bluuebunny/crossref_metadata_2025_split huggingface dataset:
Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities
Authors: Cheng Jingwei , Rozenblatt-Rosen Orit , Paulson Kelly G. , Nghiem Paul , DeCaprio James A. 
Published: March 2013

ABSTRACT
Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region.
Molecular Basis of the Receptor Binding Specificity Switch of the Hemagglutinins from both the 1918 and 2009 Pandemic Influenza A Viruses by a D225G Substitution
Authors: Zhang Wei , Shi Yi , Qi Jianxun , Gao Feng , Li Qing , Fan Zheng , Yan Jinghua , Gao George F. 
Published: March 2013

ABSTRACT
Influenza A virus uses sialic acids as cell entry receptors, and there are two main receptor forms, α2,6 linkage or α2,3 linkage to galactose, that determine virus host ranges (mammalian or avian). The receptor binding hemagglutinins (HAs) of both 1918 and 2009 pandemic H1N1 (18H1 and 09H1, respectively) influenza A viruses preferentially bind to the human α2,6 linkage receptor. A single D225G mutation in both H1s switches receptor binding specificity from α2,6 linkage binding to dual receptor binding. However, the molecular basis for this specificity switch is not fully understood. Here, we show via H1-ligand complex structures that the D225G substitution results in a loss of a salt bridge between amino acids D225 and K222, enabling the key residue Q226 to interact with the avian receptor, thereby obtaining dual receptor binding. This is further confirmed by a D225E mutant that retains human receptor binding specificity with the salt bridge intact.
Downregulation of Nipah Virus N mRNA Occurs through Interaction between Its 3′ Untranslated Region and hnRNP D
Authors: Hino Kimihiro , Sato Hiroki , Sugai Akihiro , Kato Masahiko , Yoneda Misako , Kai Chieko 
Published: March 2013

ABSTRACT

Nipah virus (NiV) is a nonsegmented, single-stranded, negative-sense RNA virus belonging to the genus
Henipavirus
, family
Paramyxoviridae
. NiV causes acute encephalitis and respiratory disease in humans, is associated with high mortality, and poses a threat in southern Asia. The genomes of henipaviruses are about 18,246 nucleotides (nt) long, which is longer than those of other paramyxoviruses (around 15,384 nt). This difference is caused by the noncoding RNA region, particularly the 3′ untranslated region (UTR), which occupies more than half of the noncoding RNA region. To determine the function(s) of the NiV noncoding RNA region, we investigated the effects of NiV 3′ UTRs on reporter gene expression. The NiV N 3′ UTR (nt 1 to 100) demonstrated strong repressor activity associated with hnRNP D protein binding to that region. Mutation of the hnRNP D binding site or knockdown of hnRNP D resulted in increased expression of the NiV N 3′ UTR reporter. Our findings suggest that NiV N expression is repressed by hnRNP D through the NiV N 3′ UTR and demonstrate the involvement of posttranscriptional regulation in the NiV life cycle. To the best of our knowledge, this provides the first report of the functions of the NiV noncoding RNA region.
Glycoprotein H and α4β1 Integrins Determine the Entry Pathway of Alphaherpesviruses
Authors: Azab Walid , Lehmann Maik J. , Osterrieder Nikolaus 
Published: March 2013

ABSTRACT
Herpesviruses enter cells either by direct fusion at the plasma membrane or from within endosomes, depending on the cell type and receptor(s). We investigated two closely related herpesviruses of horses, equine herpesvirus type 1 (EHV-1) and EHV-4, for which the cellular and viral determinants routing virus entry are unknown. We show that EHV-1 enters equine epithelial cells via direct fusion at the plasma membrane, while EHV-4 does so via an endocytic pathway, which is dependent on dynamin II, cholesterol, caveolin 1, and tyrosine kinase activity. Exchange of glycoprotein H (gH) between EHV-1 and EHV-4 resulted in rerouting of EHV-1 to the endocytic pathway, as did blocking of α4β1 integrins on the cell surface. Furthermore, a point mutation in the SDI integrin-binding motif of EHV-1 gH also directed EHV-1 to the endocytic pathway. Cumulatively, we show that viral gH and cellular α4β1 integrins are important determinants in the choice of alphaherpesvirus cellular entry pathways.
Nuclear Targeting of Human Cytomegalovirus Large Tegument Protein pUL48 Is Essential for Viral Growth
Authors: Brock Ivonne , Krüger Marc , Mertens Thomas , von Einem Jens 
Published: March 2013

