bluuebunny/crossref_metadata_2025 huggingface dataset:
Nature and nurture in dormancy: dissolved oxygen, pH, and maternal investment impact Bythotrephes longimanus resting egg emergence and neonate condition
Authors: Brown Meghan Elizabeth
Published: August 2008

Bythotrephes longimanus (Onychopoda: Cercopagidae), an invasive zooplankter in North America, requires suitable habitat to satisfy its planktonic and resting stages, which occupy the pelagia and sediment of lakes, respectively. Thousands of resting eggs from hundreds of planktonic mothers were exposed to laboratory conditions that mimicked gradients observed in lake sediment (dissolved oxygen = 1.4–11.9 mg·L–1; pH = 3–11). Eggs hatched in all treatments, which confirms the utility of dormancy and the robustness of the resting egg in B. longimanus. However, hatching success and neonate condition were greatest when dormancy conditions were maintained at near-saturated dissolved oxygen and near-neutral pH; deviations from these conditions resulted in prolonged development, smaller neonates, and the failure of many eggs to hatch. In addition to the influence of environmental conditions, heavier mothers produced larger eggs that hatched more frequently and resulted in heavier neonates. These maternal effects are likely due to greater energy investment by healthier mothers. This study suggests that nature and nurture influence dormancy success, and the results underscore that both life-cycle stages of B. longimanus need to be considered to understand its range expansion.
Absorption properties of phytoplankton in the Lower Estuary and Gulf of St. Lawrence (Canada)
Authors: Roy Suzanne , Blouin Frédérick , Jacques André , Therriault Jean-Claude
Published: August 2008

Models of ocean colour rely on information about phytoplankton absorption, which varies according to community composition and photoacclimation. Here we show that pigment packaging, which is strongly determined by the size structure of local algal populations, represents a dominant factor in the Estuary and Gulf of St. Lawrence, accounting for ~50%–80% of the reduction in phytoplankton absorption at 440 nm during the spring bloom periods and for 24%–48% before and after the blooms. This is consistent with the importance of diatoms in this environment. Comparison between three methods of estimating packaging gave average values within less than 20% of each other during the blooms. Changes in pigment composition, which also affect phytoplankton absorption, were more important outside bloom periods (particularly in the Gulf), although this influence was relatively modest (11%–13%). This was accompanied by an increase in photoprotective pigments and an absorption peak in the ultraviolet range (~330 nm). Regional variations in phytoplankton absorption reflected bloom conditions, whereas detrital particulate material was highest in the upstream Saguenay region (often more than 60% of the absorption of total particulate material at 440 nm (ap(440))) and was at least 20%–30% elsewhere. This information is a first step towards the development of regional models of ocean colour.
Landscape-scale evaluation of genetic structure among barrier-isolated populations of coastal cutthroat trout,Oncorhynchus clarkii clarkii
Authors: Guy Troy J. , Gresswell Robert E. , Banks Michael A.
Published: August 2008

Relationships among landscape structure, stochastic disturbance, and genetic diversity were assessed by examining interactions between watershed-scale environmental factors and genetic diversity of coastal cutthroat trout ( Oncorhynchus clarkii clarkii ) in 27 barrier-isolated watersheds from western Oregon, USA. Headwater populations of coastal cutthroat trout were genetically differentiated (mean FST= 0.33) using data from seven microsatellite loci (2232 individuals), but intrapopulation microsatellite genetic diversity (mean number of alleles per locus = 5, mean He= 0.60) was only moderate. Genetic diversity of coastal cutthroat trout was greater (P = 0.02) in the Coast Range ecoregion (mean alleles = 47) than in the Cascades ecoregion (mean alleles = 30), and differences coincided with indices of regional within-watershed complexity and connectivity. Furthermore, regional patterns of diversity evident from isolation-by-distance plots suggested that retention of within-population genetic diversity in the Coast Range ecoregion is higher than that in the Cascades, where genetic drift is the dominant factor influencing genetic patterns. Thus, it appears that physical landscape features have influenced genetic patterns in these populations isolated from short-term immigration.
Long-term performance of a wide embankment on soft clay improved with prefabricated vertical drains
Authors: Lo S. R. , Mak J. , Gnanendran C. T. , Zhang R. , Manivannan G.
Published: August 2008

This paper presents the long-term performance of a wide geogrid-reinforced road embankment constructed on soft clay improved with prefabricated vertical drains (PVDs) at a freeway extension site 150 km north of Sydney in Australia. The foundation soil and the embankment were instrumented and monitored for about 400 days for excess pore-water pressure, earth pressure, and reinforcement tension, and for 9 years for displacement profiles. The embankment was constructed in stages and surcharged in an attempt to reduce post-construction settlement. As the embankment width was wide relative to the thickness of the soft clay, the settlement near the centre was modelled by a unit cell analysis. The equivalent horizontal permeability was determined by back analysis of the central zone using the first 12 months of settlement data. All other soil parameters were determined from the laboratory and field testing. The predicted pore-water pressure response over the first 400 days showed reasonable agreement with measured values. The same analysis was then continued to predict settlement over a period of 9 years. The predicted settlement was, however, smaller than the measured value at the centre region of the embankment.
Limit analysis of the stability of slopes reinforced with piles against landslide in nonhomogeneous and anisotropic soils
Authors: Nian T. K. , Chen G. Q. , Luan M. T. , Yang Q. , Zheng D. F.
Published: August 2008

