bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Influenza Virus Hemagglutinin-Respiratory Syncytial Virus (RSV) Fusion Protein Subunit Vaccine against Influenza and RSV
Authors: Turner Tiffany M. , Jones Les P. , Tompkins S. Mark , Tripp Ralph A. 
Published: August 2013

ABSTRACTInfluenza A virus and respiratory syncytial virus (RSV) cause substantial morbidity and mortality afflicting the ends of the age spectrum during the autumn through winter months in the United States. The benefit of vaccination against RSV and influenza using a subunit vaccine to enhance immunity and neutralizing antibody was investigated. Influenza virus hemagglutinin (HA) and RSV fusion (F) protein were tested as vaccine components alone and in combination to explore the adjuvant properties of RSV F protein on HA immunity. Mice vaccinated with HA and F exhibited robust immunity that, when challenged, had reduced viral burden for both influenza and RSV. These studies show an enhancing and cross-protective benefit of F protein for anti-HA immunity.
Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus
Authors: Chen Yaoqing , Rajashankar Kanagalaghatta R. , Yang Yang , Agnihothram Sudhakar S. , Liu Chang , Lin Yi-Lun , Baric Ralph S. , Li Fang 
Published: August 2013

ABSTRACT
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 77 people, with a fatality rate of more than 50%. Alarmingly, the virus demonstrates the capability of human-to-human transmission, raising the possibility of global spread and endangering world health and economy. Here we have identified the receptor-binding domain (RBD) from the MERS-CoV spike protein and determined its crystal structure. This study also presents a structural comparison of MERS-CoV RBD with other coronavirus RBDs, successfully positioning MERS-CoV on the landscape of coronavirus evolution and providing insights into receptor binding by MERS-CoV. Furthermore, we found that MERS-CoV RBD functions as an effective entry inhibitor of MERS-CoV. The identified MERS-CoV RBD may also serve as a potential candidate for MERS-CoV subunit vaccines. Overall, this study enhances our understanding of the evolution of coronavirus RBDs, provides insights into receptor recognition by MERS-CoV, and may help control the transmission of MERS-CoV in humans.
C-Reactive Protein (CRP) Is Essential for Efficient Systemic Transduction of Recombinant Adeno-Associated Virus Vector 1 (rAAV-1) and rAAV-6 in Mice
Authors: Denard Jerome , Marolleau Beatrice , Jenny Christine , Rao Tata Nageswara , Fehling Hans Jörg , Voit Thomas , Svinartchouk Fedor 
Published: August 2013

ABSTRACTThe clinical relevance of gene therapy using the recombinant adeno-associated virus (rAAV) vectors often requires widespread distribution of the vector, and in this case, systemic delivery is the optimal route of administration. Humoral blood factors, such as antibodies or complement, are the first barriers met by the vectors administered systemically. We have found that other blood proteins, galectin 3 binding protein (G3BP) and C-reactive protein (CRP), can interact with different AAV serotypes in a species-specific manner. While interactions of rAAV vectors with G3BP, antibodies, or complement lead to a decrease in vector efficacy, systemic transduction of the CRP-deficient mouse and its respective control clearly established that binding to mouse CRP (mCRP) boosts rAAV vector 1 (rAAV-1) and rAAV-6 transduction efficiency in skeletal muscles over 10 times. Notably, the high efficacy of rAAV-6 in CRP-deficient mice can be restored by reconstitution of the CRP-deficient mouse with mCRP. Human CRP (hCRP) does not interact with either rAAV-1 or rAAV-6, and, consequently, the high efficiency of mCRP-mediated muscle transduction by these serotypes in mice cannot be translated to humans. No interaction of mCRP or hCRP was observed with rAAV-8 and rAAV-9. We show, for the first time, that serum components can significantly enhance rAAV-mediated tissue transduction in a serotype- and species-specific manner. Bioprocessing in body fluids should be considered when transfer of a preclinical proof of concept for AAV-based gene therapy to humans is planned.
Role of Human Herpesvirus 8 Interleukin-6-Activated gp130 Signal Transducer in Primary Effusion Lymphoma Cell Growth and Viability
Authors: Cousins Emily , Nicholas John 
Published: August 2013

