bluuebunny/crossref_metadata_2025 huggingface dataset:
EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer
Authors: Kamat Aparna A. , Coffey Donna , Merritt William M. , Nugent Elizabeth , Urbauer Diana , Lin Yvonne G. , Edwards Creighton , Broaddus Russell , Coleman Robert L. , Sood Anil K.
Published: April 2009

BACKGROUND:

EphA2 is a tyrosine kinase receptor in the ephrin family that is implicated in oncogenesis and angiogenesis. The objective of the current investigation was to study the role of EphA2 in endometrial cancer and its relation to steroid hormone receptor expression.

METHODS:

EphA2, estrogen receptor (ER), progesterone receptor (PR), and Ki‐67 expression levels were evaluated using immunohistochemistry in 139 endometrioid endometrial carcinoma (EEC) samples and in 10 benign endometrial samples. Samples were scored by 2 investigators who were blinded to clinical outcome. The results were correlated with clinicopathologic characteristics using univariate and multivariate analysis. A P value <.05 was considered statistically significant.

RESULTS:

High expression of EphA2 was detected in 48% of EEC samples versus 10% of benign samples. EphA2 overexpression was associated significantly with high disease stage (P = .04), high tumor grade (P = .003), increased depth of myometrial invasion (P = .05), low ER expression (P = .01), low PR expression (P = .006), and high Ki‐67 expression (P = .04). Low ER and PR expression levels were associated with high tumor grade, positive lymph nodes, high Ki‐67 expression, and high EphA2 expression. On univariate analysis of all patients, high EphA2 expression was associated significantly with shorter disease‐specific survival (DSS) (P < .001). On multivariate analysis, age (P < .001), high disease stage (P = .002), and high EphA2 expression (P = .04) were independent predictors of poor DSS.

CONCLUSIONS:

EphA2 overexpression was associated with aggressive phenotypic features in EEC and was associated inversely with ER and PR expression. Thus, EphA2 may be an important therapeutic target, especially in patients with hormone receptor‐negative endometrial carcinoma. Cancer 2009. © 2009 American Cancer Society.
Selectively Deposited Silver Coatings on Gold‐Capped Silicon Nanowires for Surface‐Enhanced Raman Spectroscopy
Authors: Becker M. , Stelzner Th. , Steinbrück A. , Berger A. , Liu J. , Lerose D. , Gösele U. , Christiansen S.
Published: April 2009

Gold caps on silicon nanowires are selectively coated with silver by autometallography (electroless deposition). Changing the conditions of silver deposition, a variety of different coating morphologies can be produced (see figure). The different silver coating morphologies are investigated in terms of their capabilities for surface enhanced Raman scattering (SERS) experiments.

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Gold caps on silicon nanowires are hemispherical and only a few tens of nanometers in diameter when grown from metal catalysts by the vapor‐liquid‐solid growth mechanism using chemical vapor deposition. These gold caps are capable of enhancing Raman signals based on the surface‐enhanced Raman scattering effect. The Raman signal can be enhanced even further (by at least one order of magnitude) when silver is selectively deposited onto these gold caps by autometallography (electroless deposition). By changing the silver deposition conditions, different coating morphologies can be realized on the gold caps that range from very thin, smooth layers to uneven and extremely rough coatings. The SERS signal enhancement and the spatial homogeneity of the achievable enhancement are compared for the different silver coatings using a model dye molecule.
Reversible Structural Modulation of Fe–Pt Bimetallic Surfaces and Its Effect on Reactivity
Authors: Ma Teng , Fu Qiang , Su Hai‐Yan , Liu Hong‐Yang , Cui Yi , Wang Zhen , Mu Ren‐Tao , Li Wei‐Xue , Bao Xin‐He
Published: April 2009

Tunable surface: The surface structure of the Fe–Pt bimetallic catalyst can be reversibly modulated between the iron‐oxide‐rich Pt surface and the Pt‐skin structure with subsurface Fe via alternating reduction and oxidation treatments (see figure). The regenerated active Pt‐skin structure is active in reactions involving CO and/or O.

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DFT/CCSD(T) Investigation of the Interaction of Molecular Hydrogen with Carbon Nanostructures
Authors: Rubeš Miroslav , Bludský Ota
Published: April 2009

The interaction of molecular hydrogen with carbon nanostructures is investigated within the DFT/CC correction scheme. The DFT/CC results are compared with the benchmark calculations at the CCSD(T) level of theory for benzene and naphthalene, and at the MP2 level for the more extended systems. The DFT/CC method offers a reliable alternative to the highly correlated ab initio calculations at a cost comparable to the standard DFT method. The results for H2 adsorbed on graphene as well as single‐wall carbon nanotubes (SWCNT) are presented. The DFT/CC binding energy on graphene of 5.4 kJ mol−1 is in good agreement with experiment (5.00±0.05 kJ mol−1). For (10,10)‐SWCNT, the H2 molecule is mostly stabilized inside the tube with an estimated binding energy of 7.2 kJ mol−1.
Ruthenium‐catalyzed Selective Monoamination of Vicinal Diols
Authors: Bähn Sebastian , Tillack Annegret , Imm Sebastian , Mevius Kathleen , Michalik Dirk , Hollmann Dirk , Neubert Lorenz , Beller Matthias
Published: April 2009

Highly selective monoamination of vicinal diols: The reaction of vicinal diols with primary and secondary amines is catalyzed by [Ru3(CO)12] and N‐phenyl‐2‐(dicyclohexyl‐phosphanyl)pyrrole to generate the corresponding amino alcohols with high selectivity and good yields.

