bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR2: A genetic screen for novel determinants of anoikis resistance identifies PVRL4
Authors: Pavlova Natalva N. , Elledge Stephen J. 
Published: June 2012

Abstract
Tumor cells develop resistance to detachment-induced cell death, known as anoikis, and rely on it for survival throughout the course of disease progression. Through a gain-of-function genetic screen for novel determinants of anoikis resistance, we found that PVRL4 (poliovirus receptor-like 4) promotes anchorage-independent colony formation in HMECs (human mammary epithelial cells).
PVRL4 belongs to a family of transmembrane proteins involved in early stages of adherens junction formation. PVRL4 is expressed in focally amplified in breast cancer and positively correlates with spread of cancer into lymph nodes and poor survival prognosis. PVRL4 promoted cell aggregation of HMECs, and induction of cell aggregation was sufficient to promote anchorage-independent colony formation. Cell aggregation and transformation induced by PVRL4 were abrogated in presence of a monoclonal antibody targeting its extracellular region. Furthermore, stable depletion of PVRL4 in breast cancer cells inhibited spontaneous cell aggregation and anchorage-independent growth. Taken together, our findings demonstrate the key role of PVRL4 in cellular transformation and suggest that it functions via promoting cell aggregation.
Cancer cells are known to exhibit increased cell aggregation; moreover, increased cell aggregation correlates with metastatic potential. Multicellular clusters of cancer cells are present among circulating tumor cells (CTCs) blood from cancer patients and as well as in mouse cancer models. Promotion of survival in the absence of attachment via inducing cell aggregation may therefore provide a unique advantage for CTC survival in the bloodstream and spread into distant organs. Finally, inhibition of PVRL4-induced aggregation and anchorage-independence by monoclonal antibodies demonstrates a potential new therapeutic strategy against breast cancer.
This abstract is also presented as Poster B5.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR2.
Abstract A105: Blood donation in relation to colorectal cancer risk in men
Authors: Zhang Xuehong , Ma Jing , Wu Kana , Chan Andrew T. , Fuchs Charles S. , Giovannucci Edward L. 
Published: June 2012

Abstract
Background: Excessive iron may increase colorectal cancer risk, as shown in vitro and animal studies. Human observational studies of iron intakes and body iron stores in relation to colorectal cancer risk have been conflicting, which may partly due to non-specific measurement of iron status. We used the lifetime number of blood donation, a validated determinant of serum ferritin, to investigate the iron hypothesis, which has only been examined in one prior study. Serum ferritin is a reliable measure of body iron stores. Thus, the hypothesis of the depletion of body iron stores lowering the colorectal cancer risk can be tested by comparing colorectal cancer risk between regular blood donors and non-donors.
Method: We prospectively examined the association between lifetime number of blood donations and colorectal cancer risk in the Health Professionals Follow-up Study. Information on number of blood donation and other colorectal cancer risk factors was obtained in 1992 questionnaire. A Cox proportional hazard regression was used to estimate the multivariable relative risks (RRs, 95%CIs).
Results: We documented 659 incident colorectal cancer cases during 16 years of follow-up. The age-adjusted results yielded essentially the same results as the multivariable results. Comparing with the non-donors, the multivariable RRs (95%CIs) were 0.95 (0.79, 1.15) for 1–4 donation, 0.86 (0.65, 1.13) for 5–9 donations, 0.97 (0.73, 1.29) for 10–19 donations, 0.89 (0.60, 1.31) for 20–29 donations, and 1.16 (95%CI: 0.82, 1.63) for at least 30 donations (P-value for test for trend = 0.46). In addition, the null associations did not vary by colorectal cancer sub-sites, or levels of intakes of total iron and heme iron.
Conclusion: Lifetime number of blood donation is not associated with risk of developing colorectal cancer risk in men. Our results do not support an important role of body iron stores in colorectal carcinogenesis.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A105.
Abstract A22: Sensitive detection of mutant KRAS in colorectal tissue using the multiplex QuARTS™ assay
Authors: Oldham-Haltom Rebecca , Leduc Christine , Hunt Oliver , Domanico Mike , Taylor William , Ahlquist David , Lidgard Graham 
Published: June 2012

