bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1564: Detecting low allele frequency somatic mutations using targeted amplicon sequencing and a novel double strand molecular barcoding scheme
Authors: Zhang Li Jacey , Lee Lucie Siu , Liu Yang Lily , Liu Jeff , Chen Tao , Liu Guoying , Liu Zhitong 
Published: August 2018

Abstract
Using next generation sequencing (NGS) with a noise reduction mechanism to detect somatic variants of 0.1% minor allele frequency or lower has attracted increasing interest for cancer research and diagnostics. Molecular barcoding is a technology that aims to reduce the noise and errors caused by PCR and sequencing artifacts, and improves mutation detection accuracy. Here, we report a novel multiplex PCR-based, ultra-sensitive molecular barcoding technology that drastically reduces false positive calls, additionally, barcoded sequencing reads can be assigned back to both the forward and reverse strands of the original DNA fragment, thus further remove variant call noise. While providing a simple and fast workflow, this technology does not have the base bias associated with capture hybridization. It achieves an error rate of 4 X 10-7 nucleotides, and detects allele frequencies at 0.1%.
Citation Format: Li Jacey Zhang, Lucie Siu Lee, Yang Lily Liu, Jeff Liu, Tao Chen, Guoying Liu, Zhitong Liu. Detecting low allele frequency somatic mutations using targeted amplicon sequencing and a novel double strand molecular barcoding scheme [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 1564.
Abstract 1567: Ku70, Ku80 and Rab5C as biomarkers for radiotherapy resistance in rectal tumors during neoadjuvant therapy
Authors: Martins Vilma Regina , Baptistella Antuani Rafael , Silva Petrus Paulo , Cassinela Edson Kuatelela , Marchi Fabio , Leme Adriana Fp , Begnami Maria Dirlei , Aguiar Samuel 
Published: August 2018

Abstract
Rectal cancer is the second most common cancer in the large intestine, corresponding to one-third of the total cases of colorectal cancer. The neoadjuvant chemoradiation in rectal cancer treatment reduces the risk of local recurrence, but pathologic complete response is achieved only in 10-40% of patients. The response to neoadjuvant treatment is poorly understated in rectal tumors as well as the mechanisms associated with chemoradiation resistance. In order to identify the players involved with the therapy resistance, we performed proteomic analysis of biopsies from stage II and III rectal adenocarcinoma patients before neoadjuvant treatment and compared with residual tumor tissue removed by surgery after neoadjuvant therapy. Ku70, Ku80 and Rab5C showed a significant increased expression after the chemoradiation treatment. To better understand the mechanism associated with therapy resistance, we generated an ionizing radiation-resistant rectal adenocarcinoma cell line. These cells and also their secreted exosomes exhibit overexpression of the same three proteins identified in tissue samples from patients submitted to chemoradiation. Using this in vitro model, we identified that Rab5C modulates EGFR internalization promoted by irradiation, which was also essential to regulate the expression of the DNA repair proteins Ku70 and Ku80, and cell resistance to ionizing radiation. Taken together, these findings indicate that EGFR and Rab5C are potential targets to sensitize rectal cancer cells to neoadjuvant treatment. In addition, the presence of Ku70, Ku80 and Rab5C in circulating exosomes can be explored as biomarkers to follow resistance to radiotherapy in patients under neoadjunat therapy for rectal tumors.
Citation Format: Vilma Regina Martins, Antuani Rafael Baptistella, Petrus Paulo Silva, Edson Kuatelela Cassinela, Fabio Marchi, Adriana Fp Leme, Maria Dirlei Begnami, Samuel Aguiar. Ku70, Ku80 and Rab5C as biomarkers for radiotherapy resistance in rectal tumors during neoadjuvant therapy [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 1567.
Abstract 158: GSKJ4, a selective jumonji histone H3 lysine27 demethylase inhibitor, targets ovarian cancer stem cells
Authors: Sakaki Hirotsugu 
Published: August 2018

