bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reovirus Uses Multiple Endocytic Pathways for Cell Entry
Authors: Schulz Wade L. , Haj Amelia K. , Schiff Leslie A. 
Published: September 2012

ABSTRACT

Entry of reovirus virions has been well studied in several tissue culture systems. After attachment to junctional adhesion molecule A (JAM-A), virions undergo clathrin-mediated endocytosis followed by proteolytic disassembly of the capsid and penetration to the cytoplasm. However, during
in vivo
infection of the intestinal tract, and likely in the tumor microenvironment, capsid proteolysis (uncoating) is initiated extracellularly. We used multiple approaches to determine if uncoated reovirus particles, called intermediate subviral particles (ISVPs), enter cells by directly penetrating the limiting membrane or if they take advantage of endocytic pathways to establish productive infection. We found that entry and infection by reovirus ISVPs was inhibited by dynasore, an inhibitor of dynamin-dependent endocytosis, as well as by genistein and dominant-negative caveolin-1, which block caveolar endocytosis. Inhibition of caveolar endocytosis also reduced infection by reovirus virions. Extraction of membrane cholesterol with methyl-β-cyclodextrin inhibited infection by virions but had no effect when infection was initiated with ISVPs. We found this pathway to be independent of both clathrin and caveolin. Together, these data suggest that reovirus virions can use both dynamin-dependent and dynamin-independent endocytic pathways during cell entry, and they reveal that reovirus ISVPs can take advantage of caveolar endocytosis to establish productive infection.
Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus
Authors: Sather D. Noah , Carbonetti Sara , Kehayia Jenny , Kraft Zane , Mikell Iliyana , Scheid Johannes F. , Klein Florian , Stamatatos Leonidas 
Published: September 2012

ABSTRACT

Approximately 1% of those infected with HIV-1 develop broad and potent serum cross-neutralizing antibody activities. It is unknown whether or not the development of such immune responses affects the replication of the contemporaneous autologous virus. Here, we defined a pathway of autologous viral escape from contemporaneous potent and broad serum neutralizing antibodies developed by an elite HIV-1-positive (HIV-1
+
) neutralizer. These antibodies potently neutralize diverse isolates from different clades and target primarily the CD4-binding site (CD4-BS) of the viral envelope glycoprotein. Viral escape required mutations in the viral envelope glycoprotein which limited the accessibility of the CD4-binding site to the autologous broadly neutralizing anti-CD4-BS antibodies but which allowed the virus to infect cells by utilizing CD4 receptors on their surface. The acquisition of neutralization resistance, however, resulted in reduced cell entry potential and slower viral replication kinetics. Our results indicate that
in vivo
escape from autologous broadly neutralizing antibodies exacts fitness costs to HIV-1.
Gamma Interferon (IFN-γ) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-α/β Receptor-Deficient Mice
Authors: Prestwood Tyler R. , Morar Malika M. , Zellweger Raphaël M. , Miller Robyn , May Monica M. , Yauch Lauren E. , Lada Steven M. , Shresta Sujan 
Published: September 2012

ABSTRACT

We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8
+
T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8
+
T cells in preventing DENV-induced CNS disease.
Genetic Control of Translesion Synthesis on Leading and Lagging DNA Strands in Plasmids Derived from Epstein-Barr Virus in Human Cells
Authors: Yoon Jung-Hoon , Prakash Satya , Prakash Louise 
Published: September 2012

ABSTRACT

DNA lesions in the template strand block synthesis by replicative DNA polymerases (Pols). Eukaryotic cells possess a number of specialized translesion synthesis (TLS) Pols with the ability to replicate through DNA lesions. The Epstein-Barr virus (EBV), a member of the herpesvirus family, infects human B cells and is maintained there as an extrachromosomal replicon, replicating once per cycle during S phase. Except for the requirement of the virus-encoded origin-binding protein EBNA1, replication of plasmids containing the EBV origin of replication (
oriP
) is controlled by the same cellular processes that govern chromosomal replication. Since replication of EBV plasmid closely mimics that of human chromosomal DNA, in this study we examined the genetic control of TLS in a duplex plasmid in which bidirectional replication initiates from an EBV
oriP
origin and a UV-induced
cis-
syn
TT dimer is placed on the leading- or the lagging-strand DNA template. Here we show that TLS occurs equally frequently on both the DNA strands of EBV plasmid and that the requirements of TLS Pols are the same regardless of which DNA strand carries the lesion. We discuss the implications of these observations for TLS mechanisms that operate on the two DNA strands during chromosomal replication and conclude that the same genetic mechanisms govern TLS during the replication of the leading and the lagging DNA strands in human cells.

