bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5306: SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding
Authors: Amodio Matthew , Srinivasan Krishnan , Dijk David van , Mohsen Hussein , Yim Kristina , Muhle Rebecca , Moon Kevin , Montgomery Ruth , Noonan James , Wolf Guy , Krishnaswamy Smita 
Published: August 2018

Abstract
Handling the vast amounts of single-cell RNA-sequencing and CyTOF data, now being generated in patient cohorts, presents a computational challenge due to the noise, complexity, sparsity and batch effects present. Here, we propose a unified deep neural network approach to automatically process and extract structure from these massive datasets. Our unsupervised architecture, called SAUCIE (Sparse Autoencoder for Unsupervised Clustering, Imputation, and Embedding), simultaneously performs several key tasks for single-cell data analysis including 1) clustering, 2) batch correction, 3) visualization, and 4) denoising/imputation. SAUCIE is trained to recreate its own input after reducing its dimensionality in a 2-D embedding layer which can be used to visualize the data. Additionally, it uses two novel regularizations: (1) an information dimension regularization to penalize entropy as computed on normalized activation values of the layer, and thereby encourage binary-like encodings that are amenable to clustering and (2) a Maximal Mean Discrepancy penalty to correct batch effects. Thus SAUCIE has a single architecture that denoises, batch-corrects, visualizes and clusters data using a unified representation. We show results on artificial data where ground truth is known, as well as mass cytometry data from patients undergoing immunotherapy, dengue-infected patients, and single-cell RNA-sequencing data from embryonic mouse brain.
Citation Format: Matthew Amodio, Krishnan Srinivasan, David van Dijk, Hussein Mohsen, Kristina Yim, Rebecca Muhle, Kevin Moon, Ruth Montgomery, James Noonan, Guy Wolf, Smita Krishnaswamy. SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding [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 5306.
Abstract 5313: Occupational exposure to trichloroethylene and DNA methylation: a cross-sectional study
Authors: Zhang Jinming , Zhang Luoping , Vermeulen Roel , Hu Wei , Bassig Bryan A. , Wong Jason Y. , Shen Min , Ji Bu-Tian , Reiss Boris , Purdue Mark , Smith Martyn T. , Lan Qing , Rothman Nathaniel 
Published: August 2018

Abstract
Trichloroethylene (TCE) is a chlorinated solvent that is often used in occupational settings for vapor degreasing of metal parts. In 2012, TCE was classified as a known human carcinogen (Group 1) by the International Agency for Research on Cancer, largely based on evidence for kidney cancer. Animal studies have suggested that TCE may modulate DNA methylation. We performed a cross-sectional study to examine the associations of DNA methylation of individual CpG sites with TCE exposure. We enrolled 80 workers from factories where TCE was used, as well as 96 unexposed controls from food and clothes manufacturing factories in the same region, and 69 exposed workers and 77 controls were available for analyses in this study. Personal exposure measurements (2-3 per subject) were collected for a full work shift using a 3MTM badge in both exposed workers and a subgroup of the control workers. Blood samples were collected from each subject and CpG methylation was assayed on the Illumina Infinium HumanMethylation450 BeadChip. After quality controls procedures, 485,512 CpG probes were available for analyses. We used separate multivariable linear regression models to examine the associations of TCE exposure and the methylation level at each single CpG site. All models were adjusted for age, sex, current smoking status, current alcohol consumption, recent infection, and body mass index. The median TCE exposure level in exposed subjects was 12 ppm (10th percentile: 2 ppm; 90th percentile: 45 ppm). We found 29 CpG probes that achieved genome-wide significance (p &lt; 1.04x10-7) when comparing TCE exposed workers with controls. TCE exposure was associated with hypomethylation at nearly all (28/29) of those CpG probes. Of these 29 CpG probes, 6 CpGs showed a significant (p &lt; 1.04x10-7) exposure-response relationship across the categories of controls and lower- (&lt;12ppm) and higher-exposed (≥12 ppm) workers, and were mapped to 6 different chromosomes. To our knowledge, this is the first report that TCE exposure is associated with alterations in DNA methylation in a molecular epidemiologic study. Our findings may provide insight into potential biological mechanisms linking exposure to TCE and adverse health outcomes.
Citation Format: Jinming Zhang, Luoping Zhang, Roel Vermeulen, Wei Hu, Bryan A. Bassig, Jason Y. Wong, Min Shen, Bu-Tian Ji, Boris Reiss, Mark Purdue, Martyn T. Smith, Qing Lan, Nathaniel Rothman. Occupational exposure to trichloroethylene and DNA methylation: a cross-sectional study [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 5313.
Abstract 5317: JAK2 regulates oxidative damage-induced epigenetic alterations
Authors: Ding Ning , Miller Sam , O'Hagan Heather 
Published: August 2018

