bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2276: Efficient curation and ontology mapping of clinical and phenotypic data
Authors: Edgren Henrik , Mano Beatriz , Laaksonen Maria 
Published: August 2018

Abstract
Heterogeneity within and between data sets is one of the primary impediments to sound and efficient data analysis. This heterogeneity can arise from many sources: data collection practices can change over time, even within the same study; rigorous standards for data encoding may be missing, leading to inter-individual heterogeneity in data encoding; or the data may originally have been collected for a different purpose (e.g. EHR data). Additionally, narrative text, such as medical statements, are inherently unstructured and require curation before analysis.
No matter which source(s) heterogeneity derives from, curation of the data is necessary for efficient, accurate and reproducible data analysis. This not only includes correcting errors and standardizing encoding, but also extends to enriching the data through mapping it to relevant medical ontologies, such as SNOMED CT, or other standardized terminologies, such as Research Resource Identifiers.
To solve the most common issues in clinical and phenotypic data curation, we have developed the AccurateTM data curation and ontology mapping solution. It combines an intuitive web-based user interface for data cleaning with efficient solutions for semi-automated ontology mapping of both structured data and narrative text. For structured data, tokenized and stemmed data items are mapped against ontologies indexed in Elasticsearch. Term names, their synonyms and the local ontology structure are then used to query the target ontology, with a list of best matches returned along with a quality score for the mapping. Ontology tagging of narrative text is based on a sentence-based deep learning approach, analyzing sentences to classify and ontology map identified text units. In practice, combining a bidirectional long short term memory network with a conditional random field model into a named entity recognition system (bio-NER). Preliminary benchmarking of the bio-NER system on the MIMIC III data set suggests good specificity and sensitivity for identification of biomedically relevant concepts.
In summary, we here present an intuitive and highly efficient solution for curating clinical and phenotypic data, as well as enriching it using ontology mapping of both structured and narrative data.
Citation Format: Henrik Edgren, Beatriz Mano, Maria Laaksonen. Efficient curation and ontology mapping of clinical and phenotypic data [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 2276.
Abstract 2285: Regtools: Integrated analysis of genomic and transcriptomic data for discovery of mutations associated with aberrant splicing in cancer
Authors: Feng Yang-Yang , Ramu Avinash , Skidmore Zachary L. , Kunisaki Jason , Cotto Kelsy C. , Griffith Obi L. , Griffith Malachi 
Published: August 2018

Abstract
The interpretation of variants in cancer is frequently focused on direct protein coding alterations. However, most somatic mutations are in noncoding regions of the genome, and even exonic mutations may have unidentified noncoding consequences. Here we present Regtools, a software package designed to efficiently identify variants that may cause aberrant splicing in tumors. Our tool integrates variant calls from genomic data with junctions extracted from transcriptomic data in order to examine potential cis alterations to splicing near a somatic variant. Based on user-defined parameters and position relative to known exons, variants are first annotated as splicing relevant or not. Splicing junctions are inferred from transcriptomic sequencing data, and comparison of junctions to a reference transcriptome allows for identification and annotation of novel junctions and nearby regulatory or splicing motifs. From there, mutations are associated with junctions that overlap with a flanking region. In order to evaluate Regtools, we used it to analyze the transcriptional output of tumor-sequencing data from two cohorts of cancer patients, one of hepatocellular carcinoma and one of small cell lung cancer with 28 and 21 samples, respectively. We performed whole-exome and RNA sequencing on each sample. Somatic variants were called on whole-exome alignment data. For each cohort, we compared the junctional profiles between tumors and identified numerous examples of variants for which there are elevated levels of proximal novel or known junctions. Moreover, out of 754 (153 in HCC; 601 in SCLC) variants identified as splicing relevant by our approach, only 165 (20 in HCC; 145 in SCLC) were annotated as splicing relevant by Ensembl's Variant Effect Predictor, using the recommended “per_gene” option. This preliminary analysis illustrates the importance of an efficient, user-friendly computational tool for identifying important noncoding variants that would otherwise be undervalued or perhaps even completely ignored by traditional methods and annotators. Regtools is freely available and open source (https://github.com/griffithlab/regtools).
Citation Format: Yang-Yang Feng, Avinash Ramu, Zachary L. Skidmore, Jason Kunisaki, Kelsy C. Cotto, Obi L. Griffith, Malachi Griffith. Regtools: Integrated analysis of genomic and transcriptomic data for discovery of mutations associated with aberrant splicing in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2285.
Abstract 2292: Comparison of Q Path and Aperio Image Analysis System for quantification of ER and PR by IHC in breast carcinoma TMAs
Authors: Jacobsen Max Henry , Temm Constance , Sandusky George 
Published: August 2018

