bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway during Porcine Circovirus Type 2 Infection Facilitates Cell Survival and Viral Replication
Authors: Wei Li , Zhu Shanshan , Wang Jing , Liu Jue 
Published: October 2012

ABSTRACT
Virus infection activates host cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates diverse cellular activities related to cell growth, survival, and apoptosis. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), a major causative agent of postweaning multisystemic wasting syndrome, which is an emerging and important swine disease, can transiently induce the PI3K/Akt pathway in cultured cells at an early step during PCV2 infection. Activation of the PI3K/Akt signal was also induced by UV-irradiated PCV2, indicating that virus replication was not required for this induction. Inhibition of PI3K activation leads to reduced virus yield, which is associated with decreased viral DNA replication and lower virus protein expression. However, inhibition of PI3K activation greatly enhanced apoptotic responses as evidenced by the cleavage of poly-ADP ribose polymerase and caspase-3 as well as DNA fragmentation using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining during the early stage of PCV2 infection. Furthermore, the pancaspase inhibitor zVAD.fmk alleviated the reduction in Akt phosphorylation levels by inhibiting PI3K activation, indicating that the signaling promotes cell survival and thereby favors viral replication. These results reveal that an antiapoptotic role for the PI3K/Akt pathway induced by PCV2 infection to suppress premature apoptosis for improved virus growth after infection, extending our understanding of the molecular mechanism of PCV2 infection.
Incorporation of Antigens into Viral Capsids Augments Immunogenicity of Adeno-Associated Virus Vector-Based Vaccines
Authors: Rybniker Jan , Nowag Angela , Janicki Hanna , Demant Kai , Hartmann Pia , Büning Hildegard 
Published: October 2012

ABSTRACT
Genetic modification of adeno-associated virus (AAV) capsids has previously been exploited to redirect viral tropism. Here we demonstrate that engineering of AAV capsids as scaffolds for antigen display augments antigen-specific immunogenicity. Combining antigen display with vector-mediated overexpression resulted in a single-shot prime-boost vaccine. This new class of vaccines induced immune responses significantly faster and an IgG antibody pool of higher avidity than conventional vectors, highlighting the potency of capsid modification in vaccine development.
Critical Role for Interferon Regulatory Factor 3 (IRF-3) and IRF-7 in Type I Interferon-Mediated Control of Murine Norovirus Replication
Authors: Thackray Larissa B. , Duan Erning , Lazear Helen M. , Kambal Amal , Schreiber Robert D. , Diamond Michael S. , Virgin Herbert W. 
Published: October 2012

ABSTRACT

Human noroviruses (HuNoV) are the major cause of epidemic, nonbacterial gastroenteritis in the world. The short course of HuNoV-induced symptoms has implicated innate immunity in control of norovirus (NoV) infection. Studies using murine norovirus (MNV) confirm the importance of innate immune responses during NoV infection. Type I alpha and beta interferons (IFN-α/β) limit HuNoV replicon function, restrict MNV replication in cultured cells, and control MNV replication
in vivo
. Therefore, the cell types and transcription factors involved in antiviral immune responses and IFN-α/β-mediated control of NoV infection are important to define. We used mice with floxed alleles of the IFNAR1 chain of the IFN-α/β receptor to identify cells expressing lysozyme M or CD11c as cells that respond to IFN-α/β to restrict MNV replication
in vivo
. Furthermore, we show that the transcription factors IRF-3 and IRF-7 work in concert to initiate unique and overlapping antiviral responses to restrict MNV replication
in vivo
. IRF-3 and IRF-7 restrict MNV replication in both cultured macrophages and dendritic cells, are required for induction of IFN-α/β in macrophages but not dendritic cells, and are dispensable for the antiviral effects of IFN-α/β that block MNV replication. These studies suggest that expression of the IFN-α/β receptor on macrophages/neutrophils and dendritic cells, as well as of IRF-3 and IRF-7, is critical for innate immune responses to NoV infection.
Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes
Authors: Bose Sandip K. , Meyer Keith , Di Bisceglie Adrian M. , Ray Ratna B. , Ray Ranjit 
Published: October 2012

