bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incorporation of a Genetic Factor into an Epidemiologic Model for Prediction of Individual Risk of Lung Cancer: The Liverpool Lung Project
Authors: Raji Olaide Y. , Agbaje Olorunsola F. , Duffy Stephen W. , Cassidy Adrian , Field John K. 
Published: April 2010

Abstract
The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into “low-risk” or “high-risk” group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk. Cancer Prev Res; 3(5); 664–9. ©2010 AACR.
Methylselenocysteine Resets the Rhythmic Expression of Circadian and Growth-Regulatory Genes Disrupted by Nitrosomethylurea In vivo
Authors: Fang Ming Zhu , Zhang Xun , Zarbl Helmut 
Published: April 2010

Abstract
Epidemiologic and animal studies indicate that disruption of circadian rhythm increases breast cancer risk. Previously, we showed that methylselenocysteine reduced the incidence of N-nitroso-N-methylurea (NMU)–induced mammary carcinomas in Fischer 344 rats by 63%. Methylselenocysteine also increased the expression of Period 2 (Per2) and D-binding protein (DBP), providing evidence for a link between circadian rhythm and chemoprevention. Here, we report that NMU disrupted the expression of core circadian genes (Per1, Per2, Cry1, Cry2, and RevErbAα) and circadian-controlled genes, including melatonin receptor 1α (MTNR1A), estrogen receptors (ERα and ERβ), and growth-regulatory genes (Trp53, p21, Gadd45α, and c-Myc) in mammary glands of Fischer 344 rats. By contrast, dietary methylselenocysteine (3 ppm selenium) given for 30 days, significantly enhanced the circadian expression of these genes (except for Cry1 and Cry2). The largest effect was on the levels of the Per2, MTNR1A, and ERβ mRNAs, which showed 16.5-fold, 4.7-fold, and 9.5-fold increases in their rhythm-adjusted means, respectively, and 44.5-fold, 6.5-fold, and 9.7-fold increases in amplitude as compared with the control diet, respectively. Methylselenocysteine also shifted the peak expression times of these genes to Zeitgeber time 12 (ZT12; lights off). Methylselenocysteine also induced rhythmic expression of Trp53, p21, and Gadd45α mRNAs with peak levels at ZT12, when c-Myc expression was at its lowest level. However, methylselenocysteine had no significant effect on the circadian expression of these genes in liver. These results suggest that dietary methylselenocysteine counteracted the disruptive effect of NMU on circadian expression of genes essential to normal mammary cell growth and differentiation. Cancer Prev Res; 3(5); 640–52. ©2010 AACR.
A Large Prospective Study of SEP15 Genetic Variation, Interaction with Plasma Selenium Levels, and Prostate Cancer Risk and Survival
Authors: Penney Kathryn L. , Schumacher Fredrick R. , Li Haojie , Kraft Peter , Morris J. Steven , Kurth Tobias , Mucci Lorelei A. , Hunter David J. , Kantoff Philip W. , Stampfer Meir J. , Ma Jing 
Published: April 2010

Abstract
The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency &gt;5%; R2 &gt; 0.8) within SEP15, as well as rs5859 in the 3′ untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (Pinteraction = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype. Cancer Prev Res; 3(5); 604–10. ©2010 AACR.
Social Isolation Reduces Mammary Development, Tumor Incidence, and Expression of Epigenetic Regulators in Wild-type and p53-Heterozygotic Mice
Authors: Hasen Nina S. , O'Leary Kathleen A. , Auger Anthony P. , Schuler Linda A. 
Published: April 2010

Abstract
Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that stress may contribute to social and ethnic disparities in the incidence and mortality of breast cancer. We evaluated the p53+/− FVB/N mouse as a model to investigate effects of chronic social stress on mammary gland development, gene expression, and tumorigenesis. We individually housed (IH) wild-type and p53+/− female FVB/N mice, starting at weaning. At 14 weeks of age, both wild-type and p53+/− IH mice showed strikingly reduced mammary development compared with group-housed (GH) controls, with IH mice having significantly fewer preterminal end buds. This morphologic difference was not reflected in levels of mammary transcripts for estrogen receptor-α or progestin receptor. However, IH increased levels of mRNA for the kisspeptin receptor in the medial preoptic area of the hypothalamus, associated with reduced duration of estrous cycles. Furthermore, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl-binding protein 2 and DNA methyltransferase 3b (DNMT3b), but not DNMT1 and DNMT3a, were reduced in IH compared with GH females. Interestingly, the glands of p53+/− females showed reduced expression of all these mediators compared with wild-type females. However, contrary to our initial hypothesis, IH did not increase mammary tumorigenesis. Rather, p53+/− GH females developed significantly more mammary tumors than IH mice. Together, these data suggest that social isolation initiated at puberty might confound studies of tumorigenesis by altering mammary development in mouse models. Cancer Prev Res; 3(5); 620–9. ©2010 AACR.
Premalignant Breast Neoplasia: A Paradigm of Interlesional and Intralesional Molecular Heterogeneity and Its Biological and Clinical Ramifications
Authors: Berman Hal K. , Gauthier Mona L. , Tlsty Thea D. 
Published: April 2010