Abstract
According to the Centers for Disease Control and Prevention, breast cancer is still one of the most common cancer in women, and top one or two in cancer mortality rates for all races of women. Novel drug treatments are needed to develop new treatments and clinical validation with IHC are common in research. Some common methods of validations are using Tissue MicroArrays (TMAs). In this study 5 TMAs containing approximately 100 cores each were stained with Estrogen Receptor (ER) and Progesterone Receptor (PR). Paraffin-embedded tissue blocks were obtained from the Indiana University Heath Pathology Laboratory under IRB approved protocols. Immunostainings with ER and PR antibodies (DAKO) were preformed using the DAKO-flex platform system at the IU Health Pathology Laboratory. The slides were digitally imaged using the Aperio Digital Imaging System. The SVS digital images were quantified using two different image analysis systems. One imaging system was the Aperio TMALab software, the other was Q Path image analysis software. Both systems were compared not only on the basis of performance, but among other parameters such as user friendliness and the ability to use a SVS image file type. When comparing the systems, the algorithm of Q Path was altered to closely match the algorithm of the standard Aperio positive pixel algorithm. Two measurements of antibody quantification were compared, one being positive pixel percentage, the other being an H Score. A regression line was used to show correlation between systems. Standard deviations were used to compare data against a standard pathology hand count of 0, 1, 2, and 3. The results show a strong correlation (R-squared value at or greater than 0.85) between the two imaging systems for both the positive pixel algorithm and H Score. The tightness may be due to consistent and rigorously explored in the past 20 years with both of these nuclear antibodies. Further studies should help distinguish any other possible errors using novel biomarkers and also delineate any discrepancies between a nuclear expressions against both a cytoplasmic and/or cell membranous expressions. In conclusion, Aperio Imaging analysis systems and Q path image analysis systems were in strong correlation, and therefore interchangeable in scientific research.
Citation Format: Max Henry Jacobsen, Constance Temm, George Sandusky. Comparison of Q Path and Aperio Image Analysis System for quantification of ER and PR by IHC in breast carcinoma TMAs [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 2292.
Abstract 2310: Targeting transcription-associated CDKs is an effective way to combat glioblastoma and medulloblastoma with minimal effect on primary neurons
Authors: Bhutada Isha , Chellappan Srikumar , Padmanabhan Jaya 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM) is the most prevalent and malignant brain tumor in adults. Currently there are no effective therapies to manage the disease efficiently. Medulloblastoma is the most common type of pediatric tumor and accounts for approximately 15% of all pediatric brain tumors. We aimed to determine if targeting the transcription-associated cyclin-dependent kinases, cdk7 and cdk9, using specific inhibitors, could interfere with the growth and metastatic properties of glioblastoma and medulloblastoma cell lines. We tested the effectiveness of Flavopiridol, a known inhibitor of cdk4, cdk6, pTEFb and cdk9; THZ1, a cdk7 inhibitor; and SNS032, which is known to inhibit cdk2, cdk7 and cdk9, on U87 and SNB19 glioblastoma, H4 neuroglioma and Daoy medullobastoma cells. Treatment with these pharmacological agents showed very strong cytotoxic effects on these cancer cells as measured by MTT (3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide) assay. Among these agents the cdk7 inhibitor was most effective and showed efficacy at nanomolar concentrations. Additionally, the inhibitors interfered with the cancer cell migration, as measured by wound healing assay, and anchorage independent growth, as measured by soft agar colony formation. In stark contrast, the inhibitors had no cytotoxic effects on primary neurons. Mechanistically, western blot analysis showed that the tumor cells treated with the inhibitors had reduced levels of Pol II C-terminal domain phosphorylation, indicative of its inhibition and suppression of transcription. Furthermore, inhibitor treatment resulted in a significant reduction in p70S6 kinase phosphorylation, suggesting that in addition to the transcriptional machinery, the translational machinery is also affected upon treatment with the aforementioned cdk inhibitors. Immunostaining analysis of the cells showed a marked reduction in the levels of P-Pol II and P-p70S6 kinase upon inhibitor treatment, confirming that the cdk inhibitors indeed interfere with both transcription and translation. These inhibitors appear to be working in a p53-dependent fashion. These novel findings shed light on potential mechanisms that can be targeted to combat both glioblastoma and medulloblastoma effectively. More specifically, our studies imply that cdk7 and cdk9 inhibitors may serve as potential therapies for effective management of brain tumor.
Citation Format: Isha Bhutada, Srikumar Chellappan, Jaya Padmanabhan. Targeting transcription-associated CDKs is an effective way to combat glioblastoma and medulloblastoma with minimal effect on primary neurons [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 2310.
Abstract 2353: Analysis of noncoding mutations in cancer revealed novel potentially pathogenic recurrent mutations
Authors: Koyama Takahiko , Parida Laxmi 
Published: August 2018

