bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-231: Decoding complex patterns of structural variations in hepatocellular carcinoma.
Authors: Fernandez-Banet Julio , Lee Nikki P. , Chan Kin Tak , Gao Huan , Liu Xiao , Sun Wing Kin , Tan Winnie , Fan Sheung Tat , Poon Ronnie T. , Li Shiyong , Ching Keith , Rejto Paul , Mao Mao , Kan Zhengyan 
Published: August 2014

Abstract
Elucidating the molecular basis of Hepatocellular Carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. Somatically acquired structural variations (SVs) can lead to oncogenic gene fusions and gene expression deregulation in tumors. Although recent studies have delineated HCC genomic alterations including copy number variations, somatic mutations and HBV integrations, the landscape of SVs remains poorly characterized in HCC. We have predicted 4,314 SVs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. TP53 and RB1 alterations appear to cause increased levels of genomic arrangement and chromosomal instability. Albumin (ALB) was found to be the most significantly affected by SVs and harbor genomic alterations including deactivating mutations and deletions in 10.2% of cohort. Integrative analysis revealed a causal link between genomic rearrangements and copy number variations, such as focal amplifications of the CCND1/FGF19 loci, and distinctive patterns of copy number variation flanking SV breakpoints. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3′ genes in tumors.
Citation Format: Julio Fernandez-Banet, Nikki P. Lee, Kin Tak Chan, Huan Gao, Xiao Liu, Wing Kin Sun, Winnie Tan, Sheung Tat Fan, Ronnie T. Poon, Shiyong Li, Keith Ching, Paul Rejto, Mao Mao, Zhengyan Kan. Decoding complex patterns of structural variations in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-231. doi:10.1158/1538-7445.AM2013-LB-231
Abstract LB-233: Identification of DNA palindromes in the MCF-7 breast cancer cell line.
Authors: Yang Hui , Volfovsky Natalia , Rattray Alison , Chen Xiongfong , Tanaka Hisashi , Jeffrey Strathern 
Published: August 2014

Abstract
DNA palindromes are implicated as a causative agent in cancer formation due to their association with genomic instability and DNA amplification. However, the unique properties of palindromes render them refractory to current methods of analyses including PCR amplification and cloning into bacterial vectors. Consequently, sequencing protocols that are dependent on PCR amplification fail on DNA palindromes. New tools are required for their discovery and characterization. Here we report our analysis of DNA palindromes from MCF-7, a widely used cell line model for estrogen receptor positive breast cancer. We developed a new strategy to identify and clone palindrome junctions by high throughput sequence analysis of DNA isolated by the Genome-wide Analysis of Palindrome Formation technique. We identified 35 palindrome candidates from MCF-7 and have cloned and sequenced 4 of the centers of the palindromes. None of these identified palindromes are present in other published data sets, despite the fact that MCF-7 DNA has been extensively sequenced and breakpoints analyzed, confirming that conventional methods fail on DNA palindromes. Our results provide further support for a correlation between palindromes and gene amplification in cancer, and underscore the importance of developing new tools for identifying and characterizing palindromes.
Citation Format: Hui Yang, Natalia Volfovsky, Alison Rattray, Xiongfong Chen, Hisashi Tanaka, Strathern Jeffrey. Identification of DNA palindromes in the MCF-7 breast cancer cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-233. doi:10.1158/1538-7445.AM2013-LB-233
Abstract LB-239: Mutational and clonal analyses across TCGA cancer types using the MuSiC suite of tools.
Authors: Kandoth Cyriac , McLellan Michael D. , Miller Christopher A. , Lu Charles , Dees Nathan , Ye Kai , Niu Beifang , Wendl Michael C. , Wilson Richard K. , Ding Li 
Published: August 2014

Abstract
Within the field of cancer genomics, advances in next-generation sequencing and variant detection methods have tremendously reduced the costs of generating genomic data for large cohorts of patients in translational cancer research. These large datasets have enabled statistical analyses of somatic events in tumor-normal pairs, with the ultimate goal of understanding the molecular mechanisms underlying various cancer phenotypes. Here, we present results from the suite of tools collectively called MuSiC (Mutational Significance in Cancer), specifically designed towards this goal. Somatic alterations of more than 5000 tumors across 20 cancer types are now publicly available as part of The Cancer Genome Atlas (TCGA). This includes point mutations and small indels from exome sequencing, copy-number variants from SNP arrays, and gene and allele-specific expression from mRNA sequencing. We present results from the suite that integrates these data types to identify significantly altered genes, gene families, protein domains, and pathways. Also presented are the distribution of mutation types, frequencies, and patterns across cancer types, or across histological subtypes of tumors. Further, we identify mutations that can distinguish broader expression and/or methylation subtypes and clinically relevant phenotypes across the combined pan-cancer data set. Finally, we perform clonality analysis across several cancer types by integrating copy number data to identify important mutations that drive the development of new clones.
Citation Format: Cyriac Kandoth, Michael D. McLellan, Christopher A. Miller, Charles Lu, Nathan Dees, Kai Ye, Beifang Niu, Michael C. Wendl, Richard K. Wilson, Li Ding. Mutational and clonal analyses across TCGA cancer types using the MuSiC suite of tools. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-239. doi:10.1158/1538-7445.AM2013-LB-239
Abstract LB-245: MicroRNA-100 targets silencing mediator for retinoid receptors (SMRT), reduces proliferation, and improves survival in glioblastoma.
Authors: Alrfaei Bahauddeen M. , Vemuganti Raghu , Kuo John S. 
Published: August 2014

