bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinesis
Authors: MacCormick John , Murphy Nicholas , Ramasubramanian Venugopalan , Wieder Udi , Yang Junfeng , Zhou Lidong
Published: February 2009

Kinesis is a novel data placement model for distributed storage systems. It exemplifies three design principles:
structure
(division of servers into a few failure-isolated segments),
freedom of choice
(freedom to allocate the best servers to store and retrieve data based on current resource availability), and
scattered distribution
(independent, pseudo-random spread of replicas in the system). These design principles enable storage systems to achieve balanced utilization of storage and network resources in the presence of incremental system expansions, failures of single and shared components, and skewed distributions of data size and popularity. In turn, this ability leads to significantly reduced resource provisioning costs, good user-perceived response times, and fast, parallelized recovery from independent and correlated failures.

This article validates Kinesis through theoretical analysis, simulations, and experiments on a prototype implementation. Evaluations driven by real-world traces show that Kinesis can significantly outperform the widely used Chain replica-placement strategy in terms of resource requirements, end-to-end delay, and failure recovery.
Rethinking FTP
Authors: Anastasiadis Stergios V. , Wickremesinghe Rajiv G. , Chase Jeffrey S.
Published: February 2009

Whole-file transfer is a basic primitive for Internet content dissemination. Content servers are increasingly limited by disk arm movement, given the rapid growth in disk density, disk transfer rates, server network bandwidth, and content size. Individual file transfers are sequential, but the block access sequence on a content server is effectively random when many slow clients access large files concurrently. Although larger blocks can help improve disk throughput, buffering requirements increase linearly with block size.

This article explores a novel block reordering technique that can reduce server disk traffic significantly when large content files are shared. The idea is to transfer blocks to each client in any order that is convenient for the server. The server sends blocks to each client opportunistically in order to maximize the advantage from the disk reads it issues to serve other clients accessing the same file. We first illustrate the motivation and potential impact of aggressive block reordering using simple analytical models. Then we describe a file transfer system using a simple block reordering algorithm, called Circus. Experimental results with the Circus prototype show that it can improve server throughput by a factor of two or more in workloads with strong file access locality.
GRID codes
Authors: Li Mingqiang , Shu Jiwu , Zheng Weimin
Published: February 2009

As storage systems grow in size and complexity, they are increasingly confronted with concurrent disk failures together with multiple unrecoverable sector errors. To ensure high data reliability and availability, erasure codes with high fault tolerance are required. In this article, we present a new family of erasure codes with high fault tolerance, named GRID codes. They are called such because they are a family of
strip-based codes
whose strips are arranged into multi-dimensional grids. In the construction of GRID codes, we first introduce a concept of
matched codes
and then discuss how to use matched codes to construct GRID codes. In addition, we propose an iterative reconstruction algorithm for GRID codes. We also discuss some important features of GRID codes. Finally, we compare GRID codes with several categories of existing codes. Our comparisons show that for large-scale storage systems, our GRID codes have attractive advantages over many existing erasure codes: (a) They are completely XOR-based and have very regular structures, ensuring easy implementation; (b) they can provide up to 15 and even higher fault tolerance; and (c) their storage efficiency can reach up to 80% and even higher. All the advantages make GRID codes more suitable for large-scale storage systems.
Hill-climbing SMT processor resource distribution
Authors: Choi Seungryul , Yeung Donald
Published: February 2009

The key to high performance in Simultaneous MultiThreaded (SMT) processors lies in optimizing the distribution of shared resources to active threads. Existing resource distribution techniques optimize performance only indirectly. They infer potential performance bottlenecks by observing indicators, like instruction occupancy or cache miss counts, and take actions to try to alleviate them. While the corrective actions are designed to improve performance, their actual performance impact is not known since end performance is never monitored. Consequently, potential performance gains are lost whenever the corrective actions do not effectively address the actual bottlenecks occurring in the pipeline.

We propose a different approach to SMT resource distribution that optimizes end performance directly. Our approach observes the impact that resource distribution decisions have on performance at runtime, and feeds this information back to the resource distribution mechanisms to improve future decisions. By evaluating many different resource distributions, our approach tries to
learn
the best distribution over time. Because we perform learning online, learning time is crucial. We develop a
hill-climbing algorithm
that quickly learns the best distribution of resources by following the performance gradient within the resource distribution space. We also develop several ideal learning algorithms to enable deeper insights through limit studies.

This article conducts an in-depth investigation of hill-climbing SMT resource distribution using a comprehensive suite of 63 multiprogrammed workloads. Our results show hill-climbing outperforms ICOUNT, FLUSH, and DCRA (three existing SMT techniques) by 11.4%, 11.5%, and 2.8%, respectively, under the weighted IPC metric. A limit study conducted using our ideal learning algorithms shows our approach can potentially outperform the same techniques by 19.2%, 18.0%, and 7.6%, respectively, thus demonstrating additional room exists for further improvement. Using our ideal algorithms, we also identify three bottlenecks that limit online learning speed: local maxima, phased behavior, and interepoch jitter. We define metrics to quantify these learning bottlenecks, and characterize the extent to which they occur in our workloads. Finally, we conduct a sensitivity study, and investigate several extensions to improve our hill-climbing technique.
Proinflammatory Role of Vascular Endothelial Growth Factor in the Pathogenesis of Rheumatoid Arthritis: Prospects for Therapeutic Intervention
Authors: Yoo Seung-Ah , Kwok Seung-Ki , Kim Wan-Uk
Published: February 2009