The stability of a slope with reinforcing piles in anisotropic and nonhomogeneous soils is analyzed using the kinematic approach of limit analysis combined with a strength reduction technique. A slope without piles is considered first and the limit state equation is obtained to determine both the safety factor and the critical sliding surface for a given anisotropic and nonhomogeneous slope. The solutions are compared with published data to verify the practicality of the approach. A slope stabilized by a row of piles is then analyzed. Next, mathematical optimization is used to derive analytical expressions for determining the lateral force provided by piles (this is required to increase the slope safety factor to an expected value). Numerical examples are then applied. The optimal location of piles within a slope and the effects of nonhomogeneity and anisotropy of the soil strength on the dimensionless limit stabilizing force are also studied. Finally, a simplified procedure is proposed for a structural design that stabilizes the piles against landslide.
Hydrostatic compression model for sandy soils
Authors: Vallejos Javier
Published: August 2008

Based on elastic considerations, a new four parameter model of the hydrostatic compression curves of sandy soils is presented. Using a unique set of parameters, this model is capable of accurately representing the infinite family of compression curves that result when soil is subjected to stresses below particle breakage. The parameters are readily estimated from two hydrostatic tests conducted at different initial densities during loading and unloading stages. The resulting equations are able to predict the effect of progressive stiffness increase and compressibility reduction that occur as void ratio decreases during both loading and unloading conditions. The same normalized stress scale employed for the hydrostatic compression curves can also be used to describe the steady state line, which leads to a unique framework for representing the stress–void ratio curves of sandy soils. A comprehensive series of simulations on 13 different types of sandy soils in both loose and dense states was performed under a wide range of mean stresses during loading and unloading conditions. The simulations gave very satisfactory agreement with published experimental results.
Similarity of soil variability in centrifuge models
Authors: Zhang L. L. , Zhang L. M. , Tang W. H.
Published: August 2008

The soil specimen in a centrifuge model is subject to spatial variability depending on the method of sample preparation and the stress field induced by the centrifugal acceleration, even though it is intended to be uniformly prepared. In contrast to extensive measurements for studying the variability of in situ soil properties, soil variability in centrifuge models, especially that which is based on data at very close sampling distances, is less understood. In this paper, the variability of soil density in two centrifuge models is presented. Random field theory is adopted to characterize the spatial soil variability in the two centrifuge models. The importance of taking spatial variability parameters as a model similarity requirement in centrifuge model design is illustrated and discussed. It is demonstrated that, although centrifuge models of different sizes can be designed to simulate the same prototype, the prototypes these models actually represent are not identical in terms of soil spatial variability. To achieve similarity in spatial variability between a centrifuge model and its prototype, one may need to control either the point coefficient of variation or the scale of fluctuation of the model soil so that the coefficients of variation of the spatially averaged soil property in the model and the prototype are the same.
NON-EMPTINESS OF MODULI SPACES OF COHERENT SYSTEMS
Authors: BRAMBILA-PAZ L.
Published: August 2008

Let X be a general smooth projective algebraic curve of genus g ≥ 2 over ℂ. We prove that the moduli space G(α:n,d,k) of α-stable coherent systems of type (n,d,k) over X is empty if k > n and the Brill–Noether number β := β(n,d,n + 1) = β(1,d,n + 1) = g - (n + 1)(n - d + g) < 0. Moreover, if 0 ≤ β < g or β = g, n ∤g and for some α > 0, G(α : n,d,k) ≠ ∅ then G(α : n,d,k) ≠ ∅ for all α > 0 and G(α : n,d,k) = G(α′ : n,d,k) for all α,α′ > 0 and the generic element is generated. In particular, G(α : n,d,n + 1) ≠ ∅ if 0 ≤ β ≤ g and α > 0. Moreover, if β > 0 G(α : n,d,n + 1) is smooth and irreducible of dimension β(1,d,n + 1). We define a dual span of a generically generated coherent system. We assume d < g + n1≤ g + n2and prove that for all α > 0, G(α : n1,d, n1+ n2) ≠ ∅ if and only if G(α : n2,d, n1+ n2) ≠ ∅. For g = 2, we describe G(α : 2,d,k) for k > n.
RELATIVE ENTROPY FOR MAXIMAL ABELIAN SUBALGEBRAS OF MATRICES AND THE ENTROPY OF UNISTOCHASTIC MATRICES
Authors: CHODA MARIE
Published: August 2008

Let A and B be two maximal abelian *-subalgebras of the n × n complex matrices Mn(ℂ). To study the movement of the automorphisms of Mn(ℂ), we modify the Connes–Størmer relative entropy H(A|B) and the Connes relative entropy Hϕ(A|B) with respect to a state ϕ, and introduce the two kinds of the constant h(A|B) and hϕ(A|B). For the unistochastic matrix b(u) defined by a unitary u with B = uAu*, we show that h(A|B) is the entropy H(b(u)) of b(u). This is obtained by our computation of hϕ(A|B). The h(A|B) attains to the maximal value log n if and only if the pair {A, B} is orthogonal in the sense of Popa.
ON THE MULTI-SINGULAR ELLIPTIC PROBLEM INVOLVING HARDY–SOBOLEV INEQUALITIES
Authors: KANG DONGSHENG
Published: August 2008

