bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Genomics of Innate Host Defense Molecules in Normal Human Monocytes in Response toAspergillus fumigatus
Authors: Cortez Karoll J. , Lyman Caron A. , Kottilil Shyam , Kim Hee Sup , Roilides Emmanuel , Yang Jun , Fullmer Brandie , Lempicki Richard , Walsh Thomas J.
Published: March 2006

Aspergillus fumigatusinduces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia ofA. fumigatususing DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs.Aspergillus fumigatusinduced differential regulation of expression in 1,827 genes (P< 0.05). Genes encoding cytokines and chemokines involved in host defense againstA. fumigatus, including interleukin-1β (IL-1β), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus,A. fumigatusconidia induced a coordinated expression of genes important in host defense and immunomodulation.
Inflammatory Responses to Migrating
Brugia pahangi
Third-Stage Larvae
Authors: Porthouse Kristina H. , Chirgwin Sharon R. , Coleman Sharon U. , Taylor H. Wayne , Klei Thomas R.
Published: March 2006

Despite being central to parasite establishment and subsequent host pathological and immunologic responses, host-parasite interactions during early third-stage filarial larva (L3) migration are poorly understood. These studies aimed to define early tissue migration of
Brugia pahangi
L3 in the gerbil (
Meriones unguiculatus
) and measure host cellular responses during this period. Gerbils were intradermally inoculated in the hind limb with 100
B. pahangi
L3, and necropsies were performed at various times. At 3 h, most L3 (96.3%) were recovered from tissues associated with the infection site, with marked L3 migration occurring by 24 h. Larvae were dispersed throughout the lymphatics at 7 days postinfection (dpi), and at 28 dpi, most parasites were recovered from the spermatic cord lymphatics. Parasites were identified histologically at all time points. Inflammatory cells, primarily neutrophils, were frequently observed around larvae in the dermis and muscle near the injection site at 3 h and 24 h. Levels of interleukin-6 (IL-6) and tumor necrosis factor-α mRNA peaked at 3 h in all tissues, with IL-6 levels also high in the spleen at 28 dpi. Levels of IL-4 mRNA were elevated in all tissues at 28 dpi. These observations demonstrate that L3 migrate quickly through various tissues and into lymph nodes in a predictable pattern. Migrating L3 induce an early acute inflammatory response that is modulated as parasites establish in the lymphatics. Polarization of the host response towards a dominant Th2-like profile is present at 7 dpi and is well established by 28 dpi in this permissive host.
Deletion of the Ca
BIG1
Gene Reduces β-1,6-Glucan Synthesis, Filamentation, Adhesion, and Virulence in
Candida albicans
Authors: Umeyama Takashi , Kaneko Aki , Watanabe Hiroshi , Hirai Asuka , Uehara Yoshimasa , Niimi Masakazu , Azuma Masayuki
Published: March 2006

The human fungal pathogen
Candida albicans
is able to change its shape in response to various environmental signals. We analyzed the
C. albicans BIG1
homolog, which might be involved in β-1,6-glucan biosynthesis in
Saccharomyces cerevisiae. C. albicans BIG1
is a functional homolog of an
S. cerevisiae BIG1
gene, because the slow growth of an
S. cerevisiae big1
mutant was restored by introduction of
C. albicans BIG1
. CaBig1p was expressed constitutively in both the yeast and hyphal forms. A specific localization of CaBig1p at the endoplasmic reticulum or plasma membrane similar to the subcellular localization of
S. cerevisiae
Big1p was observed in yeast form. The content of β-1,6-glucan in the cell wall was decreased in the Ca
big1
Δ strain in comparison with the wild-type or reconstituted strain. The
C. albicans BIG1
disruptant showed reduced filamentation on a solid agar medium and in a liquid medium. The Ca
big1Δ
mutant showed markedly attenuated virulence in a mouse model of systemic candidiasis. Adherence to human epithelial HeLa cells and fungal burden in kidneys of infected mice were reduced in the Ca
big1
Δ mutant. Deletion of Ca
BIG1
abolished hyphal growth and invasiveness in the kidneys of infected mice. Our results indicate that adhesion failure and morphological abnormality contribute to the attenuated virulence of the Ca
big1
Δ mutant.
CD8+T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1
Authors: Marquis Miriam , Lewandowski Daniel , Dugas Véronique , Aumont Francine , Sénéchal Serge , Jolicoeur Paul , Hanna Zaher , de Repentigny Louis
Published: March 2006

Candida albicanscauses oropharyngeal candidiasis (OPC) but rarely disseminates to deep organs in human immunodeficiency virus (HIV) infection. Here, we used a model of OPC in CD4C/HIVMuttransgenic (Tg) mice to investigate the role of polymorphonuclear leukocytes (PMNs) and CD8+T cells in limiting candidiasis to the mucosa. Numbers of circulating PMNs and their oxidative burst were both augmented in CD4C/HIVMutATg mice expressingrev,env, andnefof HIV type 1 (HIV-1), while phagocytosis and killing ofC. albicanswere largely unimpaired compared to those in non-Tg mice. Depletion of PMNs in these Tg mice did not alter oral or gastrointestinal burdens ofC. albicansor cause systemic dissemination. However, oral burdens ofC. albicanswere increased in CD4C/HIVMutGTg mice expressing only thenefgene of HIV-1 and bred on a CD8 gene-deficient background (CD8−/−), compared to control or heterozygous CD8+/−CD4C/HIVMutGTg mice. Thus, CD8+T cells contribute to the host defense against oral candidiasis in vivo, specifically in the context ofnefexpression in a subset of immune cells.
Evaluation of the Mtb72F Polyprotein Vaccine in a Rabbit Model of Tuberculous Meningitis
Authors: Tsenova Liana , Harbacheuski Ryhor , Moreira Andre L. , Ellison Evette , Dalemans Wilfried , Alderson Mark R. , Mathema Barun , Reed Steven G. , Skeiky Yasir A. W. , Kaplan Gilla
Published: March 2006