Recent experimental and clinical studies have placed new emphasis on the role of angiogenesis in chronic inflammatory disease. Vascular endothelial growth factor (VEGF) and its receptors are the best characterized system in the regulation of rheumatoid arthritis (RA) by angiogenesis. Furthermore, in addition to its angiogenic role, VEGF can act as a direct proinflammatory mediator during the pathogenesis of RA, and protect rheumatoid synoviocytes from apoptosis, which contributes to synovial hyperplasia. Therefore, the developments of synovial inflammation, hyperplasia, and angiogenesis in the joints of RA patients seem to be regulated by a common cue, namely, VEGF. Agents that target VEGF, such as anti‐VEGF antibody and aptamer, have yielded promising clinical data in patients with cancer or macular degeneration, and in RA patients, pharmacologic modulations targeting VEGF or its receptor may offer new therapeutic approaches. In this review, the authors integrate current knowledge of VEGF signaling and information on VEGF antagonists gleaned experimentally and place emphasis on the use of synthetic anti‐VEGF hexapeptide to prevent VEGF interacting with its receptor.
The Order of Generalized Hypersubstitutions of Type τ = (2)
Authors: Puninagool Wattapong , Leeratanavalee Sorasak
Published: February 2009

The order of hypersubstitutions, all idempotent elements on the monoid of all hypersubstitutions of type
τ = (2) were studied by K. Denecke and Sh. L. Wismath and all idempotent elements on the monoid of all hypersubstitutions of type τ = (2, 2)
were studied by Th. Changpas and K. Denecke. We want to study similar problems for the monoid of all generalized hypersubstitutions
of type τ = (2). In this paper, we use similar methods to characterize idempotent generalized
hypersubstitutions of type τ = (2) and determine the order of each
generalized hypersubstitution of this type. The main result is
that the order is 1,2 or infinite.
A Comparison of the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands and the Australian/Canadian Osteoarthritis Hand Index in Hand Osteoarthritis Patients
Authors: Sautner Judith , Andel Ingrid , Rintelen Bernhard , Leeb Burkhard F.
Published: February 2009

Objectives. To compare the modified score for the assessment and quantification of chronic rheumatoid affections of the hands (M-SACRAH) with the Australian/Canadian osteoarthritis hand index (AUSCAN) in hand osteoarthritis (HOA). Both are self-administered patient questionnaires, being designed to assess functional status, stiffness, and pain in affected patients, despite some differences in format, compass and arrangement of questions.Methods. 66 HOA patients (51 females), attending the outpatient clinic, were included. Patients completed the AUSCAN (15 visual analogue scales) (VAS) and the M-SACRAH (12 VAS).Results. AUSCAN-pain amounted to a mean of 41.9 (±2.9 SEM), AUSCAN-stiffness to 53.1 (3.7) and AUSCAN function to 42.6 (3.2). M-SACRAH-function amounted to 25.4 (2.4), M-SACRAH-stiffness to 42.6 (3.0), and M-SACRAH-pain to 43.7 (3.1). The total mean M-SACRAH was 37.2 (2.4) (all ). The three respective domains of the two scores correlated significantly: pain: , stiffness: , and function: (all ). The four identical items in both scores also correlated significantly. No significant gender specific differences were observed.Conclusion. Despite a different scope of items, a significant high correlation of these two scores evaluating HOA patients could be demonstrated. We conclude that both scores are equivalently valuable for the assessment of health status in these patients.
High Clusterin Expression Correlates with a Poor Outcome in Stage II Colorectal Cancers
Authors: Kevans David , Foley Jane , Tenniswood Martin , Sheahan Kieran , Hyland John , O'Donoghue Diarmuid , Mulcahy Hugh , O'Sullivan Jacintha
Published: February 2009

The role of clusterin in tumor growth and progression remains unclear. Overexpression of cytoplasmic clusterin has been studied in aggressive colon tumors; however, no correlation between clusterin expression and survival in colorectal cancer has been identified to date. We assessed levels of clusterin expression in a group of stage II colorectal cancer patients to assess its utility as a prognostic marker. The study included 251 patients with stage II colorectal cancer. Tissue microarrays were constructed and immunohistochemistry done and correlated with clinical features and long term outcome. Dual immunofluorescence and confocal microscopy were used with terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling probes and clusterin antibody to assess the degree of co localization. Percentage epithelial cytoplasmic staining was higher in tumor compared with nonadjacent normal mucosa (P < 0.001). Within the stromal compartment, percentage cytoplamic staining and intensity was lower in tumor tissue compared with normal nonadjacent mucosa (P ≤ 0.001). Survival was significantly associated with percentage epithelial cytoplasmic staining (P < 0.001), epithelial cytoplasmic staining intensity (P < 0.001), percentage stromal cytoplasmic staining (P = 0.002), and stromal cytoplasmic staining intensity (P < 0.001). Clusterin levels are associated with poor survival in stage II colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):393–9)
Race/Ethnicity, Physical Activity, and Quality of Life in Breast Cancer Survivors
Authors: Smith Ashley Wilder , Alfano Catherine M. , Reeve Bryce B. , Irwin Melinda L. , Bernstein Leslie , Baumgartner Kathy , Bowen Deborah , McTiernan Anne , Ballard-Barbash Rachel
Published: February 2009

Purpose: To examine associations between recreational physical activity and quality of life (QOL) in a multiethnic cohort of breast cancer survivors, specifically testing whether associations are consistent across racial/ethnic groups after accounting for relevant medical and demographic factors that might explain disparities in QOL outcomes.

