bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A37: Peripheral blood DNA methylation profiles are predictive of head and neck squamous cell carcinoma
Authors: Langevin Scott M. , Koestler Devin C. , Christensen Brock C. , Wiencke John K. , Nelson Heather H. , Houseman E Andres , Marsit Carmen J. , Kelsey Karl T. 
Published: June 2012

Abstract
Head and neck cancer accounts for an estimated 47,560 new cases and 11,480 deaths annually in the United States, the majority of which are squamous cell carcinomas (HNSCC). The overall 5-year survival is approximately 60% and declines with increasing stage at diagnosis, indicating a need for non-invasive tests that facilitate the detection of early disease. DNA methylation is a stable epigenetic modification that is amenable to measurement and readily available in peripheral blood. DNA methylation profiles are commonly altered in tumor tissue, including HNSCC. We applied a semi-supervised recursively partitioned mixture model (SS-RPMM) approach to identify novel blood DNA methylation markers of HNSCC using genome-wide methylation array data (26,486 autosomal CpG loci) for peripheral blood samples from 92 HNSCC cases and 92 cancer-free controls. Subjects were randomly split into training (n = 92) and testing (n = 92) sets, stratified by case-control status to ensure an equal distribution of cases and controls between sets. A series of mixed effects models were fit to the training data only and CpG loci were ranked according to absolute t-statistic. The top M loci were selected to train a classifier, where M was chosen using a nested cross-validation procedure, which was then fit to the testing data. To assess the performance of the resultant markers in the testing data, we constructed receiver operating characteristic (ROC) curves and calculated the corresponding area under the curve (AUC). Cases and controls were best differentiated by a methylation profile of 6 CpG loci (associated with FGD4, SERPINF1, WDR39, IL27, HYAL2 and PLEKHA6), resulting in 4 classes, with an AUC of 0.73 (95% CI: 0.62–0.82). After adjustment for subject age, gender, smoking, alcohol consumption and HPV16 serostatus, the AUC increased to 0.85 (95% CI: 0.76–0.92). There was no significant difference in stage at diagnosis, tumor site or HPV-16 serostatus for cases by class. We have identified a novel blood-based methylation profile that is predictive of HNSCC with a high degree of accuracy. Although not yet adequate for use in clinical settings, this profile demonstrates the potential of DNA methylation measured in blood for development of non-invasive applications for detection of head and neck cancer.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A37.
Abstract A43: PPARδ promotes colonic inflammation and inflammation-associated tumorigenesis
Authors: Wang Dingzhi , Guo Lixia , Ning Wei , DuBois Raymond N. 
Published: June 2012

Abstract
Although epidemiologic and experimental evidence strongly indicates chronic inflammation as a risk factor for cancer, it remains unclear how chronic inflammation contributes carcinogenesis. Here we show that deletion of PPARδ diminishes colonic inflammation by reducing infiltration of immune cells via downregulation of pro-inflammatory chemokines and cytokine in a mouse model of colon inflammation. These chemokines are responsible for recruitment of leukocytes from the circulation to local inflammatory sites. Our results further reveal that COX-2 is a downstream target of PPARδ and COX-2-derived PGE2 stimulates macrophages to produce pro-inflammatory chemokines and cytokine. PGE2 is a crucial mediator of colorectal carcinogenesis. More importantly, loss of PPARδ attenuated colonic inflammation-associated adenoma growth in two mouse models of inflammation-associated colorectal cancer. Our results demonstrate that PPARδ promotes chronic colonic inflammation and colitis-associated tumorigenesis. Collectively, these findings indicate that PPARδ plays a pivotal role in connecting colonic inflammation to cancer progression and may represent a potential therapeutic target for prevention or treatment of colorectal cancer.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A43.
Abstract A45: Targeting breast cancer stem cells using cancer preventive rexinoids
Authors: Zhao Jing , Zhang Yun , Hill Jamal L. , Mazumdar Abhijit , Brown Powel H. 
Published: June 2012

