bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and Epigenetic Alterations of Familial Pancreatic Cancers
Authors: Brune Kieran , Hong Seung-Mo , Li Ang , Yachida Shinichi , Abe Tadayoshi , Griffith Margaret , Yang Dawei , Omura Noriyuki , Eshleman James , Canto Marcia , Schulick Rich , Klein Alison P. , Hruban Ralph H. , Iacobuzio-Donohue Christine , Goggins Michael 
Published: December 2008

Abstract
Background: Little is known about the genetic and epigenetic changes that contribute to familial pancreatic cancers. The aim of this study was to compare the prevalence of common genetic and epigenetic alterations in sporadic and familial pancreatic ductal adenocarcinomas.
Methods: DNA was isolated from the microdissected cancers of 39 patients with familial and 36 patients with sporadic pancreatic adenocarcinoma. KRAS2 mutations were detected by BstN1 digestion and/or cycle sequencing. TP53 and SMAD4 status were determined by immunohistochemistry on tissue microarrays of 23 archival familial pancreatic adenocarcinomas and in selected cases by cycle sequencing to identify TP53 gene mutations. Methylation-specific PCR analysis of seven genes (FoxE1, NPTX2, CLDN5, P16, TFPI-2, SPARC, ppENK) was done on a subset of fresh-frozen familial pancreatic adenocarcinomas.
Results: KRAS2 mutations were identified in 31 of 39 (80%) of the familial versus 28 of 36 (78%) of the sporadic pancreatic cancers. Positive immunolabeling for p53 was observed in 57% of the familial pancreatic cancers and loss of SMAD4 labeling was observed in 61% of the familial pancreatic cancers, rates similar to those observed in sporadic pancreatic cancers. The mean prevalence of aberrant methylation in the familial pancreatic cancers was 68.4%, which was not significantly different from that observed in sporadic pancreatic cancers.
Conclusion: The prevalence of mutant KRAS2, inactivation of TP53 and SMAD4, and aberrant DNA methylation of a seven-gene panel is similar in familial pancreatic adenocarcinomas as in sporadic pancreatic adenocarcinomas. These findings support the use of markers of sporadic pancreatic adenocarcinomas to detect familial pancreatic adenocarcinomas. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3536–42)
Reproductive Factors, Age at Maximum Height, and Risk of Three Histologic Types of Breast Cancer
Authors: Beaber Elisabeth F. , Holt Victoria L. , Malone Kathleen E. , Porter Peggy L. , Daling Janet R. , Li Christopher I. 
Published: December 2008

Abstract
Numerous studies have evaluated the association between factors related to maturation and reproduction and breast cancer risk, but few have assessed how these factors are related to different histologic types of breast cancer among postmenopausal women. We used polytomous logistic regression to assess the effect of age at maximum height and reproductive factors on risk of invasive breast cancer by histologic type in three case groups (524 ductal, 324 lobular, and 196 ductal-lobular) and 469 controls enrolled in a population-based case-control study of women ages 55 to 74 years residing in the Seattle-Puget Sound region of Washington State (2000-2004). Histologic type was determined by a centralized tissue review for 83% of cases. Age at menarche and age at maximum height were inversely associated with risk of ductal-lobular carcinoma (Ptrend = 0.04 for both exposures) but not ductal or lobular carcinoma. Relative to nulliparous women, parous women had a 50% reduced risk of all histologic types of breast cancer. We observed similar increases in risk across histologic types associated with having a first live birth at ages ≥30 years compared with ages ≤19 years. Compared with parous women who never breast-fed, those who breast-fed had a reduced risk of ductal carcinoma (odds ratio, 0.7; 95% confidence interval, 0.5-0.9) but not lobular or ductal-lobular carcinoma. Further exploration of breast cancer risk by histology is merited to understand differences in the etiology of ductal, lobular, and ductal-lobular carcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3427–34)
Repeated Measurements of Urinary Methylated/Oxidative DNA Lesions, Acute Toxicity, and Mutagenicity in Coke Oven Workers
Authors: Chao Mu-Rong , Wang Chien-Jen , Wu Ming-Tsang , Pan Chih-Hong , Kuo Chung-Yih , Yang Hao-Jan , Chang Louis W. , Hu Chiung-Wen 
Published: December 2008

