bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1423: Integrative analysis predicts lncRNA regulating gene alternative splicing in breast cancer
Authors: Zhou Yunyun 
Published: August 2018

Abstract
Background: Non-coding region occupies 98% of the whole human genome and plays a
regulatory role for protein-coding genes. About 95% of the protein-coding genes undergo
alternative splicing, however, limited understandings for the complexity of alternative splicing
(AS) mechanisms. Recent studies reported that some aberrant alternative splicing are
associated with cancer development. Cancer-specific AS could be regulated by long non-
coding RNAs (lncRNAs) directly or indirectly through other intermediate molecules . LncRNAs
regulate gene splicing either by binding to their splicing factor proteins or competing with
miRNAs to influence their targeted genes. Therefore, it is critically important to develop an
effective computational framework capturing the lncRNAs regulatory mechanism in the process
of AS from heterogeneous molecular relationships.
Method: To model the complicated regulation mechanism in splicing event, we developed a
integrative analysis framework based on machine learning algorithms. We firstly identified
breast cancer-specific lncRNAs and AS genes by edgeR differential gene analysis from TCGA
RNAseq tumor (n=1101) /normal (n=139) samples. Then we built co-expression network based
on Spearman correlation pairwise distances from these cancer-specific lncRNAs and AS. We
ranked top lncRNAs regulating alternative splicing in tumorigenesis by an optimized random walk
multi-graphic method from the integrative networks of co-expression network, publically curated
epigenetic network (e.g. ENCODE) and protein-protein interaction network (e.g. STRING). Linear
regression analysis further refined individual candidate lncRNA regulation relating to their most
correlated target splicing genes. The secondary structure of binding lncRNAs to potential splicing
genes was predicted by support vector machine (SVM) algorithm to confirm the most conserved
targets.
Results: We identified 496 lncRNAs and 418 coding genes with alternative splicing isoforms
associated with breast cancer. Pathway analysis predicted the functions of 14 candidate
lncRNAs potentially regulating AS, are associated with cell migration, cell cycle progression,
and more. We detected a high confidence lncRNA MALAT1 that regulates PKM gene
alternative splicing, exclusion of either exon 9 or 10, in breast cancer tumorigenesis, which
confirms the predictive strength of our proposed method.
Conclusion: Understanding cancer-specific splicing machinery is therapeutically crucial in
targeting the molecules that can influence the splicing process. We developed a network-based
integrative framework to predict lncRNA regulations on breast cancer-specific alternative splicing
as the potential therapeutic targets.
Citation Format: Yunyun Zhou. Integrative analysis predicts lncRNA regulating gene alternative splicing in breast 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 1423.
Abstract 1425: A multi-enzyme DNA repair mix improves library quality and sequencing accuracy in FFPE tumor samples
Authors: Liu Pingfang , Heider Margaret , Song Chen , Chen Lixin , Ettwiller Laurence , Higgins Lauren , Dimalanta Eileen , Davis Theodore , Evans Thomas 
Published: August 2018

