bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial-cardiac baroreflex function: insights from repeated squat-stand maneuvers
Authors: Zhang Rong , Claassen Jurgen A. H. R. , Shibata Shigeki , Kilic Sinem , Martin-Cook Kristin , Diaz-Arrastia Ramon , Levine Benjamin D.
Published: May 2009

To assess baroreflex function under closed-loop conditions, a new approach was used to generate large and physiological perturbations in arterial pressure. Blood pressure (BP) and R-R interval were recorded continuously in 20 healthy young (33 ± 8 yr) and eight elderly subjects (66 ± 6 yr). Repeated squat-stand maneuvers at the frequencies of 0.05 and 0.1 Hz were performed to produce periodic oscillations in BP to provoke the baroreflex. To assess the effects of the muscle reflex and/or central command on the baroreflex, passive squat-stand maneuvers were conducted using a pulley system to assist changes in body position. Transfer function between changes in BP and R-R interval was estimated to assess the arterial-cardiac baroreflex. Relative to resting conditions, large and coherent oscillations in BP and R-R interval were produced during both active and passive squat-stand maneuvers. However, changes in BP were smaller during passive than during active maneuvers. Changes in R-R interval were reduced commensurately. Therefore, transfer function gain did not change between the two maneuvers. Compared with the young, transfer function gain was reduced and the phase became more negative in the elderly, demonstrating the well-known effects of aging on reducing baroreflex sensitivity. Collectively, these findings suggest that the changes in R-R interval elicited by BP perturbations during squat-stand maneuvers are mediated primarily by a baroreflex mechanism. Furthermore, baroreflex function can be assessed using the transfer function method during large perturbations in arterial pressure.
Improvement of renal hemodynamics during hypertension-induced chronic renal disease: role of EGF receptor antagonism
Authors: Helle Frank , Jouzel Charlotte , Chadjichristos Christos , Placier Sandrine , Flamant Martin , Guerrot Dominique , François Hélène , Dussaule Jean-Claude , Chatziantoniou Christos
Published: May 2009

The present study investigated mechanisms of regression of renal disease after severe proteinuria by focusing on the interaction among EGF receptors, renal hemodynamics, and structural lesions. The nitric oxide (NO) inhibitor NG-nitro-l-arginine-methyl ester (l-NAME) was administered chronically in Sprague-Dawley rats. When proteinuria exceeded 2 g/mmol creatinine, animals were divided into three groups for an experimental period of therapy of 2 wk; in one group, l-NAME was removed to allow reactivation of endogenous NO synthesis; in the two other groups, l-NAME removal was combined with EGF or angiotensin receptor type 1 (AT1) antagonism. l-NAME removal partially reduced mean arterial pressure and proteinuria and increased renal blood flow (RBF), but not microvascular hypertrophy. Progression of structural damage was stopped, but not reversed. The administration of an EGF receptor antagonist did not have an additional effect on lowering blood pressure or on renal inflammation but did normalize RBF and afferent arteriole hypertrophy; the administration of an AT1antagonist normalized all measured functional and structural parameters. Staining with a specific marker of endothelial integrity indicated loss of functional endothelial cells in the l-NAME removal group; in contrast, in the animals treated with an EGF or AT1receptor antagonist, functional endothelial cells reappeared at levels equal to control animals. In addition, afferent arterioles freshly isolated from the l-NAME removal group showed an exaggerated constrictor response to endothelin; this response was blunted in the vessels isolated from the EGF or AT1receptor antagonist groups. The EGF receptor is an important mediator of endothelial dysfunction and contributes to the decline of RBF in the chronic kidney disease induced by NO deficiency. The EGF receptor antagonist-induced improvement of RBF is important but not sufficient for a complete reversal of renal disease, because it has little effect on renal inflammation. To achieve full recovery, it is necessary to apply AT1receptor antagonism.
Novel use of ultrasound to examine regional blood flow in the mouse kidney
Authors: Sullivan Jennifer C. , Wang Bin , Boesen Erika I. , D'Angelo Gerard , Pollock Jennifer S. , Pollock David M.
Published: May 2009

Conventional methods used for measuring regional renal blood flow, such as laser-Doppler flowmetry, are highly invasive, and each measurement is restricted to a discrete location. The aim of this study was to determine whether ultrasound imaging in conjunction with enhanced contrast agent (microbubbles; Vevo MicroMarker, VisualSonics) could provide a viable noninvasive alternative. This was achieved by determining changes in renal cortical and medullary rate of perfusion in response to a bolus injection of endothelin-1 (ET-1; 0.6, 1.0, or 2.0 nmol/kg) and comparing these responses to those observed in separate groups of mice with conventional laser-Doppler methods. Intravenous infusion of ET-1 in anesthetized male C57bl/6 mice resulted in a dose-dependent increase in mean arterial pressure and a dose-dependent decrease in total renal blood flow as measured by pulse-wave Doppler. ET-1 infusion resulted in a dose-dependent decrease in regional kidney perfusion as measured by both ultrasound with enhanced contrast agent and laser-Doppler measurements, verifying the use of ultrasound to measure regional kidney perfusion. Noted limitations of ultrasound imaging compared with laser-Doppler flowmetry included a lower degree of sensitivity to changes in tissue perfusion and the inability to assess rapid or transient changes in tissue perfusion. In conclusion, ultrasound represents an effective and noninvasive method for the measurement of relatively short-term, steady-state changes in regional blood flow in the mouse kidney.
Sp1trans-activates the murine H+-K+-ATPase α2-subunit gene
Authors: Yu Zhiyuan , Li Mei , Zhang Dongyu , Xu William , Kone Bruce C.
Published: May 2009