AbstractWe conducted a repeated-measures cohort study of coke oven workers to evaluate the relationships between the traditional exposure biomarker, urinary 1-hydroxypyrene (1-OHP), and a series of biomarkers, including urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), N7-methylguanine (N7-MeG), acute toxicity, and mutagenicity. A total of eight spot urine samples were collected from each high-exposed (at topside oven area) and low-exposed workers (at side oven area) during the whole working cycle, which consisted of 6 consecutive days of working followed by 2 days off. Our results showed that the high-exposed workers had significantly higher urinary levels of 1-OHP, 8-oxodG, and N7-MeG compared with the low-exposed workers. Acute toxicity and mutagenicity of urine were also found to be markedly increased in the high-exposed workers, as determined by Microtox assay and Ames test, respectively. Multivariate regressions analysis revealed that the urinary 8-oxodG, N7-MeG, or acute toxicity was significantly correlated with 1-OHP concentrations. Overall, the present study showed that exposure to coke oven emissions increased oxidatively damaged DNA products and mutagenicity of urine, and for the very first time, such exposure was also found to increase DNA methylation and urinary acute toxicity. The potential source of methylating agents in coke oven emissions warrants further investigation. Additionally, with repeated measurements, the pattern of time course for urinary 1-OHP was found to be different from those of 8-oxodG and N7-MeG, as well as acute toxicity and mutagenicity. This finding implies that the single measurement that was often conducted in occupational healthy investigations should be used with certain precautions, because single measurement may fail to provide the proper information of interest. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3381–9)
Identification of Common Variants in the SHBG Gene Affecting Sex Hormone-Binding Globulin Levels and Breast Cancer Risk in Postmenopausal Women
Authors: Thompson Deborah J. , Healey Catherine S. , Baynes Caroline , Kalmyrzaev Bolot , Ahmed Shahana , Dowsett Mitch , Folkerd Elizabeth , Luben Robert N. , Cox David , Ballinger Dennis , Pharoah Paul D.P. , Ponder Bruce A.J. , Dunning Alison M. , Easton Douglas F. ,   The Studies in Epidemiology and Risks of Cancer Heredity Team
Published: December 2008

Abstract
Background: Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants.
Methods: We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls.
Results: Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)n polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)n repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002).
Conclusion: At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3490–8)
Lack of Association between the Functional Polymorphisms in the Estrogen-Metabolizing Genes and Risk for Hepatocellular Carcinoma
Authors: Yuan Xiaoyan , Zhou Gangqiao , Zhai Yun , Xie Weimin , Cui Ying , Cao Jia , Zhi Lianteng , Zhang Hongxing , Yang Hao , Zhang Xiaoai , Qiu Wei , Peng Yong , Zhang Xiumei , Yu Ling , Xia Xia , He Fuchu 
Published: December 2008

Abstract
Estrogens have been proposed to act as tumor promoters and induce hepatocarcinogenesis. Recently, we observed a significant association between the risk for hepatocellular carcinoma and the polymorphisms of the estrogen receptor (ESR) α (ESR1) gene, supporting the hypothesis of involvement for the estrogen-ESR axis in the estrogen-induced hepatocarcinogenesis. In this study, based on another hypothesis in which estrogen metabolites can directly cause DNA damage and affect tumor initiation, we examined whether the polymorphisms of the estrogen-metabolizing enzymes (EME), which are involved in biogenesis (CYP17, CYP19), bioavailability (CYP1A1, CYP1B1), and degradation (catechol-O-methyltransferase) of the estrogens, have any bearing on the risk for hepatocellular carcinoma. Seven functional polymorphisms in five EMEs (CYP17 MspAI site, CYP19 Trp39Arg, Ile462Val and MspI site in CYP1A1, CYP1B1 Val432Leu, and Ala72Ser and Val158Met in catechol-O-methyltransferase) were genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PCR-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk for hepatocellular carcinoma was observed with the seven polymorphisms in hepatitis B virus carriers and non–hepatitis B virus carriers after correction for multiple comparisons. After stratification by common confounding factors of hepatocellular carcinoma, the EME polymorphism remained no significant association with the hepatocellular carcinoma risk. Furthermore, no signs of gene-gene interactions were observed for each combination of the seven polymorphisms. Our findings suggest that the polymorphisms of EMEs may not contribute significantly to the risk for hepatocellular carcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3621–7)
Tamoxifen Prevents Premalignant Changes of Breast, but not Ovarian, Cancer in Rats at High Risk for Both Diseases
Authors: Ting Alison Y. , Kimler Bruce F. , Fabian Carol J. , Petroff Brian K. 
Published: December 2008

