critically important for studying development, cancer and aging. However, current procedures are prone to artifacts and to date a reliable protocol for single-cell somatic mutation analysis remains to be developed. We address the two largest sources of artifacts, i.e., DNA denaturation-related cytosine deamination and allelic bias-driven whole genome amplification errors. We first reconfigured multiple displacement amplification (MDA) into an efficient protocol for whole genome amplification of single cells without cytosine deamination artifacts, i.e., Single Cell MDA (SCMDA). We then developed a new single-cell SNV caller (SCcaller) that distinguishes real somatic mutations and amplification errors by utilizing a SNP-based localized estimate of allelic amplification bias. The procedure was validated by comparing SCMDA-amplified single cells with unamplified clones derived from single cells from the same population.
Using this highly accurate single-cell whole-genome sequencing method we analyzed human B lymphocytes from donors varying in age from birth to over 100 year, studying both genome distribution and functional impact of base substitution mutations. Mutations per cell were found to increase with age from less than 500 in cord blood to over 3,000 in cells from individuals over 100. While overall mutations were randomly distributed across the genome with all chromosomes equally affected, 24 hotspot regions were identified, five of which were part of immunoglobulin variable regions subject to somatic hypermutation. Age-related mutation accumulation was found to be significantly slower in genomic sequences directly involved in cellular function, such as exons and gene regulatory sequences. Still, on average, B lymphocytes from aged individuals contained 3-15 damaging mutations in the transcribed part of the exome identified by RNA-seq, plus 15-50 mutations in transcription factor binding sites identified by ATAC-seq. Analysis of the spontaneous mutation spectra in these normal cells revealed signatures similar to those previously found associated with B cell leukemia and other cancers. These results indicate that cancer risk is already part of age-related mutation accumulation in normal cells. Taken together, our single-cell sequencing method provides a firm foundation for analyzing cellular genetic heterogeneity in normal human tissues.
Citation Format: Xiao Dong, Lei Zhang, Moonsook Lee, Alexander Y. Maslov, Jan Vijg. Single-cell whole-genome sequencing reveals somatic mutation signatures in normal somatic cells predictive of cancer later in life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 440.
Abstract 4401: Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck cancer
Authors: Saleh Anthony D. , Place Robert F. , Cheng Hui , Das Rita , Harris Thomas M. , Childs Geoffrey , Robertson Gordon A. , Pirollo Kathleen F. , Chang Esther H. , Chen Zhong , Waes Carter Van 
Published: August 2018

Abstract
We have developed an integrative approach to elucidate the functional role of deregulated microRNAs (miRs) and identify candidates for miR replacement therapy in cancer, applied here to head and neck squamous cell carcinomas (HNSCC). Our method involves integration of results from TCGA and other validation databases of genetic and expression data, including: miR expression, mRNA expression, copy number variation, DNA methylation. This data is then intersected with functional in vitro genome-wide miR screening for anti-proliferative miR mimics. We report that the miR-30-5p family is commonly repressed and correlates with overexpression of a broad network of proliferative and metastasis-related oncogenic mRNAs, including the growth receptors EGFR, MET and IGF1R. We show that re-expression of miR-30a-5p repressed this gene program, downstream signaling, proliferation, migration, and invasion in vitro. We have developed a chemically modified mimic of miR-30-5p with 50x improved stability in human serum, and 5X improvement in IC50 in vitro by XTT assay. We have formulated our novel miR-30a-5p mimic into Transferrin Receptor targeted nanoparticles which strongly inhibited HNSCC xenograft tumor growth, and regulated miR-30-5p family targets in vivo. Together with data linking decreased miR-30 family expression with DNA copy loss and promoter hypermethylation, and clinical disease-specific survival, for the first time, we have reported a more global picture of the function of this important tumor suppressor and identified a subset of patients that may benefit from miR replacement therapy with our novel miR-30-5p based nanomedicine.
This research was supported by NIDCD intramural projects ZIA-DC-000073, 74, and NCI grant U43CA22156701.
Citation Format: Anthony D. Saleh, Robert F. Place, Hui Cheng, Rita Das, Thomas M. Harris, Geoffrey Childs, Gordon A. Robertson, Kathleen F. Pirollo, Esther H. Chang, Zhong Chen, Carter Van Waes. Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4401.
Abstract 4403: Development of 5-FU modified tumor suppressor miRNAs as a platform for miRNA based cancer therapeutics
Authors: Fesler Andrew , Guo Shixiang , Ye Zachary , Godwin Matthew , Wang Hyaizha , Ju Jingfang 
Published: August 2018

Abstract
Despite extensive efforts to develop effective delivery technologies for nucleic acid based therapeutic agents, it remains a challenge to deliver therapeutic miRNAs to cancer cells. We have recently developed a novel approach to modify miRNAs by replacing uracil with 5-Fluorouracil (5-FU) in the guide strand of the miRNA molecule (e.g. miR-129, miR-15a). This modification combines the power of 5-FU with tumor suppressor miRNAs to create a potent, and multi-targeted therapeutic molecule without altering the function of the native miRNA. miRNA with this modification have a number of unique features such as retaining target specificity, vehicle free delivery, enhanced potency, and stability. To demonstrate the general applicability of this approach to other tumor suppressor miRNAs, in this study, we have screened a number of miRNA mimics incorporating this modification (e.g. miR-215, miR-140, miR-200c, miR-194, let-7g, miR-502, miR-506) in several major cancer types including colon cancer, pancreatic cancer, and breast cancer. Our results show that the 5-FU modified miRNAs are more potent (low nM range) at inhibiting cancer cell proliferation than the native miRNAs. More importantly, the miRNA mimics are able to eliminate chemoresistant cancer stem like cells. These modified mimics can be delivered into cancer cells without the aid of a delivery vehicle. The modification also did not alter target specificity of the miRNAs, a critical feature of these miRNA mimics. This work demonstrates the potential of this modification to be applied to a broad spectrum of miRNAs in different cancers, and represents a significant advancement in the development of therapeutic miRNAs for cancer treatment.
Citation Format: Andrew Fesler, Shixiang Guo, Zachary Ye, Matthew Godwin, Hyaizha Wang, Jingfang Ju. Development of 5-FU modified tumor suppressor miRNAs as a platform for miRNA based cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4403.
Abstract 4417: MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4
Authors: Son Ji Woong , Kim Seul-Gi , Jeong In Beom , Kwon Sun Jung 
Published: August 2018

Abstract
Changes in metabolism are key contributors to tumorigenesis and metastasis. Micro RNAs (miRNA) play critical roles in glucose and lipid metabolism. In previous studies, miRNA 181a-5p (miR-181a-5p) was shown to be a significant component in down regulation of lung cancer tissue and mesenchymal-like lung cancer cell lines. To define the role of endogenous miR-181a-5p in cancer metabolism, we performed assays for luciferase, Lactate Dehydrogenase (LDH), glucose uptake and mitochondrial ATP synthase inhibitor. It was demonstrated that miR-181a-5p inhibited aerobic glycolysis and lipid metabolism and overexpression decreased LDH and lipid content in lung cancer. Furthermore, the overexpression of miR-181a-5p diminished invasion and migration by inhibition of Sirtuin 1 (SIRT1) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Together these findings suggest that miR-181a-5p might be involved with reprograming lung cancer metabolism.
Citation Format: Ji Woong Son, Seul-Gi Kim, In Beom Jeong, Sun Jung Kwon. MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4417.