Abstract
Next-generation sequencing (NGS) methods are used extensively to profile mutations present in diseased human tissues. These genomic approaches hold great promise for personalized medicine but sequencing accuracy is essential for proper patient diagnosis and determining a treatment plan. A common source of DNA for genomic profiling is formalin-fixed, paraffin-embedded (FFPE) tissue samples obtained from patient biopsy. FFPE DNA poses important challenges for preparing NGS libraries including low input amounts and poor DNA quality, resulting from extensive fixation- and storage-induced DNA damage. Additionally, these damage-induced sequencing artifacts raise the background level of mutations, making it difficult to discern true, low frequency, disease-causing variants from noise. We previously showed that a major fraction of somatic mutations described in publicly available datasets are due to such sequencing artifacts (Chen et al., Science 2017). Furthermore, we showed that enzymatic repair of DNA before library preparation improves the library quality and reduces background noise. We developed a second-generation DNA repair enzyme mix (V2) that efficiently repairs the most prevalent damage types found in FFPE DNA and further improves the quality and yield of NGS libraries. Additionally, we tested the efficacy of the V2 repair mix in improving sequencing accuracy for FFPE DNA samples obtained from different cancer tissues. We performed target enrichment on a panel of 151 cancer genes, deep sequenced, and performed variant analysis. For a subset of variants, we further validated our results using a droplet digital PCR (ddPCR) assay. Both methods showed that the V2 repair mix did not alter the overall frequency of variants identified, thus it did not introduce bias, but significantly improved the sequencing accuracy by reducing the number of false variant calls. Therefore, enzymatic repair is a critical first step in preparing FFPE DNA sequencing libraries, allowing more sensitive and robust detection of low frequency, disease variants.
Citation Format: Pingfang Liu, Margaret Heider, Chen Song, Lixin Chen, Laurence Ettwiller, Lauren Higgins, Eileen Dimalanta, Theodore Davis, Thomas Evans. A multi-enzyme DNA repair mix improves library quality and sequencing accuracy in FFPE tumor samples [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 1425.
Abstract 1429: MYH8 R1292X: A novel mutation in relapsed AML induces EMT features and poor prognosis
Authors: Park Hyejoo , Kim Daeyoon , Kim Dongchan , Park Yungyeong , Koh Youngil , Yoon Sung-Soo 
Published: August 2018

Abstract
Introduction: Recent advances in tumor genomic analysis have led to the discovery of NPM1, FLT3, CEBPA, MLL, NRAS, and RUNX1 alterations as the cause of AML. Nevertheless, there is a limit to the treatment and clarification of AML, and research for the identification of novel genetic alterations that cause AML is actively underway.
Materials and methods: In this study, we performed Whole exome sequencing (WES) with 53 AML patient's samples and conducted targeted re-sequencing using 391 AML patient's samples based on locus of somatic mutation that were found by WES. For functional validation of novel oncogenic mutations, we used CRISPR-Cas9 system to generate knock-in (KI) cell line. For characterization of mutant cells, we performed proliferation assay, cell cycle assay, adhesion assay, and wound healing assay. Epithelial to mesenchymal transition (EMT) markers were checked by western blotting.
Results: Using WES and targeted resequencing, we could identify MYH8 R1292X novel mutation as recurrent potentially oncogenic mutation. Additional validation using separate AML cohort revealed MYH8 R1292X variants in four AML patients, suggesting that MYH8 R1292X is potential oncogenic mutation. In functional validation using KI cell line, we could not find change in morphology of KI cells. However, there was a difference in proliferation – the rate of proliferation was faster in KI cells than in cells without mutation. In the cell cycle assay, the mutant cells showed more S phase DNA than the non-mutant cells. Wound healing assay showed that the mutant cells had higher migration ability and lowered the ability of adhesion in comparison. PCR and western blot showed that EMT markers except vimentin increased in mutant cells.Survival analysis based on TCGA data showed that both the overall survival and the disease-free survival curves were significantly different according to MYH8 alterations.
Conclusion: Taken together, we conclude that the novel alteration MYH8 R1292X is associated with recurrent AML and poor prognosis by increasing migration, and inducing an increase in EMT markers.
Citation Format: Hyejoo Park, Daeyoon Kim, Dongchan Kim, Yungyeong Park, Youngil Koh, Sung-Soo Yoon. MYH8 R1292X: A novel mutation in relapsed AML induces EMT features and poor prognosis [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 1429.
Abstract 1434: LSR promotes lipid metabolism via beta oxidation and contributes cell viability in epithelial ovarian cancer
Authors: Hiramatsu Kosuke , Serada Satoshi , Fujimoto Minoru , Matsuzaki Shinya , Ueda Yutaka , Yoshino Kiyoshi , Kimura Tadashi , Naka Tetsuji 
Published: August 2018