Abstract
Women at increased risk for breast cancer are at increased risk for ovarian cancer as well, reflecting common risk factors and intertwined etiology of the two diseases. We previously developed a rat model of elevated breast and ovarian cancer risk, allowing evaluation of dual-target cancer prevention strategies. Tamoxifen, a Food and Drug Administration–approved breast cancer chemoprevention drug, has been shown to promote ovarian cysts in premenopausal women; however, the effect of tamoxifen on ovarian cancer risk is still controversial. In the current experiment, Fischer 344 rats (n = 8 per treatment group) received tamoxifen (TAM) or vehicle (control) in factorial combination with combined breast and ovarian carcinogen (17β-estradiol and 7,12 dimethylbenza[a]anthracene, respectively). Mammary and ovarian morphologies were normal in the control and TAM groups. Carcinogen (CARC) treatment induced mammary dysplasia with elevated cell proliferation and reduced estrogen receptor-α expression and promoted preneoplastic changes in the ovary. In the CARC + TAM group, tamoxifen reduced preneoplastic changes and proliferation rate in the mammary gland, but not in the ovary, compared with rats treated with carcinogen alone. Putative stem cell markers (Oct-4 and aldehyde dehydrogenase 1) were also elevated in the mammary tissue by carcinogen and this expansion of the stem cell population was not reversed by tamoxifen. Our study suggests that tamoxifen prevents early progression to mammary cancer but has no effect on ovarian cancer progression in this rat model.
Dose-Dependent Inhibition of Tobacco Smoke Carcinogen–Induced Lung Tumorigenesis in A/J Mice by Indole-3-Carbinol
Authors: Kassie Fekadu , Matise Ilze , Negia Mesfin , Upadhyaya Pramod , Hecht Stephen S. 
Published: December 2008

AbstractRecently, we reported inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo(a)pyrene (BaP)–induced lung tumorigenesis in A/J mice by indole-3-carbinol (I3C; 112 μmol/g diet) administered beginning at 50% in the carcinogen treatment phase. In this study, we examined the dose-dependent and postcarcinogen tumor-inhibitory activities of I3C. A mixture of NNK plus BaP (2 μmol each) administered by gavage as eight biweekly doses caused 21.1 ± 5.2 lung tumors per mouse. Carcinogen-treated mice given diets containing I3C at 1, 10, 30, 71, and 112 μmol/g, beginning at 50% in the carcinogen treatment phase, had 17.9 ± 6.1, 10.4 ± 3.7, 9.8 ± 5.1, 5.2 ± 4.0, and 2.5 ± 2.4 lung tumors per mouse, corresponding to reductions by 15%, 51%, 53%, 75%, and 88%, respectively. All reductions, except at the lowest dose level (1 μmol I3C/g diet), were significant (P &lt; 0.001). Similarly, administration of I3C (112 μmol/g diet) beginning 1 week after the last dose of the carcinogen significantly reduced NNK plus BaP-induced lung tumor multiplicity to 5.6 ± 3.5, corresponding to a reduction by 74%. Analyses of cell proliferation and apoptosis markers revealed that I3C reduced the number of Ki-67–positive cells and expression of proliferating cell nuclear antigen, phospho-Akt, and phospho-BAD and increased cleavage of poly(ADP-ribose) polymerase, suggesting that the lung tumor inhibitory effects of I3C were mediated, at least partly, through inhibition of cell proliferation and induction of apoptosis. These results clearly show the efficacy of I3C in the prevention of tobacco carcinogen–induced lung tumorigenesis in A/J mice and provide a basis for future evaluation of this compound in clinical trials as a chemopreventive agent for current and former smokers.
AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines
Authors: Levy Dana S. , Kahana Jason A. , Kumar Rakesh 
Published: December 2008