The H+-K+-ATPase α2(HKα2) gene of the renal collecting duct and distal colon plays a central role in potassium and acid-base homeostasis, yet its transcriptional control remains poorly characterized. We previously demonstrated that the proximal 177 bp of its 5′-flanking region confers basal transcriptional activity in murine inner medullary collecting duct (mIMCD3) cells and that NF-κB and CREB-1 bind this region to alter transcription. In the present study, we sought to determine whether the −144/−135 Sp element influences basal HKα2 gene transcription in these cells. Electrophoretic mobility shift and supershift assays using probes for −154/−127 revealed Sp1-containing DNA-protein complexes in nuclear extracts of mIMCD3 cells. Chromatin immunoprecipitation (ChIP) assays demonstrated that Sp1, but not Sp3, binds to this promoter region of the HKα2 gene in mIMCD3 cells in vivo. HKα2 minimal promoter-luciferase constructs with point mutations in the −144/−135 Sp element exhibited much lower activity than the wild-type promoter in transient transfection assays. Overexpression of Sp1, but not Sp3, trans-activated an HKα2 proximal promoter-luciferase construct in mIMCD3 cells as well as in SL2 insect cells, which lack Sp factors. Conversely, small interfering RNA knockdown of Sp1 inhibited endogenous HKα2 mRNA expression, and binding of Sp1 to chromatin associated with the proximal HKα2 promoter without altering the binding or regulatory influence of NF-κB p65 or CREB-1 on the proximal HKα2 promoter. We conclude that Sp1 plays an important and positive role in controlling basal HKα2 gene expression in mIMCD3 cells in vivo and in vitro.
TNF induces caspase-dependent inflammation in renal endothelial cells through a Rho- and myosin light chain kinase-dependent mechanism
Authors: Wu Xiaoyan , Guo Rongqing , Chen Peili , Wang Quan , Cunningham Patrick N.
Published: May 2009

The pathogenesis of LPS-induced acute kidney injury (AKI) requires signaling through tumor necrosis factor-α (TNF) receptor 1 (TNFR1), which within the kidney is primarily located in the endothelium. We showed previously that caspase inhibition protected mice against LPS-induced AKI and in parallel significantly inhibited LPS-induced renal inflammation. Therefore we hypothesized that caspase activation amplifies TNF-induced inflammation in renal endothelial cells (ECs). In cultured renal ECs, TNF induced apoptosis through a caspase-8-dependent pathway. TNF caused translocation of the p65 subunit of NF-κB to the nucleus, resulting in upregulation of inflammatory markers such as adhesion molecules ICAM-1 and VCAM-1. However, the broad-spectrum caspase inhibitor Boc-d-fmk reduced NF-kB activation as assessed by gel shift assay, reduced phosphorylation of subunit IκBα, and significantly inhibited TNF-induced expression of ICAM-1 and VCAM-1 as assessed by both real-time PCR and flow cytometry. Broad-spectrum caspase inhibition markedly inhibited neutrophil adherence to the TNF-activated endothelial monolayer, supporting the functional significance of this effect. Specific inhibitors of caspases-8 and -3, but not of caspase-1, reduced TNF-induced NF-κB activation. Caspase inhibition also reduced TNF-induced myosin light chain (MLC)-2 phosphorylation, and activation of upstream regulator RhoA. Consistent with this, MLC kinase (MLCK) inhibitor ML-7 reduced TNF-induced NF-κB activation. Thus caspase activation influences NF-κB signaling via its affect on cytoskeletal changes occurring through RhoA and MLCK pathways. These cell culture experiments support a role for caspase activation in TNF-induced inflammation in the renal endothelium, a key event in LPS-induced AKI.
Expression of the RNA-stabilizing protein HuR in ischemia-reperfusion injury of rat kidney
Authors: Ayupova Dina A. , Singh Mamata , Leonard Ellen C. , Basile David P. , Lee Beth S.
Published: May 2009