Abstract
Background:Previously, we identified lipolysis-stimulated lipoprotein receptor (LSR) as a new target of epithelial ovarian cancer (EOC), and we reported inhibitory effect of our newly developed monoclonal antibody (mAb) against LSR-positive ovarian cancer cells in vitro and in vivo. We also demonstrated that LSR took in triglyceride-rich protein and promoted cell proliferation, however, LSR function in EOC cells is not investigated enough. Therefore, we aimed to reveal the function of LSR in EOC cells focusing on lipid metabolism including beta oxidation and subsequent TCA cycle.
Material and Method: Using LSR-positive ovarian cancer cell lines (OVCAR3 and RMG-I), we investigated activation of beta-oxidation by LSR after administration of VLDL which is one of the triglyceride-rich protein. Moreover, we constructed LSR-knockdown EOC cells and investigated the effect of VLDL administration in these cells. In addition, we showed inhibitory effect of our anti-LSR mAb against lipid metabolism. Expression of beta-oxidation related proteins were analyzed by western blot analysis. Production of acetyl CoA and ATP were measured using each assay kit. Cell viability was analyzed by WST-8 assay and thymidine incorporation assay.
Results: In LSR-positive EOC cells, LSR promoted uptake of VLDL in glucose restricted environment compared with LSR-knockdown cells (p &lt; 0.05) and VLDL administration promoted acetyl CoA and ATP production (p &lt; 0.05), suggesting that beta-oxidation, TCA cycle and electron transport system were activated by fatty acid from VLDL in LSR-positive cells. Moreover, in LSR-positive EOC cells, VLDL administration increased viable cells compared with LSR-knockdown cells (p &lt; 0.05), however, DNA synthesis was not promoted (p &lt; 0.05). These results showed that VLDL uptake via LSR promoted lipid metabolism and contributed cell viability. Finally, our anti-LSR mAb inhibited these processes.
Conclusion: In glucose restricted environment, LSR takes in triglyceride-rich protein, activates lipid metabolism via beta-oxidation and contributes cell viability in LSR-positive EOC cells.
Citation Format: Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Shinya Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Tadashi Kimura, Tetsuji Naka. LSR promotes lipid metabolism via beta oxidation and contributes cell viability in epithelial ovarian 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 1434.
Abstract 1442: Novel linkage of thymidine catabolism and the glycolytic pathway in human cancer cells
Authors: Tabata Sho , Yamamoto Masatatsu , Goto Hisatsugu , Nishioka Yasuhiko , Tomita Masaru , Soga Tomoyoshi , Furukawa Tatsuhiko , Akiyama Shin-ichi 
Published: August 2018

Abstract
Thymidine phosphorylase (TP), a rate-limiting enzyme in the thymidine catabolic pathway, catalyzes the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate (DR1P). We previously demonstrated that TP is identical to an anigogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). Although many reports indicate that TP has angiogenic activity and plays a pivotal role in tumor progression, the mechanism of the TP functions is not fully understood. Here, we find that TP-mediated thymidine catabolism can supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In certain procaryotes, phosphopentosemutase converts thymidine-derived DR1P to 2-deoxy-D-ribose 5-phosphate (DR5P), which is then converted to glyceraldehyde 3-phosphate (GAP) and acetaldehyde by deoxyriboaldorase (DERA). Given that GAP is an intermediate in the glycolytic pathway and the pentose phosphate pathway (PPP), we hypothesized that the activation of thymidine catabolism by TP could supply the carbon source for those pathways. However, the thymidine catabolic pathway in mammalian cells remains unclarified. We used 13C-labeled thymidine (13C5-thymidine) as a tracer and examined whether 13C5-thymidine-derived metabolites enter the glycolytic pathway and the PPP in TP-expressing cancer cells using capillary electrophoresis time-of-flight mass spectrometry. Thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, enhanced thymidine catabolism was observed in human gastric cancer. These findings suggest that the thymidine catabolism plays an important role in the survival and growth of cancer cells in a microenvironment where glucose is insufficient.
Citation Format: Sho Tabata, Masatatsu Yamamoto, Hisatsugu Goto, Yasuhiko Nishioka, Masaru Tomita, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin-ichi Akiyama. Novel linkage of thymidine catabolism and the glycolytic pathway in human 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 1442.
Abstract 1444: RhoC regulation of inflammatory breast cancer metabolism
Authors: Goo Laura E. , Yates Joel A. , Bao Liwei , Wu Zhifen , Merajver Sofia D. 
Published: August 2018