Using a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination withMycobacterium bovisbacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F+AS02A) or Mtb72F formulated in AS01B (Mtb72F+AS01B) was protective against central nervous system (CNS) challenge withMycobacterium tuberculosisH37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F+AS02A-vaccinated rabbits. In addition, protection againstM. tuberculosisH37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F+AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.
Osteopontin Participates in Th1-Mediated Host Resistance against Nonlethal Malaria ParasitePlasmodium chabaudi chabaudiInfection in Mice
Authors: Maeno Yoshimasa , Nakazawa Shusuke , Yamamoto Naoki , Shinzato Masanori , Nagashima Shigeo , Tanaka Kumiko , Sasaki Jun , Rittling Susan R. , Denhardt David T. , Uede Toshimitsu , Taniguchi Koki
Published: March 2006

Osteopontin (OPN) knockout mice (OPN-KO mice) died ofPlasmodium chabaudi chabaudiinfection, although wild-type (WT) mice had self-limiting infections. OPN was detected in the WT mice at 2 days postinfection. OPN-KO mice produced significantly smaller amounts of interleukin-12 and gamma interferon than WT mice produced. These results suggested that OPN is involved in Th1-mediated immunity against malaria infection.
Wolbachia- andOnchocerca volvulus-Induced Keratitis (River Blindness) Is Dependent on Myeloid Differentiation Factor 88
Authors: Gillette-Ferguson Illona , Hise Amy G. , Sun Yan , Diaconu Eugenia , McGarry Helen F. , Taylor Mark J. , Pearlman Eric
Published: March 2006

EndosymbioticWolbachiabacteria that infect the filarial nematodeOnchocerca volvuluswere previously found to have an essential role in the pathogenesis of river blindness. The current study demonstrates that corneal inflammation induced byWolbachiaorO. volvulusantigens containingWolbachiais completely dependent on expression of myeloid differentiation factor 88.
Boosting of Cellular Immunity against
Mycobacterium tuberculosis
and Modulation of Skin Cytokine Responses in Healthy Human Volunteers by
Mycobacterium bovis
BCG Substrain Moreau Rio de Janeiro Oral Vaccine
Authors: Cosgrove Catherine A. , Castello-Branco Luiz R. R. , Hussell Tracy , Sexton Amy , Giemza Rafaela , Phillips Richard , Williams Andrew , Griffin George E. , Dougan Gordon , Lewis David J. M.
Published: March 2006

Oral immunization of healthy adults with 10
7
CFU BCG Moreau Rio de Janeiro was well tolerated and significantly boosted gamma interferon responses to purified protein derivative, Ag85, and MPB70 from previous childhood intradermal BCG immunization. Oral BCG offers the possibility of a needle-free tuberculosis vaccine and of boosting the protective immunity from intradermal tuberculosis vaccines.
Protective CD8+T Cells Induced by Malaria Sporozoites Do Not Undergo Modulation of Interleukin-7 Receptor Expression
Authors: Morrot Alexandre , Cockburn Ian A. , Overstreet Michael , Rodríguez Dolores , Zavala Fidel
Published: March 2006

CD8+T cells induced byPlasmodium yoeliisporozoites develop into protective memory cells without undergoing changes in interleukin-7 receptor α (IL-7Rα) expression, differing from the development of memory CD8+T cells against viruses, which is associated with enhanced IL-7Rα expression. This suggests a microbe-dependent diversity in the signals determining the development of memory populations.
A MODIFIED LEARNING ALGORITHM INCORPORATING ADDITIONAL FUNCTIONAL CONSTRAINTS INTO NEURAL NETWORKS
Authors: HAN FEI , LI XU-QIN , LYU MICHAEL R. , LOK TAT-MING
Published: March 2006

In this paper, a modified learning algorithm to obtain better generalization performance is proposed. The cost terms of this new algorithm are selected based on the second-order derivatives of the neural activation at the hidden layers and the first-order derivatives of the neural activation at the output layer. It can be guaranteed that in the course of training, the additional cost terms for this algorithm can penalize both the input-to-output mapping sensitivity and the high frequency components to obtain better generalization performance. Finally, theoretical justifications and simulation results are given to verify the efficiency and effectiveness of the proposed learning algorithm.
A NEW BINARY SUPPORT VECTOR SYSTEM FOR INCREASING DETECTION RATE OF CREDIT CARD FRAUD
Authors: CHEN RONG-CHANG , CHEN TUNG-SHOU , LIN CHIH-CHIANG
Published: March 2006