IMPORTANCE
Since replication of EBV (Epstein-Barr virus) origin-based plasmids appropriates the cellular machinery for all the steps of replication, our observations that the same genetic mechanisms govern translesion synthesis (TLS) on the two DNA strands of EBV plasmids imply that the requirements of TLS Pols are not affected by any of the differences in the replicative Pols or in other proteins that may be used for the replication of the two DNA strands in human cells. These findings also have important implications for evaluating the significance of results of TLS studies with the SV40 origin-based plasmids that we have reported previously, in which we showed that TLS occurs similarly on the two DNA strands. Since the genetic control of TLS in SV40 plasmids resembles that in EBV plasmids, we conclude that TLS studies with the SV40 plasmids are as informative of TLS mechanisms that operate during cellular replication as those with the EBV plasmids.
Repression by Cyclic AMP Receptor Protein at a Distance
Authors: Lee David J. , Busby Stephen J. W. 
Published: September 2012

ABSTRACT

In a previous study of promoters dependent on the
Escherichia coli
cyclic AMP receptor protein (CRP), carrying tandem DNA sites for CRP, we found that the upstream-bound CRP could either enhance or repress transcription, depending on its location. Here, we have analyzed the interactions between CRP and the C-terminal domains of the RNA polymerase α subunits at some of these promoters. We report that the upstream-bound CRP interacts with these domains irrespective of whether it up- or downregulates promoter activity. Hence, disruption of this interaction can lead to either down- or upregulation, depending on its location.

IMPORTANCE
Many bacterial promoters carry multiple DNA sites for transcription factors. While most factors that downregulate promoter activity bind to targets that overlap or are downstream of the transcription start and −10 element, very few cases of repression from upstream locations have been reported. Since more
Escherichia coli
promoters are regulated by cyclic AMP receptor protein (CRP) than by any other transcription factor, and since multiple DNA sites for CRP are commonplace at promoters, our results suggest that promoter downregulation by transcription factors may be more prevalent than hitherto thought, and this will have implications for the annotation of promoters from new bacterial genome sequences.
FIFA Women's World Cup 2011: Pre-Competition Medical Assessment of female referees and assistant referees
Authors: Keller Dagmar I , Bizzini Mario , Feddermann Nina , Junge Astrid , Dvorak Jiri 
Published: September 2012

BackgroundPrecompetition screening was implemented for male referees during the 2010 Fédération Internationale de Football Association (FIFA) Word Cup. In contrast, female football referees have been neglected in this respect although they experience similar physical work loads compared to male referees.MethodsThe standardised football-specific Pre-Competition Medical Assessment (PCMA) was performed in 51 referees and assistant referees selected for the 2011 FIFA Women's World Cup.ResultsFamily history for sudden cardiac death (SCD) was positive in four referees (7.8%), but cardiac examinations did not reveal any pathological findings. Training-unrelated ECG changes were identified in three referees (5.9%), all without correlates in echocardiography or clinical examination. Most common echocardiography findings (66.6%, n=34) were asymptomatic tricuspid and mitral regurgitations.ConclusionsDuring the present screening, no elite female referee was identified being at risk for SCD, and no referee had to be excluded from participating in the 2011 FIFA Women's World Cup.
The role of a relative age effect in the first winter Youth Olympic Games in 2012
Authors: Raschner Christian , Müller Lisa , Hildebrandt Carolin 
Published: September 2012

BackgroundOwing to the separation into age groups at the first winter Youth Olympic Games (YOG), athletes differed in age by up to two years, leading to a potential relative age effect (RAE).ObjectiveThe purpose of this study was to define the role of the RAE in the first winter YOG with regard to sex, type of sport and performance.MethodsThe birth dates and anthropometric data of all 1021 athletes (557 male, 464 female, 14–19 years old) participating in 15 sports were analysed. A χ2test was used to assess the difference between the observed and expected birth distributions. ANOVA (analysis of variance) and Kruskal−Wallis analyses were used to investigate differences in anthropometrics.ResultsThe birth date distribution of the overall sample was significantly different from an equal distribution, with an over-representation of athletes born shortly after the cut-off date (χ2=284.7, p<0.001). A significant RAE was found in both male (χ2=245.1, p<0.001) and female competitors (χ2=74.6, p<0.001). An analysis based on the type of sport showed an RAE in all categories (strength—χ2=229.9, p<0.001, endurance—χ2=60.4, p<0.001 and technique-related sports χ2=25.2, p=0.001). Relatively older competitors were also over-represented among medal winners (χ2=47.9, p<0.001). Relatively older male competitors were significantly taller (p=0.005) and heavier (p<0.001) than younger competitors. No differences were found in female competitors.ConclusionsThe results suggest that relative age had a highly significant influence on participation in various sports regardless of sex. A possible strategy to reduce the RAE would be a fixed quota for each birth year within the two-year age group across events.
Paediatric intra-axial posterior fossa tumours: pictorial review
Authors: Rasalkar Darshana D , Chu Winnie Chiu-wing , Paunipagar Bhawan K , Cheng Frankie W T , Li C K 
Published: September 2012

