bluuebunny/crossref_metadata_2025 huggingface dataset:
Na+-K+-ATPase in rat skeletal muscle: muscle fiber-specific differences in exercise-induced changes in ion affinity and maximal activity
Authors: Juel Carsten
Published: November 2008

It is unclear whether muscle activity reduces or increases Na+-K+-ATPase maximal in vitro activity in rat skeletal muscle, and it is not known whether muscle activity changes the Na+-K+-ATPase ion affinity. The present study uses quantification of ATP hydrolysis to characterize muscle fiber type-specific changes in Na+-K+-ATPase activity in sarcolemmal membranes and in total membranes obtained from control rats and after 30 min of treadmill running. ATPase activity was measured at Na+ concentrations of 0–80 mM and K+ concentrations of 0–10 mM. Km and Vmax values were obtained from a Hill plot. Km for Na+ was higher (lower affinity) in total membranes of glycolytic muscle (extensor digitorum longus and white vastus lateralis), when compared with oxidative muscle (red gastrocnemius and soleus). Treadmill running induced a significant decrease in Km for Na+ in total membranes of glycolytic muscle, which abolished the fiber-type difference in Na+ affinity. Km for K+ (in the presence of Na+) was not influenced by running. Running only increased the maximal in vitro activity ( Vmax) in total membranes from soleus, whereas Vmax remained constant in the three other muscles tested. In conclusion, muscle activity induces fiber type-specific changes both in Na+ affinity and maximal in vitro activity of the Na+-K+-ATPase. The underlying mechanisms may involve translocation of subunits and increased association between PLM units and the αβ complex. The changes in Na+-K+-ATPase ion affinity are expected to influence muscle ion balance during muscle contraction.
Proteinuria in mice expressing PKB/SGK-resistant GSK3
Authors: Boini Krishna M. , Amann Kerstin , Kempe Daniela , Alessi Dario R. , Lang Florian
Published: November 2008

SGK1 is critically important for mineralocorticoid/salt-induced glomerular injury. SGK1 inactivates GSK3, which downregulates Snail, a DNA-binding molecule repressing the transcription of nephrin, a protein critically important for the integrity of the glomerular slit membrane. PKB/SGK-dependent GSK regulation is disrupted in mice carrying a mutation, in which the serine in the SGK/PKB-phosphorylation consensus sequence is replaced by alanine. The present study explored whether PKB/SGK-dependent GSK3 regulation influences glomerular proteinuria. Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3α,β ( gsk3KI) were compared with their wild-type littermates ( gsk3WT). gsk3KIand gsk3WTmice were implanted with DOCA release pellets and offered 1% saline as drinking water for 21 days. Under standard diet, tap water intake and absence of DOCA, urinary flow rate, glomerular filtration rate, and urinary albumin excretion were significantly larger and blood pressure was significantly higher in gsk3KIthan in gsk3WTmice. Within 18 days, DOCA/salt treatment significantly increased fluid intake and urinary flow rate, urinary protein and albumin excretion, and blood pressure in both genotypes but the respective values were significantly higher in gsk3KIthan in gsk3WTmice. Plasma albumin concentration was significantly lower in gsk3KIthan in gsk3WTmice. Proteinuria was abrogated by lowering of blood pressure with α1-blocker prazosin (1 μg/g body wt) in 8-mo-old mice. According to immunofluorescence, nephrin at 3 and 8 mo and podocin expression at 3 mo were significantly lower in gsk3KIthan in gsk3WTmice. After 18 days, DOCA/salt treatment renal glomerular sclerosis and tubulointerstitial damage were significantly more pronounced in gsk3KIthan in gsk3WTmice. The observations reveal that disruption of PKB/SGK-dependent regulation of GSK3 leads to glomerular injury with proteinuria, which may at least partially be secondary to enhanced blood pressure.
Targeting renal macrophage accumulation via c-fmskinase reduces tubular apoptosis but fails to modify progressive fibrosis in the obstructed rat kidney
Authors: Ma Frank Y. , Liu Jian , Kitching A. Richard , Manthey Carl L. , Nikolic-Paterson David J.
Published: November 2008

