bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2483: NELFE modulates chromatin accessibility to amplify the transcription of MYC-associated genes in hepatocellular carcinoma
Authors: Zhang Kai , Dang Hien , Barry Anna 
Published: September 2020

Abstract
Global transcriptomic alterations are often observed in cancers, including hepatocellular carcinoma (HCC). How these large changes are modulated remain elusive. We have previously demonstrated that the overexpression of Negative elongation factor E (NELFE) contributes to the transcriptomic imbalance in HCC through MYC signaling, which regulates more than 15% of the genome. However, how NELFE modulates MYC to enhance the transcription of pro-oncogenic mRNAs is unknown. It is known that the status of the chromatin is essential for gene expression. Previous studies have shown that NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly in Drosophila. Here, we propose that NELFE modulates the status of the chromatin to regulate gene expression to promote hepatocarcinogenesis. Accordingly, the overexpression of NELFE and MYC in the h-TERT immortalized hepatocyte cells, HHT4, significantly enhanced cancer associated phontypes, including proliferation and colony and spheroid formation. NELFE and MYC ChIP-PCR demonstrated that both NELFE and MYC co-occupy the promoter regions of two proliferative genes, cyclin E2 and PA2G4. Furthermore, the signals of MYC and H3K27ac, a histone marker associated with open and active promoter and enhancer elements, were decreased in these regions by NELFE-depletion. These results provide a possible mechanism whereby NELFE plays an essential role in modulating the status of the chromatin to regulate MYC-induced gene expression. Current studies include the use of CRISPR/Cas9 tools to generate NELFE mutants and ATAC-seq and ChIP-seq (MYC and NELFE) to explore NELFE's role in chromatin modulation genome-wide. These assays will allow us to determine the dynamic function and pro-oncogenic roles of NELFE and their effect on the MYC targets, including cyclin E2 and PA2G4 transcripts. Key words: NELFE, chromatin, transcription, HCC, liver, MYC.
Citation Format: Kai Zhang, Hien Dang, Anna Barry. NELFE modulates chromatin accessibility to amplify the transcription of MYC-associated genes in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2483.
Abstract 2487: Mutation of the STK11 gene predicts recurrence of breast cancer
Authors: Wang Chih-Yang , Chang Yung-Chieh , Kuo Yao-Lung , Lee Kuo-Ting , Chen Pai-Sheng , Cheung Chun Hei Antonio , Shen Che-Hung , Chang Chih-Peng , Lai Ming-Derg , Shen Meng-Ru , Hsu Hui-Ping 
Published: September 2020

Abstract
Introduction: Breast cancer is the most common cancer in women, and some patients develop recurrence after standard therapy. Effective predictors are urgently needed to detect recurrence earlier.
Methods: We conducted a comprehensive study via an experimental and bioinformatics approach to detect mutated genes in breast cancer. Twenty-seven breast cancer patients who developed recurrence within 24 months postoperatively and 22 control cancer patients without recurrence were enrolled from National Cheng Kung University Hospital in Taiwan. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the mutated genes.
Results: Mutations were identified in 49 breast cancer specimens, and the most frequently mutated genes were BRCA2, TP53, APC, ATM, BRCA1, NOTCH1, TET2, NF1, TSC2, PIK3CA, TSC1, PTEN, MSH2, PTCH1, PIK3R1, STK11, RB1, BAP1, CDH1 and FBXW7. Mutation of these genes was correlated with protein phosphorylation and autophosphorylation. Among these highly mutated genes, mutations of STK11 were associated with poor prognosis and increased recurrence of breast cancer. Knockdown of STK11 in triple negative breast cancer cell lines increases transcription of cytokines and modulates immune response.
Conclusion: Our findings suggest that mutation of STK11 is correlated with early recurrence of breast cancer patients and it will become a powerful prognostic marker for recurrence of breast cancer. Suppression of STK11 signaling by gene mutation may contribute to immune escape.
Citation Format: Chih-Yang Wang, Yung-Chieh Chang, Yao-Lung Kuo, Kuo-Ting Lee, Pai-Sheng Chen, Chun Hei Antonio Cheung, Che-Hung Shen, Chih-Peng Chang, Ming-Derg Lai, Meng-Ru Shen, Hui-Ping Hsu. Mutation of the STK11 gene predicts recurrence of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2487.
Abstract 2502: Genetic and functional heterogeneity of DCIS as predictors of invasive cancer
Authors: Fortunato Angelo , Mallo Diego , King Lorraine , Hardman Timothy , Hall Allison , Marks Jeffrey R. , Hwang Shelley Shelley , Maley Carlo C. 
Published: September 2020