Abstract
Background/Aim: Global increase in the trimethylation of histone H3 at lysine 27 (H3K27me3) has been associated with the differentiation of normal stem cells and cancer cells, however, the role of H3K27me3 in the control of cancer stem cells (CSCs) remains poorly understood. We investigated the impact of increased H3K27me3 on ovarian CSCs using GSKJ4, a selective jumonji H3K27 demethylase inhibitor.
Materials and Methods: The effect of GSKJ4 on the viability as well as on the self-renewal and tumor-initiating capacity of CSCs derived from A2780 and TOV21G human ovarian cancer cell line, was examined.
Results: GSKJ4 induced cell death in A2780 CSC and TOV21G CSC at a concentration non-toxic to normal human fibroblasts. Furthermore, GSKJ4 induced differentiation and inhibited sphere formation as well as stem cell marker expression of A2780 CSC and TOV21G CSC that survived GSKJ4 treatment.
Conclusion: Using ovarian CSCs as a model, we have demonstrated for the first time that GSKJ4 can target CSCs, suggesting a critical role for H3K27 methylation in their maintenance and survival. Our findings thus provide an initial clue to explore the role of GSKJ4 as a potent CSC-targeting agent for ovarian cancer and other types of human cancer.
Citation Format: Hirotsugu Sakaki. GSKJ4, a selective jumonji histone H3 lysine27 demethylase inhibitor, targets ovarian cancer stem 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 158.
Abstract 1582: The coupling of MDSCs with a computational neural network (NN) to detect solid tumors
Authors: Dominguez George A. , Maslar Kristen , Polo Alexander , Sholevar Cyrus , Campisi Anthony , Roop John , Gabrilovich Dmitry , Rauscher Frank , Kumar Amit 
Published: August 2018

Abstract
The goal of this study was to create a non-invasive cancer detection assay that analyzes flow cytometry data in an objective method. By using an artificial neural network (NN), we were able to distinguish between cancer patients (CPs) and benign/healthy donors (HDs) based upon the flow cytometry profiles of MDSCs and other leukocytes. Myeloid-derived suppressor cells (MDSCs) are known to be key contributors in supporting tumor progression and tumor escape through their ability to suppress anti-tumor responses mediated through T cell and natural killer (NK) cell activity. Several studies have demonstrated their utility as indicators of tumor progression and possible predictors of clinical outcomes, but there is significant overlap with healthy individuals preventing discrete and accurate calls. We used standard multiparametric flow cytometry techniques to immunophenotype MDSCs and other leukocytes found in the peripheral blood of 65 biopsy-confirmed CPs with solid tumors and 84 HDs. A series of NNs utilizing pattern recognition computational algorithms are then created using three data sets: 1) the training set - this ‘teaches' the two output categories of cancer and not cancer, 2) the validation set - this uses backpropagation to improve the accuracy of the trained networks, and 3) the testing set - this is used to rank the trained networks against each other. Finally, a naïve testing set is then used to determine the overall sensitivity and specificity for the top-ranking networks. Using traditional flow cytometry gating methods to analyze MDSCs as a biomarker for cancer detection, it is difficult to achieve high sensitivity and specificity due to the substantial overlap with healthy individuals. Here, we incorporated a standard 12 marker flow cytometry assay with NN technology to achieve a sensitivity of 92% and a specificity of 89%. Pairing the advanced analytical capabilities of our NN with surface biomarker based analysis of MDSCs and certain leukocytes measured in peripheral blood has enabled us the ability to objectively identify patterns indicative for the existence of a solid tumor.
Citation Format: George A. Dominguez, Kristen Maslar, Alexander Polo, Cyrus Sholevar, Anthony Campisi, John Roop, Dmitry Gabrilovich, Frank Rauscher, Amit Kumar. The coupling of MDSCs with a computational neural network (NN) to detect solid tumors [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 1582.
Abstract 1585: Evaluation of circulating free DNA in non-metastatic breast cancer
Authors: Araujo Jhajaira M. , Ponce Jaime , Murillo Alexis , Rebaza Pamela , Danos Pierina , Aguilar Alfredo , Fujita Ricardo , Gomez Henry L. , Pinto Joseph A. , Buleje Jose 
Published: August 2018