The role of macrophages in promoting interstitial fibrosis in the obstructed kidney is controversial. Macrophage depletion studies in the unilateral ureter obstruction (UUO) model have produced opposing results, presumably reflecting the subtleties of the individual depletion methods used. To address this question, we targeted the macrophage colony-stimulating factor receptor, c- fms, which is uniquely expressed by cells of the monocyte/macrophage lineage. Administration of 5, 12.5, or 30 mg/kg (bid) of a selective inhibitor of c- fms kinase activity (fms-I) resulted in a dose-dependent inhibition of renal macrophage accumulation in the rat UUO model. This was due to inhibition of local macrophage proliferation in the obstructed kidney and, at higher doses, to depletion of circulating blood monocytes. To determine the contribution of macrophages to renal pathology in the obstructed kidney, groups of animals were treated with 30 mg/kg fms-I and killed 3, 7, or 14 days later. Complete inhibition of renal macrophage accumulation prevented upregulation of the macrophage-associated proinflammatory mediators, tumor necrosis factor (TNF)-α and matrix metalloproteinase-12, and significantly reduced tubular apoptosis. Macrophage depletion caused a minor reduction of interstitial myofibroblast accumulation and deposition of interstitial collagen IV at day 3, but no difference was seen in renal fibrosis on day 7 or 14. Similarly, the upregulation of collagen IV, fibronectin, transforming growth factor-β1 and connective tissue growth factor mRNA levels on day 7 and 14 in the obstructed kidney was unaffected by macrophage depletion. In conclusion, c- fms blockade was shown to selectively prevent interstitial macrophage accumulation and to reduce tubular apoptosis in the obstructed kidney, but it had no significant impact on the development of interstitial fibrosis.
Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death
Authors: Bouvier Nicolas , Flinois Jean Pierre , Gilleron Jerome , Sauvage François-Ludovic , Legendre Christophe , Beaune Philippe , Thervet Eric , Anglicheau Dany , Pallet Nicolas
Published: November 2008

Calcineurin inhibitors cyclosporine and tacrolimus are effective immunosuppressants, but both substances have the same intrinsic nephrotoxic potential that adversely affects allograft survival in renal transplant patients and causes end-stage renal disease in other solid organ or bone marrow transplant recipients. Endothelial cells are the first biological interface between drugs and the kidney, and calcineurin inhibitors may influence endothelial function and viability in a number of ways. Notably, endothelial cells have recently been shown to contribute to the accumulation of interstitial fibroblasts in nonrenal models, through endothelial-to-mesenchymal transition. Here we demonstrate that cyclosporine, but not tacrolimus or its metabolites, induces morphological and phenotypic endothelial changes suggestive of a partial endothelial-to-mesenchymal transition in human umbilical arterial endothelial cells. We identify for the first time a contingent of interstitial myofibroblasts that coexpress endothelial markers in rat kidneys treated with cyclosporine, suggesting that endothelial-to-mesenchymal transition could occur in vivo. Finally, our findings suggest that endoplasmic reticulum stress triggered by cyclosporine induces endothelial cells to undergo endothelial phenotypic changes suggestive of a partial endothelial-to-mesenchymal transition, whereas salubrinal partially preserves the endothelial phenotype. Inversely, tacrolimus does not induce endothelial-to-mesenchymal transition or endoplasmic reticulum stress. In conclusion, this study demonstrates for the first time that cyclosporine, and not tacrolimus, induces endoplasmic reticulum stress in endothelial cells. Our findings also suggest that endoplasmic reticulum stress contributes to endothelial cell death and phenotypic changes similar to a partial endothelial-to-mesenchymal transition.
Evidence for Multisensory Spatial-to-Motor Transformations in Aiming Movements of Children
Authors: King Bradley R. , Kagerer Florian A. , Contreras-Vidal Jose L. , Clark Jane E.
Published: November 2008

The extant developmental literature investigating age-related differences in the execution of aiming movements has predominantly focused on visuomotor coordination, despite the fact that additional sensory modalities, such as audition and somatosensation, may contribute to motor planning, execution, and learning. The current study investigated the execution of aiming movements toward both visual and acoustic stimuli. In addition, we examined the interaction between visuomotor and auditory-motor coordination as 5- to 10-yr-old participants executed aiming movements to visual and acoustic stimuli before and after exposure to a visuomotor rotation. Children in all age groups demonstrated significant improvement in performance under the visuomotor perturbation, as indicated by decreased initial directional and root mean squared errors. Moreover, children in all age groups demonstrated significant visual aftereffects during the postexposure phase, suggesting a successful update of their spatial-to-motor transformations. Interestingly, these updated spatial-to-motor transformations also influenced auditory-motor performance, as indicated by distorted movement trajectories during the auditory postexposure phase. The distorted trajectories were present during auditory postexposure even though the auditory-motor relationship was not manipulated. Results suggest that by the age of 5 yr, children have developed a multisensory spatial-to-motor transformation for the execution of aiming movements toward both visual and acoustic targets.
Differential Influence of Attention on Gaze and Head Movements
Authors: Khan Aarlenne Z. , Blohm Gunnar , McPeek Robert M. , Lefèvre Philippe
Published: November 2008

A salient peripheral cue can capture attention, influencing subsequent responses to a target. Attentional cueing effects have been studied for head-restrained saccades; however, under natural conditions, the head contributes to gaze shifts. We asked whether attention influences head movements in combined eye–head gaze shifts and, if so, whether this influence is different for the eye and head components. Subjects made combined eye–head gaze shifts to horizontal visual targets. Prior to target onset, a behaviorally irrelevant cue was flashed at the same (congruent) or opposite (incongruent) location at various stimulus-onset asynchrony (SOA) times. We measured eye and head movements and neck muscle electromyographic signals. Reaction times for the eye and head were highly correlated; both showed significantly shorter latencies (attentional facilitation) for congruent compared with incongruent cues at the two shortest SOAs and the opposite pattern (inhibition of return) at the longer SOAs, consistent with attentional modulation of a common eye–head gaze drive. Interestingly, we also found that the head latency relative to saccade onset was significantly shorter for congruent than that for incongruent cues. This suggests an effect of attention on the head separate from that on the eyes.
Time Course and Stimulus Dependence of Repetition-Induced Response Suppression in Inferotemporal Cortex
Authors: Liu Yan , Murray Scott O. , Jagadeesh Bharathi
Published: November 2008