ABSTRACT
We report the identification of a functional nuclear localization signal (NLS) in the human cytomegalovirus (HCMV) large tegument protein pUL48 that is required for nuclear localization in transfected cells and is essential for viral growth. The NLS was mapped to pUL48 amino acid residues 284 to 302. This sequence contains a bipartite NLS comprising two clusters of basic residues (bC1 and bC2) separated by 9 amino acids. Deletion or mutation of bC1 or mutation of bC2 abrogated the nuclear localization of full-length pUL48 in transiently expressing cells, thus strongly implying a bipartite character of the NLS. Nuclear localization could be restored by fusion of a functional NLS together with enhanced green fluorescent protein (EGFP) to the N terminus of these mutants. In HCMV-infected cells, pUL48 was found in both nuclear and cytoplasmic fractions, supporting a function of the NLS during virus infection. NLS mutant viruses, generated by markerless bacterial artificial chromosome mutagenesis, were not viable in cell culture, whereas coexpression of pUL48 complemented growth of these mutants. The fusion of a functional NLS to the N terminus of pUL48 in a nonviable NLS mutant virus partially rescued the growth defect. Furthermore, the replacement of the bipartite pUL48 NLS by the monopartite pUL36 NLS of herpes simplex virus 1 supported viral growth to some extent but still revealed a severe defect in focus formation and release of infectious virus particles. Together, these results show that nuclear targeting of pUL48 is mediated by a bipartite NLS whose function is essential for HCMV growth.
Self-reported feelings of anger and aggression towards others in patients on levetiracetam: data from the UK antiepileptic drug register
Authors: Wieshmann Udo Carl , Baker Gus A 
Published: March 2013

ObjectivesTo ascertain the frequency of self-reported anger and depression in levetiracetam (LEV).DesignWe compared patients with epilepsy (PWE) taking LEV with PWE taking other antiepileptic drugs (AEDs).SettingAll PWE and controls submitted information to the UK AED register.ParticipantsWe analysed the data of 418 PWE and 41 control participants. 158 participants took LEV in monotherapy or as part of polypharmacotherapy, 260 PWE took other AED.Primary and secondary outcome measuresAll PWE and controls completed the Liverpool Adverse Event Profile (LAEP) which includes items on anger and depression quantified on a four-point Likert scale, with 1 indicating that there was never a problem; 2, rarely a problem; 3, sometimes a problem and 4, always or often a problem.Results49% of PWE on LEV and 39% on AED other than LEV reported anger as sometimes or always being a problem (p=0.042). 48% of PWE on LEV and 45% on AED other than LEV reported depression as sometimes or always being a problem (p=0.584). 7% of control participants reported anger as sometimes being a problem and 93% reported anger as never or rarely being a problem. Depression was never a problem in 75% of controls and rarely a problem in 25%.ConclusionsAnger and depression were more frequently reported as a problem by PWE than by control participants. Our observational register of self-reported symptoms suggested anger being more often a problem in patients taking LEV than in PWE taking other AED. PWE should be informed about this potential problem of LEV.
Learning curve of Wingspan stenting for intracranial atherosclerosis: single-center experience of 95 consecutive patients
Authors: Yu Simon Chun Ho , Leung Thomas Wai Hong , Lee Kwok Tung , Wong Lawrence Ka Sing 
Published: March 2013