Abstract
Introduction:
98% of mutations are non-coding mutations. Thus far, most non-coding mutations are ignored or merely classified as variant of unknown significance with a few exceptions, despite the fact that non-coding region plays significant role in regulations and other important biological processes. Although they would not be directly druggable, these non-coding mutations might be important for cancer etiology, response to treatments and prognosis assessments.
Method:
Mutations in non-coding genes, intron, upstream and downstream, and intergenic regions are collected from COSMIC and TCGA as defined in Ensemble GRCh37.75 gene definition and hg19 RefSeq. Over 15 million non-coding mutations are analyzed for recurrence over 10 samples. Mutations in neighborhood of IG genes and dbSNP150 polymorphisms are removed from further investigation. We analyzed remaining mutations for possible super enhancer and transcription factor binding.
Result:
911 distinct recurrent mutations are identified. Promoter mutations in protein coding genes like MPRS31, NUDFB9, SZT2, WASF3 in addition to TERT are discovered. Intronic mutations of well-known cancer genes such as HIF1A, NF1, KMT2C, and ATR are discovered with their associated cancer type specificity. As for non-coding RNA's, lincRNA CROCCP2, LINC00969 and miRNA MIR4477 appear frequently. Only 182 mutations are reluctantly classified as intergenic; intergenic loci RP11-96F8.1-KSR1P1, MLLT10P1-DEFB115, and bP-21201H5.1-IGHV1OR21-1 contain unusually high recurrent mutations.
Conclusion:
Many non-coding mutations worth further investigation are found. Still, it is quite possible that many of these mutations might be artifacts resulting from paralogous alignments, gene definition compatibility and other technical issues. Importantly, we discovered novel intronic mutations in genes already associated with treatments. Mutations in intergenic regions might be involved in regulatory mechanisms and chromosomal structures. Understanding these non-coding mutations will further refine our understanding of biology as well as cancer.
Citation Format: Takahiko Koyama, Laxmi Parida. Analysis of noncoding mutations in cancer revealed novel potentially pathogenic recurrent mutations [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 2353.
Abstract 2374: Oncogenic kinases-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like cells
Authors: Zhang Lin , Zhou Zhifen , Li Min , Yu Dihua 
Published: August 2018

Abstract
The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerated tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that PKM2 phosphorylation by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, we found that PKM2 was phosphorylated at tyrosine 105 (Y105) in MDA-MB-231 breast cancer cells; whereas PKM2 was largely unphosphorylated in non-transformed MCF10A cells. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introducing the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population partly by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted YAP nuclear localization and cancer stem-like cell population. Lapatinib, an ErbB2 kinase inhibitor, decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, in non-transformed cells, unphosphorylated PKM2 is non-oncogenic; but in tumor cells, phosphorylated PKM2-Y105 by activated kinases gains oncogenic functions partly by activating YAP downstream signaling to increase cancer stem-like cell properties.
Citation Format: Lin Zhang, Zhifen Zhou, Min Li, Dihua Yu. Oncogenic kinases-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like 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 2374.
Abstract 2397: Intracellular cholesterol regulates the DNA damage response in inflammatory breast cancer
Authors: Stecklein Shane R. , Wolfe Adam R. , Debeb Bisrat G. , Larson Richard A. , Woodward Wendy A. 
Published: August 2018