Methods: Data were collected from a population-based cohort of non-Hispanic White (n = 448), Black (n = 197), and Hispanic (n = 84) breast cancer survivors (stage 0-IIIa) in the Health, Eating, Activity, and Lifestyle Study. Physical activity was assessed ∼2.5 years after breast cancer diagnosis, with QOL assessed on average 6 to 12 months later. We used structural equation modeling to examine relationships between meeting recommended levels of physical activity and QOL, stratifying by race/ethnicity and adjusting for other demographic, comorbidity, and treatment effects.

Results: Structural equation modeling indicated that meeting recommended levels of physical activity had significant positive associations with QOL for Black and non-Hispanic White women (P < 0.05). Fewer Black women reported meeting recommended physical activity levels (P < 0.001), but meeting recommendations was associated with better QOL. Post hoc tests showed that meeting physical activity recommendations was specifically associated with better vitality, social functioning, emotional roles, and global QOL (P < 0.05 for all).

Conclusions: These results suggest that meeting recommended levels of physical activity is associated with better QOL in non-Hispanic White and Black breast cancer survivors. Findings may help support future interventions among breast cancer survivors and promote supportive care that includes physical activity, although more research is needed to determine these relationships among Hispanic and other ethnic minority women. (Cancer Epidemiol Biomarkers Prev 2009;18(2):656–63)
Smokers of Menthol and Nonmenthol Cigarettes Exhibit Similar Levels of Biomarkers of Smoke Exposure
Authors: Heck J. Daniel
Published: February 2009

There has been speculation that the addition of menthol to cigarettes may affect the manner in which cigarettes are smoked, potentially influencing smokers' exposures to smoke constituents that have been associated with smoking-related diseases. One hundred twelve male and female smokers participated in a parallel-arm study to determine whether the ad libitum smoking of menthol cigarettes results in differences in smoke constituent exposure biomarkers in blood and urine relative to those smoking nonmenthol cigarettes having similar machine-measured (Federal Trade Commission) yields of ∼9 to 10 mg “tar.” The study subjects were provided cigarettes of their preferred menthol or nonmenthol types prior to two 24-hour study intervals spaced one week apart. Carboxyhemoglobin levels were measured in blood samples drawn at midafternoon following the two 24-hour urine collection periods. Six urinary nicotine metabolites (nicotine, cotinine, trans-3′-hydroxycotinine and respective glucuronides) were determined as measures of nicotine intake, and urinary 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide were determined to assess exposure to the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridinyl)-1-butanone. Subjects' median blood carboxyhemoglobin values did not differ significantly between the cigarette types. Neither total urinary NNAL nor urinary nicotine equivalents exhibited statistically significant differences between the menthol and nonmenthol cigarette smokers. The present findings indicate that moderately heavy smokers of menthol and nonmenthol cigarettes of similar machine-generated smoke yield exhibit essentially identical levels of biomarkers of smoke constituent exposure. These results are consistent with the substantial majority of epidemiology studies to date that suggest the risks attending the smoking of menthol and nonmenthol cigarettes are similar. (Cancer Epidemiol Biomarkers Prev 2009;18(2):622–9)
Physical Activity among Lung Cancer Survivors: Changes across the Cancer Trajectory and Associations with Quality of Life
Authors: Coups Elliot J. , Park Bernard J. , Feinstein Marc B. , Steingart Richard M. , Egleston Brian L. , Wilson Donna J. , Ostroff Jamie S.
Published: February 2009

Background: Regular physical activity may offer benefits to lung cancer survivors, many of whom experience quality-of-life (QOL) impairments. However, little is know about lung cancer survivors' engagement in physical activity across the cancer trajectory. The current study addressed this research gap and also examined the association between lung cancer survivors' physical activity and their QOL.

Methods: The study participants were 175 individuals who completed surgical treatment for early-stage non-small cell lung cancer 1 to 6 years previously. Participants completed a one-time survey regarding their current QOL and their engagement in physical activities currently, during the 6 months after treatment, and during the 6 months before diagnosis.

Results: Participants' reported engagement in both moderate and strenuous intensity activities was lower during the post-treatment period compared with before diagnosis and at the current time. Engagement in light intensity activities did not differ for the three time points. Almost two-thirds of participants did not engage in sufficient activity to meet national physical activity guidelines for any of the three time points. Lung cancer survivors who currently met physical activity guidelines reported better QOL in multiple domains than less active individuals.