Recently, a new personalized model has been developed to prevent credit card fraud. This model is promising; however, there remains some problems. Existing approaches cannot identify well credit card frauds from few data with skewed distributions. This paper proposes to address the problem using a binary support vector system (BSVS). The proposed BSVS is based on the support vectors in the support vector machines (SVM) and the genetic algorithm (GA) is employed to select support vectors. To obtain a high true negative rate, self-organizing mapping (SOM) is first employed to estimate the distribution model of the input data. Then BSVS is used to best train the data according to the input data distribution to obtain a high detection rate. Experimental results show that the proposed BSVS is effective especially for predicting a high true negative rate.
SEGMENTATION OF MASS IN MAMMOGRAMS USING A NOVEL INTELLIGENT ALGORITHM
Authors: XU WEIDONG , XIA SHUNREN , DUAN HUILONG , XIAO MIN
Published: March 2006

In order to improve the performance of mass segmentation on mammograms, an intelligent algorithm is proposed in this paper. It establishes two mass models to characterize the various masses, and the ones in the denser tissue are represented with Model I, while the ones in the fatty tissue are represented with Model II. Then, it uses iterative thresholding to extract the suspicious area, as well as the rough regions of those masses matching Model II, and applies a DWT-based technique to locate those masses matching Model I, which are hidden in the high gray-level intensity and contrast area. A region growing process restricted by Canny edge detection is subsequently used to segment the rough regions of those masses matching Model I, and finally snakes are carried out to find all the mass regions roughly extracted above. Thirty patient cases with 60 mammograms and 107 masses were used for evaluation, and the experimental result has demonstrated the algorithm's better performance over the conventional methods.
MINING GENE EXPRESSION DATABASES FOR LOCAL CAUSAL RELATIONSHIPS USING A SIMPLE CONSTRAINT-BASED ALGORITHM
Authors: WANG MINGYI , LU HUIJUAN , CHEN ZUOZHOU , WU PING
Published: March 2006

There is great potential in mining gene expression microarray databases to discover causal relationships in the gene-regulation pathway. Several methods using Bayesian networks have been reported. Most of them use a heuristics search based on the criteria for choosing a network, but these methods are often computationally intractable for microarray data with thousands of genes. In this work, a simple constrained-based, local causal discovery method is presented. This method is computationally feasible but does not attempt to discover complete causal structure.

To show the effectiveness of this method, we have conducted simulations and applied this method to the data set from Hughes et al. from 300 expression profiles of yeast. Using this method, results of simulation data tests demonstrated that the accuracy ratios of causal relationships became higher when the sample size increased. From the yeast data set, a number of causal relations were found. A cursory analysis shows some of the relations have biological sense, others need further investigation.
A NEW VIEWPOINT OF S-CURVE REGRESSION MODEL AND ITS APPLICATION TO CONSTRUCTION MANAGEMENT
Authors: HSIEH TING-YA , WANG MORRIS H. L. , CHEN CHENG-WU , CHEN CHEN-YUAN , YU SHANG-EN , YANG HSIEN-CHUEH , CHEN TSUNG-HAO
Published: March 2006

The least square method is in generally used for curve fitting problems. We here propose a fuzzy S-curve regression model to deal with the case in which the observed data are given by fuzzy numbers. The fuzzy regression curve, obtained for project control and predicting the progress of large-scale or small-scale engineering, is smoothly connected by a Takagi-Sugeno (T-S) fuzzy model. This paper also proposes the concept that the upper bound and lower bound are given instead of the confidence interval when the observed data are not obtained exactly. Based on the project cash flow and progress payment records of an example project taken from the Department of Rapid Transit Systems, Taipei City Government, this model is demonstrated and tentative conclusions concerning the model are given. The S-curve equation developed here could be used in a variety of applications related to project control for the management of working capital for construction firms.
FUZZY LYAPUNOV METHOD FOR STABILITY CONDITIONS OF NONLINEAR SYSTEMS
Authors: CHEN CHENG-WU , CHIANG WEI-LING , TSAI CHUNG-HUNG , CHEN CHEN-YUAN , WANG MORRIS H. L.
Published: March 2006

This paper proposes a fuzzy Lyapunov method for stability analysis of nonlinear systems represented by Tagagi-Sugeno (T-S) fuzzy model. The fuzzy Lyapunov function is defined in fuzzy blending quadratic Lyapunov functions. Based on fuzzy Lyapunov functions, some stability conditions are derived to ensure nonlinear systems are asymptotic stable. By using parallel distributed compensation (PDC) scheme, we design a nonlinear fuzzy controller for the nonlinear system. This control problem will be reformulated into linear matrix inequalities (LMI) problem.
COOPERATION BETWEEN CD4+AND CD8+T CELLS: When, Where, and How
Authors: Castellino Flora , Germain Ronald N.
Published: March 2006