ABSTRACT

Hepatitis C virus (HCV)-mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes, when infected
in vitro
with cell culture-grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed a fibroblast-like shape and an extended life span. To understand the changes at the molecular level, we examined epithelial-mesenchymal transition (EMT) markers. Increased mRNA and protein expression levels of vimentin, snail, slug, and twist and a loss of the epithelial cell marker E-cadherin were observed. Snail and twist, when examined separately, were upregulated in chronically HCV-infected liver biopsy specimens, indicating an onset of an active EMT state in the infected liver. An increased expression level of fibroblast-specific protein 1 (FSP-1) in the infected hepatocytes was also evident, indicating a type 2 EMT state. Infected hepatocytes had significantly increased levels of phosphorylated β-catenin (Ser
552
) as an EMT mediator, which translocated into the nucleus and activated Akt. The phosphorylation level of β-catenin at Thr
41
/Ser
45
moieties was specifically higher in control than in HCV-infected hepatocytes, implicating an inactivation of β-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture-grown HCV display EMT via the activation of the Akt/β-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategies using inhibitory molecules.
A Novel Group of Avian Astroviruses in Wild Aquatic Birds
Authors: Chu Daniel K. W. , Leung Connie Y. H. , Perera Harsha K. K. , Ng Erica M. , Gilbert Martin , Joyner Priscilla H. , Grioni Alessandro , Ades Gary , Guan Yi , Peiris Joseph S. M. , Poon Leo L. M. 
Published: October 2012

ABSTRACT
Using a pan-astrovirus reverse transcription-PCR assay, a great diversity of novel avastroviruses was detected from wild bird and poultry samples. Two groups of astroviruses detected from wild birds are genetically related or highly similar to previously known viruses in poultry. Most interestingly, a novel group of astroviruses was detected in wild aquatic birds. Our results also reveal that different groups of astroviruses might have difference host ranges. This study has expanded our understanding regarding avastrovirus ecology.
Baculoviruses Modulate a Proapoptotic DNA Damage Response To Promote Virus Multiplication
Authors: Mitchell Jonathan K. , Friesen Paul D. 
Published: October 2012

ABSTRACT

The baculovirus
Autographa californica
multicapsid nucleopolyhedrovirus (AcMNPV) initiates apoptosis in diverse insects through events triggered by virus DNA (vDNA) replication. To define the proapoptotic pathway and its role in antivirus defense, we investigated the link between the host's DNA damage response (DDR) and apoptosis. We report here that AcMNPV elicits a DDR in the model insect
Drosophila melanogaster
. Replication of vDNA activated DDR kinases, as evidenced by ATM-driven phosphorylation of the
Drosophila
histone H2AX homolog (H2Av), a critical regulator of the DDR. Ablation or inhibition of ATM repressed H2Av phosphorylation and blocked virus-induced apoptosis. The DDR kinase inhibitors caffeine and KU55933 also prevented virus-induced apoptosis in cells derived from the permissive AcMNPV host,
Spodoptera frugiperda
. This block occurred at a step upstream of virus-mediated depletion of the cellular inhibitor-of-apoptosis protein, an event that initiates apoptosis in
Spodoptera
and
Drosophila
. Thus, the DDR is a conserved, proapoptotic response to baculovirus infection. DDR inhibition also repressed vDNA replication and reduced virus yields 100,000-fold, demonstrating that the DDR contributes to virus production, despite its recognized antivirus role. In contrast to virus-induced phosphorylation of
Drosophila
H2Av, AcMNPV blocked phosphorylation of the
Spodoptera
H2AX homolog (SfH2AX). Remarkably, AcMNPV also suppressed SfH2AX phosphorylation following pharmacologically induced DNA damage. These findings indicate that AcMNPV alters canonical DDR signaling in permissive cells. We conclude that AcMNPV triggers a proapoptotic DDR that is subsequently modified, presumably to stimulate vDNA replication. Thus, manipulation of the DDR to facilitate multiplication is an evolutionarily conserved strategy among DNA viruses of insects and mammals.
Comparison of traditional trigger tool to data warehouse based screening for identifying hospital adverse events
Authors: O'Leary Kevin J , Devisetty Vikram K , Patel Amitkumar R , Malkenson David , Sama Pradeep , Thompson William K , Landler Matthew P , Barnard Cynthia , Williams Mark V 
Published: October 2012