Abstract
Background: Recent research in breast biology supports the cancer stem cell hypothesis which asserts that malignancies arise in tissue stem cells through dysregulation of self-renewal. The cancer stem cell hypothesis has important implications for early detection, prevention and treatment of breast cancer. If breast cancers arise from the transformation of normal stem cells, it may be possible to target stem cells for the prevention of cancer. We have previously shown that rexinoids prevent the development of ER-negative breast cancer in transgenic mouse models. Previous studies have demonstrated a role of retinoid signaling in the regulation of normal breast stem cell self-renewal and differentiation. Bexarotene and LG100268 are rexinoids that selectively bind RXR receptors. Based on the effects of these molecularly targeted agents, we hypothesize that rexinoids prevent breast cancer development by suppressing the growth and transformation of the breast stem cell population.
Methods: We performed in vivo and in vitro studies to address our hypothesis. Cell proliferation assays were used to determine whether rexinoids can inhibit the growth of normal, pre-malignant and malignant breast cell lines (HMECs, MCF10A, DCIS.COM, SUM225, HCC1937 and HCC38 cell lines). To determine whether these agents affect stem cells, we performed mammosphere assays and FACS analysis after treatment with vehicle or rexiniods. We next conducted in vivo studies using MMTV-Wnt transgenic mice treated with LG100268 (50mg/kg) or vehicle, and studied the stem cell properties of mammary epithelial cells from these mice. The stem cell population in mammary glands was quantified by staining of CD24, CD49f and using FACS analysis and mammosphere assays.
Results: Our results showed that the rexionids LG100268 and bexarotene inhibit the growth of breast cell lines only at a high concentrations (the IC50 (concentration that reaches a 50% growth inhibiton) in most of the tested cell lines exceeded 10uM). Results of in vitro mammosphere assays showed that 100nM LG100268 reduced mammosphere formation efficiency by more than 40% in all breast cancer cell lines. Results from our in vivo experiments showed that LG100268 reduced the mammary epithelial stem cell population by 57% as defined by the CD24+/CD49f++ population identified by FACS and by 47% as measured by in vitro mammosphere assays.
Conclusion: These results from in vitro and in vivo studies demonstrate that the rexinoid LG100268 is a potent mammary stem cell inhibitor. This study shows that rexinoids suppress stem cell expansion and suggest that mammary stem cell inhibitors will be useful breast cancer preventive agents. This work is supported by a grant from the Breast Cancer Research Foundation (to PHB) and from an NIH/NCI RO1 grant (CA078480) (to PHB).
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A45.
Abstract A61: Prognostic relevance of genome-wide association studies-identified single nucleotide polymorphisms in primary breast cancer
Authors: Bayraktar Soley , Thompson Patricia A. , Yoo Suk Young , Do Kim-anh , Sahin Aysegul A. , Arun Banu , Bondy Melissa L. , Brewster Abenaa M. 
Published: June 2012

Abstract
Purpose: Several single nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS).
Methods: A cohort of 739 white women with early-stage breast carcinoma was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648, rs3803662, rs12443621, rs8051542, rs999737, rs6504950, rs4973768), using Illumina GoldenGate platform. The relationships between SNPs and breast cancer outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. The cumulative effects of SNPs were assessed by computing the number of at-risk-alleles based on the results from the univariate analyses. In addition, we explored higher-order interactions between clinical variables and SNPs using classification and regression tree (CART) analysis.
Results: Four SNPs (rs2981582, rs1219648, rs12443621 and rs6504950) were significantly associated with OS using univariate Cox proportional hazard regression analysis (P≤0.1) and there was no association with DFS. In multivariate model adjusted for age, hormonal status, clinical stage, and treatment, rs12443621 (16q12) and rs6504950 (17q23) polymorphisms remained as independent prognostic markers for OS. Compared with the GG/AG reference group, homozygous carriers of minor A allele for rs12443621 and rs6504950 had an increased risk for death (HR:1.38, 95% CI:1.01 to 1.86; P=0.04, and HR:1.80, 95% CI:1.18 to 2.77; P=0.007, respectively). In multivariate analysis, a higher risk for death was found in the sub-cohort of patients harboring 3–4 at-risk-alleles of the GWAS SNPs compared to patients carrying ≤2 at-risk-alleles (HR:1.5, 95% CI:1.14 to 1.85; P=0.002). In CART modeling, women with stage 2 breast cancer who did not receive chemotherapy and were carries of the AA genotype for rs6504950 had the highest risk for death (HR:10.0, 95% CI:3.47 to 28.78).
Conclusion: SNPs in previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), were also found to be independent prognostic markers for OS in breast cancer patients. The precise molecular mechanisms through which these SNPs influence clinical outcomes remain to be determined.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A61.
Abstract A66: Apoptosis, cell cycle, DNA repair, immune, and metabolism pathway SNPs modify bladder cancer risk, recurrence, and survival
Authors: Andrew Angeline S. , Gui Jiang , Moore Jason H. , Karagas Margaret R. , Pendleton Eben , Schned Alan R. , Mason Rebecca A. , Wyszynski Asaf , Tanyos Sam A. , Kelsey Karl T. , Marsit Carmen J. , Zens Michael S. 
Published: June 2012

