bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 236: Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women
Authors: Manni Andrea , Richie John P. , Schetter Susann E. , Calcagnotto Ana , Trushin Neil , Aliaga Cesar , El-Bayoumy Karam 
Published: July 2017

Abstract
Preclinical and epidemiologic data suggest that a unique feature of lipogenesis in cancer cells which has received limited attention is the accumulation of monounsaturated fatty acids (MUFA) which are largely derived from saturated fatty acids (SFA) by the action of stearoyl-Co-A desaturase (SCD-1). Activation of SCD-1, a delta-9 fatty acid desaturase, is considered to be an important factor in the development of obesity and several types of cancer including breast cancer. However, no data are available on how changes in SCD-1 activity induced by potential chemopreventive agents relate to established biomarkers of breast cancer risk. To address this issue, we measured the activity of SCD-1, expressed as the ratios of palmitoleic acid (C16:ln7) to palmitic acid (C16:0) (SCD-16) and oleic acid (C18:ln9) to steric acid (C18:0) (SCD-18) in plasma samples of postmenopausal women enrolled in our recently published clinical trial (Sandhu N, et al Cancer Prev Res 9:275, 2016) designed to test the individual and combined effect of the antiestrogen Raloxifene and the omega-3 preparation Lovaza on breast density, a validated biomarker of breast cancer risk. We observed that daily administration of Lovaza (1,860 mg eicosapentaenoic [EPA] + 1,500 mg docosahexaenoic [DHA]) significantly reduced SCD-1 activity, an effect which was sustained for the two-year duration of the trial. Raloxifene, on the other hand, did not significantly alter SCD-1 activity in our subjects. SCD-1 activity was positively correlated with BMI (for SCD-16, r=0.45, p&lt;01; for SCD-18, r=0.23, p&lt;0.01) and paralleled changes in BMI in the same direction over the two years of the study. These findings support the role of this enzyme in the development of obesity. Importantly, decreasing levels of SCD-1 were found to be associated with a progressive reduction in breast density in obese women (BMI≥30) (for SCD-16; r=0.47, p&lt;0.01; for SCD-18; r=0.36, p&lt;0.05). No correlation between breast density and SCD-1 was observed in non-obese subjects (r=0.02 for SCD-16 and 0.04 for SCD-18). Our results suggest that BMI-related factors play an important role in the reduction of breast density by omega-3 fatty acids. They also indicate that SCD-1 may be a useful biomarker in future clinical trials testing the benefit of nutritional interventions in reducing obesity associated breast cancer risk.
Citation Format: Andrea Manni, John P. Richie, Susann E. Schetter, Ana Calcagnotto, Neil Trushin, Cesar Aliaga, Karam El-Bayoumy. Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 236. doi:10.1158/1538-7445.AM2017-236
Abstract 2387: Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer
Authors: Yi Jie , Chen Yu , Gao Ran , Yang Zhuo , Wang Jinhua , Xu Yingchun 
Published: July 2017

Abstract
NSUN2 is a RNA methyltransferase that has been shown to be implicated in development of human cancer. However, the functional role of NSUN2, mechanism of NSUN2 overexpression and its association with clinicopathologic features in breast cancer remain unclear. To investigate alterations in the expression and functional role of NSUN2 in breast cancer, NSUN2 expression was assessed in breast cancer cells and tissues obtained from cancers at different American Joint Committee on Cancer (AJCC) stages, and its functions were investigated using breast cancer cells. NSUN2 expression was shown to be significantly higher in breast cancer cells and tissues than in normal breast epithelial cells and tissues, at both mRNA and protein levels. Overexpression of NSUN2 was shown to promote cell proliferation, migration, and invasion while NSUN2 knockdown inhibited these processes in vitro and in vivo. NSUN2 expression level was associated with the methylation level of its promoter. Our results demonstrated that the overall expression of NSUN2 significantly correlated with clinical stage (P=0.027), tumor classification (P=0.012), pathological differentiation (P=0.023), as well as with the expression levels of estrogen receptor (P&lt;0.001), progesterone receptor (P=0.001), and Ki-67 (P&lt;0.001). Our findings provide a unique insight into the roles and effects of NSUN2 overexpression in breast cancer cells, and highlight the necessity of the investigation of novel therapeutic targets, such as NSUN2, for the improvement of breast cancer treatments.
Citation Format: Jie Yi, Yu Chen, Ran Gao, Zhuo Yang, Jinhua Wang, Yingchun Xu. Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2017-2387
Abstract 2388: Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype
Authors: Liao Peter , Barnholtz-Sloan Jill 
Published: July 2017

