bluuebunny/crossref_metadata_2025 huggingface dataset:
Subtype-Specific Risk of Testicular Tumors among Immigrants and Their Descendants in Sweden, 1960 to 2007
Authors: Beiki Omid , Granath Fredrik , Allebeck Peter , Akre Olof , Moradi Tahereh
Published: April 2010

Background: Testicular cancer is the most common cancer among young male adults in several populations. We compared subtype-specific risk of testicular cancer among migrants and their descendants to that of Swedish-born men to elucidate importance of genetic and environmental factors in testicular cancer etiology and the potential timing of exposures.

Methods: We followed a nationwide cohort of 3.6 million men ages 15 to 54 years between 1960 and 2007 through linkage between Swedish National Registers. Incidence rate ratio (IRR) adjusted for age and calendar year with 95% confidence intervals (CI) was estimated using Poisson regression.

Results: A total of 5,801 cases of testicular cancer occurred during 80 million person-years of follow-up. Compared with Swedish-born men, first-generation immigrants from low-risk countries had a lower risk (IRR, 0.43; 95% CI, 0.38-0.49) and first-generation immigrants from high-risk countries had a higher risk (IRR, 1.61; 95% CI, 1.42-1.83) of testicular cancer. The risk among first-generation immigrants varied remarkably by birthplace, reflecting the risk in their countries of birth. The risk of seminomas was statistically significantly modified by age at immigration and duration of residence among immigrants born in high-risk areas. We observed a statistically significantly convergence of risk among second-generation immigrants toward the risk in Sweden (IRR, 1.02; 95% CI, 0.93-1.12). The risk among second-generation immigrants was not affected by the duration of stay of their mothers in Sweden before pregnancy.

Conclusions: Our study provides evidence that life-style and environmental factors play an important role in the etiology of testicular cancer. Cancer Epidemiol Biomarkers Prev; 19(4); 1053–65. ©2010 AACR.
European Ancestry Is Positively Associated with Breast Cancer Risk in Mexican Women
Authors: Fejerman Laura , Romieu Isabelle , John Esther M. , Lazcano-Ponce Eduardo , Huntsman Scott , Beckman Kenneth B. , Pérez-Stable Eliseo J. , González Burchard Esteban , Ziv Elad , Torres-Mejía Gabriela
Published: April 2010

The incidence of breast cancer is 35% lower in Hispanic women living in the San Francisco Bay Area than in non-Hispanic White women. We have previously described a significant association between genetic ancestry and risk for breast cancer in a sample of U.S. Hispanics/Latinas. We retested the association in women residing in Mexico because of the possibility that the original finding may be confounded by U.S. specific unmeasured environmental exposures. We genotyped a set of 106 ancestry informative markers in 846 Mexican women with breast cancer and 1,035 unaffected controls and estimated genetic ancestry using a maximum likelihood method. Odds ratios and 95% confidence intervals (95% CI) for ancestry modeled as a categorical and continuous variable were estimated using logistic regression and adjusted for reproductive and other known risk factors. Greater European ancestry was associated with increased breast cancer risk in this new and independent sample of Mexican women residing in Mexico. Compared with women with 0% to 25% European ancestry, the risk was increased for women with 51% to 75% and 76% to 100% European ancestry [odds ratios, 1.35 (95% CI, 0.96-1.91) and 2.44 (95% CI, 0.94-6.35), respectively; P for trend = 0.044]. For every 25% increase in European ancestry (modeled as a continuous variable), there was a 20% increase in risk for breast cancer (95% CI, 1.03-1.41; P = 0.019). These results suggest that nongenetic factors play a crucial role in explaining the difference in breast cancer incidence between Latinas and non-Latina White women, and it also points out to the possibility of a genetic component to this difference. Cancer Epidemiol Biomarkers Prev; 19(4); 1074–82. ©2010 AACR.
Genetic Susceptibility Variants for Chronic Lymphocytic Leukemia
Authors: Slager Susan L. , Goldin Lynn R. , Strom Sara S. , Lanasa Mark C. , Spector Logan G. , Rassenti Laura , Leis Jose F. , Camp Nicola J. , Kay Neil E. , Vachon Celine M. , Glenn Martha , Weinberg J. Brice , Rabe Kari G. , Cunningham Julie M. , Achenbach Sara J. , Hanson Curtis A. , Marti Gerald E. , Call Timothy G. , Caporaso Neil E. , Cerhan James R.
Published: April 2010

Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study of CLL identified seven genetic variants that increased the risk of CLL within a European population.

Methods: We evaluated the association of these variants, or variants in linkage disequilibrium with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.

Results: Of these seven single nucleotide polymorphisms (SNP), six had P trend < 0.05 and had estimated odds ratios (OR) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 [OR, 1.47; 95% confidence intervals (CI), 1.19-1.80; P trend = 0.0003] near IRF4 and rs735665 near GRAMD1B (OR, 1.47; 95% CI, 1.14-1.89; P trend = 0.003). However, no associations (P > 0.05) were found for rs11083846, nor were any found for any SNP in linkage disequilibrium with rs11083846.