Suppose [Formula: see text], [Formula: see text]. We deal with the existence or nonexistence conditions of ground states solution for the multi-singular elliptic problem: [Formula: see text] which involves Hardy–Sobolev inequalities. The results depend crucially on the parameters s, ai, λiand μi.
PARTITION FUNCTION OF NON-SUPERSYMMETRIC BLACK HOLES IN THE SUPERGRAVITY LIMIT
Authors: PARVIZI SHAHROKH , TAVANFAR ALIREZA
Published: August 2008

In this paper, we propose a free energy for general non-supersymmetric black hole attractors (with vanishing D0-brane charge) arising in type IIA(B) superstrings on 3-fold Calabi–Yau, in the supergravity limit. This, by definition, differs from its counterpart BPS free energy by a factor of 4. Correspondingly, a mixed ensemble for these black holes is proposed.
STORING LIMIT CYCLES USING DELAYED FEEDBACK NEURAL NETWORKS
Authors: WU GUIKUN , ZHAO HONG
Published: August 2008

We show that the delayed feedback neural networks for storing limit cycles can be trained using a global training algorithm. It is found that the storage capacity of the networks is in proportion to delay length as in the networks trained by the correlation learning based on Hebb's rule, but is much higher than in the latter. The generalization capacity of the networks is also higher than in the latter. Another interesting finding is that the spurious states or unwanted attractors totally disappear in the networks trained by the global training algorithm if the memory limit cycles are sufficiently long. The dynamics of the networks is investigated as a function of the length of limit cycles.
NOISE EFFECTS IN QUANTUM MAGIC SQUARES GAME
Authors: GAWRON PIOTR , MISZCZAK JAROSŁAW , SŁADKOWSKI JAN
Published: August 2008

In the article we analyse how noisiness of quantum channels can influence the magic squares quantum pseudo-telepathy game. We show that the probability of success can be used to determine characteristics of quantum channels. Therefore the game deserves more careful study aiming at its implementation.
ENTANGLING AND DISENTANGLING CAPACITIES OF NOISY INTERACTIONS
Authors: GROISMAN BERRY
Published: August 2008

Entangling and disentangling capacities are the key manifestation of the nonlocal content of a quantum operation. A lot of effort has been put recently into investigating (dis)entangling capacities of unitary operations, but very little is known about capacities of non-unitary operations. Here we investigate (dis)entangling capacities of unital CPTP maps acting on two qubits.
JENSEN–SHANNON DIVERGENCE AS A MEASURE OF THE DEGREE OF ENTANGLEMENT
Authors: MAJTEY A. P. , BORRAS A. , CASAS M. , LAMBERTI P. W. , PLASTINO A.
Published: August 2008

The notion of distance in Hilbert space is relevant in many scenarios. In particular, "distances" between quantum states play a central role in quantum information theory. An appropriate measure of distance is the quantum Jensen Shannon divergence (QJSD) between quantum states. Here we study this distance as a geometrical measure of entanglement and apply it to different families of states.
AN EFFICIENT QUANTUM ALGORITHM FOR COLORED JONES POLYNOMIALS
Authors: RASETTI MARIO , GARNERONE SILVANO , MARZUOLI ANNALISA
Published: August 2008

We construct a quantum algorithm to approximate efficiently the colored Jones polynomial of the plat presentation of any oriented link L at a fixed root of unity q. The construction exploits the q-deformed spin network as computational background. The complexity of such algorithm is bounded above linearly by the number of crossings of the link, and polynomially by the number of link strands.
COHERENCE CONSERVATION OF A QUBIT COUPLED TO A DISSIPATING THERMAL ENVIRONMENT
Authors: RAHIMI ROBABEH , SAITOH AKIRA , NAKAHARA MIKIO
Published: August 2008

It is shown that quantum coherence is conserved in a principal system in the case that the system is coupled to a fast dissipating environment [arXiv:0709.0562]. The phenomenon is called the quantum wipe effect. Here, this effect is reviewed and the analytical proof for a model system consisting of a one-qubit system coupled to a fast dissipating environment is extended to an environment at a thermal equilibrium.
EVALUATING MEASURES OF NONCLASSICAL CORRELATION IN A MULTIPARTITE QUANTUM SYSTEM
Authors: SAITOH AKIRA , RAHIMI ROBABEH , NAKAHARA MIKIO
Published: August 2008

We introduce and evaluate measures of nonclassical correlation defined on the basis of a paradigm claiming that a multipartite system represented by a density matrix having no product eigenbasis possesses nonclassical correlation.
EFFECTS OF COLORED NOISE IN SHORT OVERDAMPED JOSEPHSON JUNCTION
Authors: AUGELLO G. , VALENTI D. , SPAGNOLO B.
Published: August 2008

We investigate the transient dynamics of a short overdamped Josephson junction with a periodic driving signal in the presence of colored noise. We analyze noise induced phenomena, specifically resonant activation and noise enhanced stability. We find that the positions both of the minimum of RA and maximum of NES depend on the value of the noise correlation time τc. Moreover, in the range where RA is observed, we find a non-monotonic behavior of the mean switching time as a function of τc.
Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease
Authors: Matsumura Yoshihiro , Ban Nobuhiro , Inagaki Nobuya
Published: August 2008

