bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Transduced Cells, the U
S
3 Protein Kinase of Herpes Simplex Virus 1 Precludes Activation and Induction of Apoptosis by Transfected Procaspase 3
Authors: Benetti Luca , Roizman Bernard 
Published: July 2007

ABSTRACT

The U
S
3 protein kinase of herpes simplex virus 1 blocks apoptosis induced by replication-incompetent virus mutants, proapoptotic members of the Bcl-2 family of proteins, and by a variety of other agents that act at the premitochondrial level in the proapoptotic cascade. To define the role of U
S
3 in blocking apoptosis at the postmitochondrial level, we investigated the U
S
3 protein kinase in transduced cells that were either transfected with a plasmid encoding procaspase 3 or superinfected with a proapoptotic mutant virus lacking the gene encoding the infected cell protein no. 4. (i) We show that U
S
3 blocks the proteolytic cleavage that generates active caspase 3 from the transfected zymogen procaspase 3, concomitant with inhibition of apoptosis. (ii) Studies based on detection of fluorescence emitted upon cleavage of a synthetic caspase 3 substrate showed that expression of the U
S
3 kinase and appearance of the cleaved substrate were mutually exclusive. (iii) An affinity-purified glutathione
S
-transferase (GST)-U
S
3 fusion protein, but not the inactive GST-U
S
3(K220N) protein, phosphorylated procaspase 3 in vitro. The studies published earlier on the effect of U
S
3 on the upstream regulatory proteins and current studies suggest that the U
S
3 protein kinase may act on several proteins in the proapoptotic cascade to enable the virus to complete its replication.
Wild Mouse Variants of Envelope Genes of Xenotropic/Polytropic Mouse Gammaretroviruses and Their XPR1 Receptors Elucidate Receptor Determinants of Virus Entry
Authors: Yan Yuhe , Knoper Ryan C. , Kozak Christine A. 
Published: July 2007

ABSTRACT

Mouse xenotropic and polytropic leukemia viruses (XMVs and PMVs) are closely related gammaretroviruses that use the XPR1 receptor for entry. To identify amino acid residues in XPR1 important for virus entry, we tested mouse cells derived from evolutionarily divergent species for susceptibility to prototypical PMVs, XMVs, and the wild mouse isolate CasE#1. CasE#1 has a variant XMV/PMV host range, and sequence analysis of the CasE#1
env
gene identifies segments related to PMVs and XMVs. Cells from the Asian mouse species
Mus pahari
show a unique pattern of susceptibility to these three viruses; these cells are susceptible to XMVs and CasE#1 but are resistant to PMVs, whereas NIH 3T3 cells show the reciprocal pattern, susceptibility to only PMVs. The
M. pahari
XPR1 gene differs from that of NIH 3T3 in the two extracellular loops (ECLs) previously shown to mediate virus entry (M. Marin, C. S. Tailor, A. Nouri, S. L. Kozak, and D. Kabat, J. Virol. 73:9362-9368, 1999, and N. S. Van Hoeven and A. D. Miller, Retrovirology 2:76, 2005). Using transfected hamster cells expressing chimeric and mutated XPR1s, we demonstrated that the susceptibility differences between NIH 3T3 and
M. pahari
cells are receptor mediated, that PMV entry requires residues in ECL3, that the CasE#1 entry determinant is in ECL4, and that determinants for XMV entry are in both ECL3 and ECL4. Additional substitutions in ECL3 and ECL4 modulate virus susceptibility and suggest that ECL3 and ECL4 may contribute to the formation of a single virus receptor site. The position of
M. pahari
at the base of the
Mus
phylogenetic tree indicates that XPR1-mediated susceptibility to XMVs is the ancestral type in this genus and that the phenotypic variants of mouse XPR1 likely arose in conjunction with exposure to gammaretrovirus infections and coevolutionary adaptations in the viral envelope.
Overlapping Roles of the Rous Sarcoma Virus Gag p10 Domain in Nuclear Export and Virion Core Morphology
Authors: Scheifele Lisa Z. , Kenney Scott P. , Cairns Tina M. , Craven Rebecca C. , Parent Leslie J. 
Published: July 2007