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The monoamination of vicinal diols in the presence of in situ generated ruthenium catalysts has been investigated. Among the various phosphines tested in combination with [Ru3(CO)12], N‐phenyl‐2‐(dicyclohexyl‐phosphanyl)pyrrole showed the best performance. After optimization of the reaction conditions this system was applied to different secondary amines and anilines as well as a number of vicinal diols. With the exception of ethylene glycol, monoamination of the vicinal diols occurred selectively and the corresponding amino alcohols were obtained in good yields, producing water as the only side product.
Enantioseparation of cetirizine by chromatographic methods and discrimination by 1H‐NMR
Authors: Taha Elham A. , Salama Nahla N. , Wang Shudong
Published: April 2009

Cetirizine is an antihistaminic drug used to prevent and treat allergic conditions. It is currently marketed as a racemate. The H1‐antagonist activity of cetirizine is primarily due to (R)‐levocetirizine. This has led to the introduction of (R)‐levocetirizine into clinical practice, and the chiral switching is expected to be more selective and safer. The present work represents three methods for the analysis and chiral discrimination of cetirizine. The first method was based on the enantioseparation of cetirizine on silica gel TLC plates using different chiral selectors as mobile phase additives. The mobile phase enabling successful resolution was acetonitrile‐water 17: 3, (v/v) containing 1 mM of chiral selector, namely hydroxypropyl‐β‐cyclodextrin, chondroitin sulphate or vancomycin hydrochloride. The second method was a validated high performance liquid chromatography (HPLC), based on stereoselective separation of cetirizine and quantitative determination of its eutomer (R)‐levocetirizine on a monolithic C18 column using hydroxypropyl‐β‐cyclodextrin as a chiral mobile phase additive. The resolved peaks of (R)‐levocetirizine and (S)‐dextrocetirizine were confirmed by further mass spectrometry. The third method used a 1H‐NMR technique to characterize cetirizine and (R)‐levocetirizine. These methods are selective and accurate, and can be easily applied for chiral discrimination and determination of cetirizine in drug substance and drug product in quality control laboratory. Moreover, chiral purity testing of (R)‐levocetirizine can also be monitored by the chromatographic methods. Copyright © 2009 John Wiley & Sons, Ltd.
Short and Efficient Synthesis of Alkyne‐Modified Amino Glycoside Building Blocks
Authors: Klemm Claudine M. , Berthelmann Arne , Neubacher Saskia , Arenz Christoph
Published: April 2009

In the light of recent progress in RNA biology, the need for molecules that bind to RNA and thus may be suited to manipulating RNA‐mediated processes is steadily increasing. We present a very short and efficient synthetic route to alkyne‐modified neamine and 2‐deoxystreptamine derivatives on a half‐gram scale. These derivatives are suitable for constructing a library of potential divalent RNA binders by copper‐catalysed 1,3‐dipolar cycloaddition to diazides (“click chemistry”). The conjugate dimers thus formed inhibitedDicer‐mediated micro‐RNA maturation with IC50 values between 0.6 and 15 μM.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Bioactive Hydrogel Layers on Microdisk Electrode Arrays: Impedimetric Characterization and Equivalent Circuit Modeling
Authors: Rahman Abdur Rub Abdur , Justin Gusphyl , Guiseppi‐Elie Anthony
Published: April 2009

Microfabricated microdisk electrode arrays (MDEAs) of 50 μm (5184 disks), 100 μm (1296 disks) and 250 μm (207 disks) (d/r=4; A= 0.1 cm2) were coated with poly(hydroxyethylmethacrylate)‐based hydrogel membranes and studied by electrochemical impedance spectroscopy (EIS) in 1.0 mM ferrocene monocarboxylic acid (FcCO2H). Equivalent circuit modeling showed an approximate three‐fold increase in solution resistance, Rsol, and an order of magnitude increase in charge transfer resistance, Rct, resulting from a reduction in apparent diffusivity of FcCO2H. Additionally, both resistive parameters decreased while the capacitance (Q) increased with decreasing microdisk diameter; consistent with an increase in effective electroactive area. The hydrogel layer did not compromise enhanced mass transport achieved by the MDEA and thus may be used to advantage in biosensors.
Electrochemical Sensing of Aptamer‐Protein Interactions Using a Magnetic Particle Assay and Single‐Use Sensor Technology
Authors: Erdem Arzum , Karadeniz Hakan , Mayer Günter , Famulok Michael , Caliskan Ayfer
Published: April 2009

A magnetic particle assay has been designed herein that can report the interactions of DNA aptamers with their cognate protein targets lysozyme (LYS) and human thrombin (THR). Electrochemical sensing of the biomolecular recognition between each aptamer and its target was explored by using a disposable graphite electrode, PGE, in combination with differential pulse voltammetry (DPV). The magnitudes of the oxidation signals of LYS and THR were measured at +780 mV and +680 mV, respectively, after interaction with the cognate aptamers attached to the surface of magnetic particles. The detection limits estimated for signal to noise ratios above 3.0 correspond to the concentrations of 10.77 μg/mL LYS (769 nM) and 2.00 μg/mL THR (54.5 nM). Our aptamer based approach that combines magnetic particles with a disposable graphite electrode performs well compared to other aptamer‐based sensor‐formats for quantitative protein detection with respect to sensitivity, selectivity, detection limit, and reproducibility.
Sensor Array: Impedimetric Label‐Free Sensing of DNA Hybridization in Real Time for Rapid, PCR‐Based Detection of Microorganisms
Authors: Ghindilis Andrei L. , Smith Maria W. , Schwarzkopf Kevin R. , Zhan Changqing , Evans David R. , Baptista António M. , Simon Holly M.
Published: April 2009