The RNA-binding protein human antigen R (HuR) participates in the posttranscriptional regulation of mRNAs bearing 3′ AU-rich and U-rich elements, which HuR can stabilize under conditions of cellular stress. Using the LLC-PK1proximal tubule cell line model, we recently suggested a role for HuR in protecting kidney epithelia from injury during ischemic stress (Jeyaraj S, Dakhlallah D, Hill SR, Lee BS. J Biol Chem 280: 37957–37964, 2005; Jeyaraj SC, Dakhlallah D, Hill SR, Lee BS. Am J Physiol Renal Physiol 291: F1255–F1263, 2006). Here, we have extended this work to show that small interfering RNA-mediated suppression of HuR in LLC-PK1cells increased apoptosis during energy depletion, while overexpression of HuR diminished apoptosis. Suppression of HuR also resulted in diminished levels of key cell survival proteins such as Bcl-2 and Hsp70. Furthermore, rat kidneys were subjected in vivo to transient ischemia followed by varying periods of reperfusion. Ischemia and reperfusion (I/R) affected intensity and distribution of HuR in a nephron segment-specific manner. Cells of the proximal tubule, which are most sensitive to I/R injury, demonstrated a transient shift of HuR to the cytoplasm immediately following ischemia. Over a 14-day period following the onset of reperfusion, nuclear and total HuR protein gradually increased in cortical and medullary proximal tubules, but not in non-proximal tubule cells. HuR mRNA was expressed in two forms with alternate transcriptional start sites that increased over a 14-day I/R period, and in vitro studies suggest selective translatability of these two mRNAs. Baseline and I/R-stimulated levels of HuR mRNA did not parallel those of HuR protein, suggesting translational control of HuR expression, particularly in medullary proximal tubules. These findings suggest that alterations in distribution and expression of the antiaptotic protein HuR specifically in cells of the proximal tubule effect a protective mechanism during and following I/R injury in kidney.
The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability
Authors: Lee Eun Young , Chung Choon Hee , Khoury Charbel C. , Yeo Tet Kin , Pyagay Petr E. , Wang Amy , Chen Sheldon
Published: May 2009

The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-β (TGF-β) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-β type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-β-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-β were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-β signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria.
Functional Phase Response Curves: A Method for Understanding Synchronization of Adapting Neurons
Authors: Cui Jianxia , Canavier Carmen C. , Butera Robert J.
Published: May 2009

Phase response curves (PRCs) for a single neuron are often used to predict the synchrony of mutually coupled neurons. Previous theoretical work on pulse-coupled oscillators used single-pulse perturbations. We propose an alternate method in which functional PRCs (fPRCs) are generated using a train of pulses applied at a fixed delay after each spike, with the PRC measured when the phasic relationship between the stimulus and the subsequent spike in the neuron has converged. The essential information is the dependence of the recovery time from pulse onset until the next spike as a function of the delay between the previous spike and the onset of the applied pulse. Experimental fPRCs in Aplysia pacemaker neurons were different from single-pulse PRCs, principally due to adaptation. In the biological neuron, convergence to the fully adapted recovery interval was slower at some phases than that at others because the change in the effective intrinsic period due to adaptation changes the effective phase resetting in a way that opposes and slows the effects of adaptation. The fPRCs for two isolated adapting model neurons were used to predict the existence and stability of 1:1 phase-locked network activity when the two neurons were coupled. A stability criterion was derived by linearizing a coupled map based on the fPRC and the existence and stability criteria were successfully tested in two-simulated-neuron networks with reciprocal inhibition or excitation. The fPRC is the first PRC-based tool that can account for adaptation in analyzing networks of neural oscillators.
Identifying the Functional Role of Martinotti Cells in Cortical Sensory Processing
Authors: Cottam James C. H.
Published: May 2009

Inhibitory interneurons are highly diverse, although the functional significance of their diversity is not yet well understood. This presents a barrier to understanding neural computation at the local circuit level. This review focuses on a recent study by Murayama et al. who used a novel in vivo technique in neocortex to demonstrate a specific sensory processing function of dendritic-targeting Martinotti interneurons. The function of Martinotti cells arises from their interaction with layer 5 pyramidal cell dendrites.
Asymmetric Activation of Motor Cortex Controlling Human Anterior Digastric Muscles During Speech and Target-Directed Jaw Movements
Authors: Sowman Paul F. , Flavel Stanley C. , McShane Christie L. , Sakuma Shigemitsu , Miles Timothy S. , Nordstrom Michael A.
Published: May 2009

