bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis C Virus Nonstructural Protein 5B Is Involved in Virus Morphogenesis
Authors: Gouklani Hamed , Bull Rowena A. , Beyer Claudia , Coulibaly Fasséli , Gowans Eric J. , Drummer Heidi E. , Netter Hans J. , White Peter A. , Haqshenas Gholamreza 
Published: February 2012

ABSTRACT

The p7 protein of hepatitis C virus (HCV) is a viroporin that is dispensable for viral genome replication but plays a critical role in virus morphogenesis. In this study, we generated a JFH1-based intergenotypic chimeric genome that encoded a heterologous genotype 1b (GT1b) p7. The parental intergenotypic chimeric genome was nonviable in human hepatoma cells, and infectious chimeric virions were produced only when cells transfected with the chimeric genomes were passaged several times. Sequence analysis of the entire polyprotein-coding region of the recovered chimeric virus revealed one predominant amino acid substitution in nonstructural protein 2 (NS2), T23N, and one in NS5B, K151R. Forward genetic analysis demonstrated that each of these mutations
per se
restored the infectivity of the parental chimeric genome, suggesting that interactions between p7, NS2, and NS5B were required for virion assembly/maturation. p7 and NS5B colocalized in cellular compartments, and the NS5B mutation did not affect the colocalization pattern. The NS5B K151R mutation neither increased viral RNA replication in human hepatoma cells nor altered the polymerase activity of NS5B in an
in vitro
assay. In conclusion, this study suggests that HCV NS5B is involved in virus morphogenesis.
Budding of Retroviruses Utilizing Divergent L Domains Requires Nucleocapsid
Authors: Bello Nana F. , Dussupt Vincent , Sette Paola , Rudd Victoria , Nagashima Kunio , Bibollet-Ruche Frederic , Chen Chaoping , Montelaro Ronald C. , Hahn Beatrice H. , Bouamr Fadila 
Published: February 2012

ABSTRACT

We recently reported that human immunodeficiency virus type 1 (HIV-1) carrying PTAP and LYPX
n
L L domains ceased budding when the nucleocapsid (NC) domain was mutated, suggesting a role for NC in HIV-1 release. Here we investigated whether NC involvement in virus release is a property specific to HIV-1 or a general requirement of retroviruses. Specifically, we examined a possible role for NC in the budding of retroviruses relying on divergent L domains and structurally homologous NC domains that harbor diverse protein sequences. We found that NC is critical for the release of viruses utilizing the PTAP motif whether it functions within its native Gag in simian immunodeficiency virus cpzGAB2 (SIVcpzGAB2) or SIVsmmE543 or when it is transplanted into the heterologous Gag protein of equine infectious anemia virus (EIAV). In both cases, virus release was severely diminished even though NC mutant Gag proteins retained the ability to assemble spherical particles. Moreover, budding-defective NC mutants, which displayed particles tethered to the plasma membrane, were triggered to release virus when access to the cell endocytic sorting complex required for transport pathway was restored (i.e., in
trans
expression of Nedd4.2s). We also examined the role of NC in the budding of EIAV, a retrovirus relying exclusively on the (L)YPX
n
L-type L domain. We found that EIAV late budding defects were rescued by overexpression of the isolated Alix Bro1 domain (Bro1). Bro1-mediated rescue of EIAV release required the wild-type NC. EIAV NC mutants lost interactions with Bro1 and failed to produce viruses despite retaining the ability to self-assemble. Together, our studies establish a role for NC in the budding of retroviruses harboring divergent L domains and evolutionarily diverse NC sequences, suggesting the utilization of a common conserved mechanism and/or cellular factor rather than a specific motif.
Portal-Large Terminase Interactions of the Bacteriophage T4 DNA Packaging Machine Implicate a Molecular Lever Mechanism for Coupling ATPase to DNA Translocation
Authors: Hegde Shylaja , Padilla-Sanchez Victor , Draper Bonnie , Rao Venigalla B. 
Published: February 2012

ABSTRACTDNA packaging by double-stranded DNA bacteriophages and herpesviruses is driven by a powerful molecular machine assembled at the portal vertex of the empty prohead. The phage T4 packaging machine consists of three components: dodecameric portal (gp20), pentameric large terminase motor (gp17), and 11- or 12-meric small terminase (gp16). These components dynamically interact and orchestrate a complex series of reactions to produce a DNA-filled head containing one viral genome per head. Here, we analyzed the interactions between the portal and motor proteins using a direct binding assay, mutagenesis, and structural analyses. Our results show that a portal binding site is located in the ATP hydrolysis-controlling subdomain II of gp17. Mutations at key residues of this site lead to temperature-sensitive or null phenotypes. A conserved helix-turn-helix (HLH) that is part of this site interacts with the portal. A recombinant HLH peptide competes with gp17 for portal binding and blocks DNA translocation. The helices apparently provide specificity to capture the cognate prohead, whereas the loop residues communicate the portal interaction to the ATPase center. These observations lead to a hypothesis in which a unique HLH-portal interaction in the symmetrically mismatched complex acts as a lever to position the arginine finger and trigger ATP hydrolysis. Transiently connecting the critical parts of the motor; subdomain I (ATP binding), subdomain II (controlling ATP hydrolysis), and C-domain (DNA movement), the portal-motor interactions might ensure tight coupling between ATP hydrolysis and DNA translocation.
Gout and the risk for incident heart failure and systolic dysfunction
Authors: Krishnan Eswar 
Published: February 2012