Abstract
Background Circulating free DNA (cfDNA) is becoming an important tool in diagnosis and prognosis in several types of cancer. In this study we evaluated the association between cfDNA concentrations in peripheral blood with tumoral features of non-metastatic breast cancer patients.
Methods cfDNA was extracted from plasma of peripheral blood of patients with non-metastatic breast cancer and healthy controls. In patients, blood samples were collected before and after surgery, while in controls samples were collected after their results of breast cancer screening. Detection of copy number of PUM1 and RNaseP genes were performed in a QuantStudio® 3D Digital PCR System and quantification was obtained with QuantStudio® 3D AnalysisSuite™ Cloud Software. Raw values were compared among the different clinicopathologic features.
Results In total 26 patients and 25 controls were included. There were significant differences between controls and patients for levels counts of PUM1 and RNaseP genes (p&lt;0.0001 in both cases). In patients, median concentrations before and after surgery for PUM1 were 10.6 copies/uL (range: 2.2-16.3) vs. 7.6 copies/uL (range: 1.3-12.8), respectively (P=0.04) and for RNaseP were 6.6 copies/uL (range: 0.9-20.0) vs. 5.3 copies/uL (range: 0.5-16.0), respectively (P=0.103). Hormonal tumors produced more cfDNA in terms of RNaseP at diagnosis (7.9 vs. 5.6, P=0.049). When we compared patients according to their hormonal status with controls, RNaseP was able to identified positive hormonal receptors patients (P&lt;0.0001). There were no significant differences between other clinicopathologic features. There was a significant decrease after surgery of RNaseP levels in node negative tumors (P=0.049) and PUM1 levels in &gt;10mm tumors (P=0.041).
Conclusions Our results suggest that PUM1 is a better diagnostic biomarker for non-metastatic breast cancer because RNaseP loss sensitivity in negative hormone receptor cases. Hormonal tumors produced more circulating free DNA. RNaseP could be used to monitor node negative patients and PUM1 to patients with &gt;10mm tumors.
Citation Format: Jhajaira M. Araujo, Jaime Ponce, Alexis Murillo, Pamela Rebaza, Pierina Danos, Alfredo Aguilar, Ricardo Fujita, Henry L. Gomez, Joseph A. Pinto, Jose Buleje. Evaluation of circulating free DNA in non-metastatic 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 1585.
Abstract 1599: Capture of tumor cells in blood with "Universal CTC-chip"
Authors: Yoneda Kazue , Kuwata Taiji , Tanaka Fumihiro 
Published: August 2018

Abstract
Background: Circulating tumor cells (CTCs) are not only a surrogate of distant metastasis, but also useful for material of liquid biopsy. "Universal" CTC-chip is a polymeric microfluidic device that can capture CTCs according to their surface marker from whole blood. We have examined the capture efficiency of lung cancer and mesothelioma cells in the blood with CTC-chip coated with antibodies against various surface marker.
Methods: Lung cancer cell lines (PC-9) or mesothelioma cell lines (ACC-MESO-4, MSTO-211H) were used in this study. Cells were CFSE-labeled and added in the blood of healthy donor. A polymeric CTC-chip was coated with two steps: base- and capture-antibody. As capture antibody, we used anti-EpCAM, podoplanin, and EGFR antibody. After flowing these samples, capture efficiency was calculated (number of captured cells/number of flowed cells).
Results: Capture efficiency of PC-9, MESO-4, and METO-211H was 100.0%, 9.5% and 9.1% (EpCAM-chip; anti-EpCAM antibody clone HEA125); 5.8%, 85.9% and 9.0 % (podoplanin-chip; anti-podoplanin antibody clone E1); 38.6, 112.5%, 11.7% (podoplanin-chip; anti-podoplanin antibody clone NZ-1); 30.2%, 21.8%, 38.5% (EGFR-chip; anti-EGFR antibody clone 528), respectively.
Conclusion: Using "Universal CTC-chip" with various antibodies, it was possible to capture nonepithelial tumor cells such as mesothelioma cells.
Citation Format: Kazue Yoneda, Taiji Kuwata, Fumihiro Tanaka. Capture of tumor cells in blood with "Universal CTC-chip" [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 1599.
Abstract 1620: ATR inhibition for the treatment of ATM-deficient gastric cancer
Authors: Cai Mu-Yan , Reavis Hunter D. , Chen Jie-Wei , Ganesa Chirag , Kochupurakkal Bose , Shapiro Geoffrey I. , D'Andrea Alan D. 
Published: August 2018

