bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of faecal calprotectin and lactoferrin in inflammatory bowel disease
Authors: Lamb C A , Mansfield J C
Published: November 2010

Crohn's disease and ulcerative colitis are chronic relapsing gastrointestinal conditions characterised by an influx of inflammatory cells to the affected gut mucosa. The mainstay of diagnosing and re-evaluating these conditions in clinical practice and research is by invasive serological, radiological, endoscopic and histological assessment. In clinical trials, disease activity is often evaluated using a combination of the above tests plus clinical indices such as the Crohn's Disease Activity Index and Ulcerative Colitis Activity Index. These tools rely on subjective assessment of symptoms and so, often, do not correlate with mucosal inflammation or mucosal healing, which may be the preferred therapeutic end point for long-term inflammatory bowel disease (IBD) management. The faecal biomarkers calprotectin and lactoferrin are neutrophil derived proteins that are stable in faeces and can be detected by quantitative ELISA in small stool samples. Concentrations of both are raised in patients with gastrointestinal mucosal inflammation. They provide a unique, inexpensive, non-invasive method of testing for active inflammatory disease. They can be used to screen for IBD and as a surrogate marker of mucosal healing they are useful in monitoring the response to therapeutic intervention or surgery. They may also predict the clinical course of the disease. This clinical review aims to discuss the current evidence, limitations and potential future uses of these biomarkers in IBD.
Growth of the gynophore of the peanut Arachis hypogaea. 2. Regulation of growth
Authors: Shushu Deborah D. , Cutter Elizabeth G.
Published: November 2010

It was previously shown that removal of the ovary, which occupies the distal millimetre, caused cessation of growth of the gynophore and its intercalary meristem, suggesting that the ovary was a source of growth-promoting substances. Control of growth was studied in the gynophore of the peanut Arachis hypogaea L., cv. Bukene No. 2. Low concentrations of indoleacetic acid promoted growth of decapitated gynophores, whereas high levels inhibited elongation. Gibberellic acid promoted growth of the decapitated gynophores, whereas kinetin inhibited growth at all concentrations used. A combination of indoleacetic acid and gibberellic acid promoted extension growth of the decapitated gynophores above that of the intact gynophores; this was characterized, however, by a different pattern of cell division and cell elongation from that observed in the intact gynophores. Indoleacetic acid affected the "youngest" tissues, whereas gibberellic acid affected the whole length of the growing zone. High levels of indoleacetic acid caused diageotropism of the gynophores. Application of [14C] indoleacetic acid to vertical gynophores after the ovary was excised indicated that indoleacetic acid became redistributed to one side, resulting in horizontal bending. Thus an increased amount of auxin from the enlarging ovary may be involved in placing the ovary parallel to the soil surface when it reaches a suitable depth in the soil, during normal geocarpic development. Triiodobenzoic acid reduced growth when applied in lanolin as a ring between the ovary and the meristem but not when applied proximal to the meristem, suggesting that triiodobenzoic acid prevented the transport of auxin from the ovary to the meristem.
Influence of Mesh Composition, Velocity, and Run Time on the Catch and Length Composition of Juvenile Alewives (Alosa pseudoharengus) and Blueback Herring (A. aestivalis) Collected by Pushnet
Authors: Jessop B. M.
Published: October 2010

Significant main and interaction effects were found in the influence of net mesh composition, net speed, and run time on the catch per cubic metre and length composition of juvenile alewives (Alosa pseudoharengus) and blueback herring (A. aestivalis) collected by a bow-mounted pushnet at dates when fish size and species abundance differed. Significant main effects for net type and net speed occurred for both catch and mean catch length for both species in August and, with one exception, for net speed in September. Interaction effects often differed between species but, for both species, the net type × net speed interaction was most common. Seasonal decreases in abundance and increases in the size of both species resulted in fewer and generally less significant main and interaction effects. Such interactions will complicate the comparison of studies where net type, net speed, and run time differ. I conclude that quantitative sampling of juvenile Alosa of 30–90 mm total length can be accomplished using a bow-mounted pushnet with mouth dimensions of 1.5 × 1.5 m, a uniform mesh size of 12.7 mm, speeds of 1.0–1.2 m∙s−1, and run times of 5–8 min.
Potential of Parasites for Use as Biological Indicators of Migration, Feeding, and Spawning Behavior of Northwestern Atlantic Herring (Clupea harengus)
Authors: McGladdery S. E. , Burt M. D. B.
Published: October 2010