The ATP-binding cassette transporter ABCA3 mediates uptake of choline-phospholipids into intracellular vesicles and is essential for surfactant metabolism in lung alveolar type II cells. We have shown previously that ABCA3 mutations in fatal surfactant deficiency impair intracellular localization or ATP hydrolysis of ABCA3 protein. However, the mechanisms underlying the less severe phenotype of patients with ABCA3 mutation are unclear. In this study, we characterized ABCA3 mutant proteins identified in pediatric interstitial lung disease (pILD). E292V (intracellular loop 1), E690K (adjacent to Walker B motif in nucleotide binding domain 1), and T1114M (8th putative transmembrane segment) mutant proteins are localized mainly in intracellular vesicle membranes as wild-type protein. Lipid analysis and sucrose gradient fractionation revealed that the transport function of E292V mutant protein is moderately preserved, whereas those of E690K and T1114M mutant proteins are severely impaired. Vanadate-induced nucleotide trapping and photoaffinity labeling of wild-type and mutant proteins using 8-azido-[32P]ATP revealed an aberrant catalytic cycle in these mutant proteins. These results demonstrate the importance of a functional catalytic cycle in lipid transport of ABCA3 and suggest a pathophysiological mechanism of pILD due to ABCA3 mutation.
Alveolar cell apoptosis is dependent on p38 MAP kinase-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury
Authors: Le Anne , Damico Rachel , Damarla Mahendra , Boueiz Adel , Pae Hyun Hae , Skirball Jarrett , Hasan Emile , Peng Xinqi , Chesley Alan , Crow Michael T. , Reddy Sekhar P. , Tuder Rubin M. , Hassoun Paul M.
Published: August 2008

Signaling via p38 MAP kinase has been implicated in the mechanotransduction associated with mechanical stress and ventilator-induced lung injury (VILI). However, the critical downstream mediators of alveolar injury remain incompletely defined. We provide evidence that high-tidal volume mechanical ventilation (HVt MV) rapidly activates caspases within the lung, resulting in increased alveolar cell apoptosis. Antagonism of MV-induced p38 MAP kinase activity with SB-203580 suppresses both MV-induced caspase activity and alveolar apoptosis, placing p38 MAP kinase upstream of MV-induced caspase activation and programmed cell death. The reactive oxygen species (ROS)-producing enzyme xanthine oxidoreductase (XOR) is activated in a p38 MAP kinase-dependent manner following HVt MV. Allopurinol, a XOR inhibitor, also suppresses HVt MV-induced apoptosis, implicating HVt MV-induced ROS in the induction of alveolar cell apoptosis. Finally, systemic administration of the pan-caspase inhibitor, z-VAD-fmk, but not its inactive peptidyl analog, z-FA-fmk, blocks ventilator-induced apoptosis of alveolar cells and alveolar-capillary leak, indicating that caspase-dependent cell death is necessary for VILI-associated barrier dysfunction in vivo.
Acute exercise-induced changes in basal VLDL-triglyceride kinetics leading to hypotriglyceridemia manifest more readily after resistance than endurance exercise
Authors: Magkos Faidon , Tsekouras Yiannis E. , Prentzas Konstantinos I. , Basioukas Konstantinos N. , Matsama Stergoula G. , Yanni Amalia E. , Kavouras Stavros A. , Sidossis Labros S.
Published: August 2008

Resistance training is considered less effective than endurance training in lowering plasma triglyceride (TG) concentrations. Acutely, however, a single bout of strenuous exercise, whether endurance or resistance, increases the efficiency of very low-density lipoprotein (VLDL)-TG removal from the circulation and leads to hypotriglyceridemia. The comparative effects of these two types of exercise on VLDL-TG metabolism are not known. We therefore examined basal VLDL-TG kinetics by using stable isotope-labeled tracers in seven healthy, nonobese, untrained young men in the postabsorptive state, the morning after a single 90-min bout of either low-intensity endurance exercise (∼30% of peak oxygen consumption) or high-intensity resistance exercise (3 sets of 10 repetitions for 12 exercises at 80% of peak torque production), matched for total energy expenditure (∼400 kcal), or an equivalent period of rest on the preceding afternoon. Compared with rest, resistance exercise lowered fasting plasma VLDL-TG concentration by −28 ± 10% ( P = 0.034), increased VLDL-TG plasma clearance rate by 30 ± 8% ( P = 0.003), and shortened the mean residence time (MRT) of VLDL-TG in the circulation by −36 ± 11 min ( P = 0.016), whereas endurance exercise had no effect (all P > 0.05). Basal VLDL-TG plasma clearance rate was greater ( P = 0.003) and VLDL-TG MRT was shorter ( P = 0.012) the morning after resistance than endurance exercise. We conclude that, for the same total energy expenditure, resistance exercise is more potent than endurance exercise in eliciting changes in VLDL-TG metabolism that have been linked with hypotriglyceridemia, and it should thus be considered as an alternative to or in addition to endurance exercise for the control of plasma TG concentrations.
The Wilms' Tumor Antigen Is a Novel Target for Human CD4+ Regulatory T Cells: Implications for Immunotherapy
Authors: Lehe Cynthia , Ghebeh Hazem , Al-Sulaiman Abdullah , Al Qudaihi Ghofran , Al-Hussein Khaled , Almohareb Fahad , Chaudhri Naeem , Alsharif Fahad , Al-Zahrani Hazza , Tbakhi Abdelghani , Aljurf Mahmoud , Dermime Said
Published: August 2008