Abstract
Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, yet it is potentially the most treatable and preventable cancer with effective screening. Exact Sciences has developed a multi-biomarker CRC screening test that targets DNA methylation, DNA mutations, and hemoglobin in stool. The aim of this study was to evaluate the analytical accuracy of a novel assay for the detection of KRAS mutation sequences at Codons 12 and 13 in well-characterized colorectal tissues.
Methodology: A multiplexed KRAS assay was designed utilizing QuARTS (Quantitative Allele-specific Real-time Target and Signal amplification), a highly sensitive technology that combines allele-specific DNA amplification with invasive cleavage chemistry to generate signal during each amplification cycle similar to real-time PCR. The assay, which detects seven KRAS mutations and the reference gene β-actin, was used to assess 87 colorectal tissue samples (52 CRCs, 16 adenomas ≥ 1cm, and 19 normal epithelia) as determined by Mayo Clinic Pathology. Samples were obtained by microdissection of fresh frozen tissue biopsies. DNA was extracted by Mayo Clinic using a standardized chloroform/phenol methodology. The genotypes of each sample were established using dye terminator dideoxy sequencing in both the forward and reverse orientations. Copy numbers of KRAS mutations and β-actin were determined by conventional comparison against standard curves. KRAS data are reported as percent mutation and calculated by dividing mutant copies by β-actin copies and multiplying by 100.
Results: Based on sequencing data: the 52 CRC samples contained 22 KRAS mutations and 30 wild-type genotypes, the 16 adenomas ≥ 1cm contained 8 mutations and 8 wild-type genotypes, and the 19 normal tissues contained all wild-type genotypes. The QuARTS assay detected 100% of the KRAS mutations in the CRC and adenomas and provided excellent differentiation between wild-type and mutation, with the highest percent KRAS mutation of normal wild-type samples at 0.55% and the lowest percent mutation of KRAS positive samples at 8.34%. Based on this data, this assay has the potential to be more sensitive analytically than standard sequencing.
Conclusion: The QuARTS assay detects KRAS mutations in tissue with high sensitivity and specificity. This assay method could provide an accurate and high throughput approach to detection of KRAS mutations in biospecimens for multiple clinical applications.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A22.
Abstract A24: Evaluation and validation of biomarkers for prostate cancer early diagnosis
Authors: Reyes Niradiz , Bettin Alfonso , Causil Ceyla , Reyes Ismael , Geliebter Jan 
Published: June 2012

Abstract
Prostate cancer (PCa) remains the most frequently diagnosed malignancy in men and although effective treatment is possible for early stages, advanced PCa is largely incurable. PSA, the only relevant marker for this disease, has a low predictive value leading to unnecessary biopsies and associated complications. Thus, identification of better biomarkers able to accurately and reliably diagnose PCa at early stages is an important goal in prostate cancer research. Currently a number of potential biomarkers are being investigated as predictors of PCa diagnosis. Using quantitative real time PCR (qRT-PCR) we have analyzed in the PCa cell lines PWR-1E, LNCaP and PC3 the expression of a set of potential biomarkers previously identified by us in a microarray gene expression study. So far, we have found in these cell lines several differentially expressed genes, some of which encode extracellular matrix proteoglycans, cell adhesion molecules, genes related to motility, growth factor receptors, and tumor suppressor genes. We are in the process of evaluating these differentially expressed genes in cDNA panels of PCa at different disease stages and in prostate needle biopsy specimens taken from patients at diagnosis before any treatment have been established. The next step will be the validation, at the protein level in serum samples from a cohort of patients, of those genes showing an association to prostate cancer disease stages. A prospective clinical study will be necessary to confirm the clinical relevance of validated genes.
Project code: 110745921483. Supported by Colciencias Grant # RC No. 462-2008 awarded to Niradiz Reyes.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A24.
Abstract A30: Investigation of imatinib mesylate effect on vestibular schwannoma tumor by using in vivo corneal angiogenesis model
Authors: Avsar Timucin , Yener Ulas , Akgun Emel 
Published: June 2012