A parasite survey of Atlantic herring, Clupea harengus, collected from the Bay of Fundy, Nova Scotian Shelf, and Gulf of St. Lawrence, was conducted from May 1981 to November 1983. A total of 2380 herring were examined and 18 parasite species identified. These included the acanthocephalan Echinorhynchus gadi previously unreported from herring in the northwestern Atlantic and the monogenean Gyrodactyloides andriaschewski herein described from herring for the first time. The geographic distributions of the parasites, their seasonal dynamics, and relation to size of herring were recorded to determine whether they could be used as biological indicators, both to differentiate between individual herring populations and to determine their movements. Seven of the 18 species identified showed varying degrees of potential as biological indicators. Although no single parasite species was found which could clearly differentiate one population of herring from another, the differential prevalences and intensities of Anisakis simplex, Hysterothylacium aduncum, Derogenes varicus, Lecithaster gibbosus, Cryptocotyle lingua, Scolex pleuronectis, and Eimeria sardinae all provided valuable contributions to the knowledge already accumulated on herring migration, feeding, and spawning behavior. Parasite indicators, used in conjunction with other data and techniques, could eventually be used to distinguish between individual populations of herring.
Variabilité interannuelle d'un indice d'intensité des remontées d'eau dans le secteur du cap Blanc (Mauritanie)
Authors: Arfi Robert
Published: October 2010

The coastal waters along the Atlantic Sahara are characterized by intense hydrodynamic phenomena (upwellings, water mass alternations) throughout the year that deeply influence their productivity. Deep-water arrivals at surface levels are closely related to the local prevailing winds dominating all year long, the Northeast Trade winds. Working on a time series of 28 yr shows that far from being regular and constant during that period, the Trade winds were very variable. The coastal upwellings induced by these winds showed important intensity variations: after years of strong activity (1955–60) there was a period of minimal activity (1961–69), which was followed by a period of great irregularity (1970–82), showing a progressive return to the initial conditions. These important variations inducing deep hydrological consequences and modifications of water trophic potentialities can be related to the biological anomalies observed during the same time in the Northwest Africa fisheries.
Comparative Analysis of lonoregulation in Rainbow Trout (Salmo gairdneri) of Different Sizes Following Rapid and Slow Salinity Adaptation
Authors: Johnston C. E. , Cheverie J. C.
Published: October 2010

Plasma ionic values and gill (Na+,K+)-ATPase activity were compared for rainbow trout (Salmo gairdneri) of three different fork lengths (< 11, 11–15, and > 15 cm) following transference (1) from freshwater directly into seawater of 28–29‰ (DTT), (2) from freshwater directly into an estuarine environment at Fortune Bay where salinity fluctuated primarily between 17 and 29‰ (DTF), (3) from freshwater into a salinity that slowly increased to 28‰ in 22 d (SAT), and (4) from freshwater into freshwater (FC). Trout of all sizes displayed better growth, lower mortality, and better ionoregulatory capacity as judged by plasma Na+, K+, and Cl−concentrations and (Na+,K+)-ATPase activity in sea cages in Fortune Bay (DTF). The poorest ionoregulatory capacity and growth was in the direct transfer from freshwater to salinity of 28–29‰ (DTT). Failure of small trout to adapt to constantly high salinity of 28–29‰ was due to a slower development of (Na+,K+)-ATPase activity, excessively high plasma Na+and Cl−concentrations, hemoconcentration, and tissue dehydration. Except for trout severely stressed by high salinity, growth in seawater was more favorable than in freshwater. Prince Edward Island estuaries are very favorable as adaptation and rearing areas for small and large rainbow trout.
Physiological Response of Juvenile Rainbow Trout,Salmo gairdneri, to Acid and Aluminum — Prediction of Field Responses from Laboratory Data
Authors: Neville C. M.
Published: October 2010

An initial 1- to 2-h exposure of juvenile rainbow trout (Salmo gairdneri) to 2.8 μM (= μmol∙L−1) inorganic aluminum caused increased ventilation and activity responses ranging from slight to severe depending on the ambient pH. The severity of physiological response after 6–11 d of exposure was similar to that of the initial response. This was severe at pH 6.1, 4.5, and 4.0, slight to moderate at pH 5.0 and 5.5, but minimal at pH 6.5. In the severe response groups, 40–90% of the fish died after a few days of exposure. Death was due primarily to hypoxia at pH 6.1 and to electrolyte loss at pH 4.5 and 4.0. Between pH 5.5 and 5.0 there was a transition between the two mechanisms. With 8–10 mg natural organic acids∙L−1the response to the same concentration of inorganic aluminum was unchanged at pH 5.0 but was slightly increased at pH 4.5. Fish kills of salmonids that have occurred in South Norway could have been predicted from these results. In North America the presence of refuge areas and the prevalence of more tolerant species could account for the occurrence of sublethal rather than lethal responses.
A systematic neutron reflectometry study on hydrogen absorption in thin Mg1-xAlx alloy films Special issue on Neutron Scattering in Canada.
Authors: Fritzsche H. , Poirier E. , Haagsma J. , Ophus C. , Luber E. , Harrower C. T. , Mitlin D.
Published: November 2010

