bluuebunny/crossref_metadata_2025 huggingface dataset:
EXISTENCE ANDA PRIORIBOUNDS FOR ELECTROSTATIC KLEIN–GORDON–MAXWELL SYSTEMS IN FULLY INHOMOGENEOUS SPACES
Authors: DRUET OLIVIER , HEBEY EMMANUEL
Published: October 2010

We prove the existence and uniform bounds for the electrostatic Klein–Gordon–Maxwell systems in the inhomogeneous context of a compact Riemannian manifold when the mass potential, balanced by the phase, is small in a quantified sense. Phase compensation for the electrostatic Klein–Gordon–Maxwell systems and the positive mass theorem are used in a crucial way.
MODELING PREY-PREDATOR TYPE FISHERY WITH RESERVE AREA
Authors: GHOSH MINI
Published: October 2010

This paper presents a prey-predator type fishery model in two patch environment. We assume that one patch is accessible to both prey and predator while other is a refuge for prey. The prey refuge constitutes a reserve zone where fishing is not allowed. In the unreserved area there are both prey and predators and harvesting of only predators is permitted. The equilibria of the model and their stability are discussed. Also we investigate various possibilities of bionomic equilibrium. Finally, the model is simulated for varied set of parameters and sensitivity of the parameters and effect of the size of reserve on maximum yield are studied. We found that it is the best to keep the size of reserve small and increase the harvesting effort upto optimal harvesting effort to get the higher maximum yield.
EXISTENCE AND BEHAVIOR OF SOLUTION TO SOME CHEMOTAXIS MODEL WITH INTERACTING SPECIES
Authors: LI JUN-FENG , LIU WEI-AN
Published: October 2010

In this paper, we study a chemotaxis system involving two interacting species as follows: [Formula: see text] with some initial and boundary conditions.

We prove the existence of solution to the problem whose behavior is concerned with reference to some systems through sup-sub-solution method.
OPTIMAL SEASONAL BIOCONTROL FOREICHHORNIA CRASSIPES
Authors: AGUSTO F. B. , OKOSUN K. O.
Published: October 2010

This article studies the effect of reduction of an invasive species' competitive ability against another aggressive species, where the intra- and inter-species competition effect on the system is modeled as a control variable. Thus, following the example of competition between water hyacinth–water lettuce, where the competitive ability of the water hyacinth is reduced by the presence of the biological agent Neochetina eichhorniae (weevil) we apply optimal control to compare the effects of the weevil on the competitive relationship. With the effect of the reduced competitive ability been obvious during the larvae stages of the weevil. An objective functional is formulated to minimize the invasive species while minimizing the cost of implementing the control. Numerical results are examined for various parameter values.
Size Effect of Uniaxial Stress Affecting Dielectric Response in Barium Titanate
Authors: Sun Tieyu , Wang Xiaohui , Zhang Yichi , Peng Bin , Li Longtu
Published: October 2010

Size effect on uniaxial stress affecting dielectric response in barium titanate system is studied in this paper. From experiments we know that, dielectric constant decreases with increasing loading stress. The change rates of dielectric constants for different grain sizes are different, samples with finer grains have smaller change rate. In theory, we can derive out that dielectric constant will decrease with loading stress by Landau–Ginsberg–Devonshire model. Furthermore, the grain size effect is analyzed with a complex model. The volume fraction of the grain boundaries will increase, and they will bear more part of the total loading when decreasing grain size. This will reduce the change rate of dielectric constant for finer grains.
Fin and Recess-Channel Metal Oxide Semiconductor Field Effect Transistor for Sub-50 nm Dynamic Random Access Memory Cell
Authors: Song Jae Young , Kim Jong Pil , Kim Sang Wan , Oh Jeong-Hoon , Ryoo Kyung-Chang , Sun Min-Chul , Kim Garam , Yun Jang-Gn , Shin Hyungcheol , Park Byung-Gook
Published: October 2010

In this paper, we propose a novel fin and recess-channel metal oxide semiconductor field effect transistor (MOSFET) for sub-50 nm dynamic random access memory (DRAM) cell application. Also, it is compared with the recess-channel-array transistor (RCAT). In the proposed device, a silicon fin region is added to the recessed channel MOSFET. Thanks to the additional current path through the silicon fin with the wide source/drain width, the FiReFET shows excellent current drivability. To reduce gate-induced drain leakage (GIDL) current, we adopt an underlapped device structure. As a result, it is found that the optimized underlap structure helps to prevent the OFF state leakage current induced by the increase of the gate work function.
Schottky-Barrier Metal–Oxide–Semiconductor Field-Effect Transistors as Resonant Tunneling Devices
Authors: Toriyama Shuichi
Published: October 2010