Abstract
As is well established in invasive breast disease, it is becoming increasingly clear that molecular heterogeneity, both between and within lesions, is a prevalent, distinct phenotype of premalignant lesions of the breast. Key pathways of tumorigenesis modulate critical features of premalignant lesions such as proliferation, differentiation, stress response, and even the generation of diversity. Current studies show that evaluation of these lesions may provide clinically useful information on future tumor formation as well as biological insights into the origin and functional significance of this distinct phenotype. Cancer Prev Res; 3(5); 579–87. ©2010 AACR.
Long-Term Anabolic-Androgenic Steroid Use Is Associated With Left Ventricular Dysfunction
Authors: Baggish Aaron L. , Weiner Rory B. , Kanayama Gen , Hudson James I. , Picard Michael H. , Hutter Adolph M. , Pope Harrison G. 
Published: April 2010

Background—
Although illicit anabolic-androgenic steroid (AAS) use is widespread, the cardiac effects of long-term AAS use remain inadequately characterized. We compared cardiac parameters in weightlifters reporting long-term AAS use to those in otherwise similar weightlifters without prior AAS exposure.

Methods and Results—

We performed 2D tissue-Doppler and speckle-tracking echocardiography to assess left ventricular (LV) ejection fraction, LV systolic strain, and conventional indices of diastolic function in long-term AAS users (n=12) and otherwise similar AAS nonusers (n=7). AAS users (median [quartile 1, quartile 3] cumulative lifetime AAS exposure, 468 [169, 520] weeks) closely resembled nonusers in age, prior duration of weightlifting, and current intensity of weight training. LV structural parameters were similar between the two groups; however, AAS users had significantly lower LV ejection fraction (50.6% [48.4, 53.6] versus 59.1% [58.0%, 61.7%];
P
=0.003 by two-tailed Wilcoxon rank sum test), longitudinal strain (16.9% [14.0%, 19.0%] versus 21.0% [20.2%, 22.9%];
P
=0.004), and radial strain (38.3% [28.5%, 43.7%] versus 50.1% [44.3%, 61.8%];
P
=0.02). Ten of the 12 AAS users showed LV ejection fractions below the accepted limit of normal (≥55%). AAS users also demonstrated decreased diastolic function compared to nonusers as evidenced by a markedly lower early peak tissue velocity (7.4 [6.8, 7.9] cm/s versus 9.9 [8.3, 10.5] cm/s;
P
=0.005) and early-to-late diastolic filling ratio (0.93 [0.88, 1.39] versus 1.80 [1.48, 2.00];
P
=0.003).

Conclusions—
Cardiac dysfunction in long-term AAS users appears to be more severe than previously reported and may be sufficient to increase the risk of heart failure.
Global Administrative Law Dimensions of International Organizations Law
Authors: Kingsbury Benedict , Casini Lorenzo 
Published: April 2010

AbstractSeveral important legal features of the contemporary practice of international organizations (IOs) are not easily accommodated in standard approaches to international organizations law. This article argues that Global Administrative Law (GAL) approaches may strengthen analysis of operational issues such as emergency actions by IOs and the human rights implications of IO activities, structural issues such as the involvement of IOs in field missions and in public-private partnerships, and normative issues concerning the production and effects of non-treaty regulatory instruments by IOs (guidelines, best practices, national policy assessments, and other documents rather amorphously analyzed under the 'soft law' rubric). In examining these activities as forms of administration (broadly understood), subject to precepts of good administration and legal standards concerning transparency, participation, reason-giving, review, and accountability, a GAL perspective provides a basis both for critique of problematic practices, and for increasing the effectiveness and legitimacy of some beneficial IO activities which are contentious or currently not undertaken. GAL also responds to the proliferation and differentiation of IOs and other entities in global governance through applying legal standards to their interactions, bringing a principled 'inter-public' approach to the legal relations among global public entities. GAL provides a valuable, and thus far overly neglected, addition to the field of international institutional law.
The relationship between coronary slow flow phenomenon and coronary calcium score
Authors: Oz Ozgur , Bayram Nihal Akar , Durmaz Tahir , Keles Telat , Akcay Murat , Bozkurt Engin 
Published: April 2010