Compelling evidences indicate a key role for regulatory T cells (Treg) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of Tregs. We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402–restricted manner. Importantly, they recognized HLA-DRB1*04–matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4+CD25+Foxp3+GITR+CD127− Treg phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of Tregs strongly inhibited the expansion of natural killer (NK), NK T, and CD8+ T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8+ T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201–restricted peptide in the presence of Tregs strongly inhibited the induction of anti–WT1-126 CD8+ CTL responses as evidenced by both very low cytotoxic activity and IFN-γ production. Moreover, these Treg clones specifically produced granzyme B and selectively induced apoptosis in WT1-84–pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti–WT1-84 interleukin-5+/granzyme B+/Foxp3+ CD4+ Tregs in five of eight HLA-DR4+ acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of Tregs in cancer patients. [Cancer Res 2008;68(15):6350–9]
Metastasis Suppressor Function of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand-R in Mice: Implications for TRAIL-Based Therapy in Humans?
Authors: Grosse-Wilde Anne , Kemp Christopher J.
Published: August 2008

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, as it can induce apoptosis specifically in tumor cells but not in normal cells. Although earlier mouse tumor studies revealed a strong tissue dependency of TRAIL and its death receptor in suppressing primary tumorigenesis or experimental metastases, we recently found that TRAIL-R inhibits lymph node metastases without affecting primary tumor formation in a mouse model of multistage skin tumorigenesis. This finding uncouples the role of TRAIL in primary tumorigenesis from metastasis formation, likely by sensitization of previously TRAIL-resistant tumor cells upon detachment, an early step required for metastasis formation. Therefore, TRAIL-R is a novel metastasis suppressor, suggesting that TRAIL-related tumor therapy might be most effective in primary tumors and early metastatic cancers, before selection for TRAIL resistance occurs. [Cancer Res 2008;68(15):6035–7]
Carcinogen-Altered Genes in Rat Esophagus Positively Modulated to Normal Levels of Expression by Both Black Raspberries and Phenylethyl Isothiocyanate
Authors: Stoner Gary D. , Dombkowski Alan A. , Reen Rashmeet K. , Cukovic Daniela , Salagrama Sridevi , Wang Li-Shu , Lechner John F.
Published: August 2008

Our recent study identified 2,261 dysregulated genes in the esophagi of rats that received a 1-week exposure to the carcinogen N-nitrosomethylbenzylamine (NMBA). We further reported that 1,323 of these genes were positively modulated to near-normal levels of expression in NMBA-treated animals that consumed dietary phenylethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables. Herein, we report our results with companion animals that were fed a diet containing 5% freeze-dried black raspberries (BRB) instead of PEITC. We found that 462 of the 2,261 NMBA-dysregulated genes in rat esophagus were restored to near-normal levels of expression by BRB. Further, we have identified 53 NMBA-dysregulated genes that are positively modulated by both PEITC and BRB. These 53 common genes include genes involved in phase I and II metabolism, oxidative damage, and oncogenes and tumor suppressor genes that regulate apoptosis, cell cycling, and angiogenesis. Because both PEITC and BRB maintain near-normal levels of expression of these 53 genes, their dysregulation during the early phase of NMBA-induced esophageal cancer may be especially important in the genesis of the disease. [Cancer Res 2008;68(15):6460–7]
Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to AgonistIn vitroandIn vivo
Authors: Morgan Kevin , Stewart Alan J. , Miller Nicola , Mullen Peter , Muir Morwenna , Dodds Michael , Medda Federico , Harrison David , Langdon Simon , Millar Robert P.
Published: August 2008

Activation of gonadotropin-releasing hormone (GnRH) receptors inhibits proliferation of transformed cells derived from reproductive tissues and in transfected cell lines. Hence, GnRH receptors represent a therapeutic target for direct action of GnRH analogues on certain proliferating cells. However, more cell biological data are required to develop this particular application of GnRH analogues. Therefore, we compared the effects of GnRH receptor activation in transfected HEK293 cells (HEK293[SCL60]) with transfected human ovarian cancer cell lines SKOV3 and EFO21, human hepatoblastoma HepG2 cells, and rat neuroblastoma B35 cells. Marked differences in receptor levels, magnitude of inositol phosphate generation, and dynamics of inositol phosphate turnover occurred in the different cells. Activation of GnRH receptors, expressed at high or moderate levels, inhibited the growth of HEK293[SCL60] and B35 cells, respectively. Western blotting detected markers of apoptosis [cleaved poly(ADP-ribose) polymerase, caspase-9] in HEK293[SCL60] and B35 following treatment with 100 nmol/L d-Trp6-GnRH-I. Cell growth inhibition was partially or completely rescued with inhibitor Q-VD-OPh or Ro32-0432. Low levels of GnRH receptor expression in transfected SKOV3, EFO21, or HepG2 activated intracellular signaling but did not induce apoptosis or significantly affect cell proliferation. Tumor xenografts prepared from HEK293[SCL60] regressed during treatment with d-Trp6-GnRH-I and growth of xenografts derived from transfected B35 was slowed. SKOV3 xenografts were not growth inhibited. Therefore, differences in levels of GnRH receptor and signaling differentially affect the apoptotic machinery within cell lines and contribute to the cell type–specific effects of GnRH on growth. Further studies should exploit the growth-inhibitory potential of GnRH receptor activation in abnormal cells in diseased human tissues. [Cancer Res 2008;68(15):6331–40]
Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence
Authors: Costa Érico T. , Forti Fábio L. , Matos Tatiana G.F. , Dermargos Alexandre , Nakano Fábio , Salotti Jacqueline , Rocha Kátia M. , Asprino Paula F. , Yoshihara Celina K. , Koga Marianna M. , Armelin Hugo A.
Published: August 2008

