bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 824: Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets
Authors: Miller Mark S. , Thompson Matthew D. , Lubet Ronald A. , Steele Vernon E. , Seifried Harold E. , Grubbs Clinton J. 
Published: July 2016

Abstract
The methylnitrosourea-induced model of ER+ mammary cancer in female Sprague-Dawley rats has been routinely used to screen for chemopreventive agents. We recently reported that metformin was ineffective in reducing cancer formation in rats on a standard (4% fat) diet (Thompson, et al., Cancer Prev Res. 8, 231, 2015). In the present studies, rats were placed on a standard (Teklad) diet or on a Western diet (20% fat, low calcium) at 43 days of age (DOA), and administered MNU at 50 DOA. Rats were administered metformin or vehicle daily by gavage beginning at 57 days of age. Serum from the rats of the various groups was obtained both at 21 days following initial administration of metformin (or vehicle) and at the end of the study (when tumors had developed in most rats). We found an increase in the final body weights, number of mammary cancers, and the final weights of tumors in rats on western diet compared with standard diet. Furthermore, metformin failed to decrease tumor multiplicity in either diet, in fact, it increased final cancer weights (P&lt;.05). Serum from rats in the various groups were examined for approximately 500 metabolites (Metabolon; Research Triangle Park, NC). The Metabolites which were differentially expressed when comparing Western vs standard diets at either time point included myoinositol, scyllo-inositol, 2-hydroxydecanoate, carnitine, tocopherol, and nicotinamide. Certain of these were fatty acids and lipid soluble vitamins that one would expect to be altered by diet. We also compared serum from animals on standard or Western diets at the early or late time points to determine metabolites associated with cancer development. Metabolites whose levels changed in tumor bearing rats included 4-OH-butyrate, acetyl-carnitine, uranate, and threonate. Finally, we compared the effects of metformin treatment in rats on Western or standard diet and found that the metabolic changes associated with metformin treatment were dependent on the diet employed. Thus, metformin altered levels of arachidate and serotonin only in rats on standard diet, while carnnitine and N-delta-acetylornithine were only modulated in rats on Western diet. Again, the most striking result may be that we still failed to observe any efficacy of metformin in animals on standard or Western diet.
Citation Format: Mark S. Miller, Matthew D. Thompson, Ronald A. Lubet, Vernon E. Steele, Harold E. Seifried, Clinton J. Grubbs. Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 824.
Abstract 827: Polyphenon E treatment affects p73 mRNA levels
Authors: Carastro L. Michael , Cordova Ricardo A. , Cole Christopher D. , Park Jong Y. 
Published: July 2016

Abstract
Prostate cancer (PCa) is the most common malignancy among men in the USA. Polyphenon E (PolyE) is a standardized blend of polyphenols found in green tea extract, which has been shown to have chemoprevention value in PCa models, but the molecular mechanism(s) have not been elucidated. The p73 gene is a member of the p53 tumor suppressor family. A p73 dinucleotide polymorphism (DNP) (rs1801173) is a G4C14-to-A4T14 linked pair of transitions located in exon 2 and lies between the P1 and P2 gene promoters. The P1 and P2 p73 gene promoters are the transcription initiation sites for mRNAs encoding TAp73 and deltaNp73 (DNp73) isoforms, respectively. These p73 mRNA isoforms, TAp73 and áNp73, encode protein isoforms which differ in their N-termini. TAp73 isoforms include the full-length N-terminal sequence and are transcriptionally active. áNp73 isoforms lack the N-terminal trans-activation domain and are dominate negative. Recently, we reported the p73 DNP allele was associated with (1) decreased risk [OR = 0.55, 95%CI = 0.31-0.99] for aggressive PCa and (2) increased TAp73/DNp73 protein isoform ratios in ten human cancer cell lines. We hypothesize that exposure to PolyE induces changes in TAp73/DNp73 mRNA isoform ratios. Our goal for this study is to assess the effect of PolyE on total p73 mRNA levels and TAp73/DNp73 mRNA isoform ratios using two human PCa cell lines with different p73 DNP genotypes: DU145 (wild-type) and PC-3 (heterozygous). Cultured cells were treated with PolyE (100 or 200 mg/L). Cellular RNA was isolated, converted to cDNA and used in TaqMan RT-PCR assays to detect total p73, TAp73 or DNp73 isoform mRNAs. Our data from PolyE treatments of both DU145 and PC-3 cells are consistent with increased p73 mRNA levels (2.05 and 1.60 fold, respectively) and higher TAp73/DNp73 mRNA ratios (1.13 and 1.29 fold, respectively) at the low Poly E level (100 mg/L). At the high PolyE level (200 mg/L), the TAp73/DNp73 mRNA ratios significantly decreased for both DU145 and PC-3 (0.54 and 0.49 respectively). However, the overall p73 mRNA levels was not changed in DU145 (0.91 fold), but increased in PC-3 (1.60 fold) as compared with level in negative control at the high Poly E concentration. Therefore, in this exploratory study, PolyE treatment of the two PCa cell lines tested using a more moderate concentration of 100 mg/L results in higher overall p73 levels and increased TAp73/DNp73 mRNA ratios. This data could provide a potential molecular rationale for the observation that Poly E treatments provide chemopreventative impact against PCa.
Citation Format: L. Michael Carastro, Ricardo A. Cordova, Christopher D. Cole, Jong Y. Park. Polyphenon E treatment affects p73 mRNA levels. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 827.
Abstract 829: Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety
Authors: Lan Aixian , Li Wenjun , Liu Yao , Zhang Xinyan , Zhou Shanshan , Palko Olesya , Chen Hao , Kapita Mayanga , Prigge Justin , Schmidt Edward , Chen Xin , Sun Zheng , Chen Xiaoxin Luke 
Published: July 2016