Neural responses throughout the sensory system are affected by stimulus history. In the inferotemporal cortex (IT)—an area important for processing information about object shape—there is a substantially reduced response to the second presentation of an image. Understanding the mechanisms underlying repetition suppression may provide important insights into the circuitry that generates responses in IT. In addition, repetition suppression may have important perceptual consequences. The characteristics of repetition suppression in IT are poorly understood, and the details, including the interaction between the content of the first and second stimulus and the time course of suppression, are not clear. Here, we examined the time course of suppression in IT by varying both the duration and stimulus content of two stimuli presented in sequence. The data show that the degree of suppression does not depend directly on the response evoked by the first stimulus in the recorded neuron. Repetition suppression was also limited in duration, peaking at ≈ 200 ms after the onset of the second (test) image and disappearing before the end of the response. Neural selectivity to a continuum of related images was enhanced if the first stimulus produced a weak response in the cell. The dynamics of the response suggests that different parts of the input and recurrent circuitry that gives rise to neural responses in IT are differentially modulated by repetition suppression. The selectivity of the sustained response was preserved in spite of substantial suppression of the early part of the response. The data suggest that suppression in IT is a property of the input and recurrent circuitry in IT and is not directly related to the degree of response in the recorded neuron itself.
Existence and Uniqueness of Pseudo Almost Automorphic Mild Solutions to Some Classes of Partial Hyperbolic Evolution Equations
Authors: Hu Zhanrong , Jin Zhen
Published: November 2008

We will establish an existence and uniqueness theorem of pseudo almost automorphic mild solutions to the following partial hyperbolic evolution equation (d/dt)[u(t) + f(t, Bu(t))] = Au(t) + g(t, Cu(t)),   t ∈ ℝ, under some assumptions. To illustrate our abstract result, a
concrete example is given.
Regularity and Green′s Relations on a Semigroup ofTransformations with Restricted Range
Authors: Sanwong Jintana , Sommanee Worachead
Published: November 2008

Let T(X) be the full transformation semigroup on the set X and let T(X, Y) = {α ∈ T(X) : Xα⊆Y}.
Then T(X, Y) is a sub‐semigroup of T(X) determined by a nonempty subset Y of X. In this paper, we give a necessary and sufficient condition for T(X, Y) to be regular. In the case that T(X, Y) is not regular, the largest regular sub‐semigroup is obtained and this sub‐semigroup
is shown to determine the Green′s relations on T(X, Y). Also, a class
of maximal inverse sub‐semigroups of T(X, Y) is obtained.
On the Difference Equation xn+1=α+xn−m/xnk
Authors: Yalçinkaya İbrahim
Published: November 2008

We investigate the global behaviour of the difference
equation of higher order , n = 0, 1, …, where the parameters α, k ∈ (0, ∞) and the initial values x−m, x−(m−1), …, x−2, x−1, and x0 are arbitrary positive real numbers.
Laparoscopic Nephroureterectomy: The Distal Ureteral Dilemma
Authors: Srirangam Shalom J. , van Cleynenbreugel Ben , van Poppel Hein
Published: November 2008

Transitional cell carcinoma affecting the upper urinary tract, though uncommon, constitutes a serious urologic disease. Radical nephroureterectomy remains the treatment of choice but has undergone numerous modifications over the years. Although the standard technique has not been defined, the laparoscopic approach has gained in popularity in the last two decades. The most appropriate oncological management of the distal ureteral and bladder cuff has been a subject of much debate. The aim of the nephroureterectomy procedure is to remove the entire ipsilateral upper tract in continuity while avoiding extravesical transfer of tumor-containing urine during bladder surgery. A myriad of technical modifications have been described. In this article, we review the literature and present an overview of the options for dealing with the lower ureter during radical nephroureterectomy.
Review of Topical Treatment of Upper Tract Urothelial Carcinoma
Authors: Nepple Kenneth G. , Joudi Fadi N. , O'Donnell Michael A.
Published: November 2008

A select group of patients with upper tract urothelial carcinoma may be appropriate candidates for minimally invasive management. Organ-preserving endoscopic procedures may be appropriate for patients with an inability to tolerate major surgery, solitary kidney, bilateral disease, poor renal function, small tumor burden, low-grade disease, or carcinoma in situ. We review the published literature on the use of topical treatment for upper tract urothelial carcinoma and provide our approach to treatment in the office setting.
Modeling a Quantum Hall System via Elliptic Equations
Authors: Sowa Artur
Published: November 2008