Fibroblast growth factor 2 (FGF2) is considered to be a bona fide oncogenic factor, although results from our group and others call this into question. Here, we report that exogenous recombinant FGF2 irreversibly inhibits proliferation by inducing senescence in Ras-dependent malignant mouse cells, but not in immortalized nontumorigenic cell lines. We report the following findings in K-Ras–dependent malignant Y1 adrenocortical cells and H-Ras V12–transformed BALB-3T3 fibroblasts: (a) FGF2 inhibits clonal growth and tumor onset in nude and immunocompetent BALB/c mice, (b) FGF2 irreversibly blocks the cell cycle, and (c) FGF2 induces the senescence-associated β-galactosidase with no accompanying signs of apoptosis or necrosis. The tyrosine kinase inhibitor PD173074 completely protected malignant cells from FGF2. In Y1 adrenal cells, reducing the constitutively high levels of K-Ras-GTP using the dominant-negative RasN17 mutant made cells resistant to FGF2 cytotoxicity. In addition, transfection of the dominant-negative RhoA-N19 into either Y1 or 3T3-B61 malignant cell lines yielded stable clonal transfectants that were unable to activate RhoA and were resistant to the FGF2 stress response. We conclude that in Ras-dependent malignant cells, FGF2 interacts with its cognate receptors to trigger a senescence-like process involving RhoA-GTP. Surprisingly, attempts to select FGF2-resistant cells from the Y1 and 3T3-B61 cell lines yielded only rare clones that (a) had lost the overexpressed ras oncogene, (b) were dependent on FGF2 for proliferation, and (c) were poorly tumorigenic. Thus, FGF2 exerted a strong negative selection that Ras-dependent malignant cells could rarely overcome. [Cancer Res 2008;68(15):6215–23]
COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells
Authors: Mroz Edmund A. , Baird Abigail H. , Michaud William A. , Rocco James W.
Published: August 2008

The p16/pocket-protein pathway sets a balance between tumor suppression and capacity for tissue regeneration. Understanding the upstream signaling pathway that turns on the expression of p16 is required both for knowing the tumorigenic stresses from which this pathway provides protection and for appreciating the selective pressure that leads to the loss of this pathway in most human tumors. We report that COOH-terminal binding protein (CtBP), a physiologically regulated transcriptional corepressor that dimerizes to hold together repressive complexes, regulates p16 expression in primary human fibroblasts and keratinocytes. Interfering with CtBP-mediated repression increased p16 expression and accelerated senescence. CtBP had little influence on the expression of the alternate product of the CDKN2A tumor-suppressor gene, p14ARF. Loss of CtBP-mediated repression diminished the Polycomb-based epigenetic histone mark that is reported to favor silencing of p16 via DNA methylation. Enhancing CtBP-mediated repression by growing cells in low oxygen increased the association of CtBP with the p16 promoter, as assessed by chromatin immunoprecipitation, and reduced p16 expression. Stresses and stimuli that reduce CtBP-mediated repression are associated with increased p16 expression; therefore, CtBP may provide a common final target for regulating the balance among tumor suppression, regenerative capacity, and senescence. [Cancer Res 2008;68(15):6049–53]
BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins
Authors: Friday Bret B. , Yu Chunrong , Dy Grace K. , Smith Paul D. , Wang Liang , Thibodeau Stephen N. , Adjei Alex A.
Published: August 2008

AZD6244 (ARRY 142886) is a potent and selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor currently in early clinical trials. We examined the activity of AZD6244 in a panel of non–small cell lung cancer and a panel of cell lines representing many cancer types using in vitro growth assays. AZD6244 induced G0-G1 cell cycle arrest in sensitive cell lines that primarily included cells containing the BRAF V600E mutation. In these cells, G0-G1 arrest is accompanied by the up-regulation of the cell cycle inhibitors p21WAF1 and p27Kip1 and down-regulation of cyclin D1. In the majority of cell lines tested, including those with K-ras or non-V600E BRAF mutations, AZD6244 induced the accumulation of phospho-MEK, an effect not observed in the most sensitive BRAF V600E-containing cells. Accumulation of phospho-MEK in non–V600E-containing cell lines is due to abrogation of negative feedback pathways. BRAF V600E disrupts negative feedback signaling, which results in enhanced baseline phospho-MEK expression. Exogenous expression of BRAF V600E disrupts feedback inhibition but does not sensitize cells to AZD6244. Specific suppression of endogenous BRAF V600E does not confer resistance to AZD6244 but enhances sensitivity to AZD6244. Thus, our findings show that BRAF V600E marks cells with an in vitro requirement for MAPK signaling to support proliferation. These cells are exquisitely sensitive to AZD6244 (IC50, <100 nmol/L), have high baseline levels of phospho-MEK, and lack feedback inhibition between ERK and Raf. These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors. [Cancer Res 2008;68(15):6145–53]
Sorafenib Potently Inhibits Papillary Thyroid Carcinomas Harboring RET/PTC1 Rearrangement
Authors: Henderson Ying C. , Ahn Soon-Hyun , Kang Ya'an , Clayman Gary L.
Published: August 2008

