bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2324: Docosahexaenoic acid-induced Nrf2 may be correlated with cell death by amplification of oxidative stress via induction of klf9 in cervical cancer cells
Authors: Jing Kaipeng , Shin Soyeon , Han Seung-Hyeon , Jeon Young-Joo , Heo Jun-Young , Kweon Gi-Ryang , Park Seung-Kiel , Park Jong-Il , Lim Kyu 
Published: August 2018

Abstract
NF-E2-related transcription factor-2 (Nrf2) is a key transcriptional factor regulating antioxidant gene expression and protection from oxidant damage. Docosahexaenoic acid (DHA) as one of ω3-polyunsaturated fatty acids has anticancer action through several mechanisms. Here we report that DHA-induced Nrf2 is related to cell death, not survival in HeLa cell. We confirmed DHA-induced apoptotic cell death using PARP cleavage, Anexin V staing, and TUNEL positive staining assay. DHA-triggering ROS production increased the level Nrf2 and decreased keap1 in dose- and time-dependent manner. Increased Nrf2 by DHA was partially Keap1 dependent. DHA activated Nrf2 signaling by increasing its translation and the Nrf2 was translocated from cytosol to nucleus. Upregulation of DHA-mediated Nrf2 was also confirmed by increase of heme oxygenase-1 (HO-1) expression. DHA-induced Nrf2 increased the level of Kruppel-like factor 9 (klf9) and then decreased thioredoxin reductase 2 (Txnrd2) in dose- and time-dependent manner. These results suggest that DHA-induced ROS increases Nrf2 and the Nrf2 is related to cell death by increase of klf9 and decrease of Txnrd2 in HeLa cells. Thus, utilization of ω3-PUFAs may represent a promising therapeutic approach for chemoprevention and treatment of human cervical cancer [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)]
Citation Format: Kaipeng Jing, Soyeon Shin, Seung-Hyeon Han, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Docosahexaenoic acid-induced Nrf2 may be correlated with cell death by amplification of oxidative stress via induction of klf9 in cervical 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 2324.
Abstract 2347: High-throughput scRNA-seq analysis using Celsee Nano-prep 250K sequencing chip on Celsee C-PREP GENESIS
Authors: Sharma Vishal Premdev , Chow William Chiro , Boniface Brian , Gleason Kyle , Payne Austin , Gogoi Priya , Handique Kalyan 
Published: August 2018

Abstract
For effective targeted therapeutics, it is critical to identify cancer mutations in cells that are often regional and heterogenic. Recent advances in single-cell mRNA sequencing (scRNA-seq) have made it possible to study intratumor heterogeneity and its role in cancer progression, metastasis, and treatment resistance. Next-generation sequencing (NGS)-based studies have identified critical genetic alterations in a variety of malignancies. However, the current workflow of existing technologies leads to significant loss of cells and thus loss of critical information. In this study we present a technology that decreases cell loss and increases efficiency of scRNA-seq. C-PREP GENESIS is a fully automated, random-access, multiple-sample processor for single-cell sequencing preparation. C-PREP GENESIS allows automated fluid dispensing and controlled pumping through Nanochips. The instrument utilizes unitized reagent cartridge for dispensing reagents for wash, lysis, cDNA synthesis and oil (for partitioning). With its automated thermocycling (4oC- 100oC), it can achieve the single cell to cDNA synthesis on beads with unique cell barcode and UMI tags in under 2 hours with an efficiency of ~80% of the 50,000 single cells captured on the nano-PREP 250K sequencing chip. The cDNA can then be retrieved from the chip for downstream library preparation. Alternatively, users can perform a targeted library prep PCR on the same instrument. Here we present scRNA-seq analysis of single cells obtained from patient tumor biopsy samples and cancer tissue culture single cells to discuss the critical mutations observed in single cells of the heterogenic tumor populations.
Citation Format: Vishal Premdev Sharma, William Chiro Chow, Brian Boniface, Kyle Gleason, Austin Payne, Priya Gogoi, Kalyan Handique. High-throughput scRNA-seq analysis using Celsee Nano-prep 250K sequencing chip on Celsee C-PREP GENESIS [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 2347.
Abstract 2356: Prioritizing cancer gene drivers defined in large-scale cancer genome analyses using the SBCDDB
Authors: Newberg Justin Y. , Mann Michael B. , Mann Karen M. 
Published: August 2018

