bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4323: 1,25-Dihydroxyvitamin D3 inhibits oral squamous cell carcinoma cell growth via microRNA regulation
Authors: Hussein Heba Said Ismail , Wang Wei , Shan Liang , Thompson Karl , Washington Kareem , Madkour Gihane , Gu Xinbin 
Published: August 2019

Abstract
Objective: Oral squamous cell carcinomas (OSCC) is one of top ten cancers lead to death in USA. This study focused on the impacts of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on the inhibition of OSCC growth in vitro and the alteration of microRNA (miRNA) expression profile by the treatment.
Materials and Methods: 1,25(OH)2D3-associated apoptosis, cell cycle arrest, and proliferative effect in cultured OSCC cells were assessed using flow cytometry and western blotting methods. miRNA expression profiles were measured using nanoString Sprint Profiller and the Nanostring human miRNA panel. More miRNAs functional pathways were retrieved through bioinformatics using Qiagen IPA system.
Results: 1,25(OH)2D3 was found to inhibit the growth of human JHU-22 OSCC cells in a dose-dependent manner with IC50 of 1.56 x 10-6 M. High levels of apoptotic cells and related biomarkers were obtained when the cells were treated with 1,25(OH)2D3. Over 20 miRNAs were upregulated and 23 downregulated by more than two folds, in 1,25(OH)2D3 treated versus untreated JHU-22 cells. Bioinformatics analysis showed molecular functions of most dysregulated miRNAs. For example, MiR-125b-5p upregulated caspases number 2, 6, 7 in addition to upregulating apoptosis facilitator like BCL-2, BIM, and AIF.
Conclusion: Our data suggested that 1,25(OH)2D3 function as a OSCC inhibiter is through regulating miRNA expression profile and miRNA function directly or indirectly. 1,25(OH)2D3 has potential to be an anticancer agent for OSCC prevention and treatment.
Fold change of top ten unregulated and down regulated miRNAs at nine hour treatment.miRNAControl (C9)Vitamin D (D9)C9/D9hsa-miR-624-3p8283.5hsa-miR-52110272.7hsa-miR-221-5p11292.64hsa-miR-1301-3p7182.57hsa-miR-520a-3p8202.5hsa-miR-153-3p12282.33hsa-miR-122-5p16372.31hsa-miR-120615342.27hsa-miR-125b-5p68615472.26hsa-miR-450b-3p492.25hsa-miR-613219-2.33hsa-miR-147b2611-2.36hsa-miR-525-3p125-2.40hsa-miR-5196-3p+hsa-miR-6732-3p187-2.57hsa-miR-181b-5p+hsa-miR-181d-5p218-2.63hsa-miR-182-3p3212-2.67hsa-miR-941228-2.75hsa-miR-671-3p176-2.83hsa-miR-944186-3.00hsa-miR-1245b-3p246-4.00
Citation Format: Heba Said Ismail Hussein, Wei Wang, Liang Shan, Karl Thompson, Kareem Washington, Gihane Madkour, Xinbin Gu. 1,25-Dihydroxyvitamin D3 inhibits oral squamous cell carcinoma cell growth via microRNA regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4323.
Abstract 4324: Prognostic potential of DNA methylation levels of EPDR1 and CHST10 in colorectal cancer
Authors: Chu Chun-Ho , Chang Shih-Ching , Wang Hsiu-Hua , Yang Shung-Haur , Lee Te-Chang , Lai Kuo-Chu 
Published: August 2019

