bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4221: Development and evaluation of cell line-derived FFPE reference material for MSI assay validation
Authors: Matsusaka Takahiro , Surmann Eva-Maria , Constantine Sian , Child Hannah , Wickenden Julie 
Published: August 2019

Abstract
Microsatellite Instability (MSI) is defined by variance in the repeat count of microsatellite motifs and occurs in cells that are deficient in one or more mismatch repair proteins. MSI is present in varying cancer types, but is most commonly found in colorectal, gastric and endometrial cancer. Patients with early stage colorectal cancers that display MSI have a better prognosis and show a better response to chemotherapy compared to those with microsatellite stable tumors. MSI alongside additional markers such as tumor mutational burden is also a positive predictive biomarker for immune checkpoint inhibition Identification of MSI tumors in the diagnostic laboratory is traditionally performed by fluorescent multiplex PCR, evaluating the microsatellite length of two mononucleotide repeats and three dinucleotide repeats (recommended NCI Panel) or a commercially available kit, consisting of five mononucleotide markers alongside IHC staining for the four MMR proteins MSH2, MSH6, MLH1, and PMS2. With the increase in MSI testing related to the recent FDA approval of Keytruda®, several companies and laboratories are now developing newer and better PCR-based and next-generation sequencing assays to assess MSI. To control for error, we have developed a pair of cell line-derived MSI/MSS reference samples covering the most commonly used MSI biomarkers. MSI/MSS cell lines were mixed at biologically-relevant ratios and processed into FFPE to serve as a whole-process control. Our data support the suitability of this material on a variety of different platforms and with a high degree of consistency throughout various FFPE batches. In conclusion, our cell line-derived reference samples represent a commutable control to support MSI assay development and validation.
Citation Format: Takahiro Matsusaka, Eva-Maria Surmann, Sian Constantine, Hannah Child, Julie Wickenden. Development and evaluation of cell line-derived FFPE reference material for MSI assay validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4221.
Abstract 4222: Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling
Authors: Frankhouser David E. , Woelke Sarah , Sovic Michael , Bundschuh Ralf , Yan Pearlly , Yee Lisa D. 
Published: August 2019