BackgroundSymptomatic brain hemorrhage was a significant cause of periprocedural stroke or death following stenting in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which called into question the safety of Wingspan stenting for intracranial atherosclerosis. This study analyzed the role of a learning curve in the safety and outcome of Wingspan stenting from the experience of 95 consecutive patients at a single center.MethodsIn this prospective study the endpoints were major stroke or death (modified Rankin Scale score >3) within 30 days, other neurological complications, technical procedural problems, technical success in completion of angioplasty and stenting and recurrent ischemic stroke in the corresponding vascular territory after 30 days. Data splitting into quarters was used for learning curve analysis.ResultsThe periprocedural major stroke or death rate was 4.2% (4/95), minor stroke rate was 5.3% (5/95), total 9.5% (9/95). The technical procedural problem rate was 11.6% (11/95) and the technical success rate was 93.7% (89/95). The 89 patients were followed for 38.9±22.7 months (median 40.8, range 0.2–72, 3463 patient-months) after stenting. The risk of recurrent ischemic stroke in the corresponding vascular territory was 0.7% per patient per year (2/3463 patient-months). Guidewire- or angioplasty-related hemorrhage was the major cause of periprocedural major stroke or death (3/4, 75%) and did not occur in the last quarter. Periprocedural intracerebral hemorrhage was uncommon and perforator stroke did not occur.ConclusionsThere may be a learning curve for mastering the safety precautions of Wingspan stenting for intracranial atherosclerosis.
Variation in cost of newly qualified doctors' prescriptions: a review of data from a hospital electronic prescribing system
Authors: Nwulu Ugochi , Hodson James , Thomas Sarah K , Westwood David , Griffin Charlotte , Coleman Jamie J 
Published: March 2013

Abstract

Purpose of the study
To investigate the variation in the net ingredient cost (NIC) of the medications most commonly prescribed by Foundation Year 1 (F1) doctors in a teaching hospital and to compare the effects of working in different specialties and rotations on this cost.

Design of the study
Retrospective review of prescription data from 5 August 2010 to 3 August 2011 extracted from an electronic prescribing system.

Results
The F1 doctors generated 81 316 prescriptions with an estimated total cost of £579 398. The mean NIC per doctor was £7334 (SE=£430). Prescribing costs varied significantly across clinical departments and between drug classes considered in the analysis. Specifically, prescribing in the infection and respiratory drug categories and within the trauma and orthopaedics department was associated with higher prescribing costs. Significant variability was also attributable to the prescribing doctor (p&lt;0.001) with average prescription costs ranging from 72.2% lower to 193.8% higher than the median doctor.

Conclusions
There is considerable variation in the total costs of medications prescribed by F1 doctors, even after considering a range of prescription factors. This variation may suggest that some doctors are prescribing uneconomically relative to the rest of the cohort. Knowledge of which clinical areas and drug classes have higher NICs may allow an alternative focus for medicine management teams and postgraduate education.
Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer
Authors: Damiano Jason S. , Wasserman Ernesto 
Published: March 2013

Abstract
The prolactin (PRL)–prolactin receptor (PRLR) signaling complex has been implicated in the pathology of breast and prostate carcinoma. A multitude of pro-oncogenic intracellular signaling pathways are activated by PRL in breast and prostate epithelial cells, leading to enhanced cellular proliferation, survival, and tumorigenesis in numerous model systems. Emerging evidence suggests that targeting the PRL–PRLR axis in human cancer may represent an unexploited avenue for therapeutic intervention and, given the extensive cross-talk between PRLR and other signal transduction pathways, a potential means through which other anticancer agents could be rendered more efficacious in the clinic. LFA102 is a potent anti-PRLR neutralizing antibody that efficiently abrogates the function of this receptor in vivo, mediating significant antitumor effects in preclinical models. The clean safety profile of this antibody in animals and in the clinical experiences to date suggests that blocking the PRLR signaling pathway in human tumors may have few significant toxicologic consequences and may be a promising approach to treating cancer. A phase I trial in patients with breast and prostate cancer is underway to better understand the clinical utility of LFA102 and the contribution of PRL to the maintenance and progression of human cancer. Clin Cancer Res; 19(7); 1644–50. ©2013 AACR.
Elevated Cyclin D1 Expression Is Predictive for a Benefit from TPF Induction Chemotherapy in Oral Squamous Cell Carcinoma Patients with Advanced Nodal Disease
Authors: Zhong Lai-Ping , Zhu Dong-Wang , William William N. , Liu Ying , Ma Jie , Yang Cheng-Zhe , Yang Xiao , Wang Li-Zhen , Li Jiang , Myers Jeffrey N. , Lee J. Jack , Zhang Chen-Ping , Zhang Zhi-Yuan 
Published: March 2013