Abstract
Chromosomal instability (CIN), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP) are well-characterized molecular features of colorectal cancer (CRC). Aberrant DNA methylation may associate with MSI-high and CIMP-high phenotype in CRC. Studies on aberrant DNA methylation are likely to help in the identification of biomarkers clinically relevant to the process of tumorigenesis. In this study, we explored DNA methylation profile changes in CRC with MSI through genome-wide DNA methylation profiling analysis. Of 34 altered genes, three hypermethylated (pidermal growth factor, EGF; carbohydrate sulfotransferase 10, CHST10; ependymin related 1, EPDR1) candidates were further validated in 75 CRC patients. All validated genes, except EGF, were significantly correlated with MSI status. In addition, methylation of EPDR1 or CHST10 was significantly correlated with better prognosis and mutations in BRAF and TGFβR2. Beside, we found a positive correlation between the methylation of EPDR1 and CHST10. Methylation of EPDR1 was also significantly correlated with node negativity and a lower tumor stage. Negative correlations between mRNA expression and DNA methylation level of both EPDR1 and CHST10 were reported in The Cancer Genome Atlas (TCGA) dataset, revealing that DNA methylation has a crucial function in modulating expressions of EPDR1 and CHST10 in CRC cells. These results suggest that DNA methylation levels of EPDR1 and CHST10 may serve as potential prognostic markers for CRC.
Citation Format: Chun-Ho Chu, Shih-Ching Chang, Hsiu-Hua Wang, Shung-Haur Yang, Te-Chang Lee, Kuo-Chu Lai. Prognostic potential of DNA methylation levels of EPDR1 and CHST10 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4324.
Abstract 4329: Pharmaceutical means of targeting the fusion oncogene EWS-FLI1 in the Ewing family of tumors
Authors: Heisey Daniel A. , Lochmann Timothy , Calbert Marissa , Ghotra Maninderjit , Maves Yuki Kato , Boikos Sosipatros , Benes Cyril , Reynolds C. Patrick , Faber Anthony 
Published: August 2019

Abstract
The EWS-FLI1 translocation is the hallmark genomic alteration in the Ewing Family of Tumors (EWFT) a malignancy of the bone and surrounding tissue, predominantly affecting children and adolescents. Although significant progress has been made for the treatment of localized disease, patients with metastasis or who relapse after chemotherapy have less than a 30% five year survival rate. EWS-FLI is currently not pharmaceutically druggable, driving the need for more effective targeted therapies. It is well known that the EWS-FLI1 translocation induces a variety of epigenetic changes which impact tumorigenesis and disease progression. Using high throughput drug screening we have identified a novel epigenetic susceptibility in EWFT to the H3K27 demethylase inhibitor GSK-J4 (GlaxoSmithKline). Subsequent treatment with GSK-J4 leads to a decrease in H3K27 acetylation and ultimately silencing of EWS-FLI1 gene targets. We sought to fully characterize the hypersensitivity of EWFT to GSK-J4 and to elucidate the mechanisms of histone modifications caused by the EWS-FLI1 translocation in EWFT. We are examining key shifts in histone modifications at FLI1 target gene enhancer elements in the presence of GSK-J4 as a means of directly regulating FLI1 tumorigenesis. Additionally, we seek to determine the efficacy of GSK-J4 in combination with a CDK7 inhibitor (THZ1), which have shown synergy in vitro, through the utilization of patient derived xenograft models (PDX) and the identification of biomarkers of sensitivity to rationalize the use of this combination for clinical trials.
Citation Format: Daniel A. Heisey, Timothy Lochmann, Marissa Calbert, Maninderjit Ghotra, Yuki Kato Maves, Sosipatros Boikos, Cyril Benes, C. Patrick Reynolds, Anthony Faber. Pharmaceutical means of targeting the fusion oncogene EWS-FLI1 in the Ewing family of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4329.
Abstract 4338: Enhancer mapping in triple negative breast cancer as a tool for biomarker and oncogene discovery
Authors: Raisner Ryan , Bainer Russell , Gascoigne Karen 
Published: August 2019

Abstract
Triple Negative Breast Cancer (TNBC) represents a heterogeneous disease with no common drivers or effective targeted therapies. Here we use ChIP-Seq combined with RNA-Seq to map the gene-regulatory landscape of TNBC in cell lines and primary tumors. Using this approach we identify novel actionable subtypes of the disease based on enhancer activity. We also identify novel tumor-specific enhancers and associated enhancer-driven oncogenes, and confirm enhancer status as a predictive biomarker of gene dependency.
Citation Format: Ryan Raisner, Russell Bainer, Karen Gascoigne. Enhancer mapping in triple negative breast cancer as a tool for biomarker and oncogene discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4338.
Abstract 4346: PI3K pathway mediated splicing defects in ER+ breast cancers
Authors: Ladewig Erik , Fairchild Lauren , Scaltriti Maurizio , Leslie Christina , Toska Eneda , Baselga Jose 
Published: August 2019