Conclusions: Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis. Cancer Epidemiol Biomarkers Prev; 19(4); 1098–102. ©2010 AACR.
Standard Preanalytical Coding for Biospecimens: Defining the Sample PREanalytical Code
Authors: Betsou Fotini , Lehmann Sylvain , Ashton Garry , Barnes Michael , Benson Erica E. , Coppola Domenico , DeSouza Yvonne , Eliason James , Glazer Barbara , Guadagni Fiorella , Harding Keith , Horsfall David J. , Kleeberger Cynthia , Nanni Umberto , Prasad Anil , Shea Kathi , Skubitz Amy , Somiari Stella , Gunter Elaine ,   International Society for Biological and Environmental Repositories (ISBER) Working Group on Biospecimen Science
Published: April 2010

Background: Management and traceability of biospecimen preanalytical variations are necessary to provide effective and efficient interconnectivity and interoperability between Biobanks.

Methods: Therefore, the International Society for Biological and Environmental Repositories Biospecimen Science Working Group developed a “Standard PREanalytical Code” (SPREC) that identifies the main preanalytical factors of clinical fluid and solid biospecimens and their simple derivatives.

Results: The SPREC is easy to implement and can be integrated into Biobank quality management systems and databases. It can also be extended to nonhuman biorepository areas. Its flexibility allows integration of new novel technological developments in future versions. SPREC version 01 is presented in this article.

Conclusions and Impact: Implementation of the SPREC is expected to facilitate and consolidate international multicenter biomarker identification research and biospecimen research in the clinical Biobank environment. Cancer Epidemiol Biomarkers Prev; 19(4); 1004–11. ©2010 AACR.
Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study
Authors: Schmidt Lisbeth Samsø , Schüz Joachim , Lähteenmäki Päivi , Träger Catarina , Stokland Tore , Gustafson Göran , Hjalgrim Lisa , Sehested Astrid , Johansen Christoffer , Schmiegelow Kjeld
Published: April 2010

Background: The peak incidence of central nervous system (CNS) tumors in childhood indicates that intrauterine or neonatal characteristics are potential risk factors or symptoms of early onset of disease.

Methods: We conducted a registry-based case-control study nested in the childhood populations of Denmark, Finland, Sweden, and Norway on the association between indicators of fetal growth and neonatal stress and childhood CNS tumor risk diagnosed during the period 1985-2006. Each of the 3,443 cases was matched individually on date of birth, sex, and country to five controls sampled randomly from population registries. Information on birth characteristics was obtained from national birth registries. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) by conditional logistic regression analyses.

Results: We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR, 1.27; 95% CI, 1.03-1.55) and <2.0 kg (OR, 1.50; 95% CI, 1.13-1.99), the latter being attenuated after adjustment for gestational age. Moreover, small-for-gestational age (OR, 1.28; 95% CI, 0.98-1.66) and large-for-gestational age (OR, 1.26; 95% CI, 1.02-1.55) were both associated with CNS tumors. The OR for preterm births was increased per 1-week decrease in gestational age (OR, 1.58; 95% CI, 1.04-2.44). Increased ORs were also observed for head circumference >38 cm (1.80; 95% CI, 1.18-2.74), 5-minute Apgar score <7 (1.44; 95% CI, 0.98-2.12), and breech presentation (1.33; 95% CI, 1.04-1.69). The observed associations varied little by histologic subgroup.

Conclusions: This study supports intrauterine or neonatal onset of childhood CNS tumors. The findings provide insight into the natural history of childhood CNS tumors indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable. Cancer Epidemiol Biomarkers Prev; 19(4); 1042–52. ©2010 AACR.
Risk for Renal Cell Carcinoma in Chronic Hepatitis C Infection
Authors: Gordon Stuart C. , Moonka Dilip , Brown Kimberly A. , Rogers Craig , Huang Mary Ann Y. , Bhatt Neal , Lamerato Lois
Published: April 2010

Background: Chronic infection with hepatitis C virus (HCV) confers increased risk for chronic renal disease, and numerous reports suggest an association with renal cell carcinoma (RCC), a cancer with rapidly rising global incidence. We sought to determine whether HCV infection confers an increased risk for developing RCC.

Methods: With the use of administrative data from a large, integrated, and ethnically diverse healthcare system, we did a cohort study of 67,063 HCV-tested patients between 1997 and 2006 who were followed for the development of RCC until April 2008.

Results: A search of the health system cancer registry for patients with the diagnosis of kidney cancer showed that RCC was diagnosed in 0.6% (17 of 3,057) of HCV-positive patients versus 0.3% (177 of 64,006) of HCV-negative patients. The mean age at RCC diagnosis was much younger in HCV-positive individuals (54 versus 63; P < 0.001). The univariate hazard ratio for RCC among HCV patients was 2.20 (95% confidence interval, 1.32-3.67; P = 0.0025). In a multivariate model that included the risk factors age, African-American race, male gender, and chronic kidney disease, the overall hazard ratio for RCC among HCV patients was 1.77 (95% confidence interval, 1.05-2.98; P = 0.0313).

Conclusion: Chronic HCV infection confers a risk for the development of RCC.

Impact: Clinicians should consider newly identified renal lesions in patients with chronic HCV infection with a heightened suspicion for neoplasm, and newly diagnosed cases of RCC may require more careful surveillance for the presence of HCV infection. Additional studies are required to confirm these findings and to explore potential mechanisms of oncogenesis. Cancer Epidemiol Biomarkers Prev; 19(4); 1066–73. ©2010 AACR.
Reproducibility of Plasma, Red Blood Cell, and Urine Biomarkers among Premenopausal and Postmenopausal Women from the Nurses' Health Studies
Authors: Kotsopoulos Joanne , Tworoger Shelley S. , Campos Hannia , Chung Fung-Lung , Clevenger Charles V. , Franke Adrian A. , Mantzoros Christos S. , Ricchiuti Vincent , Willett Walter C. , Hankinson Susan E. , Eliassen A. Heather
Published: April 2010

Background: Temporal variability of biomarkers should be evaluated before their use in epidemiologic studies.