A novel, impedance‐based electronic sensor format was used for label‐free, real‐time detection of microbial DNA on oligonucleotide probe arrays. Detection limits of 5–10 nM were achieved for single‐stranded, PCR‐amplified DNA targets. Hybridization selectivity yielded 9‐ to 12‐fold signal increases for specific targets, and the sensor arrays were re‐used multiple times without significant signal degradation. These and other features of the SHARP Laboratories of America (SLA) sensor array, such as its ability to acquire continuous measurements of DNA as it accumulates on the array surface, make it an attractive biosensor platform for field detection and monitoring of sentinel and/or pathogenic microorganisms.
Decreased expression of miR‐125b and miR‐100 in oral cancer cells contributes to malignancy
Authors: Henson Brian J. , Bhattacharjee Samsiddhi , O'Dee Dawn M. , Feingold Eleanor , Gollin Susanne M.
Published: April 2009

Altered microRNA (miRNA) expression profiles have been observed in numerous malignancies, including oral squamous cell carcinoma (OSCC). However, their role in disease is not entirely clear. Several genetic aberrations are characteristic of OSCC, with amplification of chromosomal band 11q13 and loss of distal 11q being among the most prevalent. It is not known if the expression levels of miRNAs in these regions are altered or whether they play a role in disease. We hypothesize that the expression of miRNAs mapping to 11q are altered in OSCC because of loss or amplification of chromosomal material, and that this contributes to the development and progression of OSCC. We found that miR‐125b and miR‐100 are down‐regulated in OSCC tumor and cell lines, and that transfecting cells with exogenous miR‐125b and miR‐100 significantly reduced cell proliferation and modified the expression of target and nontarget genes, including some that are overexpressed in radioresistant OSCC cells. In conclusion, the down‐regulation of miR‐125b and miR‐100 in OSCC appears to play an important role in the development and/or progression of disease and may contribute to the loss of sensitivity to ionizing radiation. © 2009 Wiley‐Liss, Inc.
CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma—A miRNA microarray analysis
Authors: Guled Mohamed , Lahti Leo , Lindholm Pamela M. , Salmenkivi Kaisa , Bagwan Izhar , Nicholson Andrew G. , Knuutila Sakari
Published: April 2009

Malignant mesothelioma (MM) is an aggressive cancer arising from mesothelial cells, mainly due to former asbestos exposure. Little is known about the microRNA (miRNA) expression of MM. miRNAs are small noncoding RNAs, which play an essential role in the regulation of gene expression. This study was carried out to analyze the miRNA expression profile of 17 MM samples using miRNA microarray. The analysis distinguished the overall miRNA expression profiles of tumor tissue and normal mesothelium. Differentially expressed miRNAs were found in tumor samples compared with normal sample. Twelve of them, let‐7b*, miR‐1228*, miR‐195*, miR‐30b*, miR‐32*, miR‐345, miR‐483‐3p, miR‐584, miR‐595, miR‐615‐3p, and miR‐885‐3p, were highly expressed whereas the remaining nine, let‐7e*, miR‐144*, miR‐203, miR‐340*, miR‐34a*, miR‐423, miR‐582, miR‐7‐1*, and miR‐9, were unexpressed or had severely reduced expression levels. Target genes for these miRNAs include the most frequently affected genes in MM such as CDKN2A, NF2, JUN, HGF, and PDGFA. Many of the miRNAs were located in chromosomal areas known to be deleted or gained in MM such as 8q24, 1p36, and 14q32. Furthermore, we could identify specific miRNAs for each histopathological subtype of MM. Regarding risk factors such as smoking status and asbestos exposure, significantly differentially expressed miRNAs were identified in smokers versus nonsmokers (miR‐379, miR‐301a, miR‐299‐3p, miR‐455‐3p, and miR‐127‐3p), but not in asbestos‐exposed patients versus nonexposed ones. This could be related to the method of assessment of asbestos exposure as asbestos remains to be the main contributor to the development of MM. © 2009 Wiley‐Liss,Inc.
Frequent upregulation of MYC in plasma cell leukemia
Authors: Chiecchio Laura , Dagrada Gian Paolo , White Helen E. , Towsend Mark R. , Protheroe Rebecca K. M. , Cheung Kan Luk , Stockley David M. , Orchard Kim H. , Cross Nicholas C. P. , Harrison Christine J. , Ross Fiona M.
Published: April 2009