The current–voltage characteristics of double-gated Schottky-barrier metal–oxide–semiconductor field-effect transistor (MOSFET) 10 nm in length and with body thickness of 3 nm is numerically studied, illustrating a similarity between the rectangular quantum well cavity in conventional resonant tunneling diodes and the parabolic-like cavity created by a pair of Schottky junctions in scaled Schottky-barrier MOSFETs. Assuming ballistic transport for electrons within effective mass approximation, the appearance of negative differential resistance due to the resonant tunneling effect between the Schottky junctions of 0.75 eV height is confirmed by non-equilibrium Green's function simulation. In such scaled Schottky-barrier MOSFETs, the tunneling electrons by themselves determine the shape of resonant potential, through the charge terms in electrostatic field equations. Using both the Poisson equation and the Laplace equation, we highlight the importance of the self-consistency for realizing successful resonant tunneling operation in scaled Schottky-barrier MOSFETs.
Pattern Growth and Field Emission Characteristics of Flower-Like RuO2 Nanostructures
Authors: Lee Kuei-Yi , Chen Ching-An , Lian Huan-Bin , Chen Yi-Min , Huang Ying-Sheng , Keiser Gerd
Published: October 2010

A flower-like RuO2 nanostructure was selectively synthesized on a Si substrate by metal organic chemical vapor deposition (MOCVD). Bis(ethylcyclopentadienyl) ruthenium(II), Ru[(C2H5)C5H4]2, was shower sprayed onto the Si substrate with oxygen gas. Prior to the growth of the flower-like RuO2 nanostructure, patterns of Al and Fe films were deposited on the Si substrate by photolithography and electron beam (e-beam) evaporation deposition. The synthesized flower-like RuO2 nanostructures were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX) analysis, X-ray diffraction (XRD), and micro-Raman spectroscopy. The results indicated that the flower-like nanostructures were RuO2 rutile structures with high crystallinity. For the particular synthesized morphology and design pattern, the current density and long-term stability characteristics of electron field-emission characteristics demonstrated that the flower-like RuO2 nanostructure has the potential to be used in a practical field-emission display.
Field Emission from Individual Free-Standing Carbon Nanotubes
Authors: Tseng Shih-chun , Yao Bin-cheng , Tsai Chuen-horng
Published: October 2010

The field emission (FE) characteristics of individual free-standing vertically aligned carbon nanotubes (VACNTs) grown by inductively coupled plasma chemical vapor deposition (ICP-CVD) were studied. The processes comprised electron beam lithography (EBL) with various exposure periods, the deposition of nickel metal followed by lift-off, and the growth of carbon nanotubes by ICP-CVD on a <100> p-type silicon substrate. Straight tubular and stubby conical VACNFs were formed by varying the size of the graphite electrode that supports the silicon substrate. Current–voltage (I–V) curve characteristics for the tubular shape of isolated carbon nanotubes with different diameters and lengths were studied. The lowest turn-on voltage was shown to be about 24.5 V for the highest aspect ratio of a single vertically-aligned CNT. The highest field enhancement factor β determined from fitting the FN equation was about 110. In addition, the enhancement factor was proportional to the aspect ratio of the CNTs. The turn-on field at an emission current of 1 nA was 8–12 V/µm for a single straight tubular VACNT and 4–8 V/µm for a stubby conical VACNF. The stubby conical CNFs (with smaller radii of curvature of their tips) had a lower turn-on field, but a slightly lower β, than the long tubular CNTs (with higher aspect ratio).
Threading Dislocations in InGaAs CaP Layers with InGaAs Graded Layers Grown on Si Substrates
Authors: Takano Yasushi , Kobayashi Kazunobu , Uranishi Taiju , Fuke Shunro
Published: October 2010

We investigated InGaAs layers with InGaAs graded layers on GaAs layers that had been grown on Si substrates using metalorganic vapor phase epitaxy. Cross-sectional transmission electron microscopy revealed that dislocations propagating from the GaAs layer were bent in the graded layer, thereby reducing the density of threading dislocations (TDs) in the InGaAs layer. Thermal cyclic annealing (TCA) was performed for GaAs layers. The TD density in the InGaAs layer decreased with decreasing TD density in the GaAs layer. The combination of an InGaAs graded layer with TCA of the GaAs layer was effective for reducing the TD density of the InGaAs cap layer. The respective TD densities of In0.095Ga0.905As and In0.22Ga0.78As layers with InGaAs graded layers were 1.3×106 and 4.4×106 cm-2 when TCA was performed four times at 850 °C for GaAs layers.
Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling
Authors: Doherty Leo F. , Kwon Hye Eun , Taylor Hugh S.
Published: October 2010

