bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1523: Molecular typing of Chinese gastrointestinal stromal tumors using a multigene next generation sequencing panel
Authors: Xu Zhi , Hu Zhibin , Huo Xinying , Tang Chuanning , Chen Si-Yi , Chen Jinfei 
Published: May 2015

Abstract
Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.80%), KIT (33.60%), and PIK3CA (41.60%) genes. The mutations in MLH1 gene were frequently detected in the exons 2, while MET gene was frequently mutated in the exon 12. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy.
Citation Format: Zhi Xu, Zhibin Hu, Xinying Huo, Chuanning Tang, Si-Yi Chen, Jinfei Chen. Molecular typing of Chinese gastrointestinal stromal tumors using a multigene next generation sequencing panel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1523. doi:10.1158/1538-7445.AM2014-1523
Abstract 1536: Whole genome sequencing of high-grade treatment-naïve prostate tumors
Authors: Decker Brennan J. , Karyadi Danielle M. , Karlins Eric , Davis Brian W. , Tillmans Lori S. , Thibodeau Stephen N. , Ostrander Elaine A. 
Published: May 2015

Abstract
Prostate cancer (PCa) will impact one in six American men and many low-risk men endure therapy, while other men die of PCa. Optimal treatment selection depends on distinguishing indolent tumors from those that will cause prostate cancer specific mortality (PCSM). To date, sequencing of prostate tumor DNA has highlighted the fact that prostate tumors develop differently than other cancers. Instead of recurrent protein-altering mutations, many prostate tumors harbor “closed chain” structural rearrangements that may mediate tumor evolution. However, we do not yet understand which somatic mutations are involved in aggressive disease and PCSM.
To address this crucial question, we are using whole genome sequencing to pinpoint somatic genetic features in tumor/normal paired samples from four PCSM and six non-PCSM patients with treatment-naïve, Gleason 8+ tumors. Tumor and normal DNA were sequenced to a mean coverage of 95.3X and 48.3X, respectively. Tumor DNA purity ranged from 49%-79% and tumor ploidy ranged from 1.96 to 2.22. To define the genomic landscape of aggressive PCa, we will compare our findings with published studies and genotype high-priority candidates in at least 50 additional low- and high-grade tumors. We will also compare somatic mutations in PCSM versus non-PCSM cases and use network analysis to identify pathways that may be involved in progression and metastasis. Finally, we will characterize the clonal evolution of PCa tumors using deep digital sequencing to distinguish mutations that were present in the original tumor clone from subclonal mutations that arose after oncogenesis. In this way, we aim to identify potential oncogenic drivers and candidate mediators of progression and metastasis.
Ultimately, we aim to 1) Uncover somatic mutations that are specific to aggressive tumors 2) Determine whether PCSM tumors have unique genetic features, and 3) Understand the role of clonal evolution in oncogenesis and progression. As more tumors are sequenced, this approach may yield valuable markers for diagnosis, prognosis and treatment selection.
Note: This abstract was not presented at the meeting.
Citation Format: Brennan J. Decker, Danielle M. Karyadi, Eric Karlins, Brian W. Davis, Lori S. Tillmans, Stephen N. Thibodeau, Elaine A. Ostrander. Whole genome sequencing of high-grade treatment-naïve prostate tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1536. doi:10.1158/1538-7445.AM2014-1536
Abstract 1538: Molecular characterization of uterine leiomyomas, histopathological uterine leiomyoma subtypes, and uterine leiomyosarcomas
Authors: Mäkinen Netta , Kämpjärvi Kati , Bützow Ralf , Vahteristo Pia 
Published: May 2015