Abstract
Objective: Vestibular schwannomas (VSs) are histologically benign, encapsulated, and slow growing tumors that arise from Schwann cells of the vestibular branch of eighth of twelve cranial nerves (Vestibulo-cochlear nerve) that is located next to porus acusticus internus. The tested hypothesis was that gleevec reduces angiogenic capacity in patients with VSs and NF-2 associated schwannomas by using corneal angiogenesis assay. This in vivo therapeutic efficacy might induce new clinical trials in the treatment of VSs and add a medical treatment option in the armamentarium.
Methods: A total of 121 patients were treated by microsurgical VS resection at the School of Medicine, Neurosurgery Department and Institute of Neurological Sciences of Marmara University, Istanbul, Turkey between 1988–2009. Randomly selected 10 (6 sporadic VS, 4 NF-2 associated VS) samples were used. Angiogenic potential of VS and NF-2 associated VSs tumors in response to imatinib were compared with the healthy subjects by using immunohistochemistry, western blot and corneal angiogenesis assay. Results: Positive and negative control tissues showed significantly higher and lower angiogenic potential (p&lt;0.05), compared with both sporadic and NF-2 associated VS tumor groups. Imatinib activity significantly reduced angiogenic potential, in both sporadic VS and NF-2 associated VS tumor groups. PDGF-A and PDGFR-alpha as well as PDGF-B and PDGFR-beta expression in sporadic VS and NF-2 associated VS were higher than the control groups (p&lt;0.05).
Conclusion: The results of the present study indicate that NF-2 associated VSs showed significantly higher angiogenic potential than sporadic VSs. Moreoever, both sporadic and NF-2 associated VSs had significantly higher angiogenic potential compared with normal brain tissue. We conclude that, in the treatment of VS and NF-2 tumors, imatinib is an alternative approach to surgical resection and radiosurgery.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A30.
Abstract A41: The ASK1/IKK signaling axis mediates crosstalk between inflammation and apoptosis
Authors: Puckett Mary C. , Goldman Erinn , Cockrell Lisa , Khuri Fadlo , Fu Haian 
Published: June 2012

Abstract
Inflammation plays a well-established role in the promotion of tumorigenesis. The inflammatory response is mediated in large part by the inhibitor of kappa b (IKK) and nuclear factor κB (NfκB) signaling pathway. This signaling pathway can promote inflammation induced-tumorigenesis and inhibit apoptosis through protection against reactive oxygen species (ROS). The action of ROS is in part controlled by the apoptosis signal regulating kinase 1 (ASK1). ASK1 activation can initiate pro-apoptotic signaling cascades through mitogen activated protein kinases (MAPKs) Jun N-terminal Kinase (JNK) and p38. Improper regulation of ASK1 has been implicated in a wide array of diseases, including cancer. NfκB promotes tumor growth through activation of pro-growth and survival genes and decreases apoptosis through impairing JNK activation. This work has identified an unexpected, direct, non-genetic method of cell death inhibition by an upstream regulator of NfκB, IKK.
We have found that IKK can phosphorylate ASK1 Ser967, which leads to the recruitment of 14–3–3 proteins, decreased ASK1 kinase activity and ASK1-mediated apoptosis. To further elucidate the relationship between ASK1 and IKK, the interaction interface was identified and the consequences on ASK1-mediated signaling were studied. IKK and ASK1 were shown to interact in cells by immunoprecipitation of both overexpressed and endogenous proteins. Furthermore, the direct interaction between these kinases was confirmed through time resolved – fluorescence resonance energy transfer (TR-FRET). The ASK1/IKK interaction interface was dissected through iterative deletional mutagenesis and protein complementation assays. ASK1 activity was assessed by measuring H2O2 induced apoptosis, neurite outgrowth of ASK1-inducible cells, and phosphorylation of ASK1 Ser967 and downstream targets under several IKK states. IKK prevented stress-induced dephosphorylation of ASK1 and inhibited ASK1 mediated apoptosis.
These data suggest the existence of an IKK/ASK1 signaling node that negatively regulates apoptosis in response to pro-survival conditions. Characterization of this interaction could lead to development of targeted agents for ASK1 and IKK related diseases.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A41.
Abstract A8: Estrogen metabolism and mammographic density in postmenopausal women
Authors: Fuhrman Barbara J. , Brinton Louise A. , Pfeiffer Ruth M. , Teter Barbara E. , Dallal Cher , Byrne Celia , Muti Paola C. , Gierach Gretchen L. 
Published: June 2012

