bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Progressive Adaptation of a Georgian Isolate of African Swine Fever Virus to Vero Cells Leads to a Gradual Attenuation of Virulence in Swine Corresponding to Major Modifications of the Viral Genome
Authors: Krug Peter W. , Holinka Lauren G. , O'Donnell Vivian , Reese Bo , Sanford Brenton , Fernandez-Sainz Ignacio , Gladue Douglas P. , Arzt Jonathan , Rodriguez Luis , Risatti Guillermo R. , Borca Manuel V. 
Published: December 2014

ABSTRACT

African swine fever virus (ASFV) causes a contagious and often lethal disease of feral and domestic swine. Experimental vaccines derived from naturally occurring, genetically modified, or cell culture-adapted ASFV have been evaluated, but no commercial vaccine is available to control African swine fever (ASF). We report here the genotypic and phenotypic analysis of viruses obtained at different passages during the process of adaptation of a virulent ASFV field isolate from the Republic of Georgia (ASFV-G) to grow in cultured cell lines. ASFV-G was successively passaged 110 times in Vero cells. Viruses obtained at passages 30, 60, 80, and 110 were evaluated
in vitro
for the ability to replicate in Vero cells and primary swine macrophages cultures and
in vivo
for assessing virulence in swine. Replication of ASFV-G in Vero cells increased with successive passages, corresponding to a decreased replication in primary swine macrophages cultures.
In vivo
, progressive loss of virus virulence was observed with increased passages in Vero cells, and complete attenuation of ASFV-G was observed at passage 110. Infection of swine with the fully attenuated virus did not confer protection against challenge with virulent parental ASFV-G. Full-length sequence analysis of each of these viruses revealed significant deletions that gradually accumulated in specific areas at the right and left variable ends of the genome. Mutations that result in amino acid substitutions and frameshift mutations were also observed, though in a rather limited number of genes. The potential importance of these genetic changes in virus adaptation/attenuation is discussed.

IMPORTANCE
The main problem in controlling ASF is the lack of vaccines. Attempts to produce vaccines by adaptation of ASFV to cultured cell lines have been made. These attempts led to the production of attenuated viruses that conferred only homologous protection. Specifics regarding adaptation of these isolates to cell cultures have been insufficiently described. Details like the numbers of passages required to obtain attenuated viruses, genetic modifications introduced into the virus genomes along passages, and the extent of attenuation and induced protective efficacy are not readily available. In this study, we assessed the changes that lead to decreased growth in swine macrophages and to attenuation in swine. Loss of virulence, probably associated with limited replication
in vivo
, may lead to the lack of protective immunity in swine observed after challenge. This report provides valuable information that can be used to further the understanding of ASFV gene function, virus attenuation, and protection against infection.
N
-Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins
Authors: Rosales Gerpe María Carla , Renner Tyler Milston , Bélanger Kasandra , Lam Cindy , Aydin Halil , Langlois Marc-André 
Published: December 2014

ABSTRACT

Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome-encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of
N
-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor.

IMPORTANCE
APOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically,
N
-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist.
Reducing hospital-acquired infections and improving the rational use of antibiotics in a developing country: an effectiveness study
Authors: Murni Indah K , Duke Trevor , Kinney Sharon , Daley Andrew J , Soenarto Yati 
Published: December 2014

BackgroundPrevention of hospital-acquired infections (HAI) is central to providing safe and high quality healthcare. Transmission of infection between patients by health workers, and the irrational use of antibiotics have been identified as preventable aetiological factors for HAIs. Few studies have addressed this in developing countries.AimsTo implement a multifaceted infection control and antibiotic stewardship programme and evaluate its effectiveness on HAIs and antibiotic use.MethodsA before-and-after study was conducted over 27 months in a teaching hospital in Indonesia. All children admitted to the paediatric intensive care unit and paediatric wards were observed daily. Assessment of HAIs was made based on the criteria from the Centers for Disease Control and Prevention. The multifaceted intervention consisted of a hand hygiene campaign, antibiotic stewardship (using the WHO Pocket Book of Hospital Care for Children guidelines as standards of antibiotic prescribing for community-acquired infections), and other elementary infection control practices. Data were collected using an identical method in the preintervention and postintervention periods.ResultsWe observed a major reduction in HAIs, from 22.6% (277/1227 patients) in the preintervention period to 8.6% (123/1419 patients) in the postintervention period (relative risk (RR) (95% CI) 0.38 (0.31 to 0.46)). Inappropriate antibiotic use declined from 43% (336 of 780 patients who were prescribed antibiotics) to 20.6% (182 of 882 patients) (RR 0.46 (0.40 to 0.55)). Hand hygiene compliance increased from 18.9% (319/1690) to 62.9% (1125/1789) (RR 3.33 (2.99 to 3.70)). In-hospital mortality decreased from 10.4% (127/1227) to 8% (114/1419) (RR 0.78 (0.61 to 0.97)).ConclusionsMultifaceted infection control interventions are effective in reducing HAI rates, improving the rational use of antibiotics, increasing hand hygiene compliance, and may reduce mortality in hospitalised children in developing countries.
Medical rota changes and venous thromboembolism prophylaxis in orthopaedic patients
Authors: Bohler Iain , George Mackenzie Jardine Alan 
Published: December 2014