Abstract
Paediatric brain tumours commonly arise in the posterior cranial fossa. Early diagnosis is often challenging due to initial non-specific clinical symptoms, especially in very young children. The typical MR features of tumours in this region including medulloblastoma, ependymoma, juvenile pilocytic subtype of cerebellar astrocytoma, brain stem glioma and atypical teratoid–rhabdoid tumour are illustrated. Diffusion-weighted imaging and apparent diffusion coefficient values combined with signal characteristics on conventional MR sequences can usually differentiate low-grade from high-grade tumours. Prompt diagnosis is crucial as total surgical resection, which is only possible in localised disease, improves prognosis. A practical MR flow chart is introduced for differentiating different types of posterior cranial fossa tumours, which might be useful in clinical practice.
Scleritis: presentations, disease associations and management
Authors: Sims Joanne 
Published: September 2012

Abstract
Scleritis is a serious inflammatory condition that is often painful, and in severe cases can result in permanent loss of vision. Approximately half the patients affected have no identifiable cause, but 30%–40% have an underlying systemic autoimmune condition. Scleritis may be the initial manifestation of Wegener's granulomatosis or rheumatoid arthritis, and all patients with scleritis require a thorough systemic evaluation.
Scleritis has a variable presentation and disease course, and may be an acute monophasic illness, a relapsing remitting process, or take a chronic course. Treatment options include local therapy with subconjunctival steroid injections for non-necrotising scleritis, and systemic anti-inflammatory or immunosuppressive therapy. Biologic agents have been used with success in some refractory cases. Ocular and systemic morbidity is reduced by timely treatment with immunosuppressant medications.
The risk of serious adverse outcomes associated with hypoxaemia and hyperoxaemia in acute exacerbations of COPD
Authors: Cameron Laird , Pilcher Janine , Weatherall Mark , Beasley Richard , Perrin Kyle 
Published: September 2012

Abstract

Background
Prehospital high concentration oxygen therapy leads to worse clinical outcomes in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Less is known about the risks of hypoxaemia despite oxygen treatment. Current respiratory and ambulance guidelines recommend titration of supplemental oxygen to a target oxygen saturation range of 88%–92%.

Aim
To explore the association between PaO2 and risk of serious adverse clinical outcomes in AECOPD.

Methods
A retrospective review of consecutive patients presenting via ambulance to the Wellington Regional Hospital Emergency Department with AECOPD between June 2005 and January 2008. Patients with an arterial blood gas taken within 4 h of triage were included in the study and were categorised as hypoxaemic (PaO2&lt;60 mm Hg), normoxaemic (PaO2 60–100 mm Hg) or hyperoxaemic (PaO2&gt;100 mm Hg). Serious adverse outcome was defined as a composite of hypercapnic respiratory failure, assisted ventilation or inpatient death. Multivariate logistic regression analysis examined the association between PaO2 category and the composite outcome.

Results
Of the 680 patients presenting with AECOPD in the review period, 254 presentations in 180 patients had data suitable for analysis. Hyperoxaemia occurred in 61/254 (24%) presentations and was strongly associated with serious adverse outcome compared with normoxaemia (OR 9.17, 95% CI 4.08 to 20.6). Hypoxaemia was also associated with an increased risk of serious adverse outcome compared with normoxaemia (OR 2.16, 95% CI 1.11 to 4.20). Compared with the recommended target oxygen saturation range of 88%–92%, the risk of a serious adverse outcome was increased in both the &lt;88% group (OR 2.0, 95% CI 1.03 to 3.80) and the &gt;96% group (OR 2.37, 95% CI 1.34 to 4.20).