ObjectiveTo test the hypothesis that gouty arthritis (gout) is a risk factor for incidence of heart failure and for echocardiographic measures signifying subclinical heart failure.DesignPost-hoc, longitudinal and cross-sectional analyses of a prospective cohort study where data were collected in 4-year intervals since 1971.SettingsThe population-based Framingham Offspring Study.Participants4989 adults (mean age 36 years, 52% women) free of clinical heart failure at baseline.Outcome measuresIncident heart failure, echocardiographic measures of left ventricular systolic dysfunction, dilatation and hypertrophy.ResultsParticipants with gout (n=228) had two to three times higher incidence of clinical heart failure and echocardiographic measures of systolic dysfunction compared with those without. In Cox regression analyses, gout was associated with an adjusted HR of 1.74 (95% CI 1.03 to 2.93) for incident heart failure and RRs of 3.70 (95% CI 1.68 to 8.16) for abnormally low left ventricular ejection fraction and of 3.60 (95% CI 1.80 to 7.72) for global left ventricle systolic dysfunction. These risk relationships were consistently observed in all clinical subgroups. Overall, participants with gout had greater mortality than those without (adjusted HR 1.58, 95% CI 1.40 to 1.78). Mortality was elevated in subgroup of patients with gout and heart failure (adjusted HR 1.50, 95% CI 1.30 to 1.73) compared to those with heart failure but without gout.ConclusionGout is associated with increased risk for clinical heart failure, subclinical measures of systolic dysfunction and mortality.
Disparities in mortality among doctors in Taiwan: a 17-year follow-up study of 37 545 doctors
Authors: Shang Tung-Fu , Chen Pau-Chung , Wang Jung-Der 
Published: February 2012

ObjectivesThe authors used cohort data from the registry of all doctors in Taiwan to determine if the effect of health disparities exists after control of potential confounding by different occupational exposures in different specialties.DesignRetrospective cohort study, 1990–2006.SettingsThe Taiwan Medical Association.ParticipantsA total of 37 545 doctors from the registry of the doctor file maintained by the Taiwan Medical Association. The registry has been required by the governmental regulation for verification of credentials of all practicing doctors.Main outcome measuresCause-specific standardised mortality ratios for surgeons and anaesthesiologists were compared with those of the internists. The Cox proportional hazard model was constructed to explore multiple risk factors for mortality, including specialties, age, gender, geographic region of practices, regional health resources, ages of beginning practices and years of beginning practice.ResultsThe all-cause-specific standardised mortality ratios for surgeons and anaesthesiologists were marginally elevated at 1.15 (95% CI 0.98 to 1.34) and 1.62 (95% CI 0.93 to 2.64), respectively. The Cox regression model showed that the anaesthesiologists had the highest HR of 1.97, seconded by surgeons at 1.23. Localities with the doctor-to-population ratio lower than 1:500 were associated with an increased HR of doctor mortality.ConclusionsThe doctor-to-population ratio and the region of practice may influence doctor's mortality. Increasing number of doctors and/or improving the practice environment may be helpful in reducing the health disparities in regions with poor resources.
Self-rated health and mortality in individuals with diabetes mellitus: prospective cohort study
Authors: Wennberg Patrik , Rolandsson Olov , Jerdén Lars , Boeing Heiner , Sluik Diewertje , Kaaks Rudolf , Teucher Birgit , Spijkerman Annemieke , de Mesquita Bas Bueno , Dethlefsen Claus , Nilsson Peter , Nöthlings Ute 
Published: February 2012