Concepts of cell-cell interactions in adaptive immunity have alternated between the simple and the complex. The notion that one population of small, circulating lymphocytes is responsible for adaptive immunity was sequentially supplanted by the concept of separate T and B lymphocyte populations that cooperate to produce IgG antibody responses, by a three-cell model in which a myeloid APC initiates these cooperative lymphoid responses, by the recognition of T cell subsets, and by the idea that CD8+T cell subset responses to graft antigens depend on CD4+T cell subset activity. Simplicity was reintroduced with the revelation that CD8+T cells can act independently of CD4+T cells against acute viral infections. The pendulum has swung again toward complexity with recognition of the distinct and conjoint contributions of innate stimuli, APCs, NK and NKT cells, Tregs, and CD4+helper T cells to CD8+T cell behavior during acute and chronic infections or as memory cells. The renewed appreciation that multiple, sometimes rare cell types must communicate during cell-mediated immune responses has led to questions about how such interactions are orchestrated within organized lymphoid tissues. We review recent advances in deciphering the specific contribution of CD4+T cells to physiologically useful CD8+T cell responses, the signals involved in producing acute effectors versus long-lived memory cells, and the mechanisms underlying the cell-cell associations involved in delivery of such signals. We propose a model based on these new findings that may serve as a general paradigm for cellular interactions that occur in an inflamed lymph node during the initiation of immune responses.
Rate Coding and Spike-Time Variability in Cortical Neurons With Two Types of Threshold Dynamics
Authors: Tateno T. , Robinson H.P.C.
Published: March 2006

Neurons and dynamical models of spike generation display two different classes of threshold behavior: type 1 [firing frequency vs. current ( f– I) relationship is continuous at threshold] and type 2 (discontinuous f– I). With steady current or conductance stimulation, regular-spiking (RS) pyramidal neurons and fast-spiking (FS) inhibitory interneurons in layer 2/3 of somatosensory cortex exhibit type 1 and type 2 threshold behaviors, respectively. We compared the postsynaptic firing variability of type 1 RS and type 2 FS cells, during naturalistic, fluctuating conductance input. In RS neurons, increasing the level of independently random, shunting inhibition caused a monotonic increase in spike reliability, whereas in FS interneurons, there was an optimum level of shunting inhibition for achieving the most reliable spike generation and the most precise spike-time encoding. This was observed over a range of different degrees of synchrony, or correlation, in the input. RS cells displayed a progressive rise in spike jitter during natural-like transient burst inputs, whereas for FS cells, jitter was mostly kept low. Furthermore, RS cells showed encoding of the input level in the spike shape, whereas FS cells did not. These differences between the two cell types are consistent with a role of RS neurons as rate-coding integrators, and a role of FS neurons as resonators controlling the coherence of synchronous firing.
Well-Timed, Brief Inhibition Can Promote Spiking: Postinhibitory Facilitation
Authors: Dodla Ramana , Svirskis Gytis , Rinzel John
Published: March 2006

Brief synaptic inhibition can overwhelm a nearly coincident suprathreshold excitatory input to preclude spike generation. Surprisingly, a brief inhibitory event that occurs in a favorable time window preceding an otherwise subthreshold excitation can facilitate spiking. Such postinhibitory facilitation (PIF) requires that the inhibition has a short (decay) time constant τinh. The timescale ranges of τinhand of the window (width and timing) for PIF depend on the rates of neuronal subthreshold dynamics. The mechanism for PIF is general, involving reduction by hyperpolarization of some excitability-suppressing factor that is partially recruited at rest. Here we illustrate and analyze PIF, experimentally and theoretically, using brain stem auditory neurons and a conductance-based five-variable model. In this auditory case, PIF timescales are in the sub- to few millisecond range and the primary mechanistic factor is a low-threshold potassium conductance gKLT. Competing dynamic influences create the favorable time window: hyperpolarization that moves V away from threshold and hyperexcitability resulting from reduced gKLT. A two-variable reduced model that retains the dynamics only of V and gKLTdisplays a similar time window. We analyze this model in the phase plane; its geometry has generic features. Further generalizing, we show that PIF behavior may occur even in a very reduced model with linear subthreshold dynamics, by using an integrate-and-fire model with an accommodating voltage-dependent threshold. Our analyses of PIF provide insights for fast inhibition's facilitatory effects in longer trains. Periodic subthreshold excitatory inputs can lead to firing, even one for one, if brief inhibitory inputs are interleaved within a range of favorable phase lags. The temporal specificity of inhibition's facilitating effect could play a role in temporal processing, in sensitivity to inhibitory and excitatory temporal patterning, in the auditory and other neural systems.
Pituitary Growth Hormone and Growth Hormone–Releasing Hormone Receptor Genes and Associations with Mammographic Measures and Serum Growth Hormone
Authors: Mulhall Cara , Hegele Robert A. , Cao Henian , Tritchler David , Yaffe Martin , Boyd Norman F.
Published: March 2006

Background: Mammographic density is a strong risk factor for breast cancer that is heritable and associated with blood levels of growth hormone and insulin-like growth factor-I (IGF-I). We tested single nucleotide polymorphisms (SNP) in pituitary growth hormone (GH1) and growth hormone–releasing hormone receptor (GHRHR) genes for an association with mammographic density, hormones of the growth hormone/IGF-I axis, and anthropometric variables.

Methods: Mammograms from 348 women were measured using a computer-assisted method, blood collected, and DNA extracted. The SNPs genotyped were GH1 −57G>T, GH1 −75G>A, and GHRHR A57T. ANOVA and covariance were used to examine associations, adjusted for age, body mass index, ethnicity, and menopausal status, between each SNP and three measures of the mammogram: percent density, total dense area, and total nondense area. Similarly, the SNPs were tested for associations with serum growth hormone, IGF-I, IGFBP3, prolactin, and anthropometric variables.

