bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-151: REV1 has critical roles in base excision repair intermediate-mediated transversion mutations but not for O6-methylguanine-initiated mutations in vertebrate cells.
Authors: Nakamura Jun , Tian Xu , Swenberg James 
Published: August 2014

Abstract
Isogenic chicken DT40 cells deficient in various DNA repair pathways are a great tool for understanding the DNA damage response and mutagenesis caused by genotoxic agents by a comparison of mutants and parental DT40 cells. We recently found that ~55% of PIGO mutations are located at A:T sites with a high frequency of A to T transversion mutations in DT40 cells exposed to methyl methanesulfonate (MMS). These results suggest that A to T transversion mutations found in MMS exposure-derived PIGO mutant cells are due to base excision repair intermediates, such as abasic sites and single strand breaks originated from N3-methyladenine. It has been reported that DNA repair protein REV1 acts as not only as a deoxycytidine transferase across abasic sites but also as a scaffold protein to coordinate translesion DNA synthesis (TLS) polymerase switching. To address effects of REV1 on MMS-induced PIGO mutations in DT40 cells, we exposed REV1 knockout DT40 cells to low-dose MMS. REV1 knockout DT40 cells showed hyper-sensitivity in cell survival after MMS treatment with no increase in PIG-O mutations. These results indicate that PIG-O mutations in DT40 cells exposed to MMS are caused through REV1-dependent, but REV1 deoxycytidyl transferase-independent, TLS. In contrast to MMS, REV1 and parental DT40 cells showed similar toxicity and mutagenicity caused by a combination of low-dose N-methyl-N-nitrosourea and O6-benzylguanine. These results suggest that base excision repair intermediates appear to initiate REV1-dependent TLS, whereas, O6-methylguanine could be by-passed by replicative polymerases, such as polymerase delta complexes, with an associated increase in G to A transition mutations.
Citation Format: Jun Nakamura, Xu Tian, James Swenberg. REV1 has critical roles in base excision repair intermediate-mediated transversion mutations but not for O6-methylguanine-initiated mutations in vertebrate cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2013-LB-151
Abstract LB-181: Tolfenamic acid suppresses intestinal tumorigenesis through inhibiting cyclin D1 translation.
Authors: Zhang Xiaobo , Lee Seong-Ho , Li Qingwang , Baek Seung J. 
Published: August 2014

Abstract
A nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic activity is not well understood. Here, we have shown that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with the significant decrease in cyclin D1 expression. Furthermore, we have demonstrated that TA down-regulates cyclin D1 expression in different cancer cells in vitro, coupled by decreasing phosphorylated retinoblastoma protein and increasing cell cycle arrest. Subsequent observation suggests that TA promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway including phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which mediates the repression of cyclin D1 translation. Silence of pancreatic ER eIF2α kinase (PERK) restores cyclin D1 expression in the presence of TA. In conclusion, TA inhibits colorectal cancer cell growth in vitro and blocks colorectal tumorigenesis in a mouse model, at least in part, mediated by inhibiting cyclin D1 translation via ER stress.
Support: The University of Tennessee Center of Excellence in Livestock Diseases and Human Health grant (SJB), NIH grant RO1CA108975 (SJB), American Cancer Society grant (RSG-11-133-01-CCE) (S-H Lee), and a grant from the Ministry of Agriculture of the People's Republic of China (2011ZX08008-003) (QL).
Citation Format: Xiaobo Zhang, Seong-Ho Lee, Qingwang Li, Seung J. Baek. Tolfenamic acid suppresses intestinal tumorigenesis through inhibiting cyclin D1 translation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2013-LB-181
Abstract LB-188: Isoflavone pharmacokinetics and metabolism after consumption of soy and soy-almond bread in men with asymptomatic prostate cancer.
