bluuebunny/crossref_metadata_2025_split huggingface dataset:
Open Reading Frame 33 of a Gammaherpesvirus Encodes a Tegument Protein Essential for Virion Morphogenesis and Egress
Authors: Guo Haitao , Wang Lili , Peng Li , Zhou Z. Hong , Deng Hongyu 
Published: August 2009

ABSTRACT

Tegument is a unique structure of herpesvirus, which surrounds the capsid and interacts with the envelope. Morphogenesis of gammaherpesvirus is poorly understood due to lack of efficient lytic replication for Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8, which are etiologically associated with several types of human malignancies. Murine gammaherpesvirus 68 (MHV-68) is genetically related to the human gammaherpesviruses and presents an excellent model for studying de novo lytic replication of gammaherpesviruses. MHV-68 open reading frame 33 (ORF33) is conserved among
Alpha-
,
Beta-
, and
Gammaherpesvirinae
subfamilies. However, the specific role of ORF33 in gammaherpesvirus replication has not yet been characterized. We describe here that ORF33 is a true late gene and encodes a tegument protein. By constructing an ORF33-null MHV-68 mutant, we demonstrated that ORF33 is not required for viral DNA replication, early and late gene expression, viral DNA packaging or capsid assembly but is required for virion morphogenesis and egress. Although the ORF33-null virus was deficient in release of infectious virions, partially tegumented capsids produced by the ORF33-null mutant accumulated in the cytoplasm, containing conserved capsid proteins, ORF52 tegument protein, but virtually no ORF45 tegument protein and the 65-kDa glycoprotein B. Finally, we found that the defect of ORF33-null MHV-68 could be rescued by providing ORF33 in
trans
or in an ORF33-null revertant virus. Taken together, our results indicate that ORF33 is a tegument protein required for viral lytic replication and functions in virion morphogenesis and egress.
Functional Interaction between Epstein-Barr Virus Replication Protein Zta and Host DNA Damage Response Protein 53BP1
Authors: Bailey Sarah G. , Verrall Elizabeth , Schelcher Celine , Rhie Alex , Doherty Aidan J. , Sinclair Alison J. 
Published: August 2009

ABSTRACT
Epstein-Barr virus (EBV; human herpesvirus 4) poses major clinical problems worldwide. Following primary infection, EBV enters a form of long-lived latency in B lymphocytes, expressing few viral genes, and it persists for the lifetime of the host with sporadic bursts of viral replication. The switch between latency and replication is governed by the action of a multifunctional viral protein Zta (also called BZLF1, ZEBRA, and Z). Using a global proteomic approach, we identified a host DNA damage repair protein that specifically interacts with Zta: 53BP1. 53BP1 is intimately connected with the ATM signal transduction pathway, which is activated during EBV replication. The interaction of 53BP1 with Zta requires the C-terminal ends of both proteins. A series of Zta mutants that show a wild-type ability to perform basic functions of Zta, such as dimer formation, interaction with DNA, and the transactivation of viral genes, were shown to have lost the ability to induce the viral lytic cycle. Each of these mutants also is compromised in the C-terminal region for interaction with 53BP1. In addition, the knockdown of 53BP1 expression reduced viral replication, suggesting that the association between Zta and 53BP1 is involved in the viral replication cycle.
Systemic and Mucosal T-Lymphocyte Activation Induced by Recombinant Adenovirus Vaccines in Rhesus Monkeys
Authors: Sun Yue , Bailer Robert T. , Rao Srinivas S. , Mascola John R. , Nabel Gary J. , Koup Richard A. , Letvin Norman L. 
Published: August 2009

ABSTRACT

The administration of vectors designed to elicited cell-mediated immune responses may have other consequences that are clinically significant. To explore this possibility, we evaluated T-cell activation during the first 2 months after recombinant adenovirus serotype 5 (rAd5) prime or boost immunizations in rhesus monkeys. We also evaluated the kinetics of T-lymphocyte activation in both the systemic and the mucosal compartments after rAd5 administration in monkeys with preexisting immunity to Ad5. The rAd5 immunization induced lower-frequency Gag epitope-specific CD8
+
T cells in the colonic mucosa than in the peripheral blood. There was evidence of an expansion of the simian immunodeficiency virus Gag-specific CD8
+
T-cell responses, but not the Ad5 hexon-specific T-cell responses, following a homologous rAd5 boost. A striking but transient T-lymphocyte activation in both the systemic and the mucosal compartments of rhesus monkeys was observed after rAd5 immunization. These findings indicate that the administration of a vaccine vector such as Ad5 can induce a global activation of T cells.
Analysis of Human Alphaherpesvirus MicroRNA Expression in Latently Infected Human Trigeminal Ganglia
Authors: Umbach Jennifer L. , Nagel Maria A. , Cohrs Randall J. , Gilden Donald H. , Cullen Bryan R. 
Published: August 2009