Abstract
Purpose: Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer, and patients with IBC remain at high risk of locoregional recurrence after radiotherapy. We previously demonstrated that depleting intracellular cholesterol induces radiosensitivity in IBC cells in vitro, and that IBC patients with high levels of high-density lipoprotein (HDL) and those taking a statin, which inhibits de novo cholesterol biosynthesis, have improved locoregional control after radiotherapy. These results suggest that targeting cholesterol metabolism may improve the radiotherapeutic management of IBC. Here, we aimed to understand the molecular mechanism(s) linking cholesterol metabolism and radiation-induced DNA damage and DNA repair and to evaluate statin pharmacotherapy as a DNA repair inhibitor and radiotherapeutic adjunct in an in vivo pre-clinical model of IBC.
Methods: KPL4, SUM149, SUM190, and IBC3 IBC cell lines were used to examine the effect(s) of simvastatin and human serum lipoproteins on radiation-induced DNA damage induction, DNA damage signaling, DNA damage-associated G1, intra-S, and G2/M cell cycle checkpoint activation, and DNA double strand break (DSB) repair by homologous recombination (HR) and non-homologous end joining (NHEJ).
Results: We have generated multiple IBC cells lines with an integrated Traffic Light Reporter (TLR) that is capable of measuring HR and NHEJ, and demonstrate that depletion of intracellular cholesterol abrogates HR-mediated repair of DNA DSBs. We also show that intracellular cholesterol has pleiotropic effects on cell cycle distribution and DNA damage-associated cell cycle checkpoints. We also report a novel polycistronic dual bioluminescence reporter system that can robustly visualize and quantitate DNA DSB induction and repair in vitro and in vivo.
Conclusions: Cholesterol is an important determinant of intrinsic radiosensitivity in IBC, and appears to regulate repair of radiation-induced DNA DSBs. Targeting cholesterol metabolism is a potential strategy to overcome IBC radioresistance and improve the prognosis for this aggressive disease.
Citation Format: Shane R. Stecklein, Adam R. Wolfe, Bisrat G. Debeb, Richard A. Larson, Wendy A. Woodward. Intracellular cholesterol regulates the DNA damage response in inflammatory 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 2397.
Abstract 2471: Clinical significance of noncoding circHIPK3 RNA in human hepatocellular carcinoma
Authors: Kim Gyeonghwa , Yoon Jun Sik , Jang Se Young , Park Soo Young , Tak Won Young , Kweon Young-Oh , Hur Keun 
Published: August 2018

Abstract
Background and Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with poor prognosis and high risk of recurrence. Previous studies have shown that various microRNAs (miRNAs) are frequently dysregulated in HCC, which contributes to cancer development and progression. Nonetheless, the regulation mechanism of miRNAs is still unclear. Circular noncoding RNA (circRNA) is highly conserved and stable covalently closed RNA circles with gene-regulatory potential. Recently, one abundant circRNA from HIPK3 gene, circHIPK3, has been identified, and its function has been elucidated as multiple miRNAs sponge. Thus, we aimed to investigate the clinical relevance of circHIPK3 in HCC.
Materials and Methods: We analyzed clinical specimens from 152 pairs of HCC and corresponding normal liver (NL) tissues. Total RNAs were isolated from clinical tissues using Qiagen kit. CircHIPK3 expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between circHIPK3 expression and various clinicopathologic features of HCC patients.
Results: CircHIPK3 expression was significantly downregulated in HCC tissues compared to corresponding NL tissues (P=0.036). In HCC patients, circHIPK3 expression was strongly suppressed in more advanced tumors (P&lt;0.001). Further correlation analysis showed that circHIPK3 expression was significantly associated with T stage (P&lt;0.001), TNM stage (P&lt;0.001), BCLC stage (P&lt;0.001), and alpha-fetoprotein (AFP) expression (P=0.033).
Conclusions: We have determined clinical significances of circHIPK3 expression in HCC, which may provide clinical evidence for the potential of circHIPK3 as novel markers for diagnosis and predicting prognosis in HCC patients.
Citation Format: Gyeonghwa Kim, Jun Sik Yoon, Se Young Jang, Soo Young Park, Won Young Tak, Young-Oh Kweon, Keun Hur. Clinical significance of noncoding circHIPK3 RNA in human hepatocellular carcinoma [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 2471.