BackgroundResearch supports medical record review using screening triggers as the optimal method to detect hospital adverse events (AE), yet the method is labour-intensive.MethodThis study compared a traditional trigger tool with an enterprise data warehouse (EDW) based screening method to detect AEs. We created 51 automated queries based on 33 traditional triggers from prior research, and then applied them to 250 randomly selected medical patients hospitalised between 1 September 2009 and 31 August 2010. Two physicians each abstracted records from half the patients using a traditional trigger tool and then performed targeted abstractions for patients with positive EDW queries in the complementary half of the sample. A third physician confirmed presence of AEs and assessed preventability and severity.ResultsTraditional trigger tool and EDW based screening identified 54 (22%) and 53 (21%) patients with one or more AE. Overall, 140 (56%) patients had one or more positive EDW screens (total 366 positive screens). Of the 137 AEs detected by at least one method, 86 (63%) were detected by a traditional trigger tool, 97 (71%) by EDW based screening and 46 (34%) by both methods. Of the 11 total preventable AEs, 6 (55%) were detected by traditional trigger tool, 7 (64%) by EDW based screening and 2 (18%) by both methods. Of the 43 total serious AEs, 28 (65%) were detected by traditional trigger tool, 29 (67%) by EDW based screening and 14 (33%) by both.ConclusionsWe found relatively poor agreement between traditional trigger tool and EDW based screening with only approximately a third of all AEs detected by both methods. A combination of complementary methods is the optimal approach to detecting AEs among hospitalised patients.
Paediatric out-of-hospital cardiac arrests in Melbourne, Australia: improved reporting by adding coronial data to a cardiac arrest registry
Authors: Deasy Conor , Hall David , Bray Janet E , Smith Karen , Bernard Stephen A , Cameron Peter ,   on behalf of the VACAR Steering Committee
Published: October 2012

AimWe describe improved reporting of paediatric out-of-hospital cardiac arrest (OHCA) by adding coronial findings to a cardiac arrest registry.MethodsNon-traumatic OHCA occurring in paediatric patients aged less than 16 years were identified using the Victorian Ambulance Cardiac Arrest Registry and available coronial findings reviewed.ResultsBetween the years 2001 and 2009, emergency medical services (EMS) attended 26 974 non-traumatic OHCA of which 390 (1.4%) occurred in children less than 16 years of age. We successfully linked 301 patients with the coronial registry; excluding patients discharged alive from hospital (n=22) and patients with terminal illness (n=16), this represents 86% of OHCA attended by the ambulance. Agreement between the paramedic cause of OHCA and the coronial cause of death was 66.5% (κ 0.16) for presumed cardiac, 74.4% (κ 0.43) for sudden infant death syndrome (SIDS), 81.1% (κ 0.17) for respiratory, 92.7% (κ 0.18) for neurological and 98.3% (κ 0.27) for drug overdose precipitants to OHCA. Undiagnosed congenital heart disease was a rare cause of OHCA (n=3, 1%). Intentional injury was found on autopsy in 13 cases; six cases were clinically thought to be SIDS and two cases presumed cardiac. Co-sleeping was found in 35 cases (39%) of SIDS.ConclusionsThis study highlights the limitations associated with ascribing the cause of OHCA on the basis of clinical details. Improved reporting is possible by linkage with coronial data. Such robust data inform EMS service providers but also the wider healthcare system where preventive, diagnostic and treatment strategies can be maximised.
Pulmonary embolism rule-out criteria (PERC) in pulmonary embolism—revisited: A systematic review and meta-analysis
Authors: Singh Balwinder , Mommer Shannon K , Erwin Patricia J , Mascarenhas Soniya S , Parsaik Ajay K 
Published: October 2012

ObjectivesTo perform a systematic review and meta-analysis including all the current studies to assess the accuracy of pulmonary embolism rule-out criteria (PERC) in ruling out pulmonary embolism (PE).MethodsWe conducted a comprehensive search of the major databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews and Scopus) and references of potentially eligible articles and conference proceedings of major emergency medicine organisations through May 2012. We included all original research studies conducted in emergency departments on diagnostic performance of PERC. Two reviewers independently identified the eligible studies and extracted data. Sensitivity, specificity and likelihood ratios were calculated using contingency tables.Results12 studies including 13 cohorts (three retrospective, 10 prospective) were included, comprising of 14 844 patients from six countries. 12 cohorts were urban and one was rural. Pooled (95% CI) sensitivity, specificity, positive and negative likelihood ratio were 0.97 (0.96 to 0.98), 0.22 (0.22 to 0.23), 1.22 (1.16 to 1.29) and 0.17 (0.13 to 0.23), respectively. The pooled (95% CI) diagnostic OR was 7.4 (5.5–9.8). On meta-regression analysis, there was no significant difference between PE prevalence and PERC diagnostic performance (coefficient (SE) of −0.032 (0.022), p=0.173) or on relative diagnostic OR (0.97, 95% CI 0.92 to 1.02). Significant heterogeneity was observed in specificity (I2=97.4%) and positive likelihood ratio (I2=89.1%).ConclusionsBecause of the high sensitivity and low negative likelihood ratio, PERC rule can be used confidently in clinically low probability population settings.
How likely is environmental or patient cross-contamination ofChlamydia trachomatisDNA to lead to false positive results in patients attending our clinic?
Authors: Chan Sum Yee , Jose Sophie , King Rebecca , Pakianathan Mark R , Sabin Caroline , Sadiq S Tariq , Hay Phillip E , Planche Tim 
Published: October 2012