Methods: We evaluated the reproducibility, using intraclass correlation coefficients (ICC), of 27 plasma, 50 red blood cell, and 9 urinary biomarkers over 1 to 3 years among premenopausal (n = 40) and postmenopausal (n = 35-70) participants from the Nurses' Health Study and Nurses' Health Study II.

Results: Plasma and urinary stress hormones and melatonin were measured among premenopausal women, whereas melatonin and the remaining biomarkers were measured in postmenopausal women. ICCs were good to excellent for plasma carotenoids (0.73-0.88), vitamin D analytes (0.56-0.72), bioactive somatolactogens (0.62), soluble leptin receptor (0.82), resistin (0.74), and postmenopausal melatonin (0.63). Reproducibility was lower for some of the red blood cell fatty acids (0.38-0.72), plasma matrix metalloproteinases (0.07-0.91), and premenopausal melatonin (0.44). The ICCs for plasma and urinary phytoestrogens were poor (≤0.09) except for enterolactone (plasma, 0.44; urinary, 0.52). ICCs for the stress hormones among premenopausal women ranged from 0 (plasma cortisol) to 0.45 (urinary dopamine).

Conclusions: Our results indicate that for the majority of these markers, a single measurement can reliably estimate average levels over a 1- to 3-year period in epidemiologic studies. For analytes with fair to good ICCs, reproducibility data can be used for measurement error correction. Analytes with poor ICCs should only be used in settings with multiple samples per subject or in populations in which ICCs are higher.

Impact: This article summarizes the feasibility of the use of >80 biomarkers in epidemiologic studies in which only one biospecimen is available to represent longer term exposure. Cancer Epidemiol Biomarkers Prev; 19(4); 938–46. ©2010 AACR.
Measuring Serum Melatonin in Epidemiologic Studies
Authors: Hsing Ann W. , Meyer Tamra E. , Niwa Shelley , Quraishi Sabah M. , Chu Lisa W.
Published: April 2010

Background: Epidemiologic data on serum melatonin, a marker of circadian rhythms, and cancer are sparse due largely to the lack of reliable assays with high sensitivity to detect relatively low melatonin levels in serum collected during daylight, as commonly available in most epidemiologic studies.

Methods: To help expand epidemiologic research on melatonin, we assessed the reproducibility and refined a currently available melatonin RIA, and evaluated its application to epidemiologic investigations by characterizing melatonin levels in serum, urine, and/or plasma in 135 men from several ethnic groups.

Results: Reproducibility was high for the standard 1.0-mL serum [mean coefficient of variation (CV), 6.9%; intraclass correlation coefficient (ICC), 97.4%; n = 2 serum pools in triplicate] and urine-based (mean CV, 3.5%; ICC, 99.9%) assays. Reproducibility for the 0.5-mL refined-serum assay was equally good (mean CV, 6.6%; ICC, 99.0%). There was a positive correlation between morning serum melatonin and 6-sulfatoxymelatonin in 24-hour urine (r = 0.46; P = 0.008; n = 49 subjects). Melatonin levels in serum-plasma pairs had a high correlation (r = 0.97; P < 1×10−4; n = 20 pairs). Morning serum melatonin levels were five times higher than those from the afternoon (before 9 a.m. mean, 11.0 pg/mL, versus after 11 a.m. mean, 2.0 pg/mL). Chinese men had lower melatonin levels (mean, 3.4 pg/mL), whereas Caucasian, African-American, and Ghanaian men had similar levels (mean, 6.7-8.6 pg/mL).

Conclusions: These results suggest that melatonin can be detected reliably in serum samples collected in epidemiologic studies in various racial groups.

Impact: With improved assays, it may be possible to investigate the role of melatonin and the emerging circadian rhythm hypothesis in cancer etiology in epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 19(4); 932–7. ©2010 AACR.
Custodianship as an Ethical Framework for Biospecimen-Based Research
Authors: Yassin Rihab , Lockhart Nicole , González del Riego Mariana , Pitt Karen , Thomas Jeffrey W. , Weiss Linda , Compton Carolyn
Published: April 2010

Human biological specimens (biospecimens) are increasingly important for research that aims to advance human health. Yet, despite significant proliferation in specimen-based research and discoveries during the past decade, research remains challenged by the inequitable access to high-quality biospecimens that are collected under rigorous ethical standards. This is primarily caused by the complex level of control and ownership exerted by the myriad of stakeholders involved in the biospecimen research process. This article discusses the ethical model of custodianship as a framework for biospecimen-based research to promote fair research access and resolve issues of control and potential conflicts between biobanks, investigators, human research participants (human subjects), and sponsors. Custodianship is the caretaking obligation for biospecimens from initial collection to final dissemination of research findings. It endorses key practices and operating principles for responsible oversight of biospecimens collected for research. Embracing the custodial model would ensure transparency in research, fairness to human research participants, and shared accountability among all stakeholders involved in biospecimen-based research. Cancer Epidemiol Biomarkers Prev; 19(4); 1012–5. ©2010 AACR.
Pooling Biomarker Data from Different Studies of Disease Risk, with a Focus on Endogenous Hormones
Authors: Key Timothy J. , Appleby Paul N. , Allen Naomi E. , Reeves Gillian K.
Published: April 2010