AbstractEfficacy of clinical guidelines to improve patient care is highly dependent on the ability of hospital teams to interpret and implement advised standards of care. Trimester and bi-annual rotation changes often see transference and loss of acquired experience and knowledge from wards with ensuing shortfalls in patient safety and care quality. Such shortfalls were noticed in the ability of our unit to adhere to national venous thromboembolism (VTE) prophylaxis measures. A prospective quality improvement audit was embarked upon to address this.An initial audit of VTE prophylaxis in 112 patients demonstrated just 71% compliance with suggested measures. Errors were predominantly medical in origin and secondary to poor understanding, interpretation, and knowledge of VTE guidelines. Errors were also noted in nursing and patient compliance to measures.Repeated re-auditing demonstrated increased error (following initial improvement post audit) after periods of medical staff rotation. Through education of junior medical and nursing staff, and of patients, the unit was able to achieve 100% compliance.Rota changes often induce conflict of interest between maintaining adequate services and high levels of patient care or providing suitable and informed induction programmes for new medical staff. Emphasised education of VTE prophylaxis guidelines has now become part of induction of junior medical staff, whilst ward based measures ensure daily compliance. The success of the audit strategy has led to its use throughout other surgical units within the hospital.
Discrimination of sepsis stage metabolic profiles with an LC/MS-MS-based metabolomics approach
Authors: Su Longxiang , Huang Yingyu , Zhu Ying , Xia Lei , Wang Rentao , Xiao Kun , Wang Huijuan , Yan Peng , Wen Bo , Cao Lichao , Meng Nan , Luan Hemi , Liu Changting , Li Xin , Xie Lixin 
Published: December 2014

BackgroundTo identify metabolic biomarkers that can be used to differentiate sepsis from systemic inflammatory response syndrome (SIRS), assess severity and predict outcomes.Methods65 patients were involved in this study, including 35 patients with sepsis, 15 patients with SIRS and 15 normal patients. Small metabolites that were present in patient serum samples were measured by liquid chromatography mass spectrometry techniques and analysed using multivariate statistical methods.ResultsThe metabolic profiling of normal patients and patients with SIRS or sepsis was markedly different. A significant decrease in the levels of lactitol dehydrate andS-phenyl-d-cysteine and an increase in the levels ofS-(3-methylbutanoyl)-dihydrolipoamide-E andN-nonanoyl glycine were observed in patients with sepsis in comparison to patients with SIRS (p<0.05). Patients with severe sepsis and septic shock displayed lower levels of glyceryl-phosphoryl-ethanolamine, Ne, Ne dimethyllysine, phenylacetamide andd-cysteine (p<0.05) in their sera. The profiles of patients with sepsis 48 h before death illustrated an obvious state of metabolic disorder, such thatS-(3-methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z, 16Z)/0:0), glycerophosphocholine andS-succinyl glutathione were significantly decreased (p<0.05). The receiver operating characteristic curve of the differential expression of these metabolites was also performed.ConclusionsThe body produces significant evidence of metabolic disorder during SIRS or sepsis. Seven metabolites may potentially be used to diagnose sepsis.Trial registration numberClinicalTrial.gov identifierNCT01649440.
Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations
Authors: Coghlan Meghan A , Shifren Adrian , Huang Howard J , Russell Tonya D , Mitra Robi D , Zhang Qunyuan , Wegner Daniel J , Cole F Sessions , Hamvas Aaron 
Published: December 2014