Like most of the cranial muscles involved in speech, the trigeminally innervated anterior digastric muscles are controlled by descending corticobulbar projections from the primary motor cortex (M1) of each hemisphere. We hypothesized that changes in corticobulbar M1 excitability during speech production would show a hemispheric asymmetry favoring the left side, which is the dominant hemisphere for language processing in most strongly right handed subjects. Fifteen volunteers aged 24.5 ± 5.3 (SD) yr participated. All subjects were strongly right handed as reported by questionnaire. A surface electromyograph (EMG) was recorded bilaterally from digastrics and jaw movement detected by an accelerometer attached to a lower incisor. Focal transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability of the digastric representation in M1 of both hemispheres during four tasks: 1) static isometric contraction of digastrics; 2) speaking a single word; 3) visually guided, nonspeech jaw movement that matched the jaw kinematics recorded during task 2; and 4) reciting a sentence. Background EMG was well matched in all tasks and jaw kinematics were similar around the time of the TMS pulse for tasks 2–4. TMS resting thresholds and digastric muscle-evoked potential (MEP) size during isometric contraction did not differ for TMS over left versus right M1. MEPs elicited by TMS over left, but not right M1 increased in size during speech and nonspeech jaw movement compared with isometric contraction. We conclude that left corticobulbar M1 is preferentially engaged for descending control of digastric muscles during speech and the performance of a rapid jaw movement to match a target kinematic profile.
Impedance Control and Its Relation to Precision in Orofacial Movement
Authors: Laboissière Rafael , Lametti Daniel R. , Ostry David J.
Published: May 2009

Speech production involves some of the most precise and finely timed patterns of human movement. Here, in the context of jaw movement in speech, we show that spatial precision in speech production is systematically associated with the regulation of impedance and in particular, with jaw stiffness—a measure of resistance to displacement. We estimated stiffness and also variability during movement using a robotic device to apply brief force pulses to the jaw. Estimates of stiffness were obtained using the perturbed position and force trajectory and an estimate of what the trajectory would be in the absence of load. We estimated this “reference trajectory” using a new technique based on Fourier analysis. A moving-average (MA) procedure was used to estimate stiffness by modeling restoring force as the moving average of previous jaw displacements. The stiffness matrix was obtained from the steady state of the MA model. We applied this technique to data from 31 subjects whose jaw movements were perturbed during speech utterances and kinematically matched nonspeech movements. We observed systematic differences in stiffness over the course of jaw-lowering and jaw-raising movements that were correlated with measures of kinematic variability. Jaw stiffness was high and variability was low early and late in the movement when the jaw was elevated. Stiffness was low and variability was high in the middle of movement when the jaw was lowered. Similar patterns were observed for speech and nonspeech conditions. The systematic relationship between stiffness and variability points to the idea that stiffness regulation is integral to the control of orofacial movement variability.
Timing-Specific Transfer of Adapted Muscle Activity After Walking in an Elastic Force Field
Authors: Blanchette Andreanne , Bouyer Laurent J.
Published: May 2009

Human locomotion results from interactions between feedforward (central commands from voluntary and automatic drive) and feedback (peripheral commands from sensory inputs) mechanisms. Recent studies have shown that locomotion can be adapted when an external force is applied to the lower limb. To better understand the neural control of this adaptation, the present study investigated gait modifications resulting from exposure to a position-dependent force field. Ten subjects walked on a treadmill before, during, and after exposure to a force field generated by elastic tubing that pulled the foot forward and up during swing. Lower limb kinematics and electromyographic (EMG) activity were recorded during each walking period. During force field exposure, peak foot velocity was initially increased by 38%. As subjects adapted, peak foot velocity gradually returned to baseline in ≤125 strides. In the adapted state, hamstring EMG activity started earlier (16% before toe off) and remained elevated throughout swing. After force field exposure, foot velocity was initially reduced by 22% and returned to baseline in 9–51 strides. Aftereffects in hamstring EMGs consisted of increased activity around toe off. Contrary to the adapted state, this increase was not maintained during the rest of swing. Together, these results suggest that while the neural control of human locomotion can adapt to force field exposure, the mechanisms underlying this adaptation may vary according to the timing in the gait cycle. Adapted hamstring EMG activity may rely more on feedforward mechanisms around toe off and more on feedback mechanisms during the rest of swing.
Eccentric Muscle Damage Has Variable Effects on Motor Unit Recruitment Thresholds and Discharge Patterns in Elbow Flexor Muscles
Authors: Dartnall Tamara J. , Rogasch Nigel C. , Nordstrom Michael A. , Semmler John G.
Published: May 2009