In this article, we show how neutron reflectometry (NR) can provide deep insight into the absorption and desorption properties of commercially promising hydrogen storage materials. NR benefits from the large negative scattering length of hydrogen atoms, which changes the reflectivity curve substantially, so that NR can determine not only the total amount of stored hydrogen but also the hydrogen distribution along the film normal, with nanometer resolution. To use NR, the samples must have smooth surfaces, and the film thickness should range between 10 and 200 nm. We performed a systematic study on thin Mg1–xAlx alloy films (x = 0.2, 0.3, 0.4, 0.67) capped with a Pd catalyst layer. Our NR experiments showed that Mg0.7Al0.3 is the optimum alloy composition with the highest amount of stored hydrogen and the lowest desorption temperature. All the thin films expand by about 20% because of hydrogen absorption, and the hydrogen is stored only in the MgAl layer with no hydrogen content in the Pd layer.
A RIGOROUS FORMULATION OF THE COSMOLOGICAL NEWTONIAN LIMIT WITHOUT AVERAGING
Authors: OLIYNYK TODD A.
Published: October 2010

We prove the existence of a large class of one-parameter families of cosmological solutions to the Einstein–Euler equations that have a Newtonian limit. This class includes solutions that represent a finite, but otherwise arbitrary, number of compact fluid bodies. These solutions provide exact cosmological models that admit Newtonian limits but, are not, either implicitly or explicitly, averaged.
A STABILITY RESULT FOR PURELY RADIATIVE SPACETIMES
Authors: LÜBBE CHRISTIAN , VALIENTE KROON JUAN ANTONIO
Published: October 2010

A semiglobal stability result for a class of purely radiative vacuum spacetimes arising from hyperboloidal data is given. This result generalizes semiglobal existence results for Minkowski-like spacetimes to the case where the reference solution contains gravitational radiation. The analysis makes use of the extended conformal field equations and a gauge based on conformal geodesics so that the location and structure of the conformal boundary of the perturbed solutions is known a priori.
Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats
Authors: Chakrabarti Swarup K. , Wen Yeshao , Dobrian Anca D. , Cole Banumathi K. , Ma Qian , Pei Hong , Williams Michael D. , Bevard Melissa H. , Vandenhoff George E. , Keller Susanna R. , Gu Jiali , Nadler Jerry L.
Published: October 2010

Central obesity is associated with low-grade inflammation that promotes type 2 diabetes and cardiovascular disease in obese individuals. The 12- and 5-lipoxygenase (12-LO and 5-LO) enzymes have been linked to inflammatory changes, leading to the development of atherosclerosis. 12-LO has also been linked recently to inflammation and insulin resistance in adipocytes. We analyzed the expression of LO and proinflammatory cytokines in adipose tissue and adipocytes in obese Zucker rats, a widely studied genetic model of obesity, insulin resistance, and the metabolic syndrome. mRNA expression of 12-LO, 5-LO, and 5-LO-activating protein (FLAP) was upregulated in adipocytes and adipose tissue from obese Zucker rats compared with those from lean rats. Concomitant with increased LO gene expression, the 12-LO product 12-HETE and the 5-LO products 5-HETE and leukotriene B4 (LTB4) were also increased in adipocytes. Furthermore, upregulation of key proinflammatory markers interleukin (IL)-6, TNFα, and monocyte chemoattractant protein-1 were observed in adipocytes isolated from obese Zucker rats. Immunohistochemistry indicated that the positive 12-LO staining in adipose tissue represents cells in addition to adipocytes. This was confirmed by Western blotting in stromal vascular fractions. These changes were in part reversed by the novel anti-inflammatory drug lisofylline (LSF). LSF also reduced p-STAT4 in visceral adipose tissue from obese Zucker rats and improved the metabolic profile, reducing fasting plasma glucose and increasing insulin sensitivity in obese Zucker rats. In 3T3-L1 adipocytes, LSF abrogated the inflammatory response induced by LO products. Thus, therapeutic agents reducing LO or STAT4 activation may provide novel tools to reduce obesity-induced inflammation.
Enteral arginase II provides ornithine for citrulline synthesis
Authors: Marini Juan C. , Keller Bettina , Didelija Inka Cajo , Castillo Leticia , Lee Brendan
Published: October 2010