Purpose: Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy with one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the MEK/ERK signaling transduction pathway and result in the activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Sorafenib (Nexavar, BAY 43-9006) is a multikinase inhibitor, and in this study, we tested its effects on PTC cells carrying either mutation.

Experimental Design: The effects of sorafenib on cell proliferation and signaling were evaluated in vitro on PTC cells using growth curves, cell cycle analysis, and immunoblotting. Using an orthotopic mouse model, we determined the antitumor effects of sorafenib in vivo.

Results: The concentration needed for 50% growth inhibition (GI50) by sorafenib was 0.14 μmol/L for the PTC cells with the RET/PTC1 rearrangement, and 2.5 μmol/L for PTC cells with a BRAF mutation, both readily achievable serum concentrations. After 3 weeks of oral administration of sorafenib (80 mg/kg/d) in mice, small (94% reduction compared with controls) or no tumor growth was detected in mice inoculated with PTC cells bearing the RET/PTC1 rearrangement, whereas the tumor volume of the orthotopic tumor implants of PTC cells with a BRAF mutation was reduced 53% to 54% (as compared with controls).

Conclusions: PTC cells carrying the RET/PTC1 rearrangement were more sensitive to sorafenib than PTC cells carrying a BRAF mutation. Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.
Prognostic Significance of CD55 Expression in Breast Cancer
Authors: Ikeda Jun-ichiro , Morii Eiichi , Liu Yalan , Qiu Ying , Nakamichi Naoto , Jokoji Ryu , Miyoshi Yasuo , Noguchi Shinzaburo , Aozasa Katsuyuki
Published: August 2008

Purpose: Our recent study revealed that CD55-high population in breast cancer cell line was resistant to apoptosis and formed colonies in vitro more efficiently than CD55-low population. The present study was conducted to examine whether CD55-high population in breast cancer cell line possesses higher tumorigenic potential in vivo and presence of CD55-high cells in breast cancer affects clinicopathologic behavior of patients.

Experimental Design: CD55-high and CD55-low population was sorted from breast cancer cell line, injected into immunodeficient mice, and the resultant tumor volume was measured. CD55 expression was immunohistochemically examined in clinical samples from 74 cases with breast cancers, and cases with >1% of tumor cells showing high level of CD55 expression were categorized as CD55 high.

Results: The xenotransplanted tumor volume derived from CD55-high population was significantly larger than that from CD55-low population. Fifty (67.6%) of 74 cases of breast cancer were CD55-high. A significant correlation was observed between CD55-high character and relapse rate (P < 0.001). Univariate analysis showed that tumor size (P = 0.005) and CD55 expression (P = 0.005) were unfavorable prognostic factors. Multivariate analysis revealed that the tumor size (P = 0.013) and CD55 expression (P = 0.011) were independent prognostic factors.

Conclusions: CD55 play an important role in tumorigenesis of breast cancer, and presence of small population of cells with strong CD55 expression would be sufficient to predict poor prognosis of patients.
Efficacy of Systemically Administered Mutant Vesicular Stomatitis Virus (VSVΔ51) Combined with Radiation for Nasopharyngeal Carcinoma
Authors: Alajez Nehad M. , Mocanu Joseph D. , Shi Wei , Chia Marie C. , Breitbach Caroline J. , Hui Angela B.Y. , Knowles Shane , Bell John C. , Busson Pierre , Takada Kenzo , Lo Kwok-Wai , O'Sullivan Brian , Gullane Pat , Liu Fei-Fei
Published: August 2008

Purpose: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck region that is associated with EBV latency. Curative treatments for NPC achieve modest survival rates, underscoring a need to develop novel therapies. We evaluated the therapeutic potential of a mutant vesicular stomatitis virus (VSVΔ51) as single treatment modality or in combination with ionizing radiation (RT) in NPC.

Experimental Design: MTS assay was used to assess cell viability in vitro; apoptosis was measured using propidium iodide staining and caspase activation. In vivo experiments were conducted using tumor-bearing nude mice with or without local RT (4 Gy). Apoptosis was assessed in excised tumor sections with terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining.

Results: Our data showed that NPC cells are exquisitely sensitive to VSVΔ51 oncolysis, which correlated with the presence of EBV. Efficacy of VSVΔ51 against NPC cells was further augmented when combined with RT. A single systemic injection of VSVΔ51 achieved 50% survival in treated mice, which increased to 83% when combined with local tumor RT. In addition to induction of apoptosis, an antiangiogenic effect of VSVΔ51 was observed in vivo, suggesting a novel tumoricidal mechanism for VSVΔ51. This virus also prevented growth of NPC sphere-forming cells in vitro, showing potential utility in targeting NPC-initiating cells.