Abstract
ATM and ATR are central kinases in the cellular response to DNA damage and play a crucial role in maintaining genome integrity. Inactivation of ATM has been observed in multiple tumor types and pre-clinical studies suggest that inhibition of ATR is synthetic-lethal in ATM-deficient tumors. More than 10% of gastric cancers carry potentially deleterious mutations in ATM and patients with ATM-deficient gastric cancers could potentially benefit from ATR inhibitor-based therapy. This study focuses on establishing the critical parameters for clinical development of ATR inhibitors in treating gastric cancer. First, we tested the cytotoxic response to ATR inhibition of ATM-deficient and ATM-complemented derivative of human fibroblasts. Next, we utilized a panel of gastric cancer cell lines that represent the spectrum of ATM mutations and ATM expression levels to further confirm the correlation between reduced ATM activity and the cytotoxic effects of ATR inhibition. Third, we evaluated the effect of a series of missense and truncating mutations in ATM that were identified in The Cancer Genome Atlas (TCGA) project. Finally, we developed an immunohistochemistry (IHC) assay to assess the expression level of ATM in gastric tumor samples. Our results confirmed that ATM-deficient human fibroblasts were acutely sensitive to ATR inhibition compared to ATM-complemented cells. Acute sensitivity to ATR inhibition was also observed in gastric cancer cell lines that carry deleterious mutations in ATM and in those that express very low levels of ATM. Complementation experiments with mutant versions of the ATM ORF using ATM-deficient human fibroblasts identified deleterious mutations in ATM that sensitize to ATR inhibition. The IHC assay was applied to a cohort of 208 primary gastric cancers. ATM expression was undetectable in approximately 11% of the samples; an additional 26% expressed very low levels. Our findings suggest that ATR inhibition may elicit favorable responses in gastric cancer patients with tumors harboring deleterious ATM mutations or very low levels of ATM expression. Targeted exon-sequencing methods that are used widely combined with IHC for ATM may be useful for patient selection.
Citation Format: Mu-Yan Cai, Hunter D. Reavis, Jie-Wei Chen, Chirag Ganesa, Bose Kochupurakkal, Geoffrey I. Shapiro, Alan D. D'Andrea. ATR inhibition for the treatment of ATM-deficient gastric 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 1620.
Abstract 1621: Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma cells
Authors: Heo Sook-Kyoung , Noh Eui-Kyu , Jeong Yoo Kyung , Kim Jeong Yi , Choi Yunsuk , Cheon Jaekyung , Koh SuJin , Baek Jin Ho , Min Young Joo , Jo Jae-Cheol 
Published: August 2018