ABSTRACT
Analysis of cells infected by a wide range of herpesviruses has identified numerous virally encoded microRNAs (miRNAs), and several reports suggest that these viral miRNAs are likely to play key roles in several aspects of the herpesvirus life cycle. Here we report the first analysis of human ganglia for the presence of virally encoded miRNAs. Deep sequencing of human trigeminal ganglia latently infected with two pathogenic alphaherpesviruses, herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV), confirmed the expression of five HSV-1 miRNAs, miR-H2 through miR-H6, which had previously been observed in mice latently infected with HSV-1. In addition, two novel HSV-1 miRNAs, termed miR-H7 and miR-H8, were also identified. Like four of the previously reported HSV-1 miRNAs, miR-H7 and miR-H8 are encoded within the second exon of the HSV-1 latency-associated transcript. Although VZV genomic DNA was readily detectable in the three human trigeminal ganglia analyzed, we failed to detect any VZV miRNAs, suggesting that VZV, unlike other herpesviruses examined so far, may not express viral miRNAs in latently infected cells.
Coarse particles and mortality: evidence from a multi-city study in California
Authors: Malig B J , Ostro B D 
Published: August 2009

Objective:To examine the risk of all-cause and cardiovascular mortality associated with short-term coarse particle exposure in California while addressing issues of exposure misclassification by limiting the study to those residing near a pollution monitor.Methods:Deaths in 15 California counties from 1999 to 2005 were linked to coarse particulate monitoring data. Case deaths were limited to those residing in a zip code within 20 km of a pollution monitor. We used conditional logistic regression with a case-crossover design to estimate county-specific effects of coarse particles. County estimates were then pooled using random-effects meta-analysis to create overall study estimates. Effects specific to race and educational status were also analysed.Results:We observed an increased excess risk (ER) of both all-cause mortality (ER per 10 μg/m3 = 0.7%, 95% CI −0.1 to 1.5) and cardiovascular mortality (ER per 10 μg/m3 = 1.3%, 95% CI 0.1 to 2.5) from a 2-day lag in coarse particles. Greater effects were observed among Hispanics and non-high school graduates. Adjustment for fine particles and decreasing the inclusion buffer to 10 km did not substantively alter the results.Conclusions:Our study provides further evidence of an association between acute exposure to coarse particles and mortality, and supports the hypothesis that lower socioeconomic status groups may be more susceptible to its effects.
An examination of the effect on cigarette prices and promotions of Philip Morris USA penalties to stores that sell cigarettes to minors: Table 1
Authors: Feighery E C , Schleicher N C , Ribisl K M , Rogers T 
Published: August 2009

Objective:The purpose of this study was to assess the potential impact of public policies to regulate price discounting strategies on retail cigarette prices and advertising. Philip Morris USA (PM USA) has a policy designed to sanction stores violating state laws banning illegal tobacco sales to minors by temporarily suspending price discounting incentives. This study examined the impact of those sanctions on retail cigarette prices and sales promotion advertising.Method:In November 2006, the California Attorney General’s Office informed PM USA that 196 stores were found guilty of illegal underage sales. Of these, 109 stores that participated in the PM USA Retail Leaders Program were notified that their merchandising and/or promotional resources would be suspended for the month of April 2007. The remaining 87 stores were not sanctioned and served as a comparison group. Trained raters assessed advertising and prices of selected PM USA brands in these stores pre-penalty and during the penalty phase.Results:There were no significant differences between sanctioned and non-sanctioned stores on median changes in price and sales promotion advertising from the pre-penalty to the penalty phase.Conclusion:The lack of impact on cigarette prices and advertising indicate that the PM USA policy may be flawed in its design or execution. If public policies are developed to restrain cigarette price discounting strategies, they should be crafted to ensure compliance and preclude possible compensatory actions by retailers.
Distinguishing risk factors for the onset of cravings, withdrawal symptoms and tolerance in novice adolescent smokers
Authors: Wileyto P , O’Loughlin J , Lagerlund M , Meshefedjian G , Dugas E , Gervais A 
Published: August 2009