Quantum Hall systems are a suitable theme for a case study in the general area of nanotechnology.
In particular, it is a good framework to search for universal principles relevant to
nanosystem modeling and nanosystem‐specific signal processing. Recently, we have been able
to construct a partial differential equations‐based model of a quantum Hall system, which
consists of the Schrödinger equation supplemented with a special‐type nonlinear feedback
loop. This result stems from a novel theoretical approach, which in particular brings to
the fore the notion of quantum information. Here we undertake to modify the original model by
substituting the dynamics based on the Dirac operator. This leads to a model that consists
of a system of three nonlinearly coupled first‐order elliptic equations in the plane.
Two‐Phase Flow Simulations for PTS Investigation by Means of Neptune_CFD Code
Authors: Galassi Maria Cristina , Coste Pierre , Morel Christophe , Moretti Fabio
Published: November 2008

Two‐dimensional axisymmetric simulations of pressurized thermal shock (PTS) phenomena through Neptune_CFD module are presented aiming at two‐phase models validation against experimental data. Because of PTS complexity, only some thermal‐hydraulic aspects were considered. Two different flow configurations were studied, occurring when emergency core cooling (ECC) water is injected in an uncovered cold leg of a pressurized water reactor (PWR)—a plunging water jet entering a free surface, and a stratified steam‐water flow. Some standard and new implemented models were tested: modified turbulent k‐ε models with turbulence production induced by interfacial friction, models for the drag coefficient, and interfacial heat transfer models. Quite good agreement with experimental data was achieved with best performing models for both test cases, even if a further improvement in phase change modelling would be suitable for nuclear technology applications.
Social Determinants of Black-White Disparities in Breast Cancer Mortality: A Review
Authors: Gerend Mary A. , Pai Manacy
Published: November 2008

Despite the recent decline in breast cancer mortality, African American women continue to die from breast cancer at higher rates than do White women. Beyond the fact that breast cancer tends to be a more biologically aggressive disease in African American than in White women, this disparity in breast cancer mortality also reflects social barriers that disproportionately affect African American women. These barriers hinder cancer prevention and control efforts and modify the biological expression of disease. The present review focuses on delineating social, economic, and cultural factors that are potentially responsible for Black-White disparities in breast cancer mortality. This review was guided by the social determinants of health disparities model, a model that identifies barriers associated with poverty, culture, and social injustice as major causes of health disparities. These barriers, in concert with genetic, biological, and environmental factors, can promote differential outcomes for African American and White women along the entire breast cancer continuum, from screening and early detection to treatment and survival. Barriers related to poverty include lack of a primary care physician, inadequate health insurance, and poor access to health care. Barriers related to culture include perceived invulnerability, folk beliefs, and a general mistrust of the health care system. Barriers related to social injustice include racial profiling and discrimination. Many of these barriers are potentially modifiable. Thus, in addition to biomedical advancements, future efforts to reduce disparities in breast cancer mortality should address social barriers that perpetuate disparities among African American and White women in the United States. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2913–23)
Cardiovascular Medication Use and Risk for Colorectal Cancer
Authors: Boudreau Denise M. , Koehler Elizabeth , Rulyak Stephen J. , Haneuse Sebastien , Harrison Robert , Mandelson Margaret T.
Published: November 2008

Objective: To evaluate the association between lipid-lowering agents, antihypertensive medications, and colorectal cancer risk. We hypothesized a reduction in colorectal cancer risk with 3-hydroxy-3-methylglutaryl coA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors.

Methods: We conducted a case-control study at Group Health Cooperative, an integrated delivery system in Washington State. Incident colorectal cancer cases diagnosed between January 1, 2000, and December 31, 2003, were identified from the western Washington Surveillance, Epidemiology, and End Results cancer registry. Controls were matched by age, sex, and duration of enrollment. Data on medication use and potential confounders were obtained from health plan records. We estimated odds ratios and 95% confidence intervals (95% CI) using multivariate conditional logistic regression.

Results: Risk for colorectal cancer was not associated with use of statins (odds ratio, 1.02; 95% CI, 0.65-1.59), other lipid-lowering agents (odds ratio, 1.31; 95% CI, 0.70-2.47), angiotensin-converting enzyme inhibitors (odds ratio, 0.98; 95% CI, 0.67-1.43), calcium channel blockers (odds ratio, 1.06; 95% CI, 0.72-1.55), or diuretics (odds ratio, 1.00; 95% CI, 0.70-1.44). Risk did not differ by duration of medication use, including long-term use.

Conclusions: Risk for colorectal cancer was not reduced by use of statins or angiotensin-converting enzyme inhibitors. Other lipid-lowering and antihypertensive medications were also not associated with colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3076–80)
Unintended Effects of Emphasizing Disparities in Cancer Communication to African-Americans
Authors: Nicholson Robert A. , Kreuter Matthew W. , Lapka Christina , Wellborn Rachel , Clark Eddie M. , Sanders-Thompson Vetta , Jacobsen Heather M. , Casey Chris
Published: November 2008