Aim: Coronary slow flow phenomenon (CSFP) is an angiographic finding characterized by delayed distal vessel opacification without any significant epicardial coronary artery disease. Several studies have suggested that CSFP might be a form of atherosclerosis. The present study was aimed to investigate the relationship between CSFP and coronary artery calcification, which is one of the clear-cut indicators of coronary atherosclerotic plaque, by using computerized tomography. Method: Fifty-five patients were included in the study. The coronary arteries of all patients were shown by angiography to be normal. Coronary slow flow (CSF) patterns were evaluated by the thrombolysis in myocardial infarction frame count (TFC) method. Patients with normal coronary arteries and CSF were allocated into the CSF group, and patients with normal coronary arteries and normal coronary flow were allocated into the control group. Coronary artery calcium (CAC) score was measured in 28 patients with CSF and in 27 controls by 64-slice computerized tomography. Results: The CSF and control groups were similar with respect to age, gender, smoking status, presence of hypertension and diabetes mellitus, cholesterol profiles, and Framingham risk scores (p>0.05). The CSF and control groups were not significantly different with respect to CAC score (p>0.05). Sub-group analysis of cardiac risk factors in patients with or without coronary artery calcification revealed that advanced age and low high density lipoprotein (HDL) levels were significantly associated with coronary artery calcification. There wasn’t any relationship between coronary slow flow and cardiac risk factors or coronary calcium scores. Conclusion: In the present study, no association was found between the CSFP and calcified atherosclerosis. Additionally, it was demonstrated that, among the cardiac risk factors, advanced age and low HDL levels were associated with coronary artery calcification.
The Potential of Human Allogeneic Juvenile Chondrocytes for Restoration of Articular Cartilage
Authors: Adkisson H. Davis , Martin James A. , Amendola Richard L. , Milliman Curt , Mauch Kelsey A. , Katwal Arbindra B. , Seyedin Mitchell , Amendola Annuziato , Streeter Philip R. , Buckwalter Joseph A. 
Published: April 2010

Background: Donor-site morbidity, limited numbers of cells, loss of phenotype during ex vivo expansion, and age-related decline in chondrogenic activity present critical obstacles to the use of autologous chondrocyte implantation for cartilage repair. Chondrocytes from juvenile cadaveric donors may represent an alternative to autologous cells. Hypothesis/Purpose: The authors hypothesized that juvenile chondrocyte would show stronger and more stable chondrogenic activity than adult cells in vitro and that juvenile cells pose little risk of immunologic incompatibility in adult hosts. Study Design: Controlled laboratory study. Methods: Cartilage samples were from juvenile (<13 years old) and adult (>13 years old) donors. The chondrogenic activity of freshly isolated human articular chondrocytes and of expanded cells after monolayer culture was measured by proteoglycan assay, gene expression analysis, and histology. Lymphocyte proliferation assays were used to assess immunogenic activity. Results: Proteoglycan content in neocartilage produced by juvenile chondrocytes was 100-fold higher than in neocartilage produced by adult cells. Collagen type II and type IX mRNA in fresh juvenile chondrocytes were 100- and 700-fold higher, respectively, than in adult chondrocytes. The distributions of collagens II and IX were similar in native juvenile cartilage and in neocartilage made by juvenile cells. Juvenile cells grew significantly faster in monolayer cultures than adult cells ( P = .002) and proteoglycan levels produced in agarose culture was significantly higher in juvenile cells than in adult cells after multiple passages ( P < .001). Juvenile chondrocytes did not stimulate lymphocyte proliferation. Conclusion: These results document a dramatic age-related decline in human chondrocyte chondrogenic potential and show that allogeneic juvenile chondrocytes do not stimulate an immunologic response in vivo. Clinical Relevance: Juvenile human chondrocytes have greater potential to restore articular cartilage than adult cells, and may be transplanted without the fear of rejection, suggesting a new allogeneic approach to restoring articular cartilage in older individuals.
Treatment of obesity with extension of sleep duration: a randomized, prospective, controlled trial
Authors: Cizza Giovanni , Marincola Paula , Mattingly Megan , Williams Lyda , Mitler Merrill , Skarulis Monica , Csako Gyorgy 
Published: April 2010