The purpose of this study was to determine the effect of eccentric muscle damage on recruitment threshold force and repetitive discharge properties of low-threshold motor units. Ten subjects performed four tasks involving isometric contraction of elbow flexors while electromyographic (EMG) data were recorded from human biceps brachii and brachialis muscles. Tasks were 1) maximum voluntary contraction (MVC); 2) constant-force contraction at various submaximal targets; 3) motor unit recruitment threshold task; and 4) minimum motor unit discharge rate task. These tasks were performed on three separate days before, immediately after, and 24 h after eccentric exercise of elbow flexor muscles. MVC force declined (42%) immediately after exercise and remained depressed (29%) 24 h later, indicative of muscle damage. Mean motor unit recruitment threshold for biceps brachii was 8.4 ± 4.2% MVC, ( n = 34) before eccentric exercise, and was reduced by 41% (5.0 ± 3.0% MVC, n = 34) immediately after and by 39% (5.2 ± 2.5% MVC, n = 34) 24 h after exercise. No significant changes in motor unit recruitment threshold were observed in the brachialis muscle. However, for the minimum tonic discharge rate task, motor units in both muscles discharged 11% faster (10.8 ± 2.0 vs. 9.7 ± 1.7 Hz) immediately after ( n = 29) exercise compared with that before ( n = 32). The minimum discharge rate variability was greater in brachialis muscle immediately after exercise (13.8 ± 3.1%) compared with that before (11.9 ± 3.1%) and 24 h after exercise (11.7 ± 2.4%). No significant changes in minimum discharge rate variability were observed in the biceps brachii motor units after exercise. These results indicate that muscle damage from eccentric exercise alters motor unit recruitment thresholds for ≥24 h, but the effect is not the same in the different elbow flexor muscles.
Investigations on the Effects of Dietary Essential Oils and Different Husbandry Conditions on the Gut Ecology in Piglets after Weaning
Authors: Janczyk P. , Pieper R. , Urubschurov V. , Wendler K. R. , Souffrant W. B.
Published: May 2009

Essential oils (EO) are being considered as possible alternatives to in-feed antibiotic growth promoters in pig nutrition. The effects of an EO mixture consisting of limonene, eugenol and pinene (10.0, 2.0, and 4.8 mg/kg diet, resp.) on gut physiology and ecology were studied in piglets. The experiment was conducted at low (commercial farm) and high hygienic conditions (experimental farm), to elucidate interactions between EO supplementation and husbandry methods. Piglets were weaned at 28 days of age, when they were offered either a control diet (C) or C with EO. Four piglets were sacrificed in each group on day 29, 30, 33 and 39. Digesta from the third distal part of the small intestine and from the colon were sampled and analysed for pH, dry matter, lactic acid, short chain fatty acids and ammonia concentrations. Enterobacteria, enterococci, lactobacilli and yeast counts were obtained by plating. Genomic DNA was extracted from digesta and polymerase chain reaction—denaturing gradient gel electrophoresis was performed. Individual microbial communities were identified at each farm. Age affected the intestinal parameters. No effects of the EO with exception for a significant reduction in colon bacterial diversity at 39 days of age could be recorded at experimental farm.
A Link between Adolescent Nicotine Metabolism and Smoking Topography
Authors: Moolchan Eric T. , Parzynski Craig S. , Jaszyna-Gasior Maria , Collins Charles C. , Leff Michelle K. , Zimmerman Debra L.
Published: May 2009

Adult slow nicotine metabolizers have lower smoke exposure, carbon monoxide levels, and plasma nicotine levels than normal and fast metabolizers. Emerging evidence suggests nicotine metabolism influences smoking topography. This study investigated the association of nicotine metabolism (the ratio of plasma 3-hydroxycotinine to cotinine; 3OHCOT/COT) with smoking topography in adolescent smokers (n = 85; 65% female, 68% European American; mean age, 15.3 ± 1.2 years; mean cigarettes per day, 18.5 ± 8.5; mean Fagerström Test for Nicotine Dependence, 7.0 ± 1.2) presenting for a nicotine replacement therapy trial. Measures obtained included puff volume, interpuff interval, number of puffs, puff duration, and puff velocity. Linear regression analysis controlling for hormonal contraception use showed that 3OHCOT/COT ratios predicted mean puff volume in the overall sample (t = 2.126; P = 0.037; adjusted R2 = 0.067). After gender stratification, faster metabolism predicted higher mean puff volume (t = 2.81; P = 0.009; adjusted R2 = 0.192) but fewer puffs (t = −3.160; P = 0.004; adjusted R2 = 0.237) and lower mean puff duration (t = −2.06; P = 0.048; adjusted R2 = 0.101) among boys only, suggesting that as nicotine metabolism increases, puff volume increases but puffing frequency decreases. No significant relationships were found between nicotine metabolism and total puff volume, mean puff duration, interpuff interval, or puff velocity. If confirmed in a broader sample of adolescent smokers, these findings suggest that as among dependent adult smokers, rate of metabolism among adolescent boys is linked to select parameters of puffing behavior that may affect cessation ability. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1578–83)
Autoantibody to Tumor Antigen, Alpha 2-HS Glycoprotein: A Novel Biomarker of Breast Cancer Screening and Diagnosis
Authors: Yi Jae Kyo , Chang Jong Wook , Han Wonshik , Lee Jong Won , Ko Eunyoung , Kim Dong Hyun , Bae Ji-Yeon , Yu Jonghan , Lee Cheolju , Yu Myeong-Hee , Noh Dong-Young
Published: May 2009