Tryptophan 2,3-dioxygenase (TDO) is expressed in endometrium and catabolizes tryptophan, a precursor in the biosynthesis of serotonin. Tryptophan metabolism is an important mechanism for regulation of serotonin levels. Preimplantation mouse embryos are known to express serotonin receptors, specifically the 5-HT1D and 5-HT7 serotonin receptor subtypes. Here we demonstrate that Hoxa10 regulates endometrial TDO expression and improves embryo viability through increased serotonin production. Transfection of pcDNA- Hoxa10 to the murine uterus increased total TDO expression. In vitro, epithelial cell TDO expression was decreased after transfection with Hoxa10. Decreased glandular TDO in response to HOXA10 may augment serotonin production by increasing tryptophan availability. Conversely, stromal TDO expression increased with constitutive Hoxa10 expression. In mice, epithelial serotonin was increased in response to constitutive expression of Hoxa10. Embryo quality was impaired after treatment with Hoxa10 antisense. Blockade of serotonin receptors 1D and 7 also resulted in impaired embryo development, indicating an essential role for Hoxa10 induction of TDO and subsequent serotonin production in embryo development. Transfection of pcDNA- TDO also decreased the number of T cells in the endometrial stroma. We have shown a novel mechanism by which HOXA10 regulates endometrial TDO expression. In the endometrial stroma, HOXA10 increases TDO mRNA, which may increase tryptophan catabolism, allowing for immune tolerance at the time of embryo implantation. In endometrial glands, HOXA10 decreases TDO mRNA leading to increased serotonin that in turn acts to promote normal embryo development.
MicroRNAs in skin and wound healing
Authors: Banerjee Jaideep , Chan Yuk Cheung , Sen Chandan K.
Published: October 2010

MicroRNAs (miRNAs) are small endogenous RNA molecules ∼22 nt in length. miRNAs are capable of posttranscriptional gene regulation by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or suppression of translation. miRNAs have recently been shown to play pivotal roles in skin development and are linked to various skin pathologies, cancer, and wound healing. This review focuses on the role of miRNAs in cutaneous biology, the various methods of miRNA modulation, and the therapeutic opportunities in treatment of skin diseases and wound healing.
Nitrogen Uptake Rates during Spring in the NE Arabian Sea
Authors: Gandhi Naveen , Ramesh R. , Srivastava R. , Sheshshayee M. S. , Dwivedi R. M. , Raman Mini
Published: October 2010

We present new data on N uptake rates and f-ratios in the north-eastern (NE) Arabian Sea, where significant amounts of Trichodesmium were present in spring, 2006. The measured total nitrogen uptake rates ranged from 0.34 to 1.58 mmol N . fixation associated with Trichodesmium varied from 0.002 to 0.54 mmol N estimated from the abundance of Trichodesmium and specific fixation rates of 1.5 pmol N trichome. Inclusion of fixation rates significantly changes f-ratios particularly in the coastal stations. Nitrogen isotopic data of surface suspended particles suggest that recently fixed nitrogen contributes as high as ~79% of the nitrogen in surface suspended particles. In addition, water column gained ~30 mmol N in the form of nitrate, likely due to nitrification of ammonium released by Trichodesmium. For better estimations, direct measurement of fixation is recommended.
Functional Promiscuity of Homologues of the Bacterial ArsA ATPases
Authors: Castillo Rostislav , Saier Milton H.
Published: October 2010

The ArsA ATPase ofE. coliplays an essential role in arsenic detoxification. Published evidence implicates ArsA in the energization of As(III) efflux via the formation of an oxyanion-translocating complex with ArsB. In addition, eukaryotic ArsA homologues have several recognized functions unrelated to arsenic resistance. By aligning ArsA homologues, constructing phylogenetic trees, examining ArsA encoding operons, and estimating the probable coevolution of these homologues with putative transporters and auxiliary proteins unrelated to ArsB, we provide evidence for new functions for ArsA homologues. They may play roles in carbon starvation, gas vesicle biogenesis, and arsenic resistance. The results lead to the proposal that ArsA homologues energize four distinct and nonhomologous transporters, ArsB, ArsP, CstA, and Acr3.
Production and Emissions of Marine Isoprene and Monoterpenes: A Review
Authors: Shaw Stephanie L. , Gantt Brett , Meskhidze Nicholas
Published: October 2010