Abstract
Uterine leiomyomas (ULMs) are the most common tumors of the female genital tract. They originate from the smooth muscle cells of the myometrium. Despite their benign nature, ULMs can cause considerable morbidity, such as excessive bleeding, abdominal pain, and infertility. They are also the most common cause for hysterectomy. Based on histopathology, ULMs can be divided into common leiomyomas and various subtypes, such as cellular, atypical, and mitotically active leiomyomas, that mimic malignancy in one or more aspects. Histopatological ULM subtypes are responsible for approximately 5% of all ULMs. In light of the current literature, ULMs may rarely undergo malignant transformation and develop into a leiomyosarcoma. We have previously reported that mediator complex subunit 12 (MED12) exon 2 is mutated in approximately 70% of ULMs. Our subsequent studies have indicated that both histopathological ULM subtypes (17.5%) and uterine leiomyosarcomas (7%) harbor MED12 exon 2 mutations significantly less frequently than common leiomyomas. The aim of this study is to examine the frequency of other known aberrations in ULMs, such as overexpression of HMGA1 and HMGA2, in histopathological ULM subtypes and uterine leiomyosarcomas. The study material consists of 213 formalin-fixed paraffin-embedded samples including 60 common leiomyomas, 93 histopathological ULM subtypes (cellular, atypical, and mitotically active leiomyomas), and 60 uterine leiomyosarcomas. We have constructed tissue microarrays of these distinct tumor groups for immunohistochemical stainings. In addition to HMGA1 and HMGA2 antibodies, various immunohistochemical markers, commonly used in gynecological pathology, will be utilized to analyze similarities and differences between the tumor groups. It is clinically relevant to identify tumor subtypes with different molecular genetic characteristics which might then lead to improved diagnosis, personalized medical treatments, and prognosis in the future. New knowledge of the mechanisms underlying the potential progression to malignancy is also essential, because, for example in the case of uterine leiomyosarcomas, diagnosis is often accidental and postoperative.
Citation Format: Netta Mäkinen, Kati Kämpjärvi, Ralf Bützow, Pia Vahteristo. Molecular characterization of uterine leiomyomas, histopathological uterine leiomyoma subtypes, and uterine leiomyosarcomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1538. doi:10.1158/1538-7445.AM2014-1538
Abstract 1539: Fusion events in NSCLC cell lines identified by whole transcriptome analysis
Authors: Jung Seung-Hyun , Chung Yeun-Jun 
Published: May 2015

Abstract
Since the discovery of Philadelphia chromosome, human chromosomal rearrangements consequence the great deal within the distinct area of cancer biomarker discovery and targeted therapy. These events are commonly generated by breaking and re-joining the segments on either inter- or intra-chromosomal locations, creating an error within DNA repair mechanism responsible for oncogenic properties and, one of the reasons, causing cancer. Also, alteration in the programing of gene regulation changes the transcriptome structure resulting pathological conditions. Recent advances in the cancer epidemiology predicted the highest death rates within Europe and Korea due to lung cancer representing the leading cause of death within cancer patients. Therefore, we have sequenced the whole transcriptome following the highly sensitive path of RNA-seq with the combination of bioinformatics tools and experimental confirmation. The mRNA was subjected on Illumina HiSeq2000 for paired-end (PE) sequencing and bioinformatics analyses were conducted on Linux based software tools. The PE reads were aligned with Ensemble reference human genome version hg19 using TopHat2 and bowtie1. The fusion events were predicted using two different software packages, deFuse and Tophat-Fusion, and expression analysis was conducted using Cufflinks and R-package cumeRbund. The predicted fusion break-points were confirmed by target specific sanger-sequencing. Through the RNA-seq analysis, we identified a number of fusion events shared by oncogenes in non-small cell lung cancer (NSCLC) cell-lines including EML4:ALK fusion identified in recently established gefitinib resistant SNU2292 cell-line and some novel ones. Moreover, a significant increase in the expression of cell-line specific fusion genes was also observed. Our result will be helpful not only for discovering novel biomarkers but also for understanding the tumorigenesis of NSCLC.
Note: This abstract was not presented at the meeting.
Citation Format: Seung-Hyun Jung, Yeun-Jun Chung. Fusion events in NSCLC cell lines identified by whole transcriptome analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1539. doi:10.1158/1538-7445.AM2014-1539
Abstract 1562: Proteomic analysis of citrullinated targets regulated by the p53-PADI4 pathway
Authors: Tanikawa Chizu , Ueda Koji , Nakagawa Hidewaki , Nakamura Yusuke , Matsuda Koichi 
Published: May 2015

Abstract
We recently reported that p53 regulates protein citrullination through the transcriptional regulation of PADI4 that converts an arginine residue in proteins to a citrulline residue. In response to DNA damage, p53-PADI4 pathway induces citrullination of NPM1, Histone H4, and Lamin C, and subsequently promotes apoptotic pathway. To verify the clinical significance of PADI4 in human carcinogenesis, we screened the mutation of PADI4 in hepatocellular carcinoma and found three non-synonymous mutations among 104 cancer tissues (2.9%). Then we evaluated these three mutations as well as 8 somatic mutations reported by ICGC or COMP projects. We found that 8 among 11 mutations remarkably inhibited the enzymatic activity of PADI4 protein. To identify novel PADI4 substrates, we conducted proteome analysis using HEK293T cells ectopically transfected with wild type or mutant PADI4 expressing plasmid. Among more than 10000 peptides identified by the liquid chromatography MS/MS analysis, 265 peptides (2.2%) were citrullinated in PADI4-introduced cells, while less than 0.4% of total peptides were citrullinated in control or mock transfected cells. Pathway analysis revealed that RNA binding proteins such as hnRNPs are dominantly citrullinated by PADI4, indicating that possible role of protein citrullination in RNA processing.
Citation Format: Chizu Tanikawa, Koji Ueda, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Proteomic analysis of citrullinated targets regulated by the p53-PADI4 pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2014-1562
Abstract 1605: Pterostilbene, a natural phytoalexin, effectively protects against UVB-induced skin carcinogenesis by increasing antioxidant cellular defenses and preventing mutagenesis
Authors: Sirerol J. Antoni , Pulido Ines , Asensi Miguel , Ortega Angel , Estrela Jose M. 
Published: May 2015