Abstract
Genetic diversity both between and within individual tumors constitutes a challenge to personalized cancer medicine. Intra-tumor heterogeneity provides the genetic fuel for natural selection in clonal evolution and cancer progression. Tumors with high levels of genetic heterogeneity are hypothesized to be more likely to demonstrate aggressive behavior and progress to invasion and metastasis.
We analyzed the mutational loads from separate areas of pure DCIS and compared this to genetic heterogeneity in DCIS lesions found adjacent to invasive and metastatic cancer. Two spatially distinct areas of DCIS from each case were macro-dissected and the DNA extracted from FFPE samples. To analyze the data, we developed new bioinformatics methods that allowed analysis of small amounts of degraded DNA extracted from FFPE samples across multiple regions. Our bioinformatics pipeline was optimized on a series of 28 independent technical replicates of the same DNA sample sequenced twice, as training tools to find the best filtering parameters.
Whole exome sequencing was performed on each of the two geospatially separated samples for each case. Minimum coverage for inclusion in this study was 40X over at least 50% of the exome. We used the ratio of private mutations (only in 1 area) to public (found in both areas) mutations as a measure of intra-tumor heterogeneity.
We present an approach to measure clonal heterogeneity using a bulk sequencing strategy applied to geospatially distinct foci of DCIS. We found statistically significant difference between DCIS adjacent to invasive disease and metastatic patients' genetic divergence (t-test, p=0.013). Our findings suggest that genetic and functional heterogeneity may play an important evolutionary role as a driver for invasive progression.
Citation Format: Angelo Fortunato, Diego Mallo, Lorraine King, Timothy Hardman, Allison Hall, Jeffrey R. Marks, Shelley Shelley Hwang, Carlo C. Maley. Genetic and functional heterogeneity of DCIS as predictors of invasive cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2502.
Abstract 2531: The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer
Authors: Song Yi , Deng Yan , Tang Tao , Wang Chi Chiu 
Published: September 2020

Abstract
High risk Human Papillomavirus (HPVs) is a very important etiological agent in cervical cancer. HPV types have been subdivided into low-risk types and high-risk types, which are frequently associated with invasive cervical cancer. HPV16 and HPV18 count for 70% of cervical cancer. The E6, E7 genes in the early region of HPV genome are proved to have a significant impact on progression of cervical cancer. miRNA is a kind of short non-coding RNA which regulates the gene expression on post-transcriptional and translational level, and it has been proved to have a significant impact on tumor development. Our group previously investigated the correlation of miRNAs and HPV oncogenes, and identified several differentially expressed miRNAs in cervical cancer cell lines and clinical specimens. The expression level of miR-145, miR-195 and miR-142-3p were down-regulated in cervical cancer patients. However, whether the HPV oncogenes regulate miRNAs is still unknown. In order to determine the relationship between HPV oncogenes and miRNAs. We did several experiments. We found that up/down-regulate HPV 16/18 E6 and E7 caused an decrease/increase of BRCA1, miR-145 and miR-195, and BRCA1 could increase the expression of miR-145 and miR-195 in different cell lines transfected with HPV 16/18 E6 and E7 by using qRT-PCR and Western-blot. We also found the binding activity of E2F1 and MYC to the promoter region of BRCA1, which validated by ChIP-PCR and Luciferase assay. These pathways were also validated in tumor xenograft nude mice. We also tried to find the target genes of miR-145 and miR-195, and investigated how they affect tumorigenesis in cervical cancer. These findings provided a solid foundation that HPV 16/18 E6 and E7 regulated miR-145 and miR-195 via BRCA1 in cervical cancer. It can be an important pathway for the pathogenesis of cervical cancer induced by high risk HPV. These findings could provide new ways in diagnosis and treatment for cervical cancer. They also give a new insight to investigate molecular pathways for HPV-associated cancers. We believe that further investigation will be done for the mechanisms in the future.
Citation Format: Yi Song, Yan Deng, Tao Tang, Chi Chiu Wang. The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2531.
Abstract 2540: Chemoprevention of aerosolized Let-7b in mouse lung cancer model
Authors: Zhang Qi , Pan Jing , Wang Yian , Miller Mark S. , Izzotti Alberto , You Ming 
Published: September 2020