Aim:While many studies report determinants of adolescent cigarette smoking, few identify risk factors for nicotine dependence (ND). This study distinguished between risk factors for three hallmarks of ND including cravings, withdrawal symptoms and tolerance.Methods:A total of 319 novice smokers were followed every 3 months from first puff on a cigarette until the end of secondary school. Outcomes included time to first report of cravings, withdrawal symptoms and tolerance.Results:Female sex, inhalation, smoking a whole cigarette, weekly smoking, daily smoking and alcohol use each independently increased the incidence of the onset of cravings. Inhalation, weekly smoking, daily smoking and alcohol use predicted the onset of withdrawal symptoms. Withdrawal symptoms, smoking a whole cigarette, monthly smoking, daily smoking and friends and siblings smoking increased the incidence of the onset of tolerance. None of parental education, impulsivity, novelty seeking, self-esteem, depression, stress, parental smoking, physical activity, or participation in sports teams was associated with the outcomes.Conclusion:The hallmarks of early ND are related to intensity and frequency of cigarette use. Avoidance of daily smoking may be particularly important in preventing the onset of ND symptoms and sustained smoking.
Estimating missed government tax revenue from foreign tobacco: survey of discarded cigarette packs: Table 1
Authors: Wilson N , Thomson G , Edwards R , Peace J 
Published: August 2009

Aim:To clarify the extent of use of foreign (including duty free, foreign normal retail and smuggled) tobacco, and to estimate missed government tax revenue in a geographically isolated country.Methods:Discarded cigarette packs were collected on the streets of four cities and six New Zealand towns/rural locations between November 2008 and January 2009.Results:Out of a total of 1310 packs collected, 42 foreign packs were identified (3.2%, 95% CI 2.4% to 4.3%). Overall, the distribution of packs by country and company was not suggestive of any clustering that might indicate smuggling. At 3.2% of packs being “foreign”, the New Zealand government is losing around $36 million per year in tobacco-related tax relative to if all this tobacco was purchased in New Zealand. For various reasons (including that it was not possible to identify packs bought duty free within New Zealand, and other New Zealand survey data indicating duty free product use at 3.8% of packs), the figure reached is probably an underestimate of the true level.Conclusion:The New Zealand government is missing out on revenue that could be used for improving the funding of tobacco control, and smokers are being exposed to cheaper tobacco thus increasing their risk of continuing to smoke. This government and other governments can and should act at the international and national levels to end the sales of duty free tobacco.
Fixed Points of Single- and Set-Valued Mappings in Uniformly Convex Metric Spaces with No Metric Convexity
Authors: Espínola Rafa , Fernández-León Aurora , Piątek Bożena 
Published: August 2009

AbstractWe study the existence of fixed points and convergence of iterates for asymptotic pointwise contractions in uniformly convex metric spaces. We also study the existence of fixed points for set-valued nonexpansive mappings in the same class of spaces. Our results do not assume convexity of the metric which makes a big difference when studying the existence of fixed points for set-valued mappings.
GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax
Authors: Fister Stefanie , Günthert Andreas R. , Aicher Babette , Paulini Klaus W. , Emons Günter , Gründker Carsten 
Published: August 2009

Abstract
Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [d-Lys6]GnRH-II showed an EC50 value for GnRH-I receptor binding of ∼1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC50 of 13 nmol/L has been determined for [d-Lys6]GnRH-II. Antagonistic activities with EC50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist [d-Lys6]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase followed by activation of proapoptotic protein Bax. [Cancer Res 2009;69(16):6473–81]
Follicle-Stimulating Hormone Peptide Can Facilitate Paclitaxel Nanoparticles to Target Ovarian Carcinoma In vivo
Authors: Zhang Xiao-yan , Chen Jun , Zheng Yu-fang , Gao Xiao-ling , Kang Yu , Liu Jia-chi , Cheng Ming-jun , Sun Hong , Xu Cong-jian 
Published: August 2009

Abstract
Chemotherapy is an important treatment for ovarian cancer. However, conventional chemotherapy has inevitable drawbacks due to side effects from nonspecific biodistribution of the chemotherapeutic drugs. To solve such problem, targeted delivery approaches were developed. The targeted delivery approaches combine drug carriers with the targeting system and can preferentially bring drugs to the targeted sites. Follicle-stimulating hormone receptor (FSHR) is an ovarian cancer–specific receptor. By using a peptide derived from FSH (amino acids 33–53 of the FSH β chain, named as FSH33), we developed a conjugated nanoparticle, FSH33-NP, to target FSHR in ovarian cancer. FSH33-NP was tested for recognition specificity and uptake efficiency on FSHR-expressing cells. Then, the antitumor efficiency of paclitaxel (PTX)-loaded FSH33-NP (FSH33-NP-PTX) was determined. FSH33-NP-PTX displayed stronger antiproliferation and antitumor effects compared with free PTX or naked PTX-loaded nanoparticles (NP-PTX) both in vitro and in vivo. In summary, this novel FSH33-NP delivery system showed very high selectivity and efficacy for FSHR-expressing tumor tissues. Therefore, it has good potential to become a new therapeutic approach for patients with ovarian cancer. [Cancer Res 2009;69(16):6506–14]
Nucleophosmin Redistribution following Heat Shock: A Role in Heat-Induced Radiosensitization
Authors: Vanderwaal Robert P. , Maggi Leonard B. , Weber Jason D. , Hunt Clayton R. , Roti Roti Joseph L. 
Published: August 2009