Large numbers of observations are needed to provide adequate power in epidemiologic studies of biomarkers and cancer risk. However, there are currently few large mature studies with adequate numbers of cases with biospecimens available. Therefore, pooling biomarker measures from different studies is a valuable approach, enabling investigators to make robust estimates of risk and to examine associations in subgroups of the population. The ideal situation is to have standardized methods in all studies so that the biomarker data can be pooled in their original units. However, even when the studies do not have standardized methods, as with existing studies on hormones and cancer, a simple approach using study-specific quantiles or percentage increases can provide substantial information on the relationship of the biomarker with cancer risk. Cancer Epidemiol Biomarkers Prev; 19(4); 960–5. ©2010 AACR.
Comparison of mRNA and Protein Measures of Cytokines following Vaccination with Human Papillomavirus-16 L1 Virus-like Particles
Authors: Shebl Fatma M. , Pinto Ligia A. , García-Piñeres Alfonso , Lempicki Richard , Williams Marcus , Harro Clayton , Hildesheim Allan
Published: April 2010

Background: mRNA expression signatures are frequently used as surrogate measures of cellular function and pathway changes. Few studies have directly compared results obtained using gene expression and multiplex protein assays for corresponding gene products.

Methods: We used data available from a clinical trial of a human papillomavirus-16 vaccine that tracked gene expression and cytokine/chemokine production by peripheral blood mononuclear cells stimulated in culture with various antigens to evaluate the degree to which gene expression levels reflect observed levels of cytokines/chemokines. Twenty-six women enrolled in a phase II clinical trial of a human papillomavirus-16 vaccine were evaluated for gene expression (using the Affymetrix Human Genome Focus Array) and cytokine/chemokine levels (using a bead-based 22-plex cytokine assay developed by Linco Research, Inc.) before and after vaccination.

Results: Our results suggest the presence of a wide range of correlations between mRNA expression and secreted protein levels. The strongest correlation was observed for IFN-γ (R = 0.90 overall levels; R = 0.69 when vaccine induced changes were evaluated). More modest overall correlations ranging from 0.40 to 0.80 were observed for MIP1A, IP10, TNF-α, MCP1, IL-2, GM-CSF, IL-5, RANTES, and IL-8. Weaker or no correlation was observed between gene expression and protein levels for the remaining cytokines/chemokines evaluated.

Conclusion: The degree of correlation between gene expression and protein levels varied among different cytokines/chemokines.

Impact: Researchers should be cautious when using mRNA expression array results as a proxy for protein levels using existing technologies. Cancer Epidemiol Biomarkers Prev; 19(4); 978–81. ©2010 AACR.
Strengths and Limitations of Laboratory Procedures for MicroRNA Detection
Authors: Koshiol Jill , Wang Ena , Zhao Yingdong , Marincola Francesco , Landi Maria Teresa
Published: April 2010

Background: MicroRNAs (miR) are endogenous, noncoding RNAs involved in many cellular processes and have been associated with the development and progression of cancer. There are many different ways to evaluate miRs.

Methods: We described some of the most commonly used and promising miR detection methods.

Results: Each miR detection method has benefits and limitations. Microarray profiling and quantitative real-time reverse-transcription PCR are the two most common methods to evaluate miR expression. However, the results from microarray and quantitative real-time reverse-transcription PCR do not always agree. High-throughput, high-resolution next-generation sequencing of small RNAs may offer the opportunity to quickly and accurately discover new miRs and confirm the presence of known miRs in the near future.

Conclusions: All of the current and new technologies have benefits and limitations to consider when designing miR studies. Results can vary across platforms, requiring careful and critical evaluation when interpreting findings.

Impact: Although miR detection and expression analyses are rapidly improving, there are still many technical challenges to overcome. The old molecular epidemiology tenet of rigorous biomarker validation and confirmation in independent studies remains essential. Cancer Epidemiol Biomarkers Prev; 19(4); 907–11. ©2010 AACR.
Limitations of Direct Immunoassays for Measuring Circulating Estradiol Levels in Postmenopausal Women and Men in Epidemiologic Studies
Authors: Stanczyk Frank Z. , Jurow Jordan , Hsing Ann W.
Published: April 2010

Serum estradiol (E2) serves as an important diagnostic marker in a variety of clinical conditions. In epidemiologic studies, E2 is commonly used to define the etiologic role of estrogen in hormone-related cancers and chronic conditions. Having an accurate and reliable E2 assay is of critical importance in these studies, especially when measuring the very low E2 levels (<30 pg/mL) common in postmenopausal women and men, and for discerning the relatively small (usually <20%) case-control differences in E2 levels. Because E2 is metabolized to >100 metabolites in the body, some of which cross-react with E2 antibodies, direct RIAs without purification steps lack specificity for E2 and can substantially overestimate E2 levels. Although direct E2 RIAs using commercial kits are simpler, less time consuming, and less expensive and require less sample volume than conventional RIAs with preceding purification steps, their lack of sensitivity and specificity makes them invalid for measuring circulating E2 levels in epidemiologic studies of postmenopausal women or men. Instead, we recommend the use of a well-validated RIA with purification steps to improve sensitivity and specificity and to help achieve the necessary accuracy and reliability needed for epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 19(4); 903–6. ©2010 AACR.
The Gastric Cardia Is Not a Target for Human Papillomavirus–Induced Carcinogenesis
Authors: Koshiol Jill , Wei Wen-Qiang , Kreimer Aimee R. , Ren Jian-Song , Gravitt Patti , Chen Wen , Kim Esther , Abnet Christian C. , Zhang Yu , Kamangar Farin , Lin Dong-Mei , Wang Guo-Qing , Roth Mark J. , Dong Zhi-Wei , Taylor Philip R. , Qiao You-Lin , Dawsey Sanford M.
Published: April 2010

