bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3467: A DAXX-KIFC3 fusion potentiates alternative lengthening of telomeres in osteosarcoma
Authors: Soper Sarah F. Clatterbuck , Showman Soyeon A. , Driest Kathryn E. , Waterfall Joshua J. , Walker Robert L. , Pineda Marbin A. , Zhu Yuelin J. , Wang Yonghong , Ester Corbin D. , Bilke Sven , Meltzer Paul S. 
Published: July 2017

Abstract
Proliferating cells must enact a program of telomere lengthening to counteract the chromosome end replication problem. In most types of cancer cells, telomeres are maintained through the action of the ribonucleoprotein telomerase, but some cancer cells, particularly those of mesenchymal origin, utilize an alternative method of telomere repair and lengthening termed the alternative lengthening of telomeres (ALT) pathway. Since telomere maintenance is essential for tumor cell immortality, better understanding of the ALT mechanism could potentially reveal drug targets that could be used to develop novel therapies for tumors that use ALT. It has been previously observed that ALT tumors frequently carry mutations in ATRX, which partners with the protein DAXX in a chromatin remodeling complex, but how these mutations facilitate the ALT pathway is not well understood. Work in our lab identified an ALT-positive osteosarcoma cell line, identified here as OS1, in which DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. We find that knockdown of the DAXX-KIFC3 fusion neither impairs ALT nor cell proliferation, suggesting that the fusion represents a loss of function. Furthermore, inducible restoration of wild-type DAXX, reversibly abrogates ALT function in this cell line. One of the hallmarks of ALT is localization of telomeres and DNA recombination machinery to nuclear PML bodies, resulting in formation of ALT- associated PML Bodies, or APBs. Thus it may be considered that changes in PML body composition represent a key aspect of the ALT mechanism. We observe that in OS1 both DAXX and ATRX fail to localize to PML bodies. This finding is consistent with the fact that the DAXX-KIFC3 fusion results in loss of a C-terminal SUMO interaction motif that normally mediates PML body interaction. Leveraging our inducible system, using biochemical and imaging approaches, we are working to define the role of DAXX in maintaining PML body composition.
Citation Format: Sarah F. Clatterbuck Soper, Soyeon A. Showman, Kathryn E. Driest, Joshua J. Waterfall, Robert L. Walker, Marbin A. Pineda, Yuelin J. Zhu, Yonghong Wang, Corbin D. Ester, Sven Bilke, Paul S. Meltzer. A DAXX-KIFC3 fusion potentiates alternative lengthening of telomeres in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3467. doi:10.1158/1538-7445.AM2017-3467
Abstract 3489: Noncoding RNA distribution in clear cell renal cell cancer: small RNA-seq data
Authors: Koduru Srinivas V. , Ravnic Dino J. 
Published: July 2017

Abstract
Small noncoding RNAs (sncRNAs) play pivotal roles in biological processes and may prove to be a tool in cancer diagnosis, prognosis, and treatment. Noncoding RNAs such as microRNAs (miRNAs), piwi-interacting-RNAs (piRNAs), long noncoding RNA (lncRNAs) and small nuclear/nucleolar RNAs (sn/snoRNAs) have recently been investigated to identify their role in cancer. Approximately 62,700 new cases of kidney cancer are expected each year in the United States leading to 14,240 deaths, with rates rising over the past 20 years. Nearly 90% of all kidney cancers will be renal cell carcinoma, of which 70% will be a clear cell renal cell carcinoma (ccRCC) subtype. When detected early most cases can be treated effectively, however there is a lack of early detection tests. We sought to identify molecular markers for early detection and diagnosis. We downloaded publically available (NIH bioproject PRJNA162397) ccRCC small RNA sequence raw data for noncoding RNA analysis. 22 ccRCC and 11 non-tumor renal cortex patient samples were evaluated. Data was analyzed by PartekFlow software. sRNA-seq data was annotated to miRNAs with 69 miRNAs aberrantly expressed in ccRCC with 37 being upregulated (top five: miR-122, miR-210, miR155, miR-224 and miR-21) and 32 being downregulated (top five: miR-200c, miR-502, miR-20b, miR10a and miR-204). Utilizing MetaCore software for pathway analysis the majority of expressed miRNAs were involved in metabolism related signaling pathways. Examining data for piRNAs revealed 22 which were significantly expressed (8 upregulated and 14 downregulated). Investigation of lncRNAs revealed 15 to be downregulated and 27 upregulated. We also uncovered 2 mitochondrial rRNAs, 10 miscRNAs, 1 snRNA, 7 snoRNAs, and 5 rRNAs in ccRCC samples. Our comprehensive analysis of publically available small RNA-seq data identified numerous sncRNAs associated with ccRCC. Pending further validation, they may prove useful as early detection biomarkers in this common cancer.
