bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3539: Impact of formalin time on targeted NGS performance in FFPE tissue
Authors: Blomquist Thomas M. , Crawford Erin , Willey James , Xu Joshua ,   Onco-panel Working Group of the Sequencing Quality Control Phase 2 (SEQC2) Consortium
Published: August 2019

Abstract
Targeted next generation sequencing (NGS) panel testing is now a standard of care for management of advanced stage cancer. At present, most targeted NGS oncology testing occurs with formalin fixed paraffin embedded (FFPE) tissue. This is due to the established utility and prevalence of FFPE in routine histologic classification, grading, staging, and ancillary testing. In addition, FFPE materials are an optimally suited medium for determining adequacy of the specimen prior to downstream NGS targeted panel testing. For these reasons, as well as a growing trend of minimally invasive procedures, clinical specimens are increasingly prioritized for FFPE to meet the bulk of standard oncology care. Currently, formalin fixation time guidelines do exist for specific immunohistochemical and in-situ hybridization oncology tests. However, specific FFPE processing guidelines have yet to be established that would optimize targeted NGS panel testing performance.
In this study, our aim was to develop contrived FFPE materials using the FDA-led Sequencing Quality Control Phase II (SEQC2) consortium working group 2 (WG2) cell line materials. The overarching goal was to use these FFPE materials to identify an upper limit of formalin time associated with minimal impact on somatic variant calling performance in targeted NGS oncology panels. The SEQC2 - WG2 normal lymphoblast cell line was selected as a well-characterized test material to undergo systematic alteration in formalin fixation time (1, 2, 6 and 24 hours) prior to “routine” tissue processing and embedding (FFPE). These FFPE cell-block materials, derived from a single sample source (with both extracted FFPE DNA as well as shaved sections), were distributed to multiple labs running various targeted NGS amplicon and hybridization oncology panels.
The expected outcome of these studies is to provide general guidance to the community on how formalin time in FFPE specimens impacts targeted NGS oncology panel testing performance. In addition, we hope to identify genomic regions (internal control regions) that serve as markers for the full range of formalin time FFPE-effect. This information will assist in improving the lower limit of detection for variant calling (&lt;5% variant allele frequency).
Citation Format: Thomas M. Blomquist, Erin Crawford, James Willey, Joshua Xu, Onco-panel Working Group of the Sequencing Quality Control Phase 2 (SEQC2) Consortium. Impact of formalin time on targeted NGS performance in FFPE tissue [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 3539.
Abstract 3540: A complete solution for high throughput single cell targeted multiomic DNA and RNA sequencing for cancer research
Authors: Dhingra Dalia , Gokhale Kaustubh , Li Nianzhen , Mendez Pedro , Wang Shu , Manivannan Manimozhi , Sciambi Adam , Jones Keith , Silver Charlie , Eastburn Dennis , Ruff David 
Published: August 2019

Abstract
Recent advancements in single cell analysis technologies are now able to provide insights into genomic DNA content, RNA expression and protein surface markers. In bulk assays, the effect of genetic variation on gene expression would be masked by the heterogeneity inherent in tumor cells. Additionally, for cancer immunotherapy studies that rely on gene editing, single cell resolution is necessary to minimize possible off target effects. However, the ability to simultaneously interrogate multiple intracellular analytes, such as genomic DNA and RNA, have proved difficult to implement in a high throughput single cell workflow. We report the development of a complete solution that enables both targeted genomic DNA and RNA sequencing from individual cells.
This workflow relies on the Tapestri microfluidic droplet platform, where up to 20,000 cells can be sequenced in each run. Leveraging proprietary cell barcoding, novel primer design strategies and enzymatic manipulation of cellular contents, DNA and RNA multiplex targeted sequencing panels provide for independent barcoded sequence information from both overlapping mRNA and corresponding genomic DNA regions. In addition, amplification primers can be designed to target separate gDNA and non-overlapping RNA transcript. Sequencing is followed by an integrated analysis solution that assigns the reads from both the gDNA and RNA to each cell.
