bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenicity and Vaccine Efficacy of Different Clades of Asian H5N1 Avian Influenza A Viruses in Domestic Ducks
Authors: Kim Jeong-Ki , Seiler Patrick , Forrest Heather L. , Khalenkov Alexey M. , Franks John , Kumar Mahesh , Karesh William B. , Gilbert Martin , Sodnomdarjaa R. , Douangngeun Bounlom , Govorkova Elena A. , Webster Robert G. 
Published: September 2008

ABSTRACTWaterfowl represent the natural reservoir of all subtypes of influenza A viruses, including H5N1. Ducks are especially considered major contributors to the spread of H5N1 influenza A viruses because they exhibit diversity in morbidity and mortality. Therefore, as a preventive strategy against endemic as well as pandemic influenza, it is important to reduce the spread of H5N1 influenza A viruses in duck populations. Here, we describe the pathogenicity of dominant clades (clades 1 and 2) of H5N1 influenza A viruses circulating in birds in Asia. Four representatives of dominant clades of the viruses cause symptomatic infection but lead to different profiles of lethality in domestic ducks. We also demonstrate the efficacy, cross-protectiveness, and immunogenicity of three different inactivated oil emulsion whole-virus H5 influenza vaccines (derived by implementing reverse genetics) to the viruses in domestic ducks. A single dose of the vaccines containing 1 μg of hemagglutinin protein provides complete protection against a lethal A/Duck/Laos/25/06 (H5N1) influenza virus challenge, with no evidence of morbidity, mortality, or shedding of the challenge virus. Moreover, two of the three vaccines achieved complete cross-clade or cross-subclade protection against the heterologous avian influenza virus challenge. Interestingly, the vaccines induce low or undetectable titers of hemagglutination inhibition (HI), cross-HI, and/or virus neutralization antibodies. The mechanism of complete protection in the absence of detectable antibody responses remains an open question.
Mouse APOBEC3 Restricts Friend Leukemia Virus Infection and Pathogenesis In Vivo
Authors: Takeda Eri , Tsuji-Kawahara Sachiyo , Sakamoto Mayumi , Langlois Marc-André , Neuberger Michael S. , Rada Cristina , Miyazawa Masaaki 
Published: September 2008

ABSTRACTSeveral members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like complex 3 (APOBEC3) family in primates act as potent inhibitors of retroviral replication. However, lentiviruses have evolved mechanisms to specifically evade host APOBEC3. Likewise, murine leukemia viruses (MuLV) exclude mouse APOBEC3 from the virions and cleave virion-incorporated APOBEC3. Although the betaretrovirus mouse mammary tumor virus has been shown to be susceptible to mouse APOBEC3, it is not known if APOBEC3 has a physiological role in restricting more widely distributed and long-coevolved mouse gammaretroviruses. The pathogenicity of Friend MuLV (F-MuLV) is influenced by several host genes: some directly restrict the cell entry or integration of the virus, while others influence the host immune responses. Among the latter, theRfv3gene has been mapped to chromosome 15 in the vicinity of theAPOBEC3locus. Here we have shown that polymorphisms at the mouseAPOBEC3locus indeed influence F-MuLV replication and pathogenesis: theAPOBEC3alleles of F-MuLV-resistant C57BL/6 and -susceptible BALB/c mice differ in their sequences and expression levels in the hematopoietic tissues and in their abilities to restrict F-MuLV replication both in vitro and in vivo. Furthermore, upon infection with the pathogenic Friend virus complex, (BALB/c × C57BL/6)F1mice displayed an exacerbated erythroid cell proliferation when the mice carried a targeted disruption of the C57BL/6-derivedAPOBEC3allele. These results indicate, for the first time, that mouse APOBEC3 is a physiologically functioning restriction factor to mouse gammaretroviruses.
Complement Receptor 3 Promotes Severe Ross River Virus-Induced Disease
Authors: Morrison Thomas E. , Simmons Jason D. , Heise Mark T. 
Published: September 2008

ABSTRACTAlphaviruses such as Ross River virus (RRV) and chikungunya virus are mosquito-transmitted viruses that cause explosive epidemics of debilitating arthritis and myositis affecting millions of humans worldwide. Previous studies using a mouse model of RRV-induced disease demonstrated that viral infection results in a severe inflammatory arthritis and myositis and that complement component 3 (C3) contributes to the destructive phase of the inflammatory disease but not the recruitment of cellular infiltrates to the sites of RRV-induced inflammation. Here, we demonstrate that mice deficient in complement receptor 3 (CR3) (CD11b−/−), a signaling receptor activated by multiple ligands including the C3 cleavage fragment iC3b, develop less-severe disease signs and decreased tissue destruction compared to RRV-infected wild-type mice. CR3 deficiency had no effect on viral replication, nor did it diminish the magnitude, kinetics, and composition of the cellular infiltrates at the sites of inflammation. However, the genetic absence of CR3 diminished the expression of specific proinflammatory and cytotoxic effectors, including S100A9/S100A8 and interleukin-6, within the inflamed tissues, suggesting that CR3-dependent signaling at the sites of inflammation contributes to tissue damage and severe disease.
With Minimal Systemic T-Cell Expansion, CD8+T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus
Authors: Genescà Meritxell , Skinner Pamela J. , Hong Jung Joo , Li Jun , Lu Ding , McChesney Michael B. , Miller Christopher J. 
Published: September 2008