Abstract
Activating mutations in PIK3CA, the gene encoding for the catalytic subunit (p100a), are the most common oncogenic alterations in estrogen receptor-positive (ER+). The majority of PIK3CA mutations occur within two hot spots; exons 9 and exon 20 which encode the helical (E545K) and kinase domains (H1047R), respectively. These mutations result in hyperactivation of the PI3K/AKT/mTOR pathway and provide the rationale for the development of inhibitors targeting the PI3K pathway. To this end, PI3K α-specific inhibitors are showing antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. Evidence of alternative mRNA regulation and splicing in various cancers has been described in the literature. Although, the majority of events appear to have unknown clinical significance, there is evidence alternative splicing can lead to drug resistance. The role of the PI3K pathway on transcriptional regulation and mRNA processing is not well studied. Through transcriptome analysis and cell assays in mouse MEF and human MCF10A cells we demonstrate splicing defects accrue as a result of the PI3K pathway activation by the PIK3CA H1047R mutation. PI3Ka pathway inhibitors were able to restore wildtype exon inclusion levels in these mutants, suggesting a potential clinical benefit. We propose that PIK3CA H1047R imposes mRNA differential isoform regulation by acting through the most commonly mutated PI3K pathway in ER+ breast cancers and that such mutations are targetable with PI3K pathway inhibitors.
Citation Format: Erik Ladewig, Lauren Fairchild, Maurizio Scaltriti, Christina Leslie, Eneda Toska, Jose Baselga. PI3K pathway mediated splicing defects in ER+ breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4346.
Abstract 4351: Single-cell RNA sequencing reveals transcriptomic heterogeneity in response to epigenetic inhibitors
Authors: Conery Andrew R. , Park Sungmi , Steinbaugh Michael J. , Bryant Barbara M. , Apte Shruti , Keller Patricia J. , Yuan C. C. , Bradley Bill , Bommi-Reddy Archana , Sims Robert J. 
Published: August 2019

Abstract
Histone modification is a fundamental regulatory mechanism of gene transcription and is associated with multiple diseases including cancer and inflammatory diseases. The factors that place and read these modifications can be co-opted in pathological conditions to give rise to disease-promoting transcriptional states, and thus represent promising targets for therapeutic small molecule inhibition. A central challenge in the development of epigenetic cancer therapy is the identification of transcriptionally sensitive cells within a heterogeneous population as a way to maximize therapeutic efficacy. To explore this challenge, we used single cell RNA-sequencing to characterize the transcriptional response of intrinsically heterogeneous human cancer and primary cell populations to small molecule inhibitors of epigenetic factors including the BET bromodomains, EZH2 methyltransferase, and CBP/EP300 acetyltransferase. Through clustering and differential expression analysis, we show that bulk transcriptional response in a mixed population of primary or tumor cells can be driven by a profound response in a hypersensitive subpopulation. Further, through the use of trajectory analysis, we show that epigenetic inhibitors can skew cell fate or differentiation status depending on the heterogeneity of the starting population. Overall, our results demonstrate the value of single cell transcriptomics for understanding the response of cell populations to epigenetic small molecule inhibitors and for enhancing the therapeutic potential of targeting pathogenic transcriptional programs.
Citation Format: Andrew R. Conery, Sungmi Park, Michael J. Steinbaugh, Barbara M. Bryant, Shruti Apte, Patricia J. Keller, C. C. Yuan, Bill Bradley, Archana Bommi-Reddy, Robert J. Sims. Single-cell RNA sequencing reveals transcriptomic heterogeneity in response to epigenetic inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4351.
Abstract 4384: Role of EIF4G1 in non-small cell lung cancer pathogenesis and targeted therapy
Authors: Qin Zhiqiang , Dai Lu , Valle Luis Del 
Published: August 2019