Background: Thousands of people in central Asia die every year from gastric cardia adenocarcinoma (GCA). GCA arises in the transformation zone between the esophagus and the stomach, similar to cervical and oropharyngeal carcinoma, which arise in areas with transformation zone characteristics. The analogous biology of the gastric cardia to the cervix and oropharynx, where human papillomavirus (HPV) is known to cause cancer, raises the possibility that GCA could be a HPV-associated cancer. Given the availability of an effective HPV vaccine and its potential to prevent HPV-associated cancer, we decided to evaluate the prevalence of HPV DNA in GCA.

Methods: We collected tumor tissue from 144 histopathologically confirmed GCA patients at Yaocun Commune Hospital (Linxian, China), with rigorous attention to prevent DNA contamination. We tested for the presence of HPV DNA in fresh-frozen tumor specimens using PCR with sensitive L1-, E6-, and E7-based primers.

Results: DNA was adequate, as indicated by β-globin positivity, in 108 cases. Of these, all (100%; 95% confidence interval, 97-100%) were negative for HPV DNA.

Conclusions: These results suggest that HPV does not contribute to gastric cardia carcinogenesis in north central China.

Impact: Because GCA does not seem to be a HPV-associated cancer, prophylactic HPV vaccination is unlikely to affect rates of GCA in China. Cancer Epidemiol Biomarkers Prev; 19(4); 1137–9. ©2010 AACR.
Analytic Variability in Immunohistochemistry Biomarker Studies
Authors: Anagnostou Valsamo K. , Welsh Allison W. , Giltnane Jennifer M. , Siddiqui Summar , Liceaga Camil , Gustavson Mark , Syrigos Konstantinos N. , Reiter Jill L. , Rimm David L.
Published: April 2010

Background: Despite the widespread use of immunohistochemistry (IHC), there are no standardization guidelines that control for antibody probe variability. Here we describe the effect of variable antibody reagents in the assessment of cancer-related biomarkers by IHC.

Methods: Estrogen receptor (ER), epidermal growth factor receptor (EGFR) 1, and human epidermal growth factor receptor 3 (HER3) were evaluated by quantitative immunofluorescence. Correlations between ER clones 1D5, SP1, F10, and ER60c, and EGFR monoclonal 31G7, 2-18C9, H11, and 15F8, and polyclonal 2232 antibodies were assessed in 642 breast cancer patients. HER3 was measured by RTJ1, RTJ2, SGP1, M7297, RB-9211, and C-17 antibodies in 42 lung cancer patients. Survival analysis was done with the use of multiple cutoff points to reveal any prognostic classification.

Results: All ER antibodies were tightly correlated (Pearson's r2 = 0.94-0.96; P < 0.0001) and western blotting confirmed their specificity in MCF-7 and BT474 cells. All EGFR antibodies but 2232 yielded specific results in western blotting; however, only 31G7 and 2-18C9 were strongly associated (Pearson's r2 = 0.61; P < 0.0001). HER3 staining was nonspecific and nonreproducible. High EGFR–expressing patients had a worse prognosis when EGFR was measured with H11 or 31G7 (log rank P = 0.015 and P = 0.06). There was no statistically significant correlation between survival and EGFR detected by 2-18C9, 15F8, or polyclonal 2232 antibodies.

Conclusions: Antibody validation is a critical analytic factor that regulates IHC readings in biomarker studies. Evaluation of IHC proficiency and quality control are key components toward IHC standardization.

Impact: This work highlights the importance of IHC standardization and could result in the improvement of clinically relevant IHC protocols. Cancer Epidemiol Biomarkers Prev; 19(4); 982–91. ©2010 AACR.
Dermoscopy of Cutaneous Sarcoidosis
Authors: Pellicano Riccardo , Tiodorovic-Zivkovic Danica , Gourhant Jean-Yves , Catricalà Caterina , Ferrara Gerardo , Caldarola Giacomo , Argenziano Giuseppe , Zalaudek Iris
Published: April 2010

Background: The clinical variability of cutaneous sarcoidosis (CS) often makes its correct diagnosis challenging. Although traditionally employed for the diagnosis of skin tumors, during the past years dermoscopy also gained increasing interest as an aid in the clinical diagnosis of inflammatory and infectious skin manifestations in general dermatology. Objective: Our purpose was to evaluate the usefulness of dermoscopy in the differential diagnosis of CS. Methods: This was a retrospective analysis of 7 clinical and dermoscopic images of CS that were collected at dermatology clinics in France and Italy between 2005 and 2009. Results: Retrospective dermoscopic evaluation revealed small grouped, translucent orange globular structures associated with linear vessels of variable diameter in all 7 cases. In 5 cases, additional central scar-like areas were seen. Conclusion: Lesions showing dermoscopically translucent yellow to orange globular-like or structureless areas associated with linear vessels should raise the suspicion of a granulomatous skin disease, including CS.
Pharmacokinetic-Pharmacodynamic Modeling of Methylxanthine Derivatives in Mice Challenged with High-Dose Lipopolysaccharide
Authors: Wyska Elzbieta
Published: April 2010