The synthesis of citrulline from arginine in the small intestine depends on the provision of ornithine. To test the hypothesis that arginase II plays a central role in the supply of ornithine for citrulline synthesis, the contribution of dietary arginine, glutamine, and proline was determined by utilizing multitracer stable isotope protocols in arginase II knockout (AII−/−) and wild-type (WT) mice. The lack of arginase II resulted in a lower citrulline rate of appearance (121 vs. 137 μmol·kg−1·h−1) due to a reduced availability of ornithine; ornithine supplementation was able to restore the rate of citrulline production in AII−/− to levels comparable with WT mice. There were significant differences in the utilization of dietary citrulline precursors. The contribution of dietary arginine to the synthesis of citrulline was reduced from 45 to 10 μmol·kg−1·h−1 due to the lack of arginase II. No enteral utilization of arginine was observed in AII−/− mice (WT = 25 μmol·kg−1·h−1), and the contribution of dietary arginine through plasma ornithine was reduced in the transgenic mice (20 vs. 13 μmol·kg−1·h−1). Dietary glutamine and proline utilization were greater in AII−/− than in WT mice (20 vs. 13 and 1.4 vs. 3.7 μmol·kg−1·h−1, respectively). Most of the contribution of glutamine and proline was enteral rather than through plasma ornithine. The arginase isoform present in the small intestinal mucosa has the role of providing ornithine for citrulline synthesis. The lack of arginase II results in a greater contribution of plasma ornithine and dietary glutamine and proline to the synthesis of citrulline.
Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα
Authors: Wang Nasui , Ko Seung-Hyun , Chai Weidong , Li Guolian , Barrett Eugene J. , Tao Lijian , Cao Wenhong , Liu Zhenqi
Published: October 2010

Resveratrol, a polyphenol found in many plants, has antioxidant and anti-inflammatory actions. It also improves endothelial function and may be cardioprotective. Tumor necrosis factor-α (TNFα) causes oxidative stress and microvascular endothelial dysfunction. Whether resveratrol affects microvascular function in vivo and, if so, whether inflammatory cytokines antagonize its microvascular action are not clear. In cultured bovine aortic endothelial cells (BAECs), reserveratrol (100 nM) increased the phosphorylation of protein kinase B (Akt), endothelial nitric oxide (NO) synthase (eNOS), and ERK1/2 within 15 min by more than twofold, and this effect lasted for at least 2 h. Treatment of BAECs with TNFα (10 ng/ml) significantly increased the NADPH oxidase activity and the production of hydrogen peroxide and superoxide. Pretreatment of cells with resveratrol (100 nM) prevented each of these. Injection (ip) of resveratrol in rats potently increased muscle microvascular blood volume (MBV; P = 0.007) and flow (MBF; P < 0.02) within 30 min, and this was sustained for at least 2 h. The phosphorylation of Akt in liver or muscle was unchanged. Superimposed systemic infusion of l-NAME (NOS inhibitor) completely abolished resveratrol-induced increases in MBV and MBF. Similarly, systemic infusion of TNFα prevented resveratrol-induced muscle microvascular recruitment. In conclusion, resveratrol activates eNOS and increases muscle microvascular recruitment via an NO-dependent mechanism. Despite the potent antioxidant effect of resveratrol, TNFα at concentrations that block insulin-mediated muscle microvascular recruitment completely neutralized resveratrol's microvascular action. Thus, chronic inflammation, as seen in type 2 diabetes, may limit resveratrol's vasodilatory actions on muscle microvasculature.
Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas
Authors: Köhler Christina U. , Olewinski Marvin , Tannapfel Andrea , Schmidt Wolfgang E. , Fritsch Helga , Meier Juris J.
Published: October 2010

β-Cell regeneration declines with aging, but the molecular mechanisms controlling β-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins in prenatal and adult tissue and examined the association of these proteins with β-cell replication. Pancreatic tissue from a total of 20 human fetuses and adults was stained for Ki67, cyclin D3, p16 and p27, and insulin. The β-cellular expression of these cell cycle proteins was determined. The frequency of β-cell replication was lower in adult compared with prenatal β-cells (<0.5 vs. 3.4 ± 0.5%, respectively; P < 0.0001). p16 was sporadically expressed in prenatal β-cells (8.0 ± 1.1%) but highly enriched in adult β-cells (63.1 ± 5.2%, P < 0.0001). Likewise, the expression of p27 was much lower in prenatal β-cells (1.7 ± 0.4 vs. 44.1 ± 5.4%, respectively, P < 0.0001), and cyclin D3 expression increased from 24.2 ± 4.1 to 47.25 ± 5.0%, respectively ( P < 0.001), with aging. The expression of all three proteins was significantly correlated with each other ( P < 0.01 and r > 0.75, respectively). The strong expression of cyclin D3 in adult human β-cells and its correlation to p27 and p16 suggest a positive role in human β-cell cycle regulation. p16 and p27 appear to restrict β-cell replication with aging. The age dependency of cell cycle regulation in human β-cells might explain the reduced β-cell regeneration in adult humans.
Dynamic characteristics of baroreflex neural and peripheral arcs are preserved in spontaneously hypertensive rats
Authors: Kawada Toru , Shimizu Shuji , Kamiya Atsunori , Sata Yusuke , Uemura Kazunori , Sugimachi Masaru
Published: November 2010