Abstract
Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety.
Citation Format: Aixian Lan, Wenjun Li, Yao Liu, Xinyan Zhang, Shanshan Zhou, Olesya Palko, Hao Chen, Mayanga Kapita, Justin Prigge, Edward Schmidt, Xin Chen, Zheng Sun, Xiaoxin Luke Chen. Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 829.
Abstract 831: c-Myc is a novel target of prostate cancer cell growth inhibition by honokiol
Authors: Singh Krishna B. , Hahm Eun-Ryeong , Singh Shivendra V. 
Published: July 2016

Abstract
Honokiol (HNK) has been shown to inhibit human prostate cancer cell growth in vitro and in vivo, but the underlying mechanism is not fully understood. The present study demonstrates that c-Myc, a key mediator of prostate cancer growth, is a novel target of HNK. Exposure of prostate cancer cells to plasma achievable concentrations of HNK resulted in a marked decrease in levels of total and/or phosphorylated c-Myc. HNK-mediated suppression of c-Myc protein level was due in part to repression of its transcription or protein degradation. We also observed down-regulation of c-Myc in tumors from PC-3 xenografted mice upon oral administration of HNK when compared with control; although the difference was not significant. Stable overexpression of c-Myc conferred protection against HNK-mediated inhibition of colony formation and G0-G1 cell cycle arrest in PC-3 cells. Moreover, HNK suppressed the expression of c-Myc downstream target genes (Cyclin D1 and EZH2) and these effects were restored in Myc-overexpressing PC-3 cells. Consistent with these results, cells with stable knockdown of EZH2 were more sensitive to growth inhibition by HNK compared with control cells. Because androgen receptor (AR) is implicated in regulation of c-Myc expression, we explored the possibility whether AR could affect the expression of c-Myc and its target genes. Indeed, AR overexpression in PC-3 cells enhanced the expression of both c-Myc and its target genes. In conclusion, it is reasonable to postulate that HNK may be effective in retarding growth of c-Myc-driven prostate cancer. This study was supported by the grants CA101753 and CA115498 awarded by the National Cancer Institute.
Citation Format: Krishna B. Singh, Eun-Ryeong Hahm, Shivendra V. Singh. c-Myc is a novel target of prostate cancer cell growth inhibition by honokiol. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 831.
Abstract 839: Novel polypectomy system in a preclinical model of colon cancer
Authors: Ertem Furkan U. , Dashwood Wan-Mohaiza , Rajendran Praveen , Raju Gottumukkala , Rashid Asif , Dashwood Roderick 
Published: July 2016