Abstract
Background: Low grade gliomas make up a significant proportion of malignant brain tumors and possess a high degree of heterogeneity, highlighting a need for clinically useful markers for prognosis and further biologic investigation. We used an existing model of biological age based upon DNA methylation to characterize epigenetic age in low grade gliomas (LGG) according to existing molecular classifications and assessed the prognostic utility of epigenetic age.
Methods: We analyzed the full TCGA LGG cohort consisting of 516 patients; 216 grade 2 and 241 grade 3 tumors. Age at diagnosis ranged from 14-87 years with median age 43. We calculated “DNA methylation age” (DNAm age) based upon 353 CpG probes according to the epigenetic clock developed by Steve Horvath, and calculated age acceleration according to the DNAm age of tumor tissue relative to reported chronological age of patient at diagnosis. DNAm age was assessed for prognostic value using Cox proportional hazards regression. Age acceleration differences were assessed across LGG molecular classification methods using the Wilcoxon Ranked Sum test.
Results: DNAm age remained highly correlated with chronological age in LGG tumor tissue (cor=0.58, p&lt;0.001), with an average age acceleration of 33.5y. DNAm age was weakly positively correlated with mutational burden (cor=0.12, p=0.01). Higher DNAm age was positively associated with survival independent of chronologic age and Karnofsky Performance Score (p=0.003), but not when IDH mutation status was included into the Cox proportional hazards model. Further investigation showed that DNAm age acceleration was associated with IDH mutation status and was significantly increased in IDH-mutant compared to IDH-wt tumors (95% CI= 18.6-28.8y) as well as MGMT-promoter methylated versus unmethylated cases (95%CI= 18.1- 28.9y). No significant DNAm changes were observed across histological subtype or grade.
Conclusions: Although the regulation of DNAm age in cancers remains poorly understood, significant association of DNAm age acceleration with prognostically useful molecular subtypes in LGGs underscores biological differences that cannot be discerned in LGGs based upon histological classification. This association suggests that LGGs may provide an avenue for investigating DNAm age, molecular subtype, and their relation to tumor behavior and clinical prognosis.
Citation Format: Peter Liao, Jill Barnholtz-Sloan. Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2388. doi:10.1158/1538-7445.AM2017-2388
Abstract 239: Associations of polyunsaturated fat, bile acids, and gut microbiota on colorectal adenoma risk
Authors: Wang Tengteng , Brown Nicole M. , McCoy Amber N. , Sandler Robert S. , Keku Temitope O. 
Published: July 2017