Abstract
Improved therapeutic approaches are needed for the most common primary adult brain cancer, Glioblastoma (GBM) because of the current dismal median survival of less than two years. We identified and tested the differentially expressed microRNA-100 (MiR-100) as a candidate ‘tumor suppressor’ in GBM. Quantitative PCR validated differential microRNA array results showing high miR-100 expression in normal cells and low expression in multiple GBM lines. MiR-100 overexpression via transfection of 4 GBM lines with miR-100 precursor (U87, U251, patient-derived 22T and 33T) reduced proliferation on MTS assays (average 50% ± 15; p &lt; 0.05). TUNEL assays showed that transient transfection of 15 pmole of miR-100 per 500K GBM tumor cells triggered apoptosis 70% more than scrambled control miR after 24 hrs (p &lt; 0.01). SMRT was identified as a candidate miR100 target in multiple miRNA databases, and validated with miR100-specific inhibition in a luciferase-SMRT 3′UTR reporter assay. In addition, a single dose of pre-mir-100 (60 pmol) injected directly into intracranial GBM xenografts significantly extended survival 30% more than mice injected with control scrambled miRNA (p &lt; 0.01; n=8). GBM lines that stably overexpressed miR-100 two-fold over similar control transfected GBM lines were created for in vivo studies: 10x6 cells were implanted for tumor xenograft histology and survival analysis. Significantly reduced Ki-67 proliferation index was observed compared to control (mir-100 vector: 18±14% Ki-67+; empty vector: 100±11% Ki-67+; p &lt; 0.01). Two-fold over-expression of miR-100 in vivo showed an average of 70% reduction in Ki-67 proliferation index. Furthermore, miR-100 overexpressing cells were associated with significantly smaller xenografts than injection of sibling control GBM cells. These studies establish the ‘tumor suppressor’ activity of miR-100 in GBM, which may lead to further developments as novel GBM therapies.
Citation Format: Bahauddeen M. Alrfaei, Raghu Vemuganti, John S. Kuo. MicroRNA-100 targets silencing mediator for retinoid receptors (SMRT), reduces proliferation, and improves survival in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-245. doi:10.1158/1538-7445.AM2013-LB-245
Abstract LB-258: The human Aurora-A kinase Phe31Ile polymorphism affects cancer susceptibility in a knock-in mouse model.
Authors: Song Ihn Young , Kumar Atul , Delrosario Reyno , Mao Jian-Hua , Balmain Allan 
Published: August 2014

Abstract
Aurora-A kinase is a serine/threonine kinase that is essential for faithful chromosome segregation during mitosis. A single nucleotide polymorphism T91A (amino acid Phe31→Ile) present in the coding region of human Aurora-A is associated with susceptibility to multiple cancer types, yet the precise biochemical mechanisms by which these different polymorphisms function are still not well characterized. To investigate the functional differences between the two alleles of Aurora-A, we have generated a knock-in mouse that carries the human-specific Aurora-A Phe31 allele. Normally, rodents only carry the Ile allele. Homozygous (F/F) and heterozygous (F/I) mice for this knock-in allele were born healthy and fertile with no obvious phenotype. Growth rates of MEFs isolated from F/F, F/I, and I/I embryos showed no significant differences. To investigate the oncogenic properties of each variant in tumor development in the context of different p53 status, we generated a series of Aurora-A knock-in/p53-deficient double mutant mice. All mice were exposed to a single dose of 4Gy whole-body γ-radiation at 5 weeks of age and observed daily until they were moribund, then sacrificed and autopsied. While the I/I genotype conferred increased risk (reduced latency) compared to the F/F genotype in the p53+/- mice (p=0.037), the reverse was observed in the p53-/- mice (p=0.009); 43% of the I/I mice versus 25% of the F/F mice developed lymphomas in the p53+/- background, while 55% of the I/I mice versus 76% of the F/F mice developed lymphomas in the p53-/- background. These results support our hypothesis that the two polymorphisms confer differential susceptibility to lymphoma development in a p53-dependent manner. Interestingly, Aurora-A+/- heterozygous null mice (F/- and I/- on the p53+/- background) showed increased incidence and decreased latency of tumor formation compared to the Aurora-A+/+ mice. These data suggest dual roles for Aurora-A as both an oncogene and a haploinsufficient tumor suppressor in lymphomagenesis. There exist complex regulatory mechanisms between Aurora-A and p53, emphasizing that a balanced level of Aurora-A is critical for cell survival and maintenance of genome integrity. These data highlight the critical role of interactions between common inherited genetic variants in determining tumor susceptibility, a phenomenon that may underlie the “Missing heritability” noted in GWAS in human populations.
Citation Format: Ihn Young Song, Atul Kumar, Reyno Delrosario, Jian-Hua Mao, Allan Balmain. The human Aurora-A kinase Phe31Ile polymorphism affects cancer susceptibility in a knock-in mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2013-LB-258
Abstract LB-269: PPARγ maintains ERBB2-positive breast cancer stem cells.
Authors: Wang Xianhui , Sun Yan , Wong Jason , Conklin Douglas 
Published: August 2014