Conclusions: Engagement in physical activity among lung cancer survivors is particularly low during the early post-treatment period. Current engagement in physical activity is associated with better QOL. However, most lung cancer survivors do not meet physical activity guidelines and may benefit from interventions to promote engagement in regular physical activities. (Cancer Epidemiol Biomarkers Prev 2009;18(2):664–72)
Incident Invasive Breast Cancer, Geographic Location of Residence, and Reported Average Time Spent Outside
Authors: Millen Amy E. , Pettinger Mary , Freudenheim Jo L. , Langer Robert D. , Rosenberg Carol A. , Mossavar-Rahmani Yasmin , Duffy Christine M. , Lane Dorothy S. , McTiernan Anne , Kuller Lewis H. , Lopez Ana Maria , Wactawski-Wende Jean
Published: February 2009

There have been reports of greater breast cancer incidence and mortality at northern compared with southern latitudes postulated to be related to vitamin D exposure. Among 71,662 participants in the Women's Health Initiative Observational Study (WHIOS) free of cancer at baseline (1993-1998), associations were explored between incident invasive postmenopausal breast cancer (n = 2,535), over ∼8.6 years follow-up, and the following: (a) region of residence at birth, age 15 years, age 35 years; (b) region of residence at WHIOS baseline; and (c) clinic center solar irradiance. Hazard ratios and 95% confidence intervals (CI) for breast cancer were estimated after adjustment for individual level confounders. There was no difference in breast cancer risk by region of earlier life, baseline residence, or solar irradiance measured in Langelys (gm-cal) per cm2. There was an observed 15% decreased risk among women residing in areas of low versus high solar irradiance measured in Watts per m2 (95% CI, 2-26%). However, the associated Ptrend of 0.20 was not significant. Conversely, women who reported spending on average <30 minutes versus >2 hours outside in daylight year round at WHIOS year 4 follow-up (n = 46,926), had a 20% (95% CI, 2-41%; Ptrend = 0.001) increased risk of breast cancer. In conclusion, region of residence and geographic solar irradiance are not consistently related to risk of breast cancer and may not be sufficient proxy measures for sunlight/vitamin D exposure. The observed association between time spent outside and breast cancer risk support the hypothesis that vitamin D may protect against breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):495–507)
Influence of Primary Care Use on Population Delivery of Colorectal Cancer Screening
Authors: Fenton Joshua J. , Reid Robert J. , Baldwin Laura-Mae , Elmore Joann G. , Buist Diana S.M. , Franks Peter
Published: February 2009

Objective: Colorectal cancer (CRC) screening is commonly initiated during primary care visits. Thus, at the population level, limited primary care attendance may constitute a substantial barrier to CRC screening uptake. Within a defined population, we quantified the percent of CRC screening underuse that is potentially explained by low use of primary care visits.

Methods: Among 48,712 adults ages 50 to 78 years eligible for CRC screening within a Washington state health plan, we estimated the degree to which a lack of CRC screening in 2002 to 2003 (fecal occult blood testing, sigmoidoscopy, or colonoscopy) was attributable to low primary care use, expressed as the population attributable risk percent (PAR%) associated with 0 to 3 primary care visits during the 2-year period.

Results: In analyses adjusted for age, comorbidity, nonprimary care visit use, and prior preventive service use, low primary care use in 2002 to 2003 was strongly associated with a lack of CRC screening among both women and men. However, a majority of unscreened women and men had ≥4 primary care visits. Thus, whether low primary care use was defined as 0, 0 to 1, 0 to 2, or 0 to 3 primary care visits, the PAR% associated with low primary care use was large in neither women (range, 3.0-6.8%) nor men (range: 5.6-11.5%).

Conclusions: Health plan outreach efforts to encourage primary care attendance would be unlikely to substantially increase population uptake of CRC screening. In similar settings, resources might be more fruitfully devoted to the optimization of screening delivery during primary care visits that patients already attend. (Cancer Epidemiol Biomarkers Prev 2009;18(2):640–5)
Is There a Difference in the Association between Percent Mammographic Density and Subtypes of Breast Cancer? Luminal A and Triple-Negative Breast Cancer
Authors: Ma Huiyan , Luo Jianning , Press Michael F. , Wang Yaping , Bernstein Leslie , Ursin Giske
Published: February 2009

Background: Mammographic density is a potentially modifiable risk factor for breast cancer. To what extent mammographic density is a predictor for both hormone receptor-positive and hormone receptor-negative tumors is unclear. Even less is known about whether mammographic density predicts subtypes of breast cancer defined by expression status of the three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2).

Methods: We estimated the association of percent mammographic density with subtypes of invasive breast cancer among 479 population-based female breast cancer patients and 376 control subjects ages 35 to 64 years. The expression status of ER, PR, and HER-2 was assessed using immunohistochemistry methods in a single laboratory. We considered ER+ or PR+ plus HER-2- tumors as luminal A breast cancer and ER-/PR-/HER-2- tumors as triple-negative breast cancer. We used unconditional logistic regression methods to estimate odd ratios (95% confidence intervals) for both case-control and case-case comparisons.

Results: Mammographic density was associated with increased risk of both invasive breast cancer subtypes, luminal A and triple-negative, in the case-control analysis. Results from case-case comparisons yielded no differences between the two subtypes among all women combined or in analyses done separately by race (White versus African American women) or menopausal status (premenopausal versus postmenopausal women; all P values > 0.05).

Conclusions: Our results suggest that percent mammographic density is positively associated with both luminal A and triple-negative breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):479–85)
Physical Activity and Endogenous Sex Hormone Levels in Postmenopausal Women: a Cross-Sectional Study in the Prospect-EPIC Cohort
Authors: van Gils Carla H. , Peeters Petra H.M. , Schoenmakers Micha C.J. , Nijmeijer Rian M. , Onland-Moret N. Charlotte , van der Schouw Yvonne T. , Monninkhof Evelyn M.
Published: February 2009

Background: The protective effect of physical activity on breast cancer risk might be mediated by sex hormone levels. In this study, we examined the association between usual physical activity and plasma levels of estrogens, androgens, dehydroepiandrosterone sulphate (DHEAS), and sex hormone binding globulin (SHBG) in postmenopausal women.