Aims: Pentoxifylline and lisofylline are methylxanthine derivatives that exhibit anti-inflammatory activity both in vitroand in vivo. This study was designed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to describe the inhibitory effect of these compounds on TNF-α production in mice challenged with bacterial lipopolysaccharide (LPS). Methods: Male CD-1 mice received increasing intravenous doses of either compound simultaneously with high-dose LPS. A 2-compartment model with Michaelis-Menten-type elimination was used to describe the drug concentration versus time data. Serum TNF-α levels were fitted to an indirect response model. Results: Pentoxifylline and lisofylline reduced LPS-induced TNF-α serum concentrations in a dose-dependent manner. PK/PD analysis revealed an almost 2-fold higher estimate of Km for pentoxifylline in comparison to lisofylline. The production and elimination rates of TNF-α were: kin = 2,167 pg/ml · h–1 and kout = 1.65 h–1, respectively. The drug concentration causing 50% of TNF inhibition (IC50) was markedly lower for pentoxifylline (0.47 vs. 1.61 µg/ml). Conclusions:It seems that pentoxifylline is more potent than lisofylline in inhibiting TNF-α production in vivo. The proposed PK/PD model allowed a better understanding of the pharmacological properties of both methylxanthine derivatives and may be helpful in appropriate dosage selection for further studies.
Risk Perceptions and Family History of Lung Cancer: Differences by Smoking Status
Authors: Chen L.S. , Kaphingst K.A.
Published: April 2010

Background: Individuals with a family history of lung cancer have a two- to threefold increased risk for developing this disease. Family history information may be useful in lung cancer prevention and control approaches, but research is needed regarding how individuals interpret this information. This study examined associations between lung cancer family history and individuals’ risk perceptions, based on smoking status. Methods: Data were analyzed from 5,105 U.S. adult respondents to the 2005 Health Information National Trends Survey, which was conducted with a nationally representative sample. Results: In multivariate models, family history of lung cancer was positively associated with absolute and relative risk perceptions among all respondents (β = 0.60, 95% CI = 0.33–0.87 and β = 0.17, 95% CI = 0.04–0.31, respectively) and among never smokers (β = 0.40, 95% CI = 0.14–0.67 and β = 0.14, 95% CI = 0.01–0.27, respectively). However, these associations were not significant for current and former smokers. Conclusion: While perceived risk was associated with family history of lung cancer among never smokers, this was not true for other smoking status subgroups. Therefore, former and current smokers might not respond as intended to cancer prevention or cessation messages tailored based on family history. The results suggest directions for future research into how to best integrate family history information into prevention and control efforts.
Rationale and Design of INTERSTROKE: A Global Case-Control Study of Risk Factors for Stroke
Authors: O’Donnell M. , Xavier D. , Diener C. , Sacco R. , Lisheng L. , Zhang H. , Pias P. , Truelsen T. , Chin S.L. , Rangarajan S. , DeVilliers L. , Damasceno A. , Mondo C. , Lanas F. , Avezum A. , Diaz R. , Varigos J. , Hankey G. , Teal P. , Kapral M. , Ryglewicz D. , Czlonkowska A. , Skowronska M. , Lopez-Jaramillo P. , Dans T. , Langhorne P. , Yusuf S.
Published: April 2010

Stroke is a major global health problem. It is the third leading cause of death and the leading cause of adult disability. INTERHEART, a global case-control study of acute myocardial infarction in 52 countries (29,972 participants), identified nine modifiable risk factors that accounted for >90% of population-attributable risk. However, traditional risk factors (e.g. hypertension, cholesterol) appear to exert contrasting risks for stroke compared with coronary heart disease, and the etiology of stroke is far more heterogeneous. In addition, our knowledge of risk factors for stroke in low-income countries is inadequate, where a very large burden of stroke occurs. Accordingly, a similar epidemiological study is required for stroke, to inform effective population-based strategies to reduce the risk of stroke. Methods: INTERSTROKE is an international, multicenter case-control study. Cases are patients with a first stroke within 72 h of hospital presentation in whom CT or MRI is performed. Proxy respondents are used for cases unable to communicate. Etiological and topographical stroke subtype is documented for all cases. Controls are hospital- and community-based, matched for gender, ethnicity and age (±5 years). A questionnaire (cases and controls) is used to acquire information on known and proposed risk factors for stroke. Cardiovascular (e.g. blood pressure) and anthropometric (e.g. waist-to-hip ratio) measurements are obtained at the time of interview. Nonfasting blood samples and random urine samples are obtained from cases and controls. Study Significance: An effective global strategy to reduce the risk of stroke mandates systematic measurement of the contribution of the major vascular risk factors within defined ethnic groups and geographical locations.
An Investigation of Factors Associated with Depressive Symptoms among a Sample of Regular Ecstasy Consumers
Authors: Matthews A.J. , Bruno R.
Published: April 2010