Plasma cell leukemia (PCL) is a rare form of monoclonal gammopathy, which can originate de novo or evolve from multiple myeloma (MM) as a terminal leukemic phase. Previous cytogenetic studies of PCL have reported the presence of complex karyotypes with involvement of multiple unidentified chromosomal regions. We report here the analysis of 12 PCL (10 primary and two secondary) by metaphase and FISH analysis combined with oligonucleotide array data (244 k, Agilent). Interphase‐FISH results were compared with those from a series of 861 newly diagnosed patients with MM. Cytogenetic analysis was successful on 11 patients, all of whom showed clonal chromosomal abnormalities. Compared with MM, t(11;14)(q13;q32) (42% versus 15%; P = 0.027) and t(14;16)(q32;q23) (25% versus 4%; P = 0.010) were more frequent in PCL, although neither the specific partner chromosome involved in the IgH translocation nor the ploidy status predicted for survival. Chromosomes 1, 8, 13, and 16 showed the highest number of copy number alterations with 8q24 being the chromosomal region most frequently involved. In eight of 12 patients we found abnormalities (translocations, one amplification, small deletions, and duplications) that directly targeted or were very close to MYC. Only four of these changes were detected by routine FISH analysis using commercial probes with the others exclusively detected by arrays. Quantitative reverse transcription polymerase chain reaction demonstrated that these different abnormalities were associated with increased levels of MYC mRNA. We conclude that MYC dysregulation by complex mechanisms is one of the major molecular events in the oncogenesis of PCL. © 2009 Wiley‐Liss, Inc.
Association test of multiallelic gene copy numbers in family trios
Authors: Shrestha Sadeep , Aissani Brahim , Tiwari Hemant K. , Wiener Howard W.
Published: April 2009

While recent genomic surveys reveal growing numbers of di‐allelic copy number variations, it is genes with multiallelic (>2) copy numbers that have shown association with distinct phenotypes. Current high‐throughput laboratory methods are restricted to enumerating total gene copy numbers (GCNs) per individual and not the “genotype,” i.e. gene copy per chromosome. Thus, association studies of multiallelic GCNs have been limited to comparison of median copies in different groups. Our new nonparametric statistical approach is based on GCN information within a trio‐based study design. We present theoretical derivation of the statistics and results of simulation studies that show robustness of our approach and power under several genetic models. Genet. Epidemiol. 34:2–6, 2010. © 2009 Wiley‐Liss, Inc.
Operating on commission: analyzing how physician financial incentives affect surgery rates
Authors: Shafrin Jason
Published: April 2009

This paper employs a nationally representative, household‐based dataset in order to test how the compensation method of both the specialists and the primary care providers affects surgery rates. After controlling for adverse selection, I find that when specialists are paid through a fee‐for‐system scheme rather than on a capitation basis, surgery rates increase 78%. The impact of primary care physician compensation on surgery rates depends on whether or not referral restrictions are present. Copyright © 2009 John Wiley & Sons, Ltd.
Some aspects of the hydroclimatology of the Quesnel River Basin, British Columbia, Canada
Authors: Burford Jason E. , Déry Stephen J. , Holmes Richard D.
Published: April 2009

In conjunction with available climate data, surface runoff is investigated at 12 gauges in the Quesnel watershed of British Columbia to develop its long‐term (1926–2004) hydroclimatology. At Quesnel itself, annual mean values of air temperature, precipitation and runoff are 4·6 °C, 517 and 648 mm, respectively. Climate data reveal increases in precipitation, no significant trend in mean annual air temperature, but an increasing trend in mean minimum temperatures that is greatest in winter. There is some evidence of decreases in winter snow depth. On the water year scale (October–September), a strong positive correlation is found between discharge and precipitation (r = 0·70, p < 0·01) and a weak negative correlation is found between precipitation and temperature (r = − 0·36, p < 0·01). Long‐term trends using the Mann‐Kendall test indicate increasing annual discharge amounts that vary from 8 to 14% (12% for the Quesnel River, p = 0·03), and also a tendency toward an earlier spring freshet. River runoff increases at a rate of 1·26 mm yr−1 m−1 of elevation from west to east along the strong elevation gradient in the basin. Discharge, temperature and precipitation are correlated with the large‐scale climate indices of the Pacific Decadal Oscillation (PDO) and El‐Niño Southern Oscillation (ENSO). Copyright © 2009 John Wiley & Sons, Ltd.
A comprehensive catalogue of functional genetic variations in the EGFR pathway: Protein–protein interaction analysis reveals novel genes and polymorphisms important for cancer research
Authors: Savas Sevtap , Geraci Joseph , Jurisica Igor , Liu Geoffrey
Published: April 2009

The EGFR pathway is a critical signaling pathway deregulated in many solid tumors. In addition to the initiation and progression of cancer, the EGFR pathway is also implicated in variable treatment responses and prognoses. Genetic variation in the form of Single Nucleotide Polymorphisms (SNPs) can affect the function/expression of the EGFR pathway genes. Here, we applied a systematic and comprehensive approach utilizing diverse public databases and in silico analysis tools to select putative functional genetic variations from 244 genes involved in the EGFR pathway. Our data comprises 649 SNPs. Three hundred sixty SNPs are predicted to have biological consequences (functional SNPs). These SNPs can be directly used in further studies to test their association with risk, treatment response and prognosis in cancer. To systematically cover the EGFR pathway, we also performed a network‐based analysis to further select putative functional SNPs from the genes whose protein products physically interact with the EGFR pathway proteins. We utilized protein–protein interaction information and focused on 14 proteins that have a high degree of connectivity (interacting with ≥10 proteins) with the EGFR pathway genes identified to have functional SNPs (f‐EGFR genes). Two of these proteins (FYN and LCK) had interactions with 17 of the f‐EGFR genes, yet both lacked any putative functional SNP. However, our analysis indicated the presence of potentially functional SNPs in 9 other highly interactive proteins. The genes and their SNPs identified in the network‐based analysis represent potential candidates for gene–gene and SNP–SNP interaction studies in cancer research. © 2009 UICC
Incidence of cancer and antidepressant medication: Record linkage study
Authors: Haukka Jari , Sankila Risto , Klaukka Timo , Lonnqvist Jouko , Niskanen Leo , Tanskanen Antti , Wahlbeck Kristian , Tiihonen Jari
Published: April 2009