Abstract
Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor (PPAR) γ-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here we report that inhibition of the PPARγ pathway reduces the ALDH positive population in ERBB2 positive breast cancer cells. Conversely, fatty acid synthase inhibitor C75 increases the fraction of ALDH-positive cells. In vitro tumorsphere formation assays demonstrate that the PPARg antagonist GW9662 decreases the tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells, is partially due to ROS, as it can be rescued by treatment with NAC. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes including ACLY, MIG12, FASN and NR1D1; and the stem cell related genes KLF4 and ALDH in BT474 cells. GW9662 also decreased the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2 positive breast cancer cells.
Citation Format: Xianhui Wang, Yan Sun, Jason Wong, Douglas Conklin. PPARγ maintains ERBB2-positive breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-269. doi:10.1158/1538-7445.AM2013-LB-269
Abstract LB-270: Targeting USP1 decreases glioblastoma stem cell survival and tumor growth.
Authors: Oh Young Taek M. , Kim Eunhee , Lee Jeongwu , Nam Do-Hyun 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. GBM cells are highly resistant to standard-of-care therapies including radiation and chemotherapy, indicating an urgent need for the development of novel therapeutics. Recent evidence suggests that deubiquitinating enzymes are overexpressed or activated in various cancers, and they contribute to tumor progression and recurrence. Here, we report that the deubiquitinating enzyme ubiquitin-specific peptidase 1 (USP1) is highly expressed in GBMs and the targeting USP1 decreases cell survival and tumor growth. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated self-renewal and survival of GSCs. As one of the molecular mechanism that link USP1 to pro-tumorigenic roles, we found that the USP1 stabilized the inhibitor of DNA binding protein1 (ID1) and checkpoint kinase 1 (CHEK1), both of which are positive GSC regulators and implicated in radioresistance. Inhibition of USP1 in GBM cells leads to hypersensitivity to ionizing radiation through the decrease in DNA damage repair capacity. Finally, USP1 inhibition in orthotopic GBM xenografts significantly reduced tumor growth and prolonged the survival of tumor bearing mice. Together, our findings suggest that USP1 is a promising therapeutic target for GBMs and provide a rationale for positioning USP1 inhibitor as a GBM radiosensitizer.
Citation Format: Young Taek M. Oh, Eunhee Kim, Jeongwu Lee, Do-Hyun Nam. Targeting USP1 decreases glioblastoma stem cell survival and tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-270. doi:10.1158/1538-7445.AM2013-LB-270
Abstract LB-283: Prognostic significance of BRMS1 promoter methylation in operable breast cancer.
Authors: Chimonidou Maria , Kallergi Galatea , Georgoulias Vasilis , Welch Danny , Lianidou Evi 
Published: August 2014