We sought to identify a new serum biomarker for breast cancer screening and diagnosis using stepwise proteomic analysis of sera from breast cancer patients to detect the presence of autoantibodies that react with urinary protein. Two-dimensional immunoblotting was done for screening autoimmunogenic tumor antigens in the urine of breast cancer patients. Reactive spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among urinary proteins separated by two-dimensional electrophoresis, 13 spots showed strong reactivity with pooled sera from breast cancer patients or control sera. By mass spectrometry, we identified α 2-HS glycoprotein (AHSG) as a tumor antigen. Peripheral blood was obtained from 81 women diagnosed with breast cancer before surgery and 73 female donors without evidence of any malignancy for the individual analysis. In one-dimensional Western blot analysis, AHSG autoantibody was detected in 64 of 81 breast cancer patients (79.1%) and in 7 of 73 controls (9.6%). The sensitivity of this test in breast cancer patients was 79.0%. Our results suggest that AHSG and anti-AHSG autoantibody may be useful serum biomarkers for breast cancer screening and diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1357–64)
The Association between Diet and Serum Concentrations of IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 in the European Prospective Investigation into Cancer and Nutrition
Authors: Crowe Francesca L. , Key Timothy J. , Allen Naomi E. , Appleby Paul N. , Roddam Andrew , Overvad Kim , Grønbæk Henning , Tjønneland Anne , Halkjær Jutte , Dossus Laure , Boeing Heiner , Kröger Janine , Trichopoulou Antonia , Dilis Vardis , Trichopoulos Dimitrios , Boutron-Ruault Marie-Christine , De Lauzon Blandine , Clavel-Chapelon Françoise , Palli Domenico , Berrino Franco , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita H. Bas , Vrieling Alina , van Gils Carla H. , Peeters Petra H.M. , Gram Inger T. , Skeie Guri , Lund Eiliv , Rodríguez Laudina , Jakszyn Paula , Molina-Montes Esther , Tormo María J. , Barricarte Aurelio , Larrañaga Nerea , Khaw Kay-Tee , Bingham Sheila , Rinaldi Sabina , Slimani Nadia , Norat Teresa , Gallo Valentina , Riboli Elio , Kaaks Rudolf
Published: May 2009

Circulating concentrations of insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBP) have been associated with the risk of several types of cancer. Dietary correlates of IGF-I and IGFBPs are not yet well established. The objective of this study was to assess the association between dietary intake and serum concentrations of IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 in a cross-sectional analysis of 4,731 men and women taking part in the European Prospective Investigation into Cancer and Nutrition. Diet was assessed using country-specific validated dietary questionnaires. Serum concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 were measured, and the associations between diet and IGF-I and IGFBPs were assessed using multiple linear regression adjusting for sex, age, body mass index, smoking status, and alcohol and energy intake. Each 1 SD increment increase in total and dairy protein and calcium intake was associated with an increase in IGF-I concentration of 2.5%, 2.4%, and 3.3%, respectively (P for trend <0.001 for all) and a decrease in IGFBP-2 of 3.5%, 3.5%, and 5.4% (P for trend <0.001 for all), respectively. There were no significant associations between the intake of protein or calcium from nondairy sources and IGF-I. The results from this large cross-sectional analysis show that either the intake of dairy protein or calcium is an important dietary determinant of IGF-I and IGFBP-2 concentrations; however, we suggest that it is more likely to be protein from dairy products. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1333–40)
MutL-Homolog 1 Expression and Risk of Incident, Sporadic Colorectal Adenoma: Search for Prospective Biomarkers of Risk for Colorectal Cancer
Authors: Sidelnikov Eduard , Bostick Roberd M. , Flanders W. Dana , Long Qi , Cohen Vaunita L. , Dash Chiranjeev , Seabrook March E. , Fedirko Veronika
Published: May 2009

To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those ≥55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential “treatable” biomarker of risk for colorectal neoplasms. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1599–609)
Racial Variation in Sex Steroid Hormones and the Insulin-Like Growth Factor Axis in Umbilical Cord Blood of Male Neonates
Authors: Rohrmann Sabine , Sutcliffe Catherine G. , Bienstock Jessica L. , Monsegue Deborah , Akereyeni Folasade , Bradwin Gary , Rifai Nader , Pollak Michael N. , Agurs-Collins Tanya , Platz Elizabeth A.
Published: May 2009

Background: To address whether umbilical cord blood concentrations of sex steroid hormones and the insulin-like growth factor (IGF) axis differ between African-American and White male neonates.

Methods: In 2004 and 2005, venous cord blood samples were collected from 75 African-American and 38 White male full-term uncomplicated births along with birth weight, placental weight, mother's age and parity, and time of birth. Testosterone, androstanediol glucuronide, estradiol, and sex hormone binding globulin (SHBG) were measured by immunoassay, and IGF-I, IGF-2, and IGF binding protein (BP)-3 by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed.

Results: Androstanediol glucuronide, estradiol, and SHBG concentrations did not differ by race; however, the molar ratio of testosterone to SHBG was higher in African-American than White male babies after adjustment (P = 0.01). Both before and after adjustment, Whites had higher concentrations of IGF-I (adjusted; White, African-American, 93.1, 71.9 ng/mL), IGF-2 (537.3-474.8 ng/mL), and IGFBP-3 (1,673-1,482 ng/mL) than African-Americans (P < 0.05), although the molar ratio of IGF-I plus IGF-2 to IGFBP-3 did not differ by race.