ObjectivesTo investigate whether low self-rated health (SRH) is associated with increased mortality in individuals with diabetes.DesignPopulation-based prospective cohort study.SettingEnrolment took place between 1992 and 2000 in four centres (Bilthoven, Heidelberg, Potsdam, Umeå) in a subcohort nested in the European Prospective Investigation into Cancer and Nutrition.Participants3257 individuals (mean ± SD age was 55.8±7.6 years and 42% women) with confirmed diagnosis of diabetes mellitus.Primary outcome measureThe authors used Cox proportional hazards modelling to estimate HRs for total mortality controlling for age, centre, sex, educational level, body mass index, physical inactivity, smoking, insulin treatment, hypertension, hyperlipidaemia and history of myocardial infarction, stroke or cancer.ResultsDuring follow-up (mean follow-up ± SD was 8.6±2.3 years), 344 deaths (241 men/103 women) occurred. In a multivariate model, individuals with low SRH were at higher risk of mortality (HR 1.38, 95% CI 1.10 to 1.73) than those with high SRH. The association was mainly driven by increased 5-year mortality and was stronger among individuals with body mass index of <25 kg/m2than among obese individuals. In sex-specific analyses, the association was statistically significant in men only. There was no indication of heterogeneity across centres.ConclusionsLow SRH was associated with increased mortality in individuals with diabetes after controlling for established risk factors. In patients with diabetes with low SRH, the physician should consider a more detailed consultation and intensified support.
Health systems and HIV treatment in sub-Saharan Africa: matching intervention and programme evaluation strategies
Authors: Bärnighausen Till , Bloom David E , Humair Salal 
Published: February 2012

ObjectivesInternational donors financing the delivery of antiretroviral treatment in developing countries have recently emphasised their commitment to rigorous evaluation of antiretroviral treatment impact on population health. At the same time frame, but for different reasons, they have announced that they will shift funding from vertically structured (ie, disease-specific) interventions to horizontally structured interventions (ie, staff, systems and infrastructure that can deliver care for many diseases). The authors analyse likely effects of the latter shift on the feasibility of impact evaluation.MethodsThe authors examine the effect of the shift in intervention strategy on (1) outcome measurement, (2) cost measurement, (3) study-design options and the (4) technical and (5) political feasibility of programme evaluation.ResultsAs intervention structure changes from vertical to horizontal, outcome and cost measurements are likely to become more difficult (because the number of relevant outcomes and costs increases and the sources holding data on these measures become more diverse); study-design options become more limited (because it is often impossible to identify a rigorously defined counterfactual in horizontal interventions); the technical feasibility of interventions is reduced (because lag times between intervention and impact increase in length and effect-mediating and -modifying factors increase in number) and political feasibility of evaluation is decreased (because national policymakers may be reluctant to support the evaluation).ConclusionsIn the choice of intervention strategy, policymakers need to consider the effect of intervention strategy on impact evaluation. Methodological studies are needed to identify the best approaches to evaluate the population health impact of horizontal interventions.
Maintaining cost-effective access to antiretroviral drug therapy through a collaborative approach to drug procurement, consensus treatment guidelines and regular audit: the experience of London HIV commissioners and providers
Authors: Foreman Claire , Gazzard Brian , Johnson Margaret , Sharott Peter , Collins Simon 
Published: February 2012

BackgroundIn the UK, meeting the £20 billion efficiency challenge in the NHS requires new approaches to protect quality and improve productivity. In London, clinicians, people living with HIV and commissioners are collaborating to reduce the cost of antiretrovirals as part of the Quality Innovation Productivity and Prevention agenda.ObjectivesTo describe how collaboration in antiretroviral procurement in 2011/2012 aimed to significantly reduce drug acquisition costs, ensure equity of prescribing and protect the quality and experience of care and treatment for patients.MethodsGreater clinical leadership and engagement and involvement of patient representatives enabled an approach to drug procurement focused on clinical outcomes at a patient and population level while reducing cost. Consensus guidelines for implementation were developed and agreed by all London lead clinicians while people living with HIV produced a patient information leaflet to explain the tender process and outcomes. A planned audit is underway at all services to monitor prescribing changes and outcomes for those on treatment.ResultsHIV clinicians, pharmacists and patient representatives were directly involved in this novel therapeutic tendering approach to antiretroviral drug procurement. Modelling indicates that £8–£10 million savings will be released through the process over 2 years.ConclusionsClinically led therapeutic tendering of antiretroviral drugs provides an opportunity to protect quality and improve productivity in HIV. The approach is novel in HIV in the UK, and the emergent learning has implications for quality and cost improvement in HIV spending in the UK and potentially in other countries.
Preclinical Evaluation of TriMix and Antigen mRNA-Based Antitumor Therapy
Authors: Van Lint Sandra , Goyvaerts Cleo , Maenhout Sarah , Goethals Lode , Disy Aurélie , Benteyn Daphné , Pen Joeri , Bonehill Aude , Heirman Carlo , Breckpot Karine , Thielemans Kris 
Published: February 2012