Although baroreceptors are known to reset to operate in a higher pressure range in spontaneously hypertensive rats (SHR), the total profile of dynamic arterial pressure (AP) regulation remains to be clarified. We estimated open-loop transfer functions of the carotid sinus baroreflex in SHR and Wistar Kyoto (WKY) rats. Mean input pressures were set at 120 (WKY120 and SHR120) and 160 mmHg (SHR160). The neural arc transfer function from carotid sinus pressure to efferent splanchnic sympathetic nerve activity (SNA) revealed derivative characteristics in both WKY and SHR. The slope of dynamic gain (in decibels per decade) between 0.1 and 1 Hz was not different between WKY120 (10.1 ± 1.0) and SHR120 (10.4 ± 1.1) but was significantly greater in SHR160 (13.2 ± 0.8, P < 0.05 with Bonferroni correction) than in SHR120. The peripheral arc transfer function from SNA to AP showed low-pass characteristics. The slope of dynamic gain (in decibels per decade) did not differ between WKY120 (−34.0 ± 1.2) and SHR120 (−31.4 ± 1.0) or between SHR120 and SHR160 (−32.8 ± 1.3). The total baroreflex showed low-pass characteristics and the dynamic gain at 0.01 Hz did not differ between WKY120 (0.91 ± 0.08) and SHR120 (0.84 ± 0.13) or between SHR120 and SHR160 (0.83 ± 0.11). In both WKY and SHR, the declining slope of dynamic gain was significantly gentler for the total baroreflex than for the peripheral arc, suggesting improved dynamic AP response in the total baroreflex. In conclusion, the dynamic characteristics of AP regulation by the carotid sinus baroreflex were well preserved in SHR despite significantly higher mean AP.
Temporal Evolution of Oscillatory Activity Predicts Performance in a Choice-Reaction Time Reaching Task
Authors: Perfetti Bernardo , Moisello Clara , Landsness Eric C. , Kvint Svetlana , Pruski April , Onofrj Marco , Tononi Giulio , Ghilardi M. Felice
Published: November 2010

In this study, we characterized the patterns and timing of cortical activation of visually guided movements in a task with critical temporal demands. In particular, we investigated the neural correlates of motor planning and on-line adjustments of reaching movements in a choice-reaction time task. High-density electroencephalograohy (EEG, 256 electrodes) was recorded in 13 subjects performing reaching movements. The topography of the movement-related spectral perturbation was established across five 250-ms temporal windows (from prestimulus to postmovement) and five frequency bands (from theta to beta). Nine regions of interest were then identified on the scalp, and their activity was correlated with specific behavioral outcomes reflecting motor planning and on-line adjustments. Phase coherence analysis was performed between selected sites. We found that motor planning and on-line adjustments share similar topography in a fronto-parietal network, involving mostly low frequency bands. In addition, activities in the high and low frequency ranges have differential function in the modulation of attention with the former reflecting the prestimulus, top-down processes needed to promote timely responses, and the latter the planning and control of sensory-motor processes.
A Note on the Paper “Multipoint BVPs for Second‐Order Differential Equations with Impulses” by Xuxin Yang, Zhimin He, and Jianhua Shen
Authors: Liu Yiliang , Liang Jitai
Published: October 2010

We give a counter example to the comparison principle for the multipoint BVPs (by
Xuxin Yang, Zhimin He, and Jianhua Shen, in Mathematical Problems in Engineering, Volume 2009,
Article ID 258090, doi:10.1155/2009/258090). Then we suggest and prove a corrected version of
the comparison principle.
Fluid-Structure Interaction in a 3-by-3 Reduced-Scale Fuel Assembly Network
Authors: Ricciardi Guillaume , Bellizzi Sergio , Collard Bruno , Cochelin Bruno
Published: October 2010