Abstract
Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients with cancer with biomarker detection. To investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma (OSCC) who were treated in a prospective, randomized, phase III trial evaluating standard treatment with surgery and postoperative radiotherapy preceded or not by induction docetaxel, cisplatin, and 5-fluorouracil (TPF), immunohistochemical staining for cyclin D1 was conducted in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival (OS; P = 0.001), disease-free survival (P = 0.005), locoregional recurrence-free survival (P = 0.003), and distant metastasis-free survival (DMFS; P = 0.002) compared with high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater OS (P = 0.025) and DMFS (P = 0.025) when compared with high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy. Mol Cancer Ther; 12(6); 1112–21. ©2013 AACR.
Regular Physical Activity and Risk of Atrial Fibrillation
Authors: Ofman Peter , Khawaja Owais , Rahilly-Tierney Catherine R. , Peralta Adelqui , Hoffmeister Peter , Reynolds Mathew R. , Gaziano J. Michael , Djousse Luc 
Published: March 2013

Background—
Although previous studies have suggested that competitive athletes have a higher risk of atrial fibrillation than the general population, limited and inconsistent data are available on the association between regular physical activity and the risk of atrial fibrillation.

Methods and Results—
A systematic, comprehensive literature search was performed using MEDLINE, EMBASE, and COCHRANE until 2011. Extracted data from the eligible studies were meta-analyzed using fixed effects model. Four studies, which included 95 526 subjects, were eligible for meta-analysis. For all of the studies included, the extreme groups (ie, maximum versus minimal amount of physical activity) were used for the current analyses. The total number of participants belonging to the extreme groups was 43 672. The pooled odds ratio (95% confidence interval) for atrial fibrillation among regular exercisers was 1.08 (0.97–1.21).

Conclusions—
Our data do not support a statistically significant association between regular physical activity and increased incidence of atrial fibrillation.
Influence of Intracardiac Pressure on Spontaneous Ventricular Arrhythmias in Patients With Systolic Heart Failure
Authors: Reiter Michael J. , Stromberg Kurt D. , Whitman Teresa A. , Adamson Philip B. , Benditt David G. , Gold Michael R. 
Published: March 2013

Background—
The implantation of a combination hemodynamic monitor-cardioverter-defibrillator in the Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients with Chronic Heart Failure (REDUCEhf) study allowed assessment of the relationship between daily intracardiac pressure and occurrence of ventricular arrhythmic (VT/VF) events.

Methods and Results—

Median estimated pulmonary artery diastolic pressures (ePAD) were calculated every 24 hours in 378 subjects with New York Heart Association functional class II-III heart failure who had at least 60 days of hemodynamic data. Forty-six subjects experienced 140 VT/VF events on 80 unique study days in which daily median ePAD was available. The incidence of days with VT/VF events was significantly higher when the daily median ePAD for a subject was elevated, defined as >1 SD above that subject’s average median ePAD for the whole study: (2.8 episode days per patient-year compared with 1.7 episode days per patient-year;
P
=0.040). However, the incidence of days with VT/VF events was not significantly different on days when ePAD was >25 mm Hg compared with days when ePAD was <25 mm Hg. For all 378 subjects, the risk of VT/VF increased with average median ePAD calculated over the whole follow-up period (odds ratio, 1.072 for a 1-mm Hg increase; 95% confidence interval, 1.023–1.124;
P
=0.003).