Abstract
Introduction Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been studied for potential health benefits in many diseases including breast cancer. The preventive effects of n-3 PUFAs may relate in part to inhibition of chronic, low-grade inflammation. Of interest is the role of n-3 PUFAs in modulating pro-inflammatory gene expression via epigenetic factors such as DNA methylation (DNAm).
Methods DNA methylation of PBMCs obtained at 0 and 6 months of n-3 PUFA supplementation was assessed via reduced representation bisulfite sequencing (RRBS). PBMC samples were obtained from women at high risk for breast cancer during a randomized clinical trial investigating the effects of different n-3 PUFA doses. The dosing arm selected for this study was 5 g of EPA+DHA/day, with baseline and 6 month samples (n=10). DNAm was quantified using Bismark from trimmed, pass filter reads and analyzed with MethylKit to determine n-3 PUFA treatment specific DNAm changes.
Results Global DNAm showed no change after 6 months of n-3 PUFA treatment; however, we detected 30,974 differentially methylated CpGs (DMCs) across the genome. DMCs, both genome-wide and in gene promoters, where DNAm can regulate gene expression, were significantly enriched for hypermethylation events after treatment. Focusing the analysis on pro-inflammatory signaling mediators led to identification of candidate gene promoter DMCs involved in several inflammation-related pathways. Four pathways were significantly enriched for both DMCs and DMC hypermethylation events even when accounting for the genome-wide trend toward hypermethylated DMCs (hypergeometric test p-value &lt; 0.001). The Toll-Like Receptor Pathway (TLR) genes harbored the most DNAm changes post n-3 PUFA treatment.
Conclusion Our findings demonstrate that n-3 PUFA supplementation can result in inflammation-related changes stemming from PBMC methylome perturbation. The results suggest the TLR pathway as a potential mechanism for the anti-inflammatory effects of EPA and DHA. Functional studies are needed to confirm our current observation.
Citation Format: David E. Frankhouser, Sarah Woelke, Michael Sovic, Ralf Bundschuh, Pearlly Yan, Lisa D. Yee. Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4222.
Abstract 4224: SGLT2 is a diagnostic target for early stage lung adenocarcinoma
Authors: Villegas Brendon , Koziolek Eva , Liu Jie , Wallace W. Dean , Elashoff David , Aberle Denise R. , Shackelford David B. , Barrio Jorge R. , Yanagawa Jane , Dubinett Steven M. , Scafoglio Claudio 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer-related death, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis and treatment are essential; however, there are no targeted diagnostic and therapeutic approaches for early LUAD. An important hallmark of cancer is the increased glucose uptake via GLUT transporters. GLUT activity is imaged in cancer by positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG). FDG PET is a standard tool for staging advanced lung cancer, but has low sensitivity for early-stage LUAD. This is considered a consequence of slow growth and low requirement of glucose. However, we discovered a novel system of metabolic supply not detected by FDG PET: the sodium glucose transporter 2 (SGLT2)1. SGLT2 activity can be measured in vivo with the PET tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG). We identified high expression of SGLT2 in human lung premalignancy and early-stage LUAD. Me4FDG detects early-stage, FDG-negative LUAD in mouse models. Targeting SGLT2 with FDA-approved inhibitors significantly reduces tumor growth and prolongs survival in genetic and patient-derived murine models, confirming an important role of SGLT2 in early-stage LUAD2. The reliance of early stage LUAD on SGLT2 opens exciting diagnostic and therapeutic opportunities. The National Lung Screening Trial showed a 20% reduction in lung cancer mortality in high risk individuals using low-dose helical computed tomography (CT). CT is highly sensitive for detecting lung nodules, but is limited by low specificity, especially for LUAD. On CT, LUAD may appear as solid or subsolid nodules. Most subsolid nodules are not cancer, and many will remain stable or resolve; however, subsolid lesions can represent premalignant lesions or adenocarcinoma in situ. These lesions in the early spectrum of LUAD may persist for months to years before transforming into invasive disease. As a result, current standard of care is to follow these patients with CT imaging to monitor these indeterminate lesions for radiologic signs of malignant progression. The identification of novel biomarkers to predict the malignant potential of these nodules at their initial identification is of paramount importance. 1Scafoglio et al. Proc Natl Acad Sci U S A 2015;112(30):E4111-4119 2Scafoglio et al. Sci. Transl. Med. 10, eaat5933 (2018)
Citation Format: Brendon Villegas, Eva Koziolek, Jie Liu, W. Dean Wallace, David Elashoff, Denise R. Aberle, David B. Shackelford, Jorge R. Barrio, Jane Yanagawa, Steven M. Dubinett, Claudio Scafoglio. SGLT2 is a diagnostic target for early stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4224.
Abstract 4225: Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses
Authors: Krieg Carsten , Cardenas Luis , Guglietta Silvia , Wrangle John , Rubinstein Mark , Robinson Mark 
Published: August 2019

Abstract
Checkpoint inhibitors have significantly accelerated cancer treatment but still a majority of patients do not respond. Biomarker driven patient stratification early to the right immunotherapeutic might enhance response and patient survival. Here we used high-dimensional mass cytometry (CyTOF) combined with machine-learning bioinformatics for the in-depth characterization of immune responses before and during anti-PD-1 immunotherapy. CyTOF allows us to monitor protein expression of 34 markers on a single cell while running 20 samples simultaneously. The analysis is data driven, can be adapted to high throughput approaches and can model arbitrary trial designs such as batch effects and paired designs and is quantitative over millions of events. Using CyTOF as a precision medicine tool we could predict response to anti-PD-1 using liquid blood biopsies. Biobanked peripheral blood mononuclear cells (PBMCs) from 51 patients with stage IV melanoma before and after 12 weeks of anti-PD-1 therapy was analyzed. We observed a clear T cell response on therapy. The most evident difference in responders before therapy was an enhanced frequency of CD14+ CD16+HLA-DRhi classical monocytes. We validated our results using conventional flow and found a clear correlation of enhanced monocyte frequencies before therapy initiation with clinical response such as lower hazard and extended progression-free and overall survival. In a second study we used CyTOF to monitor immune response in 21 non small cell lung cancer (NSCLC) patients that initially responded and then progressed under anti-PD-1 to a novel combination immunotherapy of anti-PD-1 plus an IL-15 super-agonist (ALT-803). In this phase Ib clinical study a response in the CD8+ T cell compartment was observed. Unexpected our high dimensional unbiased analysis was able to detect and characterize a strong expansion of innate tumor-reactive effector NK cells starting around day 4 of therapy. Taken together, our unbiased artificial intelligence driven immune workflow might support patient selection prior to therapy, and serve as a novel tool for precision medicine to select the right drug combination and identify new drug-able cell populations.
Citation Format: Carsten Krieg, Luis Cardenas, Silvia Guglietta, John Wrangle, Mark Rubinstein, Mark Robinson. Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4225.
Abstract 4244: Novel expressed long non-coding RNAs in uveal melanoma
Authors: Rodriguez Daniel A. , Kuznetsov Jeffim N. , Sanchez Margaret I. , Kurtenbach Stefan , Harbour J. William 
Published: August 2019