BackgroundPrevious studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes.ObjectiveTo compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server.MethodsWe resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin5B(MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a commonMUC5Bpromoter variant that is over-represented in individuals with IPF.ResultsWe found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2(n=1),SFTPC(n=5),ABCA3(n=4) andTERT(n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most commonABCA3disease-causing variant. We did not detect an interaction between any of the mutations and theMUC5Bpromoter variant.ConclusionsRare mutations inSFTPA2,SFTPCandTERTare collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation.
Henry Culpin (1861–1912): a Yorkshire geologist and palaeontologist, and his collection in the Doncaster Museum and Art Gallery, South Yorkshire
Authors: Lomax Dean R. 
Published: December 2014

Summary
Henry Culpin was an autodidact geologist and palaeontologist; he was among the first of very few local people to understand and describe the geological outcrops, and fossils within them, around Doncaster, South Yorkshire. During his excursions, Culpin collected many fossil specimens and gifted several to Beechfield House museum, now Doncaster Museum and Art Gallery. A large percentage of these specimens are of local origin, collected from Carboniferous coal mine deposits that are no longer accessible. They represent some of the most scientifically and locally important fossils from Doncaster, collected when some of the earliest mine shafts were being sunk in the district.

Supplementary material:

The entire list of records from the Doncaster Museum accession register is available at:
http://www.geolsoc.org.uk/SUP18783
A dearth of diplobathrids (Crinoidea) from the type Devonian System, SW England
Authors: Donovan Stephen K. , Fearnhead Fiona E. 
Published: December 2014

Summary

The diverse biota from the marine deposits of the type area of the Devonian System was monographed by the Reverend George Ferris Whidborne, MA, FGS (1846–1910) between 1889 and 1907. Most well-preserved specimens of crinoids are cladids or monobathrids from the Middle and Upper Devonian of south and north Devon, respectively. The camerate crinoids are dominated by the monobathrid
Hexacrinites
spp., known from many thecae and several nominal species from the Middle Devonian Torquay Limestone Formation; other monobathrids are moderately common in the Upper Devonian. The dicyclic diplobathrid camerates are less speciose and are commonly poorly preserved. Diplobathrids include
Rhodocrinites
? sp. A (poor crown) and
Rhodocrinites
? sp. B (columnals);
Acanthocrinus
sp. (spinose thecal plate);
Gilbertsocrinus
sp. A (columnals); non
Rhipidocrinus crenatus
(Goldfuss) (possibly a monobathrid crown);
Thylacrinus
? sp. (fragment of theca); and rhodocrinitid? sp. indet. This is in stark contrast to the 5 genera and 9 nominal species of diplobathrids known from the lower Silurian, and the 3 genera and 14 nominal species in the Mississippian of the British Isles, many of which are known from multiple, well-preserved specimens. The potential reasons for this disparity are many, but must include lack of effort by collectors over the past 100+ years, limited outcrop area, poor preservation due to tectonic deformation and, probably, a genuine rarity of diplobathrids in the British Isles during the Devonian.
A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors
Authors: Bedard Philippe L. , Tabernero Josep , Janku Filip , Wainberg Zev A. , Paz-Ares Luis , Vansteenkiste Johan , Van Cutsem Eric , Pérez-García José , Stathis Anastasios , Britten Carolyn D. , Le Ngocdiep , Carter Kirsten , Demanse David , Csonka Denes , Peters Malte , Zubel Angela , Nauwelaerts Heidi , Sessa Cristiana 
Published: December 2014

Abstract
Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.
Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer.
Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.
Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.
Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program
Authors: Smith Malcolm A. , Reynolds C. Patrick , Kang Min H. , Kolb E. Anders , Gorlick Richard , Carol Hernan , Lock Richard B. , Keir Stephen T. , Maris John M. , Billups Catherine A. , Lyalin Dmitry , Kurmasheva Raushan T. , Houghton Peter J. 
Published: December 2014

Abstract
Purpose: Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan.
Experimental Design: Talazoparib was tested in vitro in combination with temozolomide (0.3–1,000 μmol/L) or topotecan (0.03–100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment.
Results: In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30–50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide.
Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. Clin Cancer Res; 21(4); 819–32. ©2014 AACR.
Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival
Authors: Busso-Lopes Ariane F. , Marchi Fábio A. , Kuasne Hellen , Scapulatempo-Neto Cristovam , Trindade-Filho José Carlos S. , de Jesus Carlos Márcio N. , Lopes Ademar , Guimarães Gustavo C. , Rogatto Silvia R. 
Published: December 2014

Abstract
The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copy-number alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT-qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1–p14.3 and gains of 3q25.31–q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status. Cancer Prev Res; 8(2); 149–56. ©2014 AACR.