Terrestrial and marine photosynthetic organisms emit trace gases, including isoprene and monoterpenes. The resulting emissions can impact the atmosphere through oxidative chemistry and formation of secondary organic aerosol. Large uncertainty exists as to the magnitude of the marine sources of these compounds, their controlling factors, and contribution to marine aerosol. In recent years, the number of relevant studies has increased substantially, necessitating the review of this topic. Isoprene emissions vary with plankton species, chlorophyll concentration, light, and other factors. Remote marine boundary layer isoprene mixing ratios can reach >300 pptv, and extrapolated global ocean fluxes range from <1 to >10 Tg C year −1. Modeling studies using surface chlorophyll concentration as an isoprene emissions proxy suggest variable atmospheric impacts. More information is needed, including emission fluxes of isoprene and monoterpenes from various biogeographical areas, the effects of species and nutrient limitation on emissions, and the aerosol yields via condensation and nucleation, in order to better quantify the atmospheric impacts of marine isoprene and monoterpenes.
CpG Oligodeoxynucleotides Enhance the Efficacy of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes by Modifying the Th1 Polarization and Local Infiltration of Th17 Cells
Authors: Xu Lin , Wang Chunhong , Wen Zhenke , Zhou Ya , Liu Zhongmin , Liang Yongjie , Xu Zengguang , Ren Tao
Published: October 2010

Adoptive cell transfer immunotherapy using tumor infiltrating lymphocytes (TILs) was an important therapeutic strategy against tumors. But the efficacy remains limited and development of new strategies is urgent. Recent evidence suggested that CpG‐ODNs might be a potent candidate for tumor immunotherapy. Here we firstly reported that CpG‐ODNs could significantly enhance the antitumor efficacy of adoptively transferred TILs in vivo accompanied by enhanced activity capacity and proliferation of CD8+ T cells and CD8+ T cells, as well as a Th1 polarization immune response. Most importantly, we found that CpG‐ODNs could significantly elevate the infiltration of Th17 cells in tumor mass, which contributed to anti‐tumor efficacy of TILs in vivo. Our findings suggested that CpG ODNs could enhance the anti‐tumor efficacy of adoptively transferred TILs through modifying Th1 polarization and local infiltration of Th17 cells, which might provide a clue for developing a new strategy for ACT based on TILs.
Oscillation for Certain Nonlinear Neutral Partial Differential Equations
Authors: Lin Quanwen , Zhuang Rongkun
Published: October 2010

We present some new oscillation criteria for second‐order neutral partial functional differential equations of the form , (x, t) ∈ Ω × R+ ≡ G, where Ω is a bounded domain in the Euclidean N‐space RN with a piecewise smooth boundary ∂Ω and Δ is the Laplacian in RN. Our results improve some known results and show that the oscillation of some second‐order linear ordinary differential equations implies the oscillation of relevant nonlinear neutral partial functional differential equations.
Pediatric Sedation: A Global Challenge
Authors: Gozal David , Mason Keira P.
Published: October 2010

Pediatric sedation is a challenge which spans all continents and has grown to encompass specialties outside of anesthesia, radiology and emergency medicine. All sedatives are not universally available and local and national regulations often limit the sedation practice to specific agents and those with specific credentials. Some specialties have established certification and credentials for sedation delivery whereas most have not. Some of the relevant sedation guidelines and recommendations of specialty organizations worldwide will be explored. The challenge facing sedation care providers moving forward in the 21st century will be to determine how to apply the local, regional and national guidelines to the individual sedation practices. A greater challenge, perhaps impossible, will be to determine whether the sedation community can come together worldwide to develop standards, guidelines and recommendations for safe sedation practice.
The Oncoprotein c-Ski Functions as a Direct Antagonist of the Transforming Growth Factor-β Type I Receptor
Authors: Ferrand Nathalie , Atfi Azeddine , Prunier Céline
Published: October 2010

The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-β (TGF-β) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-β signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-β signaling by interacting directly with the activated TGF-β type I receptor (TβRI). We explored the physiologic relevance of the c-Ski/TβRI interaction and found that it can culminate in a constitutive association of TβRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TβRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-β signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads. Cancer Res; 70(21); 8457–66. ©2010 AACR.
Protein Tyrosine Phosphatase Receptor Type γ Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia
Authors: Della Peruta Marco , Martinelli Giovanni , Moratti Elisabetta , Pintani Davide , Vezzalini Marzia , Mafficini Andrea , Grafone Tiziana , Iacobucci Ilaria , Soverini Simona , Murineddu Marco , Vinante Fabrizio , Tecchio Cristina , Piras Giovanna , Gabbas Attilio , Monne Maria , Sorio Claudio
Published: October 2010

Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34+ cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34+ cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. Cancer Res; 70(21); 8896–906. ©2010 AACR.
Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf-Mutant Human Cutaneous Melanoma Cells
Authors: Gopal Y.N. Vashisht , Deng Wanleng , Woodman Scott E. , Komurov Kakajan , Ram Prahlad , Smith Paul D. , Davies Michael A.
Published: October 2010

The majority of melanomas show constitutive activation of the RAS-RAF-MAP/ERK kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway. AZD6244 is a selective MEK1/2 inhibitor that markedly reduces tumor P-MAPK levels, but it produces few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the phosphoinositide 3-kinase (PI3K)-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines showed AZD6244-induced activation of AKT. In contrast, sensitive cell lines showed AZD6244 treatment–induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or insulin-like growth factor I receptor blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells and the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients. Cancer Res; 70(21); 8736–47. ©2010 AACR.
Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer
Authors: Bianchini Giampaolo , Iwamoto Takayuki , Qi Yuan , Coutant Charles , Shiang Christine Y. , Wang Bailang , Santarpia Libero , Valero Vicente , Hortobagyi Gabriel N. , Symmans W. Fraser , Gianni Luca , Pusztai Lajos
Published: October 2010

Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative, 7 in HER2+, and 28 in ER−/HER2− cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER−/HER2− cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER+/HER2− cancers, but not in ER−/HER2− or HER2+ cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER+/HER2− and HER2+ tumors and also predicted higher probability of pCR in HER2+ cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype. Cancer Res; 70(21); 8852–62. ©2010 AACR.
Activation of Forkhead Box O Transcription Factors by Oncogenic BRAF Promotes p21cip1-Dependent Senescence
Authors: de Keizer Peter L.J. , Packer Leisl M. , Szypowska Anna A. , Riedl-Polderman Paulien E. , van den Broek Niels J.F. , de Bruin Alain , Dansen Tobias B. , Marais Richard , Brenkman Arjan B. , Burgering Boudewijn M.T.
Published: October 2010

Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAFV600E oncogene, which arises commonly in melanoma. BRAFV600E signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH2 terminal kinase–mediated activation of FOXO4 via its phosphorylation on Thr223, Ser226, Thr447, and Thr451. BRAFV600E-induced FOXO4 phosphorylation resulted in p21cip1-mediated cell senescence independent of p16ink4a or p27kip1. Importantly, melanocyte-specific activation of BRAFV600E in vivo resulted in the formation of skin nevi expressing Thr223/Ser226-phosphorylated FOXO4 and elevated p21cip1. Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging. Cancer Res; 70(21); 8526–36. ©2010 AACR.
Cancer Stem Cells in the Central Nervous System – A Critical Review
Authors: Prestegarden Lars , Enger Per Øyvind
Published: October 2010

The cancer stem cell hypothesis postulates that tumors arise from, and are maintained by, a small subpopulation of cancer stem cells. This concept has recently become increasingly controversial, following a series of conflicting results. The cell-surface epitope CD133 has been proposed as a brain cancer stem cell marker, whereas a growing number of studies clearly show a tumorigenic potential among CD133− cells as well. Diverging results suggest that assays for isolating cancer stem cells impose a selection bias on which cells are defined as cancer stem cells. Here, we highlight some recent developments, with an emphasis on reports that call for caution in the acceptance of the brain cancer stem cell hypothesis. Cancer Res; 70(21); 8255–8. ©2010 AACR.
Tumorigenic and Metastatic Activity of Human Thyroid Cancer Stem Cells
Authors: Todaro Matilde , Iovino Flora , Eterno Vincenzo , Cammareri Patrizia , Gambara Guido , Espina Virginia , Gulotta Gaspare , Dieli Francesco , Giordano Silvia , De Maria Ruggero , Stassi Giorgio
Published: October 2010

Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDHhigh) activity and unlimited replication potential. ALDHhigh cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by constitutive activation of cMet and Akt in thyroid cancer stem cells. The identification of tumorigenic and metastagenic thyroid cancer cells may provide unprecedented preclinical tools for development and preclinical validation of novel targeted therapies. Cancer Res; 70(21); 8874–85. ©2010 AACR.
Transcriptome Analysis Reveals that p53 and β-Catenin Alterations Occur in a Group of Aggressive Adrenocortical Cancers
Authors: Ragazzon Bruno , Libé Rossella , Gaujoux Sébastien , Assié Guillaume , Fratticci Amato , Launay Pierre , Clauser Eric , Bertagna Xavier , Tissier Frédérique , de Reyniès Aurélien , Bertherat Jérôme
Published: October 2010

Adrenocortical carcinoma (ACC) is a rare disease with an overall poor but heterogeneous prognosis. This heterogeneity could reflect different mechanisms of tumor development. Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic inactivating mutations of the tumor suppressor gene TP53 and activating mutations of the proto-oncogene β-catenin (CTNNB1) are the most frequent mutations identified in ACC. This study investigates the correlation between p53 and β-catenin alterations and the molecular classification of ACC by transcriptome analysis of 51 adult sporadic ACCs. All TP53 and CTNNB1 mutations seemed to be mutually exclusive and were observed only in the poor-outcome ACC group. Most of the abnormal p53 and β-catenin immunostaining was also found in this group. Fifty-two percent of the poor-outcome ACC group had TP53 or CTNNB1 mutations and 60% had abnormal p53 or β-catenin immunostaining. Unsupervised clustering transcriptome analysis of this poor-outcome group revealed three different subgroups, two of them being associated with p53 or β-catenin alterations, respectively. Analysis of p53 and β-catenin target gene expressions in each cluster confirmed a profound and anticipated effect on tumor biology, with distinct profiles logically associated with the respective pathway alterations. The third group had no p53 or β-catenin alteration, suggesting other unidentified molecular defects. This study shows the important respective roles of p53 and β-catenin in ACC development, delineating subgroups of ACC with different tumorigenesis and outcomes. Cancer Res; 70(21); 8276–81. ©2010 AACR.
cIAP2 Upregulated by E6 Oncoprotein via Epidermal Growth Factor Receptor/Phosphatidylinositol 3-Kinase/AKT Pathway Confers Resistance to Cisplatin in Human Papillomavirus 16/18–Infected Lung Cancer
Authors: Wu Heng-Hsiung , Wu Jeng-Yuan , Cheng Ya-Wen , Chen Chi-Yi , Lee Ming-Ching , Goan Yih-Gang , Lee Huei
Published: October 2010

Purpose: Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)–infected lung cancer.

Experimental Design: Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p-AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry.

Results: Our data show that two NF-κB (−209 to −200 and −146 to −137) and one CREB (cyclic AMP–responsive element binding protein; −52 to −42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC50 was lowered to 8.6 μmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 μmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2-positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining.

Conclusions: cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer. Clin Cancer Res; 16(21); 5200–10. ©2010 AACR.
MicroRNA Expression Profiling of Exfoliated Colonocytes Isolated from Feces for Colorectal Cancer Screening
Authors: Koga Yoshikatsu , Yasunaga Masahiro , Takahashi Amane , Kuroda Junichiro , Moriya Yoshihiro , Akasu Takayuki , Fujita Shin , Yamamoto Seiichiro , Baba Hideo , Matsumura Yasuhiro
Published: October 2010

To reduce the colorectal cancer (CRC) mortality rate, we have reported several CRC screening methods using colonocytes isolated from feces. Expression analysis of oncogenic microRNA (miRNA) in peripheral blood was recently reported for CRC detection. In the present study, we conducted miRNA expression analysis of exfoliated colonocytes isolated from feces for CRC screening. Two hundred six CRC patients and 134 healthy volunteers were enrolled in the study. miRNA expression of the miR-17-92 cluster, miR-21, and miR-135 in colonocytes isolated from feces as well as frozen tissues was analyzed by quantitative real-time PCR. The expression of the miR-17-92 cluster, miR-21, and miR-135 was significantly higher in CRC tissues compared with normal tissues. The exfoliated colonocytes of 197 CRC patients and 119 healthy volunteers were analyzed because of the presence of sufficient miRNA concentration. miR-21 expression did not differ significantly between CRC patients and healthy volunteers (P = 0.6). The expression of miR-17-92 cluster and miR-135 was significantly higher in CRC patients than in healthy volunteers (P < 0.0001). The overall sensitivity and specificity by using miRNA expression was 74.1% (146/197; 95% confidence interval, 67.4-80.1) and 79.0% (94/119; 95% confidence interval, 70.6-85.9), respectively. Sensitivity was dependent only on tumor location (P = 0.0001). miRNA was relatively well conserved in exfoliated colonocytes from feces both of CRC patients and healthy volunteers. miRNA expression analysis of the isolated colonocytes may be a useful method for CRC screening. Furthermore, oncogenic miRNA highly expressed in CRC should be investigated for CRC screening tests in the future. Cancer Prev Res; 3(11); 1435–42. ©2010 AACR.
The Origins and Implications of Intratumor Heterogeneity
Authors: Michor Franziska , Polyak Kornelia
Published: October 2010