Methods: We conducted a cross-sectional study among 806 postmenopausal women participating in the Prospect-EPIC study. Usual physical activity was assessed using a short questionnaire and summarized into a simple, validated four-level index. This index combines occupational physical activity with time spent on cycling and sporting. Levels of estrone, estradiol, androstenedione, DHEAS, testosterone, and SHBG were measured in plasma. General linear models were used to examine the association between usual physical activity and sex hormone levels, adjusted for confounders.

Results: We observed an inverse association between physical activity and estradiol levels (free: inactive, 0.26 pg/mL; active, 0.23 pg/mL; P-trend = 0.045; total: inactive, 8.8 pg/mL; active, 8.0 pg/mL; P-trend = 0.08) and a positive association between physical activity and SHBG (inactive, 15.1 nmol/L; active, 19.3 nmol/L; P-trend = 0.05). These associations could largely be explained by the effects of sporting. We also observed a positive association between physical activity and DHEAS (inactive, 352.4 ng/mL; active, 460.3 ng/mL; P-trend = 0.01).

Conclusions: Our results are in accordance with the hypothesis that usual physical activity decreases estradiol levels and increases SHBG. We also found that high levels of physical activity are associated with high levels of DHEAS. Furthermore, our results suggest that vigorous forms of physical activity influence sex hormone levels most. (Cancer Epidemiol Biomarkers Prev 2009;18(2):377–83)
In vivoRole of CytochromeP450 2E1 and Glutathione-S-Transferase Activity for Acrylamide Toxicokinetics in Humans
Authors: Doroshyenko Oxana , Fuhr Uwe , Kunz Daria , Frank Dorothee , Kinzig Martina , Jetter Alexander , Reith Yvonne , Lazar Andreas , Taubert Dirk , Kirchheiner Julia , Baum Matthias , Eisenbrand Gerhard , Berger Franz-Ingo , Bertow Daniel , Berkessel Albrecht , Sörgel Fritz , Schömig Edgar , Tomalik-Scharte Dorota
Published: February 2009

Acrylamide, a potential food carcinogen in humans, is biotransformed to the epoxide glycidamide in vivo. Both acrylamide and glycidamide are conjugated with glutathione, possibly via glutathione-S-transferases (GST), and bind covalently to proteins and nucleic acids. We investigated acrylamide toxicokinetics in 16 healthy volunteers in a four-period change-over trial and evaluated the respective role of cytochrome P450 2E1 (CYP2E1) and GSTs. Participants ingested self-prepared potato chips containing acrylamide (1 mg) without comedication, after CYP2E1 inhibition (500 mg disulfiram, single dose) or induction (48 g/d ethanol for 1 week), and were phenotyped for CYP2E1 with chlorzoxazone (250 mg, single dose). Unchanged acrylamide and the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) accounted for urinary excretion [geometric mean (percent coefficient of variation)] of 2.9% (42), 65% (23), and 1.7% (65) of the acrylamide dose in the reference period. Hemoglobin adducts increased clearly following the acrylamide test-meal. The cumulative amounts of acrylamide, AAMA, and GAMA excreted and increases in AA adducts changed significantly during CYP2E1 blockade [point estimate (90% confidence interval)] to the 1.34-fold (1.14-1.58), 1.18-fold (1.02-1.36), 0.44-fold (0.31-0.61), and 1.08-fold (1.02-1.15) of the reference period, respectively, but were not changed significantly during moderate CYP2E1 induction. Individual baseline CYP2E1 activity, CYP2E1*6, GSTP1 313A>G and 341T>C single nucleotide polymorphisms, and GSTM1-and GSTT1-null genotypes had no major effect on acrylamide disposition. The changes in acrylamide toxicokinetics upon CYP2E1 blockade provide evidence that CYP2E1 is a major but not the only enzyme mediating acrylamide epoxidation in vivo to glycidamide in humans. No obvious genetic risks or protective factors in xenobiotic-metabolizing enzymes could be determined for exposed subjects. (Cancer Epidemiol Biomarkers Prev 2009;18(2):433–43)
Thyroid Function and Cancer Risk: A Prospective Population Study
Authors: Hellevik Alf Inge , Åsvold Bjørn Olav , Bjøro Trine , Romundstad Pål R. , Nilsen Tom Ivar L. , Vatten Lars J.
Published: February 2009

Background: It has been hypothesized that thyroid function may influence cancer risk, but few studies with adequate statistical power have investigated this question, and the results have not been consistent.

Methods: In a prospective study of 29,691 people (19,710 women and 9,981 men) without previously known thyroid disease, thyrotropin was measured at baseline, and cancer incidence was recorded during 9 years of follow-up. Using Cox regression analysis, we studied the associations (hazard ratios) of thyrotropin categories with total cancer risk, and specifically, with risk of lung, colon, prostate, and breast cancer adjusted for age, sex, and smoking status.