Abstract
Elevated levels of reactive oxygen species at sites of chronic inflammation cause oxidative DNA damage in epithelial cells, contributing to carcinogenesis. Aberrant silencing of key genes by promoter CpG island DNA hypermethylation occurs in many cancers that form at sites of chronic inflammation. Yet, it is not completely understood how these aberrant DNA methylation alterations are initiated. We hypothesize that the recruitment of epigenetic silencing proteins to sites of oxidative DNA damage is important for initiating DNA methylation. Here we demonstrate that after hydrogen peroxide (H2O2) treatment, mismatch repair proteins MSH2 and MSH6 become localized to sites of oxidative DNA damage, resulting in the recruitment of DNA methyltransferase 1 (DNMT1) and Polycomb repressive complex 2 (PRC2) members to chromatin. This recruitment results in the formation of repressive chromatin in the promoters of tumor-suppressor genes and the concomitant transient reduction in their expression. We sought to further understand the mechanism that drives H2O2-induced MSH2 and MSH6 chromatin binding. Janus kinase 2 (JAK2) is a kinase that is canonically known to be activated by cytokines and growth hormones and phosphorylate the transcription factor signal transducer and activator of transcription (STATs). Here, we demonstrate that in response to treatment with H2O2, but not interleukin 6 (IL-6), JAK2 translocates to the nucleus and interacts with MSH2 and MSH6. Nuclear JAK2 is important for H2O2-induced chromatin interaction of MSH2, MSH6, DNMT1 and PRC2 members. Interestingly, H2O2-induces a global and site-specific increase in trimethylation of histone H3 at lysine 27 (H3K27me3) that is also dependent on JAK2. Furthermore, by analyzing TCGA datasets, we demonstrate high JAK2 mRNA expression correlates with CpG island methylator phenotype (CIMP) status in gastric and colorectal cancer. All together, these findings suggest JAK2 plays a key role in initiating oxidative damage-induced epigenetic alterations during inflammation-driven tumorigenesis. Ultimately, understanding the mechanism of initiation of cancer-specific promoter DNA hypermethylation may lead to treatment strategies to reduce aberrant epigenetic changes induced by chronic inflammation and therefore reduce tumorigenesis.
Citation Format: Ning Ding, Sam Miller, Heather O'Hagan. JAK2 regulates oxidative damage-induced epigenetic alterations [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 5317.
Abstract 5333: Methylation profiling identifies two subclasses of cutaneous squamous cell carcinoma related to distinct cell types of origin
Authors: Paredes Manuel Rodríguez , Bormann Felix , Raddatz Günter , Gutekunst Julian , Lucena-Porcel Carlota , Köhler Florian , Wurzer Elisabeth , Schmidt Katrin , Röwert-Huber Joachim , Denisova Evgeniya , Feuerbach Lars , Herpel Esther , Nindl Ingo , Hofmann Thomas G. , Winnefeld Marc , Lyko Frank 
Published: August 2018

Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermis samples from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed keratin and enhancer methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages.
Citation Format: Manuel Rodríguez Paredes, Felix Bormann, Günter Raddatz, Julian Gutekunst, Carlota Lucena-Porcel, Florian Köhler, Elisabeth Wurzer, Katrin Schmidt, Joachim Röwert-Huber, Evgeniya Denisova, Lars Feuerbach, Esther Herpel, Ingo Nindl, Thomas G. Hofmann, Marc Winnefeld, Frank Lyko. Methylation profiling identifies two subclasses of cutaneous squamous cell carcinoma related to distinct cell types of origin [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 5333.
Abstract 5337: The epigenetic feedback loop of the CpG demethylase TET family genes in head and neck cancers
Authors: Misawa Kiyoshi , Imai Atsushi , Mochizuki Daiki , Kanazawa Takeharu 
Published: August 2018