Abstract
Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UMs can be divided into two prognostic groups based on their gene expression profile (GEP). The class 1 GEP is associated with low metastatic risk and the class 2 GEP with high metastatic risk. Class 1 tumors are associated with EIF1AX or SF3B1 mutations while Class 2 tumors are associated with inactivating mutations in the tumor suppressor BAP1. Class 1 and Class 2 UMs have been shown to differ in their expression of numerous known micro-RNAs and long non-coding RNAs (lncRNA). Here, we sought to identify novel differentially expressed lncRNAs using a publicly available RNA-Seq database. Raw RNA-Seq fastq files from 80 TCGA UM samples were obtained from the Cancer Genomics Hub (CGHub), quality controlled using FastQC (v0.11.3), and trimmed using trim-galor (v0.4.1). Sequences were aligned to the human genome (GRCh38) and accompanying general transfer format file (gtf) (Gencode v28) using STAR (v2.5). Transcript discovery was performed using Cufflinks (v2.2.1). Protein coding probability was calculated using CPC (v2.0), and transcripts predicted to be non-coding with transcript length &gt;200bps were retained. 1671 novel transcripts were added to the gtf file, and fastq files were realigned with the new annotation. Estimated counts for all known and novel transcripts were generated using RSEM (v1.3.0) after STAR alignment. A cutoff of RPKM &gt; 1 in at least 35% of tumors was used as a threshold for transcripts of interest, resulting in 61 novel transcripts, 32 of which were differentially expressed at FDR &lt; 0.05 between Class 1 and Class 2 tumors, including 7 upregulated and 25 downregulated in Class 2 tumors. Further work is underway to elucidate the function of these novel transcripts in UM pathogenesis.
Citation Format: Daniel A. Rodriguez, Jeffim N. Kuznetsov, Margaret I. Sanchez, Stefan Kurtenbach, J. William Harbour. Novel expressed long non-coding RNAs in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4244.
Abstract 4259: Defining subtle cancer subtypes using the darkest DNA
Authors: Parida Laxmi , Haferlach Claudia , Rhrissorrakrai Kahn , Utro Filippo , Levovitz Chaya , Wolfgang Kern , Nadarajah Niroshan , Hutter Stephan , Meggendorfer Manja , Walter Wencke , Baer Constance , Haferlach Torsten 
Published: August 2019

Abstract
The confluence of deep sequencing and powerful machine learning is providing an unprecedented peek at the darkest of the dark genomic matter. While deep sequencing uncovers rare tumor variants, the heterogeneity of the disease confounds the best of machine learning (ML) algorithms. Here we set out to answer if the dark-matter of the genome encompass signals that can classify the fine subtypes of disease that are otherwise gnomically indistinguishable. We introduce a novel stochastic regularization, ReVeal, that empowers ML to classify subtle cancer subtypes even from the same ‘cell of origin’. Analogous to heritability, implicitly defined on whole genome, we use predictability (F1 score) definable on portions of the genome. In an effort to classify cancer subtypes using dark-matter DNA, we applied ReVeal to a new WGS dataset from 727 patient samples with seven forms of hematological cancers and assessed the predictivity over several genomic regions including genic, non-dark, non-coding, non-genic, dark. ReVeal allowed the classification of all segments of the genome better than standard ML algorithms. The non-genic, non-coding and the dark-matter had the highest F1 scores with dark-matter having the highest level of predictability (F1 = 0.78). Based on ReVeal’s predictability of different sectors of the genome, dark matter contains signal significant enough to classify fine subtypes of disease. The agglomeration of rare variants, even in the hitherto unannotated and ill-understood regions of the genome, may play a substantial role in the disease etiology and deserve much more attention.
Citation Format: Laxmi Parida, Claudia Haferlach, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Kern Wolfgang, Niroshan Nadarajah, Stephan Hutter, Manja Meggendorfer, Wencke Walter, Constance Baer, Torsten Haferlach. Defining subtle cancer subtypes using the darkest DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4259.
Abstract 4276: Inhibition of USP14 decrease tumorigenesis via autophagy in lung cancer
Authors: PARK MINSOO , Kim Min Ji , Lee Peter Chang Whan 
Published: August 2019