Results: Low thyrotropin levels (<0.50 mU/L) were associated with increased cancer risk [adjusted hazard ratio (HR), 1.34; 95% confidence interval (CI), 1.06-1.69] compared with the euthyroid reference group. The higher risk was driven by lung cancer (adjusted HR, 2.34; 95% CI, 1.24-4.40) and prostate cancer (adjusted HR, 1.97; 95% CI, 1.04-3.76). After excluding the first 2 years of follow-up, the associations were strengthened to 2.91 (1.49-5.70) for lung cancer and 2.60 (1.36-4.99) for prostate cancer.

Conclusion: Thyrotropin levels suggestive of hyperthyroid function are associated with increased cancer risk, and specifically, with increased risk of lung and prostate cancer, whereas hypothyroid function does not seem to be associated with cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(2):570–4)
A Prospective Study of Total and Ionized Serum Calcium and Fatal Prostate Cancer
Authors: Skinner Halcyon G. , Schwartz Gary G.
Published: February 2009

We recently reported a significant positive association in the National Health and Nutrition Examination Survey between high levels of total calcium in serum, measured prospectively, and risk of fatal prostate cancer. To confirm this, we examined associations between total and ionized serum calcium and prostate cancer mortality in an independent cohort, the Third National Health and Nutrition Examination Survey. Twenty-five prostate cancer deaths occurred over 56,625 person-years of follow-up. Compared with men in the lowest tertile of total serum calcium, the multivariate-adjusted relative risk for death from prostate cancer for men in the highest tertile was 2.07 (95% confidence interval, 1.06-4.04). For ionized serum calcium, the physiologically active fraction of total serum calcium, the relative risk for men in the highest tertile was 3.18 (95% confidence interval, 1.09-9.28). These findings support the hypothesis that serum calcium is a prospective biomarker of fatal prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):575–8)
Immunosuppression and Other Risk Factors for Lip Cancer after Kidney Transplantation
Authors: van Leeuwen Marina T. , Grulich Andrew E. , McDonald Stephen P. , McCredie Margaret R.E. , Amin Janaki , Stewart John H. , Webster Angela C. , Chapman Jeremy R. , Vajdic Claire M.
Published: February 2009

Incidence of lip cancer is markedly increased after kidney transplantation. Immunosuppression and other risk factors for lip cancer were investigated in a population-based, nationwide cohort of 8,162 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry (1982-2003). Lip cancer diagnoses were ascertained using probabilistic data linkage with the Australian National Cancer Statistics Clearing House. Standardized incidence ratios were used to compare lip cancer risk by subsite of lip and during periods of transplant function and failure. Risk factors during the first functioning transplant were examined using multivariate Poisson regression. Lip cancer was diagnosed in 203 patients. All cases were of squamous cell origin and mostly (77%) affected the lower vermillion. Cases occurred predominantly during periods of transplant function, with incidence decreasing to pretransplantation level on transplant failure and cessation of immunosuppression. During transplant function, cancer of the lower vermillion was associated with increasing year of age [incidence rate ratio (IRR), 1.03; 95% confidence interval (95% CI), 1.02-1.05], greater time since transplantation (P < 0.001), smoking (IRR, 2.13; 95% CI, 1.12-4.07), and current use of azathioprine (IRR, 2.67; 95% CI, 1.39-5.15) or cyclosporine (IRR, 1.63; 95% CI, 1.00-2.65). Female sex (IRR, 0.29; 95% CI, 0.18-0.46) and non-Australian/New Zealand country of birth (P = 0.006), surrogate indices of reduced exposure to solar UV radiation, were significantly protective. Lip cancer after transplantation is strongly related to the current receipt of immunosuppression. During transplant function, lip cancer risk is associated with the duration of immunosuppression, receipt of specific immunosuppressive agents, and UV exposure. (Cancer Epidemiol Biomarkers Prev 2009;18(2):561–9)
Use of Molecular Testing to Identify a Cluster of Patients with Polycythemia Vera in Eastern Pennsylvania
Authors: Seaman Vincent , Jumaan Aisha , Yanni Emad , Lewis Brian , Neyer Jonathan , Roda Paul , Xu Mingjiang , Hoffman Ronald
Published: February 2009

Background: The role of the environment in the origin of polycythemia vera has not been well documented. Recently, molecular diagnostic tools have been developed to facilitate the diagnosis of polycythemia vera. A cluster of patients with polycythemia vera was suspected in three countries in eastern Pennsylvania where there have long been a concern about environment hazards.

Methods: Rigorous clinical criteria and JAK2 617V>F testing were used to confirm the diagnosis of polycythemia vera in patients in this area. Participants included cases of polycythemia vera from the 2001 to 2005 state cancer registry as well as self- and physician-referred cases.

Finding: A diagnosis of polycythemia vera was confirmed in 53% of 62 participants using WHO criteria, which includes JAK2 617V>F testing. A statistically significant cluster of cases (P < 0.001) was identified where the incidence of polycythemia vera was 4.3 times that of the rest of the study area. The area of the cluster contained numerous sources of hazardous material including waste-coal power plants and U.S. Environmental Protection Agency Superfund sites.