ABSTRACT
Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. HHV-8-encoded viral interleukin-6 (vIL-6) is believed to contribute to pathogenesis via proproliferative, antiapoptotic, and proangiogenic activities. In PEL cells, vIL-6 is produced in functional amounts during viral latency and promotes the growth of these cells, mediating its activity from the endoplasmic reticulum (ER), where it is predominantly localized. This vIL-6 activity is dependent, in part, on its interaction with a splice variant of vitamin K epoxide reductase complex subunit 1 (VKORC1), termed VKORC1 variant 2 (VKORC1v2). Here we report that the IL-6 signal transducer, gp130, which can support vIL-6 signaling from the ER, is also required for optimal PEL cell growth and viability. Levels of activated extracellular regulated kinases (ERKs) 1 and 2 and signal transducer and activator of transcription 1 (STAT1) and STAT3, phosphorylated following gp130 stimulation, were reduced in gp130-depleted BCBL-1 and BC-1 cells. Diminished STAT activation was also detected in JSC-1 and BC-3 cells. Effects of gp130 depletion on growth could be mimicked by short hairpin RNA targeting of ERKs 1 and 2 or by depletion of STAT3. Finally, inhibition of vIL-6–gp130 association specifically within the ER compartment suppressed cell proliferation and viability, mirroring the effects of gp130 depletion. Combined, these data demonstrate that gp130, in addition to VKORC1v2, is essential for normal PEL cell growth and survival and that ER-localized vIL-6–gp130 interactions are critical for these activities. Targeting of intracellular vIL-6–gp130 interactions could potentially provide a means of PEL therapy.
The Respiratory Syncytial Virus Fusion Protein Targets to the Perimeter of Inclusion Bodies and Facilitates Filament Formation by a Cytoplasmic Tail-Dependent Mechanism
Authors: Baviskar Pradyumna S. , Hotard Anne L. , Moore Martin L. , Oomens Antonius G. P. 
Published: August 2013

ABSTRACT
The human respiratory syncytial virus (HRSV) fusion (F) protein cytoplasmic tail (CT) and matrix (M) protein are key mediators of viral assembly, but the underlying mechanisms are poorly understood. A complementation assay was developed to systematically examine the role of the F protein CT in infectious virus production. The ability of F mutants with alanine substitutions in the CT to complement an F-null virus in generating infectious progeny was quantitated by flow cytometry. Two CT regions with impact on infectious progeny production were identified: residues 557 to 566 (CT-R1) and 569 to 572 (CT-R2). Substitutions in CT-R1 decreased infectivity by 40 to 85% and increased the level of F-induced cell-cell fusion but had little impact on assembly of viral surface filaments, which are believed to be virions. Substitutions in CT-R2, as well as deletion of the entire CT, abrogated infectious progeny production and impaired viral filament formation. However, CT-R2 mutations did not block but rather delayed the formation of viral filaments, which continued to form at a low rate and contained the viral M protein and nucleoprotein (N). Microscopy analysis revealed that substitutions in CT-R2 but not CT-R1 led to accumulation of M and F proteins within and at the perimeter of viral inclusion bodies (IBs), respectively. The accumulation of M and F at IBs and coincident strong decrease in filament formation and infectivity upon CT-R2 mutations suggest that F interaction with IBs is an important step in the virion assembly process and that CT residues 569 to 572 act to facilitate release of M-ribonucleoprotein complexes from IBs.
A cohort study of mortality predictors in patients with acute exacerbation of chronic fibrosing interstitial pneumonia
Authors: Usui Yutaka , Kaga Akiko , Sakai Fumikazu , Shiono Ayako , Komiyama Ken-ichiro , Hagiwara Koichi , Kanazawa Minoru 
Published: August 2013