AbstractThe PI3K/AKT signaling is activated in various hematologic malignancies. We evaluated the effect of a novel, pan-AKT kinase inhibitor, GSK690693, on the proliferation of 112 cell lines representing different hematologic neoplasia. Fifty-five percent of all cell lines tested were sensitive to AKT inhibitor (EC50 < 1 μM), with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and Burkitt lymphoma showing 89%, 73%, and 67% sensitivity to GSK690693, respectively. The antiproliferative effect was selective for the malignant cells, as GSK690693 did not inhibit the proliferation of normal human CD4+ peripheral T lymphocytes as well as mouse thymocytes. Phosphorylation of downstream substrates of AKT was reduced in both sensitive and insensitive cell lines on treatment with GSK690693, suggesting that the cause of resistance was not related to the lack of AKT kinase inhibition. Consistent with the role of AKT in cell survival, GSK690693 also induced apoptosis in sensitive ALL cell lines. Overall, our data provide direct evidence for the role of AKT signaling in various hematologic malignancies, especially ALL and some lymphomas.
Early Prediction of Response to Sunitinib After Imatinib Failure by 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients With Gastrointestinal Stromal Tumor
Authors: Prior John O. , Montemurro Michael , Orcurto Maria-Victoria , Michielin Olivier , Luthi François , Benhattar Jean , Guillou Louis , Elsig Valérie , Stupp Roger , Delaloye Angelika Bischof , Leyvraz Serge 
Published: December 2008

Purpose Positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. Patients and Methods Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using −25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. Conclusion Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy.
Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer
Authors: Salama Paul , Phillips Michael , Grieu Fabienne , Morris Melinda , Zeps Nik , Joseph David , Platell Cameron , Iacopetta Barry 
Published: December 2008

Purpose To determine the prognostic significance of FOXP3+ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8+ and CD45RO+ lymphocyte densities. Patients and Methods Tissue microarrays and immunohistochemistry were used to assess the densities of CD8+, CD45RO+, and FOXP3+ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results FOXP3+ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8+ and CD45RO+ cell densities were lower. FOXP3+ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3+ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8+ and CD45RO+. High FOXP3+ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3+ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion FOXP3+ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8+ and CD45RO+ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3+ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3+ Treg density may help to improve the prognostication of early-stage colorectal cancer.
Das Adam Smith Problemand Faculty Psychology in the Antebellum North
Authors: Davenport Stewart 
Published: December 2008

This essay addresses the question of what happened when the Adam Smith problem of industrializing Europe met the faculty psychology of antebellum America. Although it was not called the Adam Smith problem until the late nineteenth century, the fact that Smith wrote two books instead of one has always posed difficulties for those seeking integrity between the ethical and the economical.For two groups of antebellum Protestants—the “clerical economists” and the “pastoral moralists”—this is where faculty psychology came in. Employing the tripartite scheme of conscience, self-interest, and passions, both of these groups nevertheless sought a moral order that was binary. In other words, they wanted to understand the world in terms of good and evil—of what kind of commercial behavior was permissible and what was not.The difference, unsurprisingly, was over what each group thought about self-interest, the faculty that occupied the middle position. For their part, the clerical economists lumped self-interest in with conscience as partners in the noble republican struggle to keep the passions of individuals in check. The two were not the same, but they were close enough to serve this same utilitarian purpose.The pastoral moralists, on the other hand, wanted to divide faculty psychology's tripartite scheme in half. In their collective understanding, self-interest could go in either direction. The pastoral moralists therefore sought the point at which an individual's healthy and natural self-interest crossed the line and, as one of them put it, passed “without heeding it, the boundary which separates virtue from vice.”