Conclusions
In patients presenting via ambulance to the Emergency Department with AECOPD, serious adverse clinical outcomes are associated with both hypoxaemia and hyperoxaemia. These data provide further support for the principle of titrating supplemental oxygen therapy to target oxygen saturations.
Characterizing seismic-scale faults pre- and post-drilling; Lewisian Basement, West of Shetlands, UK
Authors: Slightam Clare 
Published: September 2012

Abstract
Three exploration wells drilled in the West of Shetlands targeted crystalline Lewisian Basement as the primary reservoir. The objective of these wells was to demonstrate the presence of movable oil in basement and the viability of fault zones within the Lewisian Basement as an exploration target. Lewisian Basement reservoir properties were defined pre-drill through a combination of fieldwork, offset well data, global basement analogues and detailed 3D seismic interpretation. Dip, azimuth and similarity attributes were analysed within the 3D seismic volume in order to delineate the fault network, complimenting manual fault interpretation. Once the fault network had been defined, two fault zones were chosen as a reservoir target for an inclined basement well, based on their length and location within the reservoir.
After drilling over a kilometre of basement across three wells, significant understanding has been gained of the basement reservoir. The comprehensive suites of log data obtained from the wells have allowed some leading edge techniques to be used to bridge the gap between wellbore data and seismic data, with fault zones identified from log data tying to fault zones that had been interpreted using seismic data. The well results have been used to feed back into the predicted fault model to increase the number of mapped faults and to constrain rock properties including lithology and fracture frequency. This paper summarizes the above process and provides specific details regarding the seismic characterization of the fault network.
Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor
Authors: Cavel Oren , Shomron Olga , Shabtay Ayelet , Vital Joseph , Trejo-Leider Leonor , Weizman Noam , Krelin Yakov , Fong Yuman , Wong Richard J. , Amit Moran , Gil Ziv 
Published: September 2012

Abstract
Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal–regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion. Cancer Res; 72(22); 5733–43. ©2012 AACR.
RhoJ Regulates Melanoma Chemoresistance by Suppressing Pathways That Sense DNA Damage
Authors: Ho Hsiang , Aruri Jayavani , Kapadia Rubina , Mehr Hootan , White Michael A. , Ganesan Anand K. 
Published: September 2012

Abstract
Melanomas resist conventional chemotherapeutics, in part, through intrinsic disrespect of apoptotic checkpoint activation. In this study, using an unbiased genome-wide RNA interference screen, we identified RhoJ and its effector PAK1, as key modulators of melanoma cell sensitivity to DNA damage. We find that RhoJ activates PAK1 in response to drug-induced DNA damage, which then uncouples ATR from its downstream effectors, ultimately resulting in a blunted DNA damage response (DDR). In addition, ATR suppression leads to the decreased phosphorylation of ATF2 and consequent increased expression of the melanocyte survival gene Sox10 resulting in a higher DDR threshold required to engage melanoma cell death. In the setting of normal melanocyte behavior, this regulatory relationship may facilitate appropriate epidermal melanization in response to UV-induced DNA damage. However, pathologic pathway activation during oncogenic transformation produces a tumor that is intrinsically resistant to chemotherapy and has the propensity to accumulate additional mutations. These findings identify DNA damage agents and pharmacologic inhibitors of RhoJ/PAK1 as novel synergistic agents that can be used to treat melanomas that are resistant to conventional chemotherapies. Cancer Res; 72(21); 5516–28. ©2012 AACR.
Efficacy of Cetuximab in Metastatic Castration-Resistant Prostate Cancer Might Depend on EGFR and PTEN Expression: Results from a Phase II Trial (SAKK 08/07)
Authors: Cathomas Richard , Rothermundt Christian , Klingbiel Dirk , Bubendorf Lukas , Jaggi Rolf , Betticher Daniel C. , Brauchli Peter , Cotting Denise , Droege Cornelia , Winterhalder Ralph , Siciliano Daniele , Berthold Dominik R. , Pless Miklos , Schiess Ralph , von Moos Roger , Gillessen Silke ,   for the Swiss Group for Clinical Cancer Research (SAKK)
Published: September 2012

Abstract
Purpose: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.
Experimental Design: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m2 every 3 weeks or 35 mg/m2 on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m2 on day 1 and then 250 mg/m2 weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted.
Results: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%–52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3–15.4). Seven patients (20%) had a confirmed ≥50% and 11 patients (31%) a confirmed ≥30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN.
Conclusions: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further. Clin Cancer Res; 18(21); 6049–57. ©2012 AACR.