Abstract
Cellular survival from radiation-induced DNA damage requires access to sites of damage for the assembly of repair complexes and the subsequent repair, particularly the repair of DNA double strand breaks (DSB). Hyperthermia causes changes in protein-protein/DNA interactions in the nucleus that block access to sites of DNA damage. Studies presented here indicate that the nucleolar protein, nucleophosmin (NPM), redistributes from the nucleolus following hyperthermia, increases its association with DNA, and blocks access to DNA DSBs. Reduction of NPM significantly reduces heat-induced radiosensitization, but reduced NPM level does not alter radiation sensitivity per se. NPM knockdown reduces heat-induced inhibition of DNA DSB repair. Also, these results suggest that NPM associates with nuclear matrix attachment region DNA in heat-shocked cells. [Cancer Res 2009;69(16):6454–62]
Targeting Janus Kinase 2 in Her2/neu-Expressing Mammary Cancer: Implications for Cancer Prevention and Therapy
Authors: Sakamoto Kazuhito , Lin Wan-chi , Triplett Aleata A. , Wagner Kay-Uwe 
Published: August 2009

Abstract
The Janus kinase 2 (Jak2) is essential for normal mammary gland development, but this tyrosine kinase and its main effector, signal transducer and activator of transcription 5, are also active in a significant subset of human breast cancers. We have recently reported that Jak2 controls the expression and nuclear accumulation of cyclin D1. Because this particular D-type cyclin has been suggested to be a key mediator for ErbB2-associated mammary tumorigenesis, we deleted Jak2 from ErbB2-expressing mammary epithelial cells prior to tumor onset and in neoplastic cells to address whether this tyrosine kinase plays a role in the initiation as well as progression of mammary cancer. Similar to cyclin D1–deficient mice, the functional ablation of Jak2 protects against the onset of mammary tumorigenesis. In contrast, the deletion of Jak2 from neoplastic cells or the acute, ligand-inducible down-regulation of this tyrosine kinase in an orthotopic transplant model did not affect the growth and survival of cancer cells. The constitutive activation of ErbB2 signaling, which is an initial event in the formation of mammary cancer, was able to override the functional role of Jak2 in regulating the expression of Akt1 and cyclin D1. This might be a compensatory mechanism that explains why Jak2 is a relevant target for preventing the initiation but not the progression of ErbB2-associated mammary cancer. [Cancer Res 2009;69(16):6642–50]
Systems Biology Reveals New Strategies for Personalizing Cancer Medicine and Confirms the Role of PTEN in Resistance to Trastuzumab
Authors: Faratian Dana , Goltsov Alexey , Lebedeva Galina , Sorokin Anatoly , Moodie Stuart , Mullen Peter , Kay Charlene , Um In Hwa , Langdon Simon , Goryanin Igor , Harrison David J. 
Published: August 2009

Abstract
Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6–5.5; P &lt; 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies. [Cancer Res 2009;69(16):6713–20]
The Peptidyl-Prolyl Isomerase Pin1 Regulates Cytokinesis through Cep55
Authors: van der Horst Armando , Khanna Kum Kum 
Published: August 2009

Abstract
Failure of cytokinesis results in tetraploidy and can increase the genomic instability frequently observed in cancer. The peptidyl-prolyl isomerase Pin1, which is deregulated in many tumors, regulates several processes, including cell cycle progression. Here, we show a novel role for Pin1 in cytokinesis. Pin1 knockout mouse embryonic fibroblasts show a cytokinesis delay, and depletion of Pin1 from HeLa cells also causes a cytokinesis defect. Furthermore, we provide evidence that Pin1 localizes to the midbody ring and regulates the final stages of cytokinesis by binding to centrosome protein 55 kDa (Cep55), an essential component of this ring. This interaction induces Polo-like kinase 1–mediated phosphorylation of Cep55, which is critical for the function of Cep55 during cytokinesis. Importantly, Pin1 knockdown does not enhance the cytokinesis defect in Cep55-depleted cells, indicating that Pin1 and Cep55 act in the same pathway. These data are the first evidence that Pin1 regulates cytokinesis and may provide a mechanistic explanation as to how pathologic levels of Pin1 can stimulate tumorigenesis. [Cancer Res 2009;69(16):6651–9]