Abstract
Purpose: The aim of this study is that clarifying the epigenetic regulation of TET family genes can provide insights into the mechanisms of tumorigenesis and the risk of disease recurrence in HNSCC.
Experimental Design: We generated methylation profiles of TET family genes in tumor samples obtained from 233 patients with head and neck squamous cell carcinoma (HNSCC); these included 57 hypopharynx, 44 larynx, 69 oral cavity, and 63 oropharynx tumor samples. TET family genes mRNA expression and promoter DNA methylation were examined via quantitative reverse transcription (Q-RT-PCR) and methylation-specific PCR (Q-MSP), respectively. Promoter methylation was compared with various clinical characteristics and methylation index.
Results: The TET methylation index (TE-MI) as the number of TET family genes methylation events was positively correlated with alcohol consumption (P = 0.004), HPV status (P = 0.004) and disease recurrence (P = 0.002). Simultaneous methylation analysis of TET family genes significantly correlated with reduced disease-free survival in unfavorable event groups (log-rank test, P = 0.026). In the multivariate Cox proportional hazards analysis, TET3 methylation of T1/2 patients, oropharyngeal cancer patients and oral cancer patients exhibited the high association with poor survival (hazard ratio: 2.64, P = 0.014; 3.55, P = 0.048; 2.63, P = 0.028, respectively). Joint analysis of tumor suppressor genes methylation index (TS-MI) showed a significant trend toward higher TE-MI increased.
Conclusions: TET family genes methylation status was independently associated with aggressive tumor behavior and forming a DNA methylation feedback loop in patients with HNSCC.
Citation Format: Kiyoshi Misawa, Atsushi Imai, Daiki Mochizuki, Takeharu Kanazawa. The epigenetic feedback loop of the CpG demethylase TET family genes in head and neck cancers [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 5337.
Abstract 5340: The methylation burden is determined by the duration of exposure to carcinogenic factors
Authors: Yamada Harumi , Takeshima Hideyuki , Niwa Tohru , Toyoda Takeshi , Yamashita Satoshi , Ushijima Toshikazu 
Published: August 2018

Abstract
Aberrant DNA methylation accumulated in normal tissues, namely methylation burden, is closely associated with risk of carcinogenesis, especially in cancers related to chronic inflammation. Methylation burden is known to be influenced by multiple factors, such as genetic factors and strengths of carcinogens. However, the impact of the duration of exposure to a carcinogen is still unclear. Here, using a Mongolian gerbil model of Helicobacter pylori (H. pylori)-induced chronic gastritis, we aimed to clarify the impact of the duration of exposure on the methylation burden in normal gastric tissues (gastric mucosae). Following infection with H. pylori, DNA methylation levels at four CpG islands, HE6, SA9, SB5, and SD2, increased, depending upon the exposure duration. After eradication of H. pylori, DNA methylation levels decreased, but tended to be higher in gastric mucosae with a longer infection period. DNA molecules with dense DNA methylation, but not those with sparse DNA methylation, increased depending upon the infection period. DNA methylation levels at one of the four CpG islands, SA9, tended to be higher in the gastric mucosae of gerbils infected with H. pylori than in those of non-infected gerbils, even 50 weeks after eradication. These results showed, for the first time, that the methylation burden in normal tissues is influenced by the duration of exposure to a carcinogenic factor.
Citation Format: Harumi Yamada, Hideyuki Takeshima, Tohru Niwa, Takeshi Toyoda, Satoshi Yamashita, Toshikazu Ushijima. The methylation burden is determined by the duration of exposure to carcinogenic factors [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 5340.
Abstract 5345: Somatic mutation status in cfDNA between therapy responders and non-responders of oropharyngeal squamous cell carcinoma patients
Authors: Khandelwal Alok R. , Greer Adam , Orgeron Rhett , Hamiter Mickie , Ma Xiaohui , Moore-Medlin Tara , Yin Hong , Mills Glenn , Nathan Cherie-Ann O. 
Published: August 2018