Results: GH1 −57G>T and GH1 −75G>A were both associated with percent density and total nondense area. GH1 −57T homozygotes had 5.2 more mean adjusted percent density than other subjects combined (P = 0.03) and 16.2 cm2 (14.6%) less nondense area (P = 0.01). GH1 −75A homozygotes had 3.4 more percent density than subjects with at least one G allele (P = 0.04) and also had 32% higher serum growth hormone levels (P = 0.02).

Conclusion: We have found associations between mammographic density and two SNPs in the pituitary growth hormone gene, one of them also associated with serum growth hormone levels. These findings suggest that the GH1 gene may also influence breast cancer risk.
Relationships between Cigarette Consumption and Biomarkers of Tobacco Toxin Exposure
Authors: Joseph Anne M. , Hecht Stephen S. , Murphy Sharon E. , Carmella Steven G. , Le Chap T. , Zhang Yan , Han Shaomei , Hatsukami Dorothy K.
Published: March 2006

Epidemiologic studies show a dose-response relationship between cigarettes per day and health outcomes such as heart and lung disease, and health outcomes are related to some biomarkers of tobacco exposure. The objective of this study was to examine the relationships between cigarettes per day and levels of selected biomarkers of tobacco toxin exposure: carbon monoxide (CO), metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons [total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 1-hydroxypyrene (1-HOP), respectively], and total cotinine (cotinine plus cotinine-N-glucuronide). We did a cross-sectional analysis of merged data from (a) two clinical trials and (b) two cohorts of light smokers (total n = 400). The mean age of participants was 50.4 years and the range of cigarette consumption was 1 to 100/d; however, few subjects smoked >45 cigarettes/d (n = 12). Results show that levels of the biomarkers CO, total NNAL, and total cotinine increase with an increase in the number of cigarettes smoked per day, but not in a linear fashion. 1-HOP is a less discriminating biomarker as levels are relatively stable regardless of the number of cigarettes smoked per day. There is considerable variability in toxin measurement, especially at high levels of smoking. There was a significant correlation between cigarettes per day and total NNAL, 1-HOP, total cotinine, and CO. Total NNAL was highly significantly correlated with total cotinine and CO and also significantly correlated with 1-HOP. These findings suggest that the number of cigarettes smoked per day is not necessarily a reliable measure of toxin exposure and may underestimate tobacco toxin exposure at low levels of smoking or overestimate exposure at high levels of smoking. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2963-8)
Discrimination of Breast Cancer by Anti-Malignin Antibody Serum Test in Women Undergoing Biopsy
Authors: Harman S. Mitchell , Gucciardo Frank , Heward Christopher B. , Granstrom Per , Barclay-White Belinda , Rogers Lowell W. , Ibarra Julio A.
Published: March 2006

Purpose: The anti-malignin antibody serum (AMAS) test (Oncolab, Boston, MA) has been reported as 97% sensitive and 95% specific for malignancies. To objectively assess accuracy of this test for discrimination of breast cancer, we studied a series of women undergoing core breast biopsy.

Subjects and Methods: Seventy-one core-needle breast biopsies were classified as malignant, suspicious, or benign by two independent pathologists blinded to AMAS results. Corresponding sera were read as AMAS positive, negative, or borderline by criteria used by Oncolab and also using criteria derived from receiver-operator curves based on values for slow (S-tag), fast (F-tag), and their difference (Net-tag) antibody reported by Oncolab. We calculated sensitivity and specificity and analyzed distributions by Fisher's exact test.

Results: Biopsies were read as 42 (59%) benign, 12 (17%) suspicious, and 17 (24%) malignant. By Oncolab criteria, sensitivity (59%) and specificity (62%) were maximized by pooling suspicious with malignant and AMAS borderline with positive (P = 0.098). Receiver-operator curves showed best sensitivity (62%) and specificity (69%) for the criterion AMAS positive if Net-Tag > 135 μg/mL or S-Tag > 220 μg/mL (P = 0.015).

Conclusions: The AMAS test discriminates suspicious and malignant from benign lesions, but sensitivity is insufficient to identify patients to be spared biopsy and false-positive rates are too high for population screening.
Interaction of Calcium Supplementation and Nonsteroidal Anti-inflammatory Drugs and the Risk of Colorectal Adenomas
Authors: Grau Maria V. , Baron John A. , Barry Elizabeth L. , Sandler Robert S. , Haile Robert W. , Mandel Jack S. , Cole Bernard F.
Published: March 2006

Background: Calcium and aspirin have both been found to be chemopreventive against colorectal neoplasia. However, the joint effect of the two agents has not been well investigated.

Methods: To explore the separate and joint effects of calcium and aspirin/nonsteroidal anti-inflammatory drugs (NSAID), we used data from two large randomized clinical trials among patients with a recent history of colorectal adenomas. In the Calcium Polyp Prevention Study, 930 eligible subjects were randomized to receive placebo or 1,200 mg of elemental calcium daily for 4 years. In the Aspirin/Folate Polyp Prevention Study, 1,121 eligible subjects were assigned to take placebo, 81 mg of aspirin, or 325 mg of aspirin daily for 3 years. In each study, subjects completed a validated food frequency questionnaire at enrollment and were asked periodically about medications and supplements used. Recurrent adenomas and advanced adenomas were the end points considered. We used generalized linear models to assess the separate and combined effects of aspirin (or NSAIDs) and calcium supplementation (or dietary calcium) and the interactions between these exposures.