Interpretation: The diagnosis of polycythemia vera based solely on clinical criteria is frequently erroneous, suggesting that our prior knowledge of the epidemiology of this disease might be inaccurate. The JAK2 617V>F mutational analysis provides diagnostic clarity and permitted the confirmation of a cluster of polycythemia vera cases not identified by traditional clinical and pathologic diagnostic criteria. The close proximity of this cluster to known areas of hazardous material exposure raises concern that such environmental factors might play a role in the origin of polycythemia vera. (Cancer Epidemiol Biomarkers Prev 2009;18(2):534–40)
Prospective Evaluation of Hepatitis B 1762T/1764A Mutations on Hepatocellular Carcinoma Development in Shanghai, China
Authors: Yuan Jian-Min , Ambinder Alex , Fan Yunhua , Gao Yu-Tang , Yu Mimi C. , Groopman John D.
Published: February 2009

Chronic infection with the hepatitis B virus (HBV) is the most important risk factor for hepatocellular carcinoma (HCC). However, determinants of HCC risk in infected individuals are not well understood. We prospectively evaluated the association between acquired HBV 1762T/1764A double mutations and HCC risk among 49 incident HCC cases and 97 controls with seropositive hepatitis B surface antigen at baseline from a cohort of 18,244 men in Shanghai, China, enrolled during 1986 to 1989. Compared with HBV carriers without the mutations, chronic HBV carriers with the HBV 1762T/1764A double mutations experienced an elevated risk of HCC (odds ratio, 2.47; 95% confidence interval, 1.04-5.85; P = 0.04). Risk increased with increasing copies of the double mutations; men with ≥500 copies/μL serum had an odds ratio of 14.57 (95% confidence interval, 2.41-87.98) relative to those without the double mutations (Ptrend = 0.004). Thus, the HBV 1762T/1764A double mutation is a codeterminant of HCC risk for people chronically infected with HBV. (Cancer Epidemiol Biomarkers Prev 2009;18(2):590–4)
Antidepressant Medications and Change in Mammographic Density in Postmenopausal Women
Authors: Chubak Jessica , Bowles Erin J.A. , Terry Mary Beth , Trentham-Dietz Amy , Buist Diana S.M.
Published: February 2009

Background: Several studies suggest antidepressant medications can increase prolactin levels. Some, but not all, studies suggest prolactin levels are positively associated with mammographic breast density, an established risk factor for breast cancer.

Methods: We evaluated 29,284 women with two routine screening mammograms 9 to 28 months apart between 1996 to 2006 to examine whether antidepressant use was associated with changes in mammographic breast density. Mammographic breast density was assigned by radiologists and coded according the Breast Imaging Reporting and Data System classification. Exposure to antidepressants was ascertained based on electronic pharmacy dispensing data, including dispensings from claims data. We used polytomous logistic regression to estimate the odds of an increase or decrease in density categories between mammograms associated with antidepressant initiation, continuation, and discontinuation compared with nonusers of any antidepressants.

Results: Initiation, continuation, and discontinuation of antidepressant medications were not associated with changes in mammographic density.

Conclusions: The lack of association between antidepressant use and breast density is consistent with recent studies that do not suggest an association between antidepressant use and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(2):676–9)
Risk Factors for Pancreatic Cancer Mortality: Extended Follow-up of the Original Whitehall Study
Authors: Batty G. David , Kivimaki Mika , Morrison David , Huxley Rachel , Smith George Davey , Clarke Robert , Marmot Michael G. , Shipley Martin J.
Published: February 2009

Given the well-established links between diabetes and elevated rates of pancreatic cancer, there are reasons to anticipate that other markers of metabolic abnormality (increased body mass index, plasma cholesterol, and blood pressure) and their correlates (physical activity and socioeconomic status) may also confer increased risk. However, to date, the results of a series of population-based cohort studies are inconclusive. We examined these associations in the original Whitehall cohort study of 17,898 men. A maximum of 38 years of follow-up gave rise to 163 deaths due to carcinoma of the pancreas. Although Poisson regression analyses confirmed established risk factor–disease associations for increasing age, smoking, and type II diabetes, there was essentially no evidence that body mass index (rate ratio, 1.01; 95% confidence interval per 1 SD increase, 0.86-1.18), plasma cholesterol (0.91; 0.78-1.07), diastolic blood pressure (0.93; 0.78-1.09), systolic blood pressure (0.98; 0.83-1.15), physical activity (sedentary versus high: 1.37; 0.89-2.12), or socioeconomic status [clerical (low) versus professional/executive, 0.95; 0.59-1.51] offered any predictive value for pancreatic cancer mortality. These results were unchanged following control for a range of covariates. (Cancer Epidemiol Biomarkers Prev 2009;18(2):673–5)
Will a once-weekly anticoagulant for the treatment and secondary prevention of thromboembolism improve adherence?
Authors: Maillardet Louise , Yavin Yshai , Cohen Alexander T.
Published: February 2009

Oral anticoagulation, most commonly with warfarin once daily, has long been the main form of long-term treatment and secondary prevention of thromboembolism. The efficacy of warfarin has been established in clinical trials, but problems with unstable anticoagulation with international normalized ratios (INRs) outside the recommended range due to incorrect dosing, drug and food interactions, and with adherence and persistence have been reported in practice. Poor adherence and persistence are serious problems because they result in out-of-range INRs. Many new thromboembolic events, such as strokes, occur when INRs are out-of-range or after warfarin discontinuation. Among the new anticoagulants currently being investigated, some offer the possibility of more stable anticoagulation and weekly administration. Less frequent dosing schedules generally improve adherence. In many cases, such as bisphosphonate treatment for osteoporosis, and the long-term treatment of depressive disorders or multiple sclerosis, adherence to, and persistence with, weekly dosing is improved compared with daily dosing, and most patients prefer weekly dosing. The advent of novel anticoagulants such as idraparinux with its long half-life offers hope for improved adherence with anticoagulation, and ultimately improved outcomes.
Contribution of (sub)domains of Staphylococcus aureus fibronectin-binding protein to the proinflammatory and procoagulant response of human vascular endothelial cells
Authors: Heying Ruth , Gevel Joke van de , Que Yok-Ai , Piroth Lionel , Moreillon Philippe , Beekhuizen Henry
Published: February 2009