Abstract
Next-generation sequencing approaches to identify molecular signatures of cancer have uncovered few frequently altered genes, many infrequently altered genes, and various transcriptional changes associated with cancer initiation/progression. Prioritization of genetic and epigentic alterations in various contexts is therefore important for biological discovery and therapy development. Comparative oncogenomics is a powerful approach to identify drivers that impact cancer development. Importantly, data integration across different experimental systems and data types is imperative to the success of these oncogenomics approaches. Sleeping Beauty (SB) insertional mutagenesis coupled with next generation sequencing forms a powerful cancer gene discovery framework widely used to identify and prioritize candidate drivers in mouse models of human cancers. SB has been used to model over 20 different human cancers and identify cooperating drivers underlying tumor development. Integration of SB data with human cancer genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) / Genomic Data Commons (GDC) is one way to identify and prioritize genes for biological validation and targeted therapies. Our group has built a resource, the Sleeping Beauty Cancer Driver Database (SBCDDB), to identify sets of cancer driver genes associated with specific tumor types or genetic aberrations underling cancer initiation. Using the SBCDDB, in combination with human mutation, copy-number alteration, and mRNA-seq datasets from the Broad Firehose, we have prioritized infrequently mutated driver genes in human tumors that are recurrently altered in SB tumors. Cancer drivers defined in both human tumors and in related mouse models of cancer, using distinct but complimentary methods to discover and catalog mutations, provide strong evidence for a causal role of detectable alteration in tumor initiation and/or progression. This work is an important step in a larger, comparative pan-cancer approach to better define molecular signatures that make up the tumor landscape.
Citation Format: Justin Y. Newberg, Michael B. Mann, Karen M. Mann. Prioritizing cancer gene drivers defined in large-scale cancer genome analyses using the SBCDDB [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 2356.
Abstract 2359: Adults with heterozygote carrier of immune deficiency variants have increased risk of cancer
Authors: Kim Daeyoon , Choi Murim , Seong Moon-woo , Yoon Sung-Soo , Koh Youngil , Yun Hongseok 
Published: August 2018

Abstract
Introduction: Relationship between several mendelian disorders and cancer has been reported. Although correlation between immune-deficiency disorder and cancer development is well known, most studies have been conducted on patients with established immunodeficient diseases. Rate of tumor development in recessive heterozygous carriers of immunodeficiency genes is not clear yet.
Methods: Using whole-genome sequence data from International Cancer Genome Consortium (ICGC) Pan-Cancer Analysis of Working Group (PCAWG) and 1000 Genome projects, we analyzed 110 genes which are associated with immunodeficiency disorder and cancer risk. The 110 genes are reported previously as pathogen of immunodeficiency disorder and present in OMIM database. We selected a pathogenic variant of the 110 genes based on the clinical database such as HGMD and Clivar.
Results: Total of 461 pathogenic variants were detected in both cohorts. The prevalence of pathogenic variants of Immunodeficiency disorder was 4.7% in the ICGC-PCAWG cohort and 3.3% in 1000 Genome cohort. Pathogenic variants were observed more frequently in ICGC-PCAWG than in 1000 Genome cohort (p=0.00267) (odds ratio 1.55, 95% confidence interval 1.16-2.06), implying that immune deficiency disorder increases cancer risk. Gallbladder cancer patients most frequently had pathogenic variants (25%, 3/12) followed by ovarian cancer patients (8%, 9/110). The gene with the strongest cancer-evoking potential was TYK2 (p= 4.978 × 10-7). In addition, seven genes were uncovered to be significantly associated with cancer development (RORC, ATM, RTEL1, CTSC, RAG1, PMS2 and IRAK4).
Conclusion: In conclusion, using large whole-genome sequencing global projects, we statistically prove the previous notion that immunodeficiency provokes cancer development. We identified specific germline variants associated with cancer, which would be considered as cancer-predisposing genes.
Citation Format: Daeyoon Kim, Murim Choi, Moon-woo Seong, Sung-Soo Yoon, Youngil Koh, Hongseok Yun. Adults with heterozygote carrier of immune deficiency variants have increased risk of 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 2359.
Abstract 2362: Comprehensive portrait of canonical and non-canonical splicing in cancer
Authors: Jayasinghe Reyka G. , Cao Song , Gao Qingsong , Wyczalkowski Matthew A. , Sengupta Sohini , Walter Matthew J. , Maher Christopher , Wendl Michael C. , Chen Feng , Eyras Eduardo , Lazar Alexander J. , Chen Ken , Shmulevich Ilya , Ding Li , Group The Splicing Analysis Working 
Published: August 2018