The consumption of antidepressants, especially selective serotonine reuptake inhibitors (SSRI) has been increasing. Because a large fraction of the population is exposed, even a small excess of risk with respect to cancer should be considered. We carried out a record linkage study in Finland utilizing nationwide databases of reimbursed medication and cancer. The study population included all antidepressant drug (AD) users in Finland who had purchased at least 1 prescription between 1998 and 2005, and who had no cancer diagnosis at the date of first purchase. A control population without AD usage (matched by age and sex) was also included. Data consisted of 418,588 pairs of individuals that cumulated 3.3 million person‐years with an average of 4.0 years of follow‐up. 19,365 cancer cases were observed. The most frequent cancers were breast, prostate, lung, colon, and brain cancer. In general, only few associations between the utilization of AD and cancer could be detected. Over four years exposure to AD showed a weak association with increased colon and breast cancer incidence, which could have been caused by bias. As conclusion, no clear evidence of neither beneficial nor harmful association between usage of antidepressant and cancer was found.
Coffee drinking and risk of endometrial cancer—A population‐based cohort study
Authors: Friberg Emilie , Orsini Nicola , Mantzoros Christos S. , Wolk Alicja
Published: April 2009

Coffee drinking has been reported to have beneficial effects on insulin resistance, which has been directly associated with endometrial cancer. Although a relationship between coffee consumption and endometrial cancer risk is biologically plausible, this hypothesis has been previously explored in only 2 prospective studies, with a small number of cases. We used data from the Swedish Mammography Cohort, a population‐based prospective cohort study of 60,634 women. During 17.6 years of follow‐up, 677 participants were diagnosed with incident endometrial cancer (adenocarcinoma). We examined the association between self‐reported coffee consumption (at baseline 1987–90 and in 1997) and endometrial cancer risk using Cox proportional hazards models. Each additional cup (200 g) of coffee per day was associated with a rate ratio (RR) of 0.90 [95% confidence interval (CI), 0.83–0.97]. In women drinking 4 or more cups of coffee a day, the RR for the risk reduction of endometrial cancer was 0.75 (95% CI, 0.58–0.97) when compared with those who drank 1 cup or less. The association seemed largely confined to overweight and obese women, who showed a respective risk reduction of 12% (95% CI, 0–23%) and 20% (95% CI, 7–31%) for every cup of coffee, but was not observed among normal‐weight women. There was a statistically significant interaction between coffee consumption and body mass index (pinteraction < 0.001). These data indicate that coffee consumption may be associated with decreased risk of endometrial cancer, especially among women with excessive body weight. If confirmed by other prospective studies, these results are of major public health significance. © 2009 UICC
Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity
Authors: Friedman Gary D. , Jiang Sheng‐Fang , Udaltsova Natalia , Quesenberry Charles P. , Chan James , Habel Laurel A.
Published: April 2009

Thorough review by the International Agency for Research on Cancer (IARC) has resulted in classifying many substances, including pharmaceuticals, as probably or possibly carcinogenic to humans, based on experiments on animals or limited data on humans. We evaluated 9 such pharmaceuticals for evidence of carcinogenicity in patients receiving them in a large medical care program with automated pharmacy records and a cancer registry. Nested case–control analyses were performed in a cohort of 6.5 million subscribers with up to 12 years of follow‐up, focusing on cancer sites suggested by previous evidence and other sites with odds ratio of at least 1.50, p < 0.01 and some evidence of dose–response. Unmeasured confounding was estimated in sensitivity analyses. We found some supportive evidence for carcinogenicity of griseofulvin, metronidazole and phenytoin and for the known carcinogen, cyclophosphamide, which was added for validation of our data and analyses. Findings for chloramphenicol, iron‐dextran complex, phenoxybenzamine and phenobarbital were essentially non‐contributory. Confounding by cigarette smoking and prior thyroid disease could account, respectively, for associations of oxazepam with lung cancer and propylthiouracil with thyroid cancer. Although not definitive, these findings should be considered in the evaluations of these pharmaceuticals. © 2009 UICC
Melanocortin receptor 1 variants and melanoma risk: A study of 2 European populations
Authors: Scherer Dominique , Nagore Eduardo , Bermejo Justo Lorenzo , Figl Adina , Botella‐Estrada Rafael , Thirumaran Ranjit Kumar , Angelini Sabrina , Hemminki Kari , Schadendorf Dirk , Kumar Rajiv
Published: April 2009

Variation within the melanocortin receptor 1 (MC1R) gene, that influences phenotypic traits and susceptibility to melanoma, is abundant across the populations. We assessed and compared the risk of melanoma in 2 European populations, German and Spanish, by genotyping MC1R variants through direct DNA sequencing from 1,185 melanoma cases and 1,582 controls. The presence of any variant in both populations was associated with a significantly increased risk of melanoma (odds ratio OR = 1.67, 95% confidence interval CI 1.40–1.99). The population attributable fractions (PAF) associated with the MC1R variants in both populations was over 25%. However, the results showed a statistically significant (p < 0.0001) higher frequency of MC1R variants in the German (70%) than in the Spanish population (60%). The red‐hair colour (RHC) variants, though associated with increased risk in both populations, were more common in the German than in the Spanish population (p < 0.0001). Interestingly, non‐RHC variants increased the disease risk in the Spanish (OR = 1.60, 95% CI 1.20–2.14) but not in the German population (OR = 1.07, 95% CI 0.80–1.44). Although RHC variants explained a major proportion of the observed PAF in the German population, in the Spanish population the major contributor to the PAF was the non‐RHC V60L variant. We also observed reduced historic linkage disequilibrium between the variants V92M and T314T in the gene in German melanoma cases. In conclusion, our data underscored the unambiguous importance of the MC1R variants towards the population burden of melanoma. However, the variants that are associated with the disease differ between the investigated populations. © 2009 UICC
Dynamic compression modulates chondrocyte proliferation and matrix biosynthesis in chitosan/gelatin scaffolds
Authors: Wang Peng‐Yuan , Chow Hsiang‐Hong , Lai Juin‐Yih , Liu Hsuan‐Liang , Tsai Wei‐Bor
Published: April 2009