ObjectivesTo assess clinical, laboratory and radiographic findings associated with outcomes and to clarify more practical ways to predict hospital mortality in patients with acute exacerbation (AE) of chronic fibrosing interstitial pneumonia (CFIP).DesignSingle-centre retrospective cohort study.SettingUniversity Hospital in Japan.ParticipantsWe identified 51 consecutive patients with AE of idiopathic CFIP through multidisciplinary discussion. Patients who had connective tissue disease, drug-induced lung disease, pneumoconiosis, hypersensitivity pneumonitis, sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis and eosinophilic pneumonia were excluded.InterventionsThere were no interventions.Main outcome measuresThe main outcome was determination of in-hospital mortality predictors. Other outcomes included clinical, laboratory and radiographic differences between non-survivors and survivors in patients with AE of CFIP.ResultsThe mean age of the patients with AE of CFIP was 71 years. Compared with survivors, non-survivors had a significantly shorter duration of symptoms before admission, lower prevalence of peripheral distribution of ground-glass opacity and centrilobular emphysema (CLE) on thin-section CT, lower peripheral lymphocyte count, higher brain natriuretic peptide titre, lower Pao2:Fio2(P:F) ratio, higher prevalence of systemic inflammatory response syndrome (SIRS) and higher SIRS score on admission (p=0.0069, 0.0032, 0.015, 0.040, 0.0098, 0.012, 9.9×10−7and 5.4×10−6, respectively). Multivariate analysis revealed SIRS (HR=6.2810, p=0.015), CLE (HR=0.0606, p=3.6×10−5) and serum procalcitonin level (HR=2.7110, p=0.022) to be independent predictors of in-hospital mortality. A Kaplan-Meier estimate on the basis of stratification according to the presence or absence of SIRS and CLE demonstrated a distinct survival curve for each subset of patients.ConclusionsDistinct survival curves documented by stratification according to the presence or absence of SIRS and CLE may provide basic information for a rational management strategy for patients with AE of CFIP on admission.
Trajectory of intensive treat-to-target disease modifying drug regimen in an observational study of an early rheumatoid arthritis cohort
Authors: White Douglas , Pahau Helen , Duggan Emily , Paul Sanjoy , Thomas Ranjeny 
Published: August 2013

ObjectivesStudies of early rheumatoid arthritis (RA) cohorts have analysed treatment response and prognostic factors at fixed time points. However, in treat-to-target protocols, therapeutic decision-making is dynamic and responsive to disease activity over time. To determine when a minimal residual disease response target should be expected, our primary objective was to identify the time-dependent therapeutic response to combination disease modifying antirheumatic drugs (DMARDs) for 12 months. Our secondary objective determined factors affecting this response trajectory.DesignObservational cohort.SettingTreat-to-target early RA clinic in Australian tertiary referral hospital.ParticipantsWe enrolled consecutive patients attending an early arthritis clinic with symptom duration less than 12 months, who were diagnosed with RA for the first time between 2004 and 2008. 101 met these eligibility criteria and data were available at baseline through 12 months.Interventionsintensive DMARDs according to a treat-to-target protocol.Primary and secondary outcome measuresWe measured disease activity scores (DAS) at each visit, then analysed therapeutic response and associated factors in a time-dependent fashion over 12 months.ResultsThe median DAS4vESR of 4.46 at baseline decreased 12 weeks later by 24%, while the proportion with DAS4v ≤ 2.6 increased (p<0.01). DAS4v continued to decrease over 52 weeks. DAS4v reduction of at least −0.45 at 4 weeks was predictive of DAS4v at 28 and 52 weeks. Female gender, current smoking, primary education and an interaction between baseline weight and C reactive protein (CRP) negatively impacted DAS4v reduction over 4 and 52 weeks. Time-varying effects of blood pressure, neutrophils, erythrocyte sedimentation rate and CRP also significantly influenced DAS4v over 52 weeks.ConclusionsTime-dependent data suggest that the largest reduction of DAS4v to combination DMARDs occurs in the first month of therapy, and this predicts subsequent response. Variables known to impact long-term treatment response in RA also impacted early DAS4v response to combination DMARDs.
A survey of radiation treatment planning peer-review activities in a provincial radiation oncology programme: current practice and future directions
Authors: Brundage Michael , Foxcroft Sophie , McGowan Tom , Gutierrez Eric , Sharpe Michael , Warde Padraig 
Published: August 2013