Conclusions: Our data represent the first report showing that EBV-positive NPC cells are exquisitely sensitive to VSVΔ51 oncolysis and documenting the successful utilization of this combinatorial regimen as a novel curative therapeutic strategy for NPC.
Gene Expression Profiling of Papillary Thyroid Carcinoma Identifies Transcripts Correlated with BRAF Mutational Status and Lymph Node Metastasis
Authors: Oler Gisele , Camacho Cléber P. , Hojaij Flávio C. , Michaluart Pedro , Riggins Gregory J. , Cerutti Janete M.
Published: August 2008

Purpose: To identify papillary thyroid carcinoma (PTC)–associated transcripts, we compared the gene expression profiles of three Serial Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue.

Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of 71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic) was investigated. The BRAFV600E mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular signal-regulated kinase signaling.

Results: We identified and validated new PTC-associated transcripts. Three genes (CST6, CXCL14, and DHRS3) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3, and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14, and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAFV600E mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway.

Conclusion: CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for PTC therapy.
Silencing of Transforming Growth Factor-β1 In situ by RNA Interference for Breast Cancer: Implications for Proliferation and Migration In vitro and Metastasis In vivo
Authors: Moore Lakisha D. , Isayeva Tatyana , Siegal Gene P. , Ponnazhagan Selvarangan
Published: August 2008

Purpose: Overexpression of transforming growth factor (TGF)-β has been implicated in promoting immune suppression, tumor angiogenesis, tumor cell migration, and invasion in many cancers, including carcinoma of the breast. Thus, targeted down-regulation of TGF-β1 expression in breast cancer in situ and determination of its implications would provide new treatment approaches for disease management.

Experimental Design: Small interfering RNA constructs targeting TGF-β1 were validated and used to develop clonal derivatives of the metastatic breast cancer cell line MDA-MB-435. The cells were used in several in vitro analyses, including migration, invasion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptosis, and signaling assays. A wound-healing assay was used to determine migration of the cells in culture and a Boyden chamber transwell assay was used for invasion. Further, the clones were used in an in vivo mouse model for the kinetics of tumor growth and gene expression in the primary site and in lungs upon metastasis.

Results: Inhibition of TGF-β1 expression in MDA-MB-435 cells showed a 35% decrease in migration and a 55% decrease in invasion in vitro, with a 50% increase in proliferation and no effect on apoptosis. In vivo analysis indicated a 90% decrease in the number of mice bearing macroscopic lung metastases; however, the primary tumors did not show any difference in the growth kinetics when compared with the parental MDA-MB-435 cells. Analysis of TGF-β signaling pathways in the clonal derivatives showed a decrease in Smad2 activation and an increase in AKT and extracellular signal-regulated kinase activation. Interestingly, analysis of TGF-β receptor expression showed a decrease in both receptor I and II expression in TGF-β1 silenced cells. These results suggest that inhibition of TGF-β1 ligand may act as a negative feedback loop to disrupt the function of all TGF-β isoforms.

Conclusions: Therapies targeting the TGF-β signaling pathway may be more effective in late-stage disease to prevent organ metastasis but not primary tumor formation and may be combined with other tumor-targeted therapies normally limited by increased circulating TGF-β levels.
Oxidation of Ovarian Epithelial Cancer Cells by Hypochlorous Acid Enhances Immunogenicity and Stimulates T Cells that Recognize Autologous Primary Tumor
Authors: Chiang Cheryl L-L. , Ledermann Jonathan A. , Aitkens Egla , Benjamin Elizabeth , Katz David R. , Chain Benjamin M.
Published: August 2008

Purpose: Hypochlorous acid, a product of neutrophil myeloperoxidase, is a powerful enhancer of antigen processing and presentation. In this study, we examine whether ovarian epithelial cells (SK-OV-3) exposed to hypochlorous acid can stimulate T cells from patients with ovarian epithelial cancer that recognize common tumor antigens as well as autologous tumor.

Experimental Design: T cells from human leukocyte antigen (HLA)-A2+ and HLA-A2− patients or healthy controls were stimulated with autologous dendritic cells cocultured with the generic ovarian tumor line SK-OV-3, previously exposed to hypochlorous acid.

Results: Hypochlorous acid–treated SK-OV-3 cells drove expansion of CD8+ T cells from HLA-A2+ individuals, which recognized the HLA-A2–restricted tumor antigen epitopes of HER-2/neu (E75 and GP2) and MUC1 (M1.1 and M1.2). Up to 4.1% of the T cells were positive for the HER-2/neu KIFGSLAFL epitope using pentamer staining. Dendritic cells loaded with oxidized SK-OV-3 cells and further matured with CD40 agonistic antibody or monophosphoryl lipid A additionally induced CD4+ class II–restricted responses. Critically, T cells stimulated with mature oxidized SK-OV-3 (but not a control oxidized melanoma cell line) directly recognized autologous tumor cells isolated from patient ascites.

Conclusions: Immunization with mature dendritic cells loaded with a generic oxidized tumor cell line stimulates a polyclonal antitumor response that recognizes autologous tumor. These findings suggest a new immunotherapeutic strategy to extend remission in ovarian cancer.