Abstract
The delivery of microRNA (miRNA) via inhalation is a potential strategy for lung cancer prevention in high risk individuals such as current and former smokers. Previous studies have shown that intratracheal or intranasal exposure of genetically engineered mice to viral vectors expressing let-7 miRNA resulted in a reduced lung tumor burden. However, these studies were done in genetically engineered mouse models that developed highly aggressive tumors more relevant for a treatment regimen. In this study, we investigated the efficacy of let-7b in lung cancer prevention. An aerosolized let-7b miRNA formulation was tested in the benzo(a)pyrene (B[a]P) mouse model. The particle size of the let-7b miRNA aerosol has been systematically characterized as particles with sizes between 1.9 to 35 nm (average size of 29.0 nm). Following the aerosol formulation evaluation, the biodistribution of let-7b in the lung by tail vein injection and aerosolized delivery were compared. The distribution of the aerosolized let-7b produced higher levels of the miRNA in the lung compared with systematic delivery. The aerosol delivery of let-7b had no effect on animal body weight nor were there any other signs of toxicity. The development of an aerosolized let-7b formulation inhibited B[a]P - induced lung adenoma volume by 72% in A/J mice. Collectively, these findings show that aerosolized miRNA is a promising approach for lung cancer prevention.
Citation Format: Qi Zhang, Jing Pan, Yian Wang, Mark S. Miller, Alberto Izzotti, Ming You. Chemoprevention of aerosolized Let-7b in mouse lung cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2540.
Abstract 2616: RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target
Authors: Abraham Hannah , Goo Laura , Little Andrew , Yates Joel , Wu Zhifen , Merajver Sofia D. 
Published: September 2020

Abstract
RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells via influencing motility, invasion, and chemokine secretion, but as yet there is no integrated model of the precise mechanism of how RhoC promotes metastasis. As these processes require disruptions in cell-cell junctions, we use wild-type and CRISPR RhoC and RhoA knockout lines of the breast cancer cell lines SUM-149 (inflammatory breast cancer, IBC) and MDA-MB-231 (triple-negative breast cancer, TNBC) in order to assess the influence of RhoC and RhoA on their cell-cell junctions. Protein lysates from these cell lines were blotted for the adherens junction markers E-cadherin and β-catenin, as well as the tight junction markers ZO-1 and Occludin. Cells were also fixed and stained for these junction markers to further assess expression and localization. In order to measure junction stability, we conducted FITC-Dextran assays, wherein cells were grown to confluency on Transwell plates, the apical chambers were incubated with FITC-Dextran solution for 24 hours, and the fluorescence of the basal chambers was subsequently measured. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM-149 IBC and MDA-MB-231 TNBC cells results in increased epithelial morphology, cell-cell connections, and tight junction marker colocalization, as measured via immunofluorescent staining. Furthermore, RhoC knockout cells have increased junctional proteins compared to wild-type cells, as measured by Western blot. In functional assessments of junction stability, RhoC knockout cells have increased barrier integrity compared to wild-type cells, by the FITC-Dextran leakage assay. These results suggest that high expression of RhoC in cancer cells destabilizes tight junctions, although loose clusters of cells are observed depending on cell type; taken together, upregulation of RhoC activation may contribute to increased metastatic potential, in part through destabilization of tight junctions. We will report on further invasion functional assays and RNA-seq data on the RhoC knockout cell lines. Taken together, these data support an important role for RhoC in tight junction modulation, thereby advancing the evidence for a potential highly specific new therapeutic target in RhoC-driven metastases control.
Citation Format: Hannah Abraham, Laura Goo, Andrew Little, Joel Yates, Zhifen Wu, Sofia D. Merajver. RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2616.
Abstract 2634: Oral bacteria effects on oral cancer initiation and progression
Authors: Kovac Stefan , Napier Tiara S. , Scoffield Jessica , Amm Hope M. 
Published: September 2020