ObjectivesEnvironmental contamination with DNA fromChlamydia trachomatis(CT) has previously been found in Genitourinary Medicine (GUM) clinics. There are no known cases of cross-contamination of clinical samples and no known nosocomial infections. We investigated whether diagnostic samples could become contaminated from the environment by running dummy sample and carrying out a patient-throughput analysis. A total of 29 748 patients attended clinics over a year. Of these, 2860 (9.6%) had a positive Chlamydia test result.Method(1) A run of dummy samples (60 urine samples and 10 swabs) were processed as normal clinic specimens. (2) Patient-throughput analysis: Patient numbers attending the GUM clinic on a given day was categorised as low, moderate or high. χ2Tests were used to look for associations between categorical variables and Chlamydia test positivity. A Poisson regression model was fitted to look at the effect of the number of people in the clinic on the number of positive results in a given day. As some clinics were only run on certain days of the week, a sensitivity analysis was later performed with attendances at non-daily clinics removed.ResultsAll dummy samples tested negative and we did not find evidence of an association between daily Chlamydia positivity and clinic attendance.ConclusionsIt is unlikely that environmental or cross-contamination of CT has lead to significant numbers of false positive results. Laboratories check for possible cross-contamination routinely. The extension of this simple routine practice to all clinical areas could provide quality assurance, improving confidence in the results in clinics.
Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer
Authors: Kondo Shunsuke , Iwata Satoshi , Yamada Taketo , Inoue Yusuke , Ichihara Hiromi , Kichikawa Yoshiko , Katayose Tomoki , Souta-Kuribara Akiko , Yamazaki Hiroto , Hosono Osamu , Kawasaki Hiroshi , Tanaka Hirotoshi , Hayashi Yuichiro , Sakamoto Michiie , Kamiya Kazunori , Dang Nam H. , Morimoto Chikao 
Published: October 2012

AbstractPurpose: In a substantial population of non–small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.Experimental Design: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.Results: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγnull mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.Conclusion: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis. Clin Cancer Res; 18(22); 6326–38. ©2012 AACR.
Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21
Authors: Ghantous Akram , Saikali Melody , Rau Tilman , Gali-Muhtasib Hala , Schneider-Stock Regine , Darwiche Nadine 
Published: October 2012

Abstract
The promotion stage in the multistep process of epidermal tumorigenesis is NF-кB–dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-кB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-кB target genes, p21 and cyclin D1.
Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6P+ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter–induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter–induced NF-кB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NF-кB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-кB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21 −/− cancer cells and showed that the loss of p21 is cytoprotective against parthenolide.
Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6P+ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NF-кB, whereas it increased p21 expression.
These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy. Cancer Prev Res; 5(11); 1298–309. ©2012 AACR.
On the Effective Capacity of the Dense-Water Reservoir for the Nordic Seas Overflow: Some Effects of Topography and Wind Stress
Authors: Yang Jiayan , Pratt Lawrence J. 
Published: October 2012

Abstract
The overflow of the dense water mass across the Greenland–Scotland Ridge (GSR) from the Nordic Seas drives the Atlantic meridional overturning circulation (AMOC). The Nordic Seas is a large basin with an enormous reservoir capacity. The volume of the dense water above the GSR sill depth in the Nordic Seas, according to previous estimates, is sufficient to supply decades of overflow transport. This large capacity buffers overflow’s responses to atmospheric variations and prevents an abrupt shutdown of the AMOC. In this study, the authors use a numerical and an analytical model to show that the effective reservoir capacity of the Nordic Seas is actually much smaller than what was estimated previously. Basin-scale oceanic circulation is nearly geostrophic and its streamlines are basically the same as the isobaths. The vast majority of the dense water is stored inside closed geostrophic contours in the deep basin and thus is not freely available to the overflow. The positive wind stress curl in the Nordic Seas forces a convergence of the dense water toward the deep basin and makes the interior water even more removed from the overflow-feeding boundary current. Eddies generated by the baroclinic instability help transport the interior water mass to the boundary current. But in absence of a robust renewal of deep water, the boundary current weakens rapidly and the eddy-generating mechanism becomes less effective. This study indicates that the Nordic Seas has a relatively small capacity as a dense water reservoir and thus the overflow transport is sensitive to climate changes.