Abstract
Clinical and laboratory studies have demonstrated that skin exposure to ultraviolet radiation (UV) is the main cause of non-melanoma skin cancer (NMSC) (≈ 99%) and melanoma (≈ 95%) development. The procarcinogenic effects of solar exposure are mainly due to UVB radiation (290-320 nm range), the same tight range that produces burning in human skin (erythema), inflammation, oxidative stress, DNA damage, etc. The number of skin cancers around the world keeps increasing and, thus, it is an urgent need to find effective protection remedies. Phytoalexins of polyphenolic structure are naturally occurring compounds involved in the defense against pathogens and environmental stresses in plants. Epidemiological studies confirm that diets enriched in plant polyphenols may offer protection against chronic diseases related to oxidative stress. In this sense polyphenols have shown anticarcinogenic and photoprotective effects (e.g. Clifford JL & DiGiovanni J. Cancer Prev Res 3:132-5, 2010). Seminal studies showed that resveratrol (trans-3,5,4′-trihydroxystilbene; Resv) exerted chemopreventive activity in a model of mouse skin carcinogenesis where topic administration of this polyphenol inhibited multistage carcinogenesis [Jang M et al. Science 275:218-20, 1997]. Pterostilbene (3,5-dimethoxy-4′-hydroxy-trans-stilbene; Pter), a Res analog, shows a higher half-life and more potent anticancer effects in vivo than Res. We compared the potential anti-UVB protection of both polyphenols in a murine model of chronic irradiation (180 mJ UVB/cm2; 3 doses/week; for a total of 30 weeks) that experimentally resembles long-term chronic human exposure to damaging sun radiations. We observed that topical pretreatment of the skin with Pter (1-2 μmol/cm2 per dose, administered right before UB exposure), but not with Resv, fully prevents chronic UVB-induced skin carcinogenesis. The molecular mechanism underlying this protective effect involves a Pter-induced increase in antioxidant skin defenses and a decrease in the rate of mutagenesis.
Citation Format: J. Antoni Sirerol, Ines Pulido, Miguel Asensi, Angel Ortega, Jose M. Estrela. Pterostilbene, a natural phytoalexin, effectively protects against UVB-induced skin carcinogenesis by increasing antioxidant cellular defenses and preventing mutagenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1605. doi:10.1158/1538-7445.AM2014-1605
Abstract 1621: Discovery of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors
Authors: Huang Hongbing , Acquaviva Lisa , Bregman Howard , Buchanan John , Chakka Nagasree , DiMauro Erin F. , Dovey Jennifer , Gunaydin Hakan , Hua Zihao , Huang Xin , Huang Liyue , Patel Vinod F. , Martin Matthew W. , Serafino Randy , Wilson Cindy 
Published: May 2015

Abstract
The canonical Wnt pathway regulates the ability of β-catenin to activate specific target genes. Aberrant activation of the Wnt pathway is believed to drive the development and growth of many cancers; for example, APC mutations were observed in &gt;80% of the sporadic colorectal cancers. The casein kinase 1 (CK1) family of serine/threonine protein kinases is highly conserved. Multiple members of the CK1 family are shown to regulate the Wnt pathway through interactions with various proteins. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We employed a structure-based approach and identified a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms, and favorable rodent PK profiles. Oral dosing of optimized lead compounds resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.
Citation Format: Hongbing Huang, Lisa Acquaviva, Howard Bregman, John Buchanan, Nagasree Chakka, Erin F. DiMauro, Jennifer Dovey, Hakan Gunaydin, Zihao Hua, Xin Huang, Liyue Huang, Vinod F. Patel, Matthew W. Martin, Randy Serafino, Cindy Wilson. Discovery of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1621. doi:10.1158/1538-7445.AM2014-1621
Abstract 1623: 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone as a potential anticancer agent: its synthesis, characterization and anticancer properties
Authors: Ishmael Don R. , Adelsteinsson Orn 
Published: May 2015