ABSTRACTThe presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8+T-cell response in SHIV-immunized monkeys by CD8+lymphocyte depletion, an intervention that abrogated SHIV-mediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8+T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8+T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8+T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effector-cytotoxic CD8+T cells can provide significant protection from vaginal SIV challenge.
The consequences of fluid motion in volcanic conduits
Authors: Gilbert Jennie S. , Lane Stephen J. 
Published: September 2008

Abstract
When volcanoes are active, there are characteristic signs such as ground movement, sounds, heat and ejected material. Each of these signs is a result of, and hence an information source for, fluid motion in volcanic conduits. Here we briefly review some of the links between these signs and fluid flow processes and suggest future directions that should allow advancement of eruption forecasting as these links become understood more fully. Cross-fertilization between increasingly realistic numerical and experimental models, diverse geophysical data sources, and chemical and physical evidence in eruptive products can be achieved by simultaneously applying these approaches to well-studied volcanoes.
Cyclic activity at Soufrière Hills Volcano, Montserrat: degassing-induced pressurization and stick-slip extrusion
Authors: Lensky N. G. , Sparks R. S. J. , Navon O. , Lyakhovsky V. 
Published: September 2008

Abstract
The growth of lava domes is often associated with cyclic variations of ground deformation, seismicity and mass flux of gas and magma. We present a model of cyclic volcanic activity which is controlled by degassing of supersaturated magma, magma flow into the conduit, gas escape from the permeable magma, deformation of the conduit walls and the friction between the walls and the plug at the top of the conduit. When the difference between magma pressure and ambient pressure exceeds the static friction, motion begins, bubbles expand and overpressure relaxes. Bubble expansion builds permeability, allows gas escape and faster depressurization. Depressurization and crystallization of the magma build supersaturation and gas diffusion from melt to bubbles. Gas flux into bubbles and magma flux from the chamber act to increase pressure. The rate of extrusion is controlled by the gas pressure, driving the motion, and by the rate- and state-dependent friction along shear zones between the plug and the host rock. When the magma overpressure drops to the dynamic strength of the slip surfaces, the plug sticks and blocks the vent. As bubble volume is now constant, exsolution of gas from the supersaturated melt leads to pressurization and begins a new cycle.
Damping of pressure waves in visco-elastic, saturated bubbly magma
Authors: Kurzon I. , Lyakhovsky V. , Navon O. , Lensky N. G. 
Published: September 2008

Abstract

The attenuation of pressure waves in a saturated bubbly magma is examined in a model, coupling seismic wave-propagation with bubble growth dynamics. This model is solved analytically and numerically, including effects of diffusion of volatiles, visco-elasticity and bubble number density. We show that wave attenuation is controlled mainly by the
Peclet
and
Deborah
numbers. The
Peclet
number is a measure of the relative importance of advection to diffusion. The
Deborah
number is a visco-elastic measure, describing the importance of elasticity in comparison to viscous melt deformation. We solve numerically for wave attenuation for various magma properties corresponding to a wide range of
Peclet
and
Deborah
numbers. We show that the numerical solution can be approximated quite well for frequencies above 1 Hz, by an analytical end-member solution, obtained for high
Peclet
and low
Deborah
numbers. For lower frequencies, volatile transport should be accounted for, leading to higher attenuation with respect to the analytical solution. However, if the
Deborah
number is increased, either by longer relaxation time or by higher frequencies, then attenuation decreases with respect to the analytical solution. Therefore, visco-elasticity leads to a significant improvement of the resonating qualities of a magma-filled conduit and widens the depth and frequency ranges where pressure waves will propagate efficiently through the conduit.
Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells
Authors: Li Zengshan , Carrier Latonya , Rowan Brian G. 
Published: September 2008

Abstract
Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10−7 mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 μmol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium. [Mol Cancer Ther 2008;7(9):3056–63]
Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism
Authors: Yu Siwang , Shen Guoxiang , Khor Tin Oo , Kim Jung-Hwan , Kong Ah-Ng Tony 
Published: September 2008

Abstract
Akt/mammalian target of rapamycin (mTOR) signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here, we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated 5′-AMP-activated protein kinase and mitogen-activated protein kinases; however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells and provides new mechanisms for the anticancer effects of curcumin. [Mol Cancer Ther 2008;7(9):2609–20]
N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine
Authors: Bettayeb Karima , Sallam Hatem , Ferandin Yoan , Popowycz Florence , Fournet Guy , Hassan Moustapha , Echalier Aude , Bernard Philippe , Endicott Jane , Joseph Benoît , Meijer Laurent 
Published: September 2008

AbstractCyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential. [Mol Cancer Ther 2008;7(9):2713–24]
hKSR-2, a vitamin D–regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells
Authors: Wang Xuening , Patel Rahul , Studzinski George P. 
Published: September 2008

AbstractRas signaling can be modulated by the scaffolding activity of kinase suppressor of Ras-1 (KSR-1) and by the hKSR-2 protein, resulting in diverse phenotypic outcomes. The mitogen-activated protein kinase cascade downstream from Ras and KSRs includes Raf-1 and extracellular signal-regulated kinase 1/2 kinases, known to enhance survival potential of a range of cell types. Because the molecular events that increase survival of HL60 cells induced to differentiate toward monocytic phenotype by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] are not known, we investigated if KSR proteins provide a survival function in these cells. We found that whereas kinase suppressor of Ras-1 had no detectable effect on cell survival in the system studied here, 1,25-(OH)2D3-induced up-regulation of hKSR-2 enhanced the resistance of HL60 cells to arabinocytosine. Knockdown of hKSR-2 by either small interfering RNA or antisense oligonucleotides increased arabinocytosine-induced apoptosis, which was accompanied by reduced Bcl-2/Bax and Bcl-2/Bad ratios, and increased caspase-3 activating cleavage. In contrast, up-regulation of Mcl-1 was not abrogated by anti-sense (AS) AS-hKSR-2, pointing to a specific role of Bcl-2 in control of 1,25-(OH)2D3-induced increased cell survival. These findings are consistent with the previously shown lack of fully differentiated monocytic cells in HL60 cultures exposed to 1,25-(OH)2D3 in which hKSR-2 was knocked down, suggesting that optimal differentiation of these cells requires enhanced antiapoptotic mechanisms provided, at least in part, by hKSR-2. Collectively, these results suggest that hKSR-2 may offer a new target for novel therapies of acute myelogenous leukemia. [Mol Cancer Ther 2008;7(9):2798–806]
Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma
Authors: Bradshaw-Pierce Erica L. , Steinhauer Courtney A. , Raben David , Gustafson Daniel L. 
Published: September 2008

AbstractDocetaxel, usually administered according to maximum tolerated dose (MTD), can inhibit endothelial cell proliferation at low nanomolar concentrations. Docetaxel may exert antiangiogenic effects if dosed so plasma levels are maintained at low nanomolar concentrations over a prolonged time. We evaluated metronomic and MTD-based dosing of docetaxel with and without vandetanib, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, in a head and neck xenograft model. A murine physiologically based pharmacokinetic model was modified to predict docetaxel distribution following i.p. administration to design dosing regimens that target prespecified plasma concentrations, for antiendothelial effects (metronomic), or exposure, to mimic 30 mg/m2 (weekly/MTD) docetaxel in humans. Animals were treated for 28 days with 1 mg/kg/d (DTX1) or 6 mg/kg q4d (DTX6) docetaxel with or without vandetanib (15 mg/kg/d p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe gastrointestinal toxicity. All treatment groups significantly reduced tumor volume, tumor proliferation (Ki-67), and tumor endothelial cell proliferation (Ki-67/von Willebrand factor) compared with control. Addition of vandetanib to docetaxel treatment significantly enhanced tumor growth inhibition over single-agent therapy. A positive correlation of tumor endothelial cell proliferation with tumor growth rates demonstrates vandetanib and docetaxel antiangiogenic effects. Due to the morbidity observed with DTX1 treatment, it is difficult to clearly ascertain if metronomic schedules will be effective for treatment. Docetaxel with vandetanib is effective in treating UMSCC2 xenografts at concentrations relevant to exposures in humans. [Mol Cancer Ther 2008;7(9):3006–17]
Azacytidine causes complex DNA methylation responses in myeloid leukemia
Authors: Stresemann Carlo , Bokelmann Imke , Mahlknecht Ulrich , Lyko Frank 
Published: September 2008

Abstract
Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be established. Both drugs have been shown the ability to deplete DNA methyltransferase enzymes and to induce DNA demethylation and epigenetic reprogramming in vitro. However, drug-induced methylation changes have remained poorly characterized in patients and therapy-related models. We have now analyzed azacytidine-induced demethylation responses in myeloid leukemia cell lines. These cells showed remarkable differences in the drug-induced depletion of DNA methyltransferases that coincided with their demethylation responses. In agreement with these data, DNA methylation analysis of blood and bone marrow samples from MDS patients undergoing azacytidine therapy also revealed substantial differences in the epigenetic responses of individual patients. Significant, transient demethylation could be observed in 3 of 6 patients and affected many hypermethylated loci in a complex pattern. Our results provide important proof-of-mechanism data for the demethylating activity of azacytidine in MDS patients and provide detailed insight into drug-induced demethylation responses. [Mol Cancer Ther 2008;7(9):2998–3005]