Conclusion: The higher cord blood testosterone to SHBG ratio in African-American compared with White male babies after taking into account maternal and birth factors is compatible with the hypothesis that differences in androgen levels in utero contribute to their higher prostate cancer risk, although we would have expected crude differences as well. Lower cord blood IGF-I and IGF-2 levels in African-American compared with White male babies are not consistent with the hypothesis that differences in growth factor levels contribute to their higher prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1484–91)
Marijuana Smoking and the Risk of Head and Neck Cancer: Pooled Analysis in the INHANCE Consortium
Authors: Berthiller Julien , Lee Yuan-chin Amy , Boffetta Paolo , Wei Qingyi , Sturgis Erich M. , Greenland Sander , Morgenstern Hal , Zhang Zuo-Feng , Lazarus Philip , Muscat Joshua , Chen Chu , Schwartz Stephen M. , Eluf Neto José , Wünsch Filho Victor , Koifman Sergio , Curado Maria Paula , Matos Elena , Fernandez Leticia , Menezes Ana , Daudt Alexander W. , Ferro Gilles , Brennan Paul , Hashibe Mia
Published: May 2009

Background: Marijuana contains carcinogens similar to tobacco smoke and has been suggested by relatively small studies to increase the risk of head and neck cancer (HNC). Because tobacco is a major risk factor for HNC, large studies with substantial numbers of never tobacco users could help to clarify whether marijuana smoking is independently associated with HNC risk.

Methods: We pooled self-reported interview data on marijuana smoking and known HNC risk factors on 4,029 HNC cases and 5,015 controls from five case-control studies within the INHANCE Consortium. Subanalyses were conducted among never tobacco users (493 cases and 1,813 controls) and among individuals who did not consume alcohol or smoke tobacco (237 cases and 887 controls).

Results: The risk of HNC was not elevated by ever marijuana smoking [odds ratio (OR), 0.88; 95% confidence intervals (95% CI), 0.67-1.16], and there was no increasing risk associated with increasing frequency, duration, or cumulative consumption of marijuana smoking. An increased risk of HNC associated with marijuana use was not detected among never tobacco users (OR, 0.93; 95% CI, 0.63-1.37; three studies) nor among individuals who did not drink alcohol and smoke tobacco (OR, 1.06; 95% CI, 0.47-2.38; two studies).

Conclusion: Our results are consistent with the notion that infrequent marijuana smoking does not confer a risk of these malignancies. Nonetheless, because the prevalence of frequent marijuana smoking was low in most of the contributing studies, we could not rule out a moderately increased risk, particularly among subgroups without exposure to tobacco and alcohol. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1544–51)
Genetic Variation in the SST Gene and its Receptors in Relation to Circulating Levels of Insulin-Like Growth Factor-I, IGFBP3, and Prostate Cancer Risk
Authors: Johansson Mattias , McKay James D. , Wiklund Fredrik , Rinaldi Sabina , Hallmans Göran , Bälter Katarina , Adami Hans-Olov , Grönberg Henrik , Stattin Pär , Kaaks Rudolf
Published: May 2009

Background: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels.

Materials and Methods: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC).

Results: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of ∼11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 × 10−5) and IGFI (P = 0.0004) hormone levels.

Conclusions: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1644–50)
Serum Folate and Cancer Mortality Among U.S. Adults: Findings from the Third National Health and Nutritional Examination Survey Linked Mortality File
Authors: Yang Quanhe , Bostick Roberd M. , Friedman J.M. , Flanders W. Dana
Published: May 2009

Background: The relation between folate status and cancer is controversial. Several epidemiologic studies have suggested that increased folate intake is associated with reduced risk of various cancers, others have found no such associations, and a few have suggested that high folate intake might increase the risk of certain cancers.

Methods: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) Mortality File, a prospective cohort study of a nationally representative sample of 14,611 U.S. adults, we conducted Cox proportional hazards regression modeling to investigate the association of baseline serum folate concentrations and all-cancer mortality determined from linked death certificate data.

Results: Relative to the lowest quintile of serum folate (<3.0 ng/mL), the multivariable-adjusted hazard ratios across quintiles 2 to 5 were: 1.61 [95% confidence interval (95% CI), 1.11-2.32], 1.00 (95% CI, 0.65-1.49), 1.39 (95% CI, 0.96-2.03), and 0.85 (95% CI, 0.59-1.22). These findings did not differ substantially by age or sex, but the higher risk for those in the second quintile appeared limited to non-Hispanic whites.