Results: In the Calcium Trial, subjects randomized to calcium who also were frequent users of NSAIDs had a reduction of risk for advanced adenomas of 65% [adjusted risk ratio (RR), 0.35; 95% confidence interval (95% CI), 0.13-0.96], and there was a highly significant statistical interaction between calcium treatment and frequent NSAID use (Pinteraction = 0.01). Similarly, in the Aspirin Trial, 81 mg aspirin and calcium supplement use together conferred a risk reduction of 80% for advanced adenomas (adjusted RR, 0.20; 95% CI, 0.05-0.81); there was a borderline significant statistical interaction between the two treatments (Pinteraction = 0.09). In this trial, we found similar trends when we considered baseline dietary calcium intake instead of calcium supplements. For all adenomas considered together, the interactive patterns were not consistent.

Conclusion: Data from two different randomized clinical trials suggest that calcium and NSAIDs may act synergistically to lower the risk of advanced colorectal neoplastic polyps.
Effect of Direct Mail as a Population-Based Strategy to Increase Mammography Use among Low-Income Underinsured Women Ages 40 to 64 Years
Authors: Slater Jonathan S. , Henly George A. , Ha Chung Nim , Malone Michael E. , Nyman John A. , Diaz Sarah , McGovern Paul G.
Published: March 2006

Women with inadequate health insurance have lower mammography rates than the general population. Finding successful strategies to enroll eligible women is an ongoing challenge for the National Breast and Cervical Cancer Early Detection Program. To test the effectiveness of a population-based strategy to increase mammography utilization among low-income underinsured women ages 40 to 64 years, a randomized trial was conducted to assess the effect of two mailed interventions on mammography utilization through Sage, the National Breast and Cervical Cancer Early Detection Program in Minnesota. Women (N = 145,467) ages 40 to 63 years [mean (SD), 49.7 (6.8)] with estimated household incomes below $50,000 (47.9% were <$35,000) from a commercial database were randomized to three groups: Mail, Mail Plus Incentive, or Control. Both the Mail and the Mail Plus Incentive groups received two simple mailings prompting them to call a toll-free number to access free mammography services. The Mail Plus Incentive intervention offered a small monetary incentive for a completed mammogram. After 1 year, both intervention groups had significantly higher Sage mammography rates than the Controls, and the Mail Plus Incentive group had a significantly higher rate than the Mail group. The Mail and Mail Plus Incentive interventions were estimated to produce increases in Sage screening rates of 0.23% and 0.75%, respectively, beyond the composite Control rate of 0.83%. Direct mail is an effective strategy for increasing mammography use through Sage. Coupling direct mail with an incentive significantly enhances the intervention's effectiveness. Direct mail should be considered as a strategy to increase mammography use among low-income, medically underserved women.
Adherence Assessment Using Medication Weight in a Phase IIb Clinical Trial of Difluoromethylornithine for the Chemoprevention of Skin Cancer
Authors: Hess Lisa M. , Saboda Kathylynn , Malone Daniel C. , Salasche Stuart , Warneke James , Alberts David S.
Published: March 2006

Objective: Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of a phase IIb topical chemoprevention trial.

Methods: One hundred and twenty-four eligible participants were randomized to one of four arms [34 to difluoromethylornithine (DFMO) plus triamcinolone, 31 to DFMO plus placebo, 31 to placebo plus triamcinolone, and 28 to double placebo] for 6 months of treatment for actinic keratosis. Adherence was assessed at each clinic visit by weighing each tube of dispensed and returned medication and the participant's study diary.

Results: Self-reported adherence was consistently higher than adherence measured by returned medication weight (96.5% versus 71.3%, 94.6% versus 82.4%, 95.3% versus 69.5%, and 95.8% versus 66.8% for DFMO, DFMO placebo, triamcinolone, and triamcinolone placebo, respectively; P < 0.001). Most participants (59.2%) recorded 100% adherence on the study diary; however, using the weight adherence, only 10.2% were completely adherent to the study regimen.

Conclusions: Self-reported diary measures seem to overestimate adherence when compared with weighing the returned medication vessel. It is recommended that future clinical trials involving topical applications incorporate medication weights as a primary measure of adherence because it is objective, quantitative, inexpensive, noninvasive, and easy to use.
Analysis of Total 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in Smokers' Blood
Authors: Carmella Steven G. , Han Shaomei , Villalta Peter W. , Hecht Stephen S.
Published: March 2006

The sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) is an excellent biomarker for uptake of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Although numerous studies have examined levels of total NNAL in the urine of people who use tobacco products, few have quantified this biomarker in blood, and the available methods used relatively large amounts of blood. A method is urgently needed for the analysis of total NNAL in blood, the fluid most commonly stored in molecular epidemiologic studies. We developed a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the analysis of total NNAL in 1-mL samples of plasma. LC-ESI-MS/MS provides both high-sensitivity and structural information supporting analyte identity. The method is practical and sensitive, with a detection limit of 8 fmol total NNAL/mL plasma. Levels of total NNAL averaged 42 ± 22 (SD) and ranged 1.7 to 88 fmol/mL plasma in 16 smokers; NNAL was not detected in the plasma of five nonsmokers. These results show that total NNAL can readily be quantified in 1-mL plasma samples.
Estrogen Bioactivation, Genetic Polymorphisms, and Ovarian Cancer
Authors: Sellers Thomas A. , Schildkraut Joellen M. , Pankratz V. Shane , Vierkant Robert A. , Fredericksen Zachary S. , Olson Janet E. , Cunningham Julie , Taylor William , Liebow Mark , McPherson Carol , Hartmann Lynn C. , Pal Tuya , Adjei Araba A.
Published: March 2006