Citation Format: Srinivas V. Koduru, Dino J. Ravnic. Noncoding RNA distribution in clear cell renal cell cancer: small RNA-seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3489. doi:10.1158/1538-7445.AM2017-3489
Abstract 3490: Interrogation of small RNA-seq data for small noncoding RNA in human colon cancer
Authors: Koduru Srinivas V. , Nyinawabera Angelique , Ravnic Dino J. , Tiwari Amit K. 
Published: July 2017

Abstract
Genomic analysis of the human transcriptome has been made possible only in last decade by next generation sequencing (NGS). Recent advancements in NGS has further allowed us to look into small non-coding RNAs (sncRNAs) such as microRNAs (miRNAs), Piwi-interacting-RNAs (piRNAs), long non-coding RNAs (lncRNAs) & small nuclear/nucleolar RNAs (sn/snoRNAs). Recently, the roles of sncRNAs in biological processes have been implicated in biomarker development for diagnosis, prognosis &therapy. In the present study, 50 colon cancer patient’s small RNA sequencing raw data was downloaded from NIH bioproject (PRJNA266667; 7 TNM stage II & 43 TNM stage III) which contained 27 female & 23 male samples. 24 samples had metachronous metastasis (MM) & 26 non-metachronous metastasis (NMM). The small RNA-seq data was analyzed using PartekFlow. In depth analysis showed aberrant expression of 48 miRNAs (all upregulated) in TNM-III vs TNM-II specimens & 20 miRNAs (17 upregulated & 3 downregulated) in MM vs NMM. Further investigation of dysregulated miRNA through pathway analysis confirmed that the majority of the miRNAs were involved in cancer signaling pathways. Analysis of piRNA found unusual expression of 60 piRNAs (57 upregulated & 3 downregulated) in TNM-III vs TNM-II & 31 piRNAs (28 upregulated & 3 downregulated) in MM vs NMM. Further analysis of long non-coding RNAs, we found 77 lncRNAs were significantly expressed in TNM-III vs TNM-II &18 lncRNAs in MM vs NMM. We also, investigated small nuclear/nucleolar RNAs (sn/snoRNAs), miscRNAs & mtRNAs, we identified 37 snRNAs, 105 snoRNAs, 28 miscRNAs & 5 mtRNAs in TNM-III vs TNM-II whereas 2 snRNAs, 11 snoRNAs, 57 miscRNAs & 8 mtRNAs in MM vs NMM were identified. In summary, our comprehensive analysis on publicly available small RNA-seq data identified multiple small non-coding RNAs that need to be further explored for their use in the prognosis, diagnosis & therapy of colon cancer.
Citation Format: Srinivas V. Koduru, Angelique Nyinawabera, Dino J. Ravnic, Amit K. Tiwari. Interrogation of small RNA-seq data for small noncoding RNA in human colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3490. doi:10.1158/1538-7445.AM2017-3490
Abstract 3496: Long non-coding RNAs in colorectal cancer
Authors: Opattova Alena , Ferreira Fábio Miguel , Horak Jozef , Vodenkova Sona , Vodicka Pavel 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third most common type of cancer worldwide and the second most common cause of cancer related deaths in Europe. Since Countries of Central Europe (Czech Republic, Slovakia, Hungary) have one of the highest rates both for incidence and mortality of CRC, CRC became a serious health, social and economic problem. CRC pathogenesis involves multiple genetic events. On behalf of a strong experimental work, there is still lack of predictive, prognostic and treatment-response related biomarkers. Long non-coding RNAs (lncRNA) are non-protein coding transcripts longer than 200 nucleotides. Deregulation of lncRNAs is often seen in a variety of human diseases, including cancer. Taken together, this makes lncRNAs the potential regulators of cancer progression, therapeutic targets or markers of treatment efficacy.
The main aim of our present study was to define expression patterns of lncRNAs in colorectal tumor tissue and define their role in cancer cell proliferation, survival and DNA damage response (DDR).