ObjectivesTo describe current patterns of practice of radiation oncology peer review within a provincial cancer system, identifying barriers and facilitators to its use with the ultimate aim of process improvement.DesignA survey of radiation oncology programmes at provincial cancer centres.SettingAll cancer centres within the province of Ontario, Canada (n=14). These are community-based outpatient facilities overseen by Cancer Care Ontario, the provincial cancer agency.ParticipantsA delegate from each radiation oncology programme filled out a single survey based on input from their multidisciplinary team.Outcome measuresRated importance of peer review; current utilisation; format of the peer-review process; organisation and timing; case attributes; outcomes of the peer-review process and perceived barriers and facilitators to expanding peer-review processes.Results14 (100%) centres responded. All rated the importance of peer review as at least 8/10 (10=extremely important). Detection of medical error and improvement of planning processes were the highest rated perceived benefits of peer review (each median 9/10). Six centres (43%) reviewed at least 50% of curative cases; four of these centres (29%) conducted peer review in more than 80% of cases treated with curative intent. Fewer than 20% of cases treated with palliative intent were reviewed in most centres. Five centres (36%) reported usually conducting peer review prior to the initiation of treatment. Five centres (36%) recorded the outcomes of peer review on the medical record. Thirteen centres (93%) planned to expand peer-review activities; a critical mass of radiation oncologists was the most important limiting factor (median 6/10).ConclusionsRadiation oncology peer-review practices can vary even within a cancer system with provincial oversight. The application of guidelines and standards for peer-review processes, and monitoring of implementation and outcomes, will require effective knowledge translation activities.
Allocating scarce resources in real-time to reduce heart failure readmissions: a prospective, controlled study
Authors: Amarasingham Ruben , Patel Parag C , Toto Kathleen , Nelson Lauren L , Swanson Timothy S , Moore Billy J , Xie Bin , Zhang Song , Alvarez Kristin S , Ma Ying , Drazner Mark H , Kollipara Usha , Halm Ethan A 
Published: August 2013

ObjectiveTo test a multidisciplinary approach to reduce heart failure (HF) readmissions that tailors the intensity of care transition intervention to the risk of the patient using a suite of electronic medical record (EMR)-enabled programmes.MethodsA prospective controlled before and after study of adult inpatients admitted with HF and two concurrent control conditions (acute myocardial infarction (AMI) and pneumonia (PNA)) was performed between 1 December 2008 and 1 December 2010 at a large urban public teaching hospital. An EMR-based software platform stratified all patients admitted with HF on a daily basis by their 30-day readmission risk using a published electronic predictive model. Patients at highest risk received an intensive set of evidence-based interventions designed to reduce readmission using existing resources. The main outcome measure was readmission for any cause and to any hospital within 30 days of discharge.ResultsThere were 834 HF admissions in the pre-intervention period and 913 in the post-intervention period. The unadjusted readmission rate declined from 26.2% in the pre-intervention period to 21.2% in the post-intervention period (p=0.01), a decline that persisted in adjusted analyses (adjusted OR (AOR)=0.73; 95% CI 0.58 to 0.93, p=0.01). In contrast, there was no significant change in the unadjusted and adjusted readmission rates for PNA and AMI over the same period. There were 45 fewer readmissions with 913 patients enrolled and 228 patients receiving intervention, resulting in a number needed to treat (NNT) ratio of 20.ConclusionsAn EMR-enabled strategy that targeted scarce care transition resources to high-risk HF patients significantly reduced the risk-adjusted odds of readmission.
Inflammatory bowel disease and exercise: results of a Crohn's and Colitis UK survey
Authors: Chan D , Robbins H , Rogers S , Clark S , Poullis A 
Published: August 2013