Abstract
Inflammatory breast cancer (IBC) is an extremely aggressive and lethal type of cancer due to its ability to rapidly metastasize. Our previous reports have shown that the metabolic characteristics of IBC are altered from those of normal breast epithelial cells. Specifically, the levels of the metabolite N-acetylaspartate (NAA) are very high in the IBC-derived triple negative cell line SUM149 relative to the triple negative cancer cell line MDA-MB-231. Recent studies have also correlated high levels of tumoral NAA with significantly lower survival rates in ovarian cancer.
N-acetylaspartate (NAA) is the second most abundant metabolite in the brain, only exceeded by glutamate. NAA is synthesized from aspartate and acetyl-CoA by the enzyme Asp-NAT, which is encoded for by the gene NAT8L. The catabolism of NAA to aspartate and acetate is carried out by the enzyme aspartoacyclase (ASPA). In the central nervous system (CNS), altered levels of NAA have been historically used as a marker for neurodegenerative diseases such as Canavan disease, a fatal genetic disorder caused by a deleterious mutation in the ASPA gene. However, the fundamental role of NAA, especially in the context of cancer remains elusive.
We seek to understand and describe the role of NAA in the adapted metabolic pathways of inflammatory breast cancer that enable proliferation and metastasis of the disease. Our previous work revealed that the pro-metastatic small GTPase RhoC acts as a regulator of NAA metabolism in SUM149 cells. Knockdown of RhoC using shRNA significantly decreases NAT8L expression. RhoC and RhoA knockout cell lines have been generated using CRIPSR-Cas9 in both SUM149 and MDA-MB-231 cells to further distinguish the relationship between NAA and RhoC in these different cell lines. We have conducted metabolic studies to determine the relative abundance of common metabolites, including NAA, throughout glycolysis, the pentose-phosphate pathway, and the tricarboxylic acid cycle. We have performed similar metabolomics using xenograft mice implanted with these CRISPR knockout cell lines to determine in vivo recapitulation of the NAA phenotypes. Our work ultimately hopes to identify promising therapeutic pathways of NAA as well as further characterize NAA's role as a potential oncometabolite.
Citation Format: Laura E. Goo, Joel A. Yates, Liwei Bao, Zhifen Wu, Sofia D. Merajver. RhoC regulation of inflammatory breast cancer metabolism [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 1444.
Abstract 1447: Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma
Authors: Ostrin Edwin J. , Fahrmann Johannes F. , Tanaka Ichidai , Celiktas Muge , Aguilar Clemente , Aguilar Mitzi , Dennison Jennifer B. , Murage Eunice , Tripathi Satyendra C. , Delgado Oliver , Wang Hong , Rodriguez-Canales Jaime , Behrens Carmen , Wistuba Ignacio I. , Taguchi Ayumu , Hanash Samir M. 
Published: August 2018

Abstract
Low tryptophan levels promote tumor immune evasion by suppressing immune function. Elucidation of the immunomodulatory effects of altered tryptophan catabolism has relevance to cancer immunotherapy. Previous studies have largely focused on the role of the rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan depletion in the microenvironment. However, IDO1 levels are highly heterogeneous in different cancers, and numerous other downstream tryptophan catabolites have also been shown to have immunomodulatory activity. We surveyed the proteomes of 123 cancer cell lines for regulators of tryptophan metabolism which revealed overexpression of kynureninase (KYNU) in KEAP1 mutant lung adenocarcinomas. Functional analysis indicated that KYNU expression is regulated through nuclear factor, erythroid 2-like (Nrf2) activation. KYNU-high cell lines exhibited increased secretion of KYNU-derived anthranilate/3-hydroxyanthranilate. Ex-vivo studies using isolated PBMCs demonstrated that 3-hydroxyanthranilate reduced CD8+ T-cell viability. KYNU mRNA expression in three independent datasets of lung adenocarcinomas and additionally KYNU protein expression in lung adenocarcinoma tissue microarrays revealed that high KYNU expression predicts poor survival and disease recurrence. Our findings indicate that KYNU promotes immune suppression and is an independent prognostic marker for lung adenocarcinoma.
Citation Format: Edwin J. Ostrin, Johannes F. Fahrmann, Ichidai Tanaka, Muge Celiktas, Clemente Aguilar, Mitzi Aguilar, Jennifer B. Dennison, Eunice Murage, Satyendra C. Tripathi, Oliver Delgado, Hong Wang, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio I. Wistuba, Ayumu Taguchi, Samir M. Hanash. Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma [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 1447.
Abstract 1448: Integrated molecular analysis reveals novel SPARC-regulated metabolic programming in ovarian cancer
Authors: Naczki Christine , John Bincy , Patel Chirayu , Lafferty Ashlyn , Ghoneum Alia , Afify Hesham , Davis Amanda , Jin Guangxu , Said Neveen 
Published: August 2018