Feasibility of the targeted nucleic acid workflow has been shown with inputs from mixed cancer cell lines. A targeted sequencing panel with overlapping mRNA and gDNA regions was designed covering oncogenes, tumor suppressor genes, and known fusions. Expected SNVs and indels were detected and gene expression measured for thousands of cells per run with high cell recovery. This complete solution for single cell multiomics on the Tapestri platform has the power to quantitatively and unambiguously link genotypic and phenotypic data, giving insight into cancer progression.
Citation Format: Dalia Dhingra, Kaustubh Gokhale, Nianzhen Li, Pedro Mendez, Shu Wang, Manimozhi Manivannan, Adam Sciambi, Keith Jones, Charlie Silver, Dennis Eastburn, David Ruff. A complete solution for high throughput single cell targeted multiomic DNA and RNA sequencing for cancer research [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 3540.
Abstract 3556: MiR-506 suppresses tumor progression by reprogramming macrophage polarization in pancreatic ductal adenocarcinoma
Authors: Sun Longhao , Song Qianqian , Tian Weijun , Zhang Zhixiang 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancy owing to its aggressive nature and tumor-associated macrophages (TAMs) significantly promote disease progression by representing an immunosuppressive phenotype in PDAC. Macrophages could be functionally reprogrammed to opposite phenotype owning to different microenvironment and STAT3 (signal transducer and activator of transcription 3) activation may play an essential role in TAM polarization, directly contributing to local immunosuppression. Our recent study demonstrated that MiR-506 functioned as a tumor suppressor in many cancer types through the regulation of multiple pathways and directly targeted STAT3 in PDAC cells. In this study, we hypothesized that MiR-506 could affect tumor microenvironment and exert a tumor suppressive function in PDAC by reprograming TAM polarization through targeting STAT3 in TAM. Our results provided evidence that MiR-506 downregulation was associated with less immunosuppressive TAMs accumulation and better prognosis in human PDAC. MiR-506 could reduce the infiltration of immunosuppressive TAMs and inhibit the PDAC progression in mouse model. MiR-506 reprogramed macrophage polarization from an immunosuppressive phenotype to immune-activated phenotype through direct targeting the STAT3 axis. Silencing and inhibiting STAT3 recapitulated the effects of MiR-506. These findings expand the known mechanisms of MiR-506-mediated tumor suppression to reprogramming TAM polarization and suggest a strategy for using MiR-506 as an anti-STAT3 approach to PDAC immunotherapy.
Citation Format: Longhao Sun, Qianqian Song, Weijun Tian, Zhixiang Zhang. MiR-506 suppresses tumor progression by reprogramming macrophage polarization in pancreatic ductal adenocarcinoma [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 3556.
Abstract 3560: MicroRNA-665 promotes metastasis of breast cancer by targeting nuclear receptor subfamily 4 group A member 3
Authors: Zhao Xinge 
Published: August 2019

Abstract
Background: It is the result of metastasis to the lymph nodes or other organs that leads breast cancer (BC) patients to death. Then the early detection of metastasis in BC is helpful to regulate progression of BC and then predict prognosis of BC patients. Since the abnormal level of miRNAs are bound up with BC and metastasis, of which may act as biomarkers to predict prognosis of BC, we find that expression level of miR-665 is ectopic up-regulated in BC patients and it may serve as an estimable biomarker of prognosis of BC patients. Methods: The expressions of miRNA were detected by our current microarray system and verified by quantitative real-time reverse transcription-PCR (qRT-PCR). In Student’s t-test and Kaplan-Meier analysis, the levels of miR-665 were positively correlated with poor survival in BC patients. Multivariate survival analysis identified either miR-665 expression or TNM stage as an independent prognostic factor of BC. Diverse roles of miR-665 played in various cellular functions were examined by loss-of-function and gain-of-function effects in vitro and in vivo. Dual-luciferase reporter gene experiment was then used to confirm the direct complementation between miR-665 and NR4A3, accompanied by activating the epithelial-mesenchymal transition (EMT). Furthermore, siRNAs targeting NR4A3 were used to rescue cell migration and invasion in miR-665 knockdown cells. Results: Expression of miR-665 was upregulated which predicted poor prognosis in BC patients. Since miR-665 may regulate key processes of tumorigenesis, targeting of NR4A3 was proved to promote cell migration and invasion by activating the EMT. Accordingly, either silencing of miR-665 or over-expressing of NR4A3 rescued the migration and invasion phenotype in vitro. Conclusions: Our study suggests that miR-665 plays an important part in progression of BC and promotes cell migration as well as invasion by down-regulation of NR4A3. The data collectively indicate that miR-665 is an onco-miRNA and may represents a potential predictor for diagnosis and prognosis of BC.