Conclusion: These findings suggest that there may be a nonlinear relationship between folate status and the risk of all-cancer mortality such that persons with low, but not grossly deficient, serum blood folate concentrations may be at increased risk. Further study is needed to determine whether these findings are due to chance, and if not, to clarify their biological basis. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1439–47)
Risk of Endometrial Cancer in Relation to Medical Conditions and Medication Use
Authors: Fortuny Joan , Sima Camelia , Bayuga Sharon , Wilcox Homer , Pulick Katherine , Faulkner Shameka , Zauber Ann G. , Olson Sara H.
Published: May 2009

We studied the relation of medical conditions related to obesity and medications used for these conditions with endometrial cancer. We also investigated the association of other medical conditions and medications with risk. This U.S. population-based case-control study included 469 endometrial cancer cases and 467 controls. Information on putative risk factors for endometrial cancer was collected through personal interviews. We asked women about their medical history and medications used for six months or longer and the number of years each medication was taken. Risk was strongly associated with increasing obesity (P for trend < 0.001). Among the conditions related to obesity, and after adjustment for age, body mass index, and other risk factors and conditions, uterine fibroids were independently related to an increased cancer risk [adjusted odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.2-2.5]. Although hypertension was not significantly related to endometrial cancer after adjustment for age and body mass index, the use of thiazide diuretics was independently associated with increased risk (OR, 1.8; 95% CI, 1.1-3.0). Anemia was associated with decreased risk (OR, 0.6; 95% CI, 0.5-0.9). Use of nonsteroidal anti-inflammatory drugs was related to a decreased risk (OR, 0.7; 95% CI, 0.5-0.97). To our knowledge, the observation about thiazide diuretics is novel and requires confirmation in other studies and populations. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1448–56)
Screening for Gastric Cancer in Korea: Population-Based Preferences for Endoscopy versus Upper Gastrointestinal Series
Authors: Choi Kui Son , Kwak Min-Son , Lee Hoo-yeon , Jun Jae Kwan , Hahm Myung-Il , Park Eun-Cheol
Published: May 2009

This study assessed the screening rates for gastric cancer by two different screening methods, upper gastrointestinal (UGI) series and endoscopy; intentions to undergo future gastric cancer screening; and the preferred method of screening. The study population was derived from the 2006 Korean National Cancer Screening Survey. The Korean National Cancer Screening Survey is an annual cross-sectional survey that uses nationally representative random sampling to investigate cancer screening rates. A total of 1,625 Koreans over 40 years of age participated in this study. Logistic regression was used to identify the factors associated with undergoing gastric cancer screening, having an intention to be screened, and preferring one of the two screening tests. Among the 1,625 subjects, 15.1% had received a UGI, 33.2% had received an endoscopy, and 43.1% had undergone either or both of the tests in the previous 2 years. About 52% of people reported the intention to be screened within the next 2 years. The odds ratio for intending to be screened was 11.8 and 6.2 higher among those who had undergone a prior UGI test and an endoscopy test within the previous 2 years, respectively, than for those who had never been screened. Among the 1,625 individuals, 67% chose endoscopy and 33% UGI for their preferred future screening method. Collectively, our results highlight the preference for endoscopy testing as a gastric cancer screening method. Providers' assessments of individuals' screening preferences in combination with intervention strategies to promote performance of the preferred test may increase patient compliance with gastric cancer screening recommendations. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1390–8)
A Decreased Ratio of Laminin-332 β3 to γ2 Subunit mRNA is Associated with Poor Prognosis in Colon Cancer
Authors: Guess Cherise M. , LaFleur Bonnie J. , Weidow Brandy L. , Quaranta Vito
Published: May 2009

Laminin-332 (Ln-332) is a heterotrimeric glycoprotein (α3β3γ2) unique to epithelial cells with crucial roles in signaling, adhesion, and migration. Altered localization or expression levels of Ln-332, particularly its γ2 subunit, are of prognostic value in a variety of cancers. However, the lack of standardized methodology and the limited quantification of previous study results have left unanswered questions, including the role of γ2 transcript variants and whether differential expression of this chain represents dysregulation of the whole heterotrimer. Herein, we test the hypothesis that mRNA changes in one or more Ln-332 encoding genes can be used to distinguish between early- and advanced-stage cancer specimens and shed light on mechanistic questions raised by previous studies. Statistical analyses of human microarray data from the publicly available expression project in Oncology (expO) dataset, including examination of the distributions of Ln-332 subunit mRNA levels, identified a significant decrease in the Ln-332 β3:γ2 mRNA ratio between normal (n = 10) and early-stage colon cancer (n = 29) specimens. The β3:γ2 ratio was further decreased in metastatic colon cancer (n = 41) compared with early-stage samples. Our findings raise the possibility that Ln-332 γ2 may be a therapeutic target against metastatic colon cancer because a lowered β3:γ2 ratio would reduce expression of heterotrimeric Ln-332 and increase monomeric γ2 secretion. Further, standardized, quantitative methods for patient prognosis and therapeutic choice could be developed based upon the Ln-332 mRNA changes we uncovered. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1584–90)