Abstract
Estrogens play important roles in the pathophysiology of breast tumors and are recognized causal factors in the etiology of breast cancer. Parent estrogens (estrone and estradiol) can be hydroxylated at the 2, 4, or 16 position of the steroid ring, resulting in metabolites with different biological activity and availability. Estrogen metabolism shows great inter-individual variation, is modifiable, and may contribute to differences among women at risk of breast cancer. We conducted a cross-sectional study to investigate whether urinary estrogens and estrogen metabolites (jointly referred to as EM) are associated with mammographic density (MD), the strongest predictor of sporadic breast cancer risk among women apart from age.
Methods: Postmenopausal women without breast cancer, aged 48–82 y, and reporting no current use of exogenous hormones were recruited and interviewed at a mammography clinic in Western NY in 2005. Concentrations of 15 EM were measured in first morning urine samples from 195 participants using liquid chromatography-tandem mass spectrometry. MD (%) was measured using computer-assisted analyses of digitized films. Linear models were used to assess associations of log-transformed EM concentrations and ratios with MD while adjusting for age, body mass index (BMI, kg/m2), and history of combination menopausal hormone therapy. We assessed effect modification by these factors and by years since menopause. Results: The median age of participants was 58, and median time since menopause was 8 years; 35% of participants were obese (BMI ≥30), and 33% had previously used combination menopausal hormones. Among all participants, urinary concentrations of parent estrogens were not associated with MD while some individual 2-pathway and 4-pathway EM had significant inverse associations with MD. Associations between EM profiles and MD were modified by years since menopause (≤8 or &gt;8 y) and by obesity. Among women with a recent menopause, MD was positively associated with parent estrogens (p=0.02), and inversely associated with 2- and 4-hydroxylation pathway EM (p=0.03 and 0.02); these associations were not observed in women with a more distant menopause (pinteraction=0.02, 0.18, 0.16, respectively). Similarly, parent estrogens were directly associated with MD (p=0.003) among women who were obese but not among thinner counterparts (pinteraction=0.08).
Conclusion: This is the first study to examine the relations between 15 EM and MD in postmenopausal women. EM profiles were most strongly associated with MD in subgroups with higher estrogen levels including obese women and those with a more recent menopause. In these groups, more extensive 2- and 4-hydroxylation of parent estrogens was associated with reduced MD. This pattern of metabolism may influence MD by facilitating clearance of estrogens from breast tissues.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A8.
Abstract A85: Paternal age at birth is associated with leukocyte telomere length in the Nurses' Health Study
Authors: Prescott Jennifer , Han Jiali , De Vivo Immaculata 
Published: June 2012