Little is known about how minority groups react to public information that highlights racial disparities in cancer. This double-blind randomized study compared emotional and behavioral reactions to four versions of the same colon cancer (CRC) information presented in mock news articles to a community sample of African-American adults (n = 300). Participants read one of four articles that varied in their framing and interpretation of race-specific CRC mortality data, emphasizing impact (CRC is an important problem for African-Americans), two dimensions of disparity (Blacks are doing worse than Whites and Blacks are improving, but less than Whites), or progress (Blacks are improving over time). Participants exposed to disparity articles reported more negative emotional reactions to the information and were less likely to want to be screened for CRC than those in other groups (both P < 0.001). In contrast, progress articles elicited more positive emotional reactions and participants were more likely to want to be screened. Moreover, negative emotional reaction seemed to mediate the influence of message type on individuals wanting to be screened for CRC. Overall, these results suggest that the way in which disparity research is reported in the medium can influence public attitudes and intentions, with reports about progress yielding a more positive effect on intention. This seems especially important among those with high levels of medical mistrust who are least likely to use the health care system and are thus the primary target of health promotion advertising. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2946–53)
The Influence of Tumor Necrosis Factor-α −308 G/A and IL-6 −174 G/C on Pain and Analgesia Response in Lung Cancer Patients Receiving Supportive Care
Authors: Reyes-Gibby Cielito C. , El Osta Badi , Spitz Margaret R. , Parsons Henrique , Kurzrock Razelle , Wu Xifeng , Shete Sanjay , Bruera Eduardo
Published: November 2008

Introduction: We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non–small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-α (TNF- α-308 G/A), interleukin (IL)-6 −174G/C, and IL-8 −251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment.

Methods: Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine.

Results: Forty-one percent (57 of 140) of the patients reported severe pain (score >7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFα −308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 −174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes.

Conclusions: We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3262–7)
Recent Trends in Black-White Disparities in Cancer Mortality
Authors: DeLancey John Oliver L. , Thun Michael J. , Jemal Ahmedin , Ward Elizabeth M.
Published: November 2008

Despite decreases in overall cancer death rates across all racial and ethnic groups since the early 1990s, racial disparities in cancer mortality persist. We examined temporal trends in Black-White disparities in cancer mortality from all sites combined, smoking-related cancers (lung and a group including oral cavity, pharynx, larynx, esophagus, pancreas, bladder, and kidney), and sites affected, or potentially affected by screening and treatment (breast, prostate, colon/rectum). Death rates, rate differences, and rate ratios comparing Blacks to Whites from 1975 through 2004 were based on mortality data from the National Center for Health Statistics. The Black-White disparity in overall cancer death rates narrowed from the early 1990s through 2004, especially in men. This reduction was driven predominantly by more rapid decreases in mortality from tobacco-related cancers in Black men than White men. In contrast, racial disparities in mortality from cancers potentially affected by screening and treatment increased over most of the interval since 1975. Coordinated efforts to improve early detection and treatment for all segments of the population are essential to eliminate racial disparities in cancer mortality. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2908–12)
Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib
Authors: Fatima Naheed , Yi Ming , Ajaz Sadia , Stephens Robert M. , Stauffer Stacey , Greenwald Peter , Munroe David J. , Ali Iqbal Unnisa
Published: November 2008

It is well established that celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) and a tested chemopreventive agent, has several COX-2–independent activities. In an attempt to better understand COX-2–independent molecular mechanisms underlying the chemopreventive activity of celecoxib, we did global transcription profiling of celecoxib-treated COX-2–positive and COX-2–deficient colorectal cancer cell lines. Celecoxib treatment resulted in significantly altered expression levels of over 1,000 to 3,000 transcripts in these cell lines, respectively. A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. Among these processes, cell proliferation and apoptotic signaling consistently ranked as the highest-scoring Gene Ontology terms and Biocarta Pathways in both COX-2 expresser and nonexpresser cell lines. Altered expression of many of the genes by celecoxib was confirmed by quantitative PCR and at the protein level by Western blotting. Many novel genes emerged from our analysis of global transcription patterns that were not previously reported to be affected by celecoxib. In the future, in-depth work on selected genes will determine if these genes may serve as potential molecular targets for more effective chemopreventive strategies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3051–61)
20 Years into the Gambia Hepatitis Intervention Study: Assessment of Initial Hypotheses and Prospects for Evaluation of Protective Effectiveness Against Liver Cancer
Authors: Viviani Simonetta , Carrieri Patrizia , Bah Ebrima , Hall Andrew J. , Kirk Gregory D. , Mendy Maimuna , Montesano Ruggero , Plymoth Amelie , Sam Omar , Van der Sande Marianne , Whittle Hilton , Hainaut Pierre ,   The Gambia Hepatitis Intervention Study
Published: November 2008