Human tumors often display startling intratumor heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. This phenotypic and genetic heterogeneity plays an important role in neoplasia, cancer progression, and therapeutic resistance. In this issue of the journal (beginning on page 1388), Merlo et al. report their use of molecular data from 239 patients with Barrett's esophagus to evaluate the propensity of major diversity indices for predicting progression to esophageal adenocarcinoma. This work helps elucidate the implications of molecular heterogeneity for the evolution of neoplasia. Cancer Prev Res; 3(11); 1361–4. ©2010 AACR.
The Nuclear Localization of CAPON in Hippocampus and Cerebral Cortex Neurons after Lipopolysaccharide Stimulation
Authors: Shao Bai , Jiang Jing , Wu Qiyun , Xu Yanyan , Lv Qingshan , Li Xiaohong , Wang Ping , Shen Aiguo , Yan Meijuan
Published: October 2010

Objective: In the brain, nitric oxide (NO) is a retrograde signalling molecule that transfers information from post- to pre-synaptic nerve endings. NO has been shown to be an important inflammatory mediator responding to lipopolysaccharide (LPS). It has been stated that the constitutive NO synthase isoforms (nNOS and eNOS) may also contribute to the inflammation. CAPON, a nNOS regulator, helps regulate nNOS stability, localization and possibly expression during synapse formation as well as muscle re-innervation. Recently, it has been reported that CAPON is associated with psychiatric illness. So we speculated that the CAPON expression-induced physiological changes may be mediated by modifications of NOS-NO signalling pathways. But little is known about the role of CAPON during the inflammation in the central nervous system, so we investigated the expression of CAPON in the brain treated with LPS. Methods and Results: Real-time PCR and Western blot showed that the expression of CAPON increased at mRNA and protein levels in the brain after LPS stimulation. Immunocytochemistry staining revealed that CAPON localized in the nuclei of neurons in the brain after peritoneal injection with LPS in vivo. The same phenomenon was also shown in primary cultured neurons in vitro incubated with LPS for 36 h. In addition, we found that CAPON had a colocalization with phosphorylated nNOS Ser847 but not with nNOS in hippocampus and cerebral cortex by double immunofluorescence. Conclusion: CAPON localized in the nuclei of neurons in hippocampus and cerebral cortex after LPS treatment. Because CAPON competed with PSD-95 for binding nNOS in neurons and nNOS was activated to produce NO through the NMDA- NMDAR pathway, we hypothesized that CAPON might play a proactive role in the process of inflammation by transferring from cytoplasm to the nucleus and through the NMDA-nNOS signal pathway. Further studies are required to clarify the mechanism of the nuclear localization of CAPON and the possible relationship with nNOS/NO signalling.
Genetic Polymorphisms in Nitric Oxide Synthase 3 Gene and Implications for Kidney Disease: A Meta-Analysis
Authors: McKnight A.J. , Patterson C.C. , Sandholm N. , Kilner J. , Buckham T.A. , Parkkonen M. , Forsblom C. , Sadlier D.M. , Groop P.H. , Maxwell A.P. ,   and the Warren 3/UK GoKinD Study Group
Published: October 2010

Background/Aims: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. Methods:We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. Results: A novel association was identified in the discovery collection (rs1800783, pgenotype = 0.006, pallele = 0.002, OR = 1.26, 95% CI: 1.08–1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r2 = 0.96 with rs1800783) in the replication collection (pgenotype = 0.002, pallele = 0.0006, OR = 1.27, 95% CI: 1.10–1.45). Conclusion: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene.
Novel Antidepressants and Panic Disorder: Evidence beyond Current Guidelines
Authors: Serretti Alessandro , Chiesa Alberto , Calati Raffaella , Perna Giampaolo , Bellodi Laura , De Ronchi Diana
Published: October 2010