Abstract
Circulating tumor DNA (ctDNA) could potentially be utilized as a biomarker in Oropharyngeal Squamous Cell Carcinoma (SCC) patients. The objective of this study was to determine if somatic variants could be detected in circulating cell-free DNA (cfDNA) of Oropharyngeal SCC patients using Next Generation Sequencing (NGS). Somatic mutations have been reported in Orophayngeal SCC cases. The identification and detection of somatic variants in circulating cell-free DNA in patient's plasma may predict response to therapy, help monitor disease progression, guide therapy, and determine likelihood of recurrence. In this study, we compared the somatic mutation status between therapy responders and non-responders among Orophayngeal SCC patients. IRB approval was obtained and 23 Oropharyngeal SCC patients were identified in our patient database. Genomic DNA was isolated from frozen tumor tissue using NucleoSpin Tissue kit by Clontech. Cell-Free (cfDNA) was then extracted from patient's plasma samples using Zymo's Quick-cfDNATM serum and plasma kit. The quality and size of DNA was determined by Agilent 2200 TapeStation. If genomic DNA contamination was identified it was removed with Zymo Select-a-Size DNA kit. Libraries were prepared with 10 to 25 ηg of cfDNA using Accel-Amplicon 56G Oncology Panel of Swift Biosciences. DNA sequencing was then performed on MiSeq platform with Miseq Reagent Kit. Variants were identified using Biomedical Genomic Workbench and Genialis's online data analysis platform for Swift Biosciences's Accel-amplicon panels. From the 23 matched samples, 8 somatic non-synonymous variants were found in both tissue and plasma, 7 of which were present in non-responders. The variants and their allele frequencies in the non-responder group were as follows (tumor DNA /cfDNA in %) HRAS Gly12Cys (36.54/0.45), TP53 Glu298* (5.48/0.21), CDKN2A Pro114Arg (48.11/1.52), TP53 Arg282Trp (46.47/1.77), FBXW7 Arg505Gly (30.17/0.58), FBXW7 Arg505Leu (30.46/0.64), TP53 Arg273Cys (38.91/2.51), and one variant in the responder group PTEN (21.07/0.67) Arg130Gln. In conclusion, somatic non-synonymous variants can be identified in cfDNA from Oropharyngeal SCC patients using NGS. The number of detected variants is far greater in the non-responder group suggesting somatic variant detection could be a prognostic marker for Oropharyngeal SCC patients.
Citation Format: Alok R. Khandelwal, Adam Greer, Rhett Orgeron, Mickie Hamiter, Xiaohui Ma, Tara Moore-Medlin, Hong Yin, Glenn Mills, Cherie-Ann O. Nathan. Somatic mutation status in cfDNA between therapy responders and non-responders of oropharyngeal squamous cell carcinoma patients [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 5345.
Abstract 5396: Identification of meningioma patients in high risk of tumor recurrence using microRNA profiling
Authors: Srovnal Josef , Balik Vladimir , Slavik Hanus , Megova Magdalena Houdova , Vaverka Miroslav , Hrabalek Lumir , Ehrmann Jiri , Staffova Katerina , Hajduch Marian 
Published: August 2018