Primary hepatocellular carcinoma is the commonest cancer in The Gambia. The Gambia Hepatitis Intervention Study (GHIS) was established in 1986 to evaluate the protective effectiveness of infant hepatitis B immunization in the prevention of chronic liver disease, particularly, hepatocellular carcinoma and cirrhosis later in adult life. This program was designed based on a series of assumptions. Here, we used data from observational and epidemiologic studies developed since 1986 to examine the validity of these assumptions. We found that (a) hepatitis B vaccine coverage was 15% more than originally assumed, (b) protection against hepatitis B virus (HBV) infection was not dependent on the number of vaccine doses received, (c) perinatal infection with HBV was of negligible importance, and (d) the HBV attributable risk of hepatocellular carcinoma at age <50 was 70% to 80%, lower than initially assumed. Based on these data, the final outcome of the GHIS should be measurable from 2017, sooner than originally assumed. The GHIS strategy takes into account-specific patterns of virus epidemiology and natural history of hepatocellular carcinoma in Africa and provides a model for integrating and evaluating new vaccines into the Expanded Programme of Immunization of sub-Saharan African countries. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3216–24)
Red Meat Intake, Doneness, Polymorphisms in Genes that Encode Carcinogen-Metabolizing Enzymes, and Colorectal Cancer Risk
Authors: Cotterchio Michelle , Boucher Beatrice A. , Manno Michael , Gallinger Steven , Okey Allan B. , Harper Patricia A.
Published: November 2008

Colorectal cancer literature regarding the interaction between polymorphisms in carcinogen-metabolizing enzymes and red meat intake/doneness is inconsistent. A case-control study was conducted to evaluate the interaction between red meat consumption, doneness, and polymorphisms in carcinogen-metabolizing enzymes. Colorectal cancer cases diagnosed 1997 to 2000, ages 20 to 74 years, were identified through the population-based Ontario Cancer Registry and recruited by the Ontario Family Colorectal Cancer Registry. Controls were sex-matched and age group-matched random sample of Ontario population. Epidemiologic and food questionnaires were completed by 1,095 cases and 1,890 controls; blood was provided by 842 and 1,251, respectively. Multivariate logistic regression was used to obtain adjusted odds ratio (OR) estimates. Increased red meat intake was associated with increased colorectal cancer risk [OR (>5 versus ≤2 servings/wk), 1.67 (1.36-2.05)]. Colorectal cancer risk also increased significantly with well-done meat intake [OR (>2 servings/wk well-done versus ≤2 servings/wk rare-regular), 1.57 (1.27-1.93)]. We evaluated interactions between genetic variants in 15 enzymes involved in the metabolism of carcinogens in overcooked meat (cytochrome P450, glutathione S-transferase, UDP-glucuronosyltransferases, SULT, NAT, mEH, and AHR). CYP2C9 and NAT2 variants were associated with colorectal cancer risk. Red meat intake was associated with increased colorectal cancer risk regardless of genotypes; however, CYP1B1 combined variant and SULT1A1-638G>A variant significantly modified the association between red meat doneness intake and colorectal cancer risk. In conclusion, well-done red meat intake was associated with an increased risk of colorectal cancer regardless of carcinogen-metabolizing genotype, although our data suggest that persons with CYP1B1 and SULT1A1 variants had the highest colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3098–107)
Cervical Cancer Control Research in Vietnamese American Communities
Authors: Taylor Victoria M. , Nguyen Tung T. , Jackson J. Carey , McPhee Stephen J.
Published: November 2008

Census data show that the U.S. Vietnamese population now exceeds 1,250,000. Cervical cancer among Vietnamese American women has been identified as an important health disparity. Available data indicate the cervical cancer disparity may be due to low Papanicolaou (Pap) testing rates rather than variations in human papillomavirus infection rates and/or types. The cervical cancer incidence rates among Vietnamese and non-Latina White women in California during 2000 to 2002 were 14.0 and 7.3 per 100,000, respectively. Only 70% of Vietnamese women who participated in the 2003 California Health Interview Survey reported a recent Pap smear compared with 84% of non-Latina White women. Higher levels of cervical cancer screening participation among Vietnamese women are strongly associated with current/previous marriage, having a usual source of care/doctor, and previous physician recommendation. Vietnamese language media campaigns and lay health worker intervention programs have been effective in increasing Pap smear use in Vietnamese American communities. Cervical cancer control programs for Vietnamese women should address knowledge deficits, enable women who are without a usual source of care to find a primary care doctor, and improve patient-provider communication by encouraging health-care providers to recommend Pap testing as well as by empowering women to ask for testing. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2924–30)
Effect of Reproductive Factors and Oral Contraceptives on Breast Cancer Risk inBRCA1/2Mutation Carriers and Noncarriers: Results from a Population-Based Study
Authors: Lee Eunjung , Ma Huiyan , McKean-Cowdin Roberta , Van Den Berg David , Bernstein Leslie , Henderson Brian E. , Ursin Giske
Published: November 2008

Background: Multiparity and breast-feeding reduce breast cancer risk, whereas oral contraceptive use may slightly increase breast cancer risk in the general population. However, the effects of these factors in BRCA1 and BRCA2 mutation carriers are less clear.

Methods: Case patients were 1,469 women from Los Angeles County ages 20 to 49 years with newly diagnosed breast cancer. Control subjects were 444 women without breast cancer, individually matched to a subset of cases on race, age, and neighborhood. BRCA1/2 genes were sequenced in the cases, and odds ratios of breast cancer associated with various reproductive and hormonal factors in BRCA1/2 mutation carriers and noncarriers were estimated using multivariable logistic regression.