Aim: The aim of the present review is to summarize available evidence about the efficacy and side effects of novel antidepressants for the treatment of panic disorder. Methods: A literature search was undertaken using MEDLINE, ISI web of knowledge and references of retrieved articles. The search included articles published in English up to September 2009. Both controlled and uncontrolled trials were included. The quality of the reviewed articles was also assessed. Results: Fourteen mainly poor-quality studies were included. Mirtazapine showed some efficacy in reducing the number and the severity of panic symptoms in many uncontrolled studies and was comparable to selective serotonin reputake inhibitors (SSRIs) in direct-comparison studies. Reboxetine was significantly more efficacious than placebo but less effective than SSRIs. Further uncontrolled studies suggested preliminary evidence for the use of milnacipran and duloxetine as well. All drugs were usually well tolerated. Discussion: Current studies do not yet provide convincing evidence supporting the efficacy of mirtazapine, reboxetine, milnacipran and duloxetine for the treatment of panic disorder patients. However, on account of positive preliminary results, further research is warranted.
Spatial Attention Determines the Nature of Nonverbal Number Representation
Authors: Hyde Daniel C. , Wood Justin N.
Published: October 2010

Coordinated studies of adults, infants, and nonhuman animals provide evidence for two systems of nonverbal number representation: a “parallel individuation” system that represents individual items and a “numerical magnitude” system that represents the approximate cardinal value of a group. However, there is considerable debate about the nature and functions of these systems, due largely to the fact that some studies show a dissociation between small (1–3) and large (>3) number representation, whereas others do not. Using event-related potentials, we show that it is possible to determine which system will represent the numerical value of a small number set (1–3 items) by manipulating spatial attention. Specifically, when attention can select individual objects, an early brain response (N1) scales with the cardinal value of the display, the signature of parallel individuation. In contrast, when attention cannot select individual objects or is occupied by another task, a later brain response (P2p) scales with ratio, the signature of the approximate numerical magnitude system. These results provide neural evidence that small numbers can be represented as approximate numerical magnitudes. Further, they empirically demonstrate the importance of early attentional processes to number representation by showing that the way in which attention disperses across a scene determines which numerical system will deploy in a given context.
The Role of Prosodic Breaks and Pitch Accents in Grouping Words during On-line Sentence Processing
Authors: Bögels Sara , Schriefers Herbert , Vonk Wietske , Chwilla Dorothee J.
Published: October 2010

The present study addresses the question whether accentuation and prosodic phrasing can have a similar function, namely, to group words in a sentence together. Participants listened to locally ambiguous sentences containing object- and subject-control verbs while ERPs were measured. In Experiment 1, these sentences contained a prosodic break, which can create a certain syntactic grouping of words, or no prosodic break. At the disambiguation, an N400 effect occurred when the disambiguation was in conflict with the syntactic grouping created by the break. We found a similar N400 effect without the break, indicating that the break did not strengthen an already existing preference. This pattern held for both object- and subject-control items. In Experiment 2, the same sentences contained a break and a pitch accent on the noun following the break. We argue that the pitch accent indicates a broad focus covering two words [see Gussenhoven, C. On the limits of focus projection in English. In P. Bosch & R. van der Sandt (Eds.), Focus: Linguistic, cognitive, and computational perspectives. Cambridge: University Press, 1999], thus grouping these words together. For object-control items, this was semantically possible, which led to a “good-enough” interpretation of the sentence. Therefore, both sentences were interpreted equally well and the N400 effect found in Experiment 1 was absent. In contrast, for subject-control items, a corresponding grouping of the words was impossible, both semantically and syntactically, leading to processing difficulty in the form of an N400 effect and a late positivity. In conclusion, accentuation can group words together on the level of information structure, leading to either a semantically “good-enough” interpretation or a processing problem when such a semantic interpretation is not possible.
Culture, Rap Music, “Bitch,” and the Development of the Censorship Frame
Authors: Schneider Christopher J.
Published: October 2010

Drawing theoretically both from cultural studies and cultural criminology, this exploratory project suggests that negative public perceptions associated with rap music are in large part informed through both formal and informal censorship agendas and campaigns, what the author terms the censorship frame. The censorship frame consists of mass media reports that proclaim the cultural association between music and collectively shared and culturally agreed-upon perceptions of deviance. The focus of this project concerns rap music and the term bitch, a relatively recent common feature of everyday language use. This article (a) investigates the increased use and acceptance of “bitch” in popular culture; (b) examines this process in relation to the demonization of rap music; and (c) demonstrates the role of both mass media and claims-makers in shaping public opinion of rap music as deviant, even while other similar messages continue to remain virtually unchallenged throughout the popular cultural milieu. Implications for future research are discussed.