Abstract
The use of tumor-associated antigen (TAA) mRNA for therapeutic purposes is under active investigation. To be effective, mRNA vaccines need to deliver activation stimuli in addition to TAAs to dendritic cells (DC). In this study, we evaluated whether intranodal delivery of TAA mRNA together with TriMix, a mix of mRNA encoding CD40 ligand, constitutive active Toll-like receptor 4 and CD70, results in the in situ modification and maturation of DCs, hence, priming of TAA-specific T cells. We showed selective uptake and translation of mRNA in vivo by lymph node resident CD11c+ cells. This process was hampered by codelivery of classical maturation stimuli but not by TriMix mRNA. Importantly, TriMix mRNA induced a T-cell–attracting and stimulatory environment, including recruitment of antigen-specific CD4+ and CD8+ T cells and CTLs against various TAAs. In several mouse tumor models, mRNA vaccination was as efficient in CTL induction and therapy response as vaccination with mRNA-electroporated DCs. Together, our findings suggest that intranodal administration of TAA mRNA together with mRNA encoding immunomodulating molecules is a promising vaccination strategy. Cancer Res; 72(7); 1661–71. ©2012 AACR.
18F-FDG-PET/CT Imaging as an Early Survival Predictor in Patients with Primary High-Grade Soft Tissue Sarcomas Undergoing Neoadjuvant Therapy
Authors: Herrmann Ken , Benz Matthias R. , Czernin Johannes , Allen-Auerbach Martin S. , Tap William D. , Dry Sarah M. , Schuster Tibor , Eckardt Jeff J. , Phelps Michael E. , Weber Wolfgang A. , Eilber Fritz C. 
Published: February 2012

AbstractPurpose: Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). We prospectively evaluated whether 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG)-PET/computed tomographic (CT) imaging after the initial cycle of neoadjuvant therapy could predict overall survival in these patients.Experimental Design: Thirty-nine patients underwent 18F-FDG-PET/CT before and after one cycle of neoadjuvant therapy. Fifty-six patients underwent end-of-treatment PET. Overall survival was, among others, correlated with changes of SUVpeak and histopathology.Results: One-, two-, and five-year survival rates were 95% ± 3.0%, 86% ± 4.6%, and 68% ± 6.6%, respectively. Median time to death was 30.9 months (mean, 27.7; range, 6.9–50.1). Optimal cutoff values for early and late decreases in SUVpeak (26% and 57%, respectively) were significant predictors of survival in univariate survival analysis [P = 0.041; HR, 0.27; 95% confidence interval (CI), 0.08–0.95 and P = 0.045; HR, 0.31; 95% CI, 0.10–0.98]. Seven of 15 early PET nonresponders but only four of 24 early PET responders died during follow-up (P = 0.068). The only other significant survival predictor was surgical margin positivity (P = 0.041; HR, 3.31; 95% CI, 1.05–10.42). By multivariable analysis, early metabolic response (P = 0.016) and positivity of surgical margins (P = 0.036) remained significant survival predictors.Conclusion: 18F-FDG-PET predicted survival after the initial cycle of neoadjuvant chemotherapy in patients with STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care. Clin Cancer Res; 18(7); 2024–31. ©2012 AACR.
Copy Number Gain of 1q25 Predicts Poor Progression-Free Survival for Pediatric Intracranial Ependymomas and Enables Patient Risk Stratification: A Prospective European Clinical Trial Cohort Analysis on Behalf of the Children's Cancer Leukaemia Group (CCLG), Société Française d'Oncologie Pédiatrique (SFOP), and International Society for Pediatric Oncology (SIOP)
Authors: Kilday John-Paul , Mitra Biswaroop , Domerg Caroline , Ward Jennifer , Andreiuolo Felipe , Osteso-Ibanez Teresa , Mauguen Audrey , Varlet Pascale , Le Deley Marie-Cecile , Lowe James , Ellison David W. , Gilbertson Richard J. , Coyle Beth , Grill Jacques , Grundy Richard G. 
Published: February 2012

Abstract
Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial ependymoma.
Experimental Design: Frequency of 1q gain was assessed across 48 ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children's Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data.
Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56–4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts.
Conclusions: This is the first study to validate a prognostic genomic marker for childhood ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. ©2012 AACR.
Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer
Authors: Ma Wen Wee , Messersmith Wells A. , Dy Grace K. , Weekes Colin D. , Whitworth Amy , Ren Chen , Maniar Manoj , Wilhelm Francois , Eckhardt S. Gail , Adjei Alex A. , Jimeno Antonio 
Published: February 2012

Abstract
Purpose: Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer.
Experimental Design: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA).
Results: Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m2): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non–dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine.
Conclusion: The RPTD established in this study is rigosertib 1,800 mg/m2 and gemcitabine 1,000 mg/m2. This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy. Clin Cancer Res; 18(7); 2048–55. ©2012 AACR.