We present experimental results on 9 reduced-scale fuel assemblies arranged in a network of 3 by 3, subjected to an axial flow. The objective is to analyse the fluid force induced by the motion of the central fuel assembly on the others fuel assemblies. The displacement of the central fuel assembly is imposed, while the others are fixed. Fluid forces acting on fuel assemblies are measured with force sensors. We observed that the coupling between fuel assemblies increases with the fluid velocity, and that the coupling in the transverse direction is not negligible compared to the coupling in the direction of excitation. We also observe that the fluid flow induces a stiffening of the central fuel assembly.
Uniform Chitosan Microparticles Prepared by a Novel Spray‐Drying Technique
Authors: Liu Wenjie , Wu Winston Duo , Selomulya Cordelia , Chen Xiao Dong
Published: November 2010

Particle size and morphology are important properties of pharmaceutical particles. Preparation of microparticles with uniform particle size and morphology is necessary in order to systematically relate these properties to the release behavior and other functionalities such as drug encapsulation and dissolution. In this study, we successfully prepared monodisperse, nonagglomerated chitosan microparticles in a single step by a novel spray‐drying technique. The control of particle size and morphology of spray‐dried microparticles was investigated experimentally. Microparticles with larger particle size can be produced when chitosan precursor of higher concentration was used. Storage time of chitosan precursor, drying temperature, and addition of lactose were shown to be crucial parameters that affect the particle morphology. Appropriate choice of the drying temperature and precursor storage time permitted control of the particle morphology, ranging from nearly spherical to cap‐shaped. Surface characteristics of the particles can be finely tuned by the amount of lactose added into the chitosan precursor.
N-3 (Omega-3) Fatty Acids in Postpartum Depression: Implications for Prevention and Treatment
Authors: Levant Beth
Published: October 2010

A growing body of clinical and epidemiological evidence suggests that low dietary intake and/or tissue levels of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) are associated with postpartum depression. Low tissue levels of n-3 PUFAs, particularly docosahexaenoic acid (DHA), are reported in patients with either postpartum or nonpuerperal depression. Moreover, the physiological demands of pregnancy and lactation put childbearing women at particular risk of experiencing a loss of DHA from tissues including the brain, especially in individuals with inadequate dietary n-3 PUFA intake or suboptimal metabolic capabilities. Animal studies indicate that decreased brain DHA in postpartum females leads to several depression-associated neurobiological changes including decreased hippocampal brain-derived neurotrophic factor and augmented hypothalamic-pituitary-adrenal responses to stress. Taken together, these findings support a role for decreased brain n-3 PUFAs in the multifactorial etiology of depression, particularly postpartum depression. These findings, and their implications for research and clinical practice, are discussed.
Nuclear Receptor COUP-TFII Controls Pancreatic Islet Tumor Angiogenesis by Regulating Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2 Signaling
Authors: Qin Jun , Chen Xinpu , Yu-Lee Li-yuan , Tsai Ming-Jer , Tsai Sophia Y.
Published: October 2010

The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy. Cancer Res; 70(21); 8812–21. ©2010 AACR.
EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF
Authors: Chou Yu-Ting , Lin Hua-Heng , Lien Yung-Chang , Wang Yuan-Hung , Hong Chun-Fu , Kao Yu-Rung , Lin Sheng-Chieh , Chang Ying-Che , Lin Shu-Yu , Chen Shu-Jen , Chen Hua-Chien , Yeh Shauh-Der , Wu Cheng-Wen
Published: October 2010

MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic “oncomiR” and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)–dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer. Cancer Res; 70(21); 8822–31. ©2010 AACR.
RETRACTED: Differential Effects of VEGFR-1 and VEGFR-2 Inhibition on Tumor Metastases Based on Host Organ Environment
Authors: Lee Yoon-Jin , Karl Daniel L. , Maduekwe Ugwuji N. , Rothrock Courtney , Ryeom Sandra , D'Amore Patricia A. , Yoon Sam S.
Published: October 2010

Tumors induce new blood vessel growth primarily from host organ microvascular endothelial cells (EC), and microvasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF or VEGF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor-2 (VEGFR-2). In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26%, whereas VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had no effect on RenCa liver metastases, whereas VEGFR-1 neutralization decreased RenCa liver metastases by 31%. For CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required to induce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the establishment of micrometastases but rather by preventing vascularization and growth of micrometastases by 55% and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of VEGFR-1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more by VEGFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results indicate that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis due to differential activity of VEGFRs on liver EC versus lung EC. Thus, therapies inhibiting specific VEGFRs should consider the targeted sites of metastatic disease. Cancer Res; 70(21); 8357–67. ©2010 AACR.
MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma
Authors: Voortman Johannes , Goto Akiteru , Mendiboure Jean , Sohn Jane J. , Schetter Aaron J. , Saito Motonobu , Dunant Ariane , Pham Trung C. , Petrini Iacopo , Lee Alan , Khan Mohammed A. , Hainaut Pierre , Pignon Jean-Pierre , Brambilla Elisabeth , Popper Helmut H. , Filipits Martin , Harris Curtis C. , Giaccone Giuseppe
Published: October 2010