BackgroundOver 250 000 people in the UK are affected with inflammatory bowel disease (IBD) and approximately 10 000 new cases are diagnosed every year. These chronic bowel conditions have been shown to affect both work and recreational activity. In the general population, regular exercise has numerous benefits to health and well-being and there are additional benefits for those with IBD. However, people with IBD face significant challenges in trying to take regular exercise.ObjectiveWith the renewed focus on sport brought about by the recent London Olympics, Crohn's and Colitis UK surveyed its members to explore their sport and fitness habits.Methods918 members participated in the survey, which is the largest survey of its kind, investigating the exercise habits of people with IBD.ResultsThe survey showed widespread uptake of exercise in those with IBD, with a large number feeling better for it. However, it also identified a considerable number of respondents who reported a significant negative impact of IBD on their ability to take up, enjoy and derive benefit from sporting activities.ConclusionAsking questions about sporting leisure activity in clinical consultations may identify those in need of help and support and possibly identify factors to be dealt with, in order to enable them to take part in these beneficial activities.
Dyna-CT-assisted percutaneous microballoon compression for trigeminal neuralgia
Authors: Huo Xiaochuan , Sun Xiaoyun , Zhang Zhenxing , Guo Wenshi , Guan Ning , Luo Junsheng 
Published: August 2013

BackgroundPercutaneous microballoon compression (PMC) for trigeminal neuralgia (TN) is a well-established technique. However, complications from cannulating the foramen ovale (FO) have been reported because direct puncture of the FO is sometimes difficult. Here we report our experience with Dyna-CT-assisted PMC for TN in cannulating the FO and determining the position and volume of the balloon.MethodsDyna-CT-assisted PMC was performed for image reconstruction in 16 cases. The optimal working projection was generated and further fluoroscopic data were used to determine the relationship of the needle with the FO during puncture. The balloon position and three-dimensional shape were verified with Dyna-CT during balloon compression and the balloon volume and puncture angle were also calculated. Patients’ prognosis is discussed.ResultsDyna-CT allows quick, safe and easy cannulation of the FO. It provided three-dimensional images which were more elaborate than the classic ‘pear shape’ images for determining correct positioning in 16 cases. The volume of the inflated balloon ranged from 568.2 mm3to 891.4 mm3(average 769.5 mm3). The angle of introducing the cannula ranged from 15.32° to 35.48° rotation to the midline (average 25.18°) and 38.47°–51.89° angulation to the Reid line (average 46.17°). All the patients were pain-free after PMC. Four patients had resolvable masseter weakness and fine touch loss. No recurrence of TN was reported on follow-up.ConclusionsDyna-CT performed by digital subtraction angiography assists PMC in three ways: (1) the FO can be better visualized independent of the patient’s position; (2) needle correction or insertion can be performed much more easily because of the direct fluoroscopic control; and (3) the needle position, balloon position, balloon configuration and the volume of the inflated balloon is more reliably determined. The use of Dyna-CT-assisted PMC has a low incidence of complications and a good prognosis.
Asymptotic Simulation Efficiency Based on Large Deviations
Authors: Glynn Peter W. , Juneja Sandeep 
Published: August 2013

Consider a simulation estimator
α
(
c
) based on expending
c
units of computer time to estimate a quantity
α
. In comparing competing estimators for
α
, a natural figure of merit is to choose the estimator that minimizes the computation time needed to reduce the error probability
P
(|
α
(
c
) −
α
| >
ε
) to below some prescribed value
δ
. In this paper, we develop large deviations results that provide approximations to the computational budget necessary to reduce the error probability to below
δ
when
δ
is small. This approximation depends critically on both the distribution of the estimator itself and that of the random amount of computer time required to generate the estimator, and leads to different conclusions regarding the choice of preferred estimator than those obtained when one requires the error tolerance
ε
to be small. The “small
ε
” regime leads to variance-based selection criteria, and has a long history in the simulation literature going back to Hammersley and Handscomb.
Docetaxel Conjugate Nanoparticles That Target α-Smooth Muscle Actin–Expressing Stromal Cells Suppress Breast Cancer Metastasis
Authors: Murakami Mami , Ernsting Mark J. , Undzys Elijus , Holwell Nathan , Foltz Warren D. , Li Shyh-Dar 
Published: August 2013

Abstract
Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel. Cancer Res; 73(15); 4862–71. ©2013 AACR.