ABSTRACT
Nucleocytoplasmic shuttling of the Rous sarcoma virus (RSV) Gag polyprotein is an integral step in virus particle assembly. A nuclear export signal (NES) was previously identified within the p10 domain of RSV Gag. Gag mutants containing deletions of the p10 NES or mutations of critical hydrophobic residues at positions 219, 222, 225, or 229 become trapped within the nucleus and exhibit defects in the efficiency of virus particle release. To investigate other potential roles for Gag nuclear trafficking in RSV replication, we created viruses bearing NES mutant Gag proteins. Viruses carrying p10 mutations produced low levels of particles, as anticipated, and those particles that were released were noninfectious. The p10 mutant viruses contained approximately normal amounts of Gag, Gag-Pol, and Env proteins and genomic viral RNA (vRNA), but several major structural defects were found. Thin-section transmission electron microscopy revealed that the mature particles appeared misshapen, while the viral cores were cylindrical, horseshoe-shaped, or fragmented, with some particles containing multiple small, electron-dense aggregates. Immature virus-like particles produced by the expression of Gag proteins bearing p10 mutations were also aberrant, with both spherical and tubular filamentous particles produced. Interestingly, the secondary structure of the encapsidated vRNA was altered; although dimeric vRNA was predominant, there was an additional high-molecular-weight fraction. Together, these results indicate that the p10 NES domain of Gag is critical for virus replication and that it plays overlapping roles required for the nuclear shuttling of Gag and for the maintenance of proper virion core morphology.
Herpes Simplex Virus Type 1 C-Terminal Variants of the Origin Binding Protein (OBP), OBPC-1 and OBPC-2, Cooperatively Regulate Viral DNA Levels In Vitro, and OBPC-2 Affects Mortality in Mice
Authors: Link Malen A. , Schaffer Priscilla A. 
Published: July 2007

ABSTRACT
Two in-frame, C-terminal isoforms of the herpes simplex virus type 1 (HSV-1) origin binding protein (OBP), OBPC-1 and OBPC-2, and a unique C-terminal transcript, UL8.5, are specified by HSV-1 DNA. As the first isoform identified, OBPC-1 was initially assumed to be the product of the UL8.5 transcript. Recent evidence has demonstrated, however, that OBPC-1 is a cathepsin B-mediated cleavage product of OBP, suggesting that OBPC-2 is the product of the UL8.5 transcript. Because both OBPC-1 and -2 contain the majority of the OBP DNA binding domain, we hypothesized that both may be involved in regulating origin-dependent, OBP-mediated viral DNA replication. In this paper, we demonstrate that OBPC-2 is, indeed, the product of the UL8.5 transcript. The translational start site of OBPC-2 was mapped, and a virus (M571A) that does not express this protein efficiently was constructed. Using M571A, we have shown that OBPC-2 is able to bind origin DNA, even though it lacks seven N-terminal amino acid residues of the previously mapped OBP DNA binding domain, resulting in a revision of the limits of the OBP DNA binding domain. Consistent with their proposed roles in regulating viral DNA replication, OBPC-1 and -2 act together to down-regulate viral DNA replication in vitro. During functional studies in vivo, OBPC-2 was identified as a factor that increases mortality in the mouse ocular model of HSV-1 infection.
5-HT2A serotoninergic receptor in the locus coeruleus participates in the first phase of lipopolysaccharide-induced fever
Authors: da Silva Alexandre O. Fernandes , Gargaglioni Luciane H. , Branco Luiz G.S. 
Published: July 2007

This study was aimed at testing the hypothesis that serotoninergic receptors in the locus coeruleus (LC) play a role in bacterial lipopolysaccharide-induced fever. To this end, 5-HT1A (WAY-100635; 3 μg/100 nL) and 5-HT2A (ketanserin; 2 μg/100 nL) antagonists were microinjected into the LC and body temperature was monitored by biotelemetry. Intra-LC microinjections of ketanserin or WAY-100635 caused no change in body temperature of euthermic animals. 5-HT2A antagonism abolished the first phase of the lipopolysaccharide-induced fever. Taken together, these results indicate that serotonin acting on 5-HT2A receptors in the LC mediates the first phase of the febrile response, whereas 5-HT1A receptors are not involved in the lipopolysaccharide-induced fever.
Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia
Authors: Boddy Alan V. , Sludden Julieann , Griffin Melanie J. , Garner Colin , Kendrick John , Mistry Pritesh , Dutreix Catherine , Newell David R. , O'Brien Stephen G. 
Published: July 2007