Abstract
We have reported a tumor suppressor effect of SPARC in ovarian cancer as both host and tumor SPARC are implicated in anti-proliferative, anti-adhesive effects as well as normalization of the peritoneal tumor microenvironment. Herein, we extend our studies using a syngeneic model of peritoneal ovarian carcinomatosis to gain comprehensive insight on the effect of SPARC on metabolic programming of the ovarian cancer ecosystem. We performed comprehensive metabolomic and transcriptomic profiling of micro-dissected ID8 omental tumors that developed after intra-peritoneal injection in SP-/- and SP+/+ mice. Integrated analysis revealed that the accelerated growth of ID8 tumors in SP-/- mice was associated with metabolic programming of cancer cells with up-regulation of the genes involved in glycolysis, fatty acid oxidation, and oxidative phosphorylation. Tumors also exhibited perturbed redox homeostasis, as well as mitochondrial and ribosomal biogenesis. Comparative analysis of the syngeneic tumors with human high grade serous ovarian cancer (HGSC) revealed upregulation of the same genes involved in metabolic programming with inverse correlation with SPARC transcript expression, implying a role of stromal-SPARC in the metabolic programming of HGSC. Bio-energetic studies revealed that SPARC inhibits basal glycolysis, glycolytic reserve, oxygen consumption rate and mitochondrial ATP synthesis. To the best of our knowledge this is the first study that characterizes the metabolic programming of the ovarian cancer ecosystem by host-SPARC.
Citation Format: Christine Naczki, Bincy John, Chirayu Patel, Ashlyn Lafferty, Alia Ghoneum, Hesham Afify, Amanda Davis, Guangxu Jin, Neveen Said. Integrated molecular analysis reveals novel SPARC-regulated metabolic programming in ovarian 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 1448.
Abstract 1457: SCAP/SREBP-1 regulates lipid metabolism reprogramming in cancer cell
Authors: cheng chunming , geng feng , cheng xiang , chakravarti arnab , guo deliang 
Published: August 2018

Abstract
Warburg initial observation shows tumorigenesis is associated with an increased glucose consumption. Recently, accumulating evidence show that lipid metabolism is reprogrammed in cancers. Elevated lipogenesis which contributes to the development of malignant phenotypes is known to meet requirements for cancer cell rapid growth. However, how they interact to promote cancer growth remain unclear.
Through biochemistry and molecular biology assays, we find that EGFR signaling, by increasing glucose uptake, promotes N-glycosylation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and consequent activation of SREBP-1, an ER-bound transcription factor with central roles in lipid metabolism. N-glycosylation promotes SCAP stabilization and dissociates from Insig-1, allowing movement of SCAP/SREBP to the Golgi and consequent SREBP activation. Blocking SCAP N-glycosylation ameliorates EGFRvIII-driven glioblastoma growth in xenograft mouse model.
These results show glucose consumption and lipogenesis are linked as reciprocal metabolic cross-talk in tumorigenesis, and targeting SCAP and its N-glycosylation may provide a promising means of more effective cancer therapy.
Citation Format: chunming cheng, feng geng, xiang cheng, arnab chakravarti, deliang guo. SCAP/SREBP-1 regulates lipid metabolism reprogramming in cancer cell [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 1457.