In the first part of our study, we analyzed the expression profile of 83 lncRNA known to be associated with cancer progression in cohort of CRC tumor tissues and adjacent mucosa. We found 12 upregulated lncRNAs (p&lt;0.05) and 10 downregulated lncRNAs (p&lt;0.05). Our results have been replicated on larger set of patients (100 CRC patients) and those lncRNAs associated with cell proliferation, survival and DNA damage response are functionally tested on colorectal cell lines (HCT116, HCT116 p53-/-) in vitro.
Definition of role of lncRNA as a tumor suppressors or oncogenes in CRC etiology may lead to better understanding of regulation of CRC carcinogenesis. Furthermore, understanding the role of lncRNA in DDR may contribute to better treatment response of CRC patients and to define markers of individual treatment response.
Acknowledgement: GACR 15-14789S, AZV 15-27580A, GAUK800216, AZV 15-26535A, SUSCEPTCOST LD14050
Citation Format: Alena Opattova, Fábio Miguel Ferreira, Jozef Horak, Sona Vodenkova, Pavel Vodicka. Long non-coding RNAs in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3496. doi:10.1158/1538-7445.AM2017-3496
Abstract 3503: Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa
Authors: Feng Lu , Houck John R. , Lohavanichbutr Pawadee , Chen Chu 
Published: July 2017

Abstract
Objective: Oral cavity and oropharyngeal squamous cell carcinoma (OSCC) is a major cancer type in the head and neck region. To better understand the roles long non-coding RNA (lncRNA) play in OSCC carcinogenesis, we compared the genome-wide gene expressions of lncRNA in OSCC and in the oral mucosa from healthy individuals.
Materials and methods: We compared the expression levels of 3,054 probe sets for lncRNAs between 167 OSCCs and 45 healthy controls using an Affymetrix HG U133 plus 2.0 array dataset. We validated the top differentially expressed lncRNAs in three independent datasets in the Gene Expression Omnibus (GEO) repository: GSE42743, GSE9844, and GSE6791. We further tested the differential expression of the three lncRNAs showing the highest fold change by quantitative RT-PCR in a subset of 20 OSCCs and 10 control samples.
Results: We found 658 lncRNA transcripts (790 probe sets) to be significantly differentially expressed between OSCC and healthy oral mucosa using a criteria of FDR&lt;0.01, with 36 of them (39 probe sets) showing more than a 2-fold change. Among the 36, 14 (15 probe sets) lncRNAs were validated in all three independent datasets using the criteria FDR&lt;0.01: LOC441178, C5orf66-AS1, HCG22, FLG-AS1, CCL14/CCL15-CCL14, LOC100506990, TRIP10, PCBP1-AS1, LINC01315, LINC00478, COX10-AS1/LOC100506974, MLLT4-AS1, MIR31HG, and DUXAP10/LINC01296. The differential expressions of LOC441178, HCG22 and C5orf66-AS1 were verified by qRT-PCR.
Conclusion: We identified a number of differentially expressed lncRNAs using transcriptomic data between OSCCs and healthy oral mucosa. Further investigations into their potential role in OSCC carcinogenesis or to serve as OSCC biomarkers and/or therapeutic targets are warranted.
Citation Format: Lu Feng, John R. Houck, Pawadee Lohavanichbutr, Chu Chen. Transcriptome analysis reveals differentially expressed lncRNAs between oral squamous cell carcinoma and healthy oral mucosa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3503. doi:10.1158/1538-7445.AM2017-3503
Abstract 3509: EWS/FLI regulates transcriptional activation via length-dependent GGAA microsatellites
Authors: Johnson Kirsten M. , Taslim Cenny , Lessnick Stephen L. 
Published: July 2017

Abstract
Objective: The purpose of this study is to investigate how EWS/FLI transcriptionally activates gene targets via polymorphic GGAA microsatellites. Ewing Sarcoma is a pediatric bone malignancy initiated by a t(11;22) chromosomal translocation that produces the EWS/FLI oncoprotein. EWS/FLI transcriptionally activates and represses its target genes to mediate oncogenic reprogramming. Expression of its up-regulated targets correlates with EWS/FLI binding to associated GGAA microsatellites, which show length polymorphisms. These microsatellite polymorphisms may critically affect EWS/FLI-responsiveness of key gene targets. For example, NR0B1 is necessary for EWS/FLI mediated oncogenic transformation, and we found a “sweet-spot” of 20-25 repeat length as optimal for EWS/FLI mediated transcriptional activity at NR0B1 through clinical observation and in vitro studies. The mechanism underlying this optimal length is unknown.