Abstract
Colonoscopy has been used for over a decade to monitor tumor progression in live animals. However, murine models typically have not involved routine resection of entire lesions, to parallel the clinical scenario in which polyps are observed and removed during a colonoscopy examination. A polyp resection (polypectomy) protocol was developed in the polyposis in rat colon (Pirc) model. Because a major cause of morbidity in such rodent models involves blockage of the colon, polypectomy can be used as a preventive strategy, helping to prolong the lifespan of the animal. Polypectomy in murine models opens the door to longitudinal prevention studies, and determining the molecular changes in resected tumors. A means of specifying the location of each lesion within the colon also was developed in order to track individual polyps in a temporal manner. The “PLC” classification system has three components: P, polyp number from the tail-end; L, location of the polyp from the tail-end; and C, clock face orientation of the polyp within the gut lumen. In summary, we developed a novel murine polypectomy protocol that closely parallels the human clinical scenario during a screening colonoscopy. The procedure employed the Pirc model, but it is directly applicable to longitudinal studies in other murine models of colon cancer. This work was supported by P01 grant CA090890 from the National Cancer Institute, by P30 grant ES023512 from the National Institute of Environmental Health Sciences, by the John S. Dunn Foundation, and by a Chancellor's Research Initiative from Texas A&M University.
Citation Format: Furkan U. Ertem, Wan-Mohaiza Dashwood, Praveen Rajendran, Gottumukkala Raju, Asif Rashid, Roderick Dashwood. Novel polypectomy system in a preclinical model of colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 839.
Abstract 842: The NALP3 inflammasome and IL-1â signaling link asbestos-induced inflammation with the development of malignant mesothelioma
Authors: Kadariya Yuwaraj , Menges Craig W. , Talarchek Jacqueline , Cai Qi , Klein-Szanto Andres J. , Pietrofesa Ralph A. , Christofidou-Solomidou Melpo , Mossman Brooke T. , Shukla Arti , Testa Joseph R. 
Published: July 2016

Abstract
Exposure to asbestos is causally associated with the development of malignant mesothelioma (MM), a cancer of cells lining the internal body cavity. MM is an aggressive cancer that is resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including MM. The NALP3 inflammasome, including the component ASC, is an important mediator of inflammation that senses extracellular insults, such as infection or asbestos, and activates a signaling cascade resulting in release of mature IL-1â and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced MM, we chronically exposed Asc-deficient mice to asbestos and evaluated tumor incidence, latency and overall survival. Asc-deficient mice showed a significant delay in tumor onset compared to wild-type animals, suggesting that the NALP3 inflammasome plays a role in MM carcinogenesis. We also tested whether inflammation-related release of IL-1â promotes tumor development in an accelerated mouse model of asbestos-induced MM. Nf2+/-;Cdkn2a+/- mice exposed to asbestos in the presence of the IL-1â antagonist, anakinra, showed a 50% longer disease-free survival than in similarly exposed mice given vehicle control, consistent with IL-1â signaling contributing significantly to MM development. Collectively, these studies provide evidence for a link between asbestos-associated inflammation/IL-1â signaling and the development of MM; furthermore, these findings provide rationale for chemoprevention strategies targeting inflammation-related IL-1â signaling in high risk, asbestos-exposed populations.
Citation Format: Yuwaraj Kadariya, Craig W. Menges, Jacqueline Talarchek, Qi Cai, Andres J. Klein-Szanto, Ralph A. Pietrofesa, Melpo Christofidou-Solomidou, Brooke T. Mossman, Arti Shukla, Joseph R. Testa. The NALP3 inflammasome and IL-1â signaling link asbestos-induced inflammation with the development of malignant mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 842.
Abstract 843: Spontaneous immortalization of human mammary epithelial cells from a woman with a germline STK11 mutation
Authors: Euhus David , Bu Dawei , Considine Michael , Cope Leslie 
Published: July 2016

Abstract
Spontaneous immortalization of benign mammary epithelial cells (MEC) in culture is very rare. Models of MEC immortalization suggest that cells escape M0 growth arrest (selection) by silencing p16 expression after
which they encounter a second growth arrest, M1 (agonescence), characterized by telomere shortening and profound genomic instability. Pre-selection, post-selection, and spontaneously immortalized MEC from a woman with a germline STK11 mutation were subjected to a comprehensive “OMICS” evaluation including miRNA, transcriptome, methylome, exome, and comparative genomic hybridization (CGH) in order to understand the molecular events associated with MEC immortalization. Principle component analysis of gene expression identified 4 significant components, the first of which showed the greatest separation between the different time points. The most notable expression changes were upregulation of FOXQ1, IL1-related genes, Ras-related genes, and fibronectin and downregulation of COL1, COL6, CK19, and CDH1. MEC gradually acquired global hypomethylation of non-CpG DNA and regional hypermethylation of CpG islands (including p16). A classifier based on methylation pattern showed that immortalized cells moved away from identity with The Cancer Genome Atlas (TCGA) benign samples towards TCGA breast cancer samples. Immortalization was associated with a modest accumulation of mutations and a modestly greater number of DNA copy number alterations than was observed in earlier passage cells but no evidence of general genomic instability. Immortal cells showed a large deletion at 10q13-15 and deletions at 10p11-15 and 17p11-13 that were associated with reduced expression of genes in those regions. Post-selection bulk cell populations are quite distinct from early passage cells, but are not direct precursors of the immortal cells as some DNA copy number alterations acquired by post-selection cells were not observed in the immortalized cells. Rather, in this instance, it is likely that post-selection cells established conditions conducive to the immortalization of a rare cell in the mix. This has implications for the development of tissue-based approaches for breast cancer risk stratification.
Citation Format: David Euhus, Dawei Bu, Michael Considine, Leslie Cope. Spontaneous immortalization of human mammary epithelial cells from a woman with a germline STK11 mutation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 843.
Abstract 845: Diet stamps on bugs: early life dietary energy intake impacts gut microbiota
Authors: Xu Jinyu , Galley Jeffrey , Bailey Michael , Thomas-Ahner Jennifer , Clinton Steven , Olivo-Marston Susan 
Published: July 2016