Abstract
Background: Intestinal microbiota, and their metabolites are increasingly recognized as important players in the genesis of colorectal adenomas and cancer. Epidemiological studies have also shown that polyunsaturated fat intake is associated with decreased risk of colorectal adenomas. This study examined the association between adherent gut microbiota and mucosal bile acids, and total polyunsaturated fat intake in relation to colorectal adenomas in a case-control study.
Methods: Participants were 217 adenoma cases and 218 adenoma-free controls who underwent screening colonoscopies and completed food frequency questionnaires. The mucosal adherent microbiota was characterized by bacterial 16S rRNA sequencing. Global metabolomics of colonic mucosal tissue was conducted by gas chromatography and mass spectrometry on a subset of samples. Genus level microbiota and bile acids were compared between cases and controls using t-test with correction for multiple comparison. Logistic regression and Pearson correlations were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs), and correlation coefficients for the association among microbiota abundance, bile acids concentration, and total polyunsaturated fat intake.
Results: Adenoma subjects had a significantly higher bacterial abundance of Sphingomonas, Marinomonas and Ralstonia, but lower abundance of Adlercreutzia compared to controls. The concentration of eleven bile acids (Chenodeoxycholate, Cholate, Deoxycholate, Glycochenodeoxycholate, Glycocholenate sulfate, 7-ketodeoxycholate; 12-dehydrocholate, Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate, Taurolithocholate 3-sulfate, and Tauroursodeoxycholate) were significantly elevated in cases compared to controls. Subjects with increased abundance of Sphingomonas and Ralstonia were significantly more likely to have adenomas (OR 2.17, 95% CI 1.31-3.57; OR 1.19, 95% CI 1.02-1.38) respectively. Subjects with increased abundance of Adlercreutzia were less likely to have adenomas (OR 0.44, 95% CI 0.21-0.93). The multivariable adjusted OR for those in the high relative to the low level of total polyunsaturated fat intake was 0.46 (95% CI 0.27-0.80). The correlations between bacterial diversity and eleven bile acids also significantly differed by case control status.
Conclusion: The interactions of the gut microbiota, bile acids and consumption of polyunsaturated fat are associated with colorectal adenoma risk.
Citation Format: Tengteng Wang, Nicole M. Brown, Amber N. McCoy, Robert S. Sandler, Temitope O. Keku. Associations of polyunsaturated fat, bile acids, and gut microbiota on colorectal adenoma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 239. doi:10.1158/1538-7445.AM2017-239
Abstract 24: HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors
Authors: Boyd-Kirkup Jerome D. , Thakkar Dipti , Ingram Piers J. 
Published: July 2017

Abstract
Gastric cancer is the second highest cause of cancer mortality in Asia. Over-expression of ErbB3, a cell surface RTK, occurs in ~60% of mGC patients where it is significantly associated with poorer survival. Ligand binding to ErbB3 triggers heterodimerization and downstream signaling through Akt. Neutralizing antibodies that inhibit ligand binding show poor efficacy in clinical trials, likely due to high levels of ligand independent activation in many tumor types. Directly inhibiting heterodimerization could be more effective, however, current methods of antibody isolation offer limited control over the site of antibody binding and, therefore, mechanism of action, requiring extensive screening of antibodies and posing significant challenges to identifying suitable candidates for therapeutic development.
Hummingbird Bioscience has used its proprietary Rational Antibody Development Platform for the design and development of novel therapeutic antibodies against ErbB3. Computational sequence and structural analyses predicted highly specific surface epitopes, with strong antigenicity and good safety profiles, where antibody binding would inhibit dimerization. Subsequently, Hummingbird’s directed evolution mouse immunization strategy efficiently isolated monoclonal antibodies that bound with low nM (Kd &lt; 5nM) affinity to these epitopes on native folded ErbB3. Furthermore, these mAbs showed ELISA cross-reactivity to ErbB3 in model organisms (mouse, rat, monkey) but no binding to other EGFR family proteins.
Antibody HMBD001 was found to strongly inhibit the phosphorylation of ErbB3 and decrease downstream signaling through the Akt pathway (90% decrease in p-ErbB3 and 60% decrease in p-AKT observed at 24 hrs) resulting in the inhibition of tumor cell proliferation in models of ErbB3+ gastric cancer (over 90% inhibition of NCI-N87 proliferation after 5 days) and breast cancer (up to 85% inhibition of BT474 proliferation after 5 days). In mouse NCI-N87 gastric cancer CDX models, weekly doses of HMBD001 achieved greater than 90% inhibition of tumor growth (at 25 days) with no observable adverse toxicity.
The first in-human trial of HMBD001 is planned for 2018.
Citation Format: Jerome D. Boyd-Kirkup, Dipti Thakkar, Piers J. Ingram. HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2017-24
Abstract 2400: Identification of histone modifying enzymes associated with tamoxifen resistance in MCF7 breast cancer cells
Authors: Lee Min-Ho , Lee Mi-Ock 
Published: July 2017