Aims/Objectives: Methylenedioxymethamphetamine affects the central serotonergic system, and there is some evidence for an association between ecstasy use (drugs sold as methylenedioxymethamphetamine) and depression. The aim of the present study was to investigate the incidence of self-reported depression and associated help-seeking among a sample of regular ecstasy users. A further aim was to examine the correlates of depressive symptomatology in this population. Materials and Methods: 100 regular ecstasy consumers (at least monthly use) were interviewed as part of the Ecstasy and Related Drug Reporting System in Tasmania, Australia. Participants were also administered epidemiological measures of depression (Center for Epidemiological Studies Depression Scale) and psychological distress (Kessler Psychological Distress Scale). Results: One quarter (23%) of participants self-reported recent experience of depression, a rate notably greater than the general population. However, only one third of these participants had attended a health professional for this issue. A range of drug use factors (e.g. frequency and quantity of ecstasy use, frequent cannabis or methamphetamine use, intravenous drug use, polydrug use, binge drug use, harmful alcohol use, and elevated psychological dependence scores for ecstasy and methamphetamine) were associated with high levels of depressive symptomatology. Conclusion: These findings are consistent with an association between depressive symptomatology and ecstasy and other drug use. Harm reduction strategies which target drug use factors such as those identified in this study may also aid in the reduction of the experience of depression. Considering the low levels of help-seeking among this population, improving awareness and access to information and treatment for depression may also be important.
Peripheral Arterial Disease as an Independent Predictor for Excess Stroke Morbidity and Mortality in Primary-Care Patients: 5-Year Results of the getABI Study
Authors: Meves Saskia H. , Diehm Curt , Berger Klaus , Pittrow David , Trampisch Hans-Joachim , Burghaus Ina , Tepohl Gerhart , Allenberg Jens-Rainer , Endres Heinz G. , Schwertfeger Markus , Darius Harald , Haberl Roman L. ,   for the getABI Study Group
Published: April 2010

Background:There is controversial evidence with regard to the significance of peripheral arterial disease (PAD) as an indicator for future stroke risk. We aimed to quantify the risk increase for mortality and morbidity associated with PAD. Methods:In an open, prospective, noninterventional cohort study in the primary care setting, a total of 6,880 unselected patients ≧65 years were categorized according to the presence or absence of PAD and followed up for vascular events or deaths over 5 years. PAD was defined as ankle-brachial index (ABI) <0.9 or history of previous peripheral revascularization and/or limb amputation and/or intermittent claudication. Associations between known cardiovascular risk factors including PAD and cerebrovascular mortality/events were analyzed in a multivariate Cox regression model. Results:During the 5-year follow-up [29,915 patient-years (PY)], 183 patients had a stroke (incidence per 1,000 PY: 6.1 cases). In patients with PAD (n = 1,429) compared to those without PAD (n = 5,392), the incidence of all stroke types standardized per 1,000 PY, with the exception of hemorrhagic stroke, was about doubled (for fatal stroke tripled). The corresponding adjusted hazard ratios were 1.6 (95% confidence interval, CI, 1.1–2.2) for total stroke, 1.7 (95% CI 1.2–2.5) for ischemic stroke, 0.7 (95% CI 0.2–2.2) for hemorrhagic stroke, 2.5 (95% CI 1.2–5.2) for fatal stroke and 1.4 (95% CI 0.9–2.1) for nonfatal stroke. Lower ABI categories were associated with higher stroke rates. Besides high age, previous stroke and diabetes mellitus, PAD was a significant independent predictor for ischemic stroke. Conclusions:The risk of stroke is substantially increased in PAD patients, and PAD is a strong independent predictor for stroke.
Prevalence and Determinants of Cognitive Complaints after Aneurysmal Subarachnoid Hemorrhage
Authors: Passier P.E.C.A. , Visser-Meily J.M.A. , van Zandvoort M.J.E. , Post M.W.M. , Rinkel G.J.E. , van Heugten C.
Published: April 2010

Background: To investigate the prevalence of cognitive complaints after subarachnoid hemorrhage (SAH) and the relationships between cognitive complaints and cognitive impairments, disability and emotional problems. Methods: Cognitive complaints were assessed with the Checklist for Cognitive and Emotional Consequences following stroke (CLCE-24) in 111 persons who visited our outpatient clinic 3 months after SAH. Associations between cognitive complaints and cognitive functioning, demographic characteristics, disability and emotional problems were examined using Spearman correlations and linear regression analysis. Results: In this study group, 105 patients (94.6%) reported at least one cognitive or emotional complaint that hampered everyday functioning. The most frequently reported cognitive complaints were mental slowness, short-term memory problems and attention deficits. All cognitive domains, disability, depressive symptoms and feelings of anxiety were significantly associated with the CLCE-24 cognition score. In the final regression model, memory functioning (β value –0.21), disability (–0.28) and depressive symptoms (0.40) were significant determinants of cognitive complaints, together explaining 35.4% of the variance. Conclusion: Cognitive complaints are common after SAH and associated with memory deficits, disability and depressive symptoms. Rehabilitation programs should focus on these symptoms and deficits.
c-Jun N-Terminal Kinase Pathway Inhibition in Intracerebral Hemorrhage
Authors: Michel-Monigadon Delphine , Bonny Christophe , Hirt Lorenz
Published: April 2010

Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH). Methods: Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 µg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH. Results: XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 ± 11 vs. 39 ± 5 mm3 in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 ± 13 vs. 26 ± 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression. Conclusions: XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The beneficial effects observed with XG-102 in ICH, as well as in ischemic stroke, open the possibility to rapidly treat stroke patients before imaging, thereby saving precious time.
Association of Platelet and Leukocyte Counts with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage
Authors: Kasius K.M. , Frijns C.J.M. , Algra A. , Rinkel G.J.E.
Published: April 2010