Abstract
Purpose: To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib.
Experimental Design: Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of 14C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS).
Results: Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the 14C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 ± 3 versus 27 ± 11 μg/mL·h), but with some variation within each individual.
Conclusions: Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.
Effect of Cytarabine and Decitabine in Combination in Human Leukemic Cell Lines
Authors: Qin Taichun , Youssef Emile M. , Jelinek Jaroslav , Chen Rong , Yang Allen S. , Garcia-Manero Guillermo , Issa Jean-Pierre J. 
Published: July 2007

Abstract
Purpose: 1-β-d-Arabinofuranosylcytosine (cytarabine; ara-C) is the most active agent in myeloid leukemia. 5-Aza-2′-deoxycytidine (DAC) is a cytosine analogue that inhibits DNA methylation and also has activity in myeloid leukemia. Therefore, we investigated combining these two drugs in human leukemia cell lines in vitro.
Experimental Design: We initially examined the effects of ara-C and DAC on human leukemia cell lines HL60, ML-1, RAji, and Jurkat. We measured IC50 of DAC and ara-C in these cell lines and calculated a combination index of these two drugs given either simultaneously or sequentially. In searching for mechanisms relative to epigenetic regulation for this effect, we examined DNA methylation of LINE and Alu repetitive elements as a surrogate for global genomic DNA methylation. In addition, we sorted Annexin V positive and negative cells and measured differences in LINE methylation between them.
Results: The combination of DAC and ara-C showed additive induction of cell death in ML-1 and synergistic induction in HL60, Raji, and Jurkat. Sequentially, DAC followed by ara-C was a synergistic combination in all cell lines. Low-dose DAC induced more hypomethylation than high doses of the drug, whereas ara-C had no effects on methylation. The combination of ara-C with DAC either together or DAC followed by ara-C resulted in inhibition of LINE demethylation in HL60. The RIL gene, which is silenced by DNA hypermethylation, was activated by DAC, but the addition of ara-C to DAC reduced RIL gene activation. DAC treatment increased H3 Lys9 acetylation of Alu elements, whereas ara-C had no effect, and the addition of ara-C to DAC inhibited this effect. Finally, we showed that after DAC exposure, Annexin V positive cells were more hypomethylated than Annexin V negative cells.
Conclusion: The combination of DAC and ara-C showed additive or synergistic effects on cell death in four human leukemia cell lines in vitro, but antagonism in terms of epigenetic effects. One possible explanation for these paradoxical observations is that hypomethylated cells are sensitized to cell killing by ara-C. These data suggest that DAC used in combination with ara-C has clinical potential in the treatment of acute myeloid leukemia.
Intraperitoneal Injection of a Hairpin RNA–Expressing Plasmid Targeting Urokinase-Type Plasminogen Activator (uPA) Receptor and uPA Retards Angiogenesis and Inhibits Intracranial Tumor Growth in Nude Mice
Authors: Gondi Christopher S. , Lakka Sajani S. , Dinh Dzung H. , Olivero William C. , Gujrati Meena , Rao Jasti S. 
Published: July 2007

Abstract
Purpose: The purpose of this study was to evaluate the therapeutic potential of using plasmid-expressed RNA interference (RNAi) targeting urokinase-type plasminogen activator (uPA) receptor (uPAR) and uPA to treat human glioma.
Experimental Design: In the present study, we have used plasmid-based RNAi to simultaneously down-regulate the expression of uPAR and uPA in SNB19 glioma cell lines and epidermal growth factor receptor (EGFR)–overexpressing 4910 human glioma xenografts in vitro and in vivo, and evaluate the i.p. route for RNAi-expressing plasmid administered to target intracranial glioma.
Results: Plasmid-mediated RNAi targeting uPAR and uPA did not induce OAS1 expression as seen from reverse transcription-PCR analysis. In 4910 EGFR-overexpressing cells, down-regulation of uPAR and uPA induced the down-regulation of EGFR and vascular endothelial growth factor and inhibited angiogenesis in both in vitro and in vivo angiogenic assays. In addition, invasion and migration were inhibited as indicated by in vitro spheroid cell migration, Matrigel invasion, and spheroid invasion assays. We did not observe OAS1 expression in mice with preestablished intracranial tumors, which were given i.p. injections of plasmid-expressing small interfering RNA–targeting uPAR and uPA. Furthermore, the small interfering RNA plasmid targeting uPAR and uPA caused regression of preestablished intracranial tumors when compared with the control mice.
Conclusion: In conclusion, the plasmid-expressed RNAi targeting uPAR and uPA via the i.p. route has potential clinical applications for the treatment of glioma.
TIMP-1 Is Significantly Associated with Objective Response and Survival in Metastatic Colorectal Cancer Patients Receiving Combination of Irinotecan, 5-Fluorouracil, and Folinic Acid
Authors: Sørensen Nanna M. , Byström Per , Christensen Ib J. , Berglund Åke , Nielsen Hans Jørgen , Brünner Nils , Glimelius Bengt 
Published: July 2007