It is well‐documented that dynamical compression stimulates biosynthesis of extracellular biomacromolecules in cartilage explant or in chondrocyte/hydrogel systems. The object of this study was to apply high‐strain dynamic compression to cell‐seeded elastic scaffolds for articular cartilage tissue engineering. Rabbit chondrocytes had been cultured in chitosan/gelatin scaffolds for 3 days before dynamic compression. The chondrocyte/scaffold constructs were subjected to short‐term (3 or 9 h) or long‐term (6 h/day for 3 weeks) cyclic compression with 40% strain and 0.1 Hz. The expression of type II collagen and aggrecan was upregulated after 3‐h of compression when compared with the free‐swelling samples. Furthermore, long‐term culture under dynamic compression facilitated cellular proliferation and deposition of glycosaminoglycan. Our results suggest that high‐strain dynamic compression combined with elastic scaffolds might benefit articular cartilage tissue engineering. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 2009
Evaluation of tooth analogs and type of restoration on the fracture resistance of post and core restored incisors
Authors: Rosentritt Martin , Naumann Michael , Hahnel Sebastian , Handel Gerhard , Reill Margarete
Published: April 2009

Objective:

In in vitro tests, metals and resins are frequently used as substitutes for human teeth. This study aims at determining the suitability of various materials for substituting human incisors in load capability tests.

Method:

Veneering composite (Adoro; n = 16) and non‐precious CoCr‐alloy (NPA; n = 16) were used for manufacturing 32 identical specimens based on the model of a maxillary central incisor resin tooth (Morita). Sixteen human incisors served as a control group. After root canal treatment, all specimens were restored with fiber‐reinforced composite posts and core build‐ups. For each group, eight specimens were chosen randomly and restored either with identical NPA crowns or with all‐ceramic crowns. Specimens were exposed to thermal cycling and mechanical loading (TCML) until failure. Statistical analysis was conducted using the Kruskal–Wallis test and the Bonferroni‐adjusted Mann Whitney U‐test.

Results:

In ceramic crowns, the highest median fracture resistance was found in alloy tooth substitutes (430 N) and natural incisors (426 N), which both showed a significantly higher fracture resistance than composite tooth substitutes (162 N). In alloy crowns, alloy tooth substitutes exhibited the highest fracture resistance (348 N), but no statistically significant difference could be detected between natural incisors (158 N) and composite tooth substitutes (117 N). No artificial tooth substitute showed fracture patterns similar to those of natural incisors.

Significance:

Mechanical parameters are significantly influenced by the type of restoration and the restorative material used. In in vitro tests, the range of artificial tooth substitutes suitable for the replacement of human incisors is limited by load capability. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 2009
Inhibitory effect of paeoniflorin on the inflammatory vicious cycle between adipocytes and macrophages
Authors: Jiang Boren , Qiao Jie , Yang Yuguo , Lu Yingli
Published: April 2009

Obesity is associated with a state of chronic, low‐grade inflammation. It is considered that the paracrine loop involving free fatty acid (FFA) and tumor necrosis factor (TNF)α between adipocytes and macrophages establishes an inflammatory vicious cycle that augments the inflammatory changes and insulin resistance in obese adipose tissue. Paeoniflorin (PF), one of the major components of Paeony root, has been shown to have anti‐inflammatory effects in vivo. We investigated the effect of PF on the production of FFA and TNFα in the interaction between adipocytes and macrophages. Coculture of 3T3‐L1 adipocytes and RAW 264.7 macrophages markedly enhanced the production of TNFα and FFA compared with the control cultures, however, treatment with PF dose‐dependently inhibited the production. We further examined the effects of PF on TNFα‐stimulated adipocyte lipolysis and on FFA‐induced macrophage TNFα expression. PF inhibited TNFα‐stimulated adipocyte lipolysis in a dose‐dependent manner, which was compatible with suppressed phosphorylation of TNFα‐activated ERK1/2 and preserved downregulation of perilipin. Palmitate, one of the most important saturated FFAs, induced macrophage TNFα upexpression, but PF partially attenuated the effect. These results indicate that PF exhibits anti‐inflammatory properties by inhibiting the vicious cycle between adipocytes and macrophages. PF may be useful for ameliorating the inflammatory changes in obese adipose tissue. J. Cell. Biochem. 113: 2560–2566, 2012. © 2009 Wiley Periodicals, Inc.
Transgenic expression of n‐3 fatty acid desaturase (fat‐1) in C57/BL6 mice: Effects on glucose homeostasis and body weight
Authors: Ji Shaonin , Hardy Robert W. , Wood Philip A.
Published: April 2009