Results: Ninety-four women had a deleterious BRCA1 or BRCA2 mutation. Number of full-term pregnancies was inversely associated with breast cancer risk regardless of BRCA1/2 mutation status. Longer breast-feeding duration was protective among noncarriers but not among mutation carriers; however, this apparent effect modification was not statistically significant (P = 0.23). Neither oral contraceptive use overall nor the use of low-dose oral contraceptives was associated with an increased risk of breast cancer in any subgroup.

Conclusions: Our results suggest that parity protects against breast cancer in BRCA1/2 mutation carriers, whereas breast-feeding does not. Our data suggest no association between oral contraceptive use and breast cancer risk in BRCA1/2 mutation carriers. Further confirmation that currently available low-dose oral contraceptives do not increase breast cancer risk in carriers is important from a public health perspective given the high prevalence of oral contraceptive use in the United States. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3170–8)
Vitamin D and Prevention of Colorectal Adenoma: A Meta-analysis
Authors: Wei Melissa Y. , Garland Cedric F. , Gorham Edward D. , Mohr Sharif B. , Giovannucci Edward
Published: November 2008

Background: Vitamin D status is associated inversely with risk of colorectal cancer, but the association with adenoma risk is less clear. This meta-analysis examined the overall relationship between circulating (plasma or serum) 25-hydroxyvitamin D [25(OH)D], vitamin D intake (dietary, supplemental, or total), and colorectal adenoma incidence in published studies.

Methods: A meta-analysis composed of 17 epidemiologic studies [1 cross-sectional, 9 case-control, and 7 cohort or nested case-control studies; 7 on 25(OH)D and 12 on vitamin D intake] published before December 2007 was done to examine the association between circulating 25(OH)D, vitamin D intake, and colorectal adenomas. Summary Peto odds ratios (OR) were computed for overall and stratified analyses.

Results: Circulating 25(OH)D was inversely associated with risk of colorectal adenomas: the OR was 0.70 [95% confidence interval (95% CI), 0.56-0.87] for high versus low circulating 25(OH)D. The highest quintile of vitamin D intake was associated with an 11% marginally decreased risk of colorectal adenomas compared with low vitamin D intake (OR, 0.89; 95% CI, 0.78-1.02). For recurrent adenomas, there was a decreased risk of 12% (95% CI, 0.72-1.07) among individuals with high versus low vitamin D intake. The inverse associations appeared stronger for advanced adenoma [OR, 0.64; 95% CI, 0.45-0.90 for serum 25(OH)D and OR, 0.77; 95% CI, 0.63-0.95 for vitamin D intake], but the number of studies was small.

Conclusions: Both circulating 25(OH)D and vitamin D intake were inversely associated with colorectal adenoma incidence and recurrent adenomas. These results further support a role of vitamin D in prevention of colorectal adenoma incidence and recurrence. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2958–69)
Breast Cancer Incidence and the Effect of Cigarette Smoking in Heterozygous Carriers of Mutations in the Ataxia-Telangiectasia Gene
Authors: Swift Michael , Lukin Jennifer L.
Published: November 2008

Background: Mutations in the ataxia-telangiectasia (A-T) gene cause an autosomal recessive syndrome in homozygotes and compound heterozygotes and predispose female heterozygous carriers to breast cancer. No environmental agent has been previously shown to increase the risk of cancer for women who carry a mutated gene that predisposes to breast cancer. This study assesses the effect of cigarette smoking on the risk of breast cancer in A-T mutation carriers and determines age-specific and cumulative incidence rates for breast cancer among such carriers.

Methods: Clinical data were collected between 1971 and 1999 from blood relatives from 274 families of patients with A-T. The A-T mutation carrier status of 973 females was determined by molecular analysis of blood and tissue samples. The breast cancer rates in carrier smokers and nonsmokers were compared. Age-specific and cumulative breast cancer rates were also compared between carriers and noncarriers using Kaplan-Meier survival curves.

Results: The cumulative incidence through age 80 years was 80% for carriers who smoked and 21% for carriers who never smoked (P = 0.01). Six cases of breast cancer were diagnosed between ages 70 and 79 years among carriers who smoked. The cumulative breast cancer incidence among A-T mutation carriers was 43% by age 80 years, compared with 17% for noncarriers (P = 0.002). Carriers had new incident breast cancers at an annual rate of 1.4% from ages 65 through 79 years; for noncarriers the rate was 0.20%.

Conclusions: A-T carrier females had an elevated risk of breast cancer, most pronounced at older ages, compared with noncarriers, and smoking increased this risk substantially. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3188–92)
Menopausal Hormone Therapy and Breast Cancer Risk in the NIH-AARP Diet and Health Study Cohort
Authors: Brinton Louise A. , Richesson Douglas , Leitzmann Michael F. , Gierach Gretchen L. , Schatzkin Arthur , Mouw Traci , Hollenbeck Albert R. , Lacey James V.
Published: November 2008

Background: Results from the Women's Health Initiative trial raise new questions regarding the effects of estrogen therapy (ET) and estrogen plus progestin therapy (EPT) on breast cancer risk.