Citation Format: Xinge Zhao. MicroRNA-665 promotes metastasis of breast cancer by targeting nuclear receptor subfamily 4 group A member 3 [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 3560.
Abstract 3566: SLCO4A1-AS1 promotes tumorigenesis of colorectal cancer by stabilizing SLCO4A1
Authors: Choi Yuri , Kwon Chae Hwa , Lee Seon Jin , Jeon Daye , Park Do Youn , Lee Sojeong , Kim Ahrong 
Published: August 2019

Abstract
Long noncoding RNAs (lncRNAs) constitute an important component of tumor biology, but the molecular mechanism through lncRNAs modulating colorectal cancer (CRC) development and progression remains unclear. Herein we analyzed RNA sequencing data of CRC patients (147 tumor and 47 matched normal tissues) to identify significant lncRNAs involved in CRC. We found 6032 lncRNAs (15%) and selected three up-expressed (ELFN1-AS1, SLCO4A1-AS1, and LINC02418) and six down-expressed (MIR22HG, BCYRN1, SATB2-AS1, LINC01752, CMAHP, and LINC01082) lncRNAs according to fold change and p-value. In Kaplan-Meier survival analysis, CRC patients with high expression of SLCO4A1-AS1 had poorer prognosis than the patients with low expression of SLCO4A1-AS1, and the other lncRNA expressions were not associated with prognosis. To concentrate on the biological function of SLCO4A1-AS1, we investigated the relationship between SLCO4A1-AS1 and SLCO4A1. They were validated in tumor and normal tissues by qRT-PCR and SLCO4A1 expression was also confirmed by immunohistochemistry, indicating their positive correlation. After knocking down of SLCO4A1-AS1, SLCO4A1 protein level was decreased and cell proliferation was suppressed in CRC cell lines. However, SLCO4A1-AS1 level was not changed by knock-down of SLCO4A1. It demonstrated that SLCO4A1-AS1 plays oncogenic role through influencing on SLCO4A1. Thus, SLCO4A1-AS1 might be useful biomarkers for CRC diagnosis and prognosis.
Note: This abstract was not presented at the meeting.
Citation Format: Yuri Choi, Chae Hwa Kwon, Seon Jin Lee, Daye Jeon, Do Youn Park, Sojeong Lee, Ahrong Kim. SLCO4A1-AS1 promotes tumorigenesis of colorectal cancer by stabilizing SLCO4A1 [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 3566.