Recent experimental evidence has shown that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of 503 incident epithelial ovarian cancer cases at the Mayo Clinic in Rochester, MN, and Jacksonville, FL, and a 48-county region in North Carolina. Six hundred nine cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood was collected for DNA isolation. Subjects were genotyped for seven common single nucleotide polymorphisms in four genes involved in catechol estrogen formation (CYP1A1 and CYP1B1) or conjugation (COMT and SULT1A1). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. None of the individual genotypes were significantly associated with ovarian cancer risk. However, an oligogenic model that considered the joint effects of the four candidate genes provided evidence for an association between combinations of these genes and ovarian cancer status (P = 0.015). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.
Life Stressors Are an Important Reason for Women Discontinuing Follow-up Care for Cervical Neoplasia
Authors: Coker Ann L. , Bond Sharon M. , Pirisi Lucia A.
Published: March 2006

Although studies have addressed psychosocial factors associated with obtaining follow-up care for an abnormal Pap test, none have explored the effect of stressful life events in predicting the receipt of follow-up care for an abnormal Pap test. Data from a program (1995-2001) that provided free follow-up care for women with low-grade cervical lesions (n = 601) was used to determine whether life stressors increased risk of study discontinuation. Women were interviewed at baseline and offered follow-up at 4- to 6-month intervals for up to 24 months. Of the 556 women recruited and interviewed (92% response rate), 53 were referred out because they had high-grade cervical lesions and 33 had a health condition precluding follow-up. Among 470 women who began follow-up, 175 (37.2%) discontinued before completing three visits. Women who discontinued were significantly more likely to report more stressful life events in the past year [age-adjusted relative risk (aRR), 1.19; 95% confidence interval (95% CI), 1.08-1.30; 17-item scale]. Events most strongly associated with discontinuation included having a problem with a boss (aRR, 1.9; 95% CI, 1.5-2.4), severe physical partner violence (aRR, 1.7; 95% CI, 1.3-2.2), being homeless (aRR, 2.1; 95% CI, 1.6-2.8), and having an unplanned pregnancy (aRR, 1.5, 95% CI, 1.2-2.1). Life stressors may be important predictors of discontinuation of free follow-up care among women in need of immediate follow-up care to prevent lesion progression. (Cancer Epidemiol Biomarkers Prev 2006;15(2):321–5)
Fruit and Vegetable Consumption and Risk of Epithelial Ovarian Cancer: The European Prospective Investigation into Cancer and Nutrition
Authors: Schulz Mandy , Lahmann Petra H. , Boeing Heiner , Hoffmann Kurt , Allen Naomi , Key Timothy J.A. , Bingham Sheila , Wirfält Elisabet , Berglund Göran , Lundin Eva , Hallmans Göran , Lukanova Annekatrin , Martínez Garcia Carmen , González Carlos A. , Tormo Maria J. , Quirós José R. , Ardanaz Eva , Larrañaga Nerea , Lund Eiliv , Gram Inger T. , Skeie Guri , Peeters Petra H.M. , van Gils Carla H. , Bueno-de-Mesquita H. Bas , Büchner Frederike L. , Pasanisi Patrizia , Galasso Rocco , Palli Domenico , Tumino Rosario , Vineis Paolo , Trichopoulou Antonia , Kalapothaki Victoria , Trichopoulos Dimitrios , Chang-Claude Jenny , Linseisen Jakob , Boutron-Ruault Marie Christine , Touillaud Marina , Clavel-Chapelon Françoise , Olsen Anja , Tjønneland Anne , Overvad Kim , Tetsche Mette , Jenab Mazda , Norat Teresa , Kaaks Rudolph , Riboli Elio
Published: March 2006

Objective: The association between consumption of fruit and vegetables and risk of ovarian cancer is still unclear from a prospective point of view.

Methods: Female participants (n = 325,640) of the European Prospective Investigation into Cancer and Nutrition study, free of any cancer at baseline, were followed on average for 6.3 years to develop ovarian cancer. During 2,049,346 person-years, 581 verified cases of primary, invasive epithelial ovarian cancer were accrued. Consumption of fruits and vegetables as well as subgroups of vegetables, estimated from validated dietary questionnaires and calibrated thereafter, was related to ovarian cancer incidence in multivariable hazard regression models. Histologic subtype specific analyses were done.

Results: Total intake of fruit and vegetables, separately or combined, as well as subgroups of vegetables (fruiting, root, leafy vegetables, cabbages) was unrelated to risk of ovarian cancer. A high intake of garlic/onion vegetables was associated with a borderline significant reduced risk of this cancer. The examination by histologic subtype indicated some differential effects of fruit and vegetable intake on ovarian cancer risk.