The fat‐1 gene, derived from Caenorhabditis elegans, encodes for a fatty acid n‐3 desaturase. In order to study the potential metabolic benefits of n‐3 fatty acids, independent of dietary fatty acids, we developed seven lines of fat‐1 transgenic mice (C57/BL6) controlled by the regulatory sequences of the adipocyte protein‐2 (aP2) gene for adipocyte‐specific expression (AP‐lines). We were unable to obtain homozygous fat‐1 transgenic offspring from the two highest expressing lines, suggesting that excessive expression of this enzyme may be lethal during gestation. Serum fatty acid analysis of fat‐1 transgenic mice (AP‐3) fed a high n‐6 unsaturated fat (HUSF) diet had an n‐6/n‐3 fatty acid ratio reduced by 23% (P < 0.025) and the n‐3 fatty acid eicosapentaenoic acid (EPA) concentration increased by 61% (P < 0.020). Docosahexaenoic acid (DHA) was increased by 19% (P < 0.015) in white adipose tissue. Male AP‐3‐fat‐1 line of mice had improved glucose tolerance and reduced body weight with no change in insulin sensitivity when challenged with a high‐carbohydrate (HC) diet. In contrast, the female AP‐3 mice had reduced glucose tolerance and no change in insulin sensitivity or body weight. These findings indicate that male transgenic fat‐1 mice have improved glucose tolerance likely due to increased insulin secretion while female fat‐1 mice have reduced glucose tolerance compared to wild‐type mice. Finally the inability of fat‐1 transgenic mice to generate homozygous offspring suggests that prolonged exposure to increased concentrations of n‐3 fatty acids may be detrimental to reproduction. J. Cell. Biochem. 107: 809–817, 2009. © 2009 Wiley‐Liss, Inc.
First‐principles calculations on the energetics, electronic structures and magnetism of SrFeO2
Authors: Huang Wen Lai
Published: April 2009

The electronic and magnetic properties of SrFeO2 with different magnetic configurations have been calculated via the plane‐wave pseudopotential density functional theory method, using the experimental lattice parameters. The results give an antiferromagnetic ground state for SrFeO2 with an absolute magnetic moment agreeing very well with the experimental report. In comparison with the counterparts whose magnetic moments are parallel to the c axis, the structures with spin moments parallel to the a (or b) axis exhibit no observable preference in total energy, but show different density distributions of the Fe 3d and Fe 3d states. The square‐planar crystal field splits the Fe 3d orbitals into a high‐level d, a low d, and intermediate dxy and dxz or dyz components. The exchange splitting is larger than the crystal‐field splitting, resulting in the high‐spin Fe 3d states. Referred to the triplet O2, the O‐vacancy formation energy from SrFeO3 to SrFeO2 has been deduced as well, along with its dependence on the temperature and O2 partial pressure. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009
Effect of metal ions on radical type and proton‐coupled electron transfer channel: σ‐Radical vs π‐radical and σ‐channel vs π‐channel in the imide units
Authors: Chen Xiaohua , Xing Dianxiang , Zhang Liang , Cukier Robert I. , Bu Yuxiang
Published: April 2009

The mechanism of proton transfer (PT)/electron transfer (ET) in imide units, and its regulation by hydrated metal ions, was explored theoretically using density functional theory in a representative model (a nearly planar and cisoid complex between uracil and its N3‐dehydrogenated radical, UU). In UU (σ‐radical), PT/ET normally occurs via a seven‐center, cyclic proton‐coupled σ‐electron σ‐channel transfer (PCσEσT) mechanism (3.8 kcal/mol barrier height) with a N3→N3′ PT and an O4→O4′ ET. Binding of hydrated metal ions to the dioxygen sites (O2/O2′ or/and O4/O4′) of UU may significantly affect its PT/ET cooperative reactivity by changing the radical type (σ‐radical ↔ π‐radical) and ET channel (σ‐channel ↔ π‐channel), leading to different mechanisms, ranging from PCσEσT, to proton‐coupled π‐electron σ‐channel transfer (PCπEσT) to proton‐coupled π‐electron π‐channel transfer (PCπEπT). This change originates from an alteration of the ordering of the UU moiety SOMO/HDMO (the singly occupied molecular orbital and the highest doubly occupied molecular orbital), induced by binding of the hydrated metal ions. It is a consequence of three associated factors: the asymmetric reactant structure, electron cloud redistribution, and fixing role of metal ions to structural backbone. The findings regarding the modulation of the PT/ET pathway via hydrated metal ions may provide valuable information for a greater understanding of PT/ET cooperative mechanisms, and an alternative way for designing imide‐based molecular devices, such as molecular switches and molecular wires. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009
Increasing the time step with mass scaling in Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations
Authors: Zheng Han , Wang Shenglong , Zhang Yingkai
Published: April 2009

Born‐Oppenheimer ab initio QM/MM molecular dynamics simulation with umbrella sampling is a state‐of‐the‐art approach to calculate free energy profiles of chemical reactions in complex systems. To further improve its computational efficiency, a mass‐scaling method with the increased time step in MD simulations has been explored and tested. It is found that by increasing the hydrogen mass to 10 amu, a time step of 3 fs can be employed in ab initio QM/MM MD simulations. In all our three test cases, including two solution reactions and one enzyme reaction, the resulted reaction free energy profiles with 3 fs time step and mass scaling are found to be in excellent agreement with the corresponding simulation results using 1 fs time step and the normal mass. These results indicate that for Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, the mass‐scaling method can significantly reduce its computational cost while has little effect on the calculated free energy profiles. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009
Differences amid bone marrow and cord blood hematopoietic stem/progenitor cell division kinetics
Authors: da Silva Cláudia Lobato , Gonçalves Raquel , Porada Christopher D. , Ascensão João L. , Zanjani Esmail D. , Cabral Joaquim M.S. , Almeida‐Porada Graça
Published: April 2009