Abstract
Introduction: Meningioma represents one of the most common intracranial tumors. They are generally thought to progress from low to high-grade lesions and relapse. However, the molecular mechanisms underlying their pathogenesis remains to be ellucidated. Identification of meningioma patients with higher risk of recurrence may have significant impact for future clinical management. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 45 meningioma patients (15 recurrent patients, 30 patients without recurrence) and 5 healthy controls (dura mater). Comprehensive clinical-pathological data were mined. There were 15 males and 30 females; median age was 54 years, range 28 - 99 years. Total RNA was purified from FFPE samples after pathological verification using miRNeasyMini kit (QIAGEN). Microarray analysis was performed using the MiRNA 4.0 Array and FlashTagTM Biotin HSR(Affymetrix). Affymetrix CEL files have been read with read.celfiles function from oligo package and preprocessed with rma function (Bioconductor). The expression dataset was analyzed with Wilcoxon exact two-sample test (exactRankTestsR package) in order to discover significantly altered miRNAs. Results: We revealed different miRNA profiles in primary meningioma tumors that will relapse in comparison with non-recurrent tumors. 54 differentially expressed miRNAs were identified in meningeoma patients at high risk of recurrence. High-risk patients had significantly higher expression of miR-572 and miR-320c, and lower expression of miR-140 and miR-16-5p. Sixteen candidate miRNAs (including miR-107, miR-16-5p, miR-320c, miR-371b-5p and miR-15a-5p) were chosen for further qPCR validation on independent dataset. Moreover, miRNA expression levels were also compared in paired samples (primary and recurrent tumors) of 15 meningioma patients. However, only small differences in miRNA expression were detected. Conclusion: We have found different miRNA profiles in meningioma patients identifying patients in high risk of recurrence. Sixteen candidate miRNAs (including miR-107, miR-16-5p, miR-320c, miR-371b-5p and miR-15a-5p) were further validated. Acknowledgment: This work was financially supported by Ministry of Health of the Czech Republic, grant nr. 15-29021A, IGA UP LF 2017_013, NPU LO1304 and NCMG LM2015091.
Citation Format: Josef Srovnal, Vladimir Balik, Hanus Slavik, Magdalena Houdova Megova, Miroslav Vaverka, Lumir Hrabalek, Jiri Ehrmann, Katerina Staffova, Marian Hajduch. Identification of meningioma patients in high risk of tumor recurrence using microRNA profiling [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 5396.
Abstract 5397: ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal cancer
Authors: Bhome Rahul , Goh Rebecca , Pillar Nir , Shomron Noam , Sayan Emre , Mirnezami Alex 
Published: August 2018

Abstract
There is urgent need for prognostic markers to stratify intermediate-stage colorectal cancer (CRC) patients for the benefit of adjuvant therapy. Tumor heterogeneity is a major obstacle in stratification attempts as rare cancer cell populations may display stem cell properties and allow generation of therapy resistance. Tumor stroma, on the other hand, is less susceptible to genetic alterations than cancer cells, providing signals that are more reproducible across patient samples. Exosome encapsulated microRNAs (exomiRs) are particularly amenable to biomarker development because they circulate, closely resemble the tissue of origin and are inherently stable. We sought to identify a stromal exomiR signature in colorectal cancer with biomarker potential. Paired primary tumor-associated and normal fibroblasts were extracted from human colonic tissue. Exosomes were isolated by differential ultracentrifugation, validated according to International Society for Extracellular Vesicles recommendations, and profiled for over 800 microRNAs (miRNAs) by NanoString. Data preprocessing and normalization was conducted prior to differential expression analysis. Candidate miRNAs were validated by qPCR. Pathway and network analyses were conducted using miRPath and Ingenuity Pathway Analysis. Forty one exomiRs were differentially present in tumor-associated and normal fibroblasts. Of these, 21 were more abundant in tumor-associated fibroblasts. Thirty-six KEGG pathways were found to be regulated by this exomiR signature, such as “PI3K-Akt” and “colorectal cancer.” A potential target of these exomiRs is PHLPP2, which encodes a phosphatase acting on AKT. In keeping with this, exposure to fibroblast exosomes increased AKT phosphorylation and that of its direct target Bad, in CRC cells, potentially due to a decrease in PHLPP2 protein abundance. Consequently, these cells were protected from drug-induced apoptosis. For the first time, stromal exomiRs have been profiled in colorectal cancer. Tumor-associated and normal stroma can be distinguished by a specific exomiR signature, which is potentially functionally important. Further mechanistic characterization is now required to identify the clinical significance of stromal exomiRs.
Citation Format: Rahul Bhome, Rebecca Goh, Nir Pillar, Noam Shomron, Emre Sayan, Alex Mirnezami. ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal 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 5397.