Abstract
Bladder cancer is the fourth most common malignancy in U.S. men. Current treatments for non-invasive bladder tumors often appear initially effective, yet the rates of recurrent disease are high. Clinically useful predictors of the recurrent bladder cancer phenotype have not yet been identified. Major biological processes involved in bladder carcinogenesis include apoptosis, cell cycle, DNA repair, immune surveillance, and xenobiotic metabolism. We hypothesized that genetic variation in genes involved in each of these pathways may modify bladder cancer susceptibility and prognosis. Methods: To examine the independent and interacting effects, we analyzed variant genotypes hypothesized to modify these processes in 818 transitional cell carcinoma cases and 1167 controls enrolled in a case – control study of incident bladder cancer conducted in New Hampshire, U.S.A. Cases were followed over time to ascertain recurrence and survival status. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR). Results: In the metabolism pathway, the variant form of the metabolism gene HSD3B2 was associated with increased risk (adjusted OR 1.85 95%CI 1.31–2.62) and ALDH2 variants had shorter time to first bladder cancer recurrence (adjusted HR non-invasive 1.94 95%CI 1.32–2.84). We observed longer survival among bladder cancer cases with non-invasive tumors associated with DNA repair XRCC4 heterozygous genotype compared with wildtype (adjusted HR 0.53 95%CI 0.38–0.74) and for invasive cases for immune pathway GATA3 heterozygotes (adjusted HR 0.11 95%CI 0.03–0.39). Conclusions: Our analysis suggests candidate SNPs for further clinical evaluation as prognostic markers and may lead to more personalized bladder cancer surveillance guidelines.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A66.
Abstract A68: Insulin-like growth factor-1, insulin-like growth factor binding protein-3, and lobule type in the Nurses' Health Study II
Authors: Rice Megan S. , Tamimi Rulla M. , Connolly James L. , Collins Laura C. , Shen Dejun , Pollak Michael N. , Rosner Bernard , Hankinson Susan E. , Tworoger Shelley S. 
Published: June 2012

Abstract
Introduction: Previous research in the Nurses' Health Study (NHS) and NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans.
Methods: We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (i.e., type 1, 2, or 3) and whether any type 1 or any type 3 lobules were present. Lobule type then was classified as: 1) predominant type 1/no type 3 lobules, which is suggestive of complete involution or 2) other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, IGF binding protein-3 (IGFBP-3), and the ratio of IGF-1-to-IGFBP-3 levels with lobule type.
Results: In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type1/no type 3 lobules (p&lt;0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (OR quartile 4 vs. quartile 1=0.37, 95%CI: 0.15–0.89). Greater ratios of IGF-1-to-IGFBP-3 levels also were associated with decreased odds of predominant type1/no type 3 lobules (OR quartile 4 vs. quartile 1=0.26, 95%CI: 0.11–0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type.
Conclusion: Higher IGF-1 levels and a greater IGF-1-to-IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of growth factors in the structure of breast lobules and lobular involution.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A68.
Abstract A75: Calorie restriction and rapamycin, but not exercise, inhibit mammary tumor growth in a mouse model of postmenopausal obesity
Authors: Nogueira Leticia , Dunlap Sarah M. , Ford Nikki A. , Hursting Stephen D. 
Published: June 2012

Abstract
Obesity is a well-established risk factor for postmenopausal breast cancer and is associated with poor outcomes in both premenopausal and postmenopausal women. Given that approximately one third of the US population is obese, interventions to reverse the detrimental effects of obesity on breast cancer progression are urgently needed. The molecular target of Rapamycin (mTOR) modulates pathways regulating energy balance and cell growth. Therefore, agents that target the mTOR pathway are promising for breaking the obesity-breast cancer link. Here, we directly compared the two most recommended strategies for reversing obesity, calorie restriction (CR) and exercise (EX), and a well-established mTOR inhibitor (rapamycin) on mammary tumor growth and metabolic profiles in obese mice.
Ovariectomized C57BL/6 mice were administered a diet-induced obesity regimen for 8 weeks, then randomized into 3 diet or exercise treatment groups: Control (AIN-76A diet fed ad libitum to maintain the obese state, n=30); 30% CR (70% of the carbohydrate calories but otherwise isonutrient relative to control, n=15); EX (control diet fed ad libitum plus treadmill exercise regimen, n=15). Mice were orthotopically implanted (4th mammary gland) with syngeneic MMTV-Wnt-1 mammary tumor cells at week 12. Of the 30 mice in the control group, 15 received rapamycin (5mg/kg, administered ip every 48hrs) starting at week 14. All other mice received vehicle treatment (saline, administered ip every 48 hrs) starting at week 14. Tumors were excised at week 18. Final tumor weights from mice in the CR (0.043 ± 0.007 g) and rapamycin (0.072 ± 0.010 g) groups, but not EX (0.380 ± 0.072 g) group, were significantly reduced compared to control (0.390 ± 0.066 g).
The crucial role of mTOR in the link between obesity and breast cancer progression was confirmed in a follow up study where constitutive activation of mTOR (mTOR) ablated the inhibitory effects of CR on mammary tumor growth. CR failed to reduce tumor weight in mice injected with cells transfected with mTOR (0.38 ± 0.05 g), compared to control (0.55 ± 0.08 g). Transfection effect bias was discarded since CR significantly reduced weight of tumors (0.29 ± 0.03 g) in mice injected with cells transfected with WT mTOR, compared to control (0.62 ± 0.12 g).
We conclude that mTOR inhibition may be a pharmacologic strategy to mimic the anticancer effects of CR and break the obesity-breast cancer progression link.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A75.
Abstract A82: Can telomere length be modified in healthy people?
Authors: Washechek-Aletto Jill R. , Engelman Corinne , Thibodeau Stephen N. , Petersen Gloria M. , Cunningham Julie M. , Boardman Lisa A. , Opyrchal Seung M. , Devine Megan M. , Viker Kimberly B. , Johnson Ruth A. , Skinner Halcyon G. , Seo Songwon , Gangnon Ronald , Litzelman Kristin 
Published: June 2012