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Grainger Elizabeth M. , Riedl Kenneth M. , Schwartz Steven J. , Vodovotz Yael 
Published: August 2014

Abstract
Background: Soy phytochemicals, particularly isoflavones, are hypothesized to have anti-prostate cancer activity. Soy isoflavones are present predominantly as glucosides but when combined with β-glucosidase activity in almond meal, a greater conversion to aglycones has been observed. We hypothesized that soy bread will serve as an excellent source of soy polyphenols and that an aglycone-rich soy-almond bread (SAB) compared to a glycoside-rich soy bread (SB) will demonstrate greater bioavailability of soy isoflavones.
Methods: SB and SAB were fed in a 20 week randomized phase II cross-over trial involving 32 men with asymptomatic metastatic prostate cancer and escalating prostate specific antigen (PSA). Isoflavones were quantitated by HPLC in soy breads and isoflavone metabolites in 24h urine. HPLC-tandem mass spectrometry evaluated isoflavone pharmacokinetics in plasma. Biomarkers were determined by chemiluminescence-based assays.
Results: The aglycone composition in the SB and SAB was 18% and 78%, respectively. Compliance was 95±14%, toxicity rare and limited to grade I GI complaints (NIH_NCI criteria). Urinary isoflavone patterns over 24hours revealed that isoflavonoid metabolites were significantly greater with soy bread consumption. Plasma pharmacokinetics following a test meal showed that daidzein (p=0.028) and genistein (p=0.010) absorption was significantly faster from the aglycone-rich SAB. Interestingly, PSA doubling time was prolonged compared to pre-enrollment, in 60% of men (n=30) with soy intervention.
Conclusions: Bread is an excellent vehicle for the delivery of soy phytochemicals with outstanding compliance. Modification of soy bread with a source of β-glucosidase may enhance the initial absorption rates of isoflavones. Food products, such as SAB, with consistent and stable composition of phytochemicals can be developed that are appropriate for long-term chemoprevention studies in humans or as an adjunct to therapy.
Citation Format: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Elizabeth M. Grainger, Kenneth M. Riedl, Steven J. Schwartz, Yael Vodovotz. Isoflavone pharmacokinetics and metabolism after consumption of soy and soy-almond bread in men with asymptomatic prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2013-LB-188
Abstract LB-206: Target validation of C4.4a (LYPD3) as a target for antibody-drug conjugates for the treatment of squamous cell carcinoma of different origin.
Authors: Leder Gabriele , Cao Yong-Jiang , Linden Lars , Golfier Sven , von Ahsen Oliver , Schneider Claudia , Willuda Joerg , McLean Kirk , Pohlenz Hans-Dieter , Kreft Bertolt , Ziegelbauer Karl 
Published: August 2014

Abstract
C4.4a (LYPD3) is a GPI-anchored cell surface protein with unknown physiological function, although it has been speculated that it might play a role in tumor invasion and metastasis formation. In addition, over-expression of C4.4a correlates with a malignant phenotype and poor prognosis in several cancer indications.
As a result of comprehensive gene expression profiling, we report that the C4.4a transcript is being significantly up-regulated in human non-small cell lung cancer (NSCLC) as well as in other tumors compared to the respective normal tissue. This finding was confirmed in IHC studies showing strong C4.4a protein expression on the surface of tumor cells particularly in lung squamous cell carcinoma. Interestingly, a high incidence of C4.4a protein expression was found in a number of additional cancers such as stomach, bladder, colorectal, ovarian, prostate, hepatocellular as well as SCC of the head and neck. In marked contrast to tumors, C4.4a expression in normal tissues is restricted to esophagus, cervix and the outer epithelial layer of skin (stratum spinosum and stratum granulosum). Employing FACS and IHC analyses, several model systems were identified expressing C4.4a in vitro and in vivo. Subsequently, Mab-Zap assays were used to demonstrate efficient internalization of C4.4a in endogenously expressing cells as well as in cells transfected to over-express C4.4a.
In summary, the observed strong over-expression of C4.4a in tumors, its very limited expression in normal tissue as well as its ability to rapidly internalize make it a promising target for the generation of antibody-drug conjugates for the treatment of several cancer indications, in particular lung squamous cell carcinoma.