Abstract
A number of compounds based on the base compound 1,4,5,8 tetrahydroxyanthraquinone have anticancer properties. One compound of this class mitoxantrone bis-5,8 hydroxyethylaminoethylamino 1,4 dihydroxy anthraquinone has been on the market a number of years and is approved by the FDA for the treatment of: acute myelogenous leukemia, various lymphomas, breast cancer, sarcoma and the non-malignant condition multiple sclerosis. However this drug has a number of drawbacks: (1) for most cancer therapies is considered less effective than the anthracyclines, (2) although it has less cardiotoxicity than anthracyclines it does still has significant cardiotoxicity, (3) it is known to rapidly induce multi-drug resistance factors, and (4) has significant bone marrow toxicity. The class of compounds of 1,4-Bis aminoalkylamino class work against cancer cells by intercalating DNA in the major groove and inhibition of topoisomerase II enzyme. There have been a number of attempts to improve the class of drugs by adding different functional groups. However no compound of this class has exceeded the utility of mitoxantrone. Attempts to make derivatives of leuco 1,4,5,8-tetrahydroxyanthraquinone utilizing the replacement of all four hydroxyl groups for the purpose additional DNA binding or alkylation has been unsuccessful. It was discovered that 1,4,5,8-tetrachloroanthraquinone can be used as a base compound for production of compounds with potential anticancer activity. The compound 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone was synthesized and highly purified. It was found to have greater cytotoxicity in the screening assay than mitoxantrone or adriamycin. The cytotoxicity screening was done using the BOT-2 human breast cancer cell line. This compounds may have an advantage over the Bis-derivatives with: 1) greater cytotoxicity in screening assay, 2) cheap intermediates, 3) high yields, 4) increased number of potential active groups sites and 7) removal of the para dihydroxyl groups from the cytotoxic 1,4 bisaminoalkylaminoanthraquinone. This might result in reducing the potential for cardiotoxicity. The 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone was purified to 97.8 purity by HPLC. Initial screening in vivo mouse model B16 melanoma was done. The response was the same for mitoxantrone with considerably less toxicity.
Citation Format: Don R. Ishmael, Orn Adelsteinsson. 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone as a potential anticancer agent: its synthesis, characterization and anticancer properties. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1623. doi:10.1158/1538-7445.AM2014-1623
Abstract 1633: Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy
Authors: Mautino Mario R. , Metz Richard A. , Jaipuri Firoz , Waldo Jesse , Kumar Sanjeev , Marcinowicz-Flick Agnieszka , Potturi Hima , Adams James T. , Allen Clarissa Van , Vahanian Nicholas N. , Link Charles J. 
Published: May 2015

Abstract
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase is an central immune checkpoint mechanism that controls peripheral immune tolerance and tumor resistance to immune attack. The IDO pathway mediates immunosuppressive effects by expression of the IDO1 gene by tumor cells and/or host antigen presenting cells. Tryptophan depletion and generation of kynurenine generate downstream signals through GCN2, WARS, mTOR and AHR that ultimately lead to anergy of tumor-specific effector CD8+ T cells and activation of Tregs. High expression of IDO correlates negatively with clinical prognosis in patients with a variety of malignancies. Recently, it has been described that tumors can also achieve immunosuppressive effects mediated by tryptophan degradation through expression of TDO, an enzyme functionally and structurally related to IDO1. Therefore, development of small molecules that can prevent tryptophan degradation mediated by IDO1, TDO or both is a prime goal for immunotherapy of cancer. Here we report the discovery of a novel class of imidazoisoindole-based compounds that show potent and selective inhibition of TDO and IDO1, as well as compounds that show potent dual inhibition of both TDO and IDO1. We present structure-activity relationship studies that explore the molecular determinants of potency and specificity for TDO and IDO1. Compounds of these classes were tested for activity in in vitro assays using purified recombinant human and murine TDO and IDO1 as well as in cells expressing IDO1 or TDO. Many of these compounds are 10-200 fold more potent (IC50 &lt; 50 nM) than previously published TDO-specific inhibitors. The pharmacokinetic properties of these compounds are being investigated and lead optimization efforts are in progress.
Citation Format: Mario R. Mautino, Richard A. Metz, Firoz Jaipuri, Jesse Waldo, Sanjeev Kumar, Agnieszka Marcinowicz-Flick, Hima Potturi, James T. Adams, Clarissa Van Allen, Nicholas N. Vahanian, Charles J. Link. Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2014-1633