Conclusions—
There is significant positive association between average daily median ePAD and risk for VT/VF. Among patients with VT/VF, elevated intracardiac pressures are associated with higher VT/VF risk only when the definition of increased pressure is subject specific.
Electrical Reconnection After Pulmonary Vein Isolation Is Contingent on Contact Force During Initial Treatment
Authors: Neuzil Petr , Reddy Vivek Y. , Kautzner Josef , Petru Jan , Wichterle Dan , Shah Dipen , Lambert Hendrik , Yulzari Aude , Wissner Erik , Kuck Karl-Heinz 
Published: March 2013

Background—
Pulmonary vein isolation is the most prevalent approach for catheter ablation of paroxysmal atrial fibrillation. Long-term success of the procedure is diminished by arrhythmia recurrences occurring predominantly because of reconnections in previously isolated pulmonary veins. The aim of the EFFICAS I multicenter study was to demonstrate the correlation between contact force (CF) parameters during initial procedure and the incidence of isolation gaps (gap) at 3-month follow-up.

Method and Results—

A radiofrequency ablation catheter with integrated CF sensor (TactiCath, Endosense, Geneva, Switzerland) was used to perform pulmonary vein isolation in 46 patients with paroxysmal atrial fibrillation. During the ablation procedure, the operator was blinded to CF information. At follow-up, an interventional diagnostic procedure was performed to assess gap location as correlated to index procedure ablation parameters. At follow-up, 65% (26/40) of patients showed ≥1 gaps. Ablations with minimum Force–Time Integral (FTI) <400 gs showed increased likelihood for reconnection (
P
<0.001). Reconnection correlated strongly with minimum CF (
P
<0.0001) and minimum FTI (
P
=0.0007) at the site of gap. Gap occurrence showed a strong trend with lower average CF and average FTI. CF and FTI are generally higher on the right side, although the left anterior segment presents a unique challenge to achieve stable position with good CF.

Conclusions—
Minimum CF and minimum FTI values are strong predictors of gap formation. Optimal CF parameter recommendations are a target CF of 20 g and a minimum FTI of 400 gs for each new lesion.
Conveyance and Convergence: Visual Culture in Medieval Cyprus
Authors: Andrews Justine 
Published: March 2013

Abstract
While the trajectory of transmission of art in the Mediterranean has often been understood as West to East, here I will consider the transmission of artistic sources to Cyprus from both the West and East. These trajectories open a dialogue regarding the question of how the many sources that underpin Cypriot medieval art converged on the island. Focusing on commissions of the Lusignan dynasty, as well as other powerful communities such as the Orthodox Greeks and the Genoese, this paper shows that the social and political identity of these groups was constantly in flux; the artistic styles they used to express themselves changed according to their shifts in status. Thus, their use of artistic and architectural styles was strategic and both reflected and shaped the family’s changing political and economic position in the Mediterranean.
Imported and Native Remedies for a Wounded “Prince”: Grave Goods from the Chungul Kurgan in the Black Sea Steppe of the Thirteenth Century
Authors: Holod Renata , Rassamakin Yuriy 
Published: March 2013

Abstract
A burial of a Turkic (Qıpčaq/Cuman/Polovtsian) prince excavated in the grasslands of southern Ukraine is witness to an exchange in objects and products throughout the Black Sea/Mediterranean littoral, the Middle East, and central and northwest Europe in the Middle Ages. The grave goods, arms and costumes, which are of unprecedented richness for a medieval Turkic burial, are datable to the first three decades of the thirteenth century. They were likely accumulated through trading and raiding or through diplomatic and marriage gifts of this Qıpčaq leader, and his tribal confederation, with the neighboring Rus’, Georgian, Armenian, Hungarian, Byzantine, Crusader and Islamic polities. Among the grave goods excavated in the tumulus/ kurgan are a variety of containers such as two complete and reused amphorae, glazed ceramic albarello and bottle and a gilded silver covered cup. The albarello and bottle could be associated with the Mediterranean pharmacological practice of shipping valuable substances in specialized containers. Other vessels, such as the covered ceremonial cup from northwest Europe, were reused likely in a complex ritual utilizing plants native to these grasslands. This paper will consider the circumstances under which these substances would have been deposited and discuss the origins and uses of the containers.