Abstract
Short constitutional telomere length has been associated with aging and cancer, but how telomere length is affected by other epidemiologic or environmental variables in health has not been thoroughly studied. Understanding these associations with telomere length in health is important for studies to evaluate the relationship of telomere length and diseases such as cancer. We measured peripheral blood leukocyte DNA telomere length with quantitative PCR in 1977 non-related healthy controls collected through the Colon Cancer Family Registry (an NCI cooperative group) and through the Mayo Biobank and Biobank for Gastrointestinal Health Research, two IRB approved prospective biospecimen collections based at Mayo Clinic, Rochester, MN. The controls were a median age of 50.6 years old, and 49.6% of the controls were male. Ninety-six percent of the controls were white; 1.8% were Asian, and &lt;1% were either black, Pacific Islander, or Native American. Less than 1% of controls were Hispanic. On univariate analysis, as age increased, telomere length decreased (Pearson correlation coefficient = −0.07, 95% CI: −0.11, −0.03). Telomeres were longer in people who consumed more fruits (p&lt;0.01) and vegetables (p&lt;0.01); took aspirin on a regular basis (p&lt;0.01); or had a family history of cancers of any type (p=0.05). Women had longer telomeres than men (p=0.03). Telomeres were shorter in people who consumed alcohol (p&lt;0.01), took folate on a regular basis (p=0.01), or who consumed red meat (p&lt;0.01). Statistical significance was not found in the following variables: tobacco use, diagnosis of diabetes, intake of calcium, use of hormone replacement therapy in women, or body mass index. On multivariate analysis, age, vegetable consumption, family history of colorectal cancer or any type of cancer, and folate intake were identified as being significantly associated with telomere length. Telomere length may be associated with multiple environmental and demographic variables in healthy individuals, and adjusting for these may be important for studies that test for an association between telomere length and diseases such as cancer.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A82.
Abstract A9: Phenotype matters in the prediction of cancer risk of oral premalignant lesions (OPL)
Authors: Zhang Lewei , Guillaud Martial , Poh Catherine , MacAulay Calum , Rosin Miriam 
Published: June 2012

Abstract
Histology remains the most reliable way for predicting cancer risk of premalignant (preinvasive) lesions if the OPLs show high-grade changes (i.e. severe dysplasia or carcinoma in situ, CIS): however, it is a poor predictor of the cancer risk of OPLs with no or low-grade (mild/moderate) dysplasia (termed LGOPL). It is possible that there are subtle histological differences between progressing LGOPLs and nonprogressing LGOPLs. In a recent retrospective study (Cancer Research 2008, 68:3099–107), we have shown that nuclear phenotypic score (NPS) as measured by a computer-driven microscope imaging system could serve as an adjunct tool to assist pathologists in judging the progression risk of LGOPLs Objective: to assess the potential of this new tool in identifying high-risk LGOPLs from an ongoing prospective study and to give an interim report of our results.
Methods: 284 primary LGOPLs from 284 patients were studied: 47 hyperplasias, 116 mild and 121 moderate dysplasias. Thoinin-Feulgen stained sections were imaged and analyzed to generate a NPS for each sample. The NPS was correlated with histopathology, clinical variables and outcome (progression to severe dysplasia, CIS or invasive cancer).
Results: Elevated NPS was significantly associated with progression: high NPS (≥ 4.5) was associated with a 4.7-fold increase in risk of progression as compared to low NPS (&lt; 4.5). Of the 199 LGOPLs with low NPS, 13 (7%) progressed as compared to 26/85 (31%) of LGOPLs with high NPS (P &lt; 0.0001). In the multivariate Cox model, high NPS was a significant risk predictor for cancer progression (P &lt; 0.0001).
Conclusions: These data support the potential utility of automated quantitative microscopy technology to assist the pathologist in assessing progressing potential of low-grade OPLs (Supported by grant R01DE13124, NIDCR).
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A9.