Methods: We explored the stoichiometry and binding affinity of EWS/FLI for different repeat lengths through biochemical studies, including fluorescence polarization, and immunoprecipitation assays, combined with bioinformatics analysis. Additionally, use of EWS/FLI mutant constructs has been critical for elucidating particular binding behavior of EWS/FLI at different microsatellite repeat lengths.
Results: Fluorescence anisotropy studies demonstrate that FLI binding affinity is independent of GGAA microsatellite length. In contrast, the stoichiometry of protein to DNA binding increases in specific incremental patterns with increasing microsatellite repeats. EWS/FLI mutants inform on binding, suggesting a complex relationship between microsatellite length and transcriptional activity.
Conclusion: Overall our data suggests a model in which the DNA binding domain of multiple FLI monomers function as independent binding units to facilitate transcriptional activity in a length-dependent manner. The EWS portion appears to be critical for in vivo binding of genomic DNA globally. We propose that GGAA microsatellites are necessary and sufficient for EWS/FLI-mediated oncogenic transformation and that repeat length affects optimal DNA binding stoichiometry and transcriptional activity.
Citation Format: Kirsten M. Johnson, Cenny Taslim, Stephen L. Lessnick. EWS/FLI regulates transcriptional activation via length-dependent GGAA microsatellites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3509. doi:10.1158/1538-7445.AM2017-3509
Abstract 3528: PTCH53 as a potential secondary modifier in Li-Fraumeni syndrome
Authors: Pan Anna J. , Brew Benjamin , Erdman Lauren , Goldenberg Anna , Malkin David 
Published: July 2017

Abstract
Germline mutations in the TP53 gene have been established as the underlying genetic event in Li-Fraumeni syndrome (LFS), predisposing affected families to a wide spectrum of early onset cancers. Despite rapid progress in elucidating the role of wild-type p53 in maintenance of genome stability, and mutant p53 in cellular transformation, much of the molecular basis underlying LFS remains unclear. Lack of predictability in age of onset, type(s) of cancers, and likelihood of subsequent malignancies prompts further research to examine secondary modifiers on the underlying TP53 genotype. Patched-domain containing 4 (a.k.a PTCHD4 or PTCH53) is a repressor of canonical Hedgehog signaling that is also described to be transcriptionally activated by p53. Furthermore, our group has identified significant hypomethylation at the PTCH53 locus in a mutant TP53 LFS cohort, compared to TP53 wildtype carriers. These results suggest a potential role of PTCH53 in modifying LFS phenotype. The study examines the expression profile of PTCH53 in the presence of different germline TP53 mutations using primary LFS patient-derived fibroblasts, and aims to elucidate the functional role of PTCH53. PTCH53 transcriptional expression was assessed using digital droplet PCR in 10 LFS non-transformed fibroblast cell lines representing a spectrum of heterozygous germline TP53 mutations. Our data demonstrate that PTCH53 expression indeed depends on TP53 genotype where different TP53 mutations correspond with varied PTCH53 mRNA levels. Nonetheless, mutant TP53 fibroblasts have overall lower PTCH53 transcripts compared to wild-type TP53 fibroblasts. Fold-change increase in PTCH53 expression was detected upon doxorubicin and γ-irradiation induced activation of the p53 protein. These results suggest that induction of p53 via DNA damage activates a signaling cascade involving PTCH53 up-regulation. Further experiments will examine the functional consequences to PTCH53 de-regulation via shRNA knockdown and CRISPR knockout models, and will examine possible modifying effects of PTCH53 on the functional phenotype (cell viability, colony formation and migration potentials) of cell lines harboring different p53 mutants. Elucidating the functional profile of PTCH53 in the context of Li-Fraumeni syndrome will contribute to understanding the complex molecular basis underlying this cancer predisposition syndrome.
Citation Format: Anna J. Pan, Benjamin Brew, Lauren Erdman, Anna Goldenberg, David Malkin. PTCH53 as a potential secondary modifier in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3528. doi:10.1158/1538-7445.AM2017-3528
Abstract 3537: Otx2 and c-Myc association drives tumor progression in medulloblastoma molecular subtypes 3/4
Authors: Lu Yining , Guda Maheedhara R. , Asuthkar Swapna , Purvis Ian , Labak Collin M. , Jain Neha , Daniels David J. , Martin Sarah E. , Tsung Andrew J. , Velpula Kiran K. 