Abstract
Oral squamous cell carcinoma (OSCC) is the most common site of head and neck squamous cell carcinoma. It is estimated to be diagnosed in 50,000 patients this year with an overall 5-year survival rate of 64%. The tumor microenvironment has been shown to play a role in the progression of many human cancers, including OSCC. Given the complexity of the oral microbiome, we hypothesize that OSCC and oral bacteria interact to affect the tumorigenic properties of OSCC.
Methods: OSCC cells were cultured in the presence of oral pathogenic (Aggregatibacter actinomycetemcomitans (Aa), Enterococcus faecalis (Ef), Fusobacterium nucleatum (Fn)) and non-pathogenic (Streptococcus parasanguinis (Sp)) bacteria. Human oral keratinocytes (HOK) and OSCC cells were treated with oral bacteria and assessed for changes in cell proliferation and gene expression.
Results: HOK treated with Ef demonstrated significantly increased proliferation and increased expression of HES1, MMP11, and CDKN1A(p21). Of the five OSCC cell lines, Ef increased proliferation in the two cell lines that were human papilloma virus positive (HPV+) (2A3, SCC152) and in one of three cell lines that were HPV negative (HPV-, Cal27). Ef increased the expression of HES1, MMP2, CDKN1A, and GLI1 in SCC152 cell and HES1, MMP11, and CDKN1A in 2A3 cells. Ef also increased the invasion of SCC152 cells in a transwell experiment. In HPV- Cal27 cells, Ef increased MMP2 and GLI1 expression. Aa also increased proliferation in 2A3 HPV+ cells. Fn did not increase proliferation of OSCC cells, but it did increase the expression of HES1, CDKN1A, and GLI1 in SCC152 HPV+ cells.
Conclusions: Oral bacteria have direct interactions with human oral keratinocytes and cancer cells. In particular, Ef may be involved in both the initiation and progression stages of oral cancer.
Citation Format: Stefan Kovac, Tiara S. Napier, Jessica Scoffield, Hope M. Amm. Oral bacteria effects on oral cancer initiation and progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2634.
Abstract 2813: Tumor models driven by EGFR: Optimizing the preclinical profiling of EGFR-targeting agents
Authors: Posch Markus , Klett Hagen , Peille Anne-Lise , Kelter Gerhard , Maier Armin , Schüler Julia , Metz Thomas M. 
Published: September 2020