Methods: We analyzed data from 126,638 females, ages 50 to 71 years at baseline, who completed two questionnaires (1995-1996 and 1996-1997) as part of the NIH-AARP Diet and Health Cohort Study and in whom 3,657 incident breast cancers were identified through June 30, 2002. Hormone-associated relative risks (RR) and 95% confidence intervals (CI) of breast cancer were estimated via multivariable regression models.

Results: Among thin women (body mass index <25 kg/m2), ET use was associated with a significant 60% excess risk after 10 years of use. EPT was associated with a significantly increased risk among women with intact uteri, with the highest risk among current, long-term (≥10 years) users (RR, 2.44; 95% CI, 2.13-2.79). These risks were slightly higher when progestins were prescribed continuously than sequentially (<15 days/mo; respective RRs of 2.76 versus 2.01). EPT associations were strongest in thin women, but elevated risks persisted among heavy women. EPT use was strongly related to estrogen receptor (ER)-positive tumors, requiring consideration of this variable when assessing relationships according to other clinical features. For instance, ER- ductal tumors were unaffected by EPT use, but all histologic subgroups of ER+ tumors were increased, especially low-grade and mixed ductal-lobular tumors.

Conclusions: Both ET and EPT were associated with breast cancer risks with the magnitude of increase varying according to body mass and clinical characteristics of the tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3150–60)
One-Carbon Metabolism Biomarkers and Risk of Colon and Rectal Cancers
Authors: Weinstein Stephanie J. , Albanes Demetrius , Selhub Jacob , Graubard Barry , Lim Unhee , Taylor Philip R. , Virtamo Jarmo , Stolzenberg-Solomon Rachael
Published: November 2008

Background: Folate intake has been associated with reduced colorectal cancer risk; however, few studies have prospectively examined circulating folate or other related one-carbon biomarkers.

Methods: We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 50- to 69-year-old Finnish men to investigate associations between serum folate, vitamin B6, vitamin B12, riboflavin, and homocysteine and risk of colon and rectal cancers. Controls were alive and cancer-free at the time of case diagnosis and matched 1:1 on age and date of baseline fasting serum collection with cases (152 colon and 126 rectal cancers). Multivariate-adjusted odds ratios and 95% confidence intervals were calculated using conditional logistic regression.

Results: Serum vitamin B6 was inversely associated with colon cancer [odds ratio, 0.30 (95% confidence interval, 0.11-0.82) in the highest versus lowest quintile]. An increased risk of colon cancer was suggested for men in the middle quintile of serum folate, but without indication of a dose-response relationship. None of the other serum biomarkers were associated with colon or rectal cancer, and we observed no interactions with alcohol consumption or methionine or protein intake. A priori combinations of the five one-carbon serum biomarkers provided no clear evidence to support a collective influence on colorectal cancer risk.

Conclusions: Our results support the hypothesis that higher vitamin B6 status may play a role in inhibiting colon cancer carcinogenesis; however, folate and other one-carbon related biomarkers were not associated with colon or rectal cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3233–40)
The CREST Biorepository: A Tool for Molecular Epidemiology and Translational Studies on Malignant Mesothelioma, Lung Cancer, and Other Respiratory Tract Diseases
Authors: Donatella Ugolini , Monica Neri , Aldo Canessa Pier , Cristina Casilli , Giuseppe Catrambone , Paolo Ivaldi Giovanni , Cecilia Lando , Paola Marroni , Michela Paganuzzi , Barbara Parodi , Paola Visconti , Riccardo Puntoni , Stefano Bonassi
Published: November 2008

Objectives: The Cancer of RESpiratory Tract (CREST) biorepository was established to investigate biological mechanisms and to develop tools and strategies for primary and secondary prevention of respiratory tract cancer. The CREST biorepository is focused on pleural malignant mesothelioma, a rare and severe cancer linked to asbestos exposure whose incidence is particularly high in the Ligurian region.

Methods: The CREST biorepository includes biological specimens from (a) patients with pleural malignant mesothelioma and lung cancer, (b) patients with nonneoplastic respiratory conditions, and (c) control subjects. Whole blood, plasma, serum, lymphocytes, pleural fluid, saliva, and biopsies are collected, and a questionnaire is administered. Collection, transportation, and storage are done according to international standards.

Results: As of January 31, 2008, the overall number of subjects recruited was 1,590 (446 lung cancer, 209 pleural malignant mesothelioma, and 935 controls). The biorepository includes a total of 10,055 aliquots (4,741 serum; 3,082 plasma; 1,599 whole blood; 633 pleural fluid; and 561 lymphocytes) and 107 biopsies. Demographic, clinical, and epidemiologic information is collected for each subject and processed in a dedicated database.

Conclusions: The CREST biorepository is a valuable tool for molecular epidemiology and translational studies. This structure relies on a network of contacts with local health districts that allows for an active search for patients. This is a particularly efficient approach, especially when the object of the study is a rare cancer type. The CREST experience suggests that the presence of limited resources can be overcome by the biorepository specialization, the high quality of the epidemiologic information, and the variety of samples. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3013–19)