Abstract
Current annotation methods typically classify mutations as disruptors of splicing if they fall on either the consensus intronic dinucleotide splice donor, GT, or the splice acceptor, AG. As a group, splice site mutations have been presumed to be invariably deleterious because of their disruption of the conserved sequences that are used to identify exon-intron boundaries. While this classification method has been useful, increasing evidence suggests that mutations outside of the canonical splice site can lead to transcriptional changes beyond disruption of the nearest junction. In this study, we have developed the MiSplice pipeline to determine the local and global effects of genomic mutations on splicing across 33 cancer types. To evaluate the local effects of mutations on splicing, we applied MiSplice to identify splice-disrupting mutations (SDMs) and splice-creating mutations (SCMs), genome-wide. We identified 1,964 novel SCMs, of which 26% and 11% were mis-annotated as missense and silent mutations and validated 10 of 11 genes in a mini-gene splicing assay. SDM identification predicted complex splicing patterns associated with canonical splice site mutations and identified a handful of mutations in proximity to the canonical junction that disrupt splicing factor binding sites. Interestingly, further investigation of the novel neoantigens produced by SCMs and SDMs are likely several folds more immunogenic than missense mutations. To explore the global impact of mutations on splicing we focused on recurrent and adjacent mutations disrupting the spliceosomal complex and related splicing factor genes from over 400 curated splice related genes. In addition, we applied HotSpot3D to identify splice-factor mutations (SFMs) that are significantly proximal to one another. Our analysis has identified novel SFMs that disrupt the spliceosomal complex and globally impact downstream splicing targets creating novel peptide sequences and alter key cancer genes. The current study has greatly extended the insight into the transcriptional ramifications of genomic alterations by integrating DNA and RNA sequencing data and painting the portrait of alternative splicing across cancer genomes.
Citation Format: Reyka G. Jayasinghe, Song Cao, Qingsong Gao, Matthew A. Wyczalkowski, Sohini Sengupta, Matthew J. Walter, Christopher Maher, Michael C. Wendl, Feng Chen, Eduardo Eyras, Alexander J. Lazar, Ken Chen, Ilya Shmulevich, Li Ding, The Splicing Analysis Working Group. Comprehensive portrait of canonical and non-canonical splicing 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 2362.
Abstract 2370: miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell lung cancer
Authors: Vassella Erik 
Published: August 2018

Abstract
Background: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease. A global understanding of underlying molecular mechanisms of EGFR signaling may improve the management of NSCLC patients. Results: Here, we defined 17 miRNAs that are regulated by the PI3K/AKT branch of the EGFR signaling pathway. Bioinformatics analysis revealed that miRNAs that are dysregulated following PI3K/AKT inhibition act in a concerted manner to enhance the activity of the EGFR signaling pathway. These findings were closely mirrored by attenuation of miR-19b expression in NSCLC cell lines, where cell cycle progression, clonogenic growth and migration were reduced and apoptosis was enhanced. Conversely, miR-19b overexpression resulted in enhanced phosphorylation of ERK, AKT and STAT in EGFR mutant NSCLC cells. Co-treatment of NSCLC cells with the tyrosine kinase inhibitor (TKI) gefitinib and anti-miR-19b construct reduced migration and clonogenic growth in a synergistic manner suggesting that EGFR and miR-19b act together to control oncogenic processes. Serine/threonine phosphatase PP2A subunit PPP2R5E and BCL2L11 encoding BIM were identified as major targets of miR-19b. Consistent with this finding, PP2A activity was strongly enhanced in NSCLC transduced with anti-miR-19b, but not in cells co-transduced with anti-miR-19b and shPPP2R5E, suggesting that PPP2R5E is a major constituent of the PP2A complex. Accordingly, proliferation enhancement by miR-19b was due to targeting PPP2R5E. In contrast, apoptosis resistance was mainly due to targeting BCL2L11. Conclusion: Our results provide insight into the importance of targeting PPP2R5E and BCL2L11 by miR-19b in oncogenic processes of NSCLC. Attenuation of miR-19b expression could potentially be exploited in adjuvant therapy of EGFR mutant NSCLC.
Citation Format: Erik Vassella. miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell lung 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 2370.
Abstract 2373: ADA-07 suppresses solar ultraviolet-induced skin carcinogenesis by directly inhibiting TOPK
Authors: Zhang Tianshun , Wang Qiushi , Gao Ge , Ann Bode , Dong Zigang 
Published: August 2018