The Staphylococcus aureus fibronectin (Fn) -binding protein A (FnBPA) is involved in bacterium-endothelium interactions which is one of the crucial events leading to infective endocarditis (IE). We previously showed that the sole expression of S. aureus FnBPA was sufficient to confer to non-invasive Lactococcus lactis bacteria the capacity to invade human endothelial cells (ECs) and to launch the typical endothelial proinflammatory and procoagulant responses that characterize IE. In the present study we further questioned whether these bacterium-EC interactions could be reproduced by single or combined FnBPA subdomains (A, B, C or D) using a large library of truncated FnBPA constructs expressed in L. lactis. Significant invasion of cultured ECs was found for L. lactis expressing the FnBPA subdomains CD (aa 604–877) or A4+16 (aa 432–559). Moreover, this correlates with the capacity of these fragments to elicit in vitro a marked increase in EC surface expression of both ICAM-1 and VCAM-1 and secretion of the CXCL8 chemokine and finally to induce a tissue factor-dependent endothelial coagulation response. We thus conclude that (sub)domains of the staphylococcal FnBPA molecule that express Fn-binding modules, alone or in combination, are sufficient to evoke an endothelial proinflammatory as well as a procoagulant response and thus account for IE severity.
Assessment of coagulation and fibrinolysis in families with unexplained thrombophilia
Authors: Tanck Michael W. T. , Meijers Joost C. M. , Lisman Ton , Reitsma Pieter H. , Rosendaal Frits R. , Büller Harry R. , Middeldorp Saskia , Wichers Iris M.
Published: February 2009

Despite knowledge of various inherited risk factors associated with venous thromboembolism (VTE), no definite cause can be found in about 50% of patients. The lack of an intermediate phenotype in VTE impedes the discovery of new familial risk factors. We set out to define an intermediate phenotype for VTE by performing global coagulation analyses in unexplained thrombophilic families. Families were selected through a proband with VTE but without one of the known thrombophilic defects and at least one 1st or two 2nd degree family members with VTE. Clinical data were collected using a standardized questionnaire. Blood samples were collected for overall haemostasis assays (i.e. thrombin generation time [TGT], endogenous thrombin potential [ETP], prothrombin fragment 1+2 [F1+2] and activated protein C-sensitivity ratio [APC-sr] and clot lysis time [CLT]). Data were analysed using logistic regression. Coagulation assays were performed in 353 individuals of whom 41 (12%) had a history of VTE; these belonged to 17 thrombophilic families. Of the tested variables only the ETP was associated with VTE (odds ratio [OR] 1.03 for each % increase, 95% confidence interval [CI] 1.01–1.05). However, the relatively low number of cases does not firmly exclude the other assays as candidate intermediate phenotypes for venous thrombosis. We found that an increased ETP may serve as an intermediate phenotype for VTE and may be used to discover novel inherited risk factors by genetic linkage analysis.
Diluted Russell viper-venom time improves identification of antiphospholipid syndrome in a lupus anticoagulant-positive patient population
Authors: Ferrard-Sasson Gisele , Dubucquoi Sylvain , Hachulla Eric , Prin Lionel , Hatron Pierre-Yves , Goudemand Jenny , Boffa Marie-Claire , Caron Claudine , Lambert Marc
Published: February 2009

The objective of this retrospective study was to evaluate the potential ability of diluted Russell viper-venom time (dRVVT) to identify antiphospholipid syndrome (APS) in a lupus anticoagulant (LA)-positive patient population, already selected by other LA clotting tests. Our cohort of positive LA patients was first identified in our outpatients population by the following sensitive LA-detecting tests: Rosner index, diluted prothrombin time (dPT) and Rosove index. Then the 227 consecutive LA-positive patients were tested for dRVVT with the same blood sample. Anticardiolipin (aCL) and anti-β2-glycoprotein-I (β2GPI) autoantibodies assays were also performed. APS using Sapporo clinical criteria revised at Sydney, was found in 116 of these 227 consecutive LA-positive patients. Results of the different tests were analysed statistically. Using univariate analysis, dRVVT, dPT, IgG aCL and IgG anti-β2GPI autoantibodies were significantly associated with APS. The receiver operating-characteristics (ROC) curve defined the best cut-off value for dRVVT ratio at 1.61 with a good specificity (78%) and a lower sensitivity (53%). A multivariate analysis using a binary logistic procedure, retained the dRVVT ratio (≥ 1.61) and IgG anti-β2GPI autoantibodies (> 15 USG) as being associated with APS (p = 0.018; odds ratio [OR] 2.39; 95% confidence interval [CI] 1.2–4.7, and p = 0.0001; OR 3.2; 95% CI 1.5–6.5, respectively). To conclude, these results agree with the need for LA criteria favouring specificity over sensitivity. The use of a threshold around 1.6 for dRVVT ratio should help discriminate APS from non-APS patients.