Abstract
Background: Radotinib is a medicine for the treatment of some types of cancer. It is approved in South Korea for use as a second-line treatment of chronic myeloid leukemia (CML). Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and of platelet-derived growth factor receptor (PDGFR). It has been little known the effects of radotinib on mantle cell lymphoma cells (MCL). Methods: First, we examined cytotoxicity of radotinib on MCL cell line, MAVER-1 and REC-1. Also, cytotoxicity of radotinib on both cell lines which have a different genetic back ground. Annexin V positive cell, caspas-3 and -9 activities, cell cycle distribution and mitochondrial membrane potential (MMP) were observed by analyzed with flow cytometric analysis. And diverse signaling pathways were investigated by Western blotting in MCL cells.
Results: Interestingly, radotinib caused cell death of MCL cells. And radotinib induces G1-phase arrest in MAVER-1 and REC-1 cells. And it also inhibited the expression of CDK2, CDK4, and cyclin D1, D3 and E. Therefore, radotinib induces G1-phase arrest via suppression of CDK2, CDK4, and cyclin D1, D3 and E. Generally, the intrinsic apoptotic pathway involves mitochondrial activation and caspase and phosphatidylserine externalization. Radotinib induced Annexin V positive cells, and caspase pathway activation including caspase-3, -7 and -9. And its treatment remarkably decreased MMP in MCL cells at 72 h. As well as we observed that cytochrome c accumulated dose dependently in the cytosol of radotinib-treated MAVER-1 and REC-1 cells. Moreover, radotinib decreased the expression of Bcl-xL and Bcl-2, and increased the expression of Bax in MCL cells. These results indicate that radotinib induces cell death of MCL cells by induction of G1-phase arrest and mitochondrial-dependent apoptosis. Furthermore, the expression of p-AKT, AKT and ERK was significantly reduced by radotinib in MCL cells. Conclusion: Radotinib may play an important role as a candidate or chemosensitizer for treatment agent in MCL. These data indicate that radotinib has a potential for anti-cancer therapy in MCL.
Citation Format: Sook-Kyoung Heo, Eui-Kyu Noh, Yoo Kyung Jeong, Jeong Yi Kim, Yunsuk Choi, Jaekyung Cheon, SuJin Koh, Jin Ho Baek, Young Joo Min, Jae-Cheol Jo. Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma 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 1621.
Abstract 1626: Sensitive detection of MET exon 14 skipping by RT-qPCR and next generation sequencing
Authors: Patel Mukund , Polur Honey , Hurban Patrick 
Published: August 2018

Abstract
The MET receptor tyrosine kinase (MET) gene is a proto-oncogene whose abnormal activation can trigger tumor growth, angiogenesis, and metastasis. Numerous mutations have been identified that lead to over-activation of the gene, including well characterized amplification and somatic mutations. Mutations that lead to the skipping of MET exon 14 are likely to be highly predictive of response to MET inhibition. Exon 14 contains a motif that is required for the efficient recruitment of the ubiquitin ligase, CBL, which targets MET for degradation. Loss of exon 14 leads to prolonged stability of the MET protein which causes increased signaling upon stimulation by hepatocyte growth factor. Over 200 distinct mutations have been identified that cause MET exon 14 skipping ranging from single nucleotide mutations to large insertion/deletions. Due to this complexity, detecting MET exon 14 skipping mutations using DNA-based NGS hybridization capture methods is challenging. RNA-based testing can circumvent the complexity of DNA-based changes. We developed a RT-qPCR assay that detects MET exon 14 skipping independent of the causal mutation. Analytical validation using RNA admixtures demonstrated 1% sensitivity of detecting MET exon 14 mutant transcripts. 100 FFPE lung adenocarcinomas were screened with the RT-qPCR assay. Of 100, two samples (2%) were identified as positive for MET exon 14 skipping. The two positive samples along with three negative samples were orthogonally confirmed using the Illumina TruSight Tumor 170 hybridization capture-based targeted panel assay that simultaneously analyzes DNA and RNA. Overall, the number of samples identified positive for MET exon 14 by RT-qPCR test is in line with the frequency observed from other studies in lung adenocarcinomas of about ~3%. The assay can detect as little as 1% transcripts with MET exon 14 skipping suggesting that we have developed an accurate and sensitive RNA-based assay for use in clinical trials.
Citation Format: Mukund Patel, Honey Polur, Patrick Hurban. Sensitive detection of MET exon 14 skipping by RT-qPCR and next generation sequencing [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 1626.