Abstract
The complex and dynamic interactions between diet, gut microbiota (GM) structure and function, and colon carcinogenesis are only beginning to be elucidated. We examined the colonic microbiota and aberrant crypt foci (ACF) in C57BL/6N female mice fed various dietary interventions (control, energy restricted and high-fat) provided during two phases (initiation and progression) of azoxymethane (AOM)-induced early colon carcinogenesis. During progression (wks. 22- 60), a high-fat diet enhanced ACF formation compared to a control or energy restricted diet. In contrast, energy restriction during initiation phase (wks. 3-21) enhanced ACF burden at 60 weeks, regardless of the diet in progression phase. Alterations in GM structure during the initiation phase diet were partially maintained after changing diets during the progression phase. However, diet during the progression phase had major effects on the mucosal GM that energy restriction in progression phase increased Firmicutes and reduced Bacteroidetes compared to a high-fat diet, regardless of initiation phase diet, suggesting that diet may have both transient effects as well as a lasting impact on GM composition. Integration of early life and adult dietary impacts on the colonic microbial structure and function with host molecular processes involved in colon carcinogenesis will be key to defining preventive strategies.
Citation Format: Jinyu Xu, Jeffrey Galley, Michael Bailey, Jennifer Thomas-Ahner, Steven Clinton, Susan Olivo-Marston. Diet stamps on bugs: early life dietary energy intake impacts gut microbiota. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 845.
Abstract 849: Improved geometric deconvolution of bulk tumor genomic data
Authors: Roman Theodore , Xie Lu , Schwartz Russell 
Published: July 2016

Abstract
We develop new methods for improved computational deconvolution of clonal populations from heterogeneous bulk genomic data. Deconvolution methods have become an important tool in resolving intratumor heterogeneity from bulk tumor genomic data, but prevailing methods are still able only to resolve only coarse-grained approximations of true clonal substructure. We seek to improve a genomic deconvolution strategy called “simplicial complex inference” that is designed to take advantage of similarity between the clonal subpopulations of single tumors or tumor regions to better infer portraits of those clonal subpopulations and their distribution across tumor samples.
We evaluate the method through application to DNA copy-number (CN) data from a 472-tumor ovarian cancer (OV) panel and a 408-tumor lung squamous small cell carcinoma (LUSC) panel from The Cancer Genome Atlas (TCGA). We deconvolved the OV data into a mixture of six clonal models, two per data sample, each interpreted as a consensus copy number profile of one recurring progression stage found in a subset of OV samples. We analyzed the resulting models for enrichment of labels derived from RNASeq-based subtyping (Verhaak et al., 2013), revealing significant correspondence by chi-squared test between tumor subclusters identified by the deconvolution and OV subtypes (p = 0.0168). We further analyzed the clonal models to identify regions of significant amplification or loss, which we tested for enrichment of gene ontology (GO) terms and pathway terms through the DAVID toolkit. Ontological analysis showed significant enrichment for GO terms connected to genetic regulation and proliferation including “DNA binding,” “DNA packing,” and “protein-DNA complex” (p &lt; 0.001). The LUSC data was partitioned into nine clonal models, three per sample. A log-rank test showed significant correspondence between mixture subclustering and survival for LUSC patients (p &lt; 0.001). Regions of significant CN gain or loss identified in the clonal models were found by DAVID to be significantly enriched for pathway terms including “Cytokine network” (p = 0.0025) and “Cytokines and Inflammatory Response” (p = 0.0043). These findings suggest that more sophisticated models of clonal population structures can enhance our ability to deconvolve heterogeneous tumor genomic data and lead to better inference of clonal substructure.
Citation Format: Theodore Roman, Lu Xie, Russell Schwartz. Improved geometric deconvolution of bulk tumor genomic data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 849.