Abstract
Introduction: Breast Cancer Metastasis Suppressor-1 (BRMS1) encodes a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. We examined the clinical relevance of BRMS1 promoter methylation in early breast cancer.
Methods: We analyzed 118 formalin-fixed paraffin embedded samples: 5 pairs of breast tumors and adjacent non-cancerous tissues, 14 non-cancerous tissues, 10 benign fibroadenomas, and 84 primary breast tumors. Peripheral blood mononuclear cells were isolated from 39/84 of these patients and were fixed in cytospins. BRMS1 methylation status was investigated in all FFPE and cytospin stained circulating tumor cells using methylation specific PCR. BRMS1 expression was examined using double-immunofluorescence in isolated PBMC cytospins using anti-BRMS1 and pancytokeratin A45-B/B3 antibodies.
Results: BRMS1 promoter methylation was observed in 0/19 noncancerous breast tissues, 0/10 benign fibroadenomas and 31/84(37.8%) breast tumors. During the follow-up period 27/84(32.1%) patients relapsed of which 19/84(22.6%) patients died as a consequence of disease progression. BRMS1 methylation was detected in 15/27(55.6%) patients that relapsed and in 10/19(52.6%) of patients that died. BRMS1 promoter methylation was associated with reduced disease-free interval (P=0.009) while a trend towards a reduced overall survival (OS) was also observed (P=0.071). Expression of BRMS1 on CTC was very heterogeneous: CTC with high BRMS1 expression were found in 7/13(53.8%) CTC positive samples while exclusively CTC with high BRMS1 were found in only 3 patients (23.0%). CTC with low BRMS1 expression were found in 3 patients. CTC negative for BRMS1 were found in 8/13(61.5%) patients. Exclusively CTC with low or negative BRMS1-expression were identified in 6/13(46.1%) patients. 4/13(30.8%) patients had both high and low or negative BRMS1 expression in their CTC.
Conclusions: BRMS1 promoter methylation provides important prognostic information for disease free survival in early breast cancer patients. BRMS1 promoter methylation and protein expression were evaluated in primary tumors and corresponding CTC for the first time. BRMS1 expression in CTC was heterogeneous in individual patient samples. CTC expressing epithelial markers but no BRMS1 seem to define a worse prognosis group of patients. These results need to be further evaluated and validated in a larger cohort of breast cancer patients.
Citation Format: Maria Chimonidou, Galatea Kallergi, Vasilis Georgoulias, Danny Welch, Evi Lianidou. Prognostic significance of BRMS1 promoter methylation in operable breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-283. doi:10.1158/1538-7445.AM2013-LB-283
Abstract LB-304: ATSP-9172, a novel Stapled Peptide inhibitor of HIF-dependent transcriptional activity with in vivo antitumor efficacy in a preclinical model of prostate cancer.
Authors: Sun Kaiming , DeMarco Steven J. , Guerlavais Vincent , Mukherjee Aditi , Irwin Sean , Shi Eric , Cai Hongliang , Darlak Krzysztof , Santiago Solimar , Pero Jessica , Olson Karen A. , Nash Huw M. , Chang Yong 
Published: August 2014

Abstract
Hypoxia-inducible transcription factors (HIF) are key regulators of cellular adaptation to hypoxia in solid tumors, and HIF-1α controls the expression of genes involved in anaerobic metabolism, angiogenesis, cell growth and survival. Hydrocarbon cross-linked alpha helical peptides (Stapled Peptides) are a breakthrough approach to create new class of drugs that modulate intracellular protein-protein interactions. Here, we have mimicked the structure and function of the CITED2 protein, an endogenous negative regulator of the interaction between HIF-1α and p300 proteins, by designing a Stapled Peptide derived from CITED2 to generate the first example of a potent and selective Stapled Peptide inhibitor of HIF-1α-dependent transcription. ATSP-9172 bound to the CH1 domain of p300 and disrupted the HIF-1α C-TAD/CH1 interaction in biochemical assays and inhibited HIF-dependent reporter gene activity in ME-180 cells. Examination of endogenous transcript levels in ME-180 cells revealed that ATSP-9172 down-regulated the transcription of HIF-1α target genes, such as adolase C, angiopoietin-like 4, and carbonic anhydrase 9 in a dose-dependent manner, but did not affect the expression of non-HIF target genes, verifying a specific and on-target mechanism of action. ATSP-9172 exhibited a dramatic improvement in solubility and plasma stability profile relative to the linear peptide, and demonstrated favorable pharmacokinetic properties in mice by providing high systemic exposure, low plasma clearance and long elimination half-life. Finally, intravenous administration of ATSP-9172 on an every other day schedule significantly inhibited tumor growth in a PC-3 human prostate tumor xenograft model (p &lt; 0.05); this inhibition was found to be dose-dependent. Our results demonstrate that a Stapled Peptide mimicking the HIF inhibitory function of the native CITED2 protein provides a novel and specific strategy to suppress HIF-1α-dependent gene expression for cancer therapy.
Citation Format: Kaiming Sun, Steven J. DeMarco, Vincent Guerlavais, Aditi Mukherjee, Sean Irwin, Eric Shi, Hongliang Cai, Krzysztof Darlak, Solimar Santiago, Jessica Pero, Karen A. Olson, Huw M. Nash, Yong Chang. ATSP-9172, a novel Stapled Peptide inhibitor of HIF-dependent transcriptional activity with in vivo antitumor efficacy in a preclinical model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-304. doi:10.1158/1538-7445.AM2013-LB-304