Abstract
Tamoxifen is widely used to treat estrogen receptor-alpha positive breast cancer. However, resistance to tamoxifen often prevent the success of endocrine therapy. Epigenetic change in tumors are associated with cancer development and progression. Although altered histone modification has been implicated in tumorigenesis, their role in endocrine resistance was little known. To identified tamoxifen-resistance associated histone methylation modifying enzyme, we examined the global histone H3 methylation patterns in tamoxifen-resistance MCF7 breast cancer cells. Our results show that, the levels of methylated histone H3 lysine 4 (H3K4) and histone H3 lysine 9 (H3K9) was upregulated in tamoxifen resistance MCF7 breast cancer cells. Next, we analysis expression levels of H3K4 and H3K9 methylation modifying enzyme in tamoxifen resistance breast cancer cells. qRT-PCR results show that H3K4 methyltransferases (KMT2A and KMT2C) is upregulated in tamoxifen resistance breast cancer cells. Moreover, we observed that si-RNA mediated knockdown of KMT2C was more susceptible to tamoxifen-induced growth inhibition. Finally, Analyses of publicly available patient data sets indicated that KMT2A and KMT2C levels are higher in patients after endocrine therapy failure (recurrence), compared to those of responders (non-recurrence). Our study indicates that elevated levels of KMT2A and KMT2C in the tamoxifen-resistance breast cancers may contributed tamoxifen resistance.
Citation Format: Min-Ho Lee, Mi-Ock Lee. Identification of histone modifying enzymes associated with tamoxifen resistance in MCF7 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2400. doi:10.1158/1538-7445.AM2017-2400
Abstract 2414: Fibromodulin expression in human prostate cancer tissue: Implications for prostate cancer progression
Authors: Padron Estebana Ines Benedetti , Marzo Angelo De , Valle Javier Baena Del , Geliebter Jan , Reyes Niradiz 
Published: July 2017

Abstract
Background: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. Recently, differential expression of fibromodulin has been shown in human prostate cancer cell lines with different cancer phenotypes and in human prostate cancer tissue compared to normal/benign tissue.
Methods: The protein expression level of fibromodulin was analyzed by immunohistochemistry using a prostate tissue microarray (TMA), constructed from archival radical prostatectomy and trans-urethral prostatectomy tissue specimens, from patients with localized prostate cancer (PCa). Stained sections from the donor blocks were evaluated, and a representative area from PCa, high grade prostatic intraepithelial neoplasia (HGPIN), proliferative inflammatory atrophy (PIA), and benign prostate tissue (BPT) was included into the TMA. Staining for each lesion was scored, using H-score, by microscopic assessment of the percentage of epithelial cells with positive staining. H-score values were compared between groups by ANOVA test, and p &lt; 0.05 was considered statistically significant. The Ethical Review Board of the academic institution approved this study.
Results: Fibromodulin expression at protein level was evaluated in 378 cores representing PCa (143 cores), HGPIN (58), PIA (102), and BPT (78). Mean fibromodulin expression in cores with PCa, HGPIN, and PIA was significantly higher than mean of fibromodulin expression in normal glands (p&lt;0.0001). There was a higher mean staining score in PCa (156, 95% CI:144–167), compared to HGPIN (131.4, 95% CI:109-153), PIA (128, 95% CI:117-138), and BPT (33.3, 95% CI:27-38). Thus, fibromodulin expression increased across the PCa progression model.
Conclusions: The expression pattern of fibromodulin showed a significant increase from benign prostate tissue through pre-cancerous lesions to PCa. These findings suggest that this proteoglycan may be involved in the process of prostate cancer progression, with low levels in pre-cancerous lesions and higher levels in cancer tissue. Additional studies are required to determine the biological role and potential clinical implications of fibromodulin in prostate cancer.
Citation Format: Estebana Ines Benedetti Padron, Angelo De Marzo, Javier Baena Del Valle, Jan Geliebter, Niradiz Reyes. Fibromodulin expression in human prostate cancer tissue: Implications for prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2414. doi:10.1158/1538-7445.AM2017-2414
Abstract 2415: Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy
Authors: Ferrari Anna C. , Sabaawy Hatem , Stein Mark , Foran David , Chen Ying , Yegnasubramanian Srinivasan 
Published: July 2017

Abstract
Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT).
Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG.
Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q&lt;10-17) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets.
Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank.
Citation Format: Anna C. Ferrari, Hatem Sabaawy, Mark Stein, David Foran, Ying Chen, Srinivasan Yegnasubramanian. Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neo-adjuvant androgen deprivation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2415. doi:10.1158/1538-7445.AM2017-2415