Abstract 3576: MALAT1 is essential for A-NHEJ pathway choice during B cell immunoglobulin class switch recombination
Authors: Zhao Jianjun , Hu Yi , Lin Jianhong , Fang Hua 
Published: August 2019

Abstract
Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been found high expressed in multiple cancer type including B cell lymphoma and multiple myeloma. In human cancer murine models, deficiency of MALAT1 reduce the tumor burden and malignancy phynotype. We have identified MALAT1 in alternative-non-homozygous end joining(A-NHEJ) pathway by binding to PARP1 and LIG3 in multiple myeloma cells, two key components of the A-NHEJ protein complex. To investigate requirments for MALAT1 in A-NHEJ pathway, by using MALAT1 deficient mice, we found that the contribution of MALAT1 in the context of AID induced DNA breaks in CSR of B cells in mice. MALAT1 is required for A-NHEJ DNA repair pathway, but not the NHEJ pathway, which is the major DNA repair pathway for CSR. To further prove the hypothesis that MALAT1 promote A-NHEJ pathway in B cells, we have engineered mice that conditionally overexpress MALAT1 in B lymphocytes confers a strong A-NHEJ activity in CSR. More importantly, we also found IgH/c-myc translocations are promoted in MALAT1 B cell specific transgenic mice. Thus, we identified MALAT1 as a critical noncoding RNA in regulating A-NHEJ pathway during CSR.
Citation Format: Jianjun Zhao, Yi Hu, Jianhong Lin, Hua Fang. MALAT1 is essential for A-NHEJ pathway choice during B cell immunoglobulin class switch recombination [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 3576.
Abstract 3585: Amino acid transporter SLC6A14: A novel drug target for colorectal cancer
Authors: Sikder Mohd Omar Faruk , Sivaprakasam Sathish , Ganapathy Vadivel 
Published: August 2019

Abstract
SLC6A14 is a Na+/Cl− -dependent amino acid transporter capable of transporting 18 of the 20 proteinogenic amino acids, including arginine, leucine (mTOR activators) and glutamine (necessary for nucleotide biosynthesis). This transporter is expressed at basal levels in normal colon but significantly upregulated in colorectal cancer (CRC). However, the relevance of this upregulation to disease progression remains unknown. We postulated that deletion of SLC6A14 or pharmacological blockade of its function would suppress CRC by depleting amino acids and interfering with mTOR signaling selectively in tumor cells. To test this postulate, we first used Slc6a14-null mice. With two different models of spontaneous CRC (Apcmin/- and DSS/AOM), we found the tumor incidence and tumor growth were much lower in mice with Slc6a14-null background than in mice with Slc6a14. To evaluate the impact of pharmacologic blockade of the transporter on tumor growth we used a syngeneic tumor mouse model with MC-38 cells (a mouse CRC cell line); blockade of Slc6a14 with alpha-methyl tryptophan (α-MT) markedly reduced tumor growth. We then determined the transcriptome profiles of colonic epithelial cells and colonic non-epithelial cells from wild type mice and Slc6a14-null mice by RNAseq. There were hundreds of genes that were either upregulated or downregulated in the null mice. Ingenuity pathway analysis (IPA) of these data revealed predictive activation of canonical AMPK signaling pathway in colonic epithelial of Slc6a14-null mice. AMPK has anticancer activities by modulating multiple pathways including negatively regulating mTOR signaling. Moreover, upstream analysis showed predictive inactivation of two important tumor growth and survival signaling pathways ERK and EGF in the colon of the null mice. Likewise, significant upregulation of APC downregulated 1 (APCDD1) in epithelial cells in null mice implies predictive suppression of canonical Wnt signaling pathway. We also found marked differences in fecal microbiota as a result of Slc6a14 deletion. There was an increase in the relative abundance of beneficial microbiota including those capable of generating short chain fatty acids and lactic acid in null mice. We conclude that deletion of Slc6a14 or its pharmacological blockade protects against CRC by inducing amino acid starvation in tumor cells, thereby causing changes in multiple signaling pathways and in colonic microbiome. These studies identify SLC6A14 as a novel drug target for the treatment of colorectal cancer.
Citation Format: Mohd Omar Faruk Sikder, Sathish Sivaprakasam, Vadivel Ganapathy. Amino acid transporter SLC6A14: A novel drug target for 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 3585.