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non–small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only. Cancer Res; 70(21); 8288–98. ©2010 AACR.
Turning on a Fuel Switch of Cancer: hnRNP Proteins Regulate Alternative Splicing of Pyruvate Kinase mRNA
Authors: Chen Mo , Zhang Jian , Manley James L.
Published: October 2010

Unlike normal cells, which metabolize glucose by oxidative phosphorylation for efficient energy production, tumor cells preferentially metabolize glucose by aerobic glycolysis, which produces less energy but facilitates the incorporation of more glycolytic metabolites into the biomass needed for rapid proliferation. The metabolic shift from oxidative phosphorylation to aerobic glycolysis is partly achieved by a switch in the splice isoforms of the glycolytic enzyme pyruvate kinase. Although normal cells express the pyruvate kinase M1 isoform (PKM1), tumor cells predominantly express the M2 isoform (PKM2). Switching from PKM1 to PKM2 promotes aerobic glycolysis and provides a selective advantage for tumor formation. The PKM1/M2 isoforms are generated through alternative splicing of two mutually exclusive exons. A recent study shows that the alternative splicing event is controlled by heterogeneous nuclear ribonucleoprotein (hnRNP) family members hnRNPA1, hnRNPA2, and polypyrimidine tract binding protein (PTB; also known as hnRNPI). These findings not only provide additional evidence that alternative splicing plays an important role in tumorigenesis, but also shed light on the molecular mechanism by which hnRNP proteins regulate cell proliferation in cancer. Cancer Res; 70(22); 8977–80. ©2010 AACR.
Ewing Tumors That Do Not Overexpress BMI-1 Are a Distinct Molecular Subclass with Variant Biology: A Report from the Children's Oncology Group
Authors: Cooper Aaron , van Doorninck John , Ji Lingyun , Russell Darren , Ladanyi Marc , Shimada Hiroyuki , Krailo Mark , Womer Richard B. , Hao-ru Hsu Jessie , Thomas Dafydd , Triche Timothy J. , Sposto Richard , Lawlor Elizabeth R.
Published: November 2010

Purpose: Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers, high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT.

Experimental Design: BMI-1 expression was assessed in 130 tumors by immunostaining and associations with clinical features and outcome determined. The molecular signatures of BMI-1–low and BMI-1–high tumors were compared using microarrays and differentially activated canonical pathways identified by gene-specific enrichment analysis. Automated quantitative analysis of phosphoproteins was used to assess relative levels of pathway activation. Sensitivity to IGF1-R inhibition was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays.

Results: BMI-1 is overexpressed by the vast majority of ESFTs. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were similar between BMI-1–high and BMI-1–low tumors, whole genome expression array analysis showed marked differences in their respective gene expression profiles. Gene-specific enrichment analysis identified that several cancer-associated canonical biological pathways, including IGF1, mTOR, and WNT, are significantly downregulated in BMI-1–low compared with BMI-1–high tumors. Consistent with these in vivo data, the response to IGF1-R inhibition in vitro was diminished in BMI-1–low compared with BMI-1–high ESFT cells.

Conclusion: ESFT that do not overexpress BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of and dependence on cancer-associated biological pathways. Clin Cancer Res; 17(1); 56–66. ©2010 AACR.
M30 Neoepitope Expression in Epithelial Cancer: Quantification of Apoptosis in Circulating Tumor Cells by CellSearch Analysis
Authors: Rossi Elisabetta , Basso Umberto , Celadin Romina , Zilio Francesca , Pucciarelli Salvatore , Aieta Michele , Barile Carmen , Sava Teodoro , Bonciarelli Giorgio , Tumolo Salvatore , Ghiotto Cristina , Magro Cristina , Jirillo Antonio , Indraccolo Stefano , Amadori Alberto , Zamarchi Rita
Published: October 2010

Purpose: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment.

Experimental Design: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer.

Results: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings.