Abstract
The ubiquitin proteasome system (UPS) is the primary pathway through which the levels of regulatory proteins are controlled. Dysregulation of components within the UPS have been linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme USP14 is associated with proteasome where it is trimming ubiquitin chain on the substrate. In our current study, we unexpectedly found that USP14 levels were elevated in lung cancer patients. USP14 inhibitor, IU1-47 and siUSP14, significantly decreased cell proliferation, migration, and invasiveness in lung cancer cells. Inhibition of USP14 induced the alteration of LC3-I to LC3-II which leads to autophagic cell death not but apoptosis. Thus our finding suggests that USP14 plays a crucial role in tumorigenesis and USP 14 inhibitor is a potent drug for lung cancer treatment.
Citation Format: MINSOO PARK, Min Ji Kim, Peter Chang Whan Lee. Inhibition of USP14 decrease tumorigenesis via autophagy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4276.
Abstract 4303: TanshinoneIIA, an isolated compound from Salvia miltiorrhiza, inhibits cell growth in colorectal cancer via activation of p38MAPK signaling pathway
Authors: Wang Yan , Zhou Lihong , Ji Qing , Sui Hua , Hu Xueqing , Cai Gang , Li Qi 
Published: August 2019

Abstract
Tanshinone IIA (TSIIA) is an active ingredient extracted from the root of Danshen (Salvia miltiorrhiza Bunge), a Chinese traditional herb. Recent studies have indicated that TSIIA is a natural anti-tumor agent, however, the underlying mechanisms remain largely unknown. We studied the anti-tumor efficacy of TSIIA on human colon cancer cell lines in vitro and in vivo, and have further demonstrated that the molecular anti-cancer property of TanIIA is dependent on its inhibition of proliferation and induction of apoptotic cell death via p38MAPK signaling pathway.
The results indicated that TanIIA were markedly more effective than control group in preventing tumor growth and increasing survival time. This phenomenon was accompanied by a decrease in cell growth in a concentration- and time-dependent manner. Hoechst 33258 stainning showed an increased number of apoptotic bodies in the cells after treatment with TanIIA. Flow cytometry analysis showed TanIIA could cause an obvious colon cacer cell apoptosis and arrest cells in the G0/G1 phase. After p38MAPK signaling pathway was blocked, the cell apoptotic rates and cell ratio of G0/G1 phase were decreased significantly. In addition, TanIIA increased p38MAPK phosphorylation, and up-regulated the protein expression of ATF-2, The ATF-2 expression was found to be significantly decreased in cells treated with p38MAPK-specific inhibitor. From our results, it is speculated that TanIIA may induce human colon cancer cells apoptosis and arrest cells in the G0/G1 phase involve up-regulation the expression of the ATF-2 mRNA via p38MAPK signal transduction pathway.
Note: This abstract was not presented at the meeting.
Citation Format: Yan Wang, Lihong Zhou, Qing Ji, Hua Sui, Xueqing Hu, Gang Cai, Qi Li. TanshinoneIIA, an isolated compound from Salvia miltiorrhiza, inhibits cell growth in colorectal cancer via activation of p38MAPK signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4303.
Abstract 4304: Anti-proliferative activity of nodosin is associated with the regulation of wnt signaling pathway in colon cancer cell
Authors: Bae Eunseo , Kim Donghwa , Byun Woong sub , Lee Sang Kook , Chin Young-Won 
Published: August 2019

Abstract
Wnt signaling is a critical mechanism of biological processes, including cell proliferation, tissue homeostasis and development. The aberrant activity of Wnt signaling pathway is highly correlated with the colorectal carcinogenesis. Therefore, the effective compounds targeting Wnt signaling pathway could be applicable for colorectal cancer treatment. The bioactivity of nodosin, a component of Isodon serra, was evaluated in HCT116 colorectal cancer cells. Nodosin exhibited a potential growth inhibition of colon cancer cells. Nodosin also showed an effective inhibition upon wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. In addition, Wnt target genes such as β-catenin, Axin2, cyclin D1 and survivin were suppressed by nodosin in HCT116 cells. The inhibition of cell proliferation by nodosin was in part associated with the G2/M phase cell cycle arrest in colon cancer cell. These findings suggest that the anti-proliferative activity of nodosin against colorectal cancer cell should be associated with the regulation of Wnt/β-catenin signaling pathway.
This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (NRF-2016M3A9B6903499).
Citation Format: Eunseo Bae, Donghwa Kim, Woong sub Byun, Sang Kook Lee, Young-Won Chin. Anti-proliferative activity of nodosin is associated with the regulation of wnt signaling pathway in colon cancer cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4304.