Background and Purpose: A proinflammatory prothrombotic state may increase the risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). We studied the relationship of levels of leukocytes, platelets, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) with the development of DCI and with clinical outcome in patients with aneurysmal SAH. Methods: In 125 patients admitted within 72 h after aneurysmal SAH, we dichotomized initial blood levels at their median values and investigated the prediction of DCI with Cox proportional hazard analysis and of poor clinical outcome with logistic regression analysis. We also analyzed concentrations before and after onset of DCI with the paired-samples t test and compared changes with those in patients without DCI. Results: During the development of DCI (unrelated to treatment), patients had a larger increase in counts of platelets (difference 49 × 109/l; 95% CI: 2–98) and leukocytes (difference 2.6 × 109/l; 95% CI: 0.4–5.0) than patients without DCI during the same period. CRP increased during DCI and decreased in patients without DCI (difference 14 mg/l; 95% CI: –29 to 58). ESR increased slightly in both groups (difference 3 mm/h; 95% CI: –15 to 20). None of the determinants at baseline predicted the development of DCI. An increased risk of poor outcome predicted by a high initial leukocyte count (OR 2.5; 95% CI: 1.1–5.7) decreased after adjustment for clinical variables (OR 2.1; 95% CI: 0.8–5.5). Conclusion: Counts of platelets and leukocytes disproportionally increase during the occurrence of DCI after aneurysmal SAH. Drugs with anti-thrombotic or anti-inflammatory properties should be studied for prevention and treatment of DCI.
Life Span Differences in Electrophysiological Correlates of Monitoring Gains and Losses during Probabilistic Reinforcement Learning
Authors: Hämmerer Dorothea , Li Shu-Chen , Müller Viktor , Lindenberger Ulman
Published: April 2010

By recording the feedback-related negativity (FRN) in response to gains and losses, we investigated the contribution of outcome monitoring mechanisms to age-associated differences in probabilistic reinforcement learning. Specifically, we assessed the difference of the monitoring reactions to gains and losses to investigate the monitoring of outcomes according to task-specific goals across the life span. The FRN and the behavioral indicators of learning were measured in a sample of 44 children, 45 adolescents, 46 younger adults, and 44 older adults. The amplitude of the FRN after gains and losses was found to decrease monotonically from childhood to old age. Furthermore, relative to adolescents and younger adults, both children and older adults (a) showed smaller differences between the FRN after losses and the FRN after gains, indicating a less differentiated classification of outcomes on the basis of task-specific goals; (b) needed more trials to learn from choice outcomes, particularly when differences in reward likelihood between the choices were small; and (c) learned less from gains than from losses. We suggest that the relatively greater loss sensitivity among children and older adults may reflect ontogenetic changes in dopaminergic neuromodulation.
The Neural Underpinnings of Event-file Management: Evidence for Stimulus-induced Activation of and Competition among Stimulus–Response Bindings
Authors: Kühn Simone , Keizer André W. , Colzato Lorenza S. , Rombouts Serge A. R. B. , Hommel Bernhard
Published: April 2010

The present fMRI study tested the assumption that a single pairing of a stimulus and a logically unrelated response is sufficient for binding the corresponding stimulus and response codes into an event representation (event file) that is automatically retrieved upon processing of at least one of its components. In particular, we investigated whether repeating a face or a house stimulus and/or a left or a right manual response induces the automatic retrieval of the response or stimulus that it previously accompanied. ROI analyses of fusiform face area, parahippocampal place area, and right and left motor cortex revealed that repeating one component of a previously encountered stimulus-response episode leads to the suppression of cortical areas processing the other components, suggesting that these components were indeed automatically retrieved and conflicted with ongoing processing. The particular pattern obtained is consistent with predictions from diffusion models of decision making, which suggest a crucial role of local competition in response selection.
A quantitative analysis of two scale characters in snakes
Authors: Moore Kevin , Jackson Kate
Published: April 2010

We quantified the effectiveness of two scale characters commonly used to identify snakes: smooth versus keeled dorsal scales and straight versus oblique dorsal scale rows. We examined 169 species of African snakes from close-up photographs of the dorsal scales. We calculated the prominence of keels (if present) along the dorsal scales and the degree of straightness or obliqueness of the dorsal scale rows. We compared our measurements to species descriptions from the literature and looked for overlap of the character states with each other. Our results show a distinct difference between keel prominence for species described as having keeled dorsal scales versus species described as having smooth dorsal scales. Our results also show considerable overlap of straightness or obliqueness between species described as having straight dorsal scale rows versus those described as having oblique dorsal scale rows. Revision of this character would be beneficial.
Caudal pseudoautotomy in the Eastern Ribbon Snake Thamnophis sauritus
Authors: Todd Josie , Wassersug Richard
Published: April 2010

Frequent tail loss has been reported in a variety of reptiles including sphenodonts, lizards, amphisbaenids, and snakes. We report evidence of non-specialized pseudoautotomy as an antipredator defense in the Eastern Ribbon Snake Thamnophis sauritus. In field studies in Nova Scotia, Canada, T. sauritus were frequently found with partial tails, during three capture attempts T. sauritus tails became completely or partially detached, and one detached tail twitched repeatedly after separation. The breakage was intervertebral, suggesting pseudoautotomy (i.e., that the snake's tail anatomy was not specialized for easy tail loss). Although tail loss patterns in T. sauritus have been well documented, to our knowledge this is the first time pseudoautotomy has been reported in T. sauritus.