Citation Format: Gabriele Leder, Yong-Jiang Cao, Lars Linden, Sven Golfier, Oliver von Ahsen, Claudia Schneider, Joerg Willuda, Kirk McLean, Hans-Dieter Pohlenz, Bertolt Kreft, Karl Ziegelbauer. Target validation of C4.4a (LYPD3) as a target for antibody-drug conjugates for the treatment of squamous cell carcinoma of different origin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-206. doi:10.1158/1538-7445.AM2013-LB-206
Abstract LB-218: Role of ERBB family negative regulator Mig6 in estimating erlotinib responsiveness.
Authors: Izumchenko Eugene , Chang Xiofei , Sidransky David 
Published: August 2014

Abstract
The sensitivity of some tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. However, such mutations are rare and the clinical benefit of a subset of patients with wild-type EGFR may be underestimated due to the lack of appropriate predictive markers to stratify them from larger number of patients who do not response.
In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that harbor no TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR, was selectively upregulated by the PI3K-AKT pathway during the evolution of resistance to the EGFR tyrosine kinase inhibitor erlotinib, resulting in decreased EGFR phosporylation. Moreover, we found that high Mig6/EGFR ratio was highly correlated with erlotinib sensitivity, AKT activity, loss of PTEN and epithelial-mesenchymal transition (EMT) status in the panel of 20 lung and head and neck cancer cell lines.
Since depletion of Mig6 in erlotinib resistant cell lines didn't render significant increase in drug sensitivity and did not affect AKT activity, we tested whether in resistant cells, activation of kinases other then ERBB family can sustain high level of AKT activation thus suspending erlotinib sensitivity in Mig6-depleted cells. Surprisingly, we found that despite significant deactivation of EGFR, HER2 and HER3 kinases in erlotinib resistant cell lines, activation of PDGFR, FGFR, VEGFR, IGFR or FAK kinases was upregulated in these cells. Here we show that combined treatment with erlotinib and regorafinib (a novel multi-target inhibitor for VEGFR, PDGFR, FGFR, Kit, RET and Raf-1) markedly enhances erlotinib-induced growth inhibition in erlotinib-resistant cells.
Collectively, our data highlights the importance of Mig6 in estimating erlotinib responsiveness. Furthermore, our data suggests that by inhibiting EGFR activity in sensitive neoplastic cells, elevated expression of Mig6 triggers acquisition of alternative growth factor pathways that can sustain high level of AKT activity, thus further promoting erlotinib resistance.
Citation Format: Eugene Izumchenko, Xiofei Chang, David Sidransky. Role of ERBB family negative regulator Mig6 in estimating erlotinib responsiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-218. doi:10.1158/1538-7445.AM2013-LB-218
Abstract LB-229: Whole genome sequencing reveals genetic landscape of hepatocellular carcinoma.
Authors: Mao Mao , Zheng Hancheng , Kan Zhengyan , Xu Jiangchun , Liu Xiao , Li Shuyu , Barber Thomas , Gong Zhuolin , Gao Huan , Hao Ke , Willard Melinda , Hauptschein Robert , Rejto Paul , Fernandez Julio , Wang Guan , Zhang Qinghui , Wang Bo , Chen Ronghua , Wang Jian , Lee Nikki , Zhou Wei , Lin Zhao , Peng Zhiyu , Yi Kang , Chen Shengpei , Li Lin , Fan Xiaomei , Yang Jie , Ye Rui , Ju Jia , Wang Kai , Estrella Heather , Deng Shibing , Wei Ping , Qiu Ming , Wulur Isabella , Liu Jiangang , Ehsani Mariam , Zhang Chunsheng , Loboda Andrey , Sung Wing Kin , Aggarwal Amit , Poon Ronnie , Fan Sheung Tat , Wang Jun , Hardwick James , Reinhard Christoph , Dai Hongyue , Li Yingrui , Luk John 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole genome sequencing (WGS) study of 88 matched HCC tumour/normal pairs, 81 of which are HBV positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find β-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumour suppressor (35.2%). The Wnt/β-catenin pathway, altered in 62.5% of cases, is likely to act as the major oncogenic driver in HCC. TP53 alterations appear to cause increased levels of genomic arrangement and chromosomal instability. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. We also identified recurrent HBV integration events at the known and putative cancer-related genes such as TERT, MLL4 and CCNE1, which showed upregulated gene expression in tumour versus normal tissue. The frequently altered genes and pathways in HCC reflect classical cancer hallmarks. This study identified several prevalent and actionable mutations that provide a path towards therapeutic intervention of the disease.