Human hematopoietic stem/progenitor cells (HSC) isolated based upon specific patterns of CD34 and CD38 expression, despite phenotypically identical, were found to be functionally heterogeneous, raising the possibility that reversible expression of these antigens may occur during cellular activation and/or proliferation. In these studies, we combined PKH67 tracking with CD34/CD38 immunostaining to compare cell division kinetics between human bone marrow (BM) and cord blood (CB)‐derived HSC expanded in a serum‐free/stromal‐based system for 14 days (d), and correlated CD34 and CD38 expression with the cell divisional history. CB cells began dividing 24 h earlier than BM cells, and significantly higher numbers underwent mitosis during the time in culture. By d10, over 55% of the CB‐cells reached the ninth generation, whereas BM‐cells were mostly distributed between the fifth and seventh generation. By d14, all CB cells had undergone multiple cell divisions, while 0.7–3.8% of BM CD34+ cells remained quiescent. Furthermore, the percentage of BM cells expressing CD34 decreased from 60.8 ± 6.3% to 30.6 ± 6.7% prior to initiating division, suggesting that downmodulation of this antigen occurred before commencement of proliferation. Moreover, with BM, all primitive CD34+CD38− cells present at the end of culture arose from proliferating CD34+CD38+ cells that downregulated CD38 expression, while in CB, a CD34+CD38− population was maintained throughout culture. These studies show that BM and CB cells differ significantly in cell division kinetics and expression of CD34 and CD38, and that the inherent modulation of these antigens during ex vivo expansion may lead to erroneous quantification of the stem cell content of the expanded graft. J. Cell. Physiol. 220: 102–111, 2009. © 2009 Wiley‐Liss, Inc.
Elevated Golgi pH impairs terminal N‐glycosylation by inducing mislocalization of Golgi glycosyltransferases
Authors: Rivinoja Antti , Hassinen Antti , Kokkonen Nina , Kauppila Annika , Kellokumpu Sakari
Published: April 2009

Acidic pH of the Golgi lumen is known to be crucial for correct glycosylation, transport and sorting of proteins and lipids during their transit through the organelle. To better understand why Golgi acidity is important for these processes, we have examined here the most pH sensitive events in N‐glycosylation by sequentially raising Golgi luminal pH with chloroquine (CQ), a weak base. We show that only a 0.2 pH unit increase (20 µM CQ) is sufficient to markedly impair terminal α(2,3)‐sialylation of an N‐glycosylated reporter protein (CEA), and to induce selective mislocalization of the corresponding α(2,3)‐sialyltransferase (ST3) into the endosomal compartments. Much higher pH increase was required to impair α(2,6)‐sialylation, or the proximal glycosylation steps such as β(1,4)‐galactosylation or acquisition of Endo H resistance, and the steady‐state localization of the key enzymes responsible for these modifications (ST6, GalT I, MANII). The overall Golgi morphology also remained unaltered, except when Golgi pH was raised close to neutral. By using transmembrane domain chimeras between the ST6 and ST3, we also show that the luminal domain of the ST6 is mainly responsible for its less pH sensitive localization in the Golgi. Collectively, these results emphasize that moderate Golgi pH alterations such as those detected in cancer cells can impair N‐glycosylation by inducing selective mislocalization of only certain Golgi glycosyltransferases. J. Cell. Physiol. 220: 144–154, 2009. © 2009 Wiley‐Liss, Inc.
Enhanced transgene expression in the mouse skeletal muscle infected by the adeno‐associated viral vector with the human elongation factor 1α promoter and a human chromatin insulator
Authors: Mori‐Uchino Mayuyo , Takeuchi Takamasa , Murakami Isao , Yano Tetsu , Yasugi Toshiharu , Taketani Yuji , Nakagawa Keiichi , Kanda Tadahito
Published: April 2009

Background

Efficient and continuous expression of a therapeutic transgene is a key factor for improving the efficacy of gene therapy. Some insulators are known to contribute to continuous high‐level expression of a therapeutic transgene.

Methods

Using the human AAVS1 insulator (DHS) found in the AAVS1 DNase I hypersensitive site, chicken β‐globin insulator (cHS4) and sea urchin arylsufatase insulator (Ars), we newly constructed three recombinant adeno‐associated virus vectors (rAAV) and examined their capability of transducing the mouse quadriceps muscle.

Results

DHS increased transgene expression from the human elongation factor 1α promoter (EF) by 1000‐fold, up to the high level achieved by the human cytomegalovirus immediate early promoter/enhancer (CMV), which comprises an extremely strong promoter for driving a transgene. cHS4 enhanced the expression by 100‐fold, whereas Ars did not. The enhanced expression was maintained for at least 24 weeks. Vector copy numbers were similar with and without DHS or cHS4; thus, the enhancement is most likely due to up‐regulated transcription. Neither DHS, nor cHS4 affected transgene expression from CMV. DHS enhanced expression from the human muscle creatine kinase promoter/enhancer by 100‐fold in mice, as did DHS from EF.

Conclusions

Although DHS was unable to further enhance high expression from the strong viral enhancer/promoter, it enhanced low expression from the human promoters by 100‐ to 1000‐fold. Thus, DHS may be useful for constructing rAAVs that express a therapeutic transgene from less efficient, tissue specific promoters. Copyright © 2009 John Wiley & Sons, Ltd.