Conclusions: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers. Clin Cancer Res; 16(21); 5233–43. ©2010 AACR.
SCH 2047069, a Novel Oral Kinesin Spindle Protein Inhibitor, Shows Single-Agent Antitumor Activity and Enhances the Efficacy of Chemotherapeutics
Authors: Basso Andrea D. , Liu Ming , Dai Chaoyang , Gray Kimberly , Nale Lissette , Tevar Seema , Lee Suining , Liang Lianzhu , Ponery Abdul , Yaremko Bohdan , Smith Elizabeth , Tang Huadong , Sheth Payal R. , Siddiqui M. Arshad , Hicklin Daniel J. , Kirschmeier Paul
Published: October 2010

Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine. Mol Cancer Ther; 9(11); 2993–3002. ©2010 AACR.
Paclitaxel-Dependent Cell Lines Reveal a Novel Drug Activity
Authors: Ganguly Anutosh , Yang Hailing , Cabral Fernando
Published: October 2010

We previously described the isolation of Tax 18 and Tax 11-6, two paclitaxel-dependent cell lines that assemble low amounts of microtubule polymer and require the drug for cell division. In the present studies, fluorescence time-lapse microscopy was used to measure microtubule dynamic instability behavior in these cells. The mutations were found to cause small decreases in microtubule growth and shortening, but the changes seemed unable to explain the defects in microtubule polymer levels or cell division. Moreover, paclitaxel further suppressed microtubule dynamics at low drug concentrations that were insufficient to rescue the mutant phenotype. Wild-type (WT) cells treated with similar low drug concentrations also had highly suppressed microtubules, yet experienced no problems with cell division. Thus, the effects of paclitaxel on microtubule dynamics seemed to be unrelated to cell division in both WT and mutant cell lines. The higher drug concentrations needed to rescue the mutant phenotype instead inhibited the formation of unstable microtubule fragments that appeared at high frequency in the drug-dependent, but not WT, cell lines. Live cell imaging revealed that the fragments were generated by microtubule detachment from centrosomes, a process that was reversed by paclitaxel. We conclude that paclitaxel rescues mutant cell division by inhibiting the detachment of microtubule minus ends from centrosomes rather than by altering plus-end microtubule dynamics. Mol Cancer Ther; 9(11); 2914–23. ©2010 AACR.
A Novel Human Dynactin-Associated Protein, dynAP, Promotes Activation of Akt, and Ergosterol-Related Compounds Induce dynAP-Dependent Apoptosis of Human Cancer Cells
Authors: Kunoh Tatsuki , Noda Takanori , Koseki Koichi , Sekigawa Masayuki , Takagi Motoki , Shin-ya Kazuo , Goshima Naoki , Iemura Shun-ichiro , Natsume Tohru , Wada Shu-ichi , Mukai Yukio , Ohta Shinji , Sasaki Ryuzo , Mizukami Tamio
Published: October 2010

There are several human genes that may encode proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the mutant yeast encouraged further characterization of this protein in human cells. This protein was designated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that comprised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was expressed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The ergosterol-related compounds identified by the yeast cell–based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the survival of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs. Mol Cancer Ther; 9(11); 2934–42. ©2010 AACR.
Constitutional Methylation of the BRCA1 Promoter Is Specifically Associated with BRCA1 Mutation-Associated Pathology in Early-Onset Breast Cancer
Authors: Wong Ee Ming , Southey Melissa C. , Fox Stephen B. , Brown Melissa A. , Dowty James G. , Jenkins Mark A. , Giles Graham G. , Hopper John L. , Dobrovic Alexander
Published: October 2010

Women carrying germline mutations in BRCA1 are at a substantially elevated risk of breast cancer and their tumors typically have distinctive morphologic features. We hypothesized that constitutional methylation of the BRCA1 promoter region could give rise to such breast cancers in women. We selected 255 women diagnosed with breast cancer before the age of 40 years for whom BRCA1 germline mutations had not been identified. Of them, 52 had five or more of nine BRCA1 mutation-associated morphologic features (group 1), 39 had four (group 2), and 164 had three or less (group 3). The prevalence of detectable BRCA1 promoter methylation in peripheral blood DNA decreased from 31% to 10% to 5% across groups 1–3, respectively (P = 0.000002), and was significantly greater than the 4% frequency in unaffected controls (P = 0.004). Peripheral blood methylation was associated with a 3.5-fold (95% CI, 1.4–10.5) increased risk of having early onset breast cancer. Methylation was consistently mosaic in the peripheral blood where the estimated allelic frequency of BRCA1 promoter methylation ranged from 0.1% to 17%. Group 1 women, but not group 3 women, with detectable methylation of peripheral blood DNA had high levels of BRCA1 promoter methylation of their tumor DNA, indicating that constitutional BRCA1 methylation strongly predisposes toward the development of BRCA1 methylated tumors that then have features resembling BRCA1 mutated tumors. Screening peripheral blood for BRCA1 promoter methylation might thus predict early-onset breast cancers. This raises the possibility of chemoprevention or other intervention to diminish the risk of developing breast cancer in these women. Cancer Prev Res; 4(1); 23–33. ©2010 AACR. Cancer Prev Res; 4(1); 23–33. ©2010 AACR.