Abstract 3606: Blockade of the PPARα metabolic checkpoint with TPST-1120 suppresses tumor growth and stimulates anti-tumor immunity
Authors: Whiting Chan C. , Stock Nick , Messmer Davorka , Olafson Traci , Metzger Derek , Enstrom Amanda , McDevitt Jennifer , Spaner David , Prasit Peppi , Panigrahy Dipak , Laport Ginna 
Published: August 2019

Abstract
Tumors evolve to modulate metabolism to promote their own survival and to suppress tumor-specific immunity. Hypoxic conditions in the tumor microenvironment (TME) induce fatty acid oxidation (FAO), and diverse malignancies are reliant on this metabolic pathway. Additionally, suppressive immune cell populations including M2 macrophages, myeloid-derived suppressor cells and regulatory T cells preferentially utilize FAO. Peroxisome proliferator-activated receptor alpha (PPARα) is the principal transcription factor that regulates the expression of FAO genes, and this metabolic checkpoint is critical for tumor proliferation. TPST1120 is a first-in-class selective competitive antagonist of the human PPARα. To test the hypothesis that blocking FAO with TPST-1120 confers anti-tumor efficacy, we assessed TPST-1120 in multiple syngeneic and xenograft mouse models. Blockade of PPARα with TPST-1120 mediated potent anti-tumor immune responses and significant tumor regression in syngeneic models of breast, lung, colon, pancreatic and melanoma in addition to xenograft models of CLL, AML, pancreatic and melanoma cancers as a monotherapy or in combination with chemotherapy. In pancreatic and breast cancer models, TPST-1120 augmented regression of tumor growth in combination with chemotherapy. In combination with anti-PD1, TPST-1120 treatment resulted in significant reduction of tumor growth in ovarian orthotopic (ID8) and colon (MC38) models; cured mice were completely protected against autologous tumor challenge, strongly suggesting immunological T cell memory against the primary tumor. Studies in genetic knock-out mice indicated that macrophages and antigen cross-presenting dendritic cells are required for TPST-1120 activity, mediated through thrombospondin-1(TSP-1) and stimulator of interferon genes (STING). Consistent with prior reports, inhibition of PPARα with TPST-1120 skewed macrophages in vivo toward an M1 effector phenotype. These results provide the rationale for evaluating TPST-1120 in patients with advanced malignancies. A Phase 1/1b open-label, dose-escalation and dose-expansion study of TPST-1120 as a single agent or in combination with systemic anti-cancer therapies is planned in early 2019.
Citation Format: Chan C. Whiting, Nick Stock, Davorka Messmer, Traci Olafson, Derek Metzger, Amanda Enstrom, Jennifer McDevitt, David Spaner, Peppi Prasit, Dipak Panigrahy, Ginna Laport. Blockade of the PPARα metabolic checkpoint with TPST-1120 suppresses tumor growth and stimulates anti-tumor immunity [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 3606.
Abstract 3635: RNA-based nanostructures for therapeutic siRNA delivery
Authors: Ke Yonggang , Shin DongMoon , Chen Georgia 
Published: August 2019

Abstract
Short interfering RNA (siRNA) has emerged as a promising molecular therapeutic tool for targeted cancer treatment. However, systemically administered siRNA has demonstrated only limited success, due to limited delivery to cancer cells. Therefore, the lack of a robust and versatile siRNA delivery system is a critical issue in translating this therapeutic tool for cancer treatment. Recent developments in DNA nanotechnology have made programmable DNA nanoparticles (DNPs) a potent drug delivery platform. This study focuses on the development of a novel RNA-based siRNA delivery system to knockdown Bcl2 gene, as a targeted cancer therapeutic. By eliminating the use of DNA, the RNA-based nanodelivery can potentially create more robust siRNA delivery vehicles for targeted cancer therapeutics.
Citation Format: Yonggang Ke, DongMoon Shin, Georgia Chen. RNA-based nanostructures for therapeutic siRNA delivery [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 3635.