Background The prevalence of chronic sleep deprivation is increasing in modern societies with negative health consequences. Recently, an association between short sleep and obesity has been reported. Purpose Primary objectives: To assess the feasibility of increasing sleep duration to a healthy length (approximately 7½ h) and to determine the effect of sleep extension on body weight. Secondary objectives: To examine the long-term effects of sleep extension on endocrine (leptin and ghrelin) and immune (cytokines) parameters, the prevalence of metabolic syndrome, body composition, psychomotor vigilance, mood, and quality of life. Methods One hundred-fifty obese participants who usually sleep less than 6½ h, are being randomized at a 2:1 ratio to either an Intervention or to a Comparison Group. They are stratified by age (above and below 35) and the presence or absence of metabolic syndrome. During the first 12 months (Efficacy Phase) of the study, participants are evaluated at bi-monthly intervals: the Intervention Group is coached to increase sleep by at least 30—60 min/night, while the Comparison Group maintains baseline sleep duration. In the second (Effectiveness) phase, participants converge into the same group and are asked to increase (Comparison Group) or maintain (Intervention Group) sleep duration and are evaluated at 6-month intervals for an additional 3 years. Non-pharmacological and behavior-based interventions are being utilized to increase sleep duration. Endocrine, metabolic, and psychological effects are monitored. The sleep, energy expenditure, and caloric intake are assessed by activity monitors and food recall questionnaires. At yearly intervals, body composition, abdominal fat, and basal metabolic rate are measured by dual energy X-ray absorptiometry (DXA), computerized tomography (CT), and indirect calorimetry, respectively. Results As of January 2010, 109 participants had been randomized, 64 to the Intervention Group and 45 to the Comparison Group (76% women, 62% minorities, average age: 40.8 years; BMI: 38.5 kg/m2). Average sleep duration at screening was less than 6 h/night, 40.3 h/week. A total of 28 Intervention and 22 Comparison participants had completed the Efficacy Phase. Limitations The study is not blinded and the sample size is relatively small. Conclusions This proof-of-concept study on a randomized sample will assess whether sleep extension is feasible and whether it influences BMI. Clinical Trials 2010; 7: 274—285. http://ctj.sagepub.com
A general inefficacy interim monitoring rule for randomized clinical trials
Authors: Freidlin Boris , Korn Edward L , Gray Robert 
Published: April 2010

Background The ultimate goal of a phase III randomized clinical trial designed to demonstrate superiority of a new versus standard therapy is to provide sufficiently compelling evidence to affect clinical practice. To balance patient interests against the need for acquiring evidence it is desirable to stop a study for inefficacy as soon as convincing evidence that the new therapy is not beneficial becomes available. Purpose To discuss potential deficiencies in some commonly used inefficacy monitoring rules and to propose a comprehensive inefficacy monitoring procedure. Methods The proposed approach is developed using clinical, logistical, and statistical considerations. The new approach is compared to the commonly used inefficacy rules in a simulation study. Results Some of the commonly used inefficacy rules are suboptimal with respect to the strength of evidence required for stopping throughout the trial: too conservative in the middle and/or too aggressive at the end. Our approach allows timely stopping (a) if the new therapy is harmful, and (b) if the interim data provides convincing evidence that the new therapy has no tangible benefit. Relative to common inefficacy rules, our procedure is shown to result in potentially fewer treated patients and shorter study duration under the null hypothesis with only a minor loss of power under the alternative hypothesis. Limitations The proposed procedure is applicable to superiority designs with well-defined clinical objectives. Conclusions The proposed inefficacy approach is attractive from statistical, clinical, and logistical standpoints. By decreasing average stopping times relative to the commonly used boundaries, our rule lessens patient exposure to inactive treatments, improves resource utilization, and accelerates dissemination of important clinical information. At the same time, the proposed rule provides a clear benchmark for providing compelling evidence that the new therapy is not beneficial. Clinical Trials 2010; 7: 197—208. http://ctj.sagepub.com