Abstract
Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, which represents the number one killer among cancers in US. The majority of lung cancer patients doesn't respond well to conventional chemo-/radio-therapeutic regimens and have a dismal 5-year survival rate of ~15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but their outcome/prognosis is far from satisfactory. The translation initiation EIF4F complex has been shown to play important roles in cancer progression. As an important component of the EIF4F complex, EIF4G1 serves as a scaffold and interacts with several other initiation factors such as EIF4E and EIF4A, and help to initiate cap-dependent translation in mammalian cells. EIF4G1 is overexpressed in a variety of cancers, but its functional role, clinical relevance and potential role as a therapeutic target in NSCLC remain largely unknown. Our recent data demonstrate that EIF4G1 expression level is much higher in NSCLC primary tumors than in paired adjacent normal tissues as well as in NSCLC cell lines than in the normal bronchial epithelial cells. Directly targeting EIF4G1 by RNAi or selective small-molecule inhibitors significantly reduce NSCLC cell proliferation, anchorage-independent growth in vitro as well as tumor progression in vivo. Our recent protein array and proteomics analyses indicate that EIF4G1: 1) has a complex interactome network in NSCLC cells; 2) appears to control the expression of a unique subset of the cellular proteome when compared to normal cells, which are closely related to NSCLC cells survival. Taken together, our data support that EIF4G1 plays a critical role in NSCLC survival, oncogenesis and tumor progression, and may serve as a novel and promising therapeutic target for improving NSCLC treatment.
Citation Format: Zhiqiang Qin, Lu Dai, Luis Del Valle. Role of EIF4G1 in non-small cell lung cancer pathogenesis and targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4384.
Abstract 4391: Disruption of the translation initiation complex by eIF4A mutant inhibits prostate tumor growth in vivo
Authors: Singh Puja , Chen Hanyong , Li Hanxuan , Chi Young-In , Liu Bin , Lu Junxuan , Li Wei , Dong Zigang , Deng Yibin 
Published: August 2019

Abstract
Translation initiation in cancer cells is the rate-limiting step of oncogenic mRNAs translation/protein synthesis and is primarily mediated by the eukaryotic translation initiation factor 4 F (eIF4F) complex that consists of three subunits: eIF4E, which binds the cap of mRNA; eIF4A, an RNA helicase implicated in unwinding mRNA structure; and a scaffold protein eIF4G. Our prior crystal structure determination of human eIF4A in complex with Heat 1 domain of eIF4GI (722-999) revealed that eIF4G interacts with both N- and C-terminal domains of human eIF4A (eIF4A1-NTD and eIF4A1-CTD). Utilizing structural information gained from this complex, we generated a series of eIF4A mutants (eIF4A1-NTD: E41K, R45D, Y48A and eIF4A1-CTD: T271A, R324D, D296A/T298A) in order to identify the crucial site(s) of interaction with eIF4G Heat 1 domain. Using in vitro binding studies, we demonstrated that amongst various mutants tested, eIF4A-CTD (eIF4A1R324D) mutant disrupted the eIF4A/eIF4G Heat 1 complex formation, mirroring the binding residue E809K mutant of eIF4G that also interrupted eIF4A/eIF4G Heat 1 interaction. Given that eIF4G has an additional eIF4A-binding site named Heat 2 domain, we further investigated whether eIF4A1R324D mutant is able to disrupt binding to full-length eIF4G protein in vivo. Surprisingly, overexpression of Flag-tagged eIF4A1R324D in prostate cancer cell line blocked interaction with exogenous eIF4G as well as endogenous eIF4G. Taken together, these results strongly suggest that eIF4A1R324 residue plays a crucial role in mediating eIF4A/eIF4G complex formation in vivo. Furthermore, overexpression of eIF4A1R324D mutant significantly blocked oncogene c-myc and Bcl-2 mRNA translation thereby inhibiting prostate tumor growth in vivo. To conclude, our studies provide a previously unexplored strategy to identify small-molecule compounds disrupting eIF4A-eIF4G complex by targeting the pocket spanning eIF4AR324 and its binding site residues on eIF4G for cancer therapy.
Citation Format: Puja Singh, Hanyong Chen, Hanxuan Li, Young-In Chi, Bin Liu, Junxuan Lu, Wei Li, Zigang Dong, Yibin Deng. Disruption of the translation initiation complex by eIF4A mutant inhibits prostate tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4391.
Abstract 4471: Commercial gene expression tests for prostate cancer prognosis provide paradoxical estimates of race-specific risk
Authors: Creed Jordan H. , Berglund Anders E. , Rounbehler Robert J. , Awasthi Shivanshu , Cleveland John L. , Park Jong Y. , Yamoah Kosj , Gerke Travis A. 
Published: August 2019