Abstract
The epidermal growth factor receptor (EGFR, HER1, ERBB1) is a driver of many human cancers. Standard of care treatment for colon, head and neck and non-small cell lung cancer includes drugs targeting EGFR. Numerous molecular alterations activating the oncogenic potential of the EGFR gene have been described including activating point mutations, point mutations causing resistance against EGFR-targeting drugs, activating deletions and truncations as well as overexpression of EGFR and its ligands, occasionally induced by gene amplification. In other situations, EGFR has been identified as a driver in the absence of any obvious molecular alterations of the EGFR gene. The discovery and development of EGFR-targeting agents depends on the availability of relevant tumor models. We provide an overview of our collection of EGFR-driven tumor models, including PDXs along with PDX-derived cell lines and human tumor cell lines. We compare sensitivity profiles of tumor models for EGFR-targeting agents obtained in vivo and in vitro and demonstrate that for EGFR-targeting agents, data obtained in 2D and 3D assays are predictive for the in vivo situation. We propose an optimized strategy for the preclinical profiling of EGFR-targeting anti-cancer agents.
Citation Format: Markus Posch, Hagen Klett, Anne-Lise Peille, Gerhard Kelter, Armin Maier, Julia Schüler, Thomas M. Metz. Tumor models driven by EGFR: Optimizing the preclinical profiling of EGFR-targeting agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2813.
Abstract 2894: XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma
Authors: Fessler Shawn , Dirksen Anouk , Collins Scott D. , Xu Ling , Lee Winnie , Wang Jason , Eydelloth Ron , Ter-Ovanesyen Elena , Zurita Jeffrey , Ditty Elizabeth , Nehilla Barrett , Clardy Susan , Clardy Susan , Carter Tyler , Avocetien Kenneth , Nazzaro Mark , Le Nam , Catcott Kalli C. , Uttard Alex , Du Bingfan , Chin Chen-Ni , Mosher Rebecca , Slocum Kelly , Qin Liuliang , Lee David , Toader Dorin , Damelin Marc , Lowinger Timothy B. 
Published: September 2020

Abstract
The Dolasynthen platform incorporates the highly potent anti-mitotic agent auristatin F-HPA (AF-HPA), with its associated DolaLock mechanism of controlled bystander effect, and enables the synthesis of antibody-drug conjugates (ADCs) with precise control of the drug-to-antibody ratio (DAR) and site-specific bioconjugation. XMT-1592 is a novel ADC comprised of an anti-NaPi2b antibody and Dolasynthen, conjugated in a site-specific manner to yield DAR 6.
NaPi2b, also known as SLC34A2, is a transmembrane sodium-phosphate transporter that is broadly expressed on tumor cells in ovarian carcinoma, NSCLC lung adenocarcinoma and other tumor types. Recent studies have shown that NaPi2b expression is enriched in the EGFR and KRAS mutant subtypes of lung adenocarcinoma.
Binding studies showed a specific, high-affinity interaction of XMT-1592 with NaPi2b that was not affected by conjugated Dolasynthen. XMT-1592 elicited potent and specific in vitro cytotoxicity against NaPi2b-expressing ovarian carcinoma cells. XMT-1592 exhibited potent and specific in vivo activity in NaPi2b-expressing tumor xenografts derived from ovarian carcinoma or lung adenocarcinoma. Consistent with the targeted delivery benefits of the ADC approach, XMT-1592 yielded high and sustained concentrations of AF-HPA to tumors but not normal tissues.
To evaluate the benefits of site-specific bioconjugation of Dolasynthen, we conducted in vitro and in vivo comparisons of XMT-1592 to a stochastically conjugated version of the ADC. XMT-1592 had improved in vivo activity, pharmacokinetics, and clinical pathology relative to its stochastic counterpart. Taken together, these results support XMT-1592 as a development candidate for the treatment of NaPi2b-expressing tumors.
Citation Format: Shawn Fessler, Anouk Dirksen, Scott D. Collins, Ling Xu, Winnie Lee, Jason Wang, Ron Eydelloth, Elena Ter-Ovanesyen, Jeffrey Zurita, Elizabeth Ditty, Barrett Nehilla, Susan Clardy, Susan Clardy, Tyler Carter, Kenneth Avocetien, Mark Nazzaro, Nam Le, Kalli C. Catcott, Alex Uttard, Bingfan Du, Chen-Ni Chin, Rebecca Mosher, Kelly Slocum, Liuliang Qin, David Lee, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2894.