Citation Format: Mao Mao, Hancheng Zheng, Zhengyan Kan, Jiangchun Xu, Xiao Liu, Shuyu Li, Thomas Barber, Zhuolin Gong, Huan Gao, Ke Hao, Melinda Willard, Robert Hauptschein, Paul Rejto, Julio Fernandez, Guan Wang, Qinghui Zhang, Bo Wang, Ronghua Chen, Jian Wang, Nikki Lee, Wei Zhou, Zhao Lin, Zhiyu Peng, Kang Yi, Shengpei Chen, Lin Li, Xiaomei Fan, Jie Yang, Rui Ye, Jia Ju, Kai Wang, Heather Estrella, Shibing Deng, Ping Wei, Ming Qiu, Isabella Wulur, Jiangang Liu, Mariam Ehsani, Chunsheng Zhang, Andrey Loboda, Wing Kin Sung, Amit Aggarwal, Ronnie Poon, Sheung Tat Fan, Jun Wang, James Hardwick, Christoph Reinhard, Hongyue Dai, Yingrui Li, John Luk. Whole genome sequencing reveals genetic landscape of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2013-LB-229
Abstract LB-23: Meta-analysis of genome-wide association studies identifies multiple loci associated with chronic lymphocytic leukemia.
Authors: Berndt Sonja I. , Skibola Christine F. , Joseph Vijai , Camp Nicola J. , Nieters Alexandra , Wang Zhaoming , Cozen Wendy , Monnereau Alain , Kelly Rachel S. , de Sanjose Silvia , Linet Martha S. , Riboli Elio , Vineis Paolo , Hjalgrim Henrik , Cerhan James R. , Chanock Stephen J. , Rothman Nathaniel , Slager Susan L. 
Published: August 2014

Abstract
Despite limited discovery stages (&lt;1,125 cases), genome-wide association studies (GWAS) have successfully identified 13 loci associated with risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL); however, these loci only explain a portion of the heritability. To identify additional genetic loci associated with CLL susceptibility, we conducted the largest meta-analysis of GWAS, to date, including 3,100 CLL cases and 7,667 controls of European ancestry from 25 independent studies genotyped on four different SNP microarrays. Association testing was conducted assuming a log-additive genetic model, adjusting for age, sex, and significant principal components. Meta-analyses were performed using the fixed effects inverse variance method based on the beta estimates and standard errors from each study. Promising loci were taken forward for replication in three additional studies totaling 788 cases and 4,872 controls. In the meta-analysis of both the discovery and replication studies, we conclusively identified ten independent SNPs in nine novel loci that reached genome-wide significance (P&lt;5 x 10−8): 10q23.31 (FAS; P=1.22x10−14), 18q21.33 (BCL2; P=2.66x10−12 and P=7.76x10−11), 11p15.5 (C11orf21; P=2.15x10−10), 4q25 (LEF1; P=4.24x10−10), 2q33.1 (CASP8; P=2.50x10−9), 9p21.3 (CDKN2B-AS1; P=1.27x10−8), 18q21.32 (PMAIP1; P=2.51x10−8), 15q15.1 (BMF; P=2.71x10−10), and 2p22.2 (QPCT; P=1.68x10−8) as well as an independent signal at an established locus (2q13, ACOXL, P=2.08x10−18). We also found evidence for two additional promising loci that reached marginal genome-wide significance (P&lt;2.0x10−7) at 8q22.3 (ODF1; P=5.40x10−8) and 5p15.33 (TERT; P=1.92x10−7). Although further studies are required, the proximity of five of the novel loci to genes involved in apoptosis suggests a possible unifying underlying biological mechanism. Together with the previously established loci, these genetic loci explain ~17% of the familial risk of CLL.