Abstract
Background: Current National Comprehensive Cancer Network (NCCN) guidelines recommend three gene expression-based tests for prostate cancer (PCa) prognosis in men with low or favorable intermediate risk disease: Decipher, Oncotype DX Prostate, and Prolaris. The three tests feature varying numbers of genes with minimal overlap. Importantly, development and validation efforts for all three panels were undertaken in predominantly European American men (EAM) cohorts, and limited research exists on the value of such signatures in African American men (AAM), who have poorer PCa outcomes. Here, we explored differences in gene expression between EAM and AAM for the three panels recommended by the NCCN for PCa prognosis.
Methods: 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using Nanostring for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. Differential expression and intrapanel co-expression by race were assessed using Mann-Whitney tests and Spearman’s correlations, respectively. A continuous expression-based risk score was approximated for each panel with higher scores indicating worse outcomes. Race-specific risks were compared using Mann-Whitney tests and Spearman’s correlations.
Results: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, though the magnitudes of expression differences were small. Co-expression patterns were more strongly preserved by race group for Oncotype DX and Decipher versus Prolaris (integrative correlations of 0.87, 0.73, and 0.62, respectively). Paradoxically, poorer prognosis was estimated in EAM versus AAM for Prolaris and Oncotype DX (p = 0.01 for both), whereas worse prognosis was predicted for AAM versus EAM using Decipher (p &lt; 0.001).
Discussion: Due to observed racial differences across three commercial gene expression panels for PCa prognosis, caution is warranted when applying these panels in clinical decision-making in AAM. Replication of our findings directly on the commercial panels with long-term follow-up is warranted.
Citation Format: Jordan H. Creed, Anders E. Berglund, Robert J. Rounbehler, Shivanshu Awasthi, John L. Cleveland, Jong Y. Park, Kosj Yamoah, Travis A. Gerke. Commercial gene expression tests for prostate cancer prognosis provide paradoxical estimates of race-specific risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4471.
Abstract 4485: Enhancing antitumor immune responses with clinical BET bromodomain inhibitor RG6146
Authors: Hogg Simon J. , Wellinger Lisa , Rohle Daniel , Johnstone Ricky W. 
Published: August 2019

Abstract
The BET family of proteins bind to acetylated lysine residues on histone proteins and transcription factors to co-activate gene expression. BET proteins regulate the expression of oncogenes and can control the activity of various oncogenic transcription programs and have thereby emerged as therapeutic targets for the treatment of cancer. RG6146 is a novel non-covalent inhibitor of BET proteins that is in early phase clinical trials for the treatment of haematological and solid malignancies. The anti-tumor activity of BET inhibitors has primarily been attributed to tumor cell intrinsic effects, however increasing evidence suggests BET inhibitors modulate anti-tumor immune responses. Here, we examined the anti-solid tumor activity of RG6146 and evaluated the ability of RG6146 to enhance anti-tumor CD8+ T-cell responses.
To model anti-tumor CD8+ T-cell responses in vitro, syngeneic colon and breast tumor cells expressing ovalbumin (Ova) antigen were co-cultured with activated CD8+ T-cells derived from OT-1 transgenic mice. RG6146 functionally increased the activity of both wild-type and perforin-deficient OT-1 T-cells, leading to significantly enhanced T cell-mediated tumor cell death in a time- and dose-dependent manner. Mechanistic studies revealed that enhanced tumor cell death induced by RG6146 was dependent upon CD8+ T-cell derived tumor necrosis factor-α (TNF-α), independent of perforin/granzyme-dependent granule exocytosis. As RG6146 did not increase TNF-α production in CD8+ T-cells, we hypothesized RG6146 may sensitize tumors cells to TNF-α. Indeed, screening of cell lines revealed that BET inhibition significantly enhanced TNF-α-induced cell death in solid tumors of diverse origin. Underlying this response, we demonstrate using RNA- and ChIP-sequencing that BET inhibition suppresses transcription of pro-survival NF-kB target genes to elicit a potent pro-apoptotic phenotype. Finally, using syngeneic solid tumor models, we demonstrated that the adaptive immune system promotes the efficacy of RG6146 and evaluated the ability of RG6146 to therapeutically augment cancer immunotherapies in vivo.
Taken together, these data demonstrate that RG6146 is a potent BET bromodomain inhibitor with multi-faceted anti-cancer activity against solid tumors. We have identified a novel immunological TNF-α-dependent mechanism of bystander tumor killing by which BET inhibitors promote anti-tumor responses in vivo. Finally, we provide evidence that BET inhibition will augment the activity of cancer immunotherapies, establishing a strong rationale to evaluate these combinations in the clinic.
Citation Format: Simon J. Hogg, Lisa Wellinger, Daniel Rohle, Ricky W. Johnstone. Enhancing antitumor immune responses with clinical BET bromodomain inhibitor RG6146 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4485.