Conclusion: Overall, a high intake of fruits and vegetables did not seem to protect from ovarian cancer. Garlic/onion vegetables may exert a beneficial effect. The study of the histologic subtype of the tumor warrants further investigation.
Urinary Thymidine Dimer as a Marker of Total Body Burden of UV-Inflicted DNA Damage in Humans
Authors: Kotova Natalia , Hemminki Kari , Segerbäck Dan
Published: March 2006

High levels of DNA damage are induced in human skin following exposure to UV radiation. Cyclobutane thymidine dimer (T = T) is the most common of these lesions, which are enzymatically removed as oligonucleotides from DNA and further degraded before excretion in urine. Analysis of such repair products in the urine could serve as a biomarker of total body burden of UV exposure. The aim of this study was to examine the kinetics of T = T excretion following a single tanning session in a commercial solarium and to validate the method by delivering different doses. Ten individuals used the solarium for a total of 35 sessions of body tanning. Urine was collected before UV exposure and daily thereafter (up to 5 or 11 days) and T = T was analyzed using a very sensitive and quantitative 32P-postlabeling technique combined with high-performance liquid chromatography. Following exposure, T = T levels increased dramatically and reached a peak 3 days later; afterwards, the T = T levels gradually decreased. The total amount of T = T excreted differed about 5-fold among subjects given an equal dose. A 50% excretion time was calculated using the excretion data for the first 5 days and it was found to be between 55 and 76 hours for different individuals. There was a good correlation between the amount of T = T excreted during days 1 to 5 and the delivered UV dose. Reducing exposure time to 50% lowered the amount of T = T to 47%; if half of the lamps were covered, T = T decreased to 44%. Our data show that urinary T = T could be a suitable noninvasive biomarker for UV exposure; a finding which could also be applicable to studies in children. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2868–72)
Smoking Rates and Topography Predict Adolescent Smoking Cessation Following Treatment with Nicotine Replacement Therapy
Authors: Franken Frederick H. , Pickworth Wallace B. , Epstein David H. , Moolchan Eric T.
Published: March 2006

Establishing measurement invariance of tobacco addiction among adolescents remains challenging. In adult smoking cessation trials, poor outcome is predicted by high cigarette consumption and large puff volume at baseline. We examined the predictive value of pretreatment smoking rates and topography variables for abstinence outcomes among 66 adolescents enrolled in a 3-month smoking cessation trial using nicotine replacement and cognitive behavioral therapy. Pretreatment variables included cigarettes per day (CPD), puff volume, puff duration, and several youth-adapted Fagerström-derived questionnaire scores. Outcome measures included prolonged abstinence at end of treatment and point-prevalent abstinence 3 months after the end of the trial. Logistic regression controlling for treatment group showed that increases in baseline CPD (odds ratio, 1.438; 95% confidence interval, 1.051-1.967) and average puff volume (odds ratio, 1.168; 95% confidence interval, 1.030-1.326) predicted continued smoking at the end of treatment. Puff volume (P = 0.013), but not CPD, predicted abstinence at the 3-month follow-up. None of the youth-adapted Fagerström questionnaires predicted outcome on either abstinence measure. If confirmed in a larger sample, our findings suggest that puff topography, and possibly CPD, might predict cessation outcome better than Fagerström scores in adolescent smokers. (Cancer Epidemiol Biomarkers Prev 2006;(15)1:154–7)
Risk Factors Associated with the Development of Intestinal Metaplasia in First-Degree Relatives of Gastric Cancer Patients
Authors: Leung Wai K. , Ng Enders K.W. , Chan Wing Y. , Auyeung Alex C.M. , Chan Kui-fat , Lam Candice C.H. , Chan Francis K.L. , Lau James Y.W. , Sung Joseph J.Y.
Published: March 2006

Family relatives of gastric cancer patients have a higher risk of gastric cancer and premalignant gastric lesions. We sought to determine the risk factors associated with the presence of intestinal metaplasia in a large cohort of gastric cancer relatives. First-degree relatives of gastric cancer patients were invited for screening gastroscopy. Endoscopic gastric biopsies were obtained from the antrum and corpus. Gastric biopsies were analyzed for Helicobacter pylori infection, severity of inflammation, and presence of intestinal metaplasia. Stepwise logistic regressions were used to identify for risk factors associated with presence of intestinal metaplasia in cancer relatives. Two hundred seventy cancer relatives underwent screening endoscopy (median age, 42; 47% male and 48% siblings). Among them, 161 (59.6%) were H. pylori positive and 81 (30%) had confirmed intestinal metaplasia. The following factors were found to be associated with the presence of intestinal metaplasia: age, male sex, H. pylori infection, birth order, alcohol use, siblings with stomach cancer, childhood living conditions, and water supply. Individuals with intestinal metaplasia had more severe acute and chronic inflammation in the antrum and corpus (P < 0.003). With multiple logistic regression, H. pylori infection [odds ratio (OR), 3.23], male gender (OR, 2.09), age (OR, 1.07), and a history of gastric cancer in siblings (OR, 1.91) were independent factors associated with the development of intestinal metaplasia in cancer relatives. In conclusion, we have identified risk factors associated with gastric intestinal metaplasia in stomach cancer relatives, which may be useful in the understanding of gastric carcinogenesis in these high-risk individuals. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2982–6)