Published: July 2017

Abstract
Medulloblastoma (MB) is a pediatric brain tumor comprising of four molecular subgroups, with Group 3 and 4 tumors characterized by particularly poor prognosis. While research has advanced our understanding of MB, there is still a pressing need for new knowledge of the functional processes underlying its progression due to a scarcity of therapeutics. Recent studies have identified Orthodenticle homeobox 2 (Otx2), a cerebellar transcription factor, to be highly expressed in MB Group 3/4 subtypes. Datamining studies from Northcott and Robinson datasets revealed co-expression of Otx2 and c-Myc in Group 3/4 tumors. DAB staining conducted in human MB specimens showed increased expression of Otx2 and c-Myc. Colocalization studies confirmed datamining results. Next, we used a clinical Otx2 inhibitor, all-trans retinoic acid (ATRA), in a PDX cell line, P9, and in UW228 cells. Western blot analysis demonstrated reduced levels of c-Myc along with Otx2. In another experiment, we used the c-Myc/Max inhibitor 10058-F4 and observed comparable results to Otx2 inhibition. Real time PCR and immunocytochemistry experiments confirmed the aforementioned results. Further, treatment with ATRA and 10058-F4 showed reduced proliferation and migratory abilities in p9 and UW228 when compared to their respective controls. Mass spectrometry conducted on immune-precipitated Otx2 in P9 cells revealed a plethora of novel interaction partners that drive tumor growth and progression. In addition, western blot analysis in ATRA treated cells showed reduced expression of Max, suggestive of the existence of a feedback loop that link with Otx2 and c-Myc. Collectively our studies highlight Otx2 as a potential contributor to the malignant phenotype and describe its role in mediating the aggressiveness of Group 3/4 medulloblastoma.
Citation Format: Yining Lu, Maheedhara R. Guda, Swapna Asuthkar, Ian Purvis, Collin M. Labak, Neha Jain, David J. Daniels, Sarah E. Martin, Andrew J. Tsung, Kiran K. Velpula. Otx2 and c-Myc association drives tumor progression in medulloblastoma molecular subtypes 3/4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2017-3537
Abstract 354: Inhibition of Smad3 signaling with a TAT fusion peptide prevented TGF-β-induced fibronectin expression and cell migration in malignant gliomas
Authors: Kang Jeonghan 
Published: July 2017

Abstract
Malignant primary brain tumors represent one of the most common causes of cancer death in the world. Grade IV gliomas (glioblastoma multiform, GBM) are routinely resistant to current chemoradiationchemo radiation therapy with a median progression-free and overall survival for glioblastoma following current chemoradiation of ~7 and 15 months, respectively. While TGF-β functions as a growth inhibitor for most normal cell types, many tumors (including GBMs) have lost this inhibitory response and TGF-β now functions to promote tumor progression and/or dissemination. As aberrant TGF-β signaling is often considered a hallmark of high-grade gliomas, we examined whether inhibition of specific components would impact the malignant phenotype of glioblastoma. The primary mediators of TGF-β action are the Smad proteins (R-Smads), Smad2 and Smad3. Following receptor activation and R-Smad phosphorylation, they translocate to the nucleus to modulate gene expression. Since we previously determined that a cell penetrating peptide conjugate of the HIV TAT protein fused to a 30 amino acid sequence from sorting nexin 9 (SNX9) prevented Smad3, but not Smad2, nuclear import and target gene expression in models of organ fibrosis, we further investigated whether it might similarly impact aspects of GBM proliferation. To that end, twenty-one patient-derived xenografts (PDXs) were examined for their responsiveness to TGF-β. Of those, TGF-β stimulated migration and fibronectin expression in seven (33%), which was prevented by inhibiting Smad3 signaling with the TAT-SNX9 peptide but not a control peptide unable to block Smad3 action. These findings indicate that the TGB-b/Smad3 axis is a potentially important mediator of glioma cell invasion in a significant minority of GBM models. specifically targeting Smad3 might be effective in a subset of gliomas.
This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences and P50 CA-108961 Developmental Pilot Award from the National Cancer Institute.
Citation Format: Jeonghan Kang. Inhibition of Smad3 signaling with a TAT fusion peptide prevented TGF-β-induced fibronectin expression and cell migration in malignant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2017-354