Citation Format: Sonja I. Berndt, Christine F. Skibola, Vijai Joseph, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Wendy Cozen, Alain Monnereau, Rachel S. Kelly, Silvia de Sanjose, Martha S. Linet, Elio Riboli, Paolo Vineis, Henrik Hjalgrim, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Susan L. Slager. Meta-analysis of genome-wide association studies identifies multiple loci associated with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-23. doi:10.1158/1538-7445.AM2013-LB-23
Abstract LB-232: Tumor clonality detection using next generation sequencing data.
Authors: Dees Nathan D. , Miller Christopher A. , White Brian S. , Schierding William , Vij Ravi , Tomasson Michael H. , Welch John S. , Graubert Timothy A. , Walter Matthew J. , Ley Timothy J. , DiPersio John F. , Mardis Elaine R. , Wilson Richard K. , Ding Li 
Published: August 2014

Abstract
A tumor's somatic variants, regardless of their significance in disease etiology, serve as genetic markers that capture the evolutionary history of clones and thus may be used for identifying them. We have previously identified steps along this evolutionary trajectory by discovering a broad range of variants, including exonic, intronic, and intergenic mutations, using whole genome sequencing (WGS) and by obtaining deep read counts of those variants using capture-based, targeted re-sequencing. Most of these variants, in most of the tumors analyzed, form clusters. This has revealed that most tumors are multi-clonal in composition with cellular sub-populations having distinct genomes harboring diverse somatic variants. Understanding the clonal diversity and composition of a tumor sample may have implications for clinical treatment, while the clonal evolution across tumor and relapse samples provides insight into disease progression.
Here we describe our approach for inferring clones using standard single nucleotide variant (SNV) and copy number alteration (CNA) data obtained from next-generation sequencing of a normal sample and one or more diseased (e.g., tumor or relapse) samples. Variants are clustered according to their deep-read-count-derived frequencies using a variational Bayesian approach to Beta mixture modeling, through which outliers and the number of clusters are identified automatically. The method's probabilistic interpretation provides a quantifiable measure of confidence in a resulting cluster, for example, through a standard error of the mean. We show that amplifications and deletions may induce artifactual clones, thus highlighting the importance of accounting for copy number events in interpreting SNV data for inferring clones. We demonstrate the performance of our approach using published acute myeloid leukemia tumor and relapse pairs as well as unpublished multiple myeloma WGS data sets. However, the approach is applicable to solid tumors as well and has been used to cluster six-dimensional variant data from a breast tumor and five relapses originating from the same patient.
Citation Format: Nathan D. Dees, Christopher A. Miller, Brian S. White, William Schierding, Ravi Vij, Michael H. Tomasson, John S. Welch, Timothy A. Graubert, Matthew J. Walter, Timothy J. Ley, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson, Li Ding. Tumor clonality detection using next generation sequencing data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-232. doi:10.1158/1538-7445.AM2013-LB-232
Abstract LB-235: Functional SNP in MICA binding to SP1 is associated with HCV-induced hepatocellular carcinoma.
Authors: Lo Paulisally H. , Tanikawa Chizu , Nakamura Yusuke , Matsuda Koichi 
Published: August 2014

Abstract
Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. To understand the genetic basis of HCV related diseases, identification of the susceptibility gene involving HCV-induced HCC is important. We previously identified the association of SNP rs2596542 in the 5′ flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region. A SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele exhibited higher transcriptional activity than that containing the A allele. SNP rs2596538 exhibited the stronger association with HCV-induced HCC (P = 1.82 x10−5 and OR = 1.34) than the marker SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with expression of MICA and risk for HCV-induced HCC.
Citation Format: Paulisally H. Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda. Functional SNP in MICA binding to SP1 is associated with HCV-induced hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-235. doi:10.1158/1538-7445.AM2013-LB-235