Abstract
Purpose: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.
Experimental Design: Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.
Results: Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P = 0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P = 0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P = 0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (loge) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P &lt; 0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P = 0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P &lt; 0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.
Conclusion: This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.
MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma
Authors: Hirata Hiroshi , Hinoda Yuji , Kikuno Nobuyuki , Kawamoto Ken , Suehiro Yutaka , Tanaka Yuichiro , Dahiya Rajvir 
Published: July 2007

Abstract
Purpose: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer.
Experimental Design: We genotyped three single nucleotide polymorphisms of three genes (p53 Arg72Pro, p21 Ser31Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves.
Results: A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg72Pro and p21 Ser31Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes.
Conclusions: This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.
Plant Species Distributions under Present Conditions and Forecasted for Warmer Climates in an Arid Mountain Range
Authors: Van de Ven Christopher M. , Weiss S. B. , Ernst W. G. 
Published: July 2007

AbstractComplex environmental gradients in the White and Inyo Mountains in eastern California produce striking variations in vegetation assemblages over short distances. Vegetation composition is dominated by elevational gradients of temperature and precipitation, but local modifications by geologic substrate, potential insolation, slope, and topographic position create finescale mosaics. Digital elevation models, geologic maps, and field data were used to map current species distributions over 6220 km2 (622 000 ha) of the White and Inyo Mountains. Species–environment relationships of 88 plant species were modeled at a scale of 54 m using canonical correspondence analysis (CCA). CCA models were calibrated from 434 field plots and evaluated with 216 plots using kappa statistics. Vegetation responses to temperature increases of 1°–6°C were modeled by shifting species tolerances along the elevational gradient according to a standard lapse rate [3°C (500 m)−1] while all other factors were kept constant. Ranges of midelevations species tended to fragment onto local peaks, whereas the ranges of many desert species merged across a major pass. In several cases, local geologic features were identified as obstacles to species’ upslope migration. As modeled temperatures increase, species contract to small populations around White Mountain Peak (4342 m) and its north-facing slopes. It is predicted that 10 of 18 modeled alpine and subalpine species will become locally extinct if temperatures increase by 6°C. These scenarios provide a detailed set of hypotheses on the structure of current species ranges and their ability to persist through rapid climate change.
Mesoscale Moisture Initialization for Monsoon and Hurricane Forecasts
Authors: Krishnamurti T. N. , Pattnaik S. , Rao D. V. Bhaskar 
Published: July 2007

Abstract
This paper addresses physical initialization of precipitation rates for a mesoscale numerical weather prediction model. This entails a slight modification of the vertical profile of the humidity variable that provides a close match between the satellite and model-based rain rates. This is based on the premise that the rain rate from a cumulus parameterization scheme such as the Arakawa–Schubert scheme is most sensitive to the vertical profiles of moist static stability. It is possible to adjust the vertical profile of moisture by a small linear perturbation by making it wetter (or drier) in the lower levels and the opposite at levels immediately above. This can provide a change in the moist static stability in order to achieve the desired rain rate. The procedure is invoked in a preforecast period between hours −24 and 0 following Krishnamurti et al. The present study is the authors’ first attempt to bring in this feature in a mesoscale model. They first noted that the procedure does indeed provide a much closer match between the satellite estimate of initial rain and that from the physical initialization for a mesoscale model. They have examined the impacts of this procedure for the initialization and short-range forecasts of a monsoon rainfall event and a hurricane. In both of these examples it became possible to improve the forecasts of rains compared with those from control runs that did not include the initialization of rains. Among these two examples, the results for the monsoon forecasts that deployed a uniform resolution of 25 km and the Grell and Devenyi scheme over the entire domain had the largest positive impact. The hurricane forecasts example also show improvement over the control run but with less impact, which may be due to heavy rains from explicit clouds in the nonhydrostatic model. Here the results did convey a strong positive impact from the use of the physical initialization; however, forecasts of very heavy rains carry smaller equitable threat scores. These require development of a more robust precipitation initialization procedure.