Abstract
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the mitogen-activated protein kinase (MAPK) cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs, and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK.
Citation Format: Tianshun Zhang, Qiushi Wang, Ge Gao, Bode Ann, Zigang Dong. ADA-07 suppresses solar ultraviolet-induced skin carcinogenesis by directly inhibiting TOPK [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 2373.
Abstract 2375: Concurrent HER or PI3K inhibition potentiates the anti-tumor effect of ERK inhibitor BVD-523 (ulixertinib) in preclinical pancreatic cancer models
Authors: Jiang Hongmei , Xu Mai , Li Lin , Highkin Maureen , Zhang Daoxiang , Li Qiong , Wang-Gillam Andrea , Lim Kian-Huat 
Published: August 2018

Abstract
To date, effective treatments for inoperable pancreatic ductal adenocarcinoma (PDAC) remain elusive. Targeting KRAS, the gene that is mutated in &gt;95% of PDAC, is a heavily pursued strategy, but unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK represents the next best strategy. However, RAF or MEK inhibitors have not shown promising clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to re-activate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. BVD-523 (ulixertinib) is a first-in-class ERK-specific inhibitor that has demonstrated anti-tumor activity in clinical trials. In this study, we showed that BVD-523 effectively inhibits transformed growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, using reverse-phase protein array analysis, we identified potential mechanisms by which PDAC cells may adopt to tolerate ERK inhibition. On this basis, we proposed and tested two rational combinatorial approaches with BVD-523 that showed promising preclinical efficacy in vitro and in mouse xenografts. Overall, we provide the first evidence that PDAC cells may readily adapt to pharmacologic ERK inhibition, and provide combinatorial therapeutic strategies that could benefit patients.
Citation Format: Hongmei Jiang, Mai Xu, Lin Li, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian-Huat Lim. Concurrent HER or PI3K inhibition potentiates the anti-tumor effect of ERK inhibitor BVD-523 (ulixertinib) in preclinical pancreatic cancer models [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 2375.
Abstract 2376: AXL receptor tyrosine kinase stimulates cell softening and cancer progression via Rac signaling pathway
Authors: Suganuma Masami , Iida Keisuke , Yokoyama Shota , Rawangkan Anchalee , Namiki Kozue , Wongsirisin Pattama 
Published: August 2018

Abstract
Cancer cells exhibit different biophysical properties, such as cell stiffness and elasticity, compared with normal cells. It is now well accepted that cell stiffness measured by atomic force microscope (AFM) is a quantitative indicator of cancer progression and metastasis. To study the role of cell softening in malignant progression, Using Transwell assays and AFM, six human non-small cell lung cancer cell lines were classified into two groups: a high motility-low stiffness (HMLS) group and a low motility-high stiffness (LMHS) group. We found a significant difference in expression of the AXL receptor tyrosine kinase, which belongs to the TAM (Tyro3, AXL, Mer) family, in the stimulation of motility and cell softening. HMLS cells expressed higher AXL and phosphorylated AXL levels than LMHS cells. Exogenous AXL gene expression in H1703 LMHS cells exhibited increased motility and decreased stiffness, along with lower levels of actin stress fibre formation. Conversely, the AXL-specific inhibitor R428 and AXL-targeting siRNA reduced motility and increased stiffness in H1299 HMLS cells. Knockdown of AXL gene stimulated both actin stress fibre formation and focal adhesion kinase phosphorylation, which inhibited tumour formation in a mouse xenograft model. Treatment with Ras/Rac inhibitor SCH 51344, which blocks disruption of actin stress fibres, exerted similar effects to AXL inactivation in H1299 and H1703-AXL cells, but not in H1703 cells (no AXL expression). Furthermore, treatment with an ROCK inhibitor, Y27632, did not show any effect in two AXL expressing cells, while it stimulated motility in H1703 cells. Considering all these results, we propose that the Ras/Rac pathway operates downstream of AXL and suppresses the Rho/ROCK pathway. Cell softening induced by AXL activation is a key biophysical property of cancer cells, and AXL is thus a new target for inhibition of malignant progression in non-small cell lung cancer.
Citation Format: Masami Suganuma, Keisuke Iida, Shota Yokoyama, Anchalee Rawangkan, Kozue Namiki, Pattama Wongsirisin. AXL receptor tyrosine kinase stimulates cell softening and cancer progression via Rac signaling pathway [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 2376.