Abstract
Despite the high heritability of telomere length, genome-wide association studies have not found common genetic variants with a strong influence on telomere length. A few studies have demonstrated significant correlations between the telomere length of offspring and maternal and/or paternal telomere lengths. Positive correlations have also been observed for parental age at birth and offspring telomere length, particularly with paternal age. We decided to investigate the relationship between parental age and female offspring telomere length in one of the largest studies to date, by using existing leukocyte telomere length (LTL) data that were measured by a high-throughput quantitative PCR assay for multiple prospective nested case-control studies of various cancers and cardiovascular disease in the Nurses' Health Study (NHS). We derived probit scores for each nested case-control study to standardize for between-batch variability before pooling data. Participants included in this analysis were free of cancer and other major diseases at blood draw and were restricted to the 6,647 NHS participants who reported the years their mother and father were born on the 1976 baseline questionnaire. We calculated Spearman correlation coefficients and also used generalized linear regression to calculate least-square (LS) means of LTL probit score by maternal and paternal age at birth categories. LS means were adjusted for the participant's age at blood draw. Analyses of maternal age at birth categories were additionally adjusted for continuous paternal age at birth and vice versa. The mean age of participants at blood draw was 59 years. Mean maternal and paternal age at birth were 28 and 32 years, respectively. Maternal age and paternal age at birth were highly correlated (rS=0.77, P&lt;0.0001). After controlling for participant's age at blood draw and maternal age at birth, paternal age at birth was positively associated with the participant's LTL at blood draw (P-trend=0.003). The adjusted LS mean LTL (probit score) across paternal age categories (15–24, 25–29, 30–34, 35–39, 40–44, and 45+ years) were −0.10, −0.01, 0.01, 0.02, 0.08, and 0.19, respectively. Among the NHS participants, a one year increase in paternal age at birth corresponded to an LT L difference observed for ∼6 months of younger age. Maternal age at birth was not associated with the participant's LTL at blood draw (P-trend=0.26). In our study population, we provide evidence of an association between older paternal age at birth and longer telomere length among female offspring, but not for maternal age at birth. These results are consistent with prior literature and support the existence of temporally-regulated paternal factors in the inheritance of leukocyte telomere length among their female offspring.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A85.
Abstract A87: The association between polymorphisms in hormone metabolism and growth factor genes and mammographic density in Norwegian postmenopausal women
Authors: Ellingjord-Dale Merete , Lee Eunjung , Ozhand Ali , Couto Elisabeth , Qureshi Samera , Hofvind Solveig , Akslen Lars , Ursin Giske 
Published: June 2012

Abstract
Mammographic density (MD) is one of the strongest known breast cancer risk factors. Estrogen and progestin therapy (EPT) has been associated with increases in MD, and is known to increase breast cancer risk possibly through increased proliferation of breast epithelial cells. It is possible that genetic factors modify the association between EPT and MD, and that certain genetic variants are particularly important in determining MD in hormone users. We evaluated the association between mammographic density and 340 SNPs (singular nucleotide polymorphisms) from about 30 putative genes in hormone metabolism / growth factor pathways among women who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004.
We assessed mammographic density on 2040 postmenopausal women aged 50–69 years using a computer assisted method (Madena, University of Southern California). We ran multiple regressions models (dominant and additive), adjusting for age, body mass index (BMI) with and without adjustments for multiple comparisons (the number of SNPs per gene). We stratified the postmenopausal women into current, past and never EPT users. For postmenopausal current EPT users there was an association between a variant in the prolactin gene (rs10946545) and MD (dominant model p=0.0002). This association was also present in women who were currently using norethisterone acetate (NETA) based EPT, a regimen common in Nordic countries. In past EPT users, we found that two variants in the catechol-O-methyltransferase gene (COMT; rs2239395 and rs5992500) were associated with MD (dominant model p=0.0112), but the association was no longer significant when we adjusted for multiple tests. Among current estrogen only users, there was an association between a variant in the cytochrome P450 gene (CYP1B1; rs4670813) and MD in current estrogen only users (dominant model p=0.0028). We also found an association between a variant in the vascular endothelial growth factor gene (VEGF; rs833052) and MD for current users of high dose NETA EPT (dominant model p=0.0021), while in low dose NETA EPT users a variant in the tumor necrosis factor gene (TNF; rs4947324) was associated with MD (dominant model p=0.0007).
We found some evidence that variants in the prolactin and COMT genes were associated with MD in current or past EPT users. We also found associations between genetic variants in TNF